Treadmill Cardiovascular Safety Study of Erenumab (AMG 334)

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02575833
• Collaborator: (none)
• Enrollment: 89
• Locations: 33
• Arms: 2
• Actual Duration (Months): 16.7
• Patients Per Site: 2.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

A phase 2a, multicenter, randomized, double-blind, placebo-controlled study in adults with stable angina to evaluate the effect of erenumab (AMG 334) compared to placebo on exercise time during an exercise treadmill test.

Condition or Disease	Intervention/Treatment	Phase
Stable Angina	Drug: Erenumab; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Nov 23, 2015
• Actual Primary Completion Date: Jan 23, 2017
• Actual Study Completion Date: Apr 13, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received a single dose of placebo administered by intravenous infusion on day 1.	Drug: Placebo; A single dose of a matching volume of placebo infused over approximately 60 minutes.
Experimental: Erenumab Participants received a single dose of erenumab 140 mg administered by intravenous infusion on day 1.	Drug: Erenumab; A single dose of erenumab 140 mg infused over approximately 60 minutes.; Other Names: AMG 334 Aimovig™

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Total Exercise Time [Baseline and day 1, after dosing]

   Total exercise time was assessed using an exercise treadmill test according to the standard Bruce protocol. The Bruce protocol is a standardized multistage treadmill test for assessing cardiovascular health, where the participant walks on an uphill treadmill in a graded exercise test with electrodes on the chest to monitor cardiac function. Every 3 minutes, the speed and incline of the treadmill are increased. There are 7 such stages for a total possible exercise time of 21 minutes.

Secondary Outcome Measures

1. Time to Onset of Exercise-induced Angina [Day 1]

   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.

2. Time to Onset of ≥ 1 mm ST-segment Depression [Day 1]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

• History of chronic stable angina or at least 3 months prior to screening, with at least 1 angina episode per month

• Ischemic heart disease documented by myocardial infarction, coronary angiography or a revascularization procedure

• Receiving stable doses of cardiac medication

• Completes 2 exercise treadmill tests during screening meeting protocol requirements

Exclusion Criteria:

• Participating in another investigational study

• Current or prior malignancy within 5 years of randomization

• Known sensitivity to any components of the investigational product

• Not able to complete all protocol required study visits

• Having the following within 3 months prior to or during screening: Unstable angina or acute coronary syndrome, transient Ischemic attack (TIA) or stroke, revascularization procedure, or instability in ST-segment depression between screening exercise treadmill tests, as assessed by the core electrocardiograph (ECG) laboratory

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Jacksonville	Florida	United States	32216
2	Research Site	Miami	Florida	United States	33125
3	Research Site	Atlanta	Georgia	United States	30342
4	Research Site	Chicago	Illinois	United States	60616
5	Research Site	Las Vegas	Nevada	United States	89128
6	Research Site	Jackson	Tennessee	United States	38305
7	Research Site	New Braunfels	Texas	United States	78130
8	Research Site	Wichita Falls	Texas	United States	76301
9	Research Site	Haskovo		Bulgaria	6300
10	Research Site	Sofia		Bulgaria	1407
11	Research Site	Sofia		Bulgaria	1431
12	Research Site	Sofia		Bulgaria	1606
13	Research Site	Brandys nad Labem		Czechia	250 01
14	Research Site	Chomutov		Czechia	430 02
15	Research Site	Praha 4		Czechia	140 21
16	Research Site	Pribram VIII		Czechia	261 01
17	Research Site	Riga		Latvia	1038
18	Research Site	Christchurch		New Zealand	8011
19	Research Site	Grafton, Auckland		New Zealand	1023
20	Research Site	Krakow		Poland	31-202
21	Research Site	Lodz		Poland	91-347
22	Research Site	Zabrze		Poland	41-800
23	Research Site	Timisoara		Romania	300244
24	Research Site	Bardejov		Slovakia	085 01
25	Research Site	Brezno		Slovakia	977 42
26	Research Site	Lucenec		Slovakia	984 01
27	Research Site	Piestany		Slovakia	921 01
28	Research Site	Presov		Slovakia	080 01
29	Research Site	Svidnik		Slovakia	089 01
30	Research Site	Trencin		Slovakia	911 01
31	Research Site	Zilina		Slovakia	010 01
32	Research Site	Parow	Western Cape	South Africa	7505
33	Research Site	Geneva 14		Switzerland	1211

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

• Study Protocol - Apr 13, 2017
• Statistical Analysis Plan - Apr 13, 2017

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Depre C, Antalik L, Starling A, Koren M, Eisele O, Lenz RA, Mikol DD. A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Erenumab on Exercise Time During a Treadmill Test in Patients With Stable Angina. Headache. 2018 May;58(5):715-723. doi: 10.1111/head.13316.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT02575833
• Other Study ID Numbers: 20140254; 2015-002322-40
• First Posted: Oct 15, 2015
• Last Update Posted: Aug 24, 2018
• Last Verified: Jul 1, 2018

• Keywords provided by Amgen: Angina; Stable Angina; Cardiovascular Disease; Exercise-induced Angina
• Additional relevant MeSH terms: Angina Pectoris; Angina, Stable; Erenumab

Study Results

Participant Flow

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 Detail	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.

Arm/Group Title	Placebo	Erenumab
Arm/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.	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.
Period Title: Overall Study
STARTED	44	45
Received Study Drug	44	44
COMPLETED	43	44
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Placebo	Erenumab	Total
Arm/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.	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.	Total of all reporting groups
Overall Participants	44	45	89
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.5 (9.6)	61.8 (10.1)	62.6 (9.9)
Age, Customized (Count of Participants)
18 - < 65 years	21 47.7%	23 51.1%	44 49.4%
65 - 85 years	23 52.3%	22 48.9%	45 50.6%
Sex: Female, Male (Count of Participants)
Female	11 25%	9 20%	20 22.5%
Male	33 75%	36 80%	69 77.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 4.5%	1 2.2%	3 3.4%
Not Hispanic or Latino	42 95.5%	44 97.8%	86 96.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 2.2%	1 1.1%
Black (or African American)	5 11.4%	1 2.2%	6 6.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
White	37 84.1%	43 95.6%	80 89.9%
Multiple	0 0%	0 0%	0 0%
Other	2 4.5%	0 0%	2 2.2%
Baseline Total Exercise Time (seconds) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [seconds]	474.8 (149.5)	490.7 (149.7)	482.7 (148.9)
Stratification Factor: Total Exercise Time (Count of Participants)
< 7 minutes	18 40.9%	18 40%	36 40.4%
≥ 7 minutes	26 59.1%	27 60%	53 59.6%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Total Exercise Time
Description	Total exercise time was assessed using an exercise treadmill test according to the standard Bruce protocol. The Bruce protocol is a standardized multistage treadmill test for assessing cardiovascular health, where the participant walks on an uphill treadmill in a graded exercise test with electrodes on the chest to monitor cardiac function. Every 3 minutes, the speed and incline of the treadmill are increased. There are 7 such stages for a total possible exercise time of 21 minutes.
Time Frame	Baseline and day 1, after dosing

Outcome Measure Data

Analysis Population Description

Participants who received study drug and completed the baseline and post-randomization exercise treadmill tests

Arm/Group Title	Placebo	Erenumab
Arm/Group Description	Participants received a single dose of placebo administered by intravenous infusion on day 1 prior to starting an exercise treadmill test.	Participants received a single dose of erenumab 140 mg administered by intravenous infusion on day 1 prior to starting an exercise treadmill test.
Measure Participants	44	42
Least Squares Mean (Standard Error) [seconds]	8.1 (14.4)	-2.9 (14.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab
	Comments	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.
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin was -90 seconds.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-11.0
	Confidence Interval	(2-Sided) 90%; -44.9 to 22.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 20.4
	Estimation Comments

2. Secondary Outcome

Title	Time to Onset of Exercise-induced Angina
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.
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Participants who received study drug and completed the post-randomization exercise treadmill test

Arm/Group Title	Placebo	Erenumab
Arm/Group Description	Participants received a single dose of placebo administered by intravenous infusion on day 1 prior to starting an exercise treadmill test.	Participants received a single dose of erenumab 140 mg administered by intravenous infusion on day 1 prior to starting an exercise treadmill test.
Measure Participants	44	44
Median (90% Confidence Interval) [seconds]	508.0	500.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab
	Comments
	Type of Statistical Test	Superiority
	Comments	The log-rank test statistic was used to compare the two treatment groups at a significance level of 0.10.
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	Stratified Log Rank
	Comments	Log rank test stratified by baseline total exercise time strata (< 7 minutes or ≥ 7 minutes).
Method of Estimation	Estimation Parameter	Normal score
	Estimated Value	1.55
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	A normal score < 0 indicates fewer than expected events for erenumab 140 mg relative to placebo and therefore a longer survival time.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	Cox Proportional Hazard
	Comments	Adjusted by stratified baseline total exercise time strata (< 7 or ≥ 7 minutes)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.11
	Confidence Interval	(2-Sided) 90%; 0.73 to 1.69
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	Cox Proportional Hazard
	Comments	Adjusted by continuous baseline total exercise time
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 90%; 0.52 to 1.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.47
	Comments
	Method	Cox Proportional Hazard
	Comments	Adjusted by baseline total exercise time strata (< 7 or ≥ 7 minutes), age group (< 65, ≥ 65), and sex.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 90%; 0.52 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

3. Secondary Outcome

Title	Time to Onset of ≥ 1 mm ST-segment Depression
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).
Time Frame	Day 1

Outcome Measure Data

Analysis Population Description

Participants who received study drug and completed the post-randomization exercise treadmill test.

Arm/Group Title	Placebo	Erenumab
Arm/Group Description	Participants received a single dose of placebo administered by intravenous infusion on day 1 prior to starting an exercise treadmill test.	Participants received a single dose of erenumab 140 mg administered by intravenous infusion on day 1 prior to starting an exercise treadmill test.
Measure Participants	44	44
Median (90% Confidence Interval) [seconds]	420.0	407.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab
	Comments
	Type of Statistical Test	Superiority
	Comments	The log-rank test statistic was used to compare the two treatment groups at a significance level of 0.10.
Statistical Test of Hypothesis	p-Value	0.59
	Comments
	Method	Stratified Log Rank
	Comments	Log rank test stratified by baseline total exercise time strata (< 7 minutes or ≥ 7 minutes).
Method of Estimation	Estimation Parameter	Normal score
	Estimated Value	2.2
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	A normal score < 0 indicates fewer than expected events for erenumab 140 mg relative to placebo and therefore a longer survival time.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.59
	Comments
	Method	Cox Proportional Hazard
	Comments	Adjusted by stratified baseline total exercise time strata (< 7 or ≥ 7 minutes)
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 90%; 0.76 to 1.69
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.75
	Comments
	Method	Cox Proportional Hazard
	Comments	Adjusted by continuous baseline total exercise time
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.08
	Confidence Interval	(2-Sided) 90%; 0.73 to 1.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	Cox Proportional Hazard
	Comments	Adjusted by baseline total exercise time strata (< 7 or ≥ 7 minutes), age group (< 65, ≥ 65), and sex.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 90%; 0.82 to 1.87
	Parameter Dispersion	Type: Value:
	Estimation Comments	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.

Adverse Events

Time Frame	12 weeks
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Placebo		Erenumab 140 mg
Arm/Group Description	Participants received a single dose of placebo administered by intravenous infusion on day 1 prior to starting an exercise treadmill test.		Participants received a single dose of erenumab 140 mg administered by intravenous infusion on day 1 prior to starting an exercise treadmill test.
All Cause Mortality
	Placebo		Erenumab 140 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/44 (0%)
Serious Adverse Events
	Placebo		Erenumab 140 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/44 (2.3%)		0/44 (0%)
Cardiac disorders
Atrial fibrillation	1/44 (2.3%)		0/44 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Erenumab 140 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/44 (13.6%)		4/44 (9.1%)
Infections and infestations
Influenza	2/44 (4.5%)		0/44 (0%)
Viral infection	2/44 (4.5%)		0/44 (0%)
Viral upper respiratory tract infection	0/44 (0%)		2/44 (4.5%)
Nervous system disorders
Headache	1/44 (2.3%)		2/44 (4.5%)
Vascular disorders
Hypotension	2/44 (4.5%)		0/44 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.