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 Chronic Migraine (OASIS PEDIATRIC [CM])

Trial ID: 2023-504928-26-00
Protocol: 20160354
Sponsor: Amgen Inc.

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Diseases & Conditions

Migraine

Objectives

The primary objective of this study is to evaluate the effect of erenumab compared with placebo on the change in monthly migraine days from baseline to week 9 through week 12 of the double-blind treatment phase in pediatric subjects with chronic migraine. This endpoint is clinically relevant as reduction in monthly migraine days represents a direct measure of disease burden and treatment efficacy in the pediatric population with chronic migraine.

The secondary objectives include:

• To evaluate the effect of erenumab compared with placebo on the change in monthly headache days from baseline to week 9 through week 12 of the double-blind treatment phase.

• To evaluate the effect of erenumab compared with placebo on the proportion of subjects with at least 50% reduction in monthly migraine days from baseline to week 9 through week 12 of the double-blind treatment phase.

• To evaluate the effect of erenumab compared with placebo on the change in monthly migraine days from baseline to the average of the first 3 months of the double-blind treatment phase.

• To evaluate the effect of erenumab compared with placebo on the change in monthly average severity of migraine attacks from baseline to week 9 through week 12 of the double-blind treatment phase.

• To evaluate the effect of erenumab compared with placebo on the change in migraine-related disability and productivity as measured by the modified Pediatric Migraine Disability Assessment from baseline to month 3 of the double-blind treatment phase.

Participants

This clinical trial enrolled a total of **176 participants** diagnosed with **chronic migraine**. The study population consisted of **children** aged 6 to less than 12 years and **adolescents** aged 12 to less than 18 years at the time of enrollment. Both **male and female** subjects were included in the trial. Participants were required to have a documented history of migraine, with or without aura, for at least 12 months prior to screening, according to the International Classification of Headache Disorders (ICHD-3) criteria. The trial population was selected based on specific migraine frequency criteria, requiring subjects to experience at least 15 headache days per month, of which at least 8 were assessed as migraine days, in each of the 3 months prior to screening. During the baseline phase, participants were required to demonstrate at least 8 migraine days and at least 15 headache days based on electronic diary (eDiary) data collected over the last 28 days. Additionally, subjects needed to show at least 80% compliance with eDiary completion during the baseline period. Written informed consent was obtained from the parent or legal representative of each participant, and developmentally appropriate formal assent was required from the subjects themselves. This trial involved a **vulnerable population** consisting of pediatric subjects.

Plans and Procedures

This is a phase 3, randomized, double-blind, placebo-controlled, parallel-group clinical trial designed to evaluate the efficacy and safety of **erenumab** in pediatric subjects with **chronic migraine**. The study population includes children aged 6 to less than 12 years and adolescents aged 12 to less than 18 years. The trial employs a **double-blind treatment phase** in which participants are randomized to receive either erenumab or **placebo**. The investigational medicinal product, erenumab, is a **solution for injection** administered via **subcutaneous use**, with a maximum daily dose of 140 mg and a maximum total dose of 2240 mg over a treatment period of up to 83 weeks. The placebo comparator is designed to match the active treatment in appearance and administration.

The primary objective of the trial is to evaluate the effect of erenumab compared with placebo on the change in **monthly migraine days** from baseline to week 9 through week 12 (month 3) of the double-blind treatment phase. The primary endpoint is specifically assessed in the target population of adolescent subjects aged 12 to less than 18 years diagnosed with chronic migraine. The treatment effect is estimated for all randomized subjects regardless of adherence to treatment, with treatment discontinuation considered as an **intercurrent event**. Secondary endpoints include change from baseline in monthly headache days, achievement of at least 50% reduction in monthly migraine days, change in monthly average severity of **migraine attacks**, and change in migraine-related disability and productivity as measured by the modified **PedMIDAS**.

Eligible participants must have a documented history of migraine with or without aura for at least 12 months prior to screening according to the **IHS Classification ICHD-3**. Subjects are required to have a history of at least 15 headache days per month, of which at least 8 days were assessed as migraine days, in each of the 3 months prior to screening. During the **baseline phase**, participants must demonstrate at least 8 migraine days and at least 15 headache days based on electronic diary (eDiary) data during the last 28 days. Compliance with the eDiary of at least 80% is required, meaning completion of diary entries for at least 23 out of the last 28 days of the baseline period. Written **informed consent** must be provided by the subject's parent or legal representative, and formal assent from the subject is required if developmentally appropriate.

The trial follows a structured sequence of study visits beginning with a **screening visit** during which eligibility criteria are assessed and informed consent is obtained. Following screening, participants enter a baseline phase during which they complete daily eDiary entries to establish baseline migraine and headache frequency. Upon meeting eligibility criteria and demonstrating adequate eDiary compliance, subjects are randomized into the double-blind treatment phase. During the double-blind treatment phase, participants attend regular **follow-up visits** for safety monitoring, efficacy assessments, and administration of study medication. The primary efficacy assessment period extends from week 9 through week 12 (month 3) of the double-blind treatment phase. Additional follow-up visits continue throughout the treatment period to evaluate secondary endpoints and monitor for adverse events. At the conclusion of the study, an **end-of-study visit** is conducted to perform final safety and efficacy assessments.

The estimated duration of participant involvement in the trial extends up to 83 weeks of treatment, with the overall trial duration spanning from the estimated recruitment start date of January 2, 2020, to the estimated end date of April 4, 2027. Conditions that may lead to **early termination** from the study include withdrawal of consent by the participant or legal representative, safety concerns as determined by the investigator, protocol violations, loss to follow-up, or administrative decisions by the sponsor. The trial design accounts for treatment discontinuation as an intercurrent event, and analysis is conducted using an intention-to-treat approach that includes all randomized subjects regardless of treatment adherence or completion status.

Treatment

The experimental medicinal product in this clinical trial is **Erenumab**, also known by the sponsor product code **AMG 334**. Erenumab is a protein-based active substance manufactured by AMGEN INC. The investigational medicinal product is formulated as a **solution for injection** intended for **subcutaneous use**. The maximum daily dose administered is **140 mg**. The maximum total dose over the treatment period is **2240 mg**, with a maximum treatment duration of **83 weeks**. Erenumab is administered during the **double-blind treatment phase** of the study, where its efficacy is evaluated based on the change in **monthly migraine days** from baseline to week 9 through week 12 (month 3). The trial is conducted in pediatric and adolescent populations, specifically children aged 6 to less than 12 years and adolescents aged 12 to less than 18 years with **chronic migraine**.

The comparator treatment used in this study is **Placebo for AMG 334**. The placebo is administered to participants in the control group during the double-blind treatment phase to enable comparison with the experimental medication. The placebo formulation is designed to match the administration characteristics of the active treatment to maintain blinding integrity throughout the study. The Manufacturing and Importation Authorization number for both the experimental product and placebo is Amgen 108520F and Fisher MIA(IMP) 18693, ensuring standardized production and quality control for both treatment arms.

Efficacy

The primary efficacy parameter is the change from baseline in **monthly migraine days** (MMD) to week 9 through week 12 (month 3) of the double-blind treatment phase. The primary analysis focuses on the adolescent population aged 12 to less than 18 years diagnosed with **chronic migraine**. The summary measure is the difference between the mean of the primary endpoint for the combined erenumab dose group and placebo. All randomized subjects will be included in the analysis regardless of adherence to treatment.

Secondary efficacy parameters include the change from baseline in monthly headache days to week 9 through week 12 (month 3) of the double-blind treatment phase, achievement of at least 50% reduction in MMD from baseline to week 9 through week 12 (month 3), change from baseline in MMD to the average of the first 3 months (week 1 through week 12), change from baseline in monthly average severity of **migraine attacks** to week 9 through week 12 (month 3), and change from baseline in migraine-related disability and productivity as measured by the modified **PedMIDAS** to month 3 of the double-blind treatment phase. Efficacy data will be collected using an electronic diary (eDiary) throughout the baseline and treatment periods.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Children (6 to < 12 years of age) or adolescent (12 to < 18 years of age) at the time of signing, if developmentally appropriate, the formal assent to participate to the study.
Subject’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 ≥ 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 subject self-report or parents’ or legal representative’s report. The following ICHD-3 specifications for pediatric migraine (subjects aged < 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 subjects have facial location of pain, which is called ‘facial migraine’ in the literature; there is no evidence that these subjects form a separate subgroup of migraine subjects. •In young children, photophobia and phonophobia may be inferred from their behavior.
History of ≥ 15 headache days per month of which ≥ 8 headache days were assessed by the subject as migraine days per month in each of the 3 months prior to screening (refer to Section 5.6 for definition of headache day).
Migraine frequency: ≥ 8 migraine days based on the eDiary data during the last 28 days of the baseline phase if ≥ 28 days in duration.
Headache frequency of ≥ 15 headache days based on the eDiary data during the last 28 days of the baseline phase if ≥ 28 days in duration.
Demonstrated at least 80% compliance with the eDiary based on the last 28 days of the baseline period, if ≥ 28 days in duration (eg, completing eDiary items for at least 23 out of the last 28 days of the baseline phase).

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Exclusion Criteria

History of cluster headache or hemiplegic migraine headache.
Chronic migraine with continuous pain, in which the subject does not have any pain free periods (of any duration) during the 1 month prior to screening.
No therapeutic response with > 3 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.
Malignancy within 5 years before screening.
History of suicidal behavior or the subject is at risk of self-harm or harm to others as evidenced by endorsement of items 4 or 5 on the C-SSRS assessed at screening.
Evidence of drug or alcohol abuse or dependence within 12 months before screening, based on medical records, subject 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 (≥ 10 at screening for adolescents or based on medical judgement of the investigator for children). Subjects with anxiety disorder and/or mild major depressive disorder (with PHQ-A score ≤ 9 for adolescents or based on medical judgement of the investigator for children) 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. Subjects must have been on a stable dose within the 3 months before the start of the baseline phase.
Use of a prohibited medication within 15 days 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 (refer to Table 7-2 for the lists of these devices and procedures, and specific exclusion periods). Subjects 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. Subjects undergoing CBT are considered on a stable, maintenance phase if they have undergone ≥ 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.
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: •Opioid or butalbital-containing analgesics on ≥ 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.
Subject has clinically significant vital signs, laboratory results, or ECG abnormality during screening that, in the opinion of the investigator, could pose a risk to subject safety or interfere with the study evaluation.
Hepatic disease by history or total bilirubin (TBL) ≥ 2.0 x upper limit of normal (ULN) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 3.0 x ULN, as assessed by the central laboratory at initial screening.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	02 Jan 2020	9
Germany	Not Recruiting	02 Jan 2020	26
Hungary	Not Recruiting	02 Jan 2020	41
Italy	Not Recruiting	02 Jan 2020	20
Poland	Not Recruiting	02 Jan 2020	5