Effect of Riocigaut on Cerebral Vasodilation and Headache Induction in Healthy Volunteers

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

Detailed Description
-----------------
The investigators believe that activation of sGC could play a role in migraine pathophysiology and propose that stimulation with riociguat causes cranial arterial dilation alongside headache in healthy volunteers. Twelve healthy volunteers 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 and register possible headache until 4 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. Leading up to the main study described above, the investigators will conduct a pilot dose-finding study (experimental arm) of increasing doses of riociguat, 2,5mg and 5mg respectively, on two separate study days in 5 healthy volunteers, to ensure an appropriate dose is applied in the main study.

Official Title
-----------------
Riociguat (BAY 63-2521), a Stimulator of Soluble Guanylate Cyclase (sGC) - Cerebral Vasodilation and Headache Induction in Healthy Volunteers

Conditions
-----------------
Headache

Intervention / Treatment
-----------------
* Drug: Dose Riociguat 2,5 or 5mg
* Drug: Riociguat
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Ability to provide written informed consent and receive participant privacy and rights information. Male or female participants aged 18-45 years. Weight between 50-100kg Non-smokers Exclusion Criteria: Any current or previous known primary or secondary headache disorder(s) apart from tension type headache ≤ 1 day per month. Headache <48 hours before study start. Daily use of any medication except contraceptives. Specifically use of nitrates or nitric oxide donors or phosphodiesterase inhibitors. Intake of any pro necessitate medication later than 4 times plasma half-life for the specific drug before study start, except for contraceptives 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 urin screening on screening day or study days. A medical history or clinical signs of Hypertension (systolic blood pressure >140mmHg and/or diastolic blood pressure >90mmHg) 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. Blood work at screening with signs of anemia. Blood work at screening with signs of abnormal kidney and liver function. A medical history or clinical signs of cardiovascular disease including cerebrovascular disease. A medical history or clinical signs of pulmonary disease. A medical history or clinical signs of liver, renal, gastrointestinal, endocrine, hematological or neurological disease. A medical history or clinical signs of psychiatric illness or substance abuse A medical history or clinical signs of drug or alcohol abuse A medical history or clinical signs of disease of any origin that the investigative doctor finds relevant for participation in the study A family history of severe cardiac disease. Any history of hypersensitivity to riociguat. Subjects who do not want information about crucial pathological findings during the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

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

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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 |
| --- | --- |
| Experimental: Dose Riociguat 2,5 or 5mg<br>Riociguat dose finding pilot experiment, 2,5mg and 5mg | Drug: Dose Riociguat 2,5 or 5mg<br>* A selective stimulator of soluble guanylate cyclase (sGC)<br>|
| Active Comparator: Riociguat<br>Riociguat orally | Drug: Riociguat<br>* A selective stimulator of soluble guanylate cyclase (sGC)<br>|
| Placebo Comparator: Placebo<br>Placebo orally | Drug: Placebo<br>* Placebo<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in superficial temporal artery (STA) diameter from baseline to 90 minutes in healthy volunteers after receiving riociguat compared to placebo, measured by high resolution ultrasonography. |  | 0 - 90 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in middle cerebral artery (MCA) blood flow velocity in healthy volunteers after receiving riociguat compared to placebo, measured by transcranial doppler from baseline until 4 hours after intake. |  | 0 - 4 hours | 
| Changes in heart rate in healthy volunteers after receiving riociguat compared to placebo. |  | 0 - 4 hours | 
| Incidence of headache (>0 on Numeric Rating Scale (NRS) from 0 to 10, 0=no pain versus 1-10=pain) in healthy volunteers until 12 hours after receiving riociguat compared to placebo. | Data will be collected with a questionnaire. | 0 - 12 hours |