Effect of Ivabradine on Levcromakalim-Induced Symptoms in Individuals With Migraine Without Aura (ILIM)

NCT ID: NCT04853797

Last Updated: 2026-01-08

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 37 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-05-11
• Study Completion Date: 2025-07-06

Brief Summary

This study aims to explore the effect of Ivabradine on Levcromakalim-induced migraine in individuals with migraine without aura.

Detailed Description

Hyperpolarization-activated cation (HCN) channels have recently been implicated in neuropathic and inflammatory pain processes through their hyperfunction and/or overexpression.

HCN channels may play a significant role in migraine pathophysiology, as 1) both an inflammatory and a neuropathic component has been hypothesized to contribute to migraine, and 2) HCN channel activity is facilitated by cyclic nucleotides, e.g. cAMP and cGMP (molecules thought to be central in migraine pathophysiology) and increases in extracellular K+ concentration.

Opening of adenosine 5'-triphosphate-sensitive potassium channels (KATP channels) using Levcromakalim causes migraine attacks with and without aura in a high proportion of patients. KATP channel activation leads to hyperpolarization, which in turn could increase the open probability of HCN channels.

This study aims to explore the effects of Ivabradine on Levcromakalim-induced migraine in individuals with migraine without aura.

The investigators anticipate that this project will contribute greatly to the current understanding of migraine pathophysiology and the hypothesized role of HCN channels in migraine pain mechanisms. This is of great interest in future research, as such knowledge is an important prerequisite for further investigation and understanding of intracellular signalling mechanisms in migraine, which in turn will lead to the development of more effective and mechanism-based drugs.

Conditions

Headache; Migraine Without Aura

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: QUADRUPLE

Study Groups

Levcromakalim - Ivabradine

Infusion of levcromakalim (2.5 nmol minutes-1 over 20 minutes) followed by oral administration of ivabradine (15 mg orally).

Group Type: ACTIVE_COMPARATOR

Levcromakalim

Intervention Type: DRUG

20 min infusion of 1 mg Levcromakalim followed by either oral Ivabradine or Placebo.

Ivabradine

Intervention Type: DRUG

15 mg oral Ivabradine.

Levcromakalim - Placebo

Infusion of levcromakalim (2.5 nmol minutes-1 over 20 minutes) followed by oral administration of placebo.

Group Type: PLACEBO_COMPARATOR

Levcromakalim

Intervention Type: DRUG

20 min infusion of 1 mg Levcromakalim followed by either oral Ivabradine or Placebo.

Placebo

Intervention Type: DRUG

Oral placebo (calcium supplements).

Interventions

Levcromakalim

20 min infusion of 1 mg Levcromakalim followed by either oral Ivabradine or Placebo.

Intervention Type: DRUG

Ivabradine

15 mg oral Ivabradine.

Intervention Type: DRUG

Placebo

Oral placebo (calcium supplements).

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Be able to give voluntary written informed consent to participate.
• Have a diagnosis of episodic migraine without aura according to The International Classification of Headache Disorders 3rd Edition.
• Be in good general health and without any cardio- or cerebrovascular diseases, psychiatric disorders or other severe comorbidities.
• Be 18-60 years of age.
• Have a weight between 50-100 kg.
• Have a normal standard resting 12-lead ECG at the screening visit with heart rate (HR) ≥ 60 bpm (the inclusion criterium of HR ≥ 60 bpm at screening has previously been used in studies with dosages of ivabradine up to 20 mg as single and multiple doses with no significant adverse events).
• Be without any chronic use of medicine.
• Have a negative urine-human chorionic gonadotropin (hCG) test at the screening visit if they are female of childbearing potential.

Exclusion Criteria

• Suffer from tension type headache, as defined by the The International Classification of Headache Disorders 3rd Edition, more than five days a month on average in the last year.
• Are diagnosed with any primary headache disorder apart from migraine without aura as de-fined in The International Classification of Headache Disorders 3rd Edition (relating to tension type headache, see above).
• Suffer from any headache 48 hours prior to the start of the experiment or any migraine 72 hours prior to the start of the experiment.
• Are allergic to ivabradine or levcromakalim.
• Are lactose intolerant (due to Ivabradine tablets containing lactose).
• Have a daily intake of any medicine other than oral contraception or use of drugs or other ed-ibles/beverages with potential serious interactions with ivabradine
• Have a history of personal/familial or clinical signs of: cardiovascular and cerebrovascular disease (Long QT Syndrome, Cardiac dysrhythmia, Bradycardia, i.e. a resting heart rate of < 60 bpm at screening, Amnestic information or clinical signs of hyper- or hypotension (Hypertension (systolic blood pressure > 150 mmHg and / or diastolic blood pressure > 100 mmHg)/Hypotension (systolic blood pressure < 90 mm Hg and / or diastolic blood pressure < 50 mmHg)), Heart failure (NYHA II or higher)); Psychiatric conditions; Drug abuse of any kind; Smoking; Other comorbidities or clinical signs of diseases of any kind considered by the investigating physician to make the participant ineligible because of safety concerns).
• Are pregnant, breastfeeding or not using appropriate contraception.
• Do not want any information on significant pathological findings in the study.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 60 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Danish Headache Center

OTHER

Sponsor Role: lead

Responsible Party

Messoud Ashina, MD

Principal investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Messoud Ashina, Prof.

Role: PRINCIPAL_INVESTIGATOR

Danish Headache Center

Locations

Danish Headache Centre, Rigshospitalet-Glostrup

Glostrup, Region Sjælland, Denmark

Danish Headache Center

Glostrup Municipality, , Denmark

Countries

Denmark

Other Identifiers

Ivabradine H-20061329

Identifier Type: -

Identifier Source: org_study_id