A Phase II, Multicentre, Randomised, Double-blind, Controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Efficacy of COMP360 in Participants With Recurrent Major Depressive Disorder

Key Inclusion Criteria:

• Aged ≥18 years at Screening

• Major depression without psychotic features (single or recurrent episode as informedby the Diagnostic and Statistical Manual of Mental Disorders, 5th edition [DSM-5])

• If the current major depressive episode is the participant's first lifetime episodeof depression, the length of the current episode must be ≥3 months and ≤2 years atScreening

• MADRS total score ≥20 at Screening and Baseline to ensure at least moderate severityof depression.

• Failure to respond to an adequate dose and duration of up to four pharmacologicaltreatment for the current episode as determined through the Massachusetts GeneralHospital Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and using thesupplementary advice on additional antidepressants not included in MGH-ATRQ.

• At Screening, agreement to discontinue all prohibited medications.

Key Exclusion Criteria:

• Prior or ongoing bipolar disorder, any psychotic disorder, including schizophrenia,schizophreniform disorder, schizoaffective disorder, brief psychotic disorder (unless substance induced or due to a medical condition), antisocial personalitydisorder as assessed by a structured clinical interview (MINI 7.0.2)

• Lifetime paranoid, schizoid, schizotypal, histrionic, narcissistic personalitydisorder, or any ongoing serious psychiatric comorbidity based on medical historyand clinical judgement

• Borderline personality disorder as demonstrated by medical history or the MiniInternational Neuropsychiatric Interview Plus (MINI plus) - borderline personalitydisorder module

• Ongoing post-traumatic stress disorder, obsessive-compulsive disorder, or anorexianervosa as assessed by medical history and a structured clinical interview (MINI 7.0.2) Psychiatric inpatient within the past 12 months prior to Screening

• Use of electroconvulsive therapy, deep brain stimulation, or vagus nerve stimulationduring the current depressive episode

• Transcranial magnetic stimulation within the past six months prior to Screening

• Current enrolment in a psychological therapy programme that will not remain stablefor the duration of the study. Psychological therapies cannot have been initiatedwithin 30 days prior to Screening

• Exposure to COMP360 psilocybin therapy prior to Screening