Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Followed by an Open-Label Extension to Evaluate the Efficacy and Safety of Fremanezumab for Preventive Treatment of Migraine in Patients with Major Depressive Disorder
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Summary
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EudraCT number |
2019-001989-15 |
Trial protocol |
DE CZ FR FI GR ES IT |
Global end of trial date |
31 Aug 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Sep 2023
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First version publication date |
15 Sep 2023
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Other versions |
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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 |
TV48125-MH-40142
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04041284 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Teva Branded Pharmaceutical Products R&D, Inc.
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Sponsor organisation address |
145 Brandywine Parkway, West Chester, United States, 19380
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Public contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., MedInfo@tevaeu.com
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Scientific contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., MedInfo@tevaeu.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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 |
31 Aug 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Aug 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Aug 2022
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective is to evaluate the efficacy of monthly subcutaneous (SC) fremanezumab in adult participants with migraine and major depressive disorder (MDD).
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Protection of trial subjects |
This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
13 Aug 2019
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Czechia: 62
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Country: Number of subjects enrolled |
Germany: 28
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Country: Number of subjects enrolled |
Spain: 9
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Country: Number of subjects enrolled |
France: 10
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Country: Number of subjects enrolled |
United Kingdom: 2
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Country: Number of subjects enrolled |
Greece: 50
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Country: Number of subjects enrolled |
Israel: 9
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Country: Number of subjects enrolled |
Italy: 24
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Country: Number of subjects enrolled |
Poland: 41
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Country: Number of subjects enrolled |
Russian Federation: 41
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Country: Number of subjects enrolled |
Ukraine: 24
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Country: Number of subjects enrolled |
United States: 53
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Worldwide total number of subjects |
353
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EEA total number of subjects |
224
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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) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
342
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From 65 to 84 years |
11
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85 years and over |
0
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Recruitment
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Recruitment details |
- | |||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Of the 540 participants screened, 353 participants were enrolled/randomized. One participant was randomized to Placebo and received placebo in the double-blind (DB) period but was summarized in the Fremanezumab treatment group in all safety summaries due to an error in recording treatment. | |||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
DB Phase (12 Weeks)
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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, Carer, Assessor | |||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||||||||||||||
Arm description |
Participants received placebo matched to fremanezumab SC during the 12-week DB period and then continued into the open-label (OL) extension period in which all participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85. | |||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||
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 |
Subcutaneous use
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Dosage and administration details |
Placebo was administered per schedule specified in the arm description.
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Arm title
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Fremanezumab | |||||||||||||||||||||||||||||||||
Arm description |
Participants received monthly doses of fremanezumab Dose 1 SC during the 12-week DB period and then continued into the OL extension period in which all participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fremanezumab
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Investigational medicinal product code |
TEV-48125, LBR-101, PF-04427429, RN307
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Fremanezumab was administered per dose and schedule specified in the arm description.
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Period 2
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Period 2 title |
OL Phase (12 Weeks)
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Is this the baseline period? |
No | |||||||||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||||||||||||||
Arm description |
Participants received placebo matched to fremanezumab subcutaneously (SC) during the 12-week double blind (DB) period and then continued into the open-label (OL) extension period in which all participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85. | |||||||||||||||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fremanezumab
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Investigational medicinal product code |
TEV-48125, LBR-101, PF-04427429, RN307
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Fremanezumab was administered per dose and schedule specified in the arm description.
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Arm title
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Fremanezumab | |||||||||||||||||||||||||||||||||
Arm description |
Participants received monthly doses of fremanezumab Dose 1 SC during the 12-week DB period and then continued into the OL extension period in which all participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85. | |||||||||||||||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fremanezumab
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Investigational medicinal product code |
TEV-48125, LBR-101, PF-04427429, RN307
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Fremanezumab was administered per dose and schedule specified in the arm description.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received placebo matched to fremanezumab SC during the 12-week DB period and then continued into the open-label (OL) extension period in which all participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fremanezumab
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Reporting group description |
Participants received monthly doses of fremanezumab Dose 1 SC during the 12-week DB period and then continued into the OL extension period in which all participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received placebo matched to fremanezumab SC during the 12-week DB period and then continued into the open-label (OL) extension period in which all participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85. | ||
Reporting group title |
Fremanezumab
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Reporting group description |
Participants received monthly doses of fremanezumab Dose 1 SC during the 12-week DB period and then continued into the OL extension period in which all participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85. | ||
Reporting group title |
Placebo
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Reporting group description |
Participants received placebo matched to fremanezumab subcutaneously (SC) during the 12-week double blind (DB) period and then continued into the open-label (OL) extension period in which all participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85. | ||
Reporting group title |
Fremanezumab
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Reporting group description |
Participants received monthly doses of fremanezumab Dose 1 SC during the 12-week DB period and then continued into the OL extension period in which all participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85. | ||
Subject analysis set title |
Double-blind Phase: Placebo
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
Participants received placebo matched to fremanezumab SC during the 12-week DB period.
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Subject analysis set title |
Double-blind Phase: Fremanezumab
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Subject analysis set type |
Modified intention-to-treat | ||
Subject analysis set description |
Participants received monthly doses of fremanezumab Dose 1 SC during the 12-week DB period.
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Subject analysis set title |
Double-blind Phase: Placebo
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Participants received placebo matched to fremanezumab SC during the 12-week DB period.
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Subject analysis set title |
Double-blind Phase: Fremanezumab
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Participants received monthly doses of fremanezumab Dose 1 SC during the 12-week DB period.
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Subject analysis set title |
Open-label Phase: Placebo/Fremanezumab Dose 2
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85.
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Subject analysis set title |
Open-label Phase: Fremanezumab Dose 1/Fremanezumab Dose 2
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85.
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End point title |
Change from Baseline in Monthly Average Number of Migraine Days During the 12-Week DB Treatment Phase After the First Dose of Study Drug | ||||||||||||
End point description |
A migraine day was defined as when at least 1 of following occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of headache meeting criteria for migraine with or without aura; at least 4 consecutive hours of headache meeting criteria for probable migraine (1 migraine criterion missing); a headache of any duration that was treated with migraine-specific medications; and a calendar day that was immediately consecutive of any day fulfilling 3 criteria above, where participants report headache of any duration. Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 12-week/number of days with assessments recorded in e-diary for 12-week)*28. Least square (LS) mean was calculated using analysis of covariance (ANCOVA). DB mITT analysis set: all randomized participants who received at least 1 dose of study drug and had at least 10 days of postrandomization efficacy assessment on primary endpoint.
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End point type |
Primary
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End point timeframe |
Baseline (Day -28 to Day -1), up to Week 12
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Double-blind Phase: Fremanezumab v Double-blind Phase: Placebo
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Number of subjects included in analysis |
353
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-2.2
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-3.16 | ||||||||||||
upper limit |
-1.21 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.5
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End point title |
Number of Participants With ≥50% Reduction in Monthly Average Number of Migraine Days During the 12 Weeks After the First Dose of Study Drug | |||||||||
End point description |
A migraine day was defined as when at least 1 of following occurred: A calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of headache meeting criteria for migraine with or without aura; at least 4 consecutive hours of headache meeting criteria for probable migraine (1 migraine criterion missing); a headache of any duration that was treated with migraine-specific medications; and a calendar day that was immediately consecutive of any day fulfilling 3 criteria above, where participants report headache of any duration. Monthly averages were derived and normalized to 28 days equivalent by formula: (number of days of efficacy variable over 12-week/number of days with assessments recorded in e-diary for 12-week)*28. DB mITT analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postrandomization efficacy assessment on the primary endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline (Day -28 to Day -1) up to Week 12
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Statistical analysis title |
Statistical Analysis 1 | |||||||||
Comparison groups |
Double-blind Phase: Placebo v Double-blind Phase: Fremanezumab
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Number of subjects included in analysis |
353
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||
P-value |
< 0.0001 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
3.26
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
1.89 | |||||||||
upper limit |
5.62 | |||||||||
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End point title |
Change from Baseline in Hamilton Depression Rating Scale-17 (HAM-D 17) Items Total Score at Week 8 | ||||||||||||
End point description |
HAM-D 17 is a list of 17 items used to determine participant’s level of depression. HAM-D total score comprises a sum of 17 individual item scores. 8 items scored in a range of 0 (none/absent) to 2 (severe symptom) include: Insomnia (early, middle, late), somatic symptoms (gastrointestinal and general), genital symptoms, loss of weight, and insight. The following 9 items are scored in a range of 0 (none/absent) to 4 (severe symptom): Agitation, depressed mood, feelings of guilt, suicide, work and activities, retardation, anxiety (psychic and somatic), and hypochondriasis. HAM-D17 total score is calculated as the sum of 17 individual symptom scores; total score can range from 0 to 52. Higher scores indicate more severe depression. LS mean was calculated using mixed-effects model for repeated measures (MMRM). DB mITT analysis set: all randomized participants who received at least 1 dose of study drug and had at least 10 days of postrandomization efficacy assessment on primary endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 8
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Double-blind Phase: Placebo v Double-blind Phase: Fremanezumab
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Number of subjects included in analysis |
353
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||
P-value |
= 0.0205 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-1.4
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-2.61 | ||||||||||||
upper limit |
-0.22 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.61
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End point title |
Change from Baseline in Migraine-Specific Quality of Life (MSQoL) Questionnaire Role Function-Restrictive and Role Function-Preventive Domain Scores at Week 12 | ||||||||||||||||||
End point description |
MSQoL v2.1 is a 14-item questionnaire. Each item is scored on a 6-point scale: 1=none of the time to 6=all of the time. MSQoL measures the degree to which performance of normal activities is limited by migraine (Role Function-Restrictive domain comprising 7 items; score range 7 to 42), the degree to which performance of normal activities is prevented by migraine (Role Function-Preventive domain comprising 4 items; score range 4 to 24), and emotional effects of migraine (Emotional Function domain comprising 3 items; score range 3 to 18). Total raw scores for each domain is the sum of final item value for all of the items in that domain. Total raw score for each domain are transformed to a 0-100 scale with higher scores indicating a better health-related quality of life. LS mean was calculated using MMRM. DB mITT analysis set: all randomized participants who received at least 1 dose of study drug and had at least 10 days of postrandomization efficacy assessment on primary endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 12
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||
Statistical analysis description |
Restrictive score: Fremanezumab versus placebo
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Comparison groups |
Double-blind Phase: Placebo v Double-blind Phase: Fremanezumab
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Number of subjects included in analysis |
353
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
P-value |
< 0.0001 | ||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||
Parameter type |
LS mean difference | ||||||||||||||||||
Point estimate |
11.3
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
6.91 | ||||||||||||||||||
upper limit |
15.59 | ||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
2.21
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Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||
Statistical analysis description |
Preventive score: Fremanezumab versus placebo
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Comparison groups |
Double-blind Phase: Placebo v Double-blind Phase: Fremanezumab
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Number of subjects included in analysis |
353
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Analysis specification |
Pre-specified
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Analysis type |
other | ||||||||||||||||||
P-value |
< 0.0001 | ||||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||||
Parameter type |
LS mean difference | ||||||||||||||||||
Point estimate |
9.9
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Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
5.73 | ||||||||||||||||||
upper limit |
14.08 | ||||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
2.12
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End point title |
Change From Baseline in Clinical Global Impression – Severity (CGI-S) Scale Score at Weeks 4, 8, and 12 | |||||||||||||||||||||
End point description |
The CGI-S is a short questionnaire filled out by the investigator that rates a participant’s mental health from 1 (normal, not at all ill) to 7 (among the most extremely ill participants). DB mITT analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postrandomization efficacy assessment on the primary endpoint.
|
|||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||
End point timeframe |
Baseline, Weeks 4, 8, and 12
|
|||||||||||||||||||||
|
||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | |||||||||||||||||||||
Statistical analysis description |
Change at Week 4: Fremanezumab versus Placebo
|
|||||||||||||||||||||
Comparison groups |
Double-blind Phase: Placebo v Double-blind Phase: Fremanezumab
|
|||||||||||||||||||||
Number of subjects included in analysis |
353
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.0915 | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
LS mean difference | |||||||||||||||||||||
Point estimate |
-0.2
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.39 | |||||||||||||||||||||
upper limit |
0.03 | |||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||
Dispersion value |
0.11
|
|||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | |||||||||||||||||||||
Statistical analysis description |
Change at Week 8: Fremanezumab versus Placebo
|
|||||||||||||||||||||
Comparison groups |
Double-blind Phase: Placebo v Double-blind Phase: Fremanezumab
|
|||||||||||||||||||||
Number of subjects included in analysis |
353
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.0006 | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
LS mean difference | |||||||||||||||||||||
Point estimate |
-0.4
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.59 | |||||||||||||||||||||
upper limit |
-0.16 | |||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||
Dispersion value |
0.11
|
|||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 3 | |||||||||||||||||||||
Statistical analysis description |
Change at Week 12: Fremanezumab versus Placebo
|
|||||||||||||||||||||
Comparison groups |
Double-blind Phase: Placebo v Double-blind Phase: Fremanezumab
|
|||||||||||||||||||||
Number of subjects included in analysis |
353
|
|||||||||||||||||||||
Analysis specification |
Pre-specified
|
|||||||||||||||||||||
Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.003 | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
LS mean difference | |||||||||||||||||||||
Point estimate |
-0.4
|
|||||||||||||||||||||
Confidence interval |
||||||||||||||||||||||
level |
95% | |||||||||||||||||||||
sides |
2-sided
|
|||||||||||||||||||||
lower limit |
-0.58 | |||||||||||||||||||||
upper limit |
-0.12 | |||||||||||||||||||||
Variability estimate |
Standard error of the mean
|
|||||||||||||||||||||
Dispersion value |
0.12
|
|||||||||||||||||||||
|
|||||||||||||
End point title |
Change From Baseline in 6-Item Headache Impact Test (HIT-6) Disability Score at Week 12 | ||||||||||||
End point description |
Migraine related disability was assessed using the HIT-6. The questionnaire measures the adverse impact of headache on social functioning, role functioning, vitality, cognitive functioning, and psychological distress. It also assesses headache severity. Each question was answered on the scale ranging with the following response options: 6 points (never), 8 points (rarely), 10 points (sometimes), 11 points (very often), and 13 points (always). The total score was obtained from summation of the 6 question points. The HIT-6 total score ranges between 36 and 78, with higher scores reflecting greater impact. DB mITT analysis set included all randomized participants who received at least 1 dose of study drug and had at least 10 days of postrandomization efficacy assessment on the primary endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline, Week 12
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Comparison groups |
Double-blind Phase: Placebo v Double-blind Phase: Fremanezumab
|
||||||||||||
Number of subjects included in analysis |
353
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
other | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Mixed models analysis | ||||||||||||
Parameter type |
LS mean difference | ||||||||||||
Point estimate |
-3.6
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-5.15 | ||||||||||||
upper limit |
-1.96 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.81
|
||||||||||||
|
||||||||||||||||
End point title |
Number of Participants With Treatment-emergent Adverse Events (TEAEs) | |||||||||||||||
End point description |
An adverse event (AE) was defined as any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious AEs (SAEs) were defined as death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized participant and required medical intervention to prevent 1 of the outcomes listed in this definition. AEs were considered TEAEs if onset occurred on or after the first dose date. A summary of other non-serious AEs and all serious AEs, regardless of causality is located in Reported AE section. DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. OL safety analysis set included all participants who received at least 1 of dose of study drug during the OL treatment period.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Baseline up to Week 24
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||
End point title |
Number of Participants With Potentially Clinically Significant Abnormal Vital Signs Values | |||||||||||||||
End point description |
Criteria for potentially clinically significant vital signs values: Pulse: ≥120 beats per minute (bpm) and increase from baseline of ≥15 bpm or ≤50 bpm and decrease from baseline of ≥15 bpm; Systolic blood pressure (SBP): ≥180 millimeters of mercury (mmHg) and increase from baseline of ≥20 mmHg or ≤90 mmHg and decrease from baseline of ≥20 mmHg; Diastolic blood pressure (DBP): ≥105 mmHg and increase from baseline of ≥15 mmHg or ≤50 mmHg and decrease from baseline of ≥15 mmHg; Respiratory rate: <10 breaths per minute; and Body temperature: ≥38.3 degrees celsius (ºC) and change from baseline of ≥1.1ºC. DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. OL safety analysis set included all participants who received at least 1 of dose of study drug during the OL treatment period. Here, 'overall number of participants analyzed' = participants evaluable for this endpoint.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Baseline up to Week 24
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||
End point title |
Number of Participants With Clinically Significant Abnormal Physical Examination Findings | |||||||||||||||
End point description |
Physical examination included height, weight, general appearance; head, eyes, ears, nose, and throat; chest and lungs; heart; abdomen; musculoskeletal; skin; lymph nodes; and neurological. Clinical significance was per investigator's discretion. DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. OL safety analysis set included all participants who received at least 1 of dose of study drug during the OL treatment period.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Baseline up to Week 24
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||||||||||||
End point title |
Number of Participants With Drug Hypersensitivity and Seasonal Allergy | |||||||||||||||||||||||||
End point description |
DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. OL safety analysis set included all participants who received at least 1 of dose of study drug during the OL treatment period.
|
|||||||||||||||||||||||||
End point type |
Secondary
|
|||||||||||||||||||||||||
End point timeframe |
Baseline up to Week 24
|
|||||||||||||||||||||||||
|
||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||
|
||||||||||||||||
End point title |
Number of Participants who Used Concomitant Medication | |||||||||||||||
End point description |
Concomitant medications included agents acting on the renin-angiotensin system, analgesics, antibacterials for systemic use, antihistamines for systemic use, anti-inflammatory and antirheumatic products, beta-blocking agents, drugs for acid related disorder, lipid modifying agents, mineral supplement, other gynecologicals, psychoanaleptics, psycholeptics, sex hormones and modulators of the genital system, thyroid therapy, vaccines, and vitamins. DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. OL safety analysis set included all participants who received at least 1 of dose of study drug during the OL treatment period.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Baseline up to Week 24
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||
End point title |
Number of Participants who Used Concomitant Medication for Migraine/Headache | |||||||||||||||
End point description |
Concomitant medications for migraine/headache included analgesics, antiepileptics, muscle relaxants, anti-inflammatory and antirheumatic products, agents acting on the renin-angiotensin system, anesthetics, antianemic preparations, antibacterials for systemic use, antihistamines for systemic use, beta-blocking agents, lipid modifying agents, mineral supplement, other gynecologicals, psychoanaleptics, psycholeptics, sex hormones and modulators of the genital system, thyroid therapy, vaccines, vitamins etc. DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. OL safety analysis set included all participants who received at least 1 of dose of study drug during the OL treatment period.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Baseline up to Week 24
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||
End point title |
Number of Participants who Did Not Complete the Study Due to AE | |||||||||||||||
End point description |
DB safety analysis set included all randomized participants who received at least 1 dose of study drug during the DB treatment period. OL safety analysis set included all participants who received at least 1 of dose of study drug during the OL treatment period.
|
|||||||||||||||
End point type |
Secondary
|
|||||||||||||||
End point timeframe |
Baseline up to Week 24
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Number of Participants Reporting Any Suicidal Ideation or Suicidal Behavior According to the Columbia Suicide Severity Rating Scale (C-SSRS) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
C-SSRS included responses for Suicidal Ideation/Behavior: 1 = Wish to be dead; 2 = Non-specific active suicidal thoughts; 3 = Active suicidal ideation with any methods without intent to act; 4 = Active suicidal ideation with some intent to act, without specific plan; 5 = Active suicidal ideation with specific plan and intent; 6 = Preparatory acts; 7 = Aborted attempt; 8 = Interrupted attempt; 9 = Non-fatal suicide attempt; and 10 = Completed suicide. Number of participants with any suicidal ideation/behavior are reported. Any Suicidal ideation/Behavior events reported as TEAEs are included in AE module. DB safety analysis set: all randomized participants who received at least 1 dose of study drug during DB treatment period. 'Overall number of participants analyzed' = participants evaluable for this endpoint. 'n' = participants evaluable at specified timepoint of the respective phase of study. ‘99999’ = data not applicable since no participants were evaluable at specified timepoint.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Weeks 4, 8, 12, and 24
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information [1]
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Baseline up to Week 24
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
DB safety analysis set and OL safety analysis set (all randomized participants who received at least 1 dose of study drug during the DB period and the OL period).
One participant was randomized to Placebo and received placebo in DB period but was summarized in the Fremanezumab group in all safety summaries due to an error in recording treatment.
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Double-blind Phase: Placebo
|
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Reporting group description |
Participants received placebo matched to fremanezumab SC during the 12-week DB period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Open-label Phase: Placebo/Fremanezumab Dose 2
|
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Reporting group description |
Participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Open-label Phase: Fremanezumab Dose 1/Fremanezumab Dose 2
|
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Reporting group description |
Participants received a single quarterly dose of fremanezumab Dose 2 SC on Day 85. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Double-blind Phase: Fremanezumab
|
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Reporting group description |
Participants received monthly doses of fremanezumab Dose 1 SC during the 12-week DB period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: No non-serious AEs were reported in this study. |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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|||
Substantial protocol amendments (globally) |
|||
| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
04 Jun 2019 |
The following major procedural changes (not all-inclusive) were made to the protocol:
• The primary reason for this amendment was to specify that the suicidality assessment to be used was the eC-SSRS in conjunction with the clinical judgment of a qualified psychiatrist. |
||
10 Oct 2019 |
The following major procedural changes (not all-inclusive) were made to the protocol:
• The primary reason for this amendment was to update the protocol based on feedback received from the Voluntary Harmonisation Procedure. |
||
04 Nov 2019 |
The following major procedural changes (not all-inclusive) were made to the protocol:
• The primary reasons for this amendment were to update the protocol to allow a qualified staff member to complete the HAM-A and HAM-D 17 assessments and to allow a qualified clinician’s judgment to be used in conjunction with the eC-SSRS instead of a psychiatrist. |
||
04 May 2020 |
The following major procedural changes (not all-inclusive) were made to the protocol:
• The primary reason for this amendment was to revise an exclusion criterion to exclude participants with a history of Stevens-Johnson Syndrome or toxic epidermal necrolysis syndrome and to allow rescreening of participants once.
• Coronavirus 2019 (COVID-19) pandemic-related operational updates were added to the study as a new appendix. |
||
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. | |||
| None reported | |||
