Clinical Trial Results:
A Phase 2a Randomized Double-blind Placebo Controlled Study to Evaluate the Efficacy and
Safety of AMG 301 in Migraine Prevention
Summary
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EudraCT number |
2017-000630-57 |
Trial protocol |
CZ DK SE FI DE AT NL |
Global end of trial date |
04 Feb 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Feb 2020
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First version publication date |
15 Feb 2020
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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 |
20150308
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03238781 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Amgen, Inc.
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Sponsor organisation address |
One Amgen Center Drive, Thousand Oaks, United States, 91320
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Public contact |
IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
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Scientific contact |
IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
04 Feb 2019
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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 |
04 Feb 2019
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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 evaluate the effect of AMG 301 compared to placebo on the change from the baseline period in
monthly migraine days in subjects with migraine.
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Protection of trial subjects |
The protocol, protocol amendments, informed consent form, Investigator’s Brochure, and
other relevant documents (eg, subject recruitment advertisements) were submitted to an
Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs) by the investigator and reviewed and approved by the IRB/IEC. A copy of the written approval of the protocol and informed consent form were received by Amgen before recruitment of subjects into the study and
shipment of Amgen investigational product.
The investigator or his/her delegated representative (a physician) explained to the subject the aims, methods, anticipated benefits, and potential hazards of the study before any protocol-specific screening procedures or any investigational product(s) were administered, and answered all questions regarding the study.
Subjects must be informed that their participation is voluntary.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
06 Sep 2017
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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 |
Canada: 24
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Country: Number of subjects enrolled |
United States: 129
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Country: Number of subjects enrolled |
Austria: 15
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Country: Number of subjects enrolled |
Czech Republic: 61
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Country: Number of subjects enrolled |
Denmark: 33
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Country: Number of subjects enrolled |
Finland: 32
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Country: Number of subjects enrolled |
Germany: 33
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Country: Number of subjects enrolled |
Sweden: 16
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Worldwide total number of subjects |
343
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EEA total number of subjects |
190
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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) |
343
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
A total of 510 subjects were screened. | ||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Participants were randomized 4:3:3 to placebo, AMG 301 210 mg Q4W, or AMG 301 420 mg Q2W, respectively. The randomization was stratified by • chronic migraine versus episodic migraine and • North America versus Rest of World. | ||||||||||||||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (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 |
Investigator, Monitor, Subject | ||||||||||||||||||||||||||||||||
Blinding implementation details |
Individual subject treatment assignments were maintained by the IVR/IWR System.
Any unplanned unblinding occurring during the study period were documented and
reported in the final clinical study report.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||
Arm description |
Participants randomized to Placebo were administered 6 subcutaneous (SC) injections on day 1 and weeks 2, 4, 6, 8 and 10 during the 12 week double-blind treatment period. | ||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo was presented in identical containers, stored/packaged the same as AMG 301. All injections were administered within 30 minutes on treatment days.
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Arm title
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AMG 301 210 mg Q4W | ||||||||||||||||||||||||||||||||
Arm description |
Participants randomized to AMG 301 210 mg every fourth week (Q4W) received a total of 3 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) plus 3 matching placebo injections on day 1 and weeks 4 and 8. Participants also received 6 SC placebo injections on weeks 2, 6, and 10 during the 12 week double-blind treatment period. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
AMG 301
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Investigational medicinal product code |
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Other name |
human monoclonal immunoglobulin G1 antagonist
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
AMG 301 was packaged in 5 mL clear glass vials containing 1 mL of 70 mg/mL of AMG 301. All injections were administered within 30 minutes on treatment days.
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Arm title
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AMG 301 420 mg Q2W | ||||||||||||||||||||||||||||||||
Arm description |
Participants randomized to AMG 301 420 mg every second week (Q2W) received a total of 6 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) on day 1 and weeks 2, 4, 6, 8, and 10 during the 12 week double-blind treatment period. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
AMG 301
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Investigational medicinal product code |
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Other name |
human monoclonal immunoglobulin G1 antagonist
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
AMG 301 was packaged in 5 mL clear glass vials containing 1 mL of 70 mg/mL of AMG 301. All injections were administered within 30 minutes on treatment days.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants randomized to Placebo were administered 6 subcutaneous (SC) injections on day 1 and weeks 2, 4, 6, 8 and 10 during the 12 week double-blind treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AMG 301 210 mg Q4W
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Reporting group description |
Participants randomized to AMG 301 210 mg every fourth week (Q4W) received a total of 3 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) plus 3 matching placebo injections on day 1 and weeks 4 and 8. Participants also received 6 SC placebo injections on weeks 2, 6, and 10 during the 12 week double-blind treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AMG 301 420 mg Q2W
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Reporting group description |
Participants randomized to AMG 301 420 mg every second week (Q2W) received a total of 6 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) on day 1 and weeks 2, 4, 6, 8, and 10 during the 12 week double-blind treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants randomized to Placebo were administered 6 subcutaneous (SC) injections on day 1 and weeks 2, 4, 6, 8 and 10 during the 12 week double-blind treatment period. | ||
Reporting group title |
AMG 301 210 mg Q4W
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Reporting group description |
Participants randomized to AMG 301 210 mg every fourth week (Q4W) received a total of 3 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) plus 3 matching placebo injections on day 1 and weeks 4 and 8. Participants also received 6 SC placebo injections on weeks 2, 6, and 10 during the 12 week double-blind treatment period. | ||
Reporting group title |
AMG 301 420 mg Q2W
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Reporting group description |
Participants randomized to AMG 301 420 mg every second week (Q2W) received a total of 6 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) on day 1 and weeks 2, 4, 6, 8, and 10 during the 12 week double-blind treatment period. |
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End point title |
Change from Baseline in Monthly Migraine Days to the Last 4 Weeks of the 12 Week Double-Blind Treatment Period | ||||||||||||||||
End point description |
A migraine day is any calendar day from the eDiary in which the participant experienced a
migraine headache. A migraine headache is a headache with or without aura, lasting for >= 4 hours, and meeting >=1 of the criteria:
a) >= 2 pain features (unilateral, throbbing, moderate to severe, exacerbated with exercise/physical activity)
b) >= 1 symptoms (nausea and/or vomiting, photophobia and phonophobia)
If the participant took a migraine-specific medication during aura or to treat headache, it was counted as a migraine day.
Days without eDiary data in each monthly interval are handled by proration.
Negative change from baseline values indicated improvement (i.e. fewer migraine days after treatment as compared to baseline).
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End point type |
Primary
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End point timeframe |
Baseline Day -28 to Day -1; Weeks 9-12
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Statistical analysis title |
Monthly Migraine Days: AMG301 210mg Q4W - Placebo | ||||||||||||||||
Statistical analysis description |
An adjusted analysis is presented that utilized a generalized linear mixed model which included treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
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Comparison groups |
Placebo v AMG 301 210 mg Q4W
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Number of subjects included in analysis |
212
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.66 [1] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
difference in least square mean | ||||||||||||||||
Point estimate |
0.26
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.88 | ||||||||||||||||
upper limit |
1.4 | ||||||||||||||||
Notes [1] - 2-sided significance level of 0.05 |
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Statistical analysis title |
Monthly Migraine Days: AMG301 420mg Q2W - Placebo | ||||||||||||||||
Statistical analysis description |
An adjusted analysis is presented that utilized a generalized linear mixed model which included treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
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Comparison groups |
Placebo v AMG 301 420 mg Q2W
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Number of subjects included in analysis |
204
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.65 [2] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
difference in least square mean | ||||||||||||||||
Point estimate |
0.27
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.89 | ||||||||||||||||
upper limit |
1.43 | ||||||||||||||||
Notes [2] - 2-sided significance level of 0.05 |
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End point title |
Percentage of Participants Who Responded, Defined as At Least a 50% Reduction from the Baseline Period in Monthly Migraine Days in the Last 4 Weeks of the 12-Week Double-Blind Treatment Period | ||||||||||||||||
End point description |
Responders are participants who had at least a 50% reduction from baseline in monthly migraine days during the last 4 weeks of treatment in the 12-week double blind period.
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End point type |
Secondary
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End point timeframe |
Baseline Day -28 to Day -1; Weeks 9-12
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Statistical analysis title |
50% Migraine Days: AMG301 210mg Q4W - Placebo | ||||||||||||||||
Statistical analysis description |
The common odds ratios and p-values are obtained from a Cochran-Mantel-Haenszel test, stratified by stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine).
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Comparison groups |
Placebo v AMG 301 210 mg Q4W
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Number of subjects included in analysis |
212
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.57 [3] | ||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||
Point estimate |
0.82
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.41 | ||||||||||||||||
upper limit |
1.62 | ||||||||||||||||
Notes [3] - 2-sided significance level of 0.05 |
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Statistical analysis title |
50% Migraine Days: AMG301 420mg Q2W - Placebo | ||||||||||||||||
Statistical analysis description |
The common odds ratios and p-values are obtained from a Cochran-Mantel-Haenszel test, stratified by stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine).
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Comparison groups |
Placebo v AMG 301 420 mg Q2W
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Number of subjects included in analysis |
204
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.45 [4] | ||||||||||||||||
Method |
Cochran-Mantel-Haenszel | ||||||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||||||
Point estimate |
0.76
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
0.37 | ||||||||||||||||
upper limit |
1.54 | ||||||||||||||||
Notes [4] - 2-sided significance level of 0.05 |
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End point title |
Change from Baseline Period in Monthly Acute Migraine-Specific Medication Days in the Last 4 Weeks of the 12-Week Double-Blind Treatment Period | ||||||||||||||||
End point description |
Number of days on which acute headache medications (triptans and ergotamine-derivatives, alone or in combination) are used as recorded in eDiary. Monthly acute headache medication treatment days at baseline are the number of acute headache medication treatment days in the baseline period. Days without eDiary data are handled by proration.
Negative change from baseline values indicate improvement (i.e. fewer days requiring acute migraine-specific medications after treatment as compared to baseline).
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End point type |
Secondary
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End point timeframe |
Baseline Day -28 to Day -1; Weeks 9-12
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Statistical analysis title |
Migraine Meds: AMG301 210mg Q4W - Placebo | ||||||||||||||||
Statistical analysis description |
Adjusted analysis utilizes a generalized linear mixed model which includes treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (CM versus EM), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
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Comparison groups |
Placebo v AMG 301 210 mg Q4W
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Number of subjects included in analysis |
187
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.94 [5] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
difference in least square mean | ||||||||||||||||
Point estimate |
-0.03
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.87 | ||||||||||||||||
upper limit |
0.81 | ||||||||||||||||
Notes [5] - 2-sided significance level of 0.05 |
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Statistical analysis title |
Migraine Meds: AMG301 420mg Q2W - Placebo | ||||||||||||||||
Comparison groups |
Placebo v AMG 301 420 mg Q2W
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Number of subjects included in analysis |
179
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Analysis specification |
Pre-specified
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Analysis type |
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P-value |
= 0.84 [6] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
difference in least square mean | ||||||||||||||||
Point estimate |
-0.09
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.94 | ||||||||||||||||
upper limit |
0.77 | ||||||||||||||||
Notes [6] - 2-sided significance level of 0.05 |
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End point title |
Change from Baseline in Mean Physical Impairment Domain Scores as Measured by the Migraine Physical Function Impact Diary (MPFID) Over the Last 4 Weeks of the 12-Week Double-Blind Treatment Period | ||||||||||||||||
End point description |
Participants complete the MPFID every day during baseline (Days -28 to Day -1) and the 12-week Double Blind Treatment Period. The MPFID has 2 domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and 1 stand-alone global question that provides an assessment of the overall impact of migraine on participants’ everyday activities. The recall period for each item is the past 24 hours.
The Physical Impairment Domain Score is reported here.
A participant's response to the difficulty of the 5 physical impairment items is measured using a 5-point scale, with difficulty measurements ranging from 1 to 5. The sum was rescaled to a 0 to 100 scale, with 0=no difficulty and 100=unable to do (maximum burden). Negative change from baseline values indicate improvement in migraine impact.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline Day -28 to Day -1; Weeks 9-12
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Phys Impair: AMG301 210mg Q4W - Placebo | ||||||||||||||||
Statistical analysis description |
An adjusted analysis is presented that utilized a generalized linear mixed model which included treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
|
||||||||||||||||
Comparison groups |
Placebo v AMG 301 210 mg Q4W
|
||||||||||||||||
Number of subjects included in analysis |
212
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
P-value |
= 0.81 [7] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
difference in least square mean | ||||||||||||||||
Point estimate |
-0.28
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-2.56 | ||||||||||||||||
upper limit |
2.01 | ||||||||||||||||
Notes [7] - 2-sided significance level of 0.05 |
|||||||||||||||||
Statistical analysis title |
Phys Impair: AMG301 420mg Q2W - Placebo | ||||||||||||||||
Statistical analysis description |
An adjusted analysis is presented that utilized a generalized linear mixed model which included treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
|
||||||||||||||||
Comparison groups |
Placebo v AMG 301 420 mg Q2W
|
||||||||||||||||
Number of subjects included in analysis |
205
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.79 [8] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
difference in least square mean | ||||||||||||||||
Point estimate |
0.31
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-2.01 | ||||||||||||||||
upper limit |
2.63 | ||||||||||||||||
Notes [8] - 2-sided significance level of 0.05 |
|
|||||||||||||||||
End point title |
Change from Baseline in Mean Impact on Everyday Activity Domain Scores as Measured by the Migraine Physical Function Impact Diary (MPFID) Over the Last 4 Weeks of the 12-Week Double-Blind Treatment Period | ||||||||||||||||
End point description |
Participants complete the MPFID every day during baseline (Days -28 to Day -1) and the 12-week Double Blind Treatment Period. The MPFID has 2 domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and 1 stand-alone global question that provides an assessment of the overall impact of migraine on participants’ everyday activities. The recall period for each item is the past 24 hours.
The Impact on Everyday Activities Domain Score is reported here.
A participant's response to the Impact on Everyday Activities 7 items is measured using a 5-point scale, with difficulty measurements ranging from 1 to 5. The sum was rescaled to a 0 to 100 scale, with 0=no difficulty and 100=unable to do (maximum burden). Negative change from baseline values indicate improvement in migraine impact.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Baseline Day -28 to Day -1; Weeks 9-12
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Everyday Act: AMG301 210mg Q4W - Placebo | ||||||||||||||||
Statistical analysis description |
An adjusted analysis is presented that utilized a generalized linear mixed model which included treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
|
||||||||||||||||
Comparison groups |
Placebo v AMG 301 210 mg Q4W
|
||||||||||||||||
Number of subjects included in analysis |
212
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
P-value |
= 0.46 [9] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
difference in least square mean | ||||||||||||||||
Point estimate |
-0.86
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-3.15 | ||||||||||||||||
upper limit |
1.44 | ||||||||||||||||
Notes [9] - 2-sided significance level of 0.05 |
|||||||||||||||||
Statistical analysis title |
Everyday Act: AMG301 420mg Q2W - Placebo | ||||||||||||||||
Statistical analysis description |
An adjusted analysis is presented that utilized a generalized linear mixed model which included treatment, visit, treatment-by-visit interaction, stratification factors of region and baseline migraine frequency (chronic migraine vs episodic migraine), and baseline value as covariates and assuming a first-order autoregressive covariance structure. The p-values for pairwise comparisons versus placebo are nominal p-values without multiplicity adjustment.
|
||||||||||||||||
Comparison groups |
Placebo v AMG 301 420 mg Q2W
|
||||||||||||||||
Number of subjects included in analysis |
205
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
|||||||||||||||||
P-value |
= 0.64 [10] | ||||||||||||||||
Method |
Mixed models analysis | ||||||||||||||||
Parameter type |
difference in least square mean | ||||||||||||||||
Point estimate |
0.56
|
||||||||||||||||
Confidence interval |
|||||||||||||||||
level |
95% | ||||||||||||||||
sides |
2-sided
|
||||||||||||||||
lower limit |
-1.77 | ||||||||||||||||
upper limit |
2.89 | ||||||||||||||||
Notes [10] - 2-sided significance level of 0.05 |
|
|||||||||||||||||||||||||||||||||||||||||
End point title |
Participants with Treatment-Emergent Adverse Events (TEAEs) | ||||||||||||||||||||||||||||||||||||||||
End point description |
Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4, where:
Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; Grade 4 = Life-threatening consequences; urgent intervention indicated Grade 5 = Death related to AE.
|
||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 1 up to Week 28 (12 weeks of double-blind treatment plus 16 weeks follow-up after last dose of investigational product)
|
||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Percentage of Participants Who Met Hy’s Law Criteria at Baseline and On Study | ||||||||||||||||||||
End point description |
Hy's law predicts potential for drug-related hepatotoxicity. Hy's Law cases have three components:
- The drug causes hepatocellular injury, generally defined as an elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) by 3-fold or greater above the upper limit of normal (ULN).
- Among participants showing such aminotransferase elevations, they also have elevation of their serum total bilirubin of greater than 2 times the ULN, without findings of cholestasis (defined as serum alkaline phosphatase activity less than 2 times the upper limit of normal).
- No other reason can be found to explain the combination of increased aminotransferase and serum total bilirubin, such as viral hepatitis, alcohol abuse, ischemia, preexisting liver disease, or another drug capable of causing the observed injury.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline: Day 1 On study: Weeks 4, 6, 12, 20, 28
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Percentage of Participants With Aminotransferase Test Abnormalities > 3 Times the Upper Limit of Normal (ULN) at Baseline and On Study | ||||||||||||||||||||||||
End point description |
Aminotransferase tests included alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Percentage of participants with results that were greater than 3 * ULN for either test are reported.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Baseline: Day 1 On study: Weeks 4, 6, 12, 20, 28
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Percentage of Participants With Total Bilirubin Test Abnormalities > 2 Times the Upper Limit of Normal (ULN) at Baseline and On Study | ||||||||||||||||||||
End point description |
Percentage of participants with total bilirubin results that were greater than 2 * ULN are reported.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Baseline: Day 1 On study: Weeks 4, 6, 12, 20, 28
|
||||||||||||||||||||
|
|||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Participants with Systolic Blood Pressure (SBP) in Categories by Visit | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Participant was expected to be in a supine position (or the most recumbent position possible) in a rested and calm state for at least 5 minutes before blood pressure assessments were conducted. Blood pressure units are millimeters of mercury (mmHg).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 1, Weeks 2, 4, 6, 8, 10, 12,16, 20, 24, 28
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Participants with Diastolic Blood Pressure (DBP) in Categories by Visit | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Participant was expected to be in a supine position (or the most recumbent position possible) in a rested and calm state for at least 5 minutes before blood pressure assessments were conducted. Blood pressure units are millimeters of mercury (mmHg).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 1, Weeks 2, 4, 6, 8, 10, 12,16, 20, 24, 28
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Participants with Pulse Rate in Categories by Visit | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Participant was expected to be in a supine position (or the most recumbent position possible) in a rested and calm state for at least 5 minutes before pulse assessments were conducted. Pulse rate units are beats per minute (BPM)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 1, Weeks 2, 4, 6, 8, 10, 12,16, 20, 24, 28
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Participants with Temperature in Categories by Visit | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Participant was expected to be in a supine position (or the most recumbent position possible) in a rested and calm state for at least 5 minutes before vital sign assessments were conducted. Temperature units are reported in degrees Celsius (C).
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 1, Weeks 2, 4, 6, 8, 10, 12,16, 20, 24, 28
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Percentage of Participants with Respiratory Rates in Categories by Visit | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Participant was expected to be in a supine position (or the most recumbent position possible) in a rested and calm state for at least 5 minutes before vital sign assessments were conducted. Respiratory rate (RR) is reported in breaths/minute.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Day 1, Weeks 2, 4, 6, 8, 10, 12,16, 20, 24, 28
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Day 1 up to Week 28 (12 weeks of double-blind treatment plus 16 weeks follow-up after last dose of investigational product)
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.1
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants randomized to Placebo were administered 6 subcutaneous (SC) injections on day 1 and weeks 2, 4, 6, 8 and 10 during the 12 week double-blind treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AMG 301 210 mg Q4W
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants randomized to AMG 301 210 mg every fourth week (Q4W) received a total of 3 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) plus 3 matching placebo injections on day 1 and weeks 4 and 8. Participants also received 6 SC placebo injections on weeks 2, 6, and 10 during the 12 week double-blind treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
AMG 301 420 mg Q2W
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Participants randomized to AMG 301 420 mg every second week (Q2W) received a total of 6 AMG 301 subcutaneous (SC) injections (70 mg/mL in each injection) on day 1 and weeks 2, 4, 6, 8, and 10 during the 12 week double-blind treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
16 May 2017 |
- Clarified the number of subjects that were to be screened
and enter baseline in order to achieve the target
randomization
- Clarified when vital signs, PK sampling, and
Headache Impact Test were to be collected during the study
- Clarified the risks and benefits of the study
- Removal of legally acceptable representative from the study
- Clarified that upon early discontinuation, a safety follow-up
visit was to be performed approximately 30 (+-5) days after
the last dosing interval of investigation product
- Added additional information for sample size calculation for
each AMG 301 group versus placebo
- Clarified that the primary analysis set was also known as the
efficacy analysis set
- Clarified which primary and secondary endpoints were to be
included in the interim analysis
- Added the responsibilities of the Data Review Team during
the double-blind treatment period
- Clarified Amgen's regulatory responsibilities when an amendment was determined to be substantial |
||
17 Oct 2017 |
- Updated schedule of activities and footnotes to maintain
consistency with the protocol
- Updated the exclusion screening criterion to maintain
accordance with the World Health Organization's guidelines
of assessing impaired glucose regulation/prediabetes with
glycosylated hemoglobin (HbA1c) values |
||
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 |