Efficacy of Erenumab in Chronic Cluster Headache

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the efficacy of erenumab in participants with chronic cluster headache.

Detailed Description
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The purpose of this study is to determine the efficacy of erenumab in a loading dose of 280mg followed by 140mg after 4 weeks compared to placebo as a prophylactic treatment in patients with chronic cluster headache. This study has a 10-week 2-arm, randomized, double-blind, parallel- group, placebo-controlled design. Data from this study will provide important information if the blockade of the CGRP receptor with erenumab is an efficacious principle for the treatment of chronic cluster headache

Official Title
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Efficacy of Erenumab in Chronic Cluster Headache: A 10 Week Double-blind, Randomized, Placebo Controlled, Multicentric Trial.

Conditions
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Cluster Headache, Trigeminal Autonomic Cephalalgias, Headache Disorders, Primary, Brain Disease

Intervention / Treatment
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* Biological: Erenumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (screening) Adults ≥18 and < 65 years of age Documented history of chronic cluster headache for ≥12 months prior to screening according to the International Classification of Headache Disorders-3rd Edition (ICHD-3) Participants are able to distinguish cluster headache attacks from other headaches. Insufficient efficacy OR tolerability OR contraindications of approved cluster headache prophylactic medications. Insufficient efficacy and tolerability as determined by the patient. Sufficient acute attack treatment with triptans or oxygen based on the patient´s history The patient is able to distinguish cluster headache attacks from other headaches (i.e. tension-type headaches). Inclusion Criteria (Baseline) At least 9 cluster headache attacks as defined by the ICHD-3 in 7 days during the baseline epoch (SPII), confirmed by patient-reported eDiary entries. Attacks must have occurred on more than 50% of days of the baseline epoch (SPII). ≥ 90% patient-reported eDiary compliance during the Baseline epoch, compliance is measured as interacting with e-Diary at least once a day. Exclusion Criteria: Diagnosis or history of other primary headache diseases according to the International Classification of Headache Disorders, 3rd Edition (ICHD-3), excluding episodic tension type headache and migraine as defined in criterion 2. Headache freedom from the historic diagnosis of migraine has to be at least one year prior to study inclusion. If patients have on average <=1 migraine attack per month within a year and can distinguish between migraine attacks and cluster attacks, they are allowed to participate. Unable to differentiate cluster headache attacks from other headaches Use of a prophylactic cluster headache medication within 5 half-lives prior to the start of the baseline phase Parallel use of an SPG stimulator, deep brain stimulation or parallel use of a device for the acute/preventive treatment of chronic cluster headache Administration of botulinum toxin type A or B in the head or neck area, within 4 months of baseline (SP II) Concurrent use of other therapeutic monoclonal antibodies. Current use or any prior exposure to any calcitonin-gene-related peptide (CGRP) antibody, any antibody to the CGRP receptor Use of other investigational drugs within 5 half-lives of enrollment, or until the expected pharmacodynamic effect has returned to baseline, whichever is longer Evidence of drug, opioid or alcohol abuse or dependence within 12 months prior to screening, based on medical records or patient self-report History of use of psilocybin (mushrooms), LSD, MDMA or 2- bromo-LSD within 2 months prior to baseline (SPII) Have a positive urine drug screen (UDS) for any substances of abuse, except cannabis or cannabinoids, prior to randomization. A retest is applicable if, in judgment of the investigator, there is a reasonable explanation for the positive result. A negative result in the retest is obligatory for entering baseline (SPII) Diagnosis or history of significant active or unstable psychiatric disease, such as bipolar disorder, schizophrenia, personality disorders, or other serious mood or anxiety disorders. Patients with anxiety disorder and/or major depressive disorder are permitted in the study if they are considered by the investigator to be stable and are taking no more than one medication per disorder. Patients must have been on a stable dose within the 3 months prior to the start of the baseline phase Score yes on item 4 or item 5 of the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale (C-SSRS), if this ideation occurred in the past month, or yes on any item of the Suicidal Behavior section, except for the Non-Suicidal Self-Injurious Behavior (item also included in the Suicidal Behavior section), if this behavior occurred in the past 3 months. Patients who do not meet this criterion, but who are considered by the judgment of the investigator to be at significant risk for suicide, must be excluded Active chronic pain syndromes (e.g., fibromyalgia or chronic pelvic pain) in which the pain has lost its guiding and warning function and has acquired an independent disease value. History or current evidence of major psychiatric disorder (such as schizophrenia, bipolar disorder or type B personality disorder that might interfere with the ability to properly report clinical outcomes) History or current severe coronary artery disease, myocardial infarction, stroke, transient ischemic attack, unstable angina, or coronary artery bypass surgery or other revascularization procedures within 12 months prior to screening History or current diagnosis of ECG abnormalities indicating significant risk of safety for patients participating in the study- Known hypersensitivity to multiple drugs, monoclonal antibodies or other therapeutic protein History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases Hepatic disease by history or total bilirubin ≥2×ULN or ALT or AST ≥3xULN as assessed by central laboratory at initial screening History of severe constipation, defined as less than 3 bowel movements /week not adequately manageable by routine medical treatment, within 3 months prior to screening Acute SARS-CoV2 Infection within 2 weeks prior to screening Women who are pregnant or nursing Known hypersensitivity to multiple drugs, monoclonal antibodies or other therapeutic proteins, or to erenumab or to any of the inactive ingredients Unlikely to be able to complete all protocol required study visits or procedures, and/or to comply with all required study procedures (e.g., independent completion of electronic diary items) to the best of the patient's and investigator's knowledge Prior known treatment with a CGRP receptor mAb (erenumab) Prior treatment with a CGRP ligand antibody. Exceptions: Patients who participated in a randomized, placebo-controlled trial with CGRP ligand antibodies and were not unblinded (i.e., have no knowledge whether they received placebo or verum) can participate in the trial. Patients, who knowingly received a CGRP ligand antibody (i.e.galcanezumab or fremanezumab) can participate in the trial if the following criteria are met: a) Administered dose was not effective versus placebo in clinical trials i.e. galcanezumab (<300 mg/month s.c.) or fremanezumab (≤675 mg loading dose followed by 225 mg s.c./month), b) Treatment duration of maximal 2 month or 2 injection cycles c) The last dose was administered at least 6 month prior to begin of screening epoche. Patients who may be dependent on the sponsor or investigator Patients who are in custody of an institution due to governmental authority decision or court order

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erenumab<br>Double-Blind Treatment Phase: Participants receive erenumab 280 mg subcutaneous (SC) injections (loading dose, week 0) followed by erenumab 140 mg s.c. in week 4. | Biological: Erenumab<br>* Pre-filled syringe; s.c. injection<br>* Other names: AMG 334;|
| Placebo Comparator: Placebo<br>Double-Blind Treatment Phase: Participants receive placebo subcutaneous (SC) injections in week 0 and week 4. | Drug: Placebo<br>* Pre-filled syring; s.c. injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of weekly cluster headache attack frequency from baseline over the last 2 weeks of the double-blind epoch (averaged for 7 days). | Number of cluster headache attacks was recorded daily by study participants in their ePRO Diary, Baseline and 6 weeks of daily data during double-blind treatment phase will be converted into 7-calendar day intervals: The baseline 7-10 day interval, Week 5+6. | Baseline; Weeks 5-6 (Days 29-42) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with a 50% or greater reduction from baseline in the weekly number of cluster headache attacks averaged per 7 days over the last 2 weeks of the DB epoch. | A 50% responder is any participant who has a ≥50% reduction from baseline in the weekly number of cluster headache attacks in a 7-day interval: Weeks 5+6 | Baseline; Weeks 5-6 (Days 29-42) | 
| Patient Global Impression of Improvement (PGI-I) at week 6. | PGI-I requests participants to mark the box that best describes their cluster headache condition since they started taking the medicine. The options in the displayed boxes are represented on a 7-point scale, with 1 = very much better, 2 = much better, 3 = a little better, 4 = no change, 5 = a little worse, 6 = much worse, and 7 = very much worse. | Baseline; Week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pain, Neurology