|E.1 Medical condition or disease under investigation
|E.1.1||Medical condition(s) being investigated ||
|Treatment-Resistant Depressive Episode or Treatment-Resistant Recurrent Depressive Disorder of moderate to severe degree withoutpsychotic features
|E.1.1.1||Medical condition in easily understood language ||
|Treatment-resistant major depression
|E.1.1.2||Therapeutic area ||Psychiatry and Psychology [F] - Mental Disorders [F03]
|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 ||
|To investigate the safety and efficacy of 25 mg psilocybin (p.o.) in comparison to 5 mg psilocybin (low dose/active placebo) and 100 mg
niacin administered in a psychotherapeutic context in treatment-resistant major depression.
|E.2.2||Secondary objectives of the trial ||
|Secondary objectives are identifying potential (neuro)biological and psychological mediating/moderating variables of the treatment response
and/or well-being and additional outcome parameters.
|E.2.3||Trial contains a sub-study || No
|E.3||Principal inclusion criteria ||
|1) 25 to 65 years of age
2) Diagnosis of major depressive disorder (single and recurrent episodes) of moderate to
severe degree (HAM-D score ≥ 17) according to the Diagnostic and Statistical Manual of
Mental Disorders (DSM-5) without psychotic features. Included ICD-10 diagnoses are
F32.1, F32.2, F33.1, F33.2.
a. If single episode, duration must be ≥ 3 months.
3) Patients must meet criteria for treatment-resistance, defined as
a. no adequate improvement despite two adequate courses of antidepressant
treatment (6 weeks each, minimum) of different pharmacological classes in the
current depressive episode. Augmentation with an add-on treatment counts as a
4) Patients have discontinued any monoaminergic psychiatric medication (i.e. SRIs,
antipsychotic medication) for at least 2 weeks (fluoxetine: 5 weeks) before the first dosing
a. Patients who are still on any monoaminergic psychiatric medication at screening
must agree to down-titrate over an individualized down-titration schedule in close
supervision by their out-patient psychiatrist and the study team. The treating
psychiatrist must agree to supervise and monitor the down-titration and to
collaborate with the study team by signing a “treatment agreement form”.
b. If the treating psychiatrist refuses to monitor the down-titration, the patient has to
agree to down-titrate under supervision of clinicians in the outpatient clinics of the
two study sites or trial physicians and to come in for weekly monitoring visits.
5) The subjects are abstinent from alcohol (breathalyzer blood alcohol concentration (BAC)
level 0.00) and have a negative urine drug screening at day of dosing.
6) The subject must be medically stable based on clinical laboratory tests, medical history,
vital signs, and 12-lead ECG performed at screening. If the results of the serum chemistry
panel, hematology, or urinalysis are outside the normal reference ranges, retesting of an
abnormal lab value(s) that may lead to exclusion will be allowed once during the screening
phase. In 12-lead ECG, QTcF should be ≤ 450 ms for males or ≤ 470 ms for females and
PR-interval < 220 ms at screening. A retest of an abnormal ECG value will be allowed once
Prof. Dr. med. Gerhard Gründer
Central Institute of Mental Health (CIMH) Mannheim
Charité Berlin, Campus Mitte
EPIsoDE_01 Study Protocol_V04_09/2021 Page 68 of 153
in the screening phase. Blood pressure will be the average of 2 measurements. The subject
may be included only if the investigator judges the abnormalities or deviations from normal
to be not clinically significant or to be appropriate and reasonable for the population under
study. This determination must be recorded in the subject's source documents and initialed
by the investigator.
7) The subject must be willing and able to adhere to the prohibitions and restrictions specified
in this protocol.
8) The subject must sign an informed consent form indicating that he/she understands the
purpose of and procedures required for the study including peripheral biomarker monitoring
(i.e., blood) and is willing to participate in the study.
|E.4||Principal exclusion criteria||
|1) Currently comorbid or previously diagnosed DSM-5 diagnosis of a
a. major depressive episode with psychotic features/major depressive disorder with psychotic features (ICD-10: F32.3)
b. schizophrenia spectrum and other psychotic disorders, including schizotypal (personality) disorders, delusional disorder, brief psychotic
disorder, schizophreniform disorder, schizoaffective disorder, substance/medication-induced psychotic disorder and psychotic disorder
due to another medical condition (ICD-10: F20 – F29)
c. bipolar and related disorders (ICD-10: F30/F31)
d. cluster A personality disorders (paranoid personality disorder, schizoid personality disorder, schizotypal personality disorder) and/or borderline personality disorder
i. Patients will be carefully screened for presence of those personality
disorders by using the SCID-5-PD.
e. Post-traumatic stress disorder (PTSD; ICD-10: F43.1)
2) A family history (first-degree relative) of psychosis and/or bipolar disorder
3) The subject has a current or recent history of clinically significant suicidal ideation within the past 6 months, corresponding to a score of 4
(active suicidal ideation with some intent to act, without specific plan) or 5 (active suicidal ideation with specific plan and intent) for ideation on
the C-SSRS, or a history of suicidal behavior within the past 1 year, as validated by the C-SSRS at screening. Subjects with a prior suicide attempt of any sort, or prior serious suicidal ideation/plan > 6 months ago, should be carefully screened for current suicidal ideation and only included at the discretion of the investigator.
4) Current comorbid psychiatric diagnosis except their major diagnosis (inclusion criterion 3) in form of
a. Diagnoses mentioned under exclusion criterion 1)
b. Substance use disorder (except tobacco-related disorders/caffeinerelated disorders)
i. Alcohol consumption must be limited to ≤ 40 gram for men and ≤ 20 gram for women per day, e.g. ≤ two/one large beer (0.5 l) for men/women.
5) Use of classical psychedelics (i.e. LSD, psilocybin, mescaline, dimethyltryptamine) in the past year and or more than five life-time
uses of classical psychedelics.
6) Failure to establish sufficient rapport with the two therapists as judged by them after the first two preparation sessions
7) Lithium intake
8) The subject has undergone electroconvulsive therapy (ECT) within twelve months prior to screening or treatment with ketamine or esketamine within six months prior to screening.
9) The subject has received any prior treatment with vagal nerve stimulation, or a deep brain stimulation device.
|E.5 End points
|E.5.1||Primary end point(s)||
|Six weeks after the first dose, the number of treatment responders (≥ 50% reduction in symptoms as measured by HAM-D) will be significantly higher with the 25 mg dose as compared to the sub-therapeutic 5 mg dose of psilocybin, after having made sure in a preliminary step that the higher dose is superior to niacin (= negative control) in terms of the responder rate.
Hamilton Depression Scale (HAM-D): treatment response defined as ≥ 50% reduction in symptoms six weeks after the first dose.
|E.5.1.1||Timepoint(s) of evaluation of this end point||
|Timepoint of evaluation of the primary endpoint: 6 weeks after the first dose
|E.5.2||Secondary end point(s)||
(i) the treatment response defined as % reduction in HAM-D and the Beck Depression
Inventory (BDI)-II total score from baseline is different between nicotinamide, 5 mg
psilocybin and 25 mg psilocybin six weeks after the first dose.
(ii) the treatment response (responder rate and % change from baseline; assessed
with the HAM-D and BDI-II) will manifest already one day (BDI-II only) and one
week, respectively, after administration of 100 mg nicotinamide, 5 mg psilocybin, or
25 mg psilocybin.
(iii) the outcome (responder rate and % change from baseline; assessed with the HAMD
and BDI-II) after 12 weeks differs between the following 4 treatment arms:
1) 100 mg nicotinamide as first dose plus 25 mg psilocybin as second dose;
2) 5 mg psilocybin as first dose plus 25 mg psilocybin as second dose;
3a) 25 mg psilocybin as first dose plus 5 mg psilocybin as second dose;
3b) 25 mg psilocybin as both first and second dose.
(iv) rates of remitters (HAM-D total score < 8 points and BDI-II < 10) after one, six and
12 weeks will differ between the 4 treatment arms.
(v) outcomes will remain significant at the follow-up assessments, six and twelve
months after the first dose (follow-up).
• Vital signs
• Blood laboratory
• Suicidality: Columbia-Suicide Severity rating Scale (C-SSRS)
• Side effects: UKU side effects rating scale
• Dissociation: DSS-4
|E.5.2.1||Timepoint(s) of evaluation of this end point||
|Timepoints of evaluation of those endpoints:
- one day (BDI-II and safety assessments only), one week, six weeks, and 12 weeks after the first dose
- follow-ups: 6 and 12 months after the first dose
|E.6 and E.7 Scope of the trial
|E.6||Scope of the trial
|E.6.9||Dose response|| 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.22.214.171.124||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.8.1.3||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.8.2|| Comparator of controlled trial
|E.8.2.1||Other medicinal product(s)|| Yes
|E.8.2.2||Placebo || No
|E.8.2.4||Number of treatment arms in the trial||3
The trial involves single site in the Member State concerned
|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
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|E.8.9.1||In the Member State concerned years||4
|E.8.9.1||In the Member State concerned months||
|E.8.9.1||In the Member State concerned days||