Investigation of Cilostazol-Induced Headache in Migraine Without Aura: A Randomized, Double-Blind, Placebo-Controlled Study in Male and Female Patients

The primary objective of this study is to investigate the role of the intracellular messenger **cAMP** in migraine by exploring potential sex-related differences in the response to **cilostazol** in individuals with migraine without aura. This is clinically relevant as it may provide insights into the pathophysiology of migraine and inform personalized treatment strategies based on sex differences. Understanding these differences could lead to more effective management of migraine, a condition that significantly impacts quality of life.

The clinical trial involves **healthy men and women** aged 18 to 65 years, diagnosed with episodic **migraine** without aura, as per the International Classification. Participants are required to weigh between 50 and 100 kg and must be fluent in Danish or English. The study population includes both genders, with no vulnerable populations selected. Participants are expected to maintain safe contraception throughout the study period. The sponsor has not provided information regarding the total number of participants. The trial population was selected based on specific inclusion criteria, ensuring a focus on individuals with the specified health condition and lifestyle considerations.

The clinical trial is designed to investigate the role of the intracellular messenger cAMP in **migraine** by exploring potential sex-related differences in response to **cilostazol** in individuals with migraine without aura. This study is a randomized, double-blind, placebo-controlled trial, integrating both Phase 1 and Phase 2 methodologies. The trial is expected to commence recruitment on November 1, 2025, and conclude by August 31, 2026. Participants will be involved in the study for a duration that includes an initial screening visit, multiple follow-up visits, and an end-of-study visit. The inclusion criteria specify that participants must be healthy men and women aged 18-65 years, with a diagnosis of episodic migraine without aura, weighing between 50-100 kg, and fluent in Danish or English. Women are required to use safe contraception throughout the study period.

The trial will involve the administration of **Cilostazol AL 100 mg Tabletten** or a placebo, with the primary endpoint being the difference in the incidence of migraine-like attacks during the observational period, up to 12 hours post-administration, between cilostazol- and placebo-treated men with migraine without aura. Secondary endpoints include differences in headache incidence, heart rate, mean arterial pressure, and adverse events during the same period. Participants will be randomly assigned to receive either the active drug or placebo, with neither the participants nor the investigators aware of the group assignments, ensuring the double-blind nature of the study.

Study visits will be sequenced as follows: an initial screening visit to confirm eligibility, followed by baseline assessments. Subsequent visits will involve the administration of the study drug or placebo, with close monitoring for any adverse effects. Follow-up visits will be scheduled to assess the primary and secondary endpoints, and the end-of-study visit will conclude the participant's involvement. The expected length of participant involvement is approximately 10 months, from the initial screening to the final visit. Conditions that may lead to early termination from the study include the occurrence of significant adverse events, non-compliance with study procedures, or withdrawal of consent by the participant.

The clinical trial involves the administration of **Cilostazol**, marketed as Cilostazol AL 100 mg Tabletten, which is a **tablet** formulation. The active substance, cilostazol, is of chemical origin and is administered orally. The dosage is 100 mg per tablet, and the frequency of administration is determined by the study protocol. This medication is provided by ALIUD PHARMA GMBH and is used to investigate its effects on individuals with migraine without aura, focusing on potential sex-related differences in response.

A **placebo** is also utilized in the study, consisting of white, round, convex tablets with a diameter of 8 mm. These tablets contain no active pharmaceutical ingredient and are composed of lactose monohydrate, potato starch, gelatin A, purified water, magnesium stearate, and talc. The placebo is prepared at the hospital pharmacy of Herlev and is administered orally to participants to serve as a control in the trial.

**Ibuprofen**, marketed as Ibuprofen Teva 400 mg, is included as an auxiliary treatment. It is provided in a **coated tablet** form, with each tablet containing 400 mg of the active substance ibuprofen, which is of chemical origin. The administration route is oral, and the medication is supplied by TEVA NEDERLAND B.V. This auxiliary treatment is used to manage symptoms as per the study protocol.

Another auxiliary treatment in the trial is **Sumatriptan**, marketed as Sumatriptan Accord 100 mg, in a **film-coated tablet** form. Each tablet contains 100 mg of sumatriptan succinate, a chemical compound. The administration is oral, and the product is provided by ACCORD HEALTHCARE B.V. This medication is used to address specific symptoms in participants as outlined in the study protocol.

Efficacy in this clinical trial will be assessed by evaluating the incidence of **migraine-like attacks** and headaches in participants with migraine without aura. The primary endpoints include the difference in the incidence of migraine-like attacks during the entire observational period, which lasts until 12 hours post-administration, between cilostazol- and placebo-treated men, as well as between cilostazol-treated men and women. Secondary endpoints will assess the difference in the incidence of headaches, heart rate, mean arterial pressure until 90 minutes post-administration, and the incidence of adverse events during the same observational period between cilostazol- and placebo-treated men.