Clinical trial NCT05582811: Effect of Riocigaut on Cerebral Vasodilation and Headache Induction in Healthy Volunteers
Official title: Riociguat (BAY 63-2521), a Stimulator of Soluble Guanylate Cyclase (sGC) - Cerebral Vasodilation and Headache Induction in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Headache
Lead sponsor: Danish Headache Center
Sponsor class: OTHER
First posted: 2022-10-17
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: OTHER

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.

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

Primary outcomes:
measure: Change in superficial temporal artery (STA) diameter from baseline to 90 minutes in healthy volunteers after receiving riociguat compared to placebo.
timeFrame: 0 - 90 minutes
Secondary outcomes:
measure: Change in middle cerebral artery (MCA) blood flow velocity in healthy volunteers after receiving riociguat compared to placebo.
timeFrame: 0 - 4 hours
measure: Changes in heart rate in healthy volunteers after receiving riociguat compared to placebo.
timeFrame: 0 - 4 hours
measure: 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.
timeFrame: 0 - 12 hours
Other outcomes:
measure: Severity of headache, if headache occurs, in healthy volunteers after receiving riociguat compared to placebo, rated on 11-point NRS from 0 ("no pain") to 10 ("worst pain imaginable") from baseline to 12 hours after intake.
timeFrame: 0 - 12 hours
measure: Headache characteristics, if headache occurs, in healthy volunteers after receiving riociguat compared to placebo, rated from baseline to 12 hours after intake.
timeFrame: 0 - 12 hours
measure: Reported use of rescue medication if headache occurs, in healthy volunteers, after receiving riociguat compared to placebo.
timeFrame: 0 - 12 hours
measure: Time course of STA diameter from baseline until 4 hours after receiving riociguat compared to placebo.
timeFrame: 0 - 4 hours
Locations:
city: Copenhagen
country: Denmark
facility: Danish Headache Center
state: Glostrup
Study officials:
affiliation: Danish Headache Center
name: Messoud Ashina, MD
role: PRINCIPAL_INVESTIGATOR
References: