The Effects of Ivabradine on Levcromakalim-induced Migraine

Study Overview
=================
Brief Summary
-----------------
Hyperpolarization-activated cation (HCN) channels have recently been implicated in neuropathic and inflammatory pain processes, and HCN channel activity is modulated by signalling molecules, such as cyclic nucleotides (cAMP, cGMP) and extracellular potassium, known to induce migraine. To uncover the role of HCN channels in migraine, the researchers will investigate the anti-migraine effect of ivabradine, the only HCN channel blocker available for clinical use, on levcromakalim-induced migraine.

Detailed Description
-----------------
Hyperpolarization-activated cation (HCN) channels have recently been implicated in neuropathic and inflammatory pain processes through their hyperfunction and/or overexpression, and HCN channels may play a significant role in migraine pathophysiology, as both an inflammatory and a neuropathic component has been hypothesized to contribute to migraine, and 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 causing Ih current amplification. Indeed, increases in cAMP or directly opening adenosine 5'-triphosphate-sensitive K+ channels (KATP channel) by levcromakalim leads to migraine attacks in a high proportion of patients, suggesting a crucial role for these channels in migraine pathophysiology. KATP channel activation leads to hyperpolarization, which in turn could increase the open probability of HCN channels. To uncover the role of HCN channels in migraine, the researchers will investigate the anti-migraine effect of ivabradine, the only HCN channel blocker available for clinical use, on levcromakalim-induced migraine. 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.

Official Title
-----------------
The Effects of Ivabradine on Levcromakalim-induced Headache in Patients With Migraine Without Aura

Conditions
-----------------
Headache, Migraine

Intervention / Treatment
-----------------
* Drug: Ivabradine
* Drug: Calcium


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ivabradine<br>Infusion of levcromakalim (2.5 nmol minutes-1 over 20 minutes) followed by oral administration of ivabradine (15 mg orally). | Drug: Ivabradine<br>* To investigate the role of ivabradine on levcromakalim-induced migraine in patients with migraine without aura.<br>|
| Placebo Comparator: Placebo<br>Infusion of levcromakalim (2.5 nmol minutes-1 over 20 minutes) followed by oral administration of placebo. | Drug: Calcium<br>* To investigate the role of calcium on levcromakalim-induced migraine in patients with migraine without aura.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Headache incidence | Difference in incidence of headache and migraine-like headache in patients with migraine without aura after administrating ivabradine or placebo and the headache-inducing compound levcromakalim. | 10 minutes before levcromakalim infusion until 12 hours after levcromakalim infusion. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in head-pain intensity rated verbally on a numerical rating scale (NRS) from 0-10 | Difference in intensity of headache and migraine-like headache in patients with migraine without aura, rated verbally on a numerical rating scale (NRS) from 0-10 (0 represents no pain, 1 an altered, pressing or throbbing but not really painful feeling, 5 moderate headache and 10 the worst possible headache), after administrating ivabradine or placebo and the headache-inducing compound levcromakalim. | 10 minutes before levcromakalim infusion until 12 hours after levcromakalim infusion. | 
| Changes in cerebral hemodynamics assessed using Transcranial Doppler Ultrasound (TCD) and high-frequency ultrasound (Dermascan C, Cortex Technology, Denmark) | Changes in cerebral hemodynamics will be assessed using Transcranial Doppler Ultrasound (TCD) (2 Mhz, DWL) to measure the velocity of middle cerebral artery (VMCA) blood flow bilaterally, and high-frequency ultrasound (Dermascan C, Cortex Technology, Denmark) to measure the diameter of the superficial temporal artery (STA) bilaterally. | 10 minutes before levcromakalim infusion until 150 minutes after levcromakalim infusion. | 
| Changes in blood pressure | Changes in blood pressure (systolic and diastolic) over time. | 10 minutes before levcromakalim infusion until 150 minutes after levcromakalim infusion. | 
| Heart rate | Changes in heart rate over time. | 10 minutes before levcromakalim infusion until 150 minutes after levcromakalim infusion. |