E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment-Resistant Depression (P-TRD) |
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E.1.1.1 | Medical condition in easily understood language |
Treatment-Resistant Depression |
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E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Mental Disorders [F03] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025454 |
E.1.2 | Term | Major depressive disorder, recurrent episode |
E.1.2 | System Organ Class | 100000004873 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025463 |
E.1.2 | Term | Major depressive disorder, single episode |
E.1.2 | System Organ Class | 100000004873 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main purpose of this study is to allow COMPASS to determine the optimal dose of psilocybin, either 10 mg or 25 mg. The intent of the primary efficacy analysis is to demonstrate superiority of at least one therapeutic dose of psilocybin (10 mg or 25 mg) versus the 1 mg psilocybin via the following objectives:
The primary objective of this study is to evaluate the efficacy of psilocybin (25 mg or 10 mg) compared to 1 mg, administered under supportive conditions to adult participants with TRD, in improving depressive symptoms, as assessed by the change in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from Baseline. Baseline is defined as the assessment score obtained on Day -1. The primary timepoint is Week 3; this variable will be analysed for the change from Baseline to Day 1, and Weeks 1, 3, 6, 9, and 12.
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
To assess the efficacy of psilocybin compared to 1 mg psilocybin on: o Proportion of participants with response defined as a ≥ 50% decrease in MADRS total score from Baseline to Week 3. This will also be assessed at Day 1 and at Weeks 1, 6, 9, and 12. o The proportion of participants who have a sustained response at Week 12. Sustained response is defined as the proportion of patients fulfilling response criteria at any visit up to and including Week 3, that also fulfills response criteria at all subsequent visits up to and including Week 12. Response is defined as ≥ 50% decrease in MADRS total score from Baseline.
To evaluate the safety and tolerability of psilocybin in participants with TRD based on adverse events (AEs), changes in vital signs, and suicidal ideation/behaviour (measured using the Columbia-Suicide Severity Rating Scale [C SSRS]) score at all visits.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Participants meeting all the following inclusion criteria at Screening (V1) should be considered for admission into the study:
1. Signed Informed Consent Form (ICF). 2. 18 years of age or older at Screening (V1). 3. At least moderate MDD (single or recurrent episode as informed by DSM-5; if single episode, duration of ≥ 3 months and ≤2 years) based on medical records, clinical assessment and documented completion of the version 7.0.2 MINI. 4. HAM-D-17 (17-item) score ≥18 at Screening (V1) and at Baseline (V2). 5. Failure to respond to an adequate dose and duration of 2, 3, or 4 pharmacological treatment for the current episode as determined through the MGH ATRQ and using the supplementary advice on additional antidepressants not included in MGH ATRQ (Appendix III). Augmentation with an add on treatment counts as a second treatment, provided it is approved for the adjunctive treatment of MDD in that country. 6. McLean Screening Instrument for Borderline Personality Disorder < 7 at Screening (V1). 7. Have successfully discontinued all antidepressant medications at least 2 weeks prior to Baseline (V2). 8. Ability to complete all protocol required assessment tools without any assistance or alteration to the copyrighted assessments, and to comply with all study visits.
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E.4 | Principal exclusion criteria |
Participants meeting any of the following exclusion criteria at Screening (V1) will not be enrolled in the study:
Psychiatric Exclusion Criteria: 1. Current or past history of schizophrenia, psychotic disorder (unless substance induced or due to a medical condition), bipolar disorder, delusional disorder, paranoid personality disorder, schizoaffective disorder, or borderline personality disorder, or any serious psychiatric comorbidity as assessed by medical history and a structure clinical interview (version 7.0.2 MINI). 2. Prior electroconvulsive therapy and/or intravenous ketamine for current episode. 3. Current cognitive behavioural therapy (CBT) that will not remain stable for the duration of the study. CBT cannot be initiated within 21 days of baseline. 4. Current (within the last year) alcohol or substance abuse as informed by DSM-5 at Screening (V1). 5. Significant suicide risk as defined by (1) suicidal ideation as endorsed on items 4 or 5 on the C-SSRS within the past year, at Screening or at Baseline, or; (2) suicidal behaviors within the past year, or; (3) clinical assessment of significant suicidal risk during subject interview. 6. Depression secondary to other severe medical conditions. 7. Other personal circumstances and behaviour judged to be incompatible with establishment of rapport or safe exposure to psilocybin, including exposure to psilocybin within the past year and use of psychedelics, such as ayahuasca, during the current depressive episode.
General Medical Exclusion Criteria: 8. Women who are pregnant, nursing, or planning a pregnancy. Participants who are sexually active must agree to use a highly effective contraceptive method throughout their participation in the study. Women of child-bearing potential must have a negative urine pregnancy test at Screening (V1) and Baseline (V2). 9. Cardiovascular conditions: recent stroke (<1 year from signing of ICF), recent myocardial infarction (<1 year from signing of ICF), hypertension (blood pressure >140/90 mmHg) or clinically significant arrhythmia within 1 year of signing the ICF. 10. Uncontrolled insulin-dependent diabetes. 11. Seizure disorder. 12. Positive urine drug screen for illicit drugs or drugs of abuse at V1 and/or V2. Any positive urine drug test will be reviewed with participants to determine the pattern of use and eligibility will be determined at the investigator’s discretion in conjunction with the medical monitor. 13. Current enrolment in any investigational drug or device study or participation in such within 30 days of Screening (V1). 14. Current enrolment in an interventional study for depression or participation in such within 30 days of Screening (V1). 15. Abnormal and clinically significant results on the physical examination, vital signs, ECG, or laboratory tests at Screening (V1). 16. Any other clinically significant cardiovascular, pulmonary, gastrointestinal, hepatic, renal or any other major concurrent illness that, in the opinion of the investigator, may interfere with the interpretation of the study results or constitute a health risk for the participant if he/she takes part in the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the change in MADRS total score from Baseline (Day -1) to 3 weeks post psilocybin. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The secondary endpoints are: • The proportion of participants with a response (defined as a ≥50% improvement in MADRS total score from Baseline) at Week 3 post-psilocybin. • The proportion of participants with remission (defined as a MADRS total score ≤10) at Week 3 post-psilocybin. • The proportion of participants who have a sustained response at Week 12.Sustained response is defined as the proportion of patients fulfilling response criteria at any visit up to and including Week 3, that also fulfills response criteria at all subsequent visits up to and including Week 12. Response is defined as ≥ 50% decrease in MADRS total score from Baseline. • Time to event measures: restart antidepressant medication for any reason, restart medication for continuing depressive symptoms, and relapse from a previously recovered state (clinical judgement, supported by the QIDS-SR-16). Participants who withdraw from the study will be censored from the time to event analysis.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
3 treatment arms: 25 mg treatement, 10 mg treatment, 1 mg treatment |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
United States |
Denmark |
Finland |
Germany |
Ireland |
Netherlands |
Norway |
Portugal |
Spain |
United Kingdom |
Czechia |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 30 |