COMP005 and COMP006: example approaches to challenges in randomized-controlled clinical trials with psychedelics

There is great interest in psychedelic treatments for a range of psychiatric conditions. Although many neuropsychiatric treatments have psychoactive effects, the acute effects of psychedelic compounds magnify challenges to designing and interpretating clinical trials. We describe some considerations in designing clinical trials with psilocybin and explore two ongoing Phase 3 registrational clinical trials with investigational COMP360 psilocybin for treatment-resistant depression (COMP 005 and COMP 006). Considerations include: (1) psychoactive drug effects that could be functionally unblinding, (2) inclusion of psychological support aimed at safeguarding patients during drug administration, and (3) how to adequately inform a non-daily treatment regimen. Ongoing trials with investigational COMP360 psilocybin include design elements to help address these considerations. COMP005 and COMP006 are double-blind RCTs designed to assess safety and efficacy. In addition to assessing efficacy, COMP005 provides safety data by comparing 25 mg COMP360 to inert placebo. COMP006 addresses some of the functional unblinding risks of an inert placebo-control by comparing the safety and efficacy of 25 mg COMP360 to a low active control dose of COMP360 (1 mg), while also including a moderately psychoactive active treatment arm (10 mg). COMP360 psilocybin is administered with non-directive psychological support rather than directive psychotherapy, and is designed as a manualized standard of care in clinical research with COMP360 psilocybin to safeguard study participants and ensure consistency across multi-site trials. Lastly, COMP005 and COMP 006 are 52-week trials that allow double-blind collection of data on the durability of effect and safety and efficacy of repeat dosing over 26 weeks.