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

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

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.

Study Overview

• Status: Completed
• Conditions: Headache
• Intervention / Treatment: Drug: Placebo; Drug: Dose Riociguat 2,5 or 5mg; Drug: Riociguat

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.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Glostrup
    • Copenhagen, Glostrup, Denmark, 2600
      • Danish Headache Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo orally	Drug: Placebo; Placebo
Experimental: Dose Riociguat 2,5 or 5mg; Riociguat dose finding pilot experiment, 2,5mg and 5mg	Drug: Dose Riociguat 2,5 or 5mg; A selective stimulator of soluble guanylate cyclase (sGC)
Active Comparator: Riociguat; Riociguat orally	Drug: Riociguat; A selective stimulator of soluble guanylate cyclase (sGC)

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
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
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.	Measured by heart rate	0 - 4 hours

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Data will be collected with a questionnaire.	0 - 12 hours
Headache characteristics, if headache occurs, in healthy volunteers after receiving riociguat compared to placebo, rated from baseline to 12 hours after intake.	Data will be collected with a questionnaire.	0 - 12 hours
Reported use of rescue medication if headache occurs, in healthy volunteers, after receiving riociguat compared to placebo.	To evaluate need for rescue medication. Data will be collected with a questionnaire.	0 - 12 hours
Time course of STA diameter from baseline until 4 hours after receiving riociguat compared to placebo.	Measured by high resolution ultrasonography.	0 - 4 hours

Collaborators and Investigators

• Sponsor: Danish Headache Center
• Investigators: Principal Investigator: Messoud Ashina, MD, Danish Headache Center

Study record dates

Study Major Dates

• Study Start (Actual): October 26, 2022
• Primary Completion (Actual): June 1, 2023
• Study Completion (Actual): June 1, 2023

Study Registration Dates

• First Submitted: October 10, 2022
• First Submitted That Met QC Criteria: October 12, 2022
• First Posted (Actual): October 17, 2022

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 3, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Headache; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Riociguat
• Other Study ID Numbers: H-22020347

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No