| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Major Depressive Disorder |
|
| E.1.1.1 | Medical condition in easily understood language |
Depression
Condition characterised by low mood and inability to enjoy normally pleasurable experiences |
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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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057840 |
| E.1.2 | Term | Major depression |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057840 |
| E.1.2 | Term | Major depression |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
|
| 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 |
| How effective is a single dose of psilocybin for major depressive disorder against an an active gold-standard medical treatment (6-weeks of escitalopram)? |
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| E.2.2 | Secondary objectives of the trial |
How do the relevant interventions affect brain activity and can brain measures be used to predict treatment response?
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Significant Other Questionnaire
We will also ask patients’ significant others for brief ratings of the patients' mood before and after the study. The Significant Other Questionnaire has ten Likert scale items, such as ‘How often does the person seem tired? 0=always 1=often 2=half the time 3=rarely 4=never’ and will need to be completed twice (pre and post intervention).
The procedures for this sub-study will be as follows: at the screening, the patient will be asked if they consent to us contacting their significant other for the purpose of receiving ratings about the patient's mood before and after the clinical intervention. We will ask for the name and postal address and telephone number of the significant other. We will contact this person to explain that we are seeking mood ratings for the patient in question. If the are interested in participating, we will send them the information sheet and consent form and ask for them to return the signed consent form to us. We will then email/post them the pre-study questionnaire, or complete this with them over the telephone. We will explain that we will contact them at some point in the next six months to complete another rating. A few days before the patient has their 6 week follow up visit (before the blind is broken) the questionnaire will be sent to the significant other again.
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| E.3 | Principal inclusion criteria |
Key inclusion criteria:
1. Major depressive disorder (DSM-IV)
2. Depression of moderate to severe degree (17+ on the 21-item HAM-D).
2. No MRI contraindications
3. No SSRI contraindications
4. Has a GP or other mental healthcare professional who can confirm diagnosis
5. 18-80 years of age
6. Males and females
7. Sufficiently competent with English language
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| E.4 | Principal exclusion criteria |
Key exclusion criteria:
1. Current or previously diagnosed psychotic disorder
2. Immediate family member with a diagnosed psychotic disorder
3. Medically significant condition rendering unsuitability for the study (e.g., diabetes, epilepsy, severe cardiovascular disease, hepatic or renal failure etc.)
4. History of suicide attempts requiring hospitalisation.
5. History of mania
6. Psychiatric condition judged to be incompatible with establishment of rapport with therapy team and/or safe exposure to psilocybin, e.g. borderline personality disorder
7. Blood or needle phobia
8. Positive pregnancy test at screening or during the study
9. Current drug or alcohol dependence
10. No email access
11. Use of contraindicated medication
12. Patients presenting with abnormal QT interval prolongation at screening or with a history of this (QTc at screening above 440ms for men and above 470ms for women)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Baseline and main endpoint = 1 week after the psilocybin dosing session |
|
| E.5.2 | Secondary end point(s) |
fMRI measures
Other clinical ratings include:
o QIDS-16 (daily measure) [82]
o BDI II (two-weekly measure) [13]
o HAM-D [14]
o MADRS [34]
o Spielberger’s Trait Anxiety Inventory (STAI) - Trait [15]
o Warwick-Edinburgh Mental Wellbeing Scale (WEMWBS) [16]
o Snaith Hamilton Anhedonia Pleasure Scale (SHAPS) [17]
o Life Orientation Test (LOT-R) [18]
o Meaning in Life Questionnaire (MLQ) [19]
o Brief Resilience Scale (BRS) [20]
o Dysfunctional Attitudes Scale (DAS) [21]
o 44-item Big Five Inventory [22]
o Peters 21-item delusional inventory (PDI) [23]
o EASE anomalous subjective experience [24]
o Ruminative Responses Scale (RRS) [25]
o White Bear Suppression Inventory (WBSI) [26]
o Barrett Impulsivity Scale (BIS) [27]
o Brief Experiential Avoidance Questionnaire [28]
o Modified Tellegen Absoprtion Questionnaire (MODTAS) [29]
o Scale To Assess the Therapeutic Relationship (STAR) [30]
o Credibility/Expectancy Questionnaire [31]
o Connectedness to Nature Scale (CNS) [32]
o Political Perspective Questionnaire (PPQ)
o Social Connectedness Scale (SCS) [33]
o Bech-Rafaelsen Mania Rating Scale (MAS/MRS) [34]
o Revised Santa Clara brief compassion scale (5 items) (SCBCS) [35]
o Gratitude Questionnaire (GQ-6) [36]
o Short Suggestibility Scale (SSS) [37]
o Self-esteem: Rosenberg Self-Esteem Scale (4 items) (RSE) [38]
o Universality subscale of the Spiritual Transcendence Scale (STS) [39]
o Oxford Questionnaire on the Emotional Side-effects of Antidepressants (OQuESA) [40]
o Lauks Emotional Intensity Scale (LEIS) [41]
o The Suicidal Ideation Attributes Scale (SIDAS) [84]
o Sexual dysfunction (PRSEXDQ-SALSEX) [83]
o Barnes Akathisia Rating Scale (BARS) [85]
o Work Productivity and Activity Impairment Questionnaire (WPAI) [87]
o The Work and Social Adjustment Scale (WSAS) [88]
o Self-constructed Connectedness Questionnaire
o Standard Assessment of Personality – Abbreviated Scale (SAPAS) [96]
o Positive and Negative Syndrome Scale (PANSS) [97]
Measures completed just before treatment will include the:
o Spielberger’s Trait Anxiety Inventory (STAI) - State [15]
o The psychedelic predictor scale (self-constructed)
o The surrender scale [65]
Behavioural tasks will include:
o Emotional processing battery [88]
o Cued autobiographical memory task (AMT) [44]
o Prediction of Future Life Events (POFLE) [45]
o Torrance Test of Creative Thinking (TTCT) [46]
o Emotional response to music [89]
o California Verbal Learning Test (CVLT) [90]
o Digit Symbol Substitution Test (DSST) [91]
The following scales will be used to measure subjective states during the dosing sessions to be filled out at the end of the dosing session:
o Ego Dissolution Inventory (EDI) [47]
o Mystical Experience Questionnaire (MEQ) [48]
o 11 Dimension Altered States of Consciousness Scale (11D ASC) [49]
o Psychotomimetic States Inventory (PSI) [50]
o Visual Analogue Scales (VAS)
o Geneva Emotional Music Scales (GEMS) [51]
o The Challenging Experience Questionnaire [52]
o The Imperial Emotional Breakthrough Inventory (EBI)
o Near-Death Experience (NDE) scale [53]
o Ten Item Personality Inventory (TIPI) [88]
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
for fMRI: Baseline and 1 week after psilocybin dosing session
for other clinical ratings: Baseline, 1 week and 6 weeks post psilocybin dosing session (unless stated otherwise above). Exceptions: daily QIDS-16 done one day before and one day after dosing session, and BDI done every 2 weeks.
Behavioural tasks will be conducted at baseline, 1 week and 6 weeks post psilocybin dosing (where appropriate).
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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 | Yes |
| E.6.4 | Safety | No |
| 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 | No |
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Yes, it will be the last 6-month post-dosing interview conducted with the last study subject. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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