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    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
    EudraCT number
    		 2015-002322-40
    Trial protocol
    		 SK   BG   DE   LV   CZ   PL  
    Global end of trial date
    13 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Apr 2018
    First version publication date
    28 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20140254
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02575833
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    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.
    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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 20
    Country: Number of subjects enrolled
    Bulgaria: 9
    Country: Number of subjects enrolled
    Czech Republic: 12
    Country: Number of subjects enrolled
    Latvia: 3
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Slovakia: 34
    Country: Number of subjects enrolled
    South Africa: 2
    Worldwide total number of subjects
    89
    EEA total number of subjects
    66
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    44
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

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    Recruitment
    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
    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
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Carer, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 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
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single dose of a matching volume of placebo infused over approximately 60 minutes.

    Arm title
    		 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
    Investigational medicinal product code
    AMG 334
    Other name
    Aimovig™
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single dose of erenumab 140 mg was infused over approximately 60 minutes.

    Number of subjects in period 1
    		Placebo Erenumab 140 mg
    Started
    44
    45
    Received study drug
    44
    44
    Completed
    43
    44
    Not completed
    1
    1
         Consent withdrawn by subject
    -
    1
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    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
    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.

    Reporting group values
    		 Placebo Erenumab 140 mg Total
    Number of subjects
    		 44 45 89
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 21 23 44
        From 65-84 years
    		 23 22 45
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.5 ( 9.6 ) 61.8 ( 10.1 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 11 9 20
        Male
    		 33 36 69
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 1 1
        Black (or African American)
    		 5 1 6
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        White
    		 37 43 80
        Multiple
    		 0 0 0
        Other
    		 2 0 2
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 2 1 3
        Not Hispanic/Latino
    		 42 44 86
    Baseline Total Exercise Time
    Measured by an exercise treadmill test. Data are provided for 44 and 43 participants in each treatment group respectively with non-missing data.
    Units: seconds
        arithmetic mean (standard deviation)
    		 474.8 ( 149.5 ) 490.7 ( 149.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    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
    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.

    Primary: Change from Baseline in Total Exercise Time

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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.
    End point type
    Primary
    End point timeframe
    Baseline and day 1, after dosing
    End point values
    		 Placebo Erenumab 140 mg
    Number of subjects analysed
    44
    42
    Units: seconds
        least squares mean (standard error)
    8.1 ( 14.4 )
    -2.9 ( 14.8 )
    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.
    Comparison groups
    Placebo v Erenumab 140 mg
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Treatment Difference
    Point estimate
    -11
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -44.9
         upper limit
    		 22.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    20.4
    Notes
    [1] - The non-inferiority margin was -90 seconds.

    Secondary: Time to Onset of Exercise-induced Angina

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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.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Placebo Erenumab 140 mg
    Number of subjects analysed
    44
    44
    Units: seconds
        median (confidence interval 90%)
    508.0 (405.0 to 572.0)
    500.0 (420.0 to 540.0)
    Statistical analysis title
    		 Analysis of Time to Exercise-induced Angina
    Comparison groups
    Placebo v Erenumab 140 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.69 [3]
    Method
    		 Stratified Log Rank
    Confidence interval
    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).
    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.
    Comparison groups
    Placebo v Erenumab 140 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.69 [4]
    Method
    		 Cox Proportional Hazard
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.69
    Notes
    [4] - Adjusted by stratified baseline total exercise time strata (< 7 or ≥ 7 minutes)
    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.
    Comparison groups
    Placebo v Erenumab 140 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.44 [5]
    Method
    		 Cox Proportional Hazard
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.81
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.26
    Notes
    [5] - Adjusted by continuous baseline total exercise time
    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.
    Comparison groups
    Placebo v Erenumab 140 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47 [6]
    Method
    		 Cox Proportional Hazard
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.82
    Confidence interval
         level
    		 90%
         sides
    2-sided
         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.

    Secondary: Time to Onset of ≥ 1 mm ST-segment Depression

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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.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Placebo Erenumab 140 mg
    Number of subjects analysed
    44
    44
    Units: seconds
        median (confidence interval 90%)
    420.0 (409.0 to 480.0)
    407.0 (380.0 to 443.0)
    Statistical analysis title
    		 Analysis of Time to ≥ 1 mm ST-segment Depression
    Comparison groups
    Placebo v Erenumab 140 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.59 [8]
    Method
    		 Stratified Log Rank
    Confidence interval
    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).
    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.
    Comparison groups
    Placebo v Erenumab 140 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59 [9]
    Method
    		 Cox Proportional Hazard
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.14
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.76
         upper limit
    		 1.69
    Notes
    [9] - Adjusted by stratified baseline total exercise time strata (< 7 or ≥ 7 minutes)
    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.
    Comparison groups
    Placebo v Erenumab 140 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.75 [10]
    Method
    		 Cox Proportional Hazard
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.08
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.6
    Notes
    [10] - Adjusted by continuous baseline total exercise time
    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.
    Comparison groups
    Placebo v Erenumab 140 mg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.39 [11]
    Method
    		 Cox Proportional Hazard
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.24
    Confidence interval
         level
    		 90%
         sides
    2-sided
         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.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Erenumab 140 mg
    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
    Reporting group description
    		 Participants received a single dose of placebo administered by intravenous infusion on day 1 prior to starting an exercise treadmill test.

    Serious adverse events
    		 Erenumab 140 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Erenumab 140 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 44 (9.09%)
    6 / 44 (13.64%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 44 (2.27%)
         occurrences all number
    3
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    2
    Viral infection
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 44 (4.55%)
         occurrences all number
    0
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 44 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Aug 2015
    - Clarified language throughout the protocol and removed references to the storage of future research samples
    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
    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
    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.

    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
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