Cluster Headache Prevention Clinical Trials Need to Focus on Efficacy, Natural History of Disease


A narrative review revealed that cluster headache trials have been limited thus far, and that future trials should include novel outcome measures and adjusted end point timing.

David W. Dodick MD, neurologist, Department of Neurology, Mayo Clinic

David W. Dodick MD

Recently, a narrative review on randomized controlled trials from Europe and the United States revealed that trial designs in cluster headache (CH) should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease.1

The authors of the review, including David W. Dodick MD, neurologist, Department of Neurology, Mayo Clinic, noted that future trials could include unique outcome measures and end point timing for chronic versus episodic cluster headache (CCH vs ECH). Present guidelines for preventive treatment on CH are only supported by a limited amount of small randomized controlled trials and are largely based on off-label therapies.

According to the narrative search, there were 27 unique placebo-controlled prevention trials in total for ECH and/or CCH. From those trials found, 12 were either ongoing, not yet recruiting, or the status was unknown. As for the remaining 15 trials from the search, 5 were terminated early, while 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size.

The term “cluster headache” was used in the search for randomized controlled clinical trials identified in the European and/or United States clinical trial registries. Also, the researchers utilized a systematic search on PubMed to identify published manuscripts that reported results from placebo-controlled preventive trials of CH. From the PubMed search, 16 publications were yielded and 7 of the trials were registered. Overall, challenges and complexities from clinical trials for the preventive treatment of CH were identified through a critical review of trial data and published manuscripts.

Dodick and colleagues wrote as an example from their search that, “the excruciating pain associated with CH demands a suitably limited baseline duration, rapid treatment efficacy onset, and poses a specific issue regarding duration of investigational treatment period and length of exposure to placebo.” The pain and cranial autonomic symptoms of CH have been linked to activation of the trigeminovascular and cranial parasympathetic systems and the hypothalamus.2-4 Also spontaneous remission, as part of natural history and the unpredictability of cluster periods across patients, presents an additional challenge in ECH.1

The findings from this report suggest some considerations for randomized controlled trials in the future for the preventive treatment of CH. One suggestion is to ensure all results are published, regardless of study outcomes, to help ensure forward movement in identifying and improving preventive treatments for CH. Another suggestion is improving the design and conduct of these trials involving patients with CH, which should be driven by both patient needs and by the natural history of the disease, according to Dodick and colleagues.

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No statistical differences were found between REN and the standard of care medications, in any of the effectiveness outcomes of pain single-treatment pain relief and pain freedom, nor in consistency of pain relief and pain freedom.

The literature analysis also suggests that outcome measures and end point timings might need to be different for ECH and CCH when conducting clinical trials. Dodick et al noted, “For ECH, prevention of the active period is the strongest outcome measure for trials evaluating the efficacy of preventive treatment; however, this is almost impossible to verify due to the lack of reliable prodromal biomarkers or prediction tools.” Additionally, they noted that although the most appropriate outcome measure for CCH is represented by the reduction of attacks over a period of weeks, an association to the persistence of the effect may only be observed over longer periods of time.

Based on the review, considerations regarding patient selection, such as including a diverse population, and trial design are equally important as this will help in effort to ensure the study results are applicable to the broader CH population.

In an ECH trial, for example, Dodick and colleague suggested that the design would require the allowance of adequate acute treatments specific for CH for relief during clinical trials, either by limiting or forgoing completely medication-free prospective baseline periods. While in a CCH trial, it could be beneficial to consider treatment of history of refractoriness, although they noted that the definition of refractory would need to be clear to avoid exclusion of eligible participants.

Dodick and colleagues wrote that “[the] observations outlined in this review based on recent successes and difficulties of clinical trials of preventive treatments for ECH and CCH may be useful considerations for the design of future clinical trials.”

1. Dodick DW, Goadsby PJ, Ashina M, et al. Challenges and complexities in designing cluster headache prevention clinical trials: A narrative review [published correction appears in Headache. 2022 Jul;62(7):932]. Headache. 2022;62(4):453-472. doi:10.1111/head.14292
2. Hoffmann J, May A. Diagnosis, pathophysiology, and management of cluster headache. Lancet Neurol. 2018;17(1):75-83. doi:10.1016/S1474-4422(17)30405-2
3. Vollesen ALH, Snoer A, Beske RP, et al. Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial. JAMA Neurol. 2018;75(10):1187-1197. doi:10.1001/jamaneurol.2018.1675
4. Wei DY, Goadsby PJ. Cluster headache pathophysiology - insights from current and emerging treatments. Nat Rev Neurol. 2021;17(5):308-324. doi:10.1038/s41582-021-00477-w

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