Safety and Efficacy of Fremanezumab for Migraine in Adult CADASIL

Study Overview
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Brief Summary
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Researchers are trying to find out more about the side effects of fremanezumab when treating patients with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) for migraine headaches.

Detailed Description
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Subjects will receive 4 to 20 weeks of placebo injections followed by 12 weeks of monthly administered fremanezumab by subcutaneous injection (225 mg split four weeks apart for 12 weeks). Following completion of the 12 weeks of therapy, the participant will return to placebo for the washout period. Both the patient and the investigator will be blinded to the timing of transition to and from placebo and the transition to and from fremanezumab.

Official Title
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A Phase II Double-Blinded Placebo Controlled Individual Subject Stepped Wedge Clinical Trial Evaluating the Safety and Efficacy of Fremanezumab for Migraine in Adult CADASIL

Conditions
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Cadasil, Migraine

Intervention / Treatment
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* Drug: Fremanezumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Age 18 to 70 years old English speaking Diagnosis of CADASIL confirmed by presence of a pathogenic NOTCH3 gene mutation Diagnosis of migraine for at least 12 months and diagnosis of chronic migraine for at least 28 days according to the International Classification of Headache Disorders MIDAS score of >10 points Ability to provide written informed consent Exclusion Criteria History of ischemic stroke within 4 weeks of screening assessment Screening blood pressure >150 mm Hg Use of onabotulinum toxin A 4 months prior to trial or other injectable/stimulatory/magnetic method of headache control Use of opiates or barbiturates 4 days prior to trial Patients with competing intracerebral pathology (e.g. history of intracerebral hemorrhage, multiple sclerosis) NYHA Class III or IV congestive heart failure History of myocardial infarction History of coronary bypass surgery or coronary stenting Pregnancy or breastfeeding Contraindication to undergoing brain MRI per standard clinical practice guidelines Vulnerable populations, including incarcerated inmates, dementia, and inability to provide consent

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Subjects with CADASIL treatment intervention<br>Subjects that have been diagnosed with both CADASIL and moderately to severely disabling migraine headaches will be treated with Fremanezumab injections. | Drug: Fremanezumab<br>* Subjects will receive a single dose total 225 mg (1 injection of 225 mg per 1.5 mL injection) followed by a single dose of 225 mg (1 1.5mL injection) at four week intervals. Both the subject and the investigator will be blinded to the timing of transition to and from placebo and the transition to and from fremanezumab.<br>* Other names: Ajovy;Drug: Placebo<br>* Placebo injections during the run in and washout serves as the control condition. Both the subject and the investigator will be blinded to the timing of transition to and from placebo and the transition to and from fremanezumab.<br>|
| Placebo Comparator: Subjects with CADASIL placebo intervention<br>Subjects that have been diagnosed with both CADASIL and moderately to severely disabling migraine headaches will be treated with placebo injections. | Drug: Fremanezumab<br>* Subjects will receive a single dose total 225 mg (1 injection of 225 mg per 1.5 mL injection) followed by a single dose of 225 mg (1 1.5mL injection) at four week intervals. Both the subject and the investigator will be blinded to the timing of transition to and from placebo and the transition to and from fremanezumab.<br>* Other names: Ajovy;Drug: Placebo<br>* Placebo injections during the run in and washout serves as the control condition. Both the subject and the investigator will be blinded to the timing of transition to and from placebo and the transition to and from fremanezumab.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in migraine-related disability | Measured using the The Migraine Disability Assessment (MIDAS) questionnaire which is a brief, self-administered questionnaire designed to quantify headache-related disability over a 3 month period using number of days | Baseline, 2 week intervals up to 48 weeks | 
| Change in headache intensity | Measured using Headache Impact Test (HIT)-6 scores with the answers being never, rarely, sometimes, very often or always and equating to 6, 8, 10, 11, and 13 points respectively. Each answer is summated to equal the final score. | Baseline, 2 week intervals up to 48 weeks | 
| Adverse events | Number of adverse events reported | 48 weeks |