Investigation of Sildenafil-Induced Headache in Male and Female Patients with Episodic Migraine Without Aura: A Randomized, Placebo-Controlled Trial

The primary objective of this clinical trial is to evaluate the **headache** and migraine-inducing effects of **sildenafil** in individuals diagnosed with episodic migraine without aura. The study aims to assess the occurrence of headache and migraine-like attacks in sildenafil- and placebo-treated men, as well as in sildenafil-treated women, who have migraine without aura. This investigation is clinically relevant as it seeks to understand the potential side effects of sildenafil, a medication commonly used for other indications, in a population susceptible to migraines. Understanding these effects is crucial for healthcare providers when considering treatment options for patients with migraine without aura.

The clinical trial involves a study population comprising **healthy** men and women diagnosed with **migraine without aura**. Participants are aged between 18 and 50 years, with a weight range of 60 to 90 kg. Both male and female subjects are included, and the trial does not involve a vulnerable population. Participants are required to be fluent in Danish or English and, for women, to use safe contraception throughout the study. The frequency of migraine attacks among participants ranges from one to six episodes within the last eight weeks. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is designed to evaluate the **headache**-inducing effects of **sildenafil** in individuals diagnosed with **migraine without aura**. This study is structured as a randomized, double-blind, placebo-controlled trial, ensuring that neither the participants nor the researchers know who is receiving the active treatment or the placebo, thus minimizing bias. The trial is expected to commence recruitment on September 1, 2024, and conclude by May 31, 2025. Participants will be involved in the study for a duration that aligns with the trial's timeline, with specific visit schedules outlined below.

Participants will first attend an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, frequency of migraine attacks, and language proficiency. Following successful screening, participants will be randomized to receive either sildenafil or a placebo. The primary endpoint is to assess the difference in the occurrence of migraine-like attacks between sildenafil- and placebo-treated men, as well as between sildenafil-treated men and women. Secondary endpoints include evaluating the difference in headache occurrence, heart rate, mean arterial pressure, and incidence of adverse events between the two groups.

Study visits will include baseline assessments, periodic follow-up visits to monitor health status and collect data on migraine occurrences, and an end-of-study visit to conclude participation. The expected length of participant involvement will be determined by the trial's duration, with conditions for early termination including non-compliance with study protocols or adverse health events. The trial aims to provide valuable insights into the effects of sildenafil on migraine without aura, contributing to the understanding of this condition and potential treatment approaches.

The clinical trial involves the administration of several treatments to evaluate their effects on individuals with **migraine** without aura. The primary experimental medication is **Sildenafil Orion 100 mg**, provided in the form of film-coated tablets. Each tablet contains the active substance **sildenafil**. The medication is administered orally, with the dosage and frequency determined by the study protocol. The purpose of this treatment is to assess its potential to induce headache and migraine-like attacks in the study population.

In addition to the experimental medication, the trial includes the use of **GLUCOSE MONOHYDRATE** as a placebo. This substance is also administered in tablet form and taken orally. The placebo is used to provide a control for comparison against the effects of sildenafil, ensuring that any observed effects can be attributed to the active treatment rather than other factors.

Furthermore, the study incorporates **Ibuprofen Teva 400 mg** film-coated tablets as an auxiliary treatment. **Ibuprofen** is a non-steroidal anti-inflammatory medication, administered orally, and is included to manage any potential inflammatory responses or pain that may arise during the trial. The dosage and administration schedule are aligned with standard clinical practices for ibuprofen use.

Another auxiliary treatment used in the trial is **Sumatriptan Accord 100 mg** film-coated tablets. **Sumatriptan succinate** is the active substance, and it is administered orally. This medication is included to provide relief from acute migraine attacks, should they occur during the study. The administration of sumatriptan follows established guidelines for its use in treating migraine episodes.

Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the protocol. This monitoring is crucial for maintaining the integrity of the study results and ensuring the safety of the participants. The trial is designed to rigorously evaluate the effects of sildenafil and other treatments on headache and migraine-like symptoms in the target population.

Efficacy in the clinical trial will be assessed by evaluating the primary and secondary endpoints related to the occurrence of migraine-like attacks and headaches in participants with **migraine without aura**. The primary endpoints include the difference in the occurrence of migraine-like attacks between sildenafil- and placebo-treated men, as well as between sildenafil-treated men and women. Secondary endpoints will assess the difference in the occurrence of headaches, heart rate, mean arterial pressure (MAP), and the incidence of adverse events between sildenafil- and placebo-treated men.