Evaluation of Psilocybine for Major Depressive Disorder in Cancer Patients: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the **efficacy** of a single 25 mg oral dose of psilocybin for treating **Major Depressive Disorder** (MDD) in patients with cancer, compared to an active placebo consisting of 1 mg psilocybin. The assessment focuses on the difference between groups in changes in depressive symptoms. This is clinically relevant as it explores a potential treatment option for MDD in cancer patients, who often experience significant psychological distress. The study targets individuals aged 20-80 years, currently experiencing a depressive episode, with a Patient Health Questionnaire (PHQ-9) score of 10 or higher, diagnosed with cancer more than one month prior, and with a life expectancy of at least 12 months. Participants must be willing to abstain from other psychotherapeutic or antidepressant treatments during the study, with a washout period of five half-lives.

The clinical trial involves participants diagnosed with **Major Depressive Disorder** and malignant tumors, classified under ICD-10 codes C00 to C97. The study population includes both male and female subjects aged between 20 and 80 years, who are currently experiencing a major depressive episode lasting at least 30 days but less than one year. Participants must have been diagnosed with cancer at least one month prior and have a life expectancy of at least 12 months. They are required to abstain from other psychotherapeutic or antidepressant treatments during the study period. The trial does not involve a vulnerable population. Participants must be able to read, speak, and understand Swedish, and they should have a physical functioning performance status of 0-2 according to WHO/ECOG criteria. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study to evaluate the efficacy of a single 25 mg oral dose of **psilocybin** in treating **Major Depressive Disorder** (MDD) in patients with a history of **malignant tumors**. The trial will involve participants aged 20 to 80 years who are experiencing a current depressive episode, have been diagnosed with cancer at least one month prior, and have a life expectancy of at least 12 months. The study will commence on May 15, 2024, and is expected to conclude by December 19, 2025, with recruitment starting on January 2, 2024.

Participants will be involved in the study for a total duration of 180 days. The trial will include several key visits: an initial screening visit to confirm eligibility, a dosing visit on Day 0, and follow-up visits on Days 8, 42, 90, and 180. The primary endpoint will be assessed using the **Montgomery-Åsberg Depression Rating Scale** (MADRS) total score from Day 0 to Day 42, with additional follow-up to monitor the initiation of antidepressant treatment or hospitalization for depression from Day 43 to Day 180. Secondary endpoints will include assessments using MADRS-S, **Sheehan Disability Scale** (SDS), **Generalized Anxiety Disorder 7-item** (GAD-7), **Hospital Anxiety and Depression Scale** (HADS), **Clinical Global Impression** (CGI), **EQ-5D-5L**, and **Assessment of Quality of Life 6D** (AQOL-6D) at various time points.

Participants will be randomly assigned to receive either the active treatment or an active placebo (1 mg psilocybin). The study will ensure blinding of both participants and investigators to the treatment allocation. Participants must agree to abstain from other psychotherapeutic or antidepressant treatments during the study period, with a washout period of five half-lives for any prior treatments. Early termination from the study may occur if a participant requires antidepressant treatment as determined by the study physician or if they are unable to adhere to study requirements.

The clinical trial involves the administration of **UCB-J**, an experimental medication formulated as an **injection**. The active substance in UCB-J is **(4R)-1-[(3-(11C)METHYLPYRIDIN-4-YL)METHYL]-4-(3,4,5-TRIFLUOROPHENYL)PYRROLIDIN-2-ONE**, which is of chemical origin. The medication is administered via **intravenous bolus injection or IV infusion**. The maximum daily dose is 400 MBq, with a total maximum dose of 1200 MBq over a treatment period of one day. Participant compliance with the dosing schedule will be monitored throughout the trial.

The study also includes the administration of **PEX010 Psilocybin Capsules**, which serve as both the test and comparator treatments. The test treatment consists of a single oral dose of **25 mg psilocybin**, while the comparator treatment involves a single oral dose of **1 mg psilocybin**. Both formulations are presented as **capsules** and are chemically derived. The maximum daily and total dose for the 25 mg capsule is 25 mg, and for the 1 mg capsule, it is 1 mg, with a treatment period of one day for each. The trial aims to evaluate the efficacy of the 25 mg dose in treating major depressive disorder in cancer patients, compared to the 1 mg dose, which acts as an active placebo. Compliance with the dosing regimen will be closely monitored to ensure adherence to the study protocol.

Efficacy in this clinical trial will be assessed by evaluating the impact of a single 25 mg oral dose of psilocybin on **major depressive disorder (MDD)** in patients with cancer-related depression. The primary endpoint for the acute phase, spanning from Day 0 to Day 42, is the endpoint score on the observer-rated Montgomery-Åsberg Depression Rating Scale (MADRS) total score. This will be analyzed using analysis of covariance (ANCOVA). For the follow-up phase, from Day 43 to Day 180, the primary endpoint is the number of days to the initiation of antidepressant treatment or hospitalization for depression, measured from Day 43 to the occurrence of either event.

Secondary endpoints include various assessments at specified time points. MADRS will be evaluated at Day 8 and at all evaluations between Day 0 and Day 42 using ANCOVA and mixed model repeated measures (MMRM), respectively. Additional assessments include the Self-Rated Montgomery-Åsberg Depression Rating Scale (MADRS-S), Sheehan Disability Scale (SDS), Generalized Anxiety Disorder 7-item scale (GAD-7), Hospital Anxiety and Depression Scale (HADS), Clinical Global Impression (CGI), EQ-5D-5L, and Assessment of Quality of Life 6-Dimension (AQOL-6D) at Day 42. Further evaluations of MADRS, MADRS-S, SDS, GAD-7, HADS, CGI, EQ-5D-5L, and AQOL-6D will occur at Day 90 and Day 180, with analyses conducted using ANCOVA and MMRM as appropriate.