TY - JOUR
T1 - Challenges and complexities in designing cluster headache prevention clinical trials
T2 - A narrative review
AU - Dodick, David W.
AU - Goadsby, Peter J.
AU - Ashina, Messoud
AU - Tassorelli, Cristina
AU - Hundemer, Hans Peter
AU - Bardos, Jennifer N.
AU - Wenzel, Richard
AU - Kemmer, Phebe
AU - Conley, Robert
AU - Martinez, James M.
AU - Oakes, Tina
N1 - Funding Information:
Sheridan Henness, PhD, and Janet Douglas, Vet MB, PhD, provided medical writing assistance for the outline and first and second drafts under the direction of the authors, on behalf of Rx Communications. Kelsey Nation, PhD, Antonia Baldo, BA, and particularly Andrea Metti, PhD, MPH, provided medical writing and editorial assistance for later drafts under the direction of the authors, on behalf of Syneos Health. Medical writing assistance was funded by Eli Lilly and Company.
Funding Information:
Sheridan Henness, PhD, and Janet Douglas, Vet MB, PhD, provided medical writing assistance for the outline and first and second drafts under the direction of the authors, on behalf of Rx Communications. Kelsey Nation, PhD, Antonia Baldo, BA, and particularly Andrea Metti, PhD, MPH, provided medical writing and editorial assistance for later drafts under the direction of the authors, on behalf of Syneos Health. Medical writing assistance was funded by Eli Lilly and Company.
Publisher Copyright:
© 2022 Eli Lilly and Company. Headache: The Journal of Head and Face Pain published by Wiley Periodicals LLC on behalf of American Headache Society.
PY - 2022/4
Y1 - 2022/4
N2 - Objective: To provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies. Background: Current guidelines for preventive treatment of CH are largely based on off-label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995. Methods/Results: Randomized controlled clinical trials were identified in the European and/or United States clinical trial registries with a search term of “cluster headache,” and manually reviewed. Cumulatively, there were 27 unique placebo-controlled prevention trials for episodic and/or chronic CH, of which 12 were either ongoing, not yet recruiting, or the status was unknown. Of the remaining 15 trials, 5 were terminated early and 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size. A systematic search of PubMed was also utilized to identify published manuscripts reporting results from placebo-controlled preventive trials of CH. This search yielded 16 publications, of which 7 were registered. Through critical review of trial data and published manuscripts, challenges and complexities encountered in clinical trials for the preventive treatment of CH were identified. For example, 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. In episodic CH, spontaneous remission as part of natural history, and the unpredictability and irregularity of cluster periods across patients present additional key challenges. Conclusions: Optimal CH trial design should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease, including unique outcome measures and endpoint timings for chronic versus episodic CH.
AB - Objective: To provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies. Background: Current guidelines for preventive treatment of CH are largely based on off-label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995. Methods/Results: Randomized controlled clinical trials were identified in the European and/or United States clinical trial registries with a search term of “cluster headache,” and manually reviewed. Cumulatively, there were 27 unique placebo-controlled prevention trials for episodic and/or chronic CH, of which 12 were either ongoing, not yet recruiting, or the status was unknown. Of the remaining 15 trials, 5 were terminated early and 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size. A systematic search of PubMed was also utilized to identify published manuscripts reporting results from placebo-controlled preventive trials of CH. This search yielded 16 publications, of which 7 were registered. Through critical review of trial data and published manuscripts, challenges and complexities encountered in clinical trials for the preventive treatment of CH were identified. For example, 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. In episodic CH, spontaneous remission as part of natural history, and the unpredictability and irregularity of cluster periods across patients present additional key challenges. Conclusions: Optimal CH trial design should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease, including unique outcome measures and endpoint timings for chronic versus episodic CH.
KW - chronic cluster headache
KW - clinical trial design
KW - episodic cluster headache
UR - http://www.scopus.com/inward/record.url?scp=85127425975&partnerID=8YFLogxK
U2 - 10.1111/head.14292
DO - 10.1111/head.14292
M3 - Review article
AN - SCOPUS:85127425975
SN - 0017-8748
VL - 62
SP - 453
EP - 472
JO - Headache
JF - Headache
IS - 4
ER -