| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe Alcohol Use Disorder |
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| E.1.1.1 | Medical condition in easily understood language |
| Severe Alcohol Use Disorder |
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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 | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10001584 |
| E.1.2 | Term | Alcohol abuse |
| E.1.2 | System Organ Class | 10037175 - Psychiatric disorders |
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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 |
Primary clinical objective:
The primary clinical objective is to compare the effect of a high dose of psilocybin (30 mg) relative to an active placebo (psilocybin, 5 mg) in conjunction with supportive psychotherapy provided during the course of a 28-day inpatient alcohol rehabilitation program, on alcohol consumption in terms of changes in the percentage of heavy drinking days from pre-hospitalization (up to 8 weeks pre-hospitalization) to 4 weeks post-hospital discharge (week 1 to 4) in patients with severe Alcohol Use Disorder (sAUD).
Primary Feasibility Objective
To assess the feasibility and safety of implementing psilocybin-assisted therapy as a complementary intervention during inpatient rehabilitation for sAUD, in terms of recruitment and retention rates (exploratory) as well as safety.
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| E.2.2 | Secondary objectives of the trial |
1. To compare the effect of a high dose psilocybin vs. active placebo in conjunction with supportive psychotherapy, on alcohol consumption: 1) changes in % of heavy drinking days 2) changes in # of drinks per day 3) changes in % days of abstinence from pre-hospitalization to 6 months post-hospital discharge.
2. To compare changes in depression, anxiety, subsyndromal trauma symptoms, alcohol craving, as well as health-related quality of life between both treatment arms.
3. To characterize the effect of a high dose of psilocybin compared to a low dose of psilocybin on neuroplasticity.
4. To characterize the effects of a high dose of psilocybin compared to a low dose of psilocybin on the two key neurocognitive systems identified by dual-process models of addiction.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Male or female patients between 21 and 64 years old, with a BMI between 17.5 and 30 kg/m2 who
- Want to stop or decrease their drinking;
- Agree to have all PATh sessions (preparation, administration, integration) and semi-structured interviews recorded;
- Have a diagnosis of Severe Alcohol Use Disorder (sAUD), according to the DSM-V (6 criteria or more), ascertained using the Mini International Neuropsychiatric Interview (M.I.N.I 7.0.2).
- Are not currently receiving any pharmacological treatment for sAUD and are willing to engage in all study requirements (including attending all study visits, preparatory sessions, integration sessions, follow-up sessions, and completing all study evaluations).
- Female participants of childbearing potential must have a negative serum pregnancy test at admission (day 1 +/-2) and a negative urine pregnancy test the day before psilocybin administration (day 19 +/-2).
- Women of childbearing potential must be using an effective, established method of contraception from inclusion until four weeks post-hospital discharge (5 weeks post-psilocybin administration). The following methods of contraception, if used properly and used for the duration of the study, are considered reliable: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: - oral, - intravaginal, - transdermal; progestogen-only hormonal contraception associated with inhibition of ovulation: - oral, - injectable, - implantable; intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomised partner (provided that partner is the sole sexual partner of the woman of child-bearing potential trial participant and that the vasectomised partner has received medical assessment of the surgical success; sexual abstinence (only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject). Note: female participants who are permanently sterilized (eg hysterectomy and/or bilateral salpingectomy) or post-menopausal (at least 48 consecutive weeks without menstruation) are not considered as being of childbearing potential.
- Men with a woman of childbearing potential partner should use a condom from inclusion until four weeks post-hospital discharge (5 weeks post-psilocybin administration).
- Good physical health with no unstable medical conditions, as determined by medical history, physical examination, routine blood labs, electrocardiogram, urine analysis, and urine toxicology.
- Willing to refrain from consuming psychoactive substances after enrolling in the study and during follow-up.
- Ability to provide voluntary written informed consent after receiving written information about the study protocol.
- Undergoing a 4-week alcohol detoxification program at the Brugmann University Hospital.
- Remaining abstinent from alcohol during the detoxification program (abstinence will be monitored using a breathalyzer during unannounced checks).
- Normal level of language comprehension (French).
- Affiliation to the Belgian social security system.
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| E.4 | Principal exclusion criteria |
- Allergy, hypersensitivity, or other adverse reaction to previous use of
psilocybin or other hallucinogens.
- Uncorrected hypertension.
- Cardiovascular diseases, hepatic diseases, gastroenterological diseases,
hematologic diseases, renal diseases, endocrine diseases, metabolic
diseases, inflammatory diseases, neurological diseases or any other somatic
condition that, in the opinion of the medical investigator (necessarily an MD),
would pose a risk to the participant's participation in the study.
- Other somatic condition that, in the opinion of the investigator, would pose a
risk to the participant's participation in the study.
- Decompensated hepatic cirrhosis, defined by Child B or C score.
- Serious abnormalities of complete blood count or chemistries, biological
abnormalities including TP < 50%, albumin < 35 g/L, total bilirubin > 35
μmol/L, leading to a Child B or C score.
- Abnormal electrocardiogram.
- Cognitive impairment (Folstein Mini Mental State Exam (Folstein et al., 1975)
score < 26).
- Alcohol withdrawal complication(s), head injury or stroke within the last 6
months.
- Current active ASD/PTSD.
- Lifetime history of schizophrenia spectrum disorders (schizophrenia,
schizoaffective disorder, unspecified), other psychotic disorders or bipolar
spectrum disorders (Type I, II, unspecified).
- Lifetime history of major depressive episode with psychotic features.
- Significant risk of suicide according to clinician assessment.
- Family history of schizophrenia spectrum disorders (schizophrenia,
schizoaffective disorder, unspecified), other psychotic disorders or bipolar
-Type I in first- or second-degree relatives.
Other substance use disorder (except for caffeine or nicotine) according to
DSM V criteria in the two months preceding inclusion to the study.
- Need to take medication with significant potential to interact with classical
psychedelics (e.g., antidepressants except SSRIs, antipsychotics,
psychostimulants, treatments for alcohol addiction as naltrexone or
acamprosate or baclofen, opioid agonist treatment as buprenorphine or
methadone, lithium, anticonvulsants, other dopaminergic or serotonergic
agents).
- History of hallucinogen use disorder, any use in the past 1 year, or >25 lifetime
uses.
- Pregnancy and breastfeeding, at screening visit and till dosing day.
- Known or suspected non-compliance.
- Previous enrolment into the current study.
- Enrolment of the investigator, his/her family members, employees and other
dependent persons.
- Patient subject to a legal protection measure (guardianship, curatorship or
safeguard of justice), patient unable to express consent and not subject to a
protection measure.
- Patients with language barrier (unable to follow the protocol or respond to clinical assessments). |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary clinical outcome: alcohol consumption in terms of changes in the percentage of heavy drinking days from baseline to four weeks post-hospital discharge, measured with the timeline follow-back method. Self-reported alcohol consumption data will be corroborated with the surrogate outcome blood phosphatidyl-ethanol concentration at four weeks post-hospital discharge.
Primary feasibility and safety outcome: recruitment rate and retention (feasibility), adverse events (safety).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Alcohol consumption will be measured at screening 1 and 2 (going back to 8 weeks pre-enrolment) as well as daily (phone diary) and weekly (medical visit) for four weeks post-hospital discharge.
Feasibility and safety: retention rate and adverse events will be recorded at each study visit and follow-up call, from screening 1 to 6 months post-hospital discharge. |
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| E.5.2 | Secondary end point(s) |
Alcohol consumption:
- changes in terms of percent heavy drinking days and drinks per days, from baseline to six months post-hospital discharge. Percent days abstinent, from hospital discharge to six months post-hospital discharge, measured with the timeline follow-back method.
(Neuro)cognitive measures:
- EEG-derived auditory long-term potentiation (neuroplasticity).
- EEG-derived-alcohol cue reactivity and inhibition.
- Brief Evaluation of Alcohol-Related Neuropsychological Impairments
Acute Psychedelic Effects:
- The Revised Mystical Experience Questionnaire-30 items,
- The Acceptance/Avoidance-Promoting Experiences Questionnaire,
- The Helioscope Questionnaire,
- A 20-item Monitor Rating Scale.
Psychological Processes:
- The Acceptance and Action Questionnaire II (psychological flexibility),
- The Multidimensional Assessment of Interoceptive Awareness Scale (interoception),
- The Watts Connectedness Scale (connectedness).
Alcohol-related parameters:
- Penn Alcohol Craving Scale (craving),
- Alcohol Abstinence Self-Efficacy Scale (abstinence self-efficacy),
- Readiness rulers (motivation to change drinking behaviour).
Additional clinical outcomes:
- Beck Depression Inventory (depressive symptoms),
- State-Trait Anxiety Inventory (anxiety symptoms),
- Substance Use Recovery Evaluator (substance use recovery),
- International Trauma Questionnaire (Subsyndromal trauma symptoms).
Expectancy and blinding:
- Blinding efficacy (belief of treatment arm allocation, therapist and participant),
- Stanford Expectations of Treatment Scale (expectancy).
Therapeutic alliance:
- Working Alliance Inventory-Short Revised.
Treatment Satisfaction:
- Visual Analog Scale.
Qualitative outcomes:
- Three semi-structured interviews to explore the evolution of participants’ expectations, representations and motivation regarding PATh, as well as characterize participant’s experience of PATh within the context of an inpatient detoxification program, and processes of changes in terms of changes in attitudes towards drinking, the self, others and the world; and resulting behavioral changes
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Alcohol: baseline, daily (diary) & weekly (visit) for 4w post-discharge, monthly (call) for next 5m. PEth: baseline & 4w post-discharge. EEG-derived LTP, alcohol cue reactivity & inhibition: pre-dosing (d13 +/-2) and 1x post-dosing (d27 +/-2). BEARNI: d14 (+/-2). 20-item Monitor RS: during psilo. session (d20 (+/-2), 5D-ASC, MEQ30: end psilo. session (d20 (+/-2). APEQ, Helioscope Q. : vd21 (+/-2). AAQII, MAIA, WCS, PACS, AASE, motivation, BDI, STAI, ITQ: baseline, 1d pre-psilo., 1w post-psilo., 4w, 3 & 6m post-discharge. SURE: baseline, 4w, 3 & 6m post-discharge. Blinding: end psilo. session (d20 (+/-2)). SETS: d1 (+/-2). WAI: d19 (+/-2). Tx Satis.: d27 (+/-2)). Interviews: d13 +/-2, d22 +/-2, d56 +/-3. |
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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 | 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 | 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 | Yes |
| 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) | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 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 | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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