Phase 3 Randomized Triple-Blind Crossover Study of Candesartan for Prophylaxis in Chronic Cluster Headache

The primary objective is to evaluate the prophylaxis efficacy of candesartan 32 mg compared to placebo in reducing the frequency of severe and very severe cluster headache attacks. This assessment is conducted across two four-week blinded periods relative to a two-week baseline phase. Secondary objectives include the evaluation of responder rates and patient reported outcomes.

The sponsor did not provide information regarding the total number of participants. The study population consists of male and female patients aged 18 to 70 years diagnosed with chronic cluster headache according to ICHD-3 criteria. Eligible individuals must have experienced the condition for more than one year, with typical headache periods lasting longer than five weeks. Participants are required to experience an average of between 4 attacks per week and 8 attacks per day of severe or very severe intensity during a two-week baseline period. Individuals with concomitant episodic migraine or episodic tension-type headache may be included if these can be clearly differentiated from cluster attacks. Women of childbearing potential must not be pregnant and are required to use specific contraception methods during the study period.

This multicenter, phase 3, randomized, placebo-controlled, triple-blind crossover study is designed to evaluate the prophylactic efficacy of candesartan 32 mg in adults diagnosed with chronic cluster headache. The research methodology involves comparing the test product against a placebo across two four-week blinded periods. The study sequence begins with a two-week baseline diary phase to establish pre-randomization attack frequency. Following this, participants undergo two distinct four-week treatment periods. The primary endpoint is the change from baseline in the weekly frequency of severe and very severe attacks. Secondary endpoints include changes in total attack frequency, responder rates, mean attack intensity, and the use of acute pharmacological therapies or inhaled oxygen. The study protocol incorporates assessments of disability, anxiety, and depression, as well as suicide-related events via the Columbia Suicide Severity Rating Scale. The overall duration of participant involvement is determined by the completion of the blinded phases and any subsequent required assessments.

The experimental medication is candesartan, an angiotensin-receptor antagonist. It is administered in the pharmaceutical form of PHF00245MIG. The dosage is 32 mg, provided via the oral route.

The comparator is a placebo consisting of encapsulated tablets designed to match the active ingredient.

This phase 3, randomized, placebo-controlled, triple-blind crossover study involves two four-week blinded periods following a two-week baseline phase. The protocol aims to evaluate the efficacy of the intervention in the prevention of chronic cluster headache by monitoring the frequency of severe and very severe attacks.

The primary efficacy endpoint is the change from baseline in the weekly frequency of severe and very severe cluster headache attacks during two four-week blinded phases. Secondary endpoints include the change from baseline in total attack frequency during the blinded phases and the 50% responder rate, defined as the proportion of participants experiencing a reduction of $\ge$50% in severe and very severe attacks per biweekly period compared to baseline. Additional responder rates are assessed at the 30% threshold for severe and very severe attacks. Other secondary measures include the time to sustained freedom of attacks for $\ge$2 months and the change in mean intensity of severe and very severe attacks. The frequency of acute pharmacological therapies and inhaled oxygen treatments is also evaluated.

Efficacy assessment includes the following parameters and instruments:

• The Patient Global Impression of Improvement (PGI-I) scale to determine the percentage of patients rating improvement at weeks 4, 12, and 20.
• The Cluster Headache Impact Questionnaire (CHIQ) to measure reductions in headache-specific disability at weeks 4, 12, and 20.
• The Hospital Anxiety and Depression Scale (HADS) subscales to identify improvements in anxiety or depression.
• The Columbia Suicide Severity Rating Scale (C-SSRS) to evaluate suicide-related events at baseline.
• The Patient Global Impression of Change (PGIC) to rate overall condition at week 8 of the open-label treatment period (OTP).