Effect of Levcromakalim in Individuals With Migraine Pretreated With Erenumab (COLLIDE)

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

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).

Study Overview

• Status: Completed
• Conditions: Migraine Without Aura
• Intervention / Treatment: Drug: Levcromakalim; Other: Placebo

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2600
    • Danish Headache Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Danish Headache Center
• Collaborators: Novartis

Study record dates

Study Major Dates

• Study Start (Actual): March 9, 2023
• Primary Completion (Actual): June 12, 2023
• Study Completion (Actual): June 12, 2023

Study Registration Dates

• First Submitted: May 25, 2023
• First Submitted That Met QC Criteria: May 25, 2023
• First Posted (Actual): June 5, 2023

Study Record Updates

• Last Update Posted (Actual): October 24, 2023
• Last Update Submitted That Met QC Criteria: October 22, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Migraine Disorders; Migraine without Aura; Physiological Effects of Drugs; Antihypertensive Agents; Vasodilator Agents; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Cromakalim
• Other Study ID Numbers: H-22031695

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No