Effect of Riocigaut on Migraine Attack Induction and Cerebral Vasodilation in Migraine Patients.

Study Overview
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Brief Summary
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This double-blind, randomized, placebo-controlled cross-over clinical trial aims to investigate the effects of riocigaut on migraine inducing properties and cerebral arteries in patients with migraine.

Detailed Description
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The investigators believe that activation of sGC could play a role in migraine pathophysiology and propose that stimulation with riociguat causes migraine attacks alongside cranial arterial dilation in patients with migraine. Twenty-one patients with migraine will participate at a screening visit and, if eligible, on two separate study days, where participants, in a randomized cross-over fashion, will ingest either riociguat (active comparator arm) or placebo (placebo comparator arm), serving as their own controls. On the two separate study days the investigators will measure change in diameter of superficial temporal artery and middle cerebral artery blood flow velocity, heart rate, blood pressure and register possible headache/migraine including associated symptoms until 6 hours after intake of riociguat or placebo. At home participants are expected to fill out a headache diary until 12 hours from intake of riociguat or placebo.

Official Title
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Riociguat (BAY 63-2521), a Stimulator of Soluble Guanylate Cyclase (sGC) - Migraine Induction and Cerebral Vasodilation in Migraine Patients.

Conditions
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Migraine Without Aura

Intervention / Treatment
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* Drug: Riociguat (BAY 63-2521)
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A history of migraine without aura for ≥ 12 months according to the classification criteria of the International Classification of Headache Disorders 3rd Edition (ICHD-3) criteria. Ability to provide written informed consent and receive participant privacy and rights information prior to initiation of any study-specific activities. Male or female participants aged 18-45 years at screening. No migraine preventive treatment at screening or during study conduction. Non-smokers Exclusion Criteria: Any current or previous history of other primary or secondary headache disorder(s) apart from tension type headache ≤ 5 days per month. Lack of ability to differentiate migraine from other headaches Headache within 24 hours before any study related procedures (Provocation Day 1 and Provocation Day 2) - Subjects are however allowed to be re-booked for provocation days according to allowed timelines. Any daily medication apart from contraceptives. Use of any antihypertensive, nitrates or nitric oxide donors or phosphodiesterase inhibitors, CYP3A4 and P-glycoprotein inhibitors, HIV-proteaseinhibitors, ciclosporin A or CYP1A1-inhibitors, antacida and acid-neutreulizing agents (such as aluminium-/magnesiumhydroxid), CYP3A4-inductors (such as bosentan, phenytoin, carbamazepin, phenobarbital and herbal remedies with perikon). Intake of any pro necessitate medication later than 4 times plasma half-life for the specific drug before study start. Women of child-bearing potential not currently using safe contraceptives. Women of child-bearing potential does not include hysterectomized women and women who have been in menopause for at least 2 years. Safe contraceptives include either IUD, birth control pills, surgical sterilization of the woman, depositary gestagen, barrier prevention or sexual abstinence. Pregnant or breastfeeding women Positive pregnancy urine screening on screening day or provocation days. A medical history or clinical signs of Hypertension (systolic blood pressure >150mmHg and/or diastolic blood pressure >100mmHg) Hypotension (systolic blood pressure <100mmHg and/or diastolic blood pressure <50mmHg) Electrocardiogram (ECG) with any clinically significant abnormalities at screening determined by the investigator, including but not limited to, prolonged PQ or QTc interval, signs of arrythmias, ischemia or left/right ventricle dysfunction/hypertrophy. A medical history or clinical signs of pulmo-/cardiovascular disease including cerebrovascular disease. A family history of severe cardiac disease. A medical history or clinical signs of clinically significant psychiatric illness per investigator opinion. The subject is at risk of self-harm or harm to others as evidenced by past suicidal behavior. A medical history or clinical signs of substance or alcohol abuse A medical 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 site investigator, would pose a risk to subject safety or interfere with study evaluation, procedures or completion. Any history of hypersensitivity to riociguat. Subjects who do not want information about crucial pathological findings during the study Subject likely to not be available to complete all protocol-required study visits or procedures, and/or comply with all required study procedures to the best of the subject and study investigator's knowledge.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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 |
| --- | --- |
| Other: Riociguat / Placebo<br>Riociguat or Placebo as oral capsule in randomized order | Drug: Riociguat (BAY 63-2521)<br>* A selective stimulator of soluble guanylate cyclase (sGC)<br>* Other names: Adempas;Other: Placebo<br>* Placebo<br>|
| Other: Placebo / Riociguat<br>Riociguat or Placebo as oral capsule in randomized order | Drug: Riociguat (BAY 63-2521)<br>* A selective stimulator of soluble guanylate cyclase (sGC)<br>* Other names: Adempas;Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in incidence of migraine attacks between riociguat and placebo during a 12-hour observational period after ingestion. | Data will be collected with a questionnaire. | 0-12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Difference in superficial temporal artery (STA) diameter between baseline and 90 minutes after receiving riociguat compared to placebo. | Measured by high resolution ultrasonography. | 0-90 minutes | 
| Difference in superficial temporal artery (STA) diameter between baseline and onset of migraine attack after receiving riociguat (maximum 6 hours after receiving riociguat) compared to placebo. | STA diameter will be measured by high resolution ultrasonography. Data on migraine attack will be collected with a questionnaire. | 0-6 hours (max) | 
| Difference in middle cerebral artery (MCA) blood flow velocity between baseline and 90 minutes after receiving riociguat compared to placebo. | Measured by transcranial doppler. | 0-90 minutes | 
| Difference in middle cerebral artery (MCA) blood flow velocity between baseline and onset of migraine attack after receiving riociguat (maximum 6 hours after receiving riociguat) compared to placebo. | MCA blood flow velocity will be measured by transcranial doppler. Data on migraine attack will be collected with a questionnaire. | 0-6 hours (max) | 
| Difference in incidence of headache (>0 on Numeric Rating Scale (NRS) from 0 to 10, where 0=no pain versus 1-10=pain) between riociguat and placebo during a 12-hour observational period after ingestion. | Data will be collected with a questionnaire. | 0-12 hours | 
| Difference in severity of headache rated on 11-point NRS from 0 (no pain) to 10 (worst pain imaginable) between riociguat and placebo during a 12-hour observational period after ingestion. | Data will be collected with a questionnaire. | 0-12 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Migraine, Pain, Riociguat, Cerebral vasodilation, Migraine Without Aura, Headache, Enzyme Activators, Neurologic Manifestations, Molecular Mechanisms of Pharmacological Action