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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Migraine

Intervention / Treatment
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* Drug: Erenumab
* Drug: Placebo
* Drug: Erenumab PFS
* Drug: Erenumab AI/Pen


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In the DBTP participants were randomized to one of four arms. In the optional CHU substudy participants were randomized into one of two treatment groups.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection during the double-blind treatment phase. In the open-label treatment phase participants received 70 mg erenumab QM from week 12 to week 264 (last dose). After Protocol Amendment 3, participants still on study had their dose increased to 140 mg QM. | Drug: Erenumab<br>* Administered by study site staff once a month (QM) as a subcutaneous injection<br>* Other names: Aimovig™;Drug: Placebo<br>* Administered by study site staff once a month (QM) as a subcutaneous injection<br>|
| Experimental: Erenumab 7 mg QM<br>Participants received erenumab 7 mg on day 1 and at weeks 4 and 8 by subcutaneous injection during the double-blind treatment phase. In the open-label treatment phase participants received 70 mg erenumab QM from week 12 to week 264 (last dose). After Protocol Amendment 3, participants still on study had their dose increased to 140 mg QM. | Drug: Erenumab<br>* Administered by study site staff once a month (QM) as a subcutaneous injection<br>* Other names: Aimovig™;|
| Experimental: Erenumab 21 mg QM<br>Participants received erenumab 21 mg on day 1 and at weeks 4 and 8 by subcutaneous injection during the double-blind treatment phase. In the open-label treatment phase participants received 70 mg erenumab QM from week 12 to week 264 (last dose). After Protocol Amendment 3, participants still on study had their dose increased to 140 mg QM. | Drug: Erenumab<br>* Administered by study site staff once a month (QM) as a subcutaneous injection<br>* Other names: Aimovig™;|
| Experimental: Erenumab 70 mg QM<br>Participants received erenumab 70 mg on day 1 and at weeks 4 and 8 by subcutaneous injection during the double-blind treatment phase. In the open-label treatment phase participants received 70 mg erenumab QM from week 12 to week 264 (last dose). After Protocol Amendment 3, participants still on study had their dose increased to 140 mg QM. | Drug: Erenumab<br>* Administered by study site staff once a month (QM) as a subcutaneous injection<br>* Other names: Aimovig™;|
| Experimental: CHU Substudy: Erenumab 140 mg PFS<br>Participants in the open-label treatment phase in the United States randomized to self-administer 140 mg erenumab via two 70 mg injections using a prefilled syringe (PFS) on CHU substudy day 1 (under study site supervision), and at home on day 29 (week 4) and day 57 (week 8). | Drug: Erenumab PFS<br>* Erenumab supplied in a single-use prefilled syringe for self-administration in the CHU substudy<br>|
| Experimental: CHU Substudy: Erenumab 140 mg AI/Pen<br>Participants in the open-label treatment phase in the United States randomized to self-administer 140 mg erenumab via two 70 mg injections using an autoinjector/pen (AI)/pen) on CHU substudy day 1 (under study site supervision), and at home on day 29 (week 4) and day 57 (week 8). | Drug: Erenumab AI/Pen<br>* Erenumab supplied in a single-use autoinjector/pen for self-administration in the CHU substudy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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. | 
| 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. | 
| 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) | 
| 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 | 
| 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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migraine, headache, prevention, prophylaxis