Efficacy and Safety of Erenumab in Pediatric Participants With Episodic Migraine

Study Overview
=================
Brief Summary
-----------------
This study will evaluate the efficacy and safety of erenumab in migraine prevention in children (6 to <12 years) and adolescents (12 to <18 years) with episodic migraine. The study hypothesis is that in pediatric participants with episodic migraine, the combined erenumab dose group has a greater reduction from baseline to week 9 through week 12 (month 3) in monthly migraine days (MMDs) when compared with placebo in the double-blind treatment phase (DBTP).

Detailed Description
-----------------
This study is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of erenumab in migraine prevention in children (6 to <12 years) and adolescents (12 to <18 years) with episodic migraine. The trial consists of four phases: screening (up to 3 weeks of initial screening and a 4-week prospective baseline phase); the DBTP (24 weeks for Group 1 participants; 12-weeks for Group 2 participants) in which participants receive placebo or Erenumab dose 1, dose 2 or dose 3 (based on participant's body weight) via subcutaneous injection once a month; the optional dose level blinded extension phase (40 weeks), in which all participants are assigned to receive dose 1, dose 2 or dose 3 of Erenumab; and a 12 weeks safety follow-up phase (16 weeks after the last dose of investigational drug). The study intends to enroll 456 participants (376 adolescents and up to 80 children).

Official Title
-----------------
A Phase 3, Randomized, Double-blind,Placebo-controlled, Parallel-group Study to Evaluate the Efficacy and Safety of Erenumab in Children (6 to < 12 Years) and Adolescents (12 to < 18 Years) With Episodic Migraine (OASIS PEDIATRIC [EM])

Conditions
-----------------
Migraine

Intervention / Treatment
-----------------
* Drug: Erenumab Dose 1
* Drug: Erenumab Dose 2
* Drug: Erenumab Dose 3
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Children (6 to less than 12 years of age) or adolescent (12 to less than 18 years of age) at the time of signing, if developmentally appropriate, the formal assent to participate to the study. Participant's parent or legal representative has provided written informed consent before initiation of any study-specific activities/procedures. History of migraine (with or without aura) for greater than or equal to 12 months before screening according to the IHS Classification ICHD-3 (Headache Classification Committee of the International Headache Society, 2013) based on medical records and/or participant self-report or parents' or legal representative's report. The following ICHD-3 specifications for pediatric migraine (participants aged less than 18 years), should be considered for the diagnosis of migraine: Attacks may last 2 to 72 hours. Migraine headache is more often bilateral than in adults; unilateral pain usually emerges in late adolescence or early adult life. Migraine headache is usually frontotemporal. Occipital headache in children is rare and calls for diagnostic caution. A subset of otherwise typical participants have facial location of pain, which is called 'facial migraine' in the literature; there is no evidence that these participants form a separate subgroup of migraine participants. In young children, photophobia and phonophobia may be inferred from their behavior. History of less than 15 headache days per month of which greater than or equal to 4 headache days were assessed by the participant as migraine days in each of the 3 months prior to screening (refer to Section 5.6 for definition of migraine day). Criteria to be assessed prospectively during the 4-week baseline phase and confirmed before randomizing the participant into the DBTP: Migraine frequency: greater than or equal 4 and less than 15 migraine days based on the eDiary data during the last 28 days of the baseline phase if greater than 28 days in duration Headache frequency: less than 15 headache days based on the eDiary data during the last 28 days of the baseline phase if greater than 28 days in duration. Demonstrated at least 80% compliance with the eDiary based on the last 28 days of the baseline period, if greater than 28 days in duration (eg, completing eDiary items for at least 23 out of the last 28 days of the baseline phase). Exclusion Criteria • History of cluster headache or hemiplegic migraine headache. No therapeutic response with greater than 2 of the following 10 medication categories for prophylactic treatment of migraine after an adequate therapeutic trial. These medication categories are: Category 1: beta blockers (eg, propranolol, atenolol, bisoprolol, metoprolol, nadolol, nebivolol, pindolol, timolol) Category 2: tricyclic antidepressants (eg, amitriptyline, nortriptyline, protriptyline) Category 3: topiramate Category 4: divalproex sodium, sodium valproate Category 5: serotonin-norepinephrine reuptake inhibitors (eg, venlafaxine, desvenlafaxine, duloxetine, milnacipran) Category 6: cyproheptadine Category 7: flunarizine, cinnarizine Category 8: botulinum toxin Category 9: lisinopril/candesartan Category 10: medications targeting the CGRP pathway. No therapeutic response is defined as no reduction in headache frequency, duration, or severity after administration of the medication for at least 6 weeks at the generally-accepted therapeutic dose(s) based on the investigator's assessment. The following scenarios do not constitute lack of therapeutic response: Lack of sustained response to a medication. Partial, suboptimal response to a medication. Failure to tolerate a therapeutic dose. Evidence of drug or alcohol abuse or dependence within 12 months before screening, based on medical records, participant self-report, or positive urine drug test performed during screening (with the exception of prescribed medications such as opioids or barbiturates). Human immunodeficiency virus (HIV) infection by history. History of seizure disorder or other significant neurological disorder other than migraine. Note: a single childhood febrile seizure is not exclusionary. History of major psychiatric disorder (such as schizophrenia, schizoaffective disorder, bipolar disorder, obsessive-compulsive disorder, or pervasive developmental disorder), or current evidence of major depressive disorder based on a patient health questionnaire-9 modified for adolescents (PHQ-A) score greater than or equal to 10 at screening. Participants with anxiety disorder and/or mild major depressive disorder (with PHQ-A score ≤ 9) are permitted in the study if they are considered by the investigator to be stable and are taking no more than 1 medication for each disorder. Participant must have been on a stable dose within the 3 months before the start of the baseline phase. Use of prohibited medication within 1 month before the start of the baseline phase and/or during the baseline phase. Use of prohibited devices (such as stimulation devices) or procedures (such as acupuncture, biofeedback, relaxation techniques, or psychotherapy) with the goal of preventing migraines, within 3 months before the start of the baseline phase and/or during the baseline phase. Participants receiving Cognitive Behavioral Therapy (CBT) are excluded unless they are on a stable, maintenance phase of a CBT program for migraine for at least 3 months before the start of the baseline phase. Participants undergoing CBT are considered on a stable, maintenance phase if they have undergone greater than or equal 6 weekly or biweekly sessions of CBT administered by adequately trained psychologists and who, for at least 3 months before the start of the baseline phase, only follow booster CBT sessions at a monthly, bimonthly or quarterly frequency. Note: Participants who have discontinued CBT within 3 months prior to the start of the baseline phase are eligible for the study provided that there is evidence of CBT failure/lack of efficacy prior to initial screening (per medical records or investigator's assessment). Received botulinum toxin in the head and/or neck region within 4 months before the start of the baseline phase or during the baseline phase. Received medication targeting the CGRP pathway within 4 months before the start of the baseline phase or during the baseline phase. Taken the following for any indication in any month during the 2 months before the start of the baseline phase, or during the baseline phase: Ergotamines or triptans on greater than or equal 10 days per month. Simple analgesics (nonsteroidal anti-inflammatory drugs [NSAIDs], acetaminophen) on greater than or equal 15 days per month. Opioid or butalbital-containing analgesics on greater than or equal 4 days per month. Currently receiving treatment in another investigational device or drug study, or less than 90 days since ending treatment on another investigational device or drug study(ies). Other investigational procedures while participating in this study are excluded. Participant has clinically significant vital signs, laboratory results, or ECG abnormality during screening that, in the opinion of the investigator, could pose a risk to participant safety or interfere with the study evaluation. Hepatic disease by history or total bilirubin (TBL) greater than or equal 2.0 x upper limit of normal (ULN) or alanine transaminase (ALT) or aspartate aminotransferase (AST) greater than or equal 3.0 x ULN, as assessed by the central laboratory at initial screening. Female participant is pregnant or breastfeeding or planning to become pregnant or breastfeed during the study and for an additional 16 weeks after the last dose of investigational product. (Females of childbearing potential should only be included in the study after a confirmed menstrual period and a negative highly sensitive urine and serum pregnancy test.) Female participants of childbearing potential unwilling to use an acceptable method of effective contraception during treatment and for an additional 16 weeks after the last dose of investigational product. Participant has known sensitivity to any of the products or components to be administered during dosing. Participant likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the participant's legal representative and investigator's knowledge. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to participant safety or interfere with the study evaluation, procedures or completion.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose level 1<br>Participants will be randomized to one of two doses determined by their body weight at Day 1. Participants who enrolled under the original protocol or protocol amendment 1 will be identified as group 1. Those enrolled under protocol amendment 2 will be identified as group 2. | Drug: Erenumab Dose 1<br>* Participants in the low body-weight group at day 1 and who are randomized to Dose Level 1 will receive this dose.<br>* Other names: Aimovig®;Drug: Erenumab Dose 2<br>* Participants in the low body-weight group at day 1 who are randomized to Dose Level 2 and subjects in the high body-weight group at day 1 who are randomized to Dose Level 1 will receive this dose.<br>* Other names: Aimovig®;|
| Experimental: Dose level 2<br>Participants will be randomized to one of two doses determined by their body weight at Day 1. Participants who enrolled under the original protocol or protocol amendment 1 will be identified as group 1. Those enrolled under protocol amendment 2 will be identified as group 2. | Drug: Erenumab Dose 2<br>* Participants in the low body-weight group at day 1 who are randomized to Dose Level 2 and subjects in the high body-weight group at day 1 who are randomized to Dose Level 1 will receive this dose.<br>* Other names: Aimovig®;Drug: Erenumab Dose 3<br>* Participants in the high body-weight group at day 1 who are randomized to Dose Level 2 will receive this dose.<br>* Other names: Aimovig®;|
| Placebo Comparator: Placebo<br>Participants will be randomized to a placebo comparator. | Other: Placebo<br>* Placebo matching dose for erenumab dose 1, 2 and 3.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in MMDs | To evaluate the effect of erenumab compared with placebo on the change in MMDs from baseline to week 9 through week 12 (month 3) of the double-blind treatment period (DBTP). | Baseline through week 12 of the double blind treatment phase | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in monthly headache days from baseline | To evaluate the effect of erenumab compared with placebo on the change from baseline in monthly headache days to week 9 through week 12 (month 3) of the DBTP | Baseline through week 12 of the double blind treatment phase | 
| Proportion of participants with at least 50% reduction in MMDs from baseline | To evaluate the effect of erenumab compared with placebo on the proportion of participants with at least 50% reduction in MMDs from baseline to week 9 through week 12 (month 3) of the DBTP | Baseline through week 12 of the double blind treatment phase | 
| Change in MMDs from baseline to the average of the first 3 months | To evaluate the effect of erenumab compared with placebo on the change in MMDs from baseline to the average of the first 3 months (week 1 through week 12) of the DBTP | Baseline through week 12 of the double blind treatment phase | 
| Change in monthly average severity of migraine attacks from baseline (measured with a visual analogue scale) | To evaluate the effect of erenumab compared with placebo on the change from baseline in monthly average severity of migraine attacks to week 9 through week 12 (month 3) of the DBTP. This will be measured in a daily electronic diary (eDiary) with a visual analogue scale. | Baseline through week 12 of the double blind treatment phase | 
| Change from baseline in migraine-related disability and productivity | To evaluate the effect of erenumab compared with placebo on the change from baseline in migraine-related disability and productivity as measured by the modified PedMIDAS to week 9 through week 12 (month 3) of the DBTP. | Baseline through week 12 of the double blind treatment phase | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Migraine, Headache, Prevention, Pediatric, Episodic Migraine