Episodic CandClus2: A randomized, placebo-controlled, triple blind study of candesartan in adults with episodic cluster headache

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Helse Bergen HF, St. Olavs Hospital HF

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

Decision date (initial)

2025-11-04

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Norwegian Regional Health Authorities’ National Program for Clinical Treatment Research: KLINBEFORSK

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The main 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 CH attacks in participants with episodic cluster headache during a three-week blinded phase, compared to a one-week baseline (pre-randomization diary phase).

Secondary objectives 2

1. Responder rates
2. Patient reported outcomes

Conditions and MedDRA coding

episodic cluster headache

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Participant must be 18 to 70 years of age inclusive, at the time of signing the informed consent
2. Participants who have episodic cluster headacheaccording to ICHD-3 criteria present at inclusion
3. Participants who have history of at least one previous bout of CH lasting > 5 weeks
4. Participants that if they have other ongoing concomitant infrequent primary headache types, such as episodic migraine or episodic tension-type headache, can clearly differentiate them from attacks of CH based on the quality of pain and associated symptoms
5. Participants must experience between 4 attacks per week and a maximum of 8 attacks per day of severe or very severe intensity on average over the one-week baseline period
6. The cluster headache bout at the time of inclusion and baseline should exhibit characteristics consistent with the participant's typical bout
7. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies: No contraceptive/barrier requirements needed for male participants; For women of childbearing potential (WOCBP), it is required that there be no ongoing pregnancy or planned pregnancies during the study period. The use of a contraception method as listed in section 10.4.2 in the protocol is mandatory.
8. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol

Exclusion criteria 26

1. Chronic cluster headache excludes the participant from the study
2. CH due to known structural lesion
3. Any previous surgical treatment for CH like deep brain stimulation, microvascular decompression, gamma knife radiosurgery, neurostimulation or other invasive treatments
4. Current chronic migraine or chronic tension-type headache (migraine or tension-type headache that has met the ICHD-3 criteria for these conditions within the past 12 months)
5. Requiring detoxification from opioids (medication overuse headache (MOH) in itself is not an exclusion criterium)
6. Pregnancy, planning to get pregnant, inability to use contraceptives (See inclusion criteria, number 7), and lactating
7. Severe depression or other psychiatric disorder that may interfere with the treatment
8. Other severe chronic pain conditions that may interfere with the study, including trigeminal neuralgia
9. History of angioneurotic edema due to candesartan or other antihypertensive medication(s)
10. Primary hyperaldosteronism (Conn’s syndrome))
11. Any history of severe renal insufficiency
12. Hypersensitivity to candesartan, placebo or any of the excipients
13. Severe hepatic impairment and/or cholestasis
14. Current or recent (within last 12 months) treatment with candesartan for any indication
15. Current use of other antihypertensive medication(s) including verapamil and metoprolol (see section 6.9)
16. Recent initiation or change in dose (<4 months) of preventive CH medication with galcanezumab or other parenteral CGRP-inhibitors, or botulinum toxin (<6 months, fewer than 3 treatment sessions). Stable dosage with CGRP-inhibitors > 4 months and/or botulinum toxin > 6 months (at least 3 treatment sessions) is allowed
17. Treatment with greater occipital nerve blocks containing steroids or oral/parental prednisone/prednisolone < 4 weeks
18. Recent initiation (< 4 weeks) of oral preventive CH medications including indomethacin or oral gepants (preventive use)
19. Current use of potassium supplements
20. Current use of spironolactone
21. Current use of Lithium
22. Current or recent (< 4 weeks) participation in other relevant clinical studies
23. Current bout of ECH lasting >4 weeks before possible initiation of IMP. The onset of the bout is defined as the period when the headache frequency (of severe or very severe intensity) ranges from one every other day to eight per day for at least 7 consecutive days
24. Abuse of alcohol or illicit drugs
25. Women of child-bearing age without contraception
26. Inability to understand study procedures and to comply with them for the entire length of the study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 17

1. Change from baseline in total attack frequency of cluster headache attacks during the three-week blinded phase
2. 50% responder rate (proportion of participants with ≥50% reduction of severe and very severe attacks/week from baseline) over the blinded phase
3. 30% responder rate (proportion of participants with ≥30% reduction of severe and very severe attacks/week from baseline) over the blinded phase
4. 50% responder rate for each week in the blinded phase
5. Time to sustained freedom of attacks for ≥2 months after the current bout
6. Change from baseline in mean intensity of severe and very severe attacks over the blinded period
7. Change from baseline in weekly number of acute pharmacological therapies over the blinded period
8. Change from baseline in weekly number of inhaled oxygen treatments over the blinded period
9. Percentage of patients who rated their improvement as 'very much better' (score of 1) or 'much better' (score of 2) on the Patient Global Impression of Improvement (PGI-I) scale at week 3, 9 and 14 after baseline.
10. Percentage of patients who showed an 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
11. Assessment and evaluation of participants for suicide-related events (behavior and/or ideation) as measured by the Columbia Suicide Severity Rating Scale (C-SSRS)
12. Percentage of patients who reported a reduction of CH-specific disability at weeks 3, 9, and 14 after baseline as measured by the Cluster Headache Impact Questionnaire (CHIQ)
13. Change in the weekly frequency of severe/very severe cluster headache attacks during the OTP compared with the weekly frequency in the blinded phase
14. Time to recurrence of severe/very severe attacks in participants during OTP who were attack-free at the end of the blinded phase
15. Proportion of participants achieving ≥50% reduction in use of weekly acute treatments in OTP compared with baseline
16. Time to recurrence of severe/very severe attacks in the wash-out phase in participants taking candesartan in the OTP
17. Proportion of participants who rate their overall condition as “much improved” or “very much improved” on PGIC at Week 8 of OTP, referenced to their status at the end of the BTP

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Helse Bergen HF

Sponsor organisation

Helse Bergen HF

Address

Haukelandsveien 22

City

Bergen

Postcode

5021

Country

Norway

Scientific contact point

Organisation

Helse Bergen HF

Contact name

Torhild Vedeler

Public contact point

Organisation

Helse Bergen HF

Contact name

CandClus studiekontakt NorHEAD

Third parties 1

St. Olavs Hospital HF

Sponsor organisation

St. Olavs Hospital HF

Address

P. O. Box 3250, Torgarden Torgarden

City

Trondheim

Postcode

7006

Country

Norway

Scientific contact point

Organisation

St. Olavs Hospital HF

Contact name

Christian Samsonsen

Public contact point

Organisation

St. Olavs Hospital HF

Contact name

NorHEAD Studieinfo

Third parties 1

Sponsor responsibilities

Article 77 compliance

Helse Bergen HF

Contact point sponsor

Helse Bergen HF

Article 77 implementation

Helse Bergen HF

Locations

2 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 29 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications