This double-blind, randomized, placebo-controlled cross-over clinical trial aims to investigate the effects of riocigaut on migraine inducing properties in people with migraine.

The investigators believe that activation of sGC could play a role in migraine pathophysiology and propose that stimulation with riociguat causes migraine attacks in people with migraine.

Twenty-one people with migraine are expected to be included. They 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 heart rate, blood pressure and register possible headache/migraine including associated symptoms until 2 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.

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.
• An estimated average of between 1-5 migraine attacks per month.
• 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.