Clinical Trial Results:
A Phase 2 Randomized, Double-Blind, Placebo-controlled, Multiple Ascending Dose Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Ambulatory Boys With Duchenne Muscular Dystrophy
Summary
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EudraCT number |
2014-002072-92 |
Trial protocol |
GB IT PL BG |
Global end of trial date |
23 Nov 2018
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Results information
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Results version number |
v1 |
This version publication date |
07 Jun 2019
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First version publication date |
07 Jun 2019
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Other versions |
v2 |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
B5161002
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02310763 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Pfizer, Inc.
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Sponsor organisation address |
235 E 42nd Street, New York, United States, NY 10017
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Public contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Scientific contact |
Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001763-PIP01-15 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
10 May 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
30 Apr 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
23 Nov 2018
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objectives of this study were to determine the safety and tolerability of multiple ascending repeat intravenous doses of domagrozumab (PF-06252616) in ambulatory boys with Duchenne Muscular dystrophy (DMD) and to demonstrate the efficacy of treatment with intravenous doses of domagrozumab based on an observed mean change from baseline on function (4 Stair Climb) as compared to placebo following 49 weeks of treatment.
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Protection of trial subjects |
This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of subjects.
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Background therapy |
Subjects were required to be on a stable dose of glucocorticosteroids. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
24 Nov 2014
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
2 Years | ||
Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Australia: 1
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Country: Number of subjects enrolled |
Bulgaria: 2
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Country: Number of subjects enrolled |
Canada: 17
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Country: Number of subjects enrolled |
Italy: 5
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Country: Number of subjects enrolled |
Japan: 11
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Country: Number of subjects enrolled |
Poland: 5
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Country: Number of subjects enrolled |
United Kingdom: 12
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Country: Number of subjects enrolled |
United States: 67
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Worldwide total number of subjects |
120
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EEA total number of subjects |
24
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
105
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Adolescents (12-17 years) |
15
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 162 subjects were screened, 121 subjects were enrolled in the study and assigned to 1 of 3 sequences. Only 120 subjects received the study treatment and 1 subject withdrew prior to dosing. | ||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Period 1 (Weeks 1 to 48)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Sequence 1 | ||||||||||||||||||||||||||||||||
Arm description |
Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Domagrozumab
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Investigational medicinal product code |
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Other name |
PF-06252616
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous drip use
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Dosage and administration details |
Domagrozumab was administered over 2 hours (minus 15 or plus 30 minutes) by intravenous infusion. Subjects were observed for 1 hour following completion of domagrozumab administration.
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Arm title
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Sequence 2 | ||||||||||||||||||||||||||||||||
Arm description |
Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects received placebo for additional 48 weeks or until early termination of the study. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Domagrozumab
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Investigational medicinal product code |
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Other name |
PF-06252616
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous drip use
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Dosage and administration details |
Domagrozumab was administered over 2 hours (minus 15 or plus 30 minutes) by intravenous infusion. Subjects were observed for 1 hour following completion of domagrozumab administration.
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Arm title
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Sequence 3 | ||||||||||||||||||||||||||||||||
Arm description |
Subjects in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), subjects received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous drip use
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Dosage and administration details |
Placebo was administered over 2 hours (minus 15 or plus 30 minutes) by intravenous infusion. Subjects were observed for 1 hour following completion of administration.
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Period 2
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Period 2 title |
Period 2 (Weeks 49 to 96)
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Is this the baseline period? |
No | ||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Sequence 1 | ||||||||||||||||||||||||||||||||
Arm description |
Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Domagrozumab
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Investigational medicinal product code |
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Other name |
PF-06252616
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous drip use
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Dosage and administration details |
Domagrozumab was administered over 2 hours (minus 15 or plus 30 minutes) by intravenous infusion. Subjects were observed for 1 hour following completion of domagrozumab administration.
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Arm title
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Sequence 2 | ||||||||||||||||||||||||||||||||
Arm description |
Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects received placebo for additional 48 weeks or until early termination of the study. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous drip use
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Dosage and administration details |
Placebo was administered over 2 hours (minus 15 or plus 30 minutes) by intravenous infusion. Subjects were observed for 1 hour following completion of administration.
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Arm title
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Sequence 3 | ||||||||||||||||||||||||||||||||
Arm description |
Subjects in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), subjects received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Domagrozumab
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Investigational medicinal product code |
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Other name |
PF-06252616
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Pharmaceutical forms |
Powder for solution for infusion
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Routes of administration |
Intravenous drip use
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Dosage and administration details |
Domagrozumab was administered over 2 hours (minus 15 or plus 30 minutes) by intravenous infusion. Subjects were observed for 1 hour following completion of domagrozumab administration.
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Baseline characteristics reporting groups
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Reporting group title |
Sequence 1
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Reporting group description |
Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sequence 2
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Reporting group description |
Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects received placebo for additional 48 weeks or until early termination of the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sequence 3
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Reporting group description |
Subjects in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), subjects received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Sequence 1
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Reporting group description |
Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study. | ||
Reporting group title |
Sequence 2
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Reporting group description |
Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects received placebo for additional 48 weeks or until early termination of the study. | ||
Reporting group title |
Sequence 3
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Reporting group description |
Subjects in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), subjects received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). | ||
Reporting group title |
Sequence 1
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Reporting group description |
Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study. | ||
Reporting group title |
Sequence 2
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Reporting group description |
Subjects in this sequence received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). From Week 49 (Period 2), subjects received placebo for additional 48 weeks or until early termination of the study. | ||
Reporting group title |
Sequence 3
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Reporting group description |
Subjects in this sequence received placebo for 48 weeks (Period 1). From Week 49 (Period 2), subjects received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). | ||
Subject analysis set title |
Placebo (Period 1)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This analysis set included subjects who received placebo from Week 1 to Week 48.
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Subject analysis set title |
Domagrozumab 5 mg/kg (Period 1)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This analysis set included subjects who received domagrozumab at a dose of 5 mg/kg by intravenous infusion over 2 hours every 4 weeks from Week 1 to Week 16 (4 doses).
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Subject analysis set title |
Domagrozumab 20 mg/kg (Period 1)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This analysis set included subjects who received domagrozumab at a dose of 20 mg/kg by intravenous infusion over 2 hours every 4 weeks from Week 17 to Week 32 (4 doses).
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Subject analysis set title |
Domagrozumab 40 mg/kg (Period 1)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This analysis set included subjects who received domagrozumab at a dose of 40 mg/kg by intravenous infusion over 2 hours every 4 weeks from Week 33 to Week 48 (4 doses).
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Subject analysis set title |
Domagrozumab (Period 1)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This analysis set included subjects who received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48. At each dose level, dosing was administered by intravenous infusion over 2 hours every 4 weeks for a total of 16 weeks (4 doses).
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Subject analysis set title |
NH Control Group (4SC, Week 49)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The natural history (NH) control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable 4 stair climb (4SC) data on Week 49 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) left ventricular ejection fraction (LVEF): >=55% or missing.
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Subject analysis set title |
NH Control Group (4SC, Week 97)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The NH control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable 4SC data on Week 97 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing.
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Subject analysis set title |
NH Control Group (FVC, Week 49)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The NH control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable forced vital capacity (FVC) data on Week 49 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing.
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Subject analysis set title |
NH Control Group (FVC, Week 97)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The NH control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable FVC data on Week 97 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing
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Subject analysis set title |
NH Control Group (NSAA, Week 49)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The NH control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable northstar ambulatory assessment (NSAA) data on Week 49 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing.
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Subject analysis set title |
NH Control Group (NSAA, Week 97)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The NH control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable NSAA data on Week 97 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing.
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Subject analysis set title |
NH Control Group (6MWD, Week 49)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The NH history control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable 6 minute walk distance (6MWD) data on Week 49 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing.
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Subject analysis set title |
NH Control Group (6MWD, Week 97)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
The NH control group was established by filtering the CINRG (Cooperative International Neuromuscular Research Group) natural history database. Subjects who met the following requirements at baseline and had evaluable 6MWD data on Week 97 were included in this analysis set: 1) age: 6 to <16 years; 2) treatment of glucocorticoid steroids >=6 months prior to baseline and continuous use until the latest visit week; 3) 4SC time: 2-15.9 seconds; 4) subjects who were ambulatory at baseline; 5) LVEF: >=55% or missing.
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Subject analysis set title |
Placebo (4SC< 3.5 seconds, Period 1)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set included subjects who received placebo from Week 1 to Week 48 and had baseline 4SC time <3.5 seconds.
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Subject analysis set title |
Domagrozumab (4SC< 3.5 seconds, Period 1)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set included subjects who received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48 and had baseline 4SC time <3.5 seconds. At each dose level, dosing was administered by intravenous infusion over 2 hours every 4 weeks for a total of 16 weeks (4 doses).
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Subject analysis set title |
Placebo(4SC>=3.5 and <=8 seconds, Period 1)
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set included subjects who received placebo from Week 1 to Week 48 and had baseline 4SC time >=3.5 seconds and <=8 seconds.
|
||
Subject analysis set title |
Domagrozumab (4SC>=3.5 and <=8 seconds, Period 1)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set included subjects who received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48 and had baseline 4SC time >=3.5 seconds and <=8 seconds. At each dose level, dosing was administered by intravenous infusion over 2 hours every 4 weeks for a total of 16 weeks (4 doses).
|
||
Subject analysis set title |
Placebo (4SC>8 seconds, Period 1)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set included subjects who received placebo from Week 1 to Week 48 and had baseline 4SC >8 seconds.
|
||
Subject analysis set title |
Domagrozumab (4SC>8 seconds, Period 1)
|
||
Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
This analysis set included subjects who received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) from Week 1 to Week 48 and had baseline 4SC time >8 seconds. At each dose level, dosing was administered by intravenous infusion over 2 hours every 4 weeks for a total of 16 weeks (4 doses).
|
||
Subject analysis set title |
Domagrozumab 5 mg/kg (Sequence 3)
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This analysis set included subjects in Sequence 3 who received domagrozumab at a dose of 5 mg/kg by intravenous infusion over 2 hours every 4 weeks from Week 49 to Week 64 (4 doses).
|
||
Subject analysis set title |
Domagrozumab 20 mg/kg (Sequence 3)
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This analysis set included subjects in Sequence 3 who received domagrozumab at a dose of 20 mg/kg by intravenous infusion over 2 hours every 4 weeks from Week 65 to Week 80 (4 doses).
|
||
Subject analysis set title |
Domagrozumab 40 mg/kg (Sequence 3)
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
This analysis set included subjects in Sequence 3 who received domagrozumab at a dose of 40 mg/kg by intravenous infusion over 2 hours every 4 weeks from Week 81 to Week 96 (4 doses).
|
|
||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) by Week 49 [1] | |||||||||||||||||||||||||||||||||||||||||||||
End point description |
An adverse event (AE) was any untoward medical occurrence in a clinical investigation subject administered a product; the event did not need to have a causal relationship with the treatment. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. AEs included both SAEs and AEs. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Severe TEAEs were TEAEs that interfered significantly with subjects' usual function. Treatment-related TEAEs were determined by the investigator. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
|||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Study Day 1 to Week 49 visit
|
|||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||
End point title |
Number of Subjects Who Discontinued From the Study Due to TEAEs by Week 49 [2] | |||||||||||||||||||||||||
End point description |
An AE was any untoward medical occurrence in a clinical investigation subject administered a product; the event did not need to have a causal relationship with the treatment. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
|||||||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||||||
End point timeframe |
Study Day 1 to Week 49 visit
|
|||||||||||||||||||||||||
Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
||||||||||||||||||||||||||
|
||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||
End point title |
Number of Subjects With Dose Reduced or Temporary Discontinuation Due to TEAEs by Week 49 [3] | |||||||||||||||||||||||||
End point description |
An AE was any untoward medical occurrence in a clinical investigation subject administered a product; the event did not need to have a causal relationship with the treatment. TEAEs were AEs occurred following the start of treatment or AEs increasing in severity during treatment. Treatment-related TEAEs were determined by the investigator. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
|||||||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||||||
End point timeframe |
Study Day 1 to Week 49 visit
|
|||||||||||||||||||||||||
Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
||||||||||||||||||||||||||
|
||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hematology [4] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Hematology evaluation included: hemoglobin, hematocrit, red blood cell (RBC) count, platelets, RBC morphology, white blood cell (WBC) count, absolute lymphocytes, absolute atypical lymphocytes, absolute total neutrophils, absolute total neutrophils count, absolute band cells, absolute basophils, absolute eosinophils, absolute monocytes and absolute myelocytes. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint. "99999" represents "not applicable" because data were not collected for specified rows of categories.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||
End point title |
Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Coagulation [5] | |||||||||||||||||||||||||
End point description |
Coagulation evaluation included activated partial thromboplastin time (aPTT) and prothrombin time (PT). All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
|||||||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
|||||||||||||||||||||||||
Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
||||||||||||||||||||||||||
|
||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Liver Function [6] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Liver function evaluation included: total/direct/indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, total protein, albumin and glutamate dehydrogenase. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint. "99999" represents "not applicable" because data were not collected for specified rows of categories.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Renal Function [7] | ||||||||||||||||||||||||||||||
End point description |
Renal function evaluation included: blood urea nitrogen (BUN), creatinine and uric acid. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
||||||||||||||||||||||||||||||
Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Electrolytes [8] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Electrolytes evaluation included: sodium, potassium, chloride, calcium, phosphate, bicarbonate, ferritin, transferrin saturation, iron, iron binding capacity and unsaturated iron binding capacity. Number of subjects with iron abnormalities was reported in different age groups. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Hormones [9] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Hormone evaluations included free thyroxine (T4), thyroid stimulating hormone (TSH), lutenizing hormone (LH), follicle stimulating hormone (FSH), and androstenedione. Numbers of subjects with abnormalities of LH, FSH and androstenedione were reported in different age groups. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint. "99999" represents "not applicable" because data were not collected for specified rows of categories.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Clinical Chemistry [10] | ||||||||||||||||||||||||||||||||||||||||
End point description |
Clinical chemistry evaluation included glucose, creatine kinase (CK), troponin I, and amylase. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
||||||||||||||||||||||||||||||||||||||||
Notes [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Urinalysis [11] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Urinalysis included: urine pH, qualitative urine glucose, qualitative urine ketones, qualitative urine protein, qualitative blood/hemoglobin, urine nitrite, urine leukocytes, urine RBC, urine WBC, urine granular casts, urine hyaline casts, urine urate (uric acid) acidic crystal, urine calcium oxalate crystals, urine amorphous crystals, urine bacteria, urine microscopic exam. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint. "99999" represents "not applicable" because data were not collected for specified rows of categories.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of Subjects With Laboratory Test Abnormalities (Without Regard to Baseline Abnormality) by Week 49 - Fecal [12] | |||||||||||||||
End point description |
Number of subjects with blood detected in fecal samples is presented. All subjects who received at least 1 dose of investigational drug and had at least 1 fecal evaluation were included in the analysis of this endpoint.
|
|||||||||||||||
End point type |
Primary
|
|||||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
|||||||||||||||
Notes [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
||||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Categorical Summary of Liver Iron Accumulation by Week 49 [13] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Magnetic resonance imaging (MRI) of Liver was obtained to quantify liver iron accumulation for safety monitoring. MRIs were sent to an independent central radiology imaging facility for calculation of the average transverse relaxation rate (R2*) value which was used to monitor for iron accumulation in the liver. Number of subjects meeting the following criteria is presented as follows: 1) normal: R2*<=75Hz at 1.5T or <=139 Hz at 3.0T; 2) above normal: R2*>75Hz and <=190Hz at 1.5T or R2* >139Hz and <=369Hz at 3.0T; 3) mild overload: R2*>190Hz at 1.5T or R2*>360Hz at 3.0T. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Screening, Weeks 13, 29 and 45
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Number of Subjects With Physical Examination Findings Reported as SAEs by Week 49 [14] | ||||||||||||
End point description |
Physical examination included head, ears, eyes, nose, mouth, skin, heart and lung examinations, lymph nodes, gastrointestinal, musculoskeletal, and neurological systems. A targeted nose and throat mucosal exam were also performed to monitor for any signs of mucosal telangiectasias. An SAE was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. Investigators determined which physical examination findings were reported as SAEs. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
||||||||||||
Notes [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Summary of Tanner Stage Rating by Week 49 [15] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Tanner staging was performed before the first dose of each dose escalation to monitor for signs of accelerated sexual development. The physical changes in pubertal development (pubic hair, penis and testes) were assessed using the system described by Marshall and Tanner. More details about the system can be referred to Tanner JM. Growth at Adolescence. Blackwell Scientific Publications 1962; 2nd edition. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||
End point title |
Number of Subjects With Vital Signs Findings Reported as SAEs by Week 49 [16] | |||||||||
End point description |
Vital signs evaluation included supine systolic and diastolic blood pressure (BP), pulse rate, and respiratory rate. An SAE was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; resulted in congenital anomaly/birth defect. Investigators determined which vital signs findings were reported as SAEs. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
|||||||||
End point type |
Primary
|
|||||||||
End point timeframe |
Baseline to Week 49 visit
|
|||||||||
Notes [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
||||||||||
|
||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Subjects With Electrocardiogram (ECG) Data Meeting Pre-specified Criteria by Week 49 [17] | ||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Number of subjects with ECG data meeting the following criteria are presented: 1) corrected QT interval using Fridericia’s formula (QTcF interval) <450msec; 2) QTcF interval>=450 and <480msec; 3) QTcF interval >=480 and <500msec; 4) QTcF interval>=500msec; 5) QTcF interval increase from baseline<30msec; 6) QTcF interval increase from baseline >=30 and <60msec; 7) QTcF interval increase from baseline >=60msec. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||
End point title |
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Compared to Placebo by Week 49 | ||||||||||||
End point description |
The LVEF was the ratio of blood ejected during systole to blood in the ventricle at the end of diastole. LVEF was measured by cardiac magnetic resonance image (MRI) or echocardiogram. The same method of cardiac imaging was used consistently within a single subject. Cardiac MRIs were read by a central imaging vendor and echocardiograms were read locally at each site. The LVEF values measured by cardiac MRI and echocardiogram are combined in the following presentation. The analysis of covariance (ANCOVA) model was used to analyze the change from baseline for domagrozumab compared to placebo on LVEF. The baseline result, age, use of angiotensin receptor blocker (ARB)/beta blocker/angiotensin converting enzyme (ACE) inhibitor and treatment were included as fixed effects in the model. All subjects who received at least 1 dose of investigational drug and had evaluable LVEF data at Week 49 were included in the analysis of this endpoint.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Comparison in LVEF by Week 49 | ||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||
Number of subjects included in analysis |
107
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [18] | ||||||||||||
P-value |
= 0.2088 [19] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
1.293
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.7343 | ||||||||||||
upper limit |
3.32 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
1.022
|
||||||||||||
Notes [18] - Least square mean difference was calculated by placebo minus domagrozumab. [19] - The significance level is 0.05. |
|
|||||||||||||||||||||||||
End point title |
Height-adjusted Z-score of Lumbar Spine Bone Mineral Density Over Time by Week 49 [20] | ||||||||||||||||||||||||
End point description |
Bone mineral density (BMD) was evaluated by Dual energy X-ray Absorptiometry (DXA). The height adjusted Z-score presented below is the number of standard deviations which compares the BMD of the subject to the average BMD matched for their age, sex and ethnicity. If the Z-score was -2 standard deviations or lower, the result was “below the expected range for age”. If the Z-score was above -2 standard deviations, the result was “within the expected range for age”. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
Screening and Week 49
|
||||||||||||||||||||||||
Notes [20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Bone Age to Chronological Age Ratio by Week 49 [21] | ||||||||||||||||||||||||
End point description |
Bone age assessment was evaluated by the ratio of the bone age to the chronological age using the X rays of the hand and wrist. Ratio of bone age to chronological age was calculated by bone age/chronological age at scan date. Chronological age at scan date was calculated by (scan date-date of birth+1)/365.25. All subjects who received at least 1 dose of investigational drug were included in the analysis of this endpoint.
|
||||||||||||||||||||||||
End point type |
Primary
|
||||||||||||||||||||||||
End point timeframe |
Screening, Weeks 17, 33 and 49
|
||||||||||||||||||||||||
Notes [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||
End point title |
Number of Subjects With Suicidal Ideation and Suicidal Behavior Reported as AEs by Week 49 [22] | |||||||||||||||
End point description |
An AE was any untoward medical occurrence in a clinical investigation subject administered a product; the event did not need to have a causal relationship with the treatment. The Columbia Suicide Severity Rating Scale (C-SSRS) was performed to identify the risk of suicide ideation or behavior. AEs of suicide ideation or behavior were determined by the investigator.
|
|||||||||||||||
End point type |
Primary
|
|||||||||||||||
End point timeframe |
Baseline to Week 49 visit
|
|||||||||||||||
Notes [22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: No statistical analysis was planned for this endpoint |
||||||||||||||||
|
||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Change From Baseline on the 4 Stair Climb (4SC) as Compared to Placebo at Weeks 17, 33 and 49 | |||||||||||||||||||||
End point description |
The 4SC quantified the time required for a subject to ascend 4 standard steps. Mixed effect model for repeated measures (MMRM) was used to analyze the change from baseline on 4SC for domagrozumab compared to placebo. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Primary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 4SC at Week 17 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [23] | |||||||||||||||||||||
P-value |
= 0.9191 [24] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.0845
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.7354 | |||||||||||||||||||||
upper limit |
1.5663 | |||||||||||||||||||||
Notes [23] - Mean difference was calculated by domagrozumab minus placebo. [24] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 4SC at Week 33 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [25] | |||||||||||||||||||||
P-value |
= 0.7642 [26] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0.5837
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-3.2978 | |||||||||||||||||||||
upper limit |
4.4652 | |||||||||||||||||||||
Notes [25] - Mean difference was calculated by domagrozumab minus placebo. [26] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 4SC at Week 49 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [27] | |||||||||||||||||||||
P-value |
= 0.9423 [28] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0.2712
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-7.3799 | |||||||||||||||||||||
upper limit |
7.9223 | |||||||||||||||||||||
Notes [27] - Mean difference was calculated by domagrozumab minus placebo. [28] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on Forced Vital Capacity (FVC) at Weeks 17, 33 and 49 | |||||||||||||||||||||
End point description |
FVC was measured by spirometry to evaluate respiratory muscle function. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on FVC at Week 17 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [29] | |||||||||||||||||||||
P-value |
= 0.9993 [30] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.0693 | |||||||||||||||||||||
upper limit |
0.0693 | |||||||||||||||||||||
Notes [29] - Mean difference was calculated by domagrozumab minus placebo. [30] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on FVC at Week 33 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [31] | |||||||||||||||||||||
P-value |
= 0.5464 [32] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.0259
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.1107 | |||||||||||||||||||||
upper limit |
0.0589 | |||||||||||||||||||||
Notes [31] - Mean difference was calculated by domagrozumab minus placebo. [32] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on FVC at Week 49 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [33] | |||||||||||||||||||||
P-value |
= 0.3041 [34] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.042
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.1227 | |||||||||||||||||||||
upper limit |
0.0386 | |||||||||||||||||||||
Notes [33] - Mean difference was calculated by domagrozumab minus placebo. [34] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on the Northstar Ambulatory Assessment (NSAA) at Weeks 17, 33 and 49 | |||||||||||||||||||||
End point description |
The NSAA was a 17-item test that measured gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance. A total score was achieved by summing all the individual items. The total score could range from 0 to 34 (fully-independent function). MMRM was used to analyze the change from baseline for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on NSAA at Week 17 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [35] | |||||||||||||||||||||
P-value |
= 0.3522 [36] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0.8
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.9 | |||||||||||||||||||||
upper limit |
2.5 | |||||||||||||||||||||
Notes [35] - Mean difference was calculated by domagrozumab minus placebo. [36] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on NSAA at Week 33 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [37] | |||||||||||||||||||||
P-value |
= 0.0061 [38] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
2.5
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
0.7 | |||||||||||||||||||||
upper limit |
4.2 | |||||||||||||||||||||
Notes [37] - Mean difference was calculated by domagrozumab minus placebo. [38] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on NSAA at Week 49 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [39] | |||||||||||||||||||||
P-value |
= 0.1268 [40] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
1.6
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.5 | |||||||||||||||||||||
upper limit |
3.8 | |||||||||||||||||||||
Notes [39] - Mean difference was calculated by domagrozumab minus placebo. [40] - The significance level is 0.05. |
|
|||||||||||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on the Ankle Range of Motion (ROM) at Weeks 17, 33 and 49 | ||||||||||||||||||||||||||||||
End point description |
ROM was evaluated by using goniometry to evaluate the loss of motion in the ankles. MMRM was used to analyze the change from baseline on ROM for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on ROM(Left ankle, Week 17) | ||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [41] | ||||||||||||||||||||||||||||||
P-value |
= 0.7337 [42] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.4
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-2.9 | ||||||||||||||||||||||||||||||
upper limit |
2.1 | ||||||||||||||||||||||||||||||
Notes [41] - Mean difference was calculated by domagrozumab minus placebo. [42] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on ROM(Left ankle, Week 33) | ||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [43] | ||||||||||||||||||||||||||||||
P-value |
= 0.8893 [44] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
0.2
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-2.4 | ||||||||||||||||||||||||||||||
upper limit |
2.7 | ||||||||||||||||||||||||||||||
Notes [43] - Mean difference was calculated by domagrozumab minus placebo. [44] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on ROM(Left ankle, Week 49) | ||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [45] | ||||||||||||||||||||||||||||||
P-value |
= 0.2939 [46] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-1.5
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-4.3 | ||||||||||||||||||||||||||||||
upper limit |
1.3 | ||||||||||||||||||||||||||||||
Notes [45] - Mean difference was calculated by domagrozumab minus placebo. [46] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on ROM(Right ankle,Week 17) | ||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [47] | ||||||||||||||||||||||||||||||
P-value |
= 0.5995 [48] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
0.8
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-2.1 | ||||||||||||||||||||||||||||||
upper limit |
3.6 | ||||||||||||||||||||||||||||||
Notes [47] - Mean difference was calculated by domagrozumab minus placebo. [48] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on ROM(Right ankle,Week 33) | ||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [49] | ||||||||||||||||||||||||||||||
P-value |
= 0.0385 [50] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
2.9
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
0.2 | ||||||||||||||||||||||||||||||
upper limit |
5.6 | ||||||||||||||||||||||||||||||
Notes [49] - Mean difference was calculated by domagrozumab minus placebo. [50] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on ROM(Right ankle,Week 49) | ||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [51] | ||||||||||||||||||||||||||||||
P-value |
= 0.9927 [52] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
0
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-3.3 | ||||||||||||||||||||||||||||||
upper limit |
3.2 | ||||||||||||||||||||||||||||||
Notes [51] - Mean difference was calculated by domagrozumab minus placebo. [52] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on the Performance of Upper Limb (PUL) Overall Score at Weeks 17, 33 and 49 | |||||||||||||||||||||
End point description |
The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into three levels: shoulder(4 items), middle(9 items) and distal(8 items).Scoring options per item may not be uniform and may vary from 0–1 and 0–6, according to the performance, with higher values corresponding to better performance. A total maximum score of 74 is achieved by adding the individual level scores. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo.The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model.Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison in PUL at Week 17 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [53] | |||||||||||||||||||||
P-value |
= 0.6049 [54] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.3
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.7 | |||||||||||||||||||||
upper limit |
1 | |||||||||||||||||||||
Notes [53] - Mean difference was calculated by domagrozumab minus placebo. [54] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison in PUL at Week 33 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [55] | |||||||||||||||||||||
P-value |
= 0.2065 [56] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
1.7
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1 | |||||||||||||||||||||
upper limit |
4.4 | |||||||||||||||||||||
Notes [55] - Mean difference was calculated by domagrozumab minus placebo. [56] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison in PUL at Week 49 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [57] | |||||||||||||||||||||
P-value |
= 0.9391 [58] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.3 | |||||||||||||||||||||
upper limit |
1.2 | |||||||||||||||||||||
Notes [57] - Mean difference was calculated by domagrozumab minus placebo. [58] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on the Six Minute Walk Distance (6MWD) score at Weeks 17, 33 and 49 | |||||||||||||||||||||
End point description |
6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 6MWD at Week 17 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [59] | |||||||||||||||||||||
P-value |
= 0.8499 [60] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
1.8
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-16.7 | |||||||||||||||||||||
upper limit |
20.3 | |||||||||||||||||||||
Notes [59] - Mean difference was calculated by domagrozumab minus placebo. [60] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 6MWD at Week 33 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [61] | |||||||||||||||||||||
P-value |
= 0.4008 [62] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
8.9
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-12 | |||||||||||||||||||||
upper limit |
29.8 | |||||||||||||||||||||
Notes [61] - Mean difference was calculated by domagrozumab minus placebo. [62] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 6MWD at Week 49 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [63] | |||||||||||||||||||||
P-value |
= 0.916 [64] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-1.5
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-30 | |||||||||||||||||||||
upper limit |
27 | |||||||||||||||||||||
Notes [63] - Mean difference was calculated by domagrozumab minus placebo. [64] - The significance level is 0.05. |
|
|||||||||||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Extension at Weeks 17, 33 and 49 | ||||||||||||||||||||||||||||||
End point description |
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left elbow extension at Week 17 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [65] | ||||||||||||||||||||||||||||||
P-value |
= 0.5726 [66] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
0.115
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.287 | ||||||||||||||||||||||||||||||
upper limit |
0.517 | ||||||||||||||||||||||||||||||
Notes [65] - Mean difference was calculated by domagrozumab minus placebo. [66] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left elbow extension at Week 33 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [67] | ||||||||||||||||||||||||||||||
P-value |
= 0.4334 [68] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.163
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.574 | ||||||||||||||||||||||||||||||
upper limit |
0.248 | ||||||||||||||||||||||||||||||
Notes [67] - Mean difference was calculated by domagrozumab minus placebo. [68] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left elbow extension at Week 49 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [69] | ||||||||||||||||||||||||||||||
P-value |
= 0.5767 [70] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.126
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.573 | ||||||||||||||||||||||||||||||
upper limit |
0.321 | ||||||||||||||||||||||||||||||
Notes [69] - Mean difference was calculated by domagrozumab minus placebo. [70] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right elbow extension at Week 17 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [71] | ||||||||||||||||||||||||||||||
P-value |
= 0.9274 [72] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.022
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.489 | ||||||||||||||||||||||||||||||
upper limit |
0.446 | ||||||||||||||||||||||||||||||
Notes [71] - Mean difference was calculated by domagrozumab minus placebo. [72] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right elbow extension at Week 33 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [73] | ||||||||||||||||||||||||||||||
P-value |
= 0.0469 [74] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.439
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.872 | ||||||||||||||||||||||||||||||
upper limit |
-0.006 | ||||||||||||||||||||||||||||||
Notes [73] - Mean difference was calculated by domagrozumab minus placebo. [74] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right elbow extension at Week 49 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [75] | ||||||||||||||||||||||||||||||
P-value |
= 0.4362 [76] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.166
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.587 | ||||||||||||||||||||||||||||||
upper limit |
0.255 | ||||||||||||||||||||||||||||||
Notes [75] - Mean difference was calculated by domagrozumab minus placebo. [76] - The significance level is 0.05. |
|
|||||||||||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on Muscle Strength of Elbow Flexion at Weeks 17, 33 and 49 | ||||||||||||||||||||||||||||||
End point description |
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left elbow flexion at Week 17 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [77] | ||||||||||||||||||||||||||||||
P-value |
= 0.5557 [78] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.156
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.679 | ||||||||||||||||||||||||||||||
upper limit |
0.367 | ||||||||||||||||||||||||||||||
Notes [77] - Mean difference was calculated by domagrozumab minus placebo. [78] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left elbow flexion at Week 33 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Domagrozumab (Period 1) v Placebo (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [79] | ||||||||||||||||||||||||||||||
P-value |
= 0.2669 [80] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.303
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.841 | ||||||||||||||||||||||||||||||
upper limit |
0.235 | ||||||||||||||||||||||||||||||
Notes [79] - Mean difference was calculated by domagrozumab minus placebo. [80] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left elbow flexion at Week 49 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [81] | ||||||||||||||||||||||||||||||
P-value |
= 0.4665 [82] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.161
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.598 | ||||||||||||||||||||||||||||||
upper limit |
0.276 | ||||||||||||||||||||||||||||||
Notes [81] - Mean difference was calculated by domagrozumab minus placebo. [82] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right elbow flexion at Week 17 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [83] | ||||||||||||||||||||||||||||||
P-value |
= 0.7335 [84] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.083
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.564 | ||||||||||||||||||||||||||||||
upper limit |
0.399 | ||||||||||||||||||||||||||||||
Notes [83] - Mean difference was calculated by domagrozumab minus placebo. [84] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right elbow flexion, Week 33
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [85] | ||||||||||||||||||||||||||||||
P-value |
= 0.1695 [86] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.361
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.877 | ||||||||||||||||||||||||||||||
upper limit |
0.156 | ||||||||||||||||||||||||||||||
Notes [85] - Mean difference was calculated by domagrozumab minus placebo. [86] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right elbow flexion at Week 49 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [87] | ||||||||||||||||||||||||||||||
P-value |
= 0.3783 [88] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.189
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.612 | ||||||||||||||||||||||||||||||
upper limit |
0.234 | ||||||||||||||||||||||||||||||
Notes [87] - Mean difference was calculated by domagrozumab minus placebo. [88] - The significance level is 0.05. |
|
|||||||||||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on Muscle Strength of Hip Abduction at Weeks 17, 33 and 49 | ||||||||||||||||||||||||||||||
End point description |
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left hip abduction at Week 17 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [89] | ||||||||||||||||||||||||||||||
P-value |
= 0.1078 [90] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.586
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.303 | ||||||||||||||||||||||||||||||
upper limit |
0.13 | ||||||||||||||||||||||||||||||
Notes [89] - Mean difference was calculated by domagrozumab minus placebo. [90] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left hip abduction at Week 33 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [91] | ||||||||||||||||||||||||||||||
P-value |
= 0.8967 [92] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
0.046
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.654 | ||||||||||||||||||||||||||||||
upper limit |
0.746 | ||||||||||||||||||||||||||||||
Notes [91] - Mean difference was calculated by domagrozumab minus placebo. [92] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left hip abduction at Week 49 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [93] | ||||||||||||||||||||||||||||||
P-value |
= 0.3196 [94] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.378
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.128 | ||||||||||||||||||||||||||||||
upper limit |
0.371 | ||||||||||||||||||||||||||||||
Notes [93] - Mean difference was calculated by domagrozumab minus placebo. [94] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right hip abduction at Week 17 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [95] | ||||||||||||||||||||||||||||||
P-value |
= 0.0526 [96] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.689
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.386 | ||||||||||||||||||||||||||||||
upper limit |
0.008 | ||||||||||||||||||||||||||||||
Notes [95] - Mean difference was calculated by domagrozumab minus placebo. [96] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right hip abduction at Week 33 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [97] | ||||||||||||||||||||||||||||||
P-value |
= 0.3739 [98] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.336
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.082 | ||||||||||||||||||||||||||||||
upper limit |
0.41 | ||||||||||||||||||||||||||||||
Notes [97] - Mean difference was calculated by domagrozumab minus placebo. [98] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right hip abduction at Week 49 was measured
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [99] | ||||||||||||||||||||||||||||||
P-value |
= 0.4019 [100] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.322
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.079 | ||||||||||||||||||||||||||||||
upper limit |
0.436 | ||||||||||||||||||||||||||||||
Notes [99] - Mean difference was calculated by domagrozumab minus placebo. [100] - The significance level is 0.05. |
|
|||||||||||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on Muscle Strength of Knee Extension at Weeks 17, 33 and 49 | ||||||||||||||||||||||||||||||
End point description |
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left knee extension at Week 17 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [101] | ||||||||||||||||||||||||||||||
P-value |
= 0.7676 [102] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.107
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.825 | ||||||||||||||||||||||||||||||
upper limit |
0.61 | ||||||||||||||||||||||||||||||
Notes [101] - Mean difference was calculated by domagrozumab minus placebo. [102] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left knee extension at Week 33 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [103] | ||||||||||||||||||||||||||||||
P-value |
= 0.4127 [104] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.322
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.098 | ||||||||||||||||||||||||||||||
upper limit |
0.454 | ||||||||||||||||||||||||||||||
Notes [103] - Mean difference was calculated by domagrozumab minus placebo. [104] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left knee extension at Week 49 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [105] | ||||||||||||||||||||||||||||||
P-value |
= 0.7815 [106] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
0.113
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.693 | ||||||||||||||||||||||||||||||
upper limit |
0.919 | ||||||||||||||||||||||||||||||
Notes [105] - Mean difference was calculated by domagrozumab minus placebo. [106] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right knee extension at Week 17 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [107] | ||||||||||||||||||||||||||||||
P-value |
= 0.4975 [108] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.236
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.924 | ||||||||||||||||||||||||||||||
upper limit |
0.451 | ||||||||||||||||||||||||||||||
Notes [107] - Mean difference was calculated by domagrozumab minus placebo. [108] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right knee extension at Week 33 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [109] | ||||||||||||||||||||||||||||||
P-value |
= 0.2646 [110] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.467
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.294 | ||||||||||||||||||||||||||||||
upper limit |
0.359 | ||||||||||||||||||||||||||||||
Notes [109] - Mean difference was calculated by domagrozumab minus placebo. [110] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right knee extension at Week 49 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [111] | ||||||||||||||||||||||||||||||
P-value |
= 0.732 [112] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.149
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.008 | ||||||||||||||||||||||||||||||
upper limit |
0.71 | ||||||||||||||||||||||||||||||
Notes [111] - Mean difference was calculated by domagrozumab minus placebo. [112] - The significance level is 0.05. |
|
|||||||||||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on Muscle Strength of Shoulder Abduction at Weeks 17, 33 and 49 | ||||||||||||||||||||||||||||||
End point description |
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. MMRM was used to analyze the change from baseline on muscle strength for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left shoulder abduction at Week 17 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [113] | ||||||||||||||||||||||||||||||
P-value |
= 0.8569 [114] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.044
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.525 | ||||||||||||||||||||||||||||||
upper limit |
0.437 | ||||||||||||||||||||||||||||||
Notes [113] - Mean difference was calculated by domagrozumab minus placebo. [114] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left shoulder abduction at Week 33 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [115] | ||||||||||||||||||||||||||||||
P-value |
= 0.5495 [116] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.154
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.663 | ||||||||||||||||||||||||||||||
upper limit |
0.355 | ||||||||||||||||||||||||||||||
Notes [115] - Mean difference was calculated by domagrozumab minus placebo. [116] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Left shoulder abduction at Week 49 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [117] | ||||||||||||||||||||||||||||||
P-value |
= 0.934 [118] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.023
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.566 | ||||||||||||||||||||||||||||||
upper limit |
0.521 | ||||||||||||||||||||||||||||||
Notes [117] - Mean difference was calculated by domagrozumab minus placebo. [118] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right shoulder abduction at Week 17 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [119] | ||||||||||||||||||||||||||||||
P-value |
= 0.3279 [120] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.236
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-0.711 | ||||||||||||||||||||||||||||||
upper limit |
0.239 | ||||||||||||||||||||||||||||||
Notes [119] - Mean difference was calculated by domagrozumab minus placebo. [120] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on Muscle Strength | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right shoulder abduction at Week 33 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [121] | ||||||||||||||||||||||||||||||
P-value |
= 0.0086 [122] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.757
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.318 | ||||||||||||||||||||||||||||||
upper limit |
-0.196 | ||||||||||||||||||||||||||||||
Notes [121] - Mean difference was calculated by domagrozumab minus placebo. [122] - The significance level is 0.05. |
|||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Comparion on Muscle Strength abduction | ||||||||||||||||||||||||||||||
Statistical analysis description |
Right shoulder abduction at Week 49 was measured.
|
||||||||||||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
||||||||||||||||||||||||||||||
Number of subjects included in analysis |
120
|
||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||
Analysis type |
superiority [123] | ||||||||||||||||||||||||||||||
P-value |
= 0.2328 [124] | ||||||||||||||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||||||||||||||||
Point estimate |
-0.439
|
||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||
lower limit |
-1.165 | ||||||||||||||||||||||||||||||
upper limit |
0.286 | ||||||||||||||||||||||||||||||
Notes [123] - Mean difference was calculated by domagrozumab minus placebo. [124] - The significance level is 0.05. |
|
|||||||||||||
End point title |
Change From Baseline to Weeks 49 on 4SC for Subjects in Sequence 3 Compared to the Natural History Control Group [125] | ||||||||||||
End point description |
The 4SC quantified the time required for a subject to ascend 4 standard steps. MMRM was used to analyze the change from baseline on 4SC for the natural history control group compared to placebo group (Sequence 3). The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. This MMRM was established to assess the appropriateness on using the natural history control group as a comparator. This analysis population included all subjects randomized in Sequence 3 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable 4SC data at Week 49.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 49
|
||||||||||||
Notes [125] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Comparison on 4SC Between Sequence 3 and NH group | ||||||||||||
Comparison groups |
Sequence 3 v NH Control Group (4SC, Week 49)
|
||||||||||||
Number of subjects included in analysis |
90
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence [126] | ||||||||||||
P-value |
= 0.8908 [127] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
0.211
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.8353 | ||||||||||||
upper limit |
3.2573 | ||||||||||||
Notes [126] - Mean difference was calculated by Sequence 3 minus NH control group. [127] - The significance level is 0.05. |
|
|||||||||||||
End point title |
Change From Baseline to Weeks 97 on 4SC for Subjects in Sequence 1 Compared to the Natural History Control Group [128] | ||||||||||||
End point description |
The 4SC quantified the time required for a subject to ascend 4 standard steps. MMRM was used to analyze the change from baseline on 4SC for domagrozumab compared to the natural history control group. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. This analysis population included all subjects randomized in Sequence 1 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable 4SC data at Week 97.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 97
|
||||||||||||
Notes [128] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Comparison on 4SC Between Sequence 1 and NH group | ||||||||||||
Comparison groups |
Sequence 1 v NH Control Group (4SC, Week 97)
|
||||||||||||
Number of subjects included in analysis |
95
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [129] | ||||||||||||
P-value |
= 0.4748 [130] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
0.819
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-1.4514 | ||||||||||||
upper limit |
3.0895 | ||||||||||||
Notes [129] - Mean difference was calculated by Sequence 1 minus NH control group. [130] - The significance level is 0.05. |
|
|||||||||||||
End point title |
Change From Baseline to Week 49 on FVC for Subjects in Sequence 3 Compared to the Natural History Control Group [131] | ||||||||||||
End point description |
FVC was measured by spirometry to evaluate respiratory muscle function. MMRM was used to analyze the change from baseline on FVC for the natural history control group compared to placebo group (Sequence 3). The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. This MMRM was established to match the natural history control group with the placebo group. This MMRM was established to assess the appropriateness on using the natural history control group as a comparator. This analysis population included all subjects randomized in Sequence 3 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable FVC data at Week 49.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 49
|
||||||||||||
Notes [131] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Comparison on FVC Between Sequence 3 and NH group | ||||||||||||
Comparison groups |
Sequence 3 v NH Control Group (FVC, Week 49)
|
||||||||||||
Number of subjects included in analysis |
87
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence [132] | ||||||||||||
P-value |
= 0.807 [133] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
0.0097
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.0692 | ||||||||||||
upper limit |
0.0887 | ||||||||||||
Notes [132] - Mean difference was calculated by Sequence 3 minus NH control group. [133] - The significance level is 0.05. |
|
|||||||||||||
End point title |
Change From Baseline to Week 97 on FVC for Subjects in Sequence 1 Compared to the Natural History Control Group [134] | ||||||||||||
End point description |
FVC was measured by spirometry to evaluate respiratory muscle function. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to the natural history control group. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. This analysis population included all subjects randomized in Sequence 1 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable FVC data at Week 97.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 97
|
||||||||||||
Notes [134] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Comparison on FVC Between Sequence 1 and NH Group | ||||||||||||
Comparison groups |
Sequence 1 v NH Control Group (FVC, Week 97)
|
||||||||||||
Number of subjects included in analysis |
108
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [135] | ||||||||||||
P-value |
= 0.3643 [136] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
0.0506
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.0594 | ||||||||||||
upper limit |
0.1607 | ||||||||||||
Notes [135] - Mean difference was calculated by Sequence 1 minus NH control group. [136] - The significance level is 0.05. |
|
|||||||||||||
End point title |
Change From Baseline to Week 49 on NSAA for Subjects in Sequence 3 Compared to the Natural History Control Group [137] | ||||||||||||
End point description |
The NSAA is a 17-item test that measured gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance.The total score could range from 0 to 34 (fully-independent function).MMRM was used to analyze the change from baseline for natural history control group compared to placebo group (Sequence 3).The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model.Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.This MMRM was established to assess the appropriateness on using natural history control group as a comparator.This analysis population included all subjects randomized in Sequence 3 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable NSAA data at Week 49.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 49
|
||||||||||||
Notes [137] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Comparison on NSAA Between Sequence 3 and NH Group | ||||||||||||
Comparison groups |
Sequence 3 v NH Control Group (NSAA, Week 49)
|
||||||||||||
Number of subjects included in analysis |
55
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence [138] | ||||||||||||
P-value |
= 0.0483 [139] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-2.9
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-5.7 | ||||||||||||
upper limit |
0 | ||||||||||||
Notes [138] - Mean difference was calculated by Sequence 3 minus NH control group. [139] - The significance level is 0.05. |
|
|||||||||||||
End point title |
Change From Baseline to Week 97 on NSAA for Subjects in Sequence 1 Compared to the Natural History Control Group [140] | ||||||||||||
End point description |
The NSAA is a 17-item test that measured gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance.The total score ranged from 0 to 34 (fully-independent function). MMRM was used to analyze the change from baseline for domagrozumab compared to natural history control group.The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.This analysis population included all subjects randomized in Sequence 1 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable NSAA data at Week 97.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 97
|
||||||||||||
Notes [140] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Comparison on NSAA Between Sequence 1 and NH Group | ||||||||||||
Comparison groups |
Sequence 1 v NH Control Group (NSAA, Week 97)
|
||||||||||||
Number of subjects included in analysis |
36
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [141] | ||||||||||||
P-value |
= 0.0146 [142] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-3.9
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-7 | ||||||||||||
upper limit |
-0.8 | ||||||||||||
Notes [141] - Mean difference was calculated by Sequence 1 minus NH control group. [142] - The significance level is 0.05. |
|
|||||||||||||
End point title |
Change From Baseline to Week 49 on 6MWD for Subjects in Sequence 3 Compared to Natural History Control Group [143] | ||||||||||||
End point description |
6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. MMRM was used to analyze the change from baseline on 6MWD for the natural history control group compared to placebo group (Sequence 3). The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. This MMRM was established to assess the appropriateness on using the natural history control group as a comparator. This analysis population included all subjects randomized in Sequence 3 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable 6MWD data at Week 49.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 49
|
||||||||||||
Notes [143] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Comparison on 6MWD Between Sequence 3 and NH Group | ||||||||||||
Comparison groups |
Sequence 3 v NH Control Group (6MWD, Week 49)
|
||||||||||||
Number of subjects included in analysis |
47
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
equivalence [144] | ||||||||||||
P-value |
= 0.1669 [145] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-31.6
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-76.9 | ||||||||||||
upper limit |
13.6 | ||||||||||||
Notes [144] - Mean difference was calculated by Sequence 3 minus NH control group. [145] - The significance level is 0.05. |
|
|||||||||||||
End point title |
Change From Baseline to Week 97 on 6MWD for Subjects in Sequence 1 Compared to the Natural History Control Group [146] | ||||||||||||
End point description |
6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to the natural history control group. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. This analysis population included all subjects randomized in Sequence 1 and received at least 1 dose of randomized treatment, and the natural history control group who had evaluable 6MWD data at Week 97.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 97
|
||||||||||||
Notes [146] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this endpoint |
|||||||||||||
|
|||||||||||||
Statistical analysis title |
Comparion on 6MWD Between Sequence 1 and NH Group | ||||||||||||
Comparison groups |
Sequence 1 v NH Control Group (6MWD, Week 97)
|
||||||||||||
Number of subjects included in analysis |
29
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority [147] | ||||||||||||
P-value |
= 0.0267 [148] | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||
Point estimate |
-66.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-124.5 | ||||||||||||
upper limit |
-8.1 | ||||||||||||
Notes [147] - Mean difference was calculated by Sequence 1 minus NH control group. [148] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on 4SC at Week 17 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
The 4SC quantified the time required for a subject to ascend 4 standard steps. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 17
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 4SC in Subsets | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were measured.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [149] | |||||||||||||||||||||
P-value |
= 0.7033 [150] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.0692
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.4345 | |||||||||||||||||||||
upper limit |
0.2961 | |||||||||||||||||||||
Notes [149] - Mean difference was calculated by domagrozumab minus placebo. [150] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 4SC in Subsets | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <= 8 seconds were measured.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [151] | |||||||||||||||||||||
P-value |
= 0.6893 [152] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0.2114
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.8472 | |||||||||||||||||||||
upper limit |
1.27 | |||||||||||||||||||||
Notes [151] - Mean difference was calculated by domagrozumab minus placebo. [152] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 4SC in Subsets | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were measured.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [153] | |||||||||||||||||||||
P-value |
= 0.6469 [154] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-2.6439
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-14.4292 | |||||||||||||||||||||
upper limit |
9.1414 | |||||||||||||||||||||
Notes [153] - Mean difference was calculated by domagrozumab minus placebo. [154] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on 4SC at Week 33 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
The 4SC quantified the time required for a subject to ascend 4 standard steps. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. Mixed effect model for repeated measures (MMRM) was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 33
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 4SC in Subsets | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were measured.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
103
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [155] | |||||||||||||||||||||
P-value |
= 0.1353 [156] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.3289
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.7649 | |||||||||||||||||||||
upper limit |
0.1072 | |||||||||||||||||||||
Notes [155] - Mean difference was calculated by domagrozumab minus placebo. [156] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 4SC in Subsets | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <=8 seconds
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
103
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [157] | |||||||||||||||||||||
P-value |
= 0.7648 [158] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0.3457
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.9614 | |||||||||||||||||||||
upper limit |
2.6528 | |||||||||||||||||||||
Notes [157] - Mean difference was calculated by domagrozumab minus placebo. [158] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 4SC in Subsets | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were measured.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
103
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [159] | |||||||||||||||||||||
P-value |
= 0.3562 [160] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
8.2893
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-9.6409 | |||||||||||||||||||||
upper limit |
26.2194 | |||||||||||||||||||||
Notes [159] - Mean difference was calculated by domagrozumab minus placebo. [160] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on 4SC at Week 49 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
The 4SC quantified the time required for a subject to ascend 4 standard steps. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. Mixed effect model for repeated measures (MMRM) was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 49
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 4SC in Subsets | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were measured.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
95
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [161] | |||||||||||||||||||||
P-value |
= 0.1163 [162] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.5582
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.2615 | |||||||||||||||||||||
upper limit |
0.1451 | |||||||||||||||||||||
Notes [161] - Mean difference was calculated by domagrozumab minus placebo. [162] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 4SC in Subsets | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
95
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [163] | |||||||||||||||||||||
P-value |
= 0.2947 [164] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-11.2881
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-32.8328 | |||||||||||||||||||||
upper limit |
10.2566 | |||||||||||||||||||||
Notes [163] - Mean difference was calculated by domagrozumab minus placebo. [164] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 4SC in Subsets | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <=8 seconds were measured.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
95
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [165] | |||||||||||||||||||||
P-value |
= 0.9503 [166] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0.0944
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-3.0798 | |||||||||||||||||||||
upper limit |
3.2686 | |||||||||||||||||||||
Notes [165] - Mean difference was calculated by domagrozumab minus placebo. [166] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on FVC at Week 17 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
FVC was measured by spirometry to evaluate respiratory muscle function. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 17
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on FVC in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
118
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [167] | |||||||||||||||||||||
P-value |
= 0.8229 [168] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0.0159
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.127 | |||||||||||||||||||||
upper limit |
0.1588 | |||||||||||||||||||||
Notes [167] - Mean difference was calculated by domagrozumab minus placebo. [168] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on FVC in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
118
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [169] | |||||||||||||||||||||
P-value |
= 0.7709 [170] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.0132
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.1036 | |||||||||||||||||||||
upper limit |
0.0772 | |||||||||||||||||||||
Notes [169] - Mean difference was calculated by domagrozumab minus placebo. [170] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on FVC in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
118
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [171] | |||||||||||||||||||||
P-value |
= 0.3746 [172] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0.0889
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.1219 | |||||||||||||||||||||
upper limit |
0.2996 | |||||||||||||||||||||
Notes [171] - Mean difference was calculated by domagrozumab minus placebo. [172] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on FVC at Week 33 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
FVC was measured by spirometry to evaluate respiratory muscle function. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 33
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on FVC in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [173] | |||||||||||||||||||||
P-value |
= 0.2294 [174] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.0934
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.2481 | |||||||||||||||||||||
upper limit |
0.0613 | |||||||||||||||||||||
Notes [173] - Mean difference was calculated by domagrozumab minus placebo. [174] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on FVC in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <= 8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [175] | |||||||||||||||||||||
P-value |
= 0.8485 [176] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.0117
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.1339 | |||||||||||||||||||||
upper limit |
0.1105 | |||||||||||||||||||||
Notes [175] - Mean difference was calculated by domagrozumab minus placebo. [176] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on FVC in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [177] | |||||||||||||||||||||
P-value |
= 0.6645 [178] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0.0562
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.2187 | |||||||||||||||||||||
upper limit |
0.3312 | |||||||||||||||||||||
Notes [177] - Mean difference was calculated by domagrozumab minus placebo. [178] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on FVC at Week 49 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
FVC was measured by spirometry to evaluate respiratory muscle function. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline on FVC for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 49
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on FVC in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
112
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [179] | |||||||||||||||||||||
P-value |
= 0.2101 [180] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.1013
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.2622 | |||||||||||||||||||||
upper limit |
0.0597 | |||||||||||||||||||||
Notes [179] - Mean difference was calculated by domagrozumab minus placebo. [180] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on FVC in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <= 8 seconds wrere analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
112
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [181] | |||||||||||||||||||||
P-value |
= 0.4603 [182] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.0359
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.1326 | |||||||||||||||||||||
upper limit |
0.0608 | |||||||||||||||||||||
Notes [181] - Mean difference was calculated by domagrozumab minus placebo. [182] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on FVC in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
112
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [183] | |||||||||||||||||||||
P-value |
= 0.3739 [184] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0.1039
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.1386 | |||||||||||||||||||||
upper limit |
0.3463 | |||||||||||||||||||||
Notes [183] - Mean difference was calculated by domagrozumab minus placebo. [184] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on NSAA at Week 17 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
The NSAA is a 17-item test measuring gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance. A total score was achieved by summing all the individual items. The total score could range from 0 to 34 (fully-independent function). A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 sec, 2)>=3.5 sec and <=8 sec, 3) >8 sec. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 17
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on NSAA in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
115
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [185] | |||||||||||||||||||||
P-value |
= 0.8925 [186] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.3
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-4.5 | |||||||||||||||||||||
upper limit |
3.9 | |||||||||||||||||||||
Notes [185] - Mean difference was calculated by domagrozumab minus placebo. [186] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on NSAA in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
115
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [187] | |||||||||||||||||||||
P-value |
= 0.2107 [188] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
1.2
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.7 | |||||||||||||||||||||
upper limit |
3.2 | |||||||||||||||||||||
Notes [187] - Mean difference was calculated by domagrozumab minus placebo. [188] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on NSAA in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
115
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [189] | |||||||||||||||||||||
P-value |
= 0.2298 [190] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
1.3
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.9 | |||||||||||||||||||||
upper limit |
3.5 | |||||||||||||||||||||
Notes [189] - Mean difference was calculated by domagrozumab minus placebo. [190] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on NSAA at Week 33 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
The NSAA is a 17-item test measuring gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance. A total score was achieved by summing all the individual items. The total score could range from 0 to 34 (fully-independent function). A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 sec, 2)>=3.5 sec and <=8 sec, 3) >8 sec. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 33
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on NSAA in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [191] | |||||||||||||||||||||
P-value |
= 0.0554 [192] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
3.5
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.1 | |||||||||||||||||||||
upper limit |
7.1 | |||||||||||||||||||||
Notes [191] - Mean difference was calculated by domagrozumab minus placebo. [192] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on NSAA in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <= 8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [193] | |||||||||||||||||||||
P-value |
= 0.2027 [194] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
1.6
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.9 | |||||||||||||||||||||
upper limit |
4 | |||||||||||||||||||||
Notes [193] - Mean difference was calculated by domagrozumab minus placebo. [194] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on NSAA in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [195] | |||||||||||||||||||||
P-value |
= 0.0926 [196] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
2.9
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.5 | |||||||||||||||||||||
upper limit |
6.3 | |||||||||||||||||||||
Notes [195] - Mean difference was calculated by domagrozumab minus placebo. [196] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on NSAA at Week 49 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
The NSAA is a 17-item test measuring gross motor function. Each individual item received a score of 0-unable to perform independently, 1-able to perform with assistance, or 2-able to perform without assistance. A total score was achieved by summing all the individual items. The total score could range from 0 to 34 (fully-independent function). A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 sec, 2)>=3.5 sec and <=8 sec, 3) >8 sec. MMRM was used to analyze the change from baseline for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 49
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on NSAA in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
110
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [197] | |||||||||||||||||||||
P-value |
= 0.3597 [198] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
2
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-2.4 | |||||||||||||||||||||
upper limit |
6.3 | |||||||||||||||||||||
Notes [197] - Mean difference was calculated by domagrozumab minus placebo. [198] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on NSAA in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
110
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [199] | |||||||||||||||||||||
P-value |
= 0.7345 [200] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0.5
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-2.3 | |||||||||||||||||||||
upper limit |
3.3 | |||||||||||||||||||||
Notes [199] - Mean difference was calculated by domagrozumab minus placebo. [200] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on NSAA in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
110
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [201] | |||||||||||||||||||||
P-value |
= 0.032 [202] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
4
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
0.4 | |||||||||||||||||||||
upper limit |
7.7 | |||||||||||||||||||||
Notes [201] - Mean difference was calculated by domagrozumab minus placebo. [202] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on PUL Overall Scores at Week 17 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into three levels: shoulder (4 items), middle (9 items) and distal (8 items). Scoring options per item may not be uniform and may vary from 0–1 and 0–6, according to the performance, with higher values corresponding to better performance. A total maximum score of 74 is achieved by adding the individual level scores. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time. MMRM was used to analyze the change from baseline .The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 17
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on PUL in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were measured.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
118
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [203] | |||||||||||||||||||||
P-value |
= 0.3345 [204] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
1.2
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.3 | |||||||||||||||||||||
upper limit |
3.8 | |||||||||||||||||||||
Notes [203] - Mean difference was calculated by domagrozumab minus placebo. [204] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on PUL in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <= 8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
118
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [205] | |||||||||||||||||||||
P-value |
= 0.14 [206] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-1.2
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-2.9 | |||||||||||||||||||||
upper limit |
0.4 | |||||||||||||||||||||
Notes [205] - Mean difference was calculated by domagrozumab minus placebo. [206] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on PUL in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were anlyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
118
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [207] | |||||||||||||||||||||
P-value |
= 0.6764 [208] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.9
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-5.4 | |||||||||||||||||||||
upper limit |
3.6 | |||||||||||||||||||||
Notes [207] - Mean difference was calculated by domagrozumab minus placebo. [208] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on PUL Overall Score at Week 33 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into three levels: shoulder (4 items), middle (9 items) and distal (8 items). Scoring options per item may not be uniform and may vary from 0–1 and 0–6, according to the performance, with higher values corresponding to better performance. A total maximum score of 74 is achieved by adding the individual level scores. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time. MMRM was used to analyze the change from baseline.The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 33
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on PUL in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [209] | |||||||||||||||||||||
P-value |
= 0.097 [210] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
6.5
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.2 | |||||||||||||||||||||
upper limit |
14.2 | |||||||||||||||||||||
Notes [209] - Mean difference was calculated by domagrozumab minus placebo. [210] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on PUL in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [211] | |||||||||||||||||||||
P-value |
= 0.6919 [212] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.3
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.9 | |||||||||||||||||||||
upper limit |
1.3 | |||||||||||||||||||||
Notes [211] - Mean difference was calculated by domagrozumab minus placebo. [212] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on PUL in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [213] | |||||||||||||||||||||
P-value |
= 0.6736 [214] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-1
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-5.8 | |||||||||||||||||||||
upper limit |
3.9 | |||||||||||||||||||||
Notes [213] - Mean difference was calculated by domagrozumab minus placebo. [214] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on PUL Overall Score at Week 49 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
The PUL was used to assess motor performance of the upper limb. The PUL scale includes 22 items; an entry item defining the starting functional level, and 21 items subdivided into three levels: shoulder(4 items), middle(9 items) and distal(8 items). Scoring options per item may not be uniform and may vary from 0–1 and 0–6, according to the performance, with higher values corresponding to better performance. A total maximum score of 74 is achieved by adding the individual level scores. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time. MMRM was used to analyze the change from baseline.The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 49
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on PUL in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [215] | |||||||||||||||||||||
P-value |
= 0.9582 [216] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.5 | |||||||||||||||||||||
upper limit |
1.5 | |||||||||||||||||||||
Notes [215] - Mean difference was calculated by domagrozumab minus placebo. [216] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on PUL in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <= 8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [217] | |||||||||||||||||||||
P-value |
= 0.8629 [218] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.1
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.8 | |||||||||||||||||||||
upper limit |
1.5 | |||||||||||||||||||||
Notes [217] - Mean difference was calculated by domagrozumab minus placebo. [218] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on PUL in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
113
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [219] | |||||||||||||||||||||
P-value |
= 0.6746 [220] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-0.9
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-5.5 | |||||||||||||||||||||
upper limit |
3.7 | |||||||||||||||||||||
Notes [219] - Mean difference was calculated by domagrozumab minus placebo. [220] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on 6MWD at Week 17 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 17
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 6MWD in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
110
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [221] | |||||||||||||||||||||
P-value |
= 0.7483 [222] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-5.8
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-42.4 | |||||||||||||||||||||
upper limit |
30.7 | |||||||||||||||||||||
Notes [221] - Mean difference was calculated by domagrozumab minus placebo. [222] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 6MWD in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
110
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [223] | |||||||||||||||||||||
P-value |
= 0.9053 [224] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-1.3
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-23.9 | |||||||||||||||||||||
upper limit |
21.2 | |||||||||||||||||||||
Notes [223] - Mean difference was calculated by domagrozumab minus placebo. [224] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 6MWD in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
110
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [225] | |||||||||||||||||||||
P-value |
= 0.6896 [226] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
13.1
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-53.4 | |||||||||||||||||||||
upper limit |
79.7 | |||||||||||||||||||||
Notes [225] - Mean difference was calculated by domagrozumab minus placebo. [226] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on 6MWD at Week 33 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 33
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 6MWD in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
101
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [227] | |||||||||||||||||||||
P-value |
= 0.8117 [228] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-3.7
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-34.8 | |||||||||||||||||||||
upper limit |
27.5 | |||||||||||||||||||||
Notes [227] - Mean difference was calculated by domagrozumab minus placebo. [228] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 6MWD in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
101
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [229] | |||||||||||||||||||||
P-value |
= 0.6018 [230] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
7.3
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-20.6 | |||||||||||||||||||||
upper limit |
35.2 | |||||||||||||||||||||
Notes [229] - Mean difference was calculated by domagrozumab minus placebo. [230] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 6MWD in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
101
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [231] | |||||||||||||||||||||
P-value |
= 0.7152 [232] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
16.3
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-73.4 | |||||||||||||||||||||
upper limit |
106 | |||||||||||||||||||||
Notes [231] - Mean difference was calculated by domagrozumab minus placebo. [232] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Change From Baseline as Compared to Placebo on 6MWD at Week 49 in Pre-specified Subsets | |||||||||||||||||||||
End point description |
6MWD evaluated ambulation ability by measuring the distance walked in 6 minutes. A subset analysis was performed by categorizing subjects into 3 subsets according to the baseline 4SC time: 1) <3.5 seconds, 2)>=3.5 seconds and <=8 seconds, 3) >8 seconds. MMRM was used to analyze the change from baseline on 6MWD for domagrozumab compared to placebo in subsets. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Week 49
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 6MWD in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC<3.5 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
91
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [233] | |||||||||||||||||||||
P-value |
= 0.719 [234] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
7
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-32.1 | |||||||||||||||||||||
upper limit |
46.1 | |||||||||||||||||||||
Notes [233] - Mean difference was calculated by domagrozumab minus placebo. [234] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 6MWD in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>=3.5 and <=8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
91
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [235] | |||||||||||||||||||||
P-value |
= 0.4634 [236] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
-15.8
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-58.9 | |||||||||||||||||||||
upper limit |
27.3 | |||||||||||||||||||||
Notes [235] - Mean difference was calculated by domagrozumab minus placebo. [236] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Statistical Comparison on 6MWD in Subset | |||||||||||||||||||||
Statistical analysis description |
Subjects with baseline 4SC>8 seconds were analyzed.
|
|||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
91
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [237] | |||||||||||||||||||||
P-value |
= 0.94 [238] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
3.9
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-100.7 | |||||||||||||||||||||
upper limit |
108.5 | |||||||||||||||||||||
Notes [237] - Mean difference was calculated by domagrozumab minus placebo. [238] - The significance level is 0.05. |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change From Baseline on Muscle Strength at Weeks 17, 33 and 49 in Pre-specified Subset (Baseline 4SC <3.5 Seconds) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. Change from baseline on muscle strength in all randomized subjects who had received at least 1 dose of randomized treatment and had baseline 4SC <3.5 seconds are presented below.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change From Baseline on Muscle Strength at Weeks 17, 33 and 49 in Pre-specified Subset (Baseline 4SC >=3.5 Seconds and <=8 Seconds) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. Change from baseline on muscle strength in all randomized subjects who had received at least 1 dose of randomized treatment and had baseline 4SC >=3.5 seconds and <=8 seconds are presented below.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Change From Baseline on Muscle Strength at Weeks 17, 33 and 49 in Pre-specified Subset (Baseline 4SC >8 seconds) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Muscle strength was quantified by means of a handheld dynamometer. The following muscle groups were evaluated: knee extension, elbow flexion, hip abduction, elbow extension and shoulder abduction. Change from baseline on muscle strength in all randomized subjects who had received at least 1 dose of randomized treatment and had baseline 4SC >8 seconds are presented below.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
||||||||||||||||||||||
End point title |
Percent Change From Baseline in Whole Thigh Muscle Volume as Compared to Placebo by Weeks 17, 33 and 49 | |||||||||||||||||||||
End point description |
The whole thigh muscle volume was measured by the proton density weighted sequence with magnetic resonance imaging (MRI) which was used to segment the entire thigh region into 3 primary regions for volumetric measure including 1) muscle; 2) inter/intra-muscular fat, 3) subcutaneous fat. MMRM was used to analyze the percent change from baseline for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in the analysis of this endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Comparison on Thigh Muscle Volume at Week 17 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [239] | |||||||||||||||||||||
P-value |
= 0.1323 [240] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
2.189
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.6721 | |||||||||||||||||||||
upper limit |
5.0506 | |||||||||||||||||||||
Notes [239] - Mean difference was calculated by domagrozumab minus placebo. [240] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Comparison on Thigh Muscle Volume at Week 49 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [241] | |||||||||||||||||||||
P-value |
= 0.2035 [242] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
2.864
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.5718 | |||||||||||||||||||||
upper limit |
7.2994 | |||||||||||||||||||||
Notes [241] - Mean difference was calculated by domagrozumab minus placebo. [242] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Comparison on Thigh Muscle Volume at Week 33 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [243] | |||||||||||||||||||||
P-value |
= 0.2102 [244] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
2.11
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.2078 | |||||||||||||||||||||
upper limit |
5.4279 | |||||||||||||||||||||
Notes [243] - Mean difference was calculated by domagrozumab minus placebo. [244] - The significance level is 0.05. |
|
||||||||||||||||||||||
End point title |
Percent Change From Baseline as Compared to Placebo in Whole Thigh Muscle Volume Index by Weeks 17, 33 and 49 | |||||||||||||||||||||
End point description |
The thigh muscle volume index was derived from the thigh muscle volume measurements as a fraction of the total thigh tissue that was the lean muscle. MMRM was used to analyze the percent change from baseline for domagrozumab compared to placebo. The stratification factor, baseline result, treatment, time and treatment by time interaction were included as fixed effects in the model. Subjects were included as a random effect and the model was fit with an unstructured covariance for the repeated measures. All subjects randomized and who had received at least 1 dose of randomized treatment were included in this endpoint's analysis set.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33 and 49
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Comparison on Muscle Volume Index at Week 17 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [245] | |||||||||||||||||||||
P-value |
= 0.4921 [246] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
0.761
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.4272 | |||||||||||||||||||||
upper limit |
2.9491 | |||||||||||||||||||||
Notes [245] - Mean difference was calculated by domagrozumab minus placebo. [246] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Comparison on Muscle Volume Index at Week 33 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [247] | |||||||||||||||||||||
P-value |
= 0.1866 [248] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
1.755
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.8621 | |||||||||||||||||||||
upper limit |
4.3729 | |||||||||||||||||||||
Notes [247] - Mean difference was calculated by domagrozumab minus placebo. [248] - The significance level is 0.05. |
||||||||||||||||||||||
Statistical analysis title |
Comparison on Muscle Volume Index at Week 49 | |||||||||||||||||||||
Comparison groups |
Placebo (Period 1) v Domagrozumab (Period 1)
|
|||||||||||||||||||||
Number of subjects included in analysis |
120
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
superiority [249] | |||||||||||||||||||||
P-value |
= 0.2414 [250] | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Mean difference (net) | |||||||||||||||||||||
Point estimate |
1.98
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-1.3513 | |||||||||||||||||||||
upper limit |
5.3112 | |||||||||||||||||||||
Notes [249] - Mean difference was calculated by domagrozumab minus placebo. [250] - The significance level is 0.05 |
|
|||||||||||||||||||||||||||||||||
End point title |
Change From Baseline in Whole Thigh Muscle Volume Through Week 97 | ||||||||||||||||||||||||||||||||
End point description |
The whole thigh muscle volume was measured by the proton density weighted sequence with magnetic resonance imaging (MRI) which was used to segment the entire thigh region into 3 primary regions for volumetric measure including 1) muscle; 2) inter/intra-muscular fat, 3) subcutaneous fat. All subjects randomized and who had received at least 1 dose of randomized treatment were included in this endpoint's analysis set.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33, 49 and 97
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||
End point title |
Change From Baseline in Whole Thigh Muscle Volume Index Through Week 97 | ||||||||||||||||||||||||||||||||
End point description |
The thigh muscle volume index was derived from the thigh muscle volume measurements as the fraction of total thigh tissue that was the lean muscle. All subjects randomized and who had received at least 1 dose of randomized treatment were included in this endpoint's analysis set.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 17, 33, 49 and 97
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Concentration of Growth Differentiation Factor 8 (GDF-8) at Time 0 (pre-dose),(C0(GDF-8) ) | ||||||||||||||||
End point description |
GDF-8, also called myostatin, is the target of domagrozumab. C0(GDF-8) was observed directly from data. All enrolled subjects in whom at least 1 GDF-8 concentration value was reported were included in this endpoint's analysis set. Subjects without contributing to the summary statistics are excluded below.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Predose on Day 1 of Week 1
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Trough Serum Concentration of GDF-8 (Ctrough,(GDF-8)) for Subjects Receiving Domagrozumab in Period 1 | ||||||||||||||||
End point description |
GDF-8, also called myostatin, is the target of domagrozumab. Ctrough,(GDF-8) was observed directly from data. This endpoint's analysis set included all enrolled subjects of Sequence 1 and 2 and in whom at least 1 GDF-8 concentration value was reported. Subjects without contributing to the summary statistics are excluded below.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Every 4 weeks on dosing day (at predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 1 to Week 48
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Ctrough,(GDF-8) for Subjects of Sequence 3 in Period 2 | ||||||||||||||||
End point description |
GDF-8, also called myostatin, is the target of domagrozumab. Ctrough,(GDF-8) was observed directly from data.This endpoint's analysis set included all enrolled subjects of Sequence 3 and in whom at least 1 GDF-8 concentration value was reported. Subjects without contributing to the summary statistics are excluded below.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Every 4 weeks on dosing day (predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 49 to Week 96
|
||||||||||||||||
|
|||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Trough (pre-dose) Serum Concentration (Ctrough) of Domagrozumab | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Ctrough was observed directly from data. This endpoint's analysis set included all subjects who received at least 1 dose of domagrozumab and in whom at least 1 concentration value was reported. Subjects without contributing to the summary statistics are excluded below. "99999" represents "not applicable" because data were not collected for specified rows of time points. The geometric coefficient of variation for Sequence 2 at Week 1 is 99999 because only 1 subject was analyzed for Ctrough at Week 1 and thus the geometric mean is an individual data.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Every 4 weeks on dosing day (predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 1 to Week 96 for Sequence 1; from Week 1 to Week 48 for Sequence 2; from Week 49 to Week 96 for Sequence 3
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No statistical analyses for this end point |
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End point title |
Maximum Serum Concentration (Cmax) of Domagrozumab | ||||||||||||||||
End point description |
Cmax was observed directly from data.
|
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End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Every 4 weeks on dosing day (predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 1 to Week 96 for Sequence 1; from Week 1 to Week 48 for Sequence 2; from Week 49 to Week 96 for Sequence 3
|
||||||||||||||||
|
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Notes [251] - Data were not collected and analyzed due to study early termination. [252] - Data were not collected and analyzed due to study early termination. [253] - Data were not collected and analyzed due to study early termination. |
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No statistical analyses for this end point |
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End point title |
Time for Cmax (Tmax) of Domagrozumab | ||||||||||||||||
End point description |
Tmax was observed directly from the data.
|
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End point type |
Secondary
|
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End point timeframe |
Every 4 weeks on dosing day (predose, end of 2-hour infusion and 6 hours since start of infusion) from Week 1 to Week 96 for Sequence 1; from Week 1 to Week 48 for Sequence 2; from Week 49 to Week 96 for Sequence 3
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Notes [254] - Data were not collected and analyzed due to study early termination. [255] - Data were not collected and analyzed due to study early termination. [256] - Data were not collected and analyzed due to study early termination. |
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No statistical analyses for this end point |
|
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End point title |
Terminal Half-life (t1/2) for Subjects in Sequence 2 After the Last Dose of Domagrozumab [257] | ||||||||
End point description |
t1/2 was calculated by Loge(2)/kel, where kel was the terminal phase rate constant calculated by a linear regression of the log-linear concentration-time curve. Subjects in Sequence 2 received the last dose of domagrozumab at Week 45.
|
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End point type |
Secondary
|
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End point timeframe |
At predose, end of 2-hour infusion and 6 hours since start of infusion at Week 45
|
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Notes [257] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this endpoint |
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|
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Notes [258] - Data were not collected and analyzed due to study early termination. |
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No statistical analyses for this end point |
|
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End point title |
Area Under the Serum Concentration-time Curve Over the Dosing Interval tau (AUCtau) of Domagrozumab | ||||||||||||||||||||||||||||||||||||||||
End point description |
The dosing interval tau was 672 hours (4 weeks). AUCtau was obtained by linear/log trapezoidal method. The AUCtau was assessed to fully characterize PK data and it was only assessed on the first 12 subjects enrolled in the study who were required to complete additional PK visits. This endpoint's analysis set included subjects who were among the first 12 subjects enrolled in the study, had received at least 1 dose of domagrozumab and in whom at least 1 of the PK parameters of interest was calculated. Subjects without contributing to the summary statistics are excluded below. "99999" represents "not applicable" because data were not collected for specified rows of time points.
|
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End point type |
Secondary
|
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End point timeframe |
At predose, end of 2-hour infusion,6 hours and 168 hours since start of infusion on Weeks 1, 13, 17, 29, 33 and 45
|
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Notes [259] - Subjects received placebo in Period 1. |
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No statistical analyses for this end point |
|
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End point title |
Average Serum Concentration Over the Dosing Interval (Cav) of Domagrozumab | ||||||||||||||||||||||||||||||||||||||||
End point description |
Cav was calculated by AUCtau/tau. The Cav was assessed to fully characterize PK data and it was only assessed on the first 12 subjects enrolled in the study who were required to complete additional PK visits. This endpoint's analysis set included subjects who were among the first 12 subjects enrolled in the study, had received at least 1 dose of domagrozumab and in whom at least 1 of the PK parameters of interest was calculated. Subjects without contributing to the summary statistics are excluded below. "99999" represents "not applicable" because data were not collected for specified rows of time points.
|
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End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
At predose, end of 2-hour infusion, 6 hours and 168 hours since start of infusion on Weeks 1, 13, 17, 29, 33 and 45
|
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|
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Notes [260] - Subjects received placebo in Period 1. |
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No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||
End point title |
Clearance (CL) of Domagrozumab | ||||||||||||||||||||||||||||
End point description |
CL was calculated by Dose/AUCtau. The CL was assessed to fully characterize PK data and it was only assessed on the first 12 subjects enrolled in the study who were required to complete additional PK visits. This endpoint's analysis set included subjects who were among the first 12 subjects enrolled in the study, had received at least 1 dose of domagrozumab and in whom at least 1 of the PK parameters of interest was calculated. Subjects without contributing to the summary statistics are excluded below. "99999" represents "not applicable" because data were not collected for specified rows of time points.
|
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End point type |
Secondary
|
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End point timeframe |
At predose, end of 2-hour infusion, 6 hours and 168 hours since start of infusion on Weeks 13, 29 and 45
|
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Notes [261] - Subjects received placebo in Period 1. |
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No statistical analyses for this end point |
|
|||||||||
End point title |
Volume of distribution at steady state (Vss) of Domagrozumab for Subjects in Sequence 2 Required for Additional PK Assessment [262] | ||||||||
End point description |
Vss was calculated by CL*MRT, where MRT was the mean residence time. Vss was assessed to fully characterize PK data.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
At predose, end of 2-hour infusion, 6 hours and 168 hours since start of infusion on Week 45
|
||||||||
Notes [262] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: No statistical analysis was planned for this endpoint |
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Notes [263] - Data were not collected and analyzed due to study early termination. |
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No statistical analyses for this end point |
|
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End point title |
Number of Subjects With Anti-drug Antibodies (ADA) Development by Week 97 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The criterion for positive result of ADA samples was ADA titer >=1.88. All subjects who received at least 1 dose of investigational drug were included in this endpoint's analysis set. "99999" represents "not applicable" because data were not collected for specified rows of time points.
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End point type |
Secondary
|
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End point timeframe |
Baseline, every 4 weeks from Week 5 to Week 97 visit or early termination
|
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No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Area Under the Curve From Time Zero to Last Quantifiable Serum Concentration (AUClast) of Domagrozumab | ||||||||||||||||
End point description |
AUClast was calculated by linear/log trapezoidal method. AUCtau was obtained by linear/log trapezoidal method. AUClast was assessed to fully characterize PK data and it was only assessed on the first 12 subjects enrolled in the study who were required to complete additional PK visits.
|
||||||||||||||||
End point type |
Other pre-specified
|
||||||||||||||||
End point timeframe |
At predose, end of 2-hour infusion, 6 hours and 168 hours since start of infusion on Weeks 1, 13, 17, 29, 33 and 45
|
||||||||||||||||
|
|||||||||||||||||
Notes [264] - Data were not collected and analyzed due to study early termination. [265] - Data were not collected and analyzed due to study early termination. [266] - Data were not collected and analyzed due to study early termination. |
|||||||||||||||||
No statistical analyses for this end point |
|
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Adverse events information
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Timeframe for reporting adverse events |
105 weeks
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Adverse event reporting additional description |
The same event may appear as both an AE and an SAE. An event may be categorized as serious in one subject and as non-serious in another subject, or one subject may have experienced both a serious and non-serious event during the study. Total number at risk below refers to the number of subjects evaluable for SAEs or AEs.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
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Reporting groups
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Reporting group title |
Sequence 1, Period 2
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
From Week 49 (Period 2), subjects received domagrozumab intravenously at the maximum tolerated dose (40 mg/kg) every 4 weeks for additional 48 weeks or until early termination of the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sequence 1, Period 1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). Subjects in this sequence continued to receive domagrozumab at the maximum tolerated dose (40 mg/kg) in the next period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sequence 2, Period 2
|
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Reporting group description |
From Week 49 (Period 2), subjects received placebo for additional 48 weeks or until early termination of the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sequence 2, Period 1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Subjects received domagrozumab in a dose escalating fashion (5, 20 and 40mg/kg) for 48 weeks (Period 1). At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). Subjects in this sequence received placebo in the next period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sequence 3, Period 2
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
From Week 49 (Period 2), subjects received domagrozumab in a dose escalating fashion (5, 20 and 40 mg/kg) for additional 48 weeks or until early termination of the study. At each dose level, dosing was administered over 2 hours by intravenous infusion every 4 weeks for a total of 16 weeks (4 doses). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Sequence 3, Period 1
|
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Reporting group description |
Subjects received placebo for 48 weeks (Period 1). Subjects in this sequence received active treatment in a dose escalating fashion in the next period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
This study was terminated because the primary efficacy objective (the efficacy of treatment with domagrozumab based on a mean change from baseline on 4 Stair Climb as compared to placebo following 48 weeks of treatment) was not met. |