Efficacy and Safety of Psilocybin (COMP360) in Adults with Treatment-Resistant Depression: A Phase III Randomized, Double-Blind, Controlled Trial

The primary objective of this Phase III, multicentre, randomised, double-blind, controlled study is to investigate the **efficacy** of two administrations of COMP360 (25 mg compared to 1 mg), administered with psychological support, in adult participants with treatment-resistant depression (TRD). The aim is to assess the improvement in symptoms of depression at Week 6. This is clinically relevant as treatment-resistant depression poses significant challenges in mental health management, and effective interventions are crucial for improving patient outcomes.

Secondary objectives include evaluating the **tolerability** of the treatment, which is essential for understanding the safety profile and potential side effects associated with the use of COMP360 in this patient population.

The clinical trial involves a total of **430 participants** diagnosed with **treatment-resistant depression**. The study population includes both male and female adults aged 18 years and older. Participants were selected based on specific criteria, including a diagnosis of major depression without psychotic features and a history of inadequate response to at least two different pharmacological treatments for the current depressive episode. The trial population is characterized by individuals who have successfully discontinued prohibited medications at least two weeks prior to the baseline visit. The study does not specify particular lifestyle considerations such as diet or physical activity. The inclusion of a vulnerable population is noted, although specific details are not provided. The trial aims to assess the efficacy of COMP360 in improving depressive symptoms over a six-week period.

The clinical trial is a **Phase III**, multicenter, randomized, double-blind, controlled study designed to evaluate the efficacy, safety, and tolerability of two initial administrations of COMP360 in participants with **treatment-resistant depression**. The trial involves the administration of **psilocybin** in capsule form, with doses of 25 mg and 1 mg, administered orally. The primary objective is to assess the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6. The trial is expected to commence recruitment on November 17, 2023, and conclude by November 29, 2025.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to determine eligibility based on criteria such as age (≥18 years), major depression without psychotic features, and a MADRS total score of ≥20. The screening will also confirm the presence of treatment-resistant depression, defined as a lack of response to at least two different pharmacological treatments. Following successful screening, participants will be randomized to receive either 25 mg or 1 mg of COMP360. The study includes follow-up visits to monitor the participants' response to treatment and any adverse events. The end-of-study visit will assess the final outcomes and gather data on the long-term effects of the treatment.

The expected duration of participant involvement is approximately 46 weeks, which includes the treatment period and follow-up assessments. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events. The trial is conducted under strict regulatory guidelines to ensure the safety and well-being of all participants.

The clinical trial involves the administration of **Psilocybin**, a chemical compound, in the form of a **capsule**. The product, identified by the sponsor product code COMP360, is manufactured by COMPASS PATHFINDER LIMITED. The active substance, **psilocybine**, is administered orally. The trial includes two different dosages: 25 mg and 1 mg. The maximum daily dose is 25 mg, with a total maximum dose of 100 mg over the course of the treatment period. The treatment period is set to a maximum of 46 days. The administration of the medication is conducted under controlled conditions, with psychological support provided to participants.

In this study, the **Psilocybin** capsules are used as the experimental treatment to assess their efficacy, safety, and tolerability in participants with treatment-resistant depression. The trial is designed as a Phase III, multicentre, randomised, double-blind, controlled study. The primary objective is to evaluate the improvement in symptoms of depression at Week 6 following two initial administrations of the medication. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol.

The efficacy of the investigational product, **Psilocybin**, will be assessed in a Phase III, multicentre, randomised, double-blind, controlled clinical trial. The primary endpoint for evaluating efficacy is the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6. This endpoint will compare the effects of two different doses of COMP360, specifically 25 mg versus 1 mg, administered with psychological support in participants with treatment-resistant depression (TRD).

The MADRS is a validated scale used to measure the severity of depressive episodes in patients with mood disorders. The total score will be collected at baseline and at Week 6 to determine the efficacy of the treatment. The trial aims to investigate the improvement in symptoms of depression following two administrations of COMP360. The study will include adult participants aged 18 years and older, diagnosed with major depression without psychotic features, and who have not responded to an adequate dose and duration of two to four different pharmacological treatments for the current episode.