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])

Trial ID: 2023-504930-23-00
Protocol: 20150125
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 (MMD) from baseline to week 9 through week 12 (month 3) of the double-blind treatment phase. This endpoint is clinically relevant as it directly measures the reduction in migraine frequency, a key indicator of therapeutic efficacy in pediatric patients with episodic 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 (month 3) of the double-blind treatment phase.

• To evaluate the effect of erenumab compared with placebo on the proportion of subjects achieving at least 50% reduction in MMD from baseline to week 9 through week 12 (month 3) of the double-blind treatment phase.

• To evaluate the effect of erenumab compared with placebo on the change in MMD from baseline to the average of the first 3 months (week 1 through week 12) 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 (month 3) 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 (PedMIDAS) from baseline to week 9 through week 12 (month 3) of the double-blind treatment phase.

Participants

The clinical trial enrolled a total of **212 participants** diagnosed with **episodic migraine** with or without aura. 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 for at least 12 months prior to screening, consistent with the International Classification of Headache Disorders, Third Edition (ICHD-3) criteria, with specific pediatric considerations applied. The trial population was selected based on migraine frequency, requiring subjects to experience at least 4 but fewer than 15 migraine days per month, and fewer than 15 total headache days per month during the baseline phase. Participants demonstrated adequate compliance with electronic diary completion during the baseline period. This study involved a **vulnerable population** due to the inclusion of pediatric subjects, with parental or legal representative consent obtained prior to study participation.

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 children aged 6 to less than 12 years and adolescents aged 12 to less than 18 years with **episodic migraine**. The investigational medicinal product erenumab is administered as a **solution for injection** via **subcutaneous use** using a **pre-filled syringe**, with a maximum daily dose of 140 mg and a maximum total dose of 2240 mg over a treatment period of 83 days. The comparator is a **placebo** for AMG 334. The trial commenced recruitment in December 2019 and is estimated to be completed by July 2027.

The primary objective of the trial is to evaluate the effect of erenumab compared with placebo on the change in **monthly migraine days** (MMD) from baseline to week 9 through week 12 (month 3) of the **double-blind treatment phase** (DBTP). Secondary objectives include assessing the change from baseline in monthly headache days, achievement of at least 50% reduction in MMD, change in MMD over the first 3 months, change in monthly average severity of migraine attacks, and change in migraine-related disability and productivity as measured by the **modified PedMIDAS**, all evaluated during the DBTP.

Eligible participants include children and adolescents with a history of migraine (with or without aura) for at least 12 months prior to screening according to the **IHS Classification ICHD-3**, with a history of fewer than 15 headache days per month, of which at least 4 were migraine days, in each of the 3 months prior to screening. During the baseline phase, participants must demonstrate a migraine frequency of at least 4 and fewer than 15 migraine days and a headache frequency of fewer than 15 headache days based on electronic diary (**eDiary**) data during the last 28 days. Participants must also demonstrate at least 80% compliance with the eDiary during the baseline period. Written informed consent must be provided by the parent or legal representative, and formal assent must be obtained from the child or adolescent if developmentally appropriate.

The trial involves a baseline phase during which participants complete an eDiary to record headache and migraine days, followed by the double-blind treatment phase lasting 12 weeks. Study visits include a screening visit to assess eligibility criteria, baseline assessments, and multiple follow-up visits during the DBTP to monitor efficacy and safety outcomes. The primary efficacy endpoint is assessed at week 9 through week 12 (month 3) of the DBTP. An end-of-study visit is conducted upon completion of the treatment phase. The expected duration of participant involvement is approximately 83 days of treatment plus the baseline and follow-up periods. Early termination from the study may occur if participants fail to meet eligibility criteria, withdraw consent, experience unacceptable adverse events, or fail to maintain adequate eDiary compliance.

Treatment

The experimental medication under investigation is **Erenumab**, also designated by the sponsor product code **AMG 334**. Erenumab is a protein-based therapeutic agent formulated as a **solution for injection** in a pre-filled syringe. The active substance is erenumab, classified as a protein of other origin. The medication is administered via the **subcutaneous route**. The maximum daily dose is **140 mg**, with a maximum total dose of **2240 mg** over the treatment period. The maximum treatment duration is **83 weeks**. The investigational medicinal product is manufactured by AMGEN INC and holds the European Medicinal Product number PRD527181 and European Substance number SUB183612. Manufacturing authorization is documented under MIA(IMP) 18693, 108520F.

The study includes a **placebo** comparator designated as Placebo for AMG 334. This placebo formulation is matched to the experimental medication to maintain blinding during the double-blind treatment phase. The placebo is administered according to the same schedule and route as the active treatment to ensure consistency in study procedures and to facilitate valid comparison of efficacy and safety outcomes between treatment groups. Manufacturing authorization for the placebo is also documented under MIA(IMP) 18693, 108520F.

Efficacy

The primary efficacy endpoint is the change from baseline in **monthly migraine days** to week 9 through week 12 (month 3) of the double-blind treatment phase. Secondary efficacy endpoints include the change from baseline in monthly headache days to week 9 through week 12 (month 3) of the double-blind treatment phase, the achievement of at least 50% reduction in **monthly migraine days** from baseline to week 9 through week 12 (month 3) of the double-blind treatment phase, the change from baseline in **monthly migraine days** to the average of the first 3 months (week 1 through week 12) of the double-blind treatment phase, the change from baseline in monthly average severity of **migraine** attacks to week 9 through week 12 (month 3) of the double-blind treatment phase, and 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 double-blind treatment phase. Efficacy data will be collected using an electronic diary (eDiary) throughout the baseline and treatment phases, with subjects required to demonstrate at least 80% compliance with eDiary completion during the baseline period.

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 epresentative 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 ≥ 4 headache days were assessed by the subject as migraine days in each of the 3 months prior to screening.
Migraine frequency: ≥ 4 and < 15 migraine days based on the eDiary data during the last 28 days of the baseline phase if ≥28 days in duration.
Headache frequency: < 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.
No therapeutic response with > 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 Category 2: tricyclic antidepressants Category 3: topiramate Category 4: divalproex sodium, sodium valproate Category 5: serotonin-norepinephrine reuptake inhibitors 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 pediatric Columbia-suicide Severity Rating Scale (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.
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 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. 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: Ergotamines or triptans on ≥ 10 days per month. Simple analgesics (nonsteroidal anti-inflammatory drugs [NSAIDs], acetaminophen) on ≥ 15 days per month. 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 transaminase (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	16 Dec 2019	9
Germany	Not Recruiting	16 Dec 2019	20
Hungary	Not Recruiting	16 Dec 2019	56
Italy	Not Recruiting	16 Dec 2019	30
Poland	Not Recruiting	16 Dec 2019	87
Portugal	Not Recruiting	16 Dec 2019	14
Spain	Not Recruiting	16 Dec 2019	17