Clinical trial NCT04853797: Effect of Ivabradine on Levcromakalim-Induced Symptoms in Individuals With Migraine Without Aura (ILIM)
Official title: Effect of Ivabradine on Levcromakalim-Induced Symptoms in Individuals With Migraine Without Aura: A Randomized Double-Blind Two-Way Crossover Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Headache
Migraine Without Aura
Lead sponsor: Danish Headache Center
Sponsor class: OTHER
First posted: 2021-04-21
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

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.

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.

Primary outcomes:
measure: Incidence of migraine attacks
timeFrame: Assessed from baseline to 12 hours after infusion of levcromakalim
Secondary outcomes:
measure: Incidence of headache
timeFrame: Assessed from baseline to 12 hours after infusion of levcromakalim
measure: Intensity of headache
timeFrame: Assessed from baseline to 12 hours after infusion of levcromakalim
measure: Changes in cerebral hemodynamics (velocity of blood flow in middle cerebral artery and diameter of superficial temporal artery) assessed using Transcranial Doppler Ultrasound (TCD) and high-frequency ultrasound (Dermascan C, Cortex Technology, Denmark)
timeFrame: Assessed from baseline until 150 minutes after levcromakalim infusion.
measure: Changes in blood pressure
timeFrame: Assessed from baseline until 150 minutes after levcromakalim infusion.
measure: Heart rate
timeFrame: Assessed from baseline until 150 minutes after levcromakalim infusion.
measure: Incidence of adverse events
timeFrame: Assessed from baseline to 12 hours after infusion of Levcromakalim.
Other outcomes:
Locations:
city: Glostrup
country: Denmark
facility: Danish Headache Centre, Rigshospitalet-Glostrup
state: Zealand
city: Glostrup
country: Denmark
facility: Danish Headache Center
Study officials:
affiliation: Danish Headache Center
name: Messoud Ashina, Prof.
role: PRINCIPAL_INVESTIGATOR
References: