The Effect of Anti-calcitonin Gene-related Peptide (CGRP) Receptor Antibodies on the Headache Inducing Properties of CGRP and Cilostazol in Migraine Patients

Study Overview
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Brief Summary
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A randomized, double-blind, placebo-controlled, parallel study to investigate the effect of erenumab in calcitonin-gene related peptide and cilostazol experimental models of migraine in humans. Followed by a 6-month open-label extension.

Official Title
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The Effect of Anti-calcitonin Gene-related Peptide (CGRP) Receptor Antibodies on the Headache Inducing Properties of CGRP and Cilostazol in Migraine Patients

Conditions
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Migraine, Migraine Without Aura, Migraine With Aura

Intervention / Treatment
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* Drug: Erenumab
* Drug: Placebo
* Drug: Calcitonin gene-related peptide
* Drug: Cilostazol


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with migraine with or without aura according to the International Classification of Headache Disorders with a frequency of ≥4 migraine days per month 50-100 kg weight Participants of childbearing potential must use safe contraception (birth control) or be sexually abstinent Exclusion Criteria: Any other primary headache disorder according to the International Classification of Headache Disorders except for tension-type headache Any secondary headache disorder according to the International Classification of Headache Disorders Migraine attack during the preceding 48 hours on provocation day Headache during the preceding 24 hours on provocation day Treatment with monoclonal antibodies or participation in clinical trials with monoclonal antibodies during the preceding year Daily consumption of any other drug/medication than oral contraception (birth control) Consumption of any other drug/medication later than four times the plasma half-time of the drug on provocation day except for oral contraception Pregnant or active breastfeeding participants Any cardiovascular diseases including cerebrovascular disorders Information in patient history or during physical examination indicating psychiatric disorders or substance abuse Information in patient history or during physical examination that the screening physician deems relevant for participation in the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized, double-blinded, placebo-controlled, parallel study followed by a 6-month open-label extension.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Randomized treatment phase: Erenumab<br>Erenumab 140 mg single subcutaneous injection at baseline | Drug: Erenumab<br>* Subcutaneous injection of 140 mg erenumab.<br>* Other names: Aimovig®;Drug: Calcitonin gene-related peptide<br>* Intravenous infusion of 1.5ug/min calcitonin gene-related peptide over 20 minutes.<br>Drug: Cilostazol<br>* Oral intake of 200 mg cilostazol.<br>|
| Placebo Comparator: Randomized treatment phase: Placebo<br>Saline placebo single subcutaneous injection at baseline | Drug: Placebo<br>* Subcutaneous injection of saline placebo.<br>* Other names: Saline placebo;Drug: Calcitonin gene-related peptide<br>* Intravenous infusion of 1.5ug/min calcitonin gene-related peptide over 20 minutes.<br>Drug: Cilostazol<br>* Oral intake of 200 mg cilostazol.<br>|
| Other: Open-label extension treatment phase: Erenumab<br>Erenumab 140 mg monthly subcutaneous injection for six months after completion of the randomized, double-blinded, placebo-controlled study phase during the open-label extension | Drug: Erenumab<br>* Subcutaneous injection of 140 mg erenumab.<br>* Other names: Aimovig®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Migraine-like attack | The incidence of migraine-like attack after administration of calcitonin-gene related peptide or cilostazol in patients with migraine pretreated with erenumab compared to patients with migraine pretreated with placebo. A migraine-like attack is defined attack fulfilling either (i) or (ii): (i) Headache fulfilling criteria C and D for migraine without aura according to the International Headache Society criteria: C. Headache has at least two of the following characteristics: unilateral location; pulsating quality; moderate or severe pain intensity (moderate to severe pain intensity is considered ≥4 on verbal rating scale); aggravation by cough (in-hospital phase) or causing avoidance of routine physical activity (out-hospital phase); D. During headache at least one of the following: nausea and/or vomiting; photophobia and phonophobia; and (ii) Headache described as mimicking the patient's usual migraine attack and treated with acute migraine medication (rescue medication). | Before (-5 min) and after administration of (+12 hours) of experimental trigger | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Headache intensity | Change in headache intensity after administration of calcitonin-gene related peptide or cilostazol in patients with migraine pretreated with erenumab compared to patients with migraine pretreated with placebo. Headache intensity scores are measured by a numerical rating scale (NRS). It is a verbally declared scale from 0 to 10, where 0 is no pain; 10 is the worst pain imaginable. | Before (-5 min) and after administration of (+12 hours) of experimental trigger | 
| Hemodynamics (superficial temporal artery) | Change in diameter (mm) of superficial temporal artery after administration of calcitonin-gene related peptide or cilostazol in patients with migraine pretreated with erenumab compared to patients with migraine pretreated with placebo. | Before (-5 min) and after administration of (+90 minutes) of experimental trigger | 
| Hemodynamics (radial artery) | Change in diameter (mm) of radial artery after administration of calcitonin-gene related peptide or cilostazol in patients with migraine pretreated with erenumab compared to patients with migraine pretreated with placebo. | Before (-5 min) and after administration of (+90 minutes) of experimental trigger | 
| Neuropeptide plasma concentrations (CGRP) | Change in plasma concentrations of calcitonin gene-related peptide (CGRP) after administration of calcitonin-gene related peptide or cilostazol in patients with migraine pretreated with erenumab compared to patients with migraine pretreated with placebo. Change in plasma concentrations of calcitonin gene-related peptide during the open-label treatment phase. | (1) Before (-5 min) and after administration of (+60 minutes) of experimental trigger; (2) 24-week open-label treatment phase | 
| Neuropeptide plasma concentrations (VIP) | Change in plasma concentrations of vasoactive intestinal peptide (VIP) after administration of calcitonin-gene related peptide or cilostazol in patients with migraine pretreated with erenumab compared to patients with migraine pretreated with placebo. Change in plasma concentrations of vasoactive intestinal peptide (VIP) during the open-label treatment phase. | (1) Before (-5 min) and after administration of (+60 minutes) of experimental trigger; (2) 24-week open-label treatment phase | 
| Neuropeptide plasma concentrations (PACAP) | Change in plasma concentrations of pituitary adenylate cyclase-activating peptide (PACAP) after administration of calcitonin-gene related peptide or cilostazol in patients with migraine pretreated with erenumab compared to patients with migraine pretreated with placebo. Change in plasma concentrations of pituitary adenylate cyclase-activating peptide (PACAP) during the open-label treatment phase. | (1) Before (-5 min) and after administration of (+60 minutes) of experimental trigger; (2) 24-week open-label treatment phase | 
| Facial flushing | Change in facial skin flushing after administration of calcitonin-gene related peptide or cilostazol in patients with migraine pretreated with erenumab compared to patients with migraine pretreated with placebo. | Before (-5 min) and after administration of (+90 minutes) of experimental trigger | 
| Facial temperature | Change in facial temperature after administration of calcitonin-gene related peptide or cilostazol in patients with migraine pretreated with erenumab compared to patients with migraine pretreated with placebo. | Before (-5 min) and after administration of (+90 minutes) of experimental trigger | 
| Headache day | Change in number of headache days per month after administration of erenumab from baseline compared to the last 3 months (months 4, 5, and 6) of the 24-week open-label treatment phase. | Baseline and the last 3 months (months 4, 5, and 6) of the 24-week open-label treatment phase | 
| Migraine day | Change in number of migraine days per month after administration of erenumab from baseline compared to the last 3 months (months 4, 5, and 6) of the 24-week open-label treatment phase. | Baseline and the last 3 months (months 4, 5, and 6) of the 24-week open-label treatment phase | 
| ≥50% responder rate | Proportion of participants with a ≥50% reduction in number of migraine days per month after administration of erenumab from baseline compared to the last 3 months (months 4, 5, and 6) of the 24-week open-label treatment phase. | Baseline and the last 3 months (months 4, 5, and 6) of the 24-week open-label treatment phase |