Effect of Levcromakalim in Individuals With Migraine Pretreated With Erenumab

Study Overview
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Brief Summary
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An outstanding scientific question, that merits further investigation, is whether dilation of intracranial arteries is implicated in the pathogenesis of cephalic pain in migraine. Here, we hypothesize that experimentally-induced dilation of intracranial arteries using intravenous infusion of levcromakalim (a potent vasodilator) induces cephalic pain with migraine-like features in people with migraine, who prior to the infusion are administered erenumab (anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody).

Official Title
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Effect of Levcromakalim in Individuals With Migraine Pretreated With Erenumab: A Randomized Double-Blind Placebo-Controlled Two-Way Crossover Trial

Conditions
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Migraine Without Aura

Intervention / Treatment
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* Drug: Levcromakalim
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has provided informed consent prior to initiation of any study-specific activities/procedures. Age ≥18 years upon entry into screening. History of migraine without aura for ≥12 months with a frequency of 1-5 migraine attacks per month before screening according to the International Headache Society (IHS) Classification ICHD-3 (Headache Classification Committee of the International Headache Society, 2018), based on medical records and/or patient self-report. Exclusion Criteria: History of any primary headache disorder other than migraine without aura, or tension-type headache with a frequency of ≥5 headache days per month before screening according to the International Headache Society (IHS) Classification ICHD-3 (Headache Classification Committee of the International Headache Society, 2018), based on medical records and/or patient self-report. History of any secondary headache disorder before screening according to the International Headache Society (IHS) Classification ICHD-3 (Headache Classification Committee of the International Headache Society, 2018) based on medical records and/or patient self-report. Intake of prophylactic migraine medication within ≤30 days or 5 plasma half-lives (whichever is longer) prior to screening. Prior intake of therapies targeting the CGRP signaling pathway, including anti-CGRP ligand monoclonal antibodies, anti-CGRP receptor monoclonal antibodies, and small molecule CGRP receptor antagonists. The participant is at risk of self-harm or harm to others as evidenced by past suicidal behavior. History or evidence of any other clinically significant disorder, condition, or disease (with the exception of those outlined above) that, in the opinion of the investigator will pose a risk to participant safety or interfere with the study evaluation, procedures or completion. Female participants of childbearing potential with a positive pregnancy test assessed at screening or day 1 by a urine pregnancy test. Female participants who are pregnant or breastfeeding or plan to become pregnant or breastfeed during participation in the study. Evidence of current pregnancy or breastfeeding per participant self-report or medical records. Participants likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the participants' and investigator's knowledge.

Ages Eligible for Study
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Minimum Age: 18 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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Levcromakalim<br> | Drug: Levcromakalim<br>* Continuous intravenous infusion of 20 mL levcromakalim (0.05 mg/min (50 μg/ mL) over 20 minutes<br>|
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* Continuous intravenous infusion of 20 mL isotonic saline over 20 minutes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of migraine attack | Difference in incidence of migraine attack (0 to 12 hours) between levcromakalim and placebo. A migraine attack is defined as an 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 (ii) Headache described as mimicking the patient's usual migraine attack and treated with acute migraine medication (rescue medication). | 12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of headache | Difference in incidence of headache (0 to 12 hours) between levcromakalim and placebo. Incidence of headache is defined as headache intensity ≥1 as measured by a numerical rating scale (NRS) from 0 to 10. It is a verbally declared scale from 0 to 10, where 0 is no pain; 10 is the worst pain imaginable. | 12 hours | 
| Intensity of headache | Difference in area under the curve (AUC) for headache intensity scores (0 to 12 hours) between levcromakalim and 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. | 12 hours | 
| Diameter of superficial temporal artery | Diameter (mm) of superficial temporal artery is measured as a continuous outcome. | 1 hour |