OBJECTIVES: Cluster Headache is a rare type of headache that affects about 1 to 2 people in every 1,000. It has been described as one of the most painful conditions. The objective of this study was to review the trends in design of pivotal clinical trials for Cluster Headache Disorder. METHODS: Systematic review was conducted to identify new and on-going pivotal clinical for Cluster Headache Disorder. The inclusion criteria were the indication of Cluster Headache Disorder and study start date of 2001 or after. The data field extracted were study title, intervention, sponsor, age subgroups, planned enrollment, study type, study design, completion date and outcome measures. RESULTS: Overall, 10 Phase III clinical studies with total enrollment of 830 patients were identified. The median enrollment for the studies was 60 patients. Eight of the 10 studies were for drugs and 2 were for devices. For primary outcomes 7 of the 10 trials measured frequency of headaches and only 1 trial measured headache relief (at 60 and 30 minutes). For secondary outcomes, most trials measured adverse events and proportion of patients with reduction in headache frequency. One of the trials also measured quality of life using instruments such as Pittsburgh Sleep Quality Index (PSQI, sleep), Clinical Global Impression (CGI-E), BDI-II (depression) and Functional Outcomes of Sleep Questionaire (FOSQ, sleep). Regarding sponsorship, 6 of 10 were sponsored by the industry (3 by Winston Laboratories, 2 by Eli Lilly and 1 by GlaxoSmithKline). CONCLUSIONS: This review provides an overview of on-going and future Phase III clinical trials for Cluster Headache Disorder. Study findings might be useful for design and conduct of new studies.