ARISE: Study to Evaluate the Efficacy and Safety of Erenumab (AMG 334) Compared to Placebo in Migraine Prevention

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02483585
• Collaborator: (none)
• Enrollment: 577
• Locations: 76
• Arms: 2
• Actual Duration (Months): 20
• Patients Per Site: 7.6
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

To evaluate the effect of erenumab compared to placebo on the change from baseline in monthly migraine days, in adults with episodic migraine.

Condition or Disease	Intervention/Treatment	Phase
Migraine	Drug: Erenumab; Drug: Placebo	Phase 3

Detailed Description

Adults with a history of migraine with or without aura for ≥ 12 months and who experience ≥ 4 to < 15 migraine days per month with < 15 headache days per month will be randomized 1:1 to placebo or erenumab. Double-blind erenumab or placebo will be administered during the 12-week double-blind treatment phase and open-label erenumab will be administered during the 28-week open-label treatment phase.

Study Design

• Study Type: Interventional
• Actual Enrollment: 577 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention
• Actual Study Start Date: Jul 20, 2015
• Actual Primary Completion Date: Jul 11, 2016
• Actual Study Completion Date: Mar 20, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. At week 12 participants began treatment with erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the open-label treatment phase.	Drug: Placebo; Administered once a month by subcutaneous injection
Experimental: Erenumab Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. Participants continued to receive erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the open-label treatment phase.	Drug: Erenumab; Administered once a month by subcutaneous injection; Other Names: AMG 334 Aimovig™

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Monthly Migraine Days at Week 12 [4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase]

   A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine with or without aura. The change from baseline in monthly migraine days was calculated as the number of migraine days during the last 4 weeks of the 12-week double-blind treatment phase - the number of migraine days during the 4-week baseline phase.

Secondary Outcome Measures

1. Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days at Week 12 [4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase]

   A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine without aura or a migraine with aura. Monthly migraine days were calculated as the number of migraine days in the 4-week baseline phase and during the last 4 weeks of double-blind treatment. At least a 50% reduction from baseline in monthly migraine days was determined if the change in monthly migraine days from the 4-week baseline phase to the last 4 weeks of the 12-week double-blind treatment phase * 100 / baseline monthly migraine days was less than or equal to -50%.

2. Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days at Week 12 [4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase]

   Monthly acute migraine-specific medication treatment days is the number of days on which migraine specific medications were used between monthly doses of study drug. Migraine-specific medications includes two categories of medications: triptan-based migraine medications and ergotamine-based migraine medications. The change from baseline in monthly acute migraine-specific treatment days was calculated as the number of migraine-specific treatment days during the last 4 weeks of the 12-week double-blind treatment phase - the number of migraine-specific treatment days during the 4-week baseline phase.

3. Percentage of Participants With at Least a 5-point Reduction From Baseline in Average Impact on Everyday Activities Domain Score Measured by MPFID at Week 12 [4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase]

   The Migraine Physical Function Impact Diary (MPFID) is a self-administered 13-item instrument measuring physical functioning. It has two domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and one stand-alone global question. Participants completed the MPFID daily in an electronic diary based on the past 24 hours. Participants responded to each item on a 5-point scale, with difficulty items ranging from "Without any difficulty" (1) to "Unable to do" (5) and frequency items ranging from "None of the time" (1) to "All of the time" (5). For each domain, the scores were calculated as the sum of the responses and rescaled to 0 - 100, with higher scores representing greater impact of migraine. Achievement of at least a 5 point reduction from baseline in the monthly average domain score was calculated as (monthly average domain score during the last 4 weeks of the 12-week double-blind treatment phase - baseline monthly average domain score) was ≤ -5.

4. Percentage of Participants With at Least a 5-Point Reduction From Baseline in Average Impact on Physical Impairment Domain Score Measured by MPFID at Week 12 [4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase]

   The Migraine Physical Function Impact Diary (MPFID) is a self-administered 13-item instrument measuring physical functioning. It has two domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and one stand-alone global question. Participants completed the MPFID daily in an electronic diary based on the past 24 hours. Participants responded to each item on a 5-point scale, with difficulty items ranging from "Without any difficulty" (1) to "Unable to do" (5) and frequency items ranging from "None of the time" (1) to "All of the time" (5). For each domain, the scores were calculated as the sum of the responses and rescaled to 0 - 100, with higher scores representing greater impact of migraine. Achievement of at least a 5 point reduction from baseline in the monthly average domain score was calculated as (monthly average domain score during the last 4 weeks of the 12-week double-blind treatment phase - baseline monthly average domain score) was ≤ -5.

5. Number of Participants With Adverse Events [From first dose of study drug up to 12 weeks after the last dose. The double-blind treatment phase was 12 weeks and the open-label treatment phase was 28 weeks.]

   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.

6. Number of Participants Who Developed Antibodies to Erenumab [Baseline (the period prior to the first dose erenumab 70 mg) and post-baseline (the period after the first dose of erenumab 70 mg until 12 weeks after last dose, up to 48 weeks total)]

   Blood samples were first tested in an electrochemiluminescence (ECL)-based bridging immunoassay to detect anti-drug antibodies (ADA) against erenumab. Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based bioassay to determine neutralizing activity against erenumab (Neutralizing Antibody Assay). Developing antibody incidence indicates participants with a negative or no result at baseline and a positive result at any time post-baseline. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies. Transient indicates a negative result at the participant's last time point tested, for those participants with a positive binding/neutralizing result post-baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• History of migraines (with or without aura) for ≥ 12 months

• Migraine frequency: ≥ 4 and < 15 migraine days per month on average acrossthe 3 months prior to screening

• Headache (ie, migraine and non-migraine headache) frequency: < 15 headache days per month on average across the 3 months prior to screening

• Demonstrated compliance with the eDiary

Exclusion Criteria:

• Older than 50 years of age at migraine onset.

• History of cluster headache or hemiplegic migraine headache.

• Unable to differentiate migraine from other headaches

• No therapeutic response with > 2 categories for prophylactic treatment of migraine after an adequate therapeutic trial.

• Concomitant use of 2 or more medications with possible migraine prophylactic effects within 2 months prior to the start of the baseline phase or during the baseline phase. If only 1 prophylactic medication is used, the dose must be stable within 2 months prior to the start of the baseline phase and throughout the study

• Used a prohibited medication, device, or procedure within 2 months prior to the start of the baseline phase or during the baseline phase.

• Received botulinum toxin

• Anticipated to require any excluded medication, device, or procedure during the study.

• Active chronic pain syndromes (such as fibromyalgia and chronic pelvic pain).

• History of major psychiatric disorder.

• History of seizure disorder or other significant neurological conditions other than migraine.

• Human immunodeficiency virus (HIV) infection by history.

• Myocardial infarction (MI), stroke, transient ischemic attack (TIA), unstable angina, or coronary artery bypass surgery or other revascularization procedure within 12 months prior to screening.

• The subject is at risk of self-harm or harm to others. Previously randomized into an AMG 334 study.

• Unlikely to be able to complete all protocol required study visits or procedures, and/or to comply with all required study procedures.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States	35216
2	Research Site	Phoenix	Arizona	United States	85018
3	Research Site	Culver City	California	United States	90230
4	Research Site	Long Beach	California	United States	90806
5	Research Site	Sacramento	California	United States	95821
6	Research Site	San Diego	California	United States	92103
7	Research Site	Santa Monica	California	United States	90404
8	Research Site	Walnut Creek	California	United States	94598
9	Research Site	Colorado Springs	Colorado	United States	80907
10	Research Site	Fairfield	Connecticut	United States	06824
11	Research Site	Hollywood	Florida	United States	33021
12	Research Site	Jacksonville	Florida	United States	32216
13	Research Site	Orlando	Florida	United States	32806
14	Research Site	Oviedo	Florida	United States	32765
15	Research Site	Palm Beach Gardens	Florida	United States	33410
16	Research Site	Atlanta	Georgia	United States	30342
17	Research Site	Gurnee	Illinois	United States	60031
18	Research Site	Indianapolis	Indiana	United States	46256
19	Research Site	Lenexa	Kansas	United States	66214
20	Research Site	Lexington	Kentucky	United States	40513
21	Research Site	Baltimore	Maryland	United States	21208
22	Research Site	Boston	Massachusetts	United States	02131
23	Research Site	Ann Arbor	Michigan	United States	48104
24	Research Site	Kalamazoo	Michigan	United States	49009
25	Research Site	Princeton	New Jersey	United States	08540
26	Research Site	Albuquerque	New Mexico	United States	87102
27	Research Site	Williamsville	New York	United States	14221
28	Research Site	Asheville	North Carolina	United States	28806
29	Research Site	Winston-Salem	North Carolina	United States	27103
30	Research Site	Cincinnati	Ohio	United States	45245
31	Research Site	Oklahoma City	Oklahoma	United States	73112
32	Research Site	Philadelphia	Pennsylvania	United States	19114
33	Research Site	Warwick	Rhode Island	United States	02886
34	Research Site	Mount Pleasant	South Carolina	United States	29464
35	Research Site	Chattanooga	Tennessee	United States	37421
36	Research Site	Austin	Texas	United States	78759
37	Research Site	Dallas	Texas	United States	75214
38	Research Site	Salt Lake City	Utah	United States	84121
39	Research Site	Virginia Beach	Virginia	United States	23454
40	Research Site	Seattle	Washington	United States	98105
41	Research Site	Aalborg		Denmark	9000
42	Research Site	Ballerup		Denmark	2750
43	Research Site	Glostrup		Denmark	2600
44	Research Site	Vejle		Denmark	7100
45	Research Site	Bordeaux Cedex		France	33076
46	Research Site	Nice cedex 1		France	06003
47	Research Site	Paris		France	75010
48	Research Site	Paris		France	75014
49	Research Site	Pringy Cedex		France	74374
50	Research Site	Athens		Greece	11521
51	Research Site	Athens		Greece	11525
52	Research Site	Athens		Greece	16675
53	Research Site	Thessaloniki		Greece	54645
54	Research Site	Amadora		Portugal	2720-276
55	Research Site	Lisboa		Portugal	1500-650
56	Research Site	Lisboa		Portugal	1649-035
57	Research Site	Torres Vedras		Portugal	2560-280
58	Research Site	Moscow		Russian Federation	119435
59	Research Site	Moscow		Russian Federation	121467
60	Research Site	Novosibirsk		Russian Federation	630091
61	Research Site	Saint Petersburg		Russian Federation	197022
62	Research Site	Ufa		Russian Federation	450083
63	Research Site	Zaragoza	Aragón	Spain	50009
64	Research Site	Santander	Cantabria	Spain	39008
65	Research Site	Valladolid	Castilla León	Spain	47005
66	Research Site	Barcelona	Cataluña	Spain	08035
67	Research Site	Valencia	Comunidad Valenciana	Spain	46010
68	Research Site	Valencia	Comunidad Valenciana	Spain	46026
69	Research Site	Santiago de Compostela	Galicia	Spain	15706
70	Research Site	Madrid		Spain	28040
71	Research Site	Bad Zurzach		Switzerland	5330
72	Research Site	Biel		Switzerland	2502
73	Research Site	Geneve		Switzerland	1205
74	Research Site	Lugano		Switzerland	6903
75	Research Site	St Gallen		Switzerland	9007
76	Research Site	Zollikon		Switzerland	8702

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AmgenTrials clinical trials website

Publications

• Cheng S, Picard H, Zhang F, Eisele O, Mikol DD. Efficacy and safety of erenumab for migraine prevention: an overview. Japanese Journal of Headache. 2019; 45 : 493-505.
• Dodick DW, Ashina M, Brandes JL, Kudrow D, Lanteri-Minet M, Osipova V, Palmer K, Picard H, Mikol DD, Lenz RA. ARISE: A Phase 3 randomized trial of erenumab for episodic migraine. Cephalalgia. 2018 May;38(6):1026-1037. doi: 10.1177/0333102418759786. Epub 2018 Feb 22.
• Kawata AK, Ladd MK, Lipton RB, Buse DC, Bensink M, Shah S, Hareendran A, Mannix S, Mikol D. Reducing the physical, social, and emotional impact of episodic migraine: Results from erenumab STRIVE and ARISE phase III randomized trials. Headache. 2022 Feb;62(2):159-168. doi: 10.1111/head.14258. Epub 2022 Feb 8.
• Zhou Y, Zhang F, Starcevic Manning M, Hu Z, Hsu CP, Chen PW, Peng C, Loop B, Mytych DT, Paiva da Silva Lima G. Immunogenicity of erenumab: A pooled analysis of six placebo-controlled trials with long-term extensions. Cephalalgia. 2022 Jul;42(8):749-760. doi: 10.1177/03331024221075621. Epub 2022 Mar 10.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT02483585
• Other Study ID Numbers: 20120297; 2014-004463-20
• First Posted: Jun 29, 2015
• Last Update Posted: Jul 22, 2022
• Last Verified: Jul 1, 2022

• Keywords provided by Amgen: Migraine; Headache; Episodic; Prevention; Prophylaxis
• Additional relevant MeSH terms: Migraine Disorders; Erenumab

Study Results

Participant Flow

Recruitment Details	This study was conducted at 69 centers in Denmark, France, Greece, Portugal, Russia, Spain, Switzerland, and the USA. Participants were enrolled from 20 July 2015 to 19 April 2016.
Pre-assignment Detail	Participants were randomized 1:1 to placebo or erenumab 70 mg once a month (QM). Randomization was stratified by region (North America vs Other) and treatment status with migraine prophylactic medication (current, prior, or no prior or current migraine prophylactic medication treatment).

Arm/Group Title	Placebo	Erenumab 70 mg QM
Arm/Group Description	Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. At week 12 participants began treatment with erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.	Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. Participants continued to receive erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.
Period Title: Double-blind Treatment Phase
STARTED	291	286
Received Treatment	289	283
COMPLETED	275	271
NOT COMPLETED	16	15
Period Title: Double-blind Treatment Phase
STARTED	270	268
COMPLETED	243	243
NOT COMPLETED	27	25

Baseline Characteristics

Arm/Group Title	Placebo	Erenumab 70 mg QM	Total
Arm/Group Description	Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. At week 12 participants began treatment with erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.	Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. Participants continued to receive erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.	Total of all reporting groups
Overall Participants	291	286	577
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	42.2 (11.5)	42.3 (11.4)	42.3 (11.4)
Age, Customized (Count of Participants)
18 - 64 years	290 99.7%	283 99%	573 99.3%
65 - 74 years	1 0.3%	3 1%	4 0.7%
Sex: Female, Male (Count of Participants)
Female	247 84.9%	245 85.7%	492 85.3%
Male	44 15.1%	41 14.3%	85 14.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	34 11.7%	23 8%	57 9.9%
Not Hispanic or Latino	257 88.3%	263 92%	520 90.1%
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%	2 0.7%	2 0.3%
Black or African American	27 9.3%	24 8.4%	51 8.8%
Multiple	2 0.7%	1 0.3%	3 0.5%
Native Hawaiian or Other Pacific Islander	1 0.3%	0 0%	1 0.2%
White	259 89%	259 90.6%	518 89.8%
Other	2 0.7%	0 0%	2 0.3%
Region (Count of Participants)
North America	170 58.4%	168 58.7%	338 58.6%
Other	121 41.6%	118 41.3%	239 41.4%
Treatment Status with Migraine Prophylactic Medication (Count of Participants)
Current migraine prophylactic medication treatment	18 6.2%	17 5.9%	35 6.1%
Prior migraine prophylactic treatment only	120 41.2%	119 41.6%	239 41.4%
No prior / current migraine prophylactic treatment	153 52.6%	150 52.4%	303 52.5%
Disease Duration of Migraine With or Without Aura (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	20.03 (12.08)	21.70 (12.62)	20.86 (12.37)
Monthly Migraine Days (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	8.38 (2.60)	8.14 (2.65)	8.26 (2.62)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Monthly Migraine Days at Week 12
Description	A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine with or without aura. The change from baseline in monthly migraine days was calculated as the number of migraine days during the last 4 weeks of the 12-week double-blind treatment phase - the number of migraine days during the 4-week baseline phase.
Time Frame	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase

Outcome Measure Data

Analysis Population Description

The analysis was conducted in the efficacy analysis set which includes participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in monthly migraine days in the double-blind treatment phase.

Arm/Group Title	Placebo	Erenumab 70 mg QM
Arm/Group Description	Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. At week 12 participants began treatment with erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.	Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. Participants continued to receive erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.
Measure Participants	288	282
Least Squares Mean (Standard Error) [migraine days / month]	-1.84 (0.21)	-2.88 (0.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab 70 mg QM
	Comments	The primary endpoint was analyzed using a linear mixed effects model including treatment group, baseline value, stratification factors (region and prior/current treatment with migraine prophylactic medication), scheduled visit, and the interaction of treatment group with scheduled visit.
	Type of Statistical Test	Superiority
	Comments	A sequential testing procedure, specifically, the hierarchical gate-keeping procedures and Hochberg method, was used to maintain the 2-sided study-wise type I error at 0.05 between the primary and efficacy secondary endpoints.
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	Generalized Linear Mixed Model
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.04
	Confidence Interval	(2-Sided) 95%; -1.61 to -0.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days at Week 12
Description	A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine without aura or a migraine with aura. Monthly migraine days were calculated as the number of migraine days in the 4-week baseline phase and during the last 4 weeks of double-blind treatment. At least a 50% reduction from baseline in monthly migraine days was determined if the change in monthly migraine days from the 4-week baseline phase to the last 4 weeks of the 12-week double-blind treatment phase * 100 / baseline monthly migraine days was less than or equal to -50%.
Time Frame	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase

Outcome Measure Data

Analysis Population Description

The analysis was conducted in the efficacy analysis set which includes participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in monthly migraine days in the double-blind treatment phase. Participants with missing data at week 12 were counted as non-responders.

Arm/Group Title	Placebo	Erenumab 70 mg QM
Arm/Group Description	Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. At week 12 participants began treatment with erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.	Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. Participants continued to receive erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.
Measure Participants	288	282
Number [percentage of participants]	29.5 10.1%	39.7 13.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab 70 mg QM
	Comments	Analyzed using a Cochran-Mantel-Haenszel (CMH) test after the missing data were imputed as nonresponse, stratified by stratification factors (region and prior/current treatment with migraine prophylactic medication).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.59
	Confidence Interval	(2-Sided) 95%; 1.12 to 2.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days at Week 12
Description	Monthly acute migraine-specific medication treatment days is the number of days on which migraine specific medications were used between monthly doses of study drug. Migraine-specific medications includes two categories of medications: triptan-based migraine medications and ergotamine-based migraine medications. The change from baseline in monthly acute migraine-specific treatment days was calculated as the number of migraine-specific treatment days during the last 4 weeks of the 12-week double-blind treatment phase - the number of migraine-specific treatment days during the 4-week baseline phase.
Time Frame	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase

Outcome Measure Data

Analysis Population Description

The analysis was conducted in the efficacy analysis set which includes participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in monthly acute migraine-specific treatment days in the double-blind treatment phase.

Arm/Group Title	Placebo	Erenumab 70 mg QM
Arm/Group Description	Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. At week 12 participants began treatment with erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.	Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. Participants continued to receive erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.
Measure Participants	288	282
Least Squares Mean (Standard Error) [acute migraine treatment days / month]	-0.62 (0.14)	-1.21 (0.14)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab 70 mg QM
	Comments	Analyzed using a linear mixed effects model including treatment group, baseline value, stratification factors (region and prior/current treatment with migraine prophylactic medication), scheduled visit, and the interaction of treatment group with scheduled visit.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Generalized Linear Mixed Model
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.59
	Confidence Interval	(2-Sided) 95%; -0.96 to -0.21
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants With at Least a 5-point Reduction From Baseline in Average Impact on Everyday Activities Domain Score Measured by MPFID at Week 12
Description	The Migraine Physical Function Impact Diary (MPFID) is a self-administered 13-item instrument measuring physical functioning. It has two domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and one stand-alone global question. Participants completed the MPFID daily in an electronic diary based on the past 24 hours. Participants responded to each item on a 5-point scale, with difficulty items ranging from "Without any difficulty" (1) to "Unable to do" (5) and frequency items ranging from "None of the time" (1) to "All of the time" (5). For each domain, the scores were calculated as the sum of the responses and rescaled to 0 - 100, with higher scores representing greater impact of migraine. Achievement of at least a 5 point reduction from baseline in the monthly average domain score was calculated as (monthly average domain score during the last 4 weeks of the 12-week double-blind treatment phase - baseline monthly average domain score) was ≤ -5.
Time Frame	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase

Outcome Measure Data

Analysis Population Description

The analysis was conducted in the efficacy analysis set including participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in MPFID average impact on everyday activities domain score in the double-blind treatment phase. Participants with missing post-baseline data were counted as non-responders.

Arm/Group Title	Placebo	Erenumab 70 mg QM
Arm/Group Description	Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. At week 12 participants began treatment with erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.	Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. Participants continued to receive erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.
Measure Participants	288	282
Number [percentage of participants]	35.8 12.3%	40.4 14.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab 70 mg QM
	Comments	Analyzed using a Cochran-Mantel-Haenszel (CMH) test after the missing data were imputed as nonresponse, stratified by stratification factors (region and prior/current treatment with migraine prophylactic medication).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.26
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants With at Least a 5-Point Reduction From Baseline in Average Impact on Physical Impairment Domain Score Measured by MPFID at Week 12
Description	The Migraine Physical Function Impact Diary (MPFID) is a self-administered 13-item instrument measuring physical functioning. It has two domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and one stand-alone global question. Participants completed the MPFID daily in an electronic diary based on the past 24 hours. Participants responded to each item on a 5-point scale, with difficulty items ranging from "Without any difficulty" (1) to "Unable to do" (5) and frequency items ranging from "None of the time" (1) to "All of the time" (5). For each domain, the scores were calculated as the sum of the responses and rescaled to 0 - 100, with higher scores representing greater impact of migraine. Achievement of at least a 5 point reduction from baseline in the monthly average domain score was calculated as (monthly average domain score during the last 4 weeks of the 12-week double-blind treatment phase - baseline monthly average domain score) was ≤ -5.
Time Frame	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase

Outcome Measure Data

Analysis Population Description

The analysis was conducted in the efficacy analysis set including participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in MPFID average impact on physical impairment domain score in the double-blind treatment phase. Participants with missing post-baseline data were counted as non-responders.

Arm/Group Title	Placebo	Erenumab 70 mg QM
Arm/Group Description	Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. At week 12 participants began treatment with erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.	Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. Participants continued to receive erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.
Measure Participants	288	282
Number [percentage of participants]	27.1 9.3%	33.0 11.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Erenumab 70 mg QM
	Comments	Analyzed using a Cochran-Mantel-Haenszel (CMH) test after the missing data were imputed as nonresponse, stratified by stratification factors (region and prior/current treatment with migraine prophylactic medication).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 95%; 0.92 to 1.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Number of Participants With Adverse Events
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.
Time Frame	From first dose of study drug up to 12 weeks after the last dose. The double-blind treatment phase was 12 weeks and the open-label treatment phase was 28 weeks.

Outcome Measure Data

Analysis Population Description

For the double-blind treatment phase adverse events were analyzed for all randomized participants who received at least one dose of study drug. For the open-label treatment phase adverse events were analyzed for all participants who received at least one dose of study drug in the open-label treatment phase.

Arm/Group Title	Double-blind Treatment Phase (12 Weeks): Placebo	Double-blind Treatment Phase (12 Weeks): Erenumab 70 mg QM	Open-label Treatment Phase (28 Weeks): Erenumab 70 mg QM
Arm/Group Description	Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.	Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.	Participants received erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 during the open-label treatment phase.
Measure Participants	289	283	538
Any adverse event	158 54.3%	136 47.6%	337 58.4%
Adverse event Grade ≥ 2	96 33%	72 25.2%	245 42.5%
Adverse event Grade ≥ 3	8 2.7%	6 2.1%	34 5.9%
Adverse event Grade ≥ 4	0 0%	0 0%	2 0.3%
Serious adverse events	5 1.7%	3 1%	15 2.6%
AE leading to discontinuation of study drug	1 0.3%	5 1.7%	13 2.3%
Fatal adverse events	0 0%	0 0%	0 0%

7. Secondary Outcome

Title	Number of Participants Who Developed Antibodies to Erenumab
Description	Blood samples were first tested in an electrochemiluminescence (ECL)-based bridging immunoassay to detect anti-drug antibodies (ADA) against erenumab. Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based bioassay to determine neutralizing activity against erenumab (Neutralizing Antibody Assay). Developing antibody incidence indicates participants with a negative or no result at baseline and a positive result at any time post-baseline. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies. Transient indicates a negative result at the participant's last time point tested, for those participants with a positive binding/neutralizing result post-baseline.
Time Frame	Baseline (the period prior to the first dose erenumab 70 mg) and post-baseline (the period after the first dose of erenumab 70 mg until 12 weeks after last dose, up to 48 weeks total)

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of erenumab and with post-baseline data are included in the analysis.

Arm/Group Title	Placebo	Erenumab 70 mg QM
Arm/Group Description	Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. At week 12 participants began treatment with erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.	Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase. Participants continued to receive erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 in the 28-week open-label treatment phase.
Measure Participants	269	279
Binding antibody positive	25 8.6%	24 8.4%
-Transient binding antibody positive	10 3.4%	11 3.8%
Neutralizing antibody positive	0 0%	2 0.7%
-Transient neutralizing antibody positive	0 0%	2 0.7%

Adverse Events

Time Frame	From first dose of study drug up to 12 weeks after the last dose. The double-blind treatment phase was 12 weeks and the open-label treatment phase was 28 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	Double-blind Treatment Phase (12 Weeks): Placebo		Double-blind Treatment Phase (12 Weeks): Erenumab 70 mg QM		Open-label Treatment Phase (28 Weeks): Erenumab 70 mg QM
Arm/Group Description	Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection in the double-blind treatment phase.		Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection the double-blind treatment phase.		Participants received erenumab 70 mg administered by subcutaneous injection at weeks 12, 16, 20, 24, 28, 32, and 36 during the open-label treatment phase
All Cause Mortality
	Double-blind Treatment Phase (12 Weeks): Placebo		Double-blind Treatment Phase (12 Weeks): Erenumab 70 mg QM		Open-label Treatment Phase (28 Weeks): Erenumab 70 mg QM
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Double-blind Treatment Phase (12 Weeks): Placebo		Double-blind Treatment Phase (12 Weeks): Erenumab 70 mg QM		Open-label Treatment Phase (28 Weeks): Erenumab 70 mg QM
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/289 (1.7%)		3/283 (1.1%)		15/538 (2.8%)
Cardiac disorders
Atrial fibrillation	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Myocardial ischaemia	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Eye disorders
Iridocyclitis	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Visual acuity reduced	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Gastrointestinal disorders
Abdominal pain lower	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Hepatobiliary disorders
Cholecystitis acute	1/289 (0.3%)		0/283 (0%)		0/538 (0%)
Immune system disorders
Hypersensitivity	1/289 (0.3%)		0/283 (0%)		0/538 (0%)
Infections and infestations
Pneumococcal bacteraemia	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Pneumonia	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Post procedural infection	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Tooth abscess	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Urinary tract infection	0/289 (0%)		1/283 (0.4%)		0/538 (0%)
Injury, poisoning and procedural complications
Ligament rupture	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Post procedural pulmonary embolism	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Metabolism and nutrition disorders
Hyponatraemia	1/289 (0.3%)		0/283 (0%)		0/538 (0%)
Musculoskeletal and connective tissue disorders
Flank pain	1/289 (0.3%)		0/283 (0%)		0/538 (0%)
Intervertebral disc protrusion	0/289 (0%)		1/283 (0.4%)		0/538 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Papillary thyroid cancer	0/289 (0%)		0/283 (0%)		2/538 (0.4%)
Uterine leiomyoma	1/289 (0.3%)		0/283 (0%)		1/538 (0.2%)
Nervous system disorders
Migraine	1/289 (0.3%)		1/283 (0.4%)		0/538 (0%)
Syncope	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Psychiatric disorders
Depression	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Reproductive system and breast disorders
Endometriosis	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Laryngeal haematoma	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Skin and subcutaneous tissue disorders
Urticaria	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Surgical and medical procedures
Nasal septal operation	0/289 (0%)		0/283 (0%)		1/538 (0.2%)
Other (Not Including Serious) Adverse Events
	Double-blind Treatment Phase (12 Weeks): Placebo		Double-blind Treatment Phase (12 Weeks): Erenumab 70 mg QM		Open-label Treatment Phase (28 Weeks): Erenumab 70 mg QM
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	46/289 (15.9%)		54/283 (19.1%)		140/538 (26%)
General disorders
Injection site pain	12/289 (4.2%)		17/283 (6%)		30/538 (5.6%)
Infections and infestations
Upper respiratory tract infection	14/289 (4.8%)		18/283 (6.4%)		41/538 (7.6%)
Viral upper respiratory tract infection	17/289 (5.9%)		17/283 (6%)		53/538 (9.9%)
Nervous system disorders
Migraine	7/289 (2.4%)		5/283 (1.8%)		28/538 (5.2%)

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.