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

Migraine Clinical Trial

Official title:

A Phase 2, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of AMG 334 in Migraine Prevention

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01952574
• Other study ID #: 20120178
• Secondary ID: 2012-005331-90
• Status: Completed
• Phase: Phase 2
• Start date: August 6, 2013
• Est. completion date: November 12, 2019

Study information

• Verified date: October 2022
• Source: Amgen
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

A study to evaluate the effect of erenumab compared to placebo on the change from baseline in monthly migraine days in participants with episodic migraine.

Description:

The study is composed of an initial screening phase (up to 3 weeks), a 4-week baseline phase, a 12-week double-blind treatment phase (DBTP), an open-label treatment phase (OLTP) for up to 256 weeks, and an 8-week safety follow-up (12 weeks after the last dose of investigational product [IP]).

In the DBTP participants were to be randomized in a 3:2:2:2 ratio to placebo, erenumab 7 mg, erenumab 21 mg, or erenumab 70 mg.

During the open-label treatment phase, participants were to receive erenumab 70 mg QM from week 12 to week 264. After implementation of Protocol Amendment 3 (07 April 2016), participants remaining in the OLTP increased their dose to erenumab 140 mg QM up to week 264. The safety follow-up increased from an 8-week safety follow-up to a 12-week safety follow-up (16 weeks after the last dose of investigational product).

During the OLTP participants enrolled at sites in the United States could enroll in an optional clinical home use (CHU) substudy, per a country-specific protocol amendment dated 20 June 2016. Participants in the CHU substudy were to be randomized 1:1 into 1 of 2 treatment groups: erenumab 140 mg using a prefilled syringe or erenumab 140 mg using an autoinjector/pen. Day 1 of the CHU substudy corresponded with any OLTP study visit up through Week 256, as long as the participant had received at least 2 doses of erenumab 140 mg. During the CHU substudy, participants initially self-administered IP under site supervision on substudy day 1, and then self-administered IP at home on substudy days 29 and 57.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 483
• Est. completion date: November 12, 2019
• Est. primary completion date: September 25, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• History of migraine for more than12 months prior to screening

• Migraine frequency: = 4 and = 14 migraine days per month in each of the 3 months prior to screening and during baseline phase

• Headache frequency: < 15 headache days per month (with > 50% of the headache days being migraine days) in each of the 3 months prior to screening and during baseline phase

• Demonstrated at least 80% compliance with the eDiary during baseline phase

Exclusion Criteria:

• Older than 50 years of age at migraine onset

• History of cluster headache or basilar or hemiplegic migraine headache

• Unable to differentiate migraine from other headaches

• No therapeutic response with > 2 of the following eight medication categories for prophylactic treatment of migraine after an adequate therapeutic trial. Medication categories are:

• Category 1: Divalproex sodium, sodium valproate

• Category 2: Topiramate

• Category 3: Beta blockers (for example: atenolol, bisoprolol, metoprolol, nadolol, nebivolol, pindolol, propranolol, timolol)

• Category 4: Tricyclic antidepressants (for example: amitriptyline, nortriptyline, protriptyline)

• Category 5: Venlafaxine, desvenlafaxine, duloxetine, milnacipran

• Category 6: Flunarizine, verapamil

• Category 7: Lisinopril, candesartan

• Category 8: Butterbur, feverfew, magnesium (= 600 mg/day), riboflavin (= 100 mg/day)

• Overuse of acute migraine medications in any month during the 3 months prior to screening or during screening

Related Conditions & MeSH terms

• Migraine
• Migraine Disorders

Intervention

Drug:
• Erenumab
Administered by study site staff once a month (QM) as a subcutaneous injection
• Placebo
Administered by study site staff once a month (QM) as a subcutaneous injection
• Erenumab PFS
Erenumab supplied in a single-use prefilled syringe for self-administration in the CHU substudy
• Erenumab AI/Pen
Erenumab supplied in a single-use autoinjector/pen for self-administration in the CHU substudy

Locations

Country	Name	City	State
Canada	Research Site	Montreal	Quebec
Canada	Research Site	Toronto	Ontario
Denmark	Research Site	Aarhus C
Denmark	Research Site	Glostrup
Finland	Research Site	Helsinki
Finland	Research Site	Mikkeli
Finland	Research Site	Oulu
Finland	Research Site	Tampere
Finland	Research Site	Turku
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Bochum
Germany	Research Site	Essen
Germany	Research Site	Hamburg
Germany	Research Site	Leipzig
Norway	Research Site	Ålesund
Norway	Research Site	Hamar
Norway	Research Site	Sandvika
Norway	Research Site	Stavanger
Sweden	Research Site	Falköping
Sweden	Research Site	Lund
Sweden	Research Site	Stockholm
Sweden	Research Site	Stockholm
Sweden	Research Site	Vällingby
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Arlington	Texas
United States	Research Site	Austin	Texas
United States	Research Site	Bradenton	Florida
United States	Research Site	Dallas	Texas
United States	Research Site	Dallas	Texas
United States	Research Site	Danbury	Connecticut
United States	Research Site	Decatur	Georgia
United States	Research Site	Fairfield	Connecticut
United States	Research Site	Falls Church	Virginia
United States	Research Site	Greensboro	North Carolina
United States	Research Site	Houston	Texas
United States	Research Site	Kalamazoo	Michigan
United States	Research Site	Lexington	Kentucky
United States	Research Site	Long Beach	California
United States	Research Site	Louisville	Kentucky
United States	Research Site	Melbourne	Florida
United States	Research Site	Nashville	Tennessee
United States	Research Site	National City	California
United States	Research Site	Newport Beach	California
United States	Research Site	Palm Beach Gardens	Florida
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Phoenix	Arizona
United States	Research Site	Plymouth	Minnesota
United States	Research Site	Raleigh	North Carolina
United States	Research Site	Rochester	New York
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Salt Lake City	Utah
United States	Research Site	Salt Lake City	Utah
United States	Research Site	San Francisco	California
United States	Research Site	Santa Monica	California
United States	Research Site	Sherman Oaks	California
United States	Research Site	Southfield	Michigan
United States	Research Site	Spring Valley	California
United States	Research Site	Springfield	Missouri
United States	Research Site	Stamford	Connecticut
United States	Research Site	Virginia Beach	Virginia
United States	Research Site	Watertown	Massachusetts
United States	Research Site	West Palm Beach	Florida
United States	Research Site	Wichita	Kansas
United States	Research Site	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Amgen

Countries where clinical trial is conducted

United States,  Canada,  Denmark,  Finland,  Germany,  Norway,  Sweden, 

References & Publications (9)

Ashina M, Dodick D, Goadsby PJ, Reuter U, Silberstein S, Zhang F, Gage JR, Cheng S, Mikol DD, Lenz RA. Erenumab (AMG 334) in episodic migraine: Interim analysis of an ongoing open-label study. Neurology. 2017 Sep 19;89(12):1237-1243. doi: 10.1212/WNL.0000000000004391. Epub 2017 Aug 23. — View Citation

Ashina M, Goadsby PJ, Reuter U, Silberstein S, Dodick D, Rippon GA, Klatt J, Xue F, Chia V, Zhang F, Cheng S, Mikol DD. Long-term safety and tolerability of erenumab: Three-plus year results from a five-year open-label extension study in episodic migraine. Cephalalgia. 2019 Oct;39(11):1455-1464. doi: 10.1177/0333102419854082. Epub 2019 May 30. — View Citation

Ashina M, Goadsby PJ, Reuter U, Silberstein S, Dodick DW, Xue F, Zhang F, Paiva da Silva Lima G, Cheng S, Mikol DD. Long-term efficacy and safety of erenumab in migraine prevention: Results from a 5-year, open-label treatment phase of a randomized clinical trial. Eur J Neurol. 2021 May;28(5):1716-1725. doi: 10.1111/ene.14715. Epub 2021 Jan 20. — View Citation

Ashina M, Kudrow D, Reuter U, Dolezil D, Silberstein S, Tepper SJ, Xue F, Picard H, Zhang F, Wang A, Zhou Y, Hong F, Klatt J, Mikol DD. Long-term tolerability and nonvascular safety of erenumab, a novel calcitonin gene-related peptide receptor antagonist for prevention of migraine: A pooled analysis of four placebo-controlled trials with long-term extensions. Cephalalgia. 2019 Dec;39(14):1798-1808. doi: 10.1177/0333102419888222. Epub 2019 Nov 10. — View Citation

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.

Kudrow D, Pascual J, Winner PK, Dodick DW, Tepper SJ, Reuter U, Hong F, Klatt J, Zhang F, Cheng S, Picard H, Eisele O, Wang J, Latham JN, Mikol DD. Vascular safety of erenumab for migraine prevention. Neurology. 2020 Feb 4;94(5):e497-e510. doi: 10.1212/WNL.0000000000008743. Epub 2019 Dec 18. Erratum in: Neurology. 2020 Jun 9;94(23):1052. — View Citation

Sakai F, Takeshima T, Tatsuoka Y, Hirata K, Cheng S, Numachi Y, Peng C, Xue F, Mikol DD. Long-term efficacy and safety during open-label erenumab treatment in Japanese patients with episodic migraine. Headache. 2021 Apr;61(4):653-661. doi: 10.1111/head.14096. Epub 2021 Mar 25. — View Citation

Sun H, Dodick DW, Silberstein S, Goadsby PJ, Reuter U, Ashina M, Saper J, Cady R, Chon Y, Dietrich J, Lenz R. Safety and efficacy of AMG 334 for prevention of episodic migraine: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Apr;15(4):382-90. doi: 10.1016/S1474-4422(16)00019-3. Epub 2016 Feb 12. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Monthly Migraine Days at Week 12	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 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.	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase
Primary	CHU Substudy: Number of Participants Who Self-administered a Full Dose, Partial Dose, or No Dose of Erenumab	To assess participants ability to administer a full dose of erenumab in home-use at day 29 (week 4) and day 57 (week 8), site staff called participants and asked whether the participant administered a full, partial, or no dose of erenumab. A full dose means that the entire volume of both prefilled syringes or autoinjector/pens were injected. Discontinued prior to dosing day indicates participants who had discontinued the investigational product and did not attempt to self-administer on day 29 or 57.	CHU substudy day 29 (week 4) and day 57 (week 8)
Secondary	Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days at Week 12	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%.	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase
Secondary	Change From Baseline in Monthly Migraine Attacks at Week 12	A migraine attack is an episode of any qualified migraine headache or migraine specific medication intakes for aura only. A migraine attack that was interrupted by sleep or that temporarily remits and then recurs within 48 hours or an attack treated successfully with medication but that relapses within 48 hours was considered to be one attack.; The change from baseline in monthly migraine attacks was calculated as the number of migraine attacks during the last 4 weeks of the 12-week double-blind treatment phase - the number of migraine attacks during the 4-week baseline phase.	4-week baseline phase and the last 4 weeks of the 12-week double-blind treatment phase
Secondary	Number of Participants With Treatment-emergent Adverse Events in the Double-blind Treatment Phase	An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition and laboratory value changes that require treatment or adjustment in current therapy.; AEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03: Mild; asymptomatic or mild symptoms; Moderate; minimal, local or noninvasive intervention indicated; limiting daily activities; Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling; limiting self-care; Life-threatening consequences; urgent intervention indicated; Death related to AE; A serious adverse event is an AE that meets at least 1 of the following criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event	From first dose of study drug in the double-blind treatment phase until the first dose of study drug in the open-label treatment phase (12 weeks) or up to 12 weeks after last dose for participants who did not enter the open-label treatment phase.
Secondary	Number of Participants With Treatment-emergent Adverse Events in the Open-label Treatment Phase	An adverse event (AE) is any untoward medical occurrence in a clinical trial subject, including worsening of a pre-existing medical condition and laboratory value changes that require treatment or adjustment in current therapy.; AEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03: Mild; asymptomatic or mild symptoms; Moderate; minimal, local or noninvasive intervention indicated; limiting daily activities; Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling; limiting self-care; Life-threatening consequences; urgent intervention indicated; Death related to AE; A serious adverse event is an AE that meets at least 1 of the following criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event	From first dose in the open-label treatment phase up to 12 weeks (participants receiving 70 mg only) or 16 weeks (participants with dose increased to 140 mg) after the last dose; a maximum of 268 weeks.
Secondary	CHU Substudy: Number of Participants With Treatment-emergent Adverse Events During the CHU Substudy	AEs were graded using the CTCAE version 4.03: Mild; asymptomatic or mild symptoms; Moderate; minimal, local or noninvasive intervention indicated; limiting daily activities; Severe or medically significant but not immediately life-threatening; hospitalization indicated; disabling; limiting self-care; Life-threatening consequences; urgent intervention indicated; Death related to AE; A serious adverse event is an AE that meets at least 1 of the following criteria: fatal; life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; congenital anomaly/birth defect; other medically important serious event An adverse device effect is any AE related to the use of a medical device, including AEs resulting from insufficient or inadequate instructions for use, any malfunction of the device, or use error or from intentional misuse of the device.	From first dose in the CHU substudy to end of substudy (up to 12 weeks)
Secondary	Number of Participants Who Developed Anti-erenumab Antibodies During the Double-blind Treatment Phase	Two validated assays were used to detect the presence of anti-erenumab antibodies. First, an electrochemiluminescent bridging immunoassay was used to detect binding antibodies (screening assay) and confirm antibodies (confirmatory assay) capable of binding erenumab. Second, a cell-based bioassay was used to test positive binding antibody samples for neutralizing activity against erenumab.; Participants who developed anti-erenumab antibodies are participants who were negative or had no result at baseline but positive at any time postbaseline during the DBTP.; If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the participant was defined as positive for neutralizing antibodies.	12 weeks
Secondary	Number of Participants Who Developed Anti-erenumab Antibodies During the Open-label Treatment Phase	Two validated assays were used to detect the presence of anti-erenumab antibodies. First, an electrochemiluminescent bridging immunoassay was used to detect binding antibodies (screening assay) and confirm antibodies (confirmatory assay) capable of binding erenumab. Second, a cell-based bioassay was used to test positive binding antibody samples for neutralizing activity against erenumab.; Participants who developed anti-erenumab antibodies are participants who were negative prior to the first OLTP dose but positive at any time during the OLTP, or participants with no data prior to first dose in OLTP with any post-baseline positive results.; If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the participant was defined as positive for neutralizing antibodies.	From week 12 up to 12 weeks (participants receiving 70 mg only) or 16 weeks (participants with dose increased to 140 mg) after the last dose; maximum 268 weeks.

External Links

•   AmgenTrials clinical trials website