Clinical Trial Results:
A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effect of AMG 334 on Exercise Time During a Treadmill Test in Subjects With Stable Angina
Summary
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EudraCT number |
2015-002322-40 |
Trial protocol |
SK BG DE LV CZ PL |
Global end of trial date |
13 Apr 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
28 Apr 2018
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First version publication date |
28 Apr 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 |
20140254
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02575833 | ||
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, CA, 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 |
13 Apr 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 |
13 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 |
The primary objective of the study was to evaluate the effect of erenumab compared to placebo on exercise capacity in subjects with stable angina as measured by total exercise time during an exercise treadmill test.
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Protection of trial subjects |
This study was conducted in accordance with International Council of Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, the GCPs applicable to all regions where the study was conducted and in accordance with the ethical principles set forth in the Declaration of Helsinki. All centers complied with local regulations.
The study protocol and all amendments, the informed consent form, and any accompanying materials provided to subjects were reviewed and approved by an Independent Ethics Committee (IEC) or Institutional Review Board (IRB), as appropriate, at each center/country.
The investigator or his/her designee informed the subject of all aspects pertaining to the subject’s participation in the study before any screening procedures were performed.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
23 Nov 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 20
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Country: Number of subjects enrolled |
Bulgaria: 9
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Country: Number of subjects enrolled |
Czech Republic: 12
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Country: Number of subjects enrolled |
Latvia: 3
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Country: Number of subjects enrolled |
New Zealand: 1
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Country: Number of subjects enrolled |
Poland: 1
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Country: Number of subjects enrolled |
Romania: 7
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Country: Number of subjects enrolled |
Slovakia: 34
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Country: Number of subjects enrolled |
South Africa: 2
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Worldwide total number of subjects |
89
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EEA total number of subjects |
66
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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) |
44
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From 65 to 84 years |
45
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted at 35 centers across the United States, South Africa, New Zealand, and the European Union (EU). Participants were enrolled from November 2015 to January 2017. | |||||||||||||||||||||
Pre-assignment
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Screening details |
Participants were randomized in a 1:1 ratio to receive either a single dose of erenumab 140 mg or placebo intravenously (IV) prior to starting an exercise treadmill test. Randomization was stratified by the total exercise time average (< 7 minutes or ≥ 7 minutes) of the 2 qualifying exercise treadmill tests performed during screening. | |||||||||||||||||||||
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, Carer, Assessor, Subject | |||||||||||||||||||||
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 receive a single dose of placebo administered by intravenous infusion on day 1 prior to starting an exercise treadmill test. | |||||||||||||||||||||
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 |
Intravenous use
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Dosage and administration details |
A single dose of a matching volume of placebo infused over approximately 60 minutes.
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Arm title
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Erenumab 140 mg | |||||||||||||||||||||
Arm description |
Participants randomized to receive a single dose of erenumab 140 mg administered by intravenous infusion on day 1 prior to starting an exercise treadmill test. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Erenumab
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Investigational medicinal product code |
AMG 334
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Other name |
Aimovig™
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
A single dose of erenumab 140 mg was infused over approximately 60 minutes.
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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 receive a single dose of placebo administered by intravenous infusion on day 1 prior to starting an exercise treadmill test. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Erenumab 140 mg
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Reporting group description |
Participants randomized to receive a single dose of erenumab 140 mg administered by intravenous infusion on day 1 prior to starting an exercise treadmill test. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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 receive a single dose of placebo administered by intravenous infusion on day 1 prior to starting an exercise treadmill test. | ||
Reporting group title |
Erenumab 140 mg
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Reporting group description |
Participants randomized to receive a single dose of erenumab 140 mg administered by intravenous infusion on day 1 prior to starting an exercise treadmill test. |
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End point title |
Change from Baseline in Total Exercise Time | ||||||||||||
End point description |
Total exercise time was assessed using an exercise treadmill test.
The analysis includes participants who received study drug and completed the baseline and post-randomization exercise treadmill tests.
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End point type |
Primary
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End point timeframe |
Baseline and day 1, after dosing
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Statistical analysis title |
Primary Analysis | ||||||||||||
Statistical analysis description |
The primary endpoint was analyzed using an analysis of variance model with terms for treatment group and randomization strata (< 7 or ≥ 7 minutes). If the lower bound of the 90% confidence interval (CI) of the difference in change from baseline in exercise duration was above the non-inferiority margin of -90 seconds, then the hypothesis that erenumab does not decrease exercise duration would be supported.
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Comparison groups |
Placebo v Erenumab 140 mg
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Number of subjects included in analysis |
86
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Analysis specification |
Pre-specified
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Analysis type |
non-inferiority [1] | ||||||||||||
Method |
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Parameter type |
Treatment Difference | ||||||||||||
Point estimate |
-11
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
-44.9 | ||||||||||||
upper limit |
22.9 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
20.4
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Notes [1] - The non-inferiority margin was -90 seconds. |
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End point title |
Time to Onset of Exercise-induced Angina | ||||||||||||
End point description |
Time to onset of angina was defined as the time the participant received study drug to the time of event onset during the exercise treadmill test. If no event occurred the participant was censored at the exercise treadmill test stop time.
The analysis includes participants who received study drug and completed the post-randomization exercise treadmill test.
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End point type |
Secondary
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End point timeframe |
Day 1
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Statistical analysis title |
Analysis of Time to Exercise-induced Angina | ||||||||||||
Comparison groups |
Placebo v Erenumab 140 mg
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority [2] | ||||||||||||
P-value |
= 0.69 [3] | ||||||||||||
Method |
Stratified Log Rank | ||||||||||||
Confidence interval |
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Notes [2] - The log-rank test statistic was used to compare the two treatment groups at a significance level of 0.10. [3] - Log rank test stratified by baseline total exercise time strata (< 7 minutes or ≥ 7 minutes). |
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Statistical analysis title |
Secondary Analysis | ||||||||||||
Statistical analysis description |
Hazard ratio estimates were obtained from the Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a lower average event rate and a longer exercise-induced angina free survival for erenumab 140 mg relative to placebo.
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Comparison groups |
Placebo v Erenumab 140 mg
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.69 [4] | ||||||||||||
Method |
Cox Proportional Hazard | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.11
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
0.73 | ||||||||||||
upper limit |
1.69 | ||||||||||||
Notes [4] - Adjusted by stratified baseline total exercise time strata (< 7 or ≥ 7 minutes) |
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Statistical analysis title |
Secondary Analysis | ||||||||||||
Statistical analysis description |
Hazard ratio estimates were obtained from the Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a lower average event rate and a longer exercise-induced angina free survival for erenumab 140 mg relative to placebo.
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Comparison groups |
Placebo v Erenumab 140 mg
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.44 [5] | ||||||||||||
Method |
Cox Proportional Hazard | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.81
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
0.52 | ||||||||||||
upper limit |
1.26 | ||||||||||||
Notes [5] - Adjusted by continuous baseline total exercise time |
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Statistical analysis title |
Secondary Analysis | ||||||||||||
Statistical analysis description |
Hazard ratio estimates were obtained from the Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a lower average event rate and a longer exercise-induced angina free survival for erenumab 140 mg relative to placebo.
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Comparison groups |
Placebo v Erenumab 140 mg
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.47 [6] | ||||||||||||
Method |
Cox Proportional Hazard | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
0.82
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
0.52 | ||||||||||||
upper limit |
1.28 | ||||||||||||
Notes [6] - Adj1usted by baseline total exercise time strata (< 7 or ≥ 7 minutes), age group (< 65, ≥ 65), and sex. |
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End point title |
Time to Onset of ≥ 1 mm ST-segment Depression | ||||||||||||
End point description |
Time to onset of ≥ 1 mm ST-segment depression was defined as the time the participant received study drug to the time of event onset during the exercise treadmill test. If no event occurred the participant was censored at the exercise treadmill test stop time.
Heart rate and rhythm were monitored during the exercise treadmill test by electrocardiography (ECG).
The analysis includes participants who received study drug and completed the post-randomization exercise treadmill test.
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End point type |
Secondary
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End point timeframe |
Day 1
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Statistical analysis title |
Analysis of Time to ≥ 1 mm ST-segment Depression | ||||||||||||
Comparison groups |
Placebo v Erenumab 140 mg
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority [7] | ||||||||||||
P-value |
= 0.59 [8] | ||||||||||||
Method |
Stratified Log Rank | ||||||||||||
Confidence interval |
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Notes [7] - The log-rank test statistic was used to compare the two treatment groups at a significance level of 0.10. [8] - Log rank test stratified by baseline total exercise time strata (< 7 minutes or ≥ 7 minutes). |
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Statistical analysis title |
Secondary Analysis | ||||||||||||
Statistical analysis description |
Hazard ratio estimates were obtained from the Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a lower average event rate and a longer exercise-induced ST-segment depression free survival for erenumab 140 mg relative to placebo.
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Comparison groups |
Placebo v Erenumab 140 mg
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.59 [9] | ||||||||||||
Method |
Cox Proportional Hazard | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.14
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
0.76 | ||||||||||||
upper limit |
1.69 | ||||||||||||
Notes [9] - Adjusted by stratified baseline total exercise time strata (< 7 or ≥ 7 minutes) |
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Statistical analysis title |
Secondary Analysis | ||||||||||||
Statistical analysis description |
Hazard ratio estimates were obtained from the Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a lower average event rate and a longer exercise-induced ST-segment depression free survival for erenumab 140 mg relative to placebo.
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Comparison groups |
Placebo v Erenumab 140 mg
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.75 [10] | ||||||||||||
Method |
Cox Proportional Hazard | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.08
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
0.73 | ||||||||||||
upper limit |
1.6 | ||||||||||||
Notes [10] - Adjusted by continuous baseline total exercise time |
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Statistical analysis title |
Secondary Analysis | ||||||||||||
Statistical analysis description |
Hazard ratio estimates were obtained from the Cox Proportional Hazard Model. A hazard ratio < 1.0 indicates a lower average event rate and a longer exercise-induced ST-segment depression free survival for erenumab 140 mg relative to placebo.
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Comparison groups |
Placebo v Erenumab 140 mg
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Number of subjects included in analysis |
88
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.39 [11] | ||||||||||||
Method |
Cox Proportional Hazard | ||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||
Point estimate |
1.24
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Confidence interval |
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level |
90% | ||||||||||||
sides |
2-sided
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lower limit |
0.82 | ||||||||||||
upper limit |
1.87 | ||||||||||||
Notes [11] - Adjusted by baseline total exercise time strata (< 7 or ≥ 7 minutes), age group (< 65, ≥ 65), and sex. |
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Adverse events information
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Timeframe for reporting adverse events |
12 weeks
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
Erenumab 140 mg
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Reporting group description |
Participants received a single dose of erenumab 140 mg administered by intravenous infusion on day 1 prior to starting an exercise treadmill test. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received a single dose of placebo administered by intravenous infusion on day 1 prior to starting an exercise treadmill test. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 3% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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06 Aug 2015 |
- Clarified language throughout the protocol and removed references to the storage of future research samples |
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17 Nov 2015 |
- Added a 12-lead electrocardiogram to be conducted 4 hours after the completion of the Exercise Treadmill Test on day 1
- Added an assessment of anti-AMG 334 antibodies at day 1, week 4, and End of Study
- Added a summary of clinical safety data to the Background and Rationale section
- Clarified language throughout the protocol |
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27 Jan 2016 |
- Increased the number of study centers
- Supported decreasing the screen failure rate by:
- Allowing for the use of 2 out of 3 screening exercise treadmill tests to qualify patients for enrollment
- Removing the restriction for antianginal medication on the morning of the exercise treadmill test
- Reworded inclusion criteria for clarification purposes
- Clarified the background safety information of AMG 334 use in patients with migraine.
- Clarified the definition of the Columbia-Suicidality Severity Scale
- Clarified adverse event, drug related event, and serious adverse event reporting instructions
- Aligned with changes made to the updated standard Amgen protocol template |
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28 Oct 2016 |
- Change in primary hypotheses, specifically to change the non-inferiority margin from -60 seconds to -90 seconds.
- Sample size was changed from 120 subjects to at least 54 subjects.
- Clarification of rescreening of screen failures due to technical difficulties will be reviewed by Amgen to determine if rescreening is permitted.
- Clarification of text regarding dosage adjustments, delays, rules for withholding or restarting, or permanent discontinuation
- Clarification of timing use of antianginals post exercise treadmill test
- Clarification of who will be blinded and timing of unblinding
- Clarification of primary analysis
- Clarification of primary efficacy endpoint
- Schedule of Assessments: Day 1 visits moved to occur within on study visits, as these were previously shown incorrectly within the screening period. An instructional footnote was also added for screening visits. |
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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 |