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 Episodic Migraine
Summary
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EudraCT number |
2015-004598-34 |
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 |
16 Jun 2018
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First version publication date |
16 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-30050
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02629861 | ||
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, 001 215-591-3000, Info.era-clinical@teva.de
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Scientific contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc, 001 215-591-3000, 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 |
20 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 2 dose regimens of TEV-48125, as assessed by the decrease in the monthly average number of migraine days during 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 TEV-48125 in the preventive treatment of episodic migraine (EM)
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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 Feb 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: 20
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Country: Number of subjects enrolled |
Spain: 5
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Country: Number of subjects enrolled |
Czech Republic: 37
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Country: Number of subjects enrolled |
Finland: 7
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Country: Number of subjects enrolled |
Canada: 14
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Country: Number of subjects enrolled |
Israel: 13
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Country: Number of subjects enrolled |
Japan: 75
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Country: Number of subjects enrolled |
Russian Federation: 25
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Country: Number of subjects enrolled |
United States: 679
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Worldwide total number of subjects |
875
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EEA total number of subjects |
69
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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) |
853
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From 65 to 84 years |
22
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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 2995 patients with migraine provided written informed consent. Of the 2995 patients screened, 875 met entry criteria, including diagnostic criteria for episodic migraine (EM) and diary compliance during the run-in period, and were randomized into this study from 123 study centers by 123 investigators. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection on 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 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 |
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 initial dose of 675 mg on Day 0 was given
as 3 injections. Study drug was administered at the clinical site.
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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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Arm title
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Fremanezumab 225/225/225 mg | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Arm description |
Patients who were randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 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 initial dose of 275 mg on Day 0 was repeated on Days 28 and 56. 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 randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection 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 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 225/225/225 mg
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Reporting group description |
Patients who were randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 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 randomized to receive placebo received three 1.5-mL placebo injections on Day 0, and a single 1.5-mL placebo injection 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 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 225/225/225 mg
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Reporting group description |
Patients who were randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56. |
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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 |
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] - Full analysis set [2] - Full analysis set [3] - Full analysis set |
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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 |
Fremanezumab 675 mg/placebo/placebo v Placebo
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Number of subjects included in analysis |
578
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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 225/225/225 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 |
Fremanezumab 225/225/225 mg v Placebo
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Number of subjects included in analysis |
577
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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 [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 |
Percentage of Participants With At Least 50% Reduction In Monthly Average Number of Migraine Days During the 12-Week Period After the First Dose of Study Drug | ||||||||||||||||||||||||||||||||
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
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End point type |
Secondary
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End point timeframe |
Baseline (Days -28 to Day -1), Treatment Month 1, Month 2, Month 3, Month 1-3 (Days 1 – Week 12)
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Notes [10] - Full analysis set [11] - Full analysis set [12] - Full analysis set |
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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.
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Comparison groups |
Fremanezumab 675 mg/placebo/placebo v Placebo
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Number of subjects included in analysis |
578
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
< 0.0001 [13] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
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Notes [13] - 0.05 level of significance |
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Statistical analysis title |
Month 1: Active 225/225/225 to Placebo | ||||||||||||||||||||||||||||||||
Statistical analysis description |
P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
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Comparison groups |
Fremanezumab 225/225/225 mg v Placebo
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Number of subjects included in analysis |
577
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
< 0.0001 [14] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [14] - 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 |
Fremanezumab 675 mg/placebo/placebo v Placebo
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
578
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
= 0.0032 [15] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [15] - 0.05 level of significance |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Month 2: Active 225/225/225 to Placebo | ||||||||||||||||||||||||||||||||
Statistical analysis description |
P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
|
||||||||||||||||||||||||||||||||
Comparison groups |
Fremanezumab 225/225/225 mg v Placebo
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
577
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
= 0.001 [16] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [16] - 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 |
Fremanezumab 675 mg/placebo/placebo v Placebo
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
578
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
= 0.0048 [17] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [17] - 0.05 level of significance |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Month 3: Active 225/225/225 to Placebo | ||||||||||||||||||||||||||||||||
Statistical analysis description |
P-value based on Cochran-Mantel-Haenszel test stratified by baseline preventive medication use.
|
||||||||||||||||||||||||||||||||
Comparison groups |
Fremanezumab 225/225/225 mg v Placebo
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
577
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
= 0.0003 [18] | ||||||||||||||||||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [18] - 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 |
Fremanezumab 675 mg/placebo/placebo v Placebo
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
578
|
||||||||||||||||||||||||||||||||
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 |
Overall: Active 225/225/225 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 |
Fremanezumab 225/225/225 mg v Placebo
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
577
|
||||||||||||||||||||||||||||||||
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 |
|
|||||||||||||||||
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 [21] - Full analysis set [22] - Full analysis set [23] - Full analysis set |
|||||||||||||||||
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 Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint
|
||||||||||||||||
Comparison groups |
Placebo v Fremanezumab 675 mg/placebo/placebo
|
||||||||||||||||
Number of subjects included in analysis |
578
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [24] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [24] - 0.05 level of significance |
|||||||||||||||||
Statistical analysis title |
Active 225/225/225 to Placebo | ||||||||||||||||
Statistical analysis description |
Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint
|
||||||||||||||||
Comparison groups |
Fremanezumab 225/225/225 mg v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
577
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [25] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [25] - 0.05 level of significance |
|
|||||||||||||||||
End point title |
Change from Baseline in the Number of Migraine Days During the 4 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.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline (Days -28 to Day -1), Treatment (Days 1 – Week 4)
|
||||||||||||||||
|
|||||||||||||||||
Notes [26] - Full analysis set [27] - Full analysis set [28] - Full analysis set |
|||||||||||||||||
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 Wilcoxon rank-sum test
was conducted as the primary analysis for each active treatment group and placebo treatment group for
this endpoint
|
||||||||||||||||
Comparison groups |
Fremanezumab 675 mg/placebo/placebo v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
575
|
||||||||||||||||
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 225/225/225 to Placebo | ||||||||||||||||
Statistical analysis description |
Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test
was conducted as the primary analysis for each active treatment group and placebo treatment group for
this endpoint
|
||||||||||||||||
Comparison groups |
Fremanezumab 225/225/225 mg v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
577
|
||||||||||||||||
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 Monthly Average Number of Migraine Days 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.
A migraine day has been previously defined.
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 [31] - FAS of subjects who did not receive concomitant migraine prevention medication [32] - FAS of subjects who did not receive concomitant migraine prevention medication [33] - FAS of subjects who did not receive concomitant migraine prevention medication |
|||||||||||||||||
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 Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint.
|
||||||||||||||||
Comparison groups |
Fremanezumab 675 mg/placebo/placebo v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
460
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [34] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [34] - 0.05 level of significance |
|||||||||||||||||
Statistical analysis title |
Active 225/225/225 to Placebo | ||||||||||||||||
Statistical analysis description |
Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test was conducted as the primary analysis for each active treatment group and placebo treatment group for this endpoint.
|
||||||||||||||||
Comparison groups |
Fremanezumab 225/225/225 mg v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
455
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
< 0.0001 [35] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [35] - 0.05 level of significance |
|
|||||||||||||||||
End point title |
Change from Baseline in Migraine-Related Disability Score (MIDAS), As Measured by the Migraine Disability Assessment At 4 Weeks After the Last (3rd) Dose of Study Drug | ||||||||||||||||
End point description |
The MIDAS questionnaire is a 5-item instrument developed to assess headache-related disability based on lost days of activity in 3 domains (work, household work, and nonwork) over the previous 3 months. The total score, ie, the sum of the # lost days answered for the first 5 questions, is used for grading of
disability, with scores of 0-5 lost days = grade 1 (little or no disability), 6-10 lost days =grade 2 (mild disability), 11-20 lost days = grade 3 (moderate disability), and ≥21 lost days interpreted as grade 4 (severe disability). Negative change from baseline scores indicate a reduction (improvement) in headache-related disability.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline (Day 0), Treatment Week 12 (4 weeks after the 3rd dose)
|
||||||||||||||||
|
|||||||||||||||||
Notes [36] - Full analysis set [37] - Full analysis set [38] - Full analysis set |
|||||||||||||||||
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 Wilcoxon rank-sum test
was conducted as the primary analysis for each active treatment group and placebo treatment group for
this endpoint.
|
||||||||||||||||
Comparison groups |
Fremanezumab 675 mg/placebo/placebo v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
578
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0023 [39] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [39] - 0.05 level of significance |
|||||||||||||||||
Statistical analysis title |
Active 225/225/225 to Placebo | ||||||||||||||||
Statistical analysis description |
Due to the deviation from the normal distribution assumption of the data, the Wilcoxon rank-sum test
was conducted as the primary analysis for each active treatment group and placebo treatment group for
this endpoint.
|
||||||||||||||||
Comparison groups |
Fremanezumab 225/225/225 mg v Placebo
|
||||||||||||||||
Number of subjects included in analysis |
577
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0021 [40] | ||||||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [40] - 0.05 level of significance |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Electrocardiogram Finding 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 early withdrawal)
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
Notes [41] - Safety population of participants with both baseline and posttreatment ECGs [42] - Safety population of participants with both baseline and posttreatment ECGs [43] - 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 at least one participant showing potentially clinically significant abnormal findings included:
- 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
|
||||||||||||||||||||||||||||||||||||
End point timeframe |
Treatment Days 28, 56 and 84. Changes from previous reading may reflect the baseline reading performed on Day 0.
|
||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||
Notes [44] - Safety population of participants with both baseline and posttreatment values for each vital sign. [45] - Safety population of participants with both baseline and posttreatment values for each vital sign. [46] - Safety population of participants with both baseline and posttreatment values for each vital sign. |
|||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
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
- Bilirubin High: >=34.2 umol/L
- Alanine Aminotransferase (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
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Treatment Days 28, 56 and 84 (or early withdrawal)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [47] - Safety population of participants with at least one postbaseline result for the tests. [48] - Safety population of participants with at least one postbaseline result for the tests. [49] - Safety population of participants with at least one postbaseline result for the tests. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||
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
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Treatment Days 28, 56 and 84. Changes from previous reading reflect the baseline reading performed on Day 0.
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
Notes [50] - Safety population of participants with at least one postbaseline result for the tests. [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. |
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||
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
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline (Day 0), Treatment Endpoint (Week 12)
|
||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||
Notes [53] - Safety population of participants with both baseline and posttreatment values [54] - Safety population of participants with both baseline and posttreatment values [55] - Safety population of participants with both baseline and posttreatment values |
|||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 [56] - Safety population [57] - Safety population [58] - Safety population |
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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 [59] - Safety [60] - Safety [61] - 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 randomized to receive placebo received three 1.5-mL placebo injections Day 0, and a single 1.5-mL placebo injection 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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Fremanezumab 225/225/225 mg
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Reporting group description |
Patients who were randomized to receive fremanezumab 225/225/225 mg received 1 active injection (225 mg/1.5 mL) on Days 0, 28 and 56. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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30 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, respectively |
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |