A phase 3 randomized, placebo-controlled, triple blind parallel-group study of candesartan in adults with episodic cluster headache (Episodic CandClus2)

The primary objective of this study is to assess the prophylactic efficacy of the angiotensin-receptor antagonist candesartan 32 mg compared with placebo in reducing the frequency of severe and very severe cluster headache attacks in participants with episodic cluster headache during a three-week blinded phase, compared to a one-week baseline pre-randomization diary phase. This objective addresses the clinical need for effective preventive treatment options in patients experiencing episodic cluster headache, a debilitating primary headache disorder characterized by severe unilateral pain and associated autonomic symptoms.

The secondary objectives include:

• Evaluation of responder rates to determine the proportion of participants achieving clinically meaningful reductions in attack frequency

• Assessment of patient reported outcomes to capture the impact of treatment on quality of life and symptom burden from the patient perspective

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population consisted of adults with **episodic cluster headache** according to **ICHD-3 criteria**, aged between **18 and 70 years** at the time of informed consent. Both **male and female participants** were included in the trial. Eligible participants were required to have a history of at least one previous bout of cluster headache lasting more than 5 weeks and must have been experiencing between 4 attacks per week and a maximum of 8 attacks per day of **severe or very severe intensity** on average during the one-week baseline period. The cluster headache bout at inclusion had to exhibit characteristics consistent with the participant's typical bout. Participants with other infrequent primary headache types, such as **episodic migraine** or **episodic tension-type headache**, were eligible provided they could clearly differentiate these from cluster headache attacks based on pain quality and associated symptoms. Women of childbearing potential were required to use appropriate contraceptive methods and confirm no ongoing or planned pregnancies during the study period. The trial did not involve vulnerable populations.

This is a phase 3 randomized, placebo-controlled, triple-blind, parallel-group clinical trial evaluating the prophylactic efficacy of candesartan in adults with episodic cluster headache. The study compares candesartan 32 mg administered orally with matching placebo to assess reduction in the frequency of severe and very severe cluster headache attacks. Candesartan, an angiotensin-receptor antagonist and antihypertensive drug, will be administered as overencapsulated tablets to ensure blinding of the investigational products. The maximum daily dose is 32 mg with a maximum total dose of 560 mg over a treatment period of 3 weeks during the blinded phase.

Eligible participants must be between 18 and 70 years of age and meet ICHD-3 criteria for episodic cluster headache at inclusion. Participants must have a history of at least one previous bout of cluster headache lasting more than 5 weeks and experience between 4 attacks per week and a maximum of 8 attacks per day of severe or very severe intensity on average during the one-week baseline period. The cluster headache bout at the time of inclusion should exhibit characteristics consistent with the participant's typical bout. Participants must be capable of differentiating cluster headache from other primary headache types such as episodic migraine or episodic tension-type headache based on pain quality and associated symptoms. Women of childbearing potential must use appropriate contraception methods and have no ongoing or planned pregnancies during the study period.

The primary endpoint is the change in weekly frequency of severe and very severe cluster headache attacks from the pre-randomization diary period during the three-week blinded phase. Secondary endpoints include change from baseline in total attack frequency, 50% and 30% responder rates over the blinded phase, 50% responder rate for each week in the blinded phase, time to sustained freedom of attacks for at least 2 months after the current bout, change in mean intensity of severe and very severe attacks, and change in weekly number of acute pharmacological therapies and inhaled oxygen treatments. Additional secondary endpoints assess patient-reported outcomes using the Patient Global Impression of Improvement scale, Hospital Anxiety and Depression Scale subscales, Columbia Suicide Severity Rating Scale, and Cluster Headache Impact Questionnaire at multiple time points. Further endpoints evaluate outcomes during the open-label treatment phase including changes in attack frequency, time to recurrence of attacks, reduction in use of acute treatments, and patient global impression of change.

The study includes a one-week pre-randomization baseline diary phase followed by a three-week blinded treatment phase. Participants who complete the blinded phase may continue into an open-label treatment phase and subsequent wash-out phase. The total estimated duration of the trial extends from the estimated recruitment start date in November 2025 to the estimated end date in December 2036. Participant involvement duration varies depending on progression through study phases. Conditions that may lead to early termination from the study include non-compliance with protocol requirements, withdrawal of informed consent, safety concerns, or investigator decision based on participant's best interest.

The experimental medication investigated in this trial is **candesartan**, an **angiotensin-receptor antagonist** classified as an antihypertensive drug. Candesartan is administered in **encapsulated tablet** form to ensure blinding of the investigational products. The encapsulation involves overencapsulation of commercially sourced candesartan tablets. The **active substance** is candesartan of chemical origin. The **route of administration** is **oral**. The **dosage** is **32 mg** as the maximum daily dose. The **maximum total dose** administered during the treatment period is **560 mg**. The **treatment period** extends for **3 weeks** during the blinded phase of the study. The dosage is expressed in **milligrams**.

The comparator treatment used in this trial is a **placebo** matching the active ingredient. The placebo is provided as **encapsulated tablets** to maintain blinding and ensure that the placebo is indistinguishable from the active treatment. The placebo formulation is designed to match the appearance and administration characteristics of the candesartan encapsulated tablets. The route of administration for the placebo is also oral, consistent with the active treatment arm.

Efficacy will be assessed through multiple parameters evaluating the impact of treatment on **cluster headache** attack frequency, severity, and patient-reported outcomes. The primary endpoint is the change in the weekly frequency of severe and very severe **cluster headache** attacks from the pre-randomization diary during the three-week blinded phase. Secondary endpoints include the change from baseline in total attack frequency of **cluster headache** attacks during the three-week blinded phase, 50% responder rate (proportion of participants with ≥50% reduction of severe and very severe attacks per week from baseline) over the blinded phase, and 30% responder rate (proportion of participants with ≥30% reduction of severe and very severe attacks per week from baseline) over the blinded phase. Additional secondary endpoints comprise 50% responder rate for each week in the blinded phase, time to sustained freedom of attacks for ≥2 months after the current bout, and change from baseline in mean intensity of severe and very severe attacks over the blinded period.

Efficacy assessment also includes changes in treatment utilization, specifically the change from baseline in weekly number of acute pharmacological therapies over the blinded period and the change from baseline in weekly number of inhaled oxygen treatments over the blinded period. Patient-reported outcomes will be evaluated using the Patient Global Impression of Improvement (PGI-I) scale at week 3, 9, and 14 after baseline, with measurement of the percentage of patients who rated their improvement as 'very much better' or 'much better'. The Hospital Anxiety and Depression Scale (HADS) will assess improvement of more than 1 point on the HADS Anxiety (HADS-A) and/or Depression (HADS-D) subscales at weeks 3, 9, and 14 after baseline. The Columbia Suicide Severity Rating Scale (C-SSRS) will be used for assessment and evaluation of participants for suicide-related events (behavior and/or ideation). The Cluster Headache Impact Questionnaire (CHIQ) will measure the percentage of patients who reported a reduction of **cluster headache**-specific disability at weeks 3, 9, and 14 after baseline.

During the open treatment phase, efficacy parameters include the change in the weekly frequency of severe/very severe **cluster headache** attacks compared with the weekly frequency in the blinded phase, time to recurrence of severe/very severe attacks in participants who were attack-free at the end of the blinded phase, and proportion of participants achieving ≥50% reduction in use of weekly acute treatments compared with baseline. Additional assessments during the open treatment phase include time to recurrence of severe/very severe attacks in the wash-out phase in participants taking **candesartan** in the open treatment phase and proportion of participants who rate their overall condition as "much improved" or "very much improved" on Patient Global Impression of Change (PGIC) at Week 8 of the open treatment phase, referenced to their status at the end of the blinded treatment phase.