Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Comparing the Efficacy and Safety of 2 Dose Regimens of Subcutaneous Administration of TEV-48125 Versus Placebo for the Preventive Treatment of Chronic Migraine
Summary
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EudraCT number |
2015-004549-23 |
Trial protocol |
DE CZ ES FI DK |
Global end of trial date |
10 Apr 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Jun 2018
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First version publication date |
15 Jun 2018
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Other versions |
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-CNS-30049
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02621931 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Teva Branded Pharmaceutical Products R&D, Inc
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Sponsor organisation address |
41 Moores Road, Frazer, Pennsylvania, United States, 19355
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Public contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc., 1 215-591-3000, Info.era-clinical@teva.de
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Scientific contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc., 1 215-591-3000, Info.era-clinical@teva.de
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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 |
19 Sep 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
10 Apr 2017
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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 |
• to demonstrate the efficacy of 2 dose regimens of TEV-48125, as assessed by the decrease in the monthly average number of headache days of at least moderate severity during the 12-week period after the 1st dose of study drug relative to the baseline period • to evaluate the safety and tolerability of 2 dose regimens of TEV-48125 in the preventive treatment of chronic migraine (CM)
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Protection of trial subjects |
This study was conducted in full accordance with the International Council on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (eg, Code of Federal Regulations Title 21, Parts 50, 54, 56, 312, and 314; European Union Directive 2001/20/EC on the approximation of the laws, regulations, and administrative provisions of the Member States relating to the implementation of GCP in the conduct of clinical trials on medicinal products for human use). Each investigator was responsible for performing the study in accordance with the protocol, ICH guidelines, and GCP, and for collecting, recording, and reporting the data accurately and properly. Agreement of each investigator to conduct and administer this study in accordance with the protocol was documented in separate study agreements with the sponsor and other forms as required by national authorities in the country where the study center is located. Written and/or oral information about the study was provided to all patients in a language understandable by the patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each patient before any study procedures or assessments were done. It was explained to the patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment. Each patient’s willingness to participate in the study was documented in writing in a consent form that was signed by the patient with the date of that signature indicated. Each investigator kept the original consent forms, and copies were given to the patients.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
22 Mar 2016
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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 |
Poland: 28
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Country: Number of subjects enrolled |
Spain: 14
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Country: Number of subjects enrolled |
Czech Republic: 47
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Country: Number of subjects enrolled |
Finland: 36
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Country: Number of subjects enrolled |
Canada: 39
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Country: Number of subjects enrolled |
Israel: 20
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Country: Number of subjects enrolled |
Japan: 109
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Country: Number of subjects enrolled |
Russian Federation: 41
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Country: Number of subjects enrolled |
United States: 796
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Worldwide total number of subjects |
1130
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EEA total number of subjects |
125
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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) |
1106
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From 65 to 84 years |
24
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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 3148 patients with migraine provided written informed consent and were screened for entry into either Study TV48125-CNS-30049 or Study TV48125-CNS-30050. Of the 3148 patients screened, 1130 met the entry criteria, including diagnostic criteria for CM and diary compliance during the run-in period, and were randomized into this study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Trial (overall period)
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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, Monitor, Data analyst | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
The sponsor, investigators, study staff (except for staff involved in bioanalytical analyses), and patients were blinded to treatment assignment.
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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 |
Patients who were randomized to receive placebo received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 . | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo 2.25-mL pre-filled syringes identical in appearance to active intervention. Patients were dosed once approximately every 28 days for a total of 3 times. Study drug was administered at the clinical site.
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Arm title
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Fremanezumab 675 mg/placebo/placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients who were randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo 2.25-mL pre-filled syringes identical in appearance to active intervention. Patients were dosed with placebo on Days 28 and 56. Study drug was administered at the clinical site.
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Investigational medicinal product name |
Fremanezumab
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Investigational medicinal product code |
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Other name |
TEV-48125, anti-calcitonin gene-related peptide (anti-CGRP)
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Fremanezumab was provided as a sterile, unpreserved, aqueous solution for injection, supplied in a 2.25-mL pre-filled syringe for single-use administration. The 675 mg dose on Day 0 was given as 3 injections. Study drug was administered at the clinical site.
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Arm title
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Fremanezumab 675/225/225 mg | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients who were randomized to receive fremanezumab 675/225/225 mg received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Fremanezumab
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Investigational medicinal product code |
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Other name |
TEV-48125, anti-calcitonin gene-related peptide (anti-CGRP)
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Fremanezumab was provided as a sterile, unpreserved, aqueous solution for injection, supplied in a 2.25-mL pre-filled syringe for single-use administration. The 675 mg dose on Day 0 was given as 3 injections; doses of 225 mg on Days 28 and 56 were given as a single injection. Study drug was administered at the clinical site.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Patients who were randomized to receive placebo received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 . | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fremanezumab 675 mg/placebo/placebo
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Reporting group description |
Patients who were randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fremanezumab 675/225/225 mg
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Reporting group description |
Patients who were randomized to receive fremanezumab 675/225/225 mg received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Patients who were randomized to receive placebo received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 . | ||
Reporting group title |
Fremanezumab 675 mg/placebo/placebo
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Reporting group description |
Patients who were randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56. | ||
Reporting group title |
Fremanezumab 675/225/225 mg
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Reporting group description |
Patients who were randomized to receive fremanezumab 675/225/225 mg received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56. | ||
Subject analysis set title |
Fremanezumab
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The first dose was 675 mg by subcutaneous injection for both fremanezumab treatment groups; therefore the data from both groups were combined for this comparison during the first 4 weeks of treatment.
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Subject analysis set title |
Placebo: no concomitant preventive migraine meds
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients who were randomized to receive placebo received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56. Patients in this sub-group did not receive concomitant preventive migraine medication during the study.
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Subject analysis set title |
Active 675/placebo/p: no concomitant preventive migraine meds
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients who were randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56. Patients in this sub-group did not receive concomitant preventive migraine medication during the study.
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Subject analysis set title |
Active 675/225/225: no concomitant preventive migraine meds
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Subject analysis set type |
Sub-group analysis | ||
Subject analysis set description |
Patients who were randomized to receive fremanezumab 675/225/225 mg received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56. Patients in this sub-group did not receive concomitant preventive migraine medication during the study.
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End point title |
Change from Baseline in the Monthly Average Number of Headache Days of At Least Moderate Severity During the 12-Week Period After the First Dose of Study Drug | ||||||||||||||||
End point description |
Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of at least moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value – baseline value. Full analysis set (FAS) included those in the ITT population who received at least 1 dose of study drug and had at least 10 days of post-baseline efficacy assessments on the primary endpoint.
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End point type |
Primary
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End point timeframe |
Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 12)
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Notes [1] - FAS [2] - FAS [3] - FAS |
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Statistical analysis title |
Primary: Active 675/placebo/placebo to Placebo | ||||||||||||||||
Statistical analysis description |
Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
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Comparison groups |
Placebo v Fremanezumab 675 mg/placebo/placebo
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Number of subjects included in analysis |
746
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [4] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
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Notes [4] - 0.05 level of significance |
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Statistical analysis title |
Primary: Active 675/225/225 to Placebo | ||||||||||||||||
Statistical analysis description |
Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
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Comparison groups |
Placebo v Fremanezumab 675/225/225 mg
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Number of subjects included in analysis |
746
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [5] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
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Notes [5] - 0.05 level of significance |
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End point title |
Participants with Adverse Events (AEs) [6] | ||||||||||||||||||||||||||||||||||||
End point description |
An adverse event was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an AE which prevents usual activities. Relationship of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, 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 the patient and required medical intervention to prevent the previously listed serious outcomes.
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End point type |
Primary
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End point timeframe |
Day 1 to Week 12
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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 intention to make inference based on stat analysis; the intent is to support clinical judgement. |
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Notes [7] - Safety population [8] - Safety population [9] - Safety population |
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No statistical analyses for this end point |
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End point title |
Change from Baseline in the Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug | ||||||||||||||||
End point description |
A migraine day was defined as when at least 1 of the following situations occurred: - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for migraine with or without aura - a calendar day (0:00 to 23:59) demonstrating at least 4 consecutive hours of a headache endorsing criteria for probable migraine, a migraine subtype where only 1 migraine criterion is missing - a calendar day (0:00 to 23:59) demonstrating a headache of any duration that was treated with migraine-specific medications (triptans and ergot compounds) Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value – baseline value.
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End point type |
Secondary
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||||||||||||||||
End point timeframe |
Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 12)
|
||||||||||||||||
|
|||||||||||||||||
Notes [10] - FAS [11] - FAS [12] - FAS |
|||||||||||||||||
Statistical analysis title |
Active 675/placebo/placebo to Placebo | ||||||||||||||||
Comparison groups |
Placebo v Fremanezumab 675 mg/placebo/placebo
|
||||||||||||||||
Number of subjects included in analysis |
746
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [13] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LSM difference | ||||||||||||||||
Point estimate |
-1.7
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-2.48 | ||||||||||||||||
upper limit |
-0.97 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.39
|
||||||||||||||||
Notes [13] - 0.05 level of significance |
|||||||||||||||||
Statistical analysis title |
Active 675/225/225 to Placebo | ||||||||||||||||
Comparison groups |
Placebo v Fremanezumab 675/225/225 mg
|
||||||||||||||||
Number of subjects included in analysis |
746
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [14] | ||||||||||||||||
Method |
ANCOVA | ||||||||||||||||
Parameter type |
LSM difference | ||||||||||||||||
Point estimate |
-1.8
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-2.61 | ||||||||||||||||
upper limit |
-1.09 | ||||||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||||||
Dispersion value |
0.39
|
||||||||||||||||
Notes [14] - 0.05 level of significance |
|
|||||||||||||||||||||||||||||||||
End point title |
Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Headache Days of At Least Moderate Severity | ||||||||||||||||||||||||||||||||
End point description |
Responder rates were defined as the percentage of total subjects who reached at least a 50% reduction in the monthly average of headache days (as subjectively reported by participants in the study diary) of at least moderate severity relative to the baseline period. For the overall analysis (Month 1-3), patients who discontinued early were considered nonresponders. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The percentage reduction in monthly average is calculated as: ((baseline value - postbaseline value) / baseline value) * 100
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (Days -28 to Day -1), Treatment: Month 1, Month 2, Month 3, Month 1-3 (Days 1 – Week 12)
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
Notes [15] - FAS minus one subject who had 0 headache days of >= moderate severity during baseline and treatment [16] - FAS [17] - FAS minus one subject who had 0 headache days of >= moderate severity during baseline and treatment |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Month 1: Active 675/placebo/placebo to Placebo | ||||||||||||||||||||||||||||||||
Statistical analysis description |
P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
|
||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Fremanezumab 675 mg/placebo/placebo
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
745
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
< 0.0001 [18] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [18] - 0.05 level of significance |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Month 1: Active 675/225/225 to Placebo | ||||||||||||||||||||||||||||||||
Statistical analysis description |
P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
|
||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Fremanezumab 675/225/225 mg
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
744
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
< 0.0001 [19] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [19] - 0.05 level of significance |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Month 2: Active 675/placebo/placebo to Placebo | ||||||||||||||||||||||||||||||||
Statistical analysis description |
P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
|
||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Fremanezumab 675 mg/placebo/placebo
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
745
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
< 0.0001 [20] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [20] - 0.05 level of significance |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Month 2: Active 675/225/225 to Placebo | ||||||||||||||||||||||||||||||||
Statistical analysis description |
P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
|
||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Fremanezumab 675/225/225 mg
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
744
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
< 0.0001 [21] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [21] - 0.05 level of significance |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Month 3: Active 675/placebo/placebo to Placebo | ||||||||||||||||||||||||||||||||
Statistical analysis description |
P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
|
||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Fremanezumab 675 mg/placebo/placebo
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
745
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
< 0.0001 [22] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [22] - 0.05 level of significance |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Month 3: Active 675/225/225 to Placebo | ||||||||||||||||||||||||||||||||
Statistical analysis description |
P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
|
||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Fremanezumab 675/225/225 mg
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
744
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
< 0.0001 [23] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [23] - 0.05 level of significance |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Overall: Active 675/placebo/placebo to Placebo | ||||||||||||||||||||||||||||||||
Statistical analysis description |
P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use. For the overall analysis, patients who discontinued early were considered nonresponders.
|
||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Fremanezumab 675 mg/placebo/placebo
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
745
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
< 0.0001 [24] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [24] - 0.05 level of significance |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Overall: Active 675/225/225 to Placebo | ||||||||||||||||||||||||||||||||
Statistical analysis description |
P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use. For the overall analysis, patients who discontinued early were considered nonresponders.
|
||||||||||||||||||||||||||||||||
Comparison groups |
Placebo v Fremanezumab 675/225/225 mg
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
744
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
< 0.0001 [25] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [25] - 0.05 level of significance |
|
|||||||||||||||||
End point title |
Change from Baseline in the Monthly Average Number of Days of Use of Any Acute Headache Medicine During the 12 Week Period After the First Dose of Study Drug | ||||||||||||||||
End point description |
Patients recorded any migraine medications (name of drug, number of tablets/capsules, and the dose in milligrams per tablet/capsule) taken on each day in their electronic headache diary device. Acute migraine-specific medication included triptans or ergots. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. The change is calculated as postbaseline value – baseline value.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 12)
|
||||||||||||||||
|
|||||||||||||||||
Notes [26] - FAS [27] - FAS [28] - FAS |
|||||||||||||||||
Statistical analysis title |
Active 675/placebo/placebo to Placebo | ||||||||||||||||
Statistical analysis description |
Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
|
||||||||||||||||
Comparison groups |
Fremanezumab 675 mg/placebo/placebo v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
746
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [29] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [29] - 0.05 level of significance |
|||||||||||||||||
Statistical analysis title |
Active 675/225/225 to Placebo | ||||||||||||||||
Statistical analysis description |
Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
|
||||||||||||||||
Comparison groups |
Placebo v Fremanezumab 675/225/225 mg
|
||||||||||||||||
Number of subjects included in analysis |
746
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [30] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [30] - 0.05 level of significance |
|
|||||||||||||
End point title |
Change from Baseline in the Number of Headache Days of At Least Moderate Severity During the 4 Week Period After the First Dose of Study Drug [31] | ||||||||||||
End point description |
Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of at least moderate severity was defined as a calendar day (00:00 to 23:59) where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of at least moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. The change is calculated as postbaseline value – baseline value. Full analysis set (FAS) included those in the ITT population who received at least 1 dose of study drug and had at least 10 days of post-baseline efficacy assessments on the primary endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 4)
|
||||||||||||
Notes [31] - 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: This warning is a system artifact since there is a statistical analysis that compares the Placebo treatment group to the combined Fremanezumab analysis set. |
|||||||||||||
|
|||||||||||||
Notes [32] - FAS [33] - FAS |
|||||||||||||
Statistical analysis title |
Change in Headache Days Over 4 Weeks | ||||||||||||
Comparison groups |
Placebo v Fremanezumab
|
||||||||||||
Number of subjects included in analysis |
1121
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 [34] | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LSM difference | ||||||||||||
Point estimate |
-2.3
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-2.95 | ||||||||||||
upper limit |
-1.73 | ||||||||||||
Variability estimate |
Standard error of the mean
|
||||||||||||
Dispersion value |
0.31
|
||||||||||||
Notes [34] - 0.05 level of significance |
|
|||||||||||||||||
End point title |
Change from Baseline in the Monthly Average Number of Headache Days of At Least Moderate Severity During the 12 Week Period After the First Dose of Study Medication in Patients Not Receiving Concomitant Preventive Migraine Medications | ||||||||||||||||
End point description |
A subset of patients (specified in the protocol not to exceed 30%) were allowed to use 1 concomitant migraine preventive medication. This outcome only includes those participants who did not take concomitant preventive migraine medication during this study. Headaches were subjectively rated by participants as mild, moderate or severe. A headache day of >= moderate severity was defined as a calendar day where the patient (using the electronic headache diary device) reports: - a day with headache pain that lasts ≥4 hours with a peak severity of >= moderate severity or - a day when the patient used acute migraine-specific medication (triptans or ergots) to treat a headache of any severity or duration. Monthly averages are derived and normalized to 28 days equivalent by the following formula: (# days of efficacy variable over relevant period / # days with assessments recorded in the e-diary over the relevant period) * 28. Change is postbaseline value – baseline value
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 12)
|
||||||||||||||||
|
|||||||||||||||||
Notes [35] - FAS [36] - FAS [37] - FAS |
|||||||||||||||||
Statistical analysis title |
Active 675/placebo/placebo to Placebo | ||||||||||||||||
Statistical analysis description |
Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
|
||||||||||||||||
Comparison groups |
Placebo: no concomitant preventive migraine meds v Active 675/placebo/p: no concomitant preventive migraine meds
|
||||||||||||||||
Number of subjects included in analysis |
592
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [38] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [38] - 0.05 level of significance |
|||||||||||||||||
Statistical analysis title |
Active 675/225/225 to Placebo | ||||||||||||||||
Statistical analysis description |
Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
|
||||||||||||||||
Comparison groups |
Placebo: no concomitant preventive migraine meds v Active 675/225/225: no concomitant preventive migraine meds
|
||||||||||||||||
Number of subjects included in analysis |
584
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [39] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [39] - 0.05 level of significance |
|
|||||||||||||||||
End point title |
Change from Baseline in Migraine-Related Disability Score, As Measured by the 6-Item Headache Impact Test (HIT) At Week 12 | ||||||||||||||||
End point description |
The HIT-6 was developed by Kosinski et al (2003) as a short form for reliably assessing the adverse headache impact in clinical practice and clinical research settings. The questionnaire measures the adverse impact of headache on social functioning, role functioning, vitality, cognitive functioning, and psychological distress. It also assesses headache severity. Scores range from 36 to 78, where a higher score indicates a greater impact of headache on the daily life of the patient, ie, scores ≤49 represent little or no impact, scores between 50 and 55 represent some impact, scores between 56 and 59 represent substantial impact; and scores ≥60 indicate severe impact. Negative change from baseline values indicate less adverse impact of headache.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline (Day 0), Treatment Week 12 (4 weeks after the 3rd dose)
|
||||||||||||||||
|
|||||||||||||||||
Notes [40] - FAS [41] - FAS [42] - FAS |
|||||||||||||||||
Statistical analysis title |
HIT-6: Active 675/placebo/placebo to Placebo | ||||||||||||||||
Statistical analysis description |
Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
|
||||||||||||||||
Comparison groups |
Fremanezumab 675 mg/placebo/placebo v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
746
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0004 [43] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [43] - 0.05 level of significance |
|||||||||||||||||
Statistical analysis title |
HIT-6: Active 675/225/225 to Placebo | ||||||||||||||||
Statistical analysis description |
Due to the deviation from the normal distribution assumption of the data, the primary analysis was conducted using the Wilcoxon rank-sum test as outlined in the SAP.
|
||||||||||||||||
Comparison groups |
Fremanezumab 675/225/225 mg v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
746
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [44] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [44] - 0.05 level of significance |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Electrocardiogram (ECG) Findings Shifts From Baseline to Overall | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
12-lead ECGs were performed before other assessments (eg, blood draws and administration of questionnaires) and performed in triplicate. The worst postbaseline finding for the patient is summarized. Only patients with both baseline and postbaseline ECGs are included. The ECG was evaluated by the investigator at the time of recording (signed and dated), and the printout was kept in the source documentation file. When potentially clinically significant findings were detected by the investigator, a cardiologist at a central diagnostic center was consulted for a definitive interpretation. Any ECG finding that was judged by the investigator as a potentially clinically significant change (worsening) compared with a baseline value was considered an adverse event. NCS = abnormal, not clinically significant CS= abnormal, clinically significant Shift format is: baseline finding / worst postbaseline finding
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (Day 0), Treatment Week 12 (or endpoint)
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
Notes [45] - Safety population of participants with both baseline and posttreatment ECGs [46] - Safety population of participants with both baseline and posttreatment ECGs [47] - Safety population of participants with both baseline and posttreatment ECGs |
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Participants With Vital Signs Potentially Clinically Significant Abnormal Values | ||||||||||||||||||||||||||||||||||||||||
End point description |
Vital signs were performed before other assessments (eg, blood draws and administration of questionnaires). Vital signs with potentially clinically significant abnormal findings included: - Pulse Rate High: >=120 and increase of >=15 beats per minute - Pulse Rate Low: <=50 and decrease of >=15 beats per minute - Systolic Blood Pressure Low: <=90 mmHg and decrease of >=20 mmHg - Diastolic Blood Pressure High: >=105 mmHg and increase of >=15 mmHg - Diastolic Blood Pressure Low: <=50 mmHg and decrease of >=15 mmHg - Respiratory Rate Low: <10 breaths / minute
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
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End point timeframe |
Treatment Days 28, 56 and 84 (or endpoint). Changes from previous reading may reflect the baseline reading performed on Day 0.
|
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Notes [48] - Safety population of participants with both baseline and posttreatment values for each vital sign. [49] - Safety population of participants with both baseline and posttreatment values for each vital sign. [50] - Safety population of participants with both baseline and posttreatment values for each vital sign. |
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No statistical analyses for this end point |
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End point title |
Participants with Serum Chemistry and Hematology Potentially Clinically Significant Abnormal Results | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Serum chemistry and hematology laboratory tests with potentially clinically significant abnormal findings included: - Blood Urea Nitrogen (BUN) High: >=10.71 mmol/L - Creatinine High: >=177 umol/L - Bilirubin High: >=34.2 umol/L - Alanine Aminotransfrase (ALT): >=3*upper limit of normal (ULN) - Aspartate Aminotransferase (AST): >=3*upper limit of normal (ULN) - Gamma Glutamyl Transferase (GGT): >=3*upper limit of normal (ULN) - Hemoglobin: Male: <115 g/L or Female: <=95 g/L - Hematocrit: Male: <0.37 L/L or Female: <0.32 L/L - Leukocytes: >=20*10^9/L or <=3*10^9/L - Eosinophils/Leukocytes: >=10% - Platelets: >=700*10^9/L or <=75*10^9/L
|
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End point type |
Secondary
|
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End point timeframe |
Treatment Days 28, 56 and 84 (or endpoint).
|
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Notes [51] - Safety population of participants with at least one postbaseline result for the tests. [52] - Safety population of participants with at least one postbaseline result for the tests. [53] - Safety population of participants with at least one postbaseline result for the tests. |
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No statistical analyses for this end point |
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End point title |
Participants with Urinalysis Laboratory Tests Potentially Clinically Significant Abnormal Results | ||||||||||||||||||||||||||||||||
End point description |
Urinalysis with potentially clinically significant abnormal findings included: - Blood: >=2 unit increase from baseline - Urine Glucose (mg/dL): >=2 unit increase from baseline - Ketones (mg/dL): >=2 unit increase from baseline - Urine Protein (mg/dL): >=2 unit increase from baseline
|
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End point type |
Secondary
|
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End point timeframe |
Treatment Days 28, 56 and 84 (or endpoint). Changes from previous reading reflect the baseline reading performed on Day 0.
|
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|
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Notes [54] - Safety population of participants with at least one postbaseline result for the tests. [55] - Safety population of participants with at least one postbaseline result for the tests. [56] - Safety population of participants with at least one postbaseline result for the tests. |
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No statistical analyses for this end point |
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End point title |
Prothrombin Time Shifts from Baseline to Endpoint | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Shifts in prothrombin time from baseline to endpoint were summarized using patient counts grouped into three categories: - Low (below normal range) - Normal (within the normal range of 9.4 to 12.5 seconds) - High (above normal range) Shift format is: baseline finding / endpoint finding
|
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End point type |
Secondary
|
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End point timeframe |
Baseline (Day 0), Treatment Endpoint (Week 12)
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Notes [57] - Safety population of participants with both baseline and posttreatment values [58] - Safety population of participants with both baseline and posttreatment values. [59] - Safety population of participants with both baseline and posttreatment values. |
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No statistical analyses for this end point |
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End point title |
Injection Site Reaction Adverse Events | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Counts of participants who reported treatment-emergent injection site reactions as AEs are summarized. Preferred terms from MedDRA version 18.1 are offered without a threshold applied.
|
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End point type |
Secondary
|
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End point timeframe |
Day 1 to Week 12
|
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Notes [60] - Safety [61] - Safety [62] - Safety |
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No statistical analyses for this end point |
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End point title |
Participants with Positive Electronic Columbia Suicide Severity Rating Scale Results After the First Dose of Study Drug | ||||||||||||||||||||||||
End point description |
The electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) was used to assess the patient’s suicidal ideation (severity and intensity) and behavior (Posner et al 2011). The eC-SSRS Baseline/Screening version was completed by the patient at visit 2, and the eC-SSRS Since Last Visit version was completed by the patient at all other time points. Any positive findings on the eC-SSRS Since Last Visit version required evaluation by a physician or doctoral-level psychologist. Findings after the first dose of study drug using the eC-SSRS Since Last Visit version are summarized.
|
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End point type |
Secondary
|
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End point timeframe |
Day 1 to Week 12
|
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Notes [63] - Safety [64] - Safety [65] - Safety |
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Day 1 to Week 12
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
|
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Reporting group title |
Placebo
|
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Reporting group description |
Patients who were randomized to receive placebo received three 1.5-mL placebo injections at Day 0 and a single 1.5-mL placebo injection at Days 28 and 56 . | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fremanezumab 675/225/225 mg
|
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Reporting group description |
Patients who were randomized to receive fremanezumab 675/225/225 mg received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0 and 225 mg of fremanezumab as 1 active injection (225 mg/1.5 mL) on Days 28 and 56. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fremanezumab 675 mg/placebo/placebo
|
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Reporting group description |
Patients who were randomized to receive fremanezumab 675 mg/placebo/placebo received 675 mg of fremanezumab as 3 active injections (225 mg/1.5 mL) on Day 0, and placebo as a single 1.5-mL injection on Days 28 and 56. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 |
||
29 Mar 2016 |
Amendment 1 to the protocol was issued while 3 patients were enrolled into the study. The following major procedural changes (not all-inclusive) were made to the protocol: - incorporation of required revisions based on health authority input from the European Medicines Agency, FDA, and Pharmaceuticals and Medical Devices Agency - provision of clarifying language for the inclusion and exclusion criteria - clarification of allowed and disallowed preventive medications - revision of protocol-defined adverse events of special interest and addition of clinical criteria for diagnosing anaphylaxis - update and/or clarification of versions of certain exploratory endpoints, including the EQ-5D (now -5L) and PGIC |
||
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 |