Psilocybin - a strategy of rapid antidepressant response in depression comorbid with cancer,a randomized double-blind study with the possibility of entering open extension

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Narodni Ustav Dusevniho Zdravi

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Psychiatry and Psychology [F] - Mental Disorders [F03]

Trial duration

22 Jul 2022 → ongoing

Decision date (initial)

2024-11-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Academic clinical trial is financially supported by grants and the sponsor organization

External identifiers

EU CT number

2024-517747-31-00

EudraCT number

2020-005037-32

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

evaluation of the effectiveness of psilocybin (active substance 1) in depression comorbid to oncological disease treatement in 4 weeks
(day 28) from its administration, compared to ketamine (active substance 2) and midazolam (control
substance)

Secondary objectives 11

1. evaluation of the onset and duration of the antidepressant effect of psilocybin and ketamine
2. evaluation of the rate of onset of the antidepressant effect of psilocybin and ketamine during the Substance Session (F4, OF4) using the BECK self-rating scale, which will be administered before the administration of the study medication at the beginning of the day and after the administration of the study medication at the end of the day
3. evaluation of the effect of psilocybin and ketamine (compared to midazolam) on quality of life, well-being and their potential mediators
4. evaluating the efficacy of psilocybin and ketamine (compared to midazolam) on nonspecific anxiety
5. the effect of psilocybin and ketamine on the patient subjectively perceived shift in life values ​​and the effect of psilocybin on existential distress including the patient's subjective attitude to life, subjectively perceived hopelessness and demoralization
6. the effect of psilocybin and ketamine on the patient's subjective perception of pain
7. evaluation of potential mediators of clinical response
8. comparison of the antidepressant effect of psilocybin and ketamine depending on the use of standard antidepressants during the clinical trial
9. evaluation of the antidepressant effect of psilocybin and ketamine in the open label part of the study
10. evaluation of the quality of the blinding of the study medication
11. evaluation of the safety and tolerability of psilocybin in patients with comorbid depression

Conditions and MedDRA coding

Depressive disorder comorbid with cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. Men and women aged 18‒75 years
2. A diagnosis meeting diagnostic criteria for a depressive syndrome (F41.2, F32.1, F32.2) comorbid with an oncological disease that: and) is at an advanced stage according to the judgment of the referring oncologist/hematoncologist/internist/paliatrician, or b) is with a poor prognosis (median survival of 5 years or less), or c) currently progressing, or d) shows recurrence, or e) is in the phase of controlled disease, since the oncological dg. at least 6 months have passed, but the patient still has reactive depressive comorbidity
3. In terms of antidepressant treatment, patients who: a) have not used and do not regularly use any standard antidepressants (SSRI, SNRI NaSSA, SARI, tricyclic and tetracyclic AD), b) are currently using standard antidepressants (SSRI, SNRI NaSSA, SARI, tricyclic and tetracyclic AD) for at least 6 weeks in a stable dose, but the treatment did not provide them with a satisfactory psychological state, c) they underwent psychosocial interventions (counseling, psychotherapy, consultation of the support and palliative team), but these interventions did not provide them with a satisfactory state.
4. The patient's cognitive ability to fully understand the information about CT and the study questionnaires.
5. Each patient must have a secured caregiver (close relative, relative) who will accompany the patient to the 1st visit, pick up the patient upon discharge after (each) session with the substance (or after discharge from hospitalization) and will be in personal contact with the patient for at least 5 days in week. This caregiver must be available throughout the clinical trial.
6. Participants of childbearing age/preserved fertility must agree to use prescribed methods of contraception and avoid pregnancy for the duration of participation in the clinical trial: a) Women – we require the correct use of at least a barrier contraceptive method (non-hormonal intrauterine device and/or condom and/or vaginal pessary) or sexual abstinence. Hormonal contraception is not required (combined hormonal contraception - in oral, vaginal or transdermal drug form / progestagen hormonal contraception combined with ovulation inhibition - in oral or injectable drug form / intrauterine device), but is accepted if the patient is already using it and it is not contraindicated due to to oncology dg.) b) Men – use of at least an adequate barrier contraceptive method (condom) or sexual abstinence.

Exclusion criteria 31

1. Oncological disease with known invasion of the CNS or other serious CNS disease (the exception is asymptomatic CNS involvement in hematological diseases that have been treated with intrathecal cytostatics or radiotherapy). In case of risk of invasion of the underlying disease into the CNS, the patient can only be included in the study if CNS imaging (CT/MR) was performed with negative findings.
2. Myocardial infarction less than 6 months ago
3. A stroke and/or TIA less than 6 months ago
4. Clinically significant peripheral vascular diseases (acute venous thrombosis, chronic venous insufficiency in the stage of leg ulcers, ischemic disease of the lower limbs in the stage of claudication)
5. Dyspnea of ​​any etiology higher than NYHA II, acute respiratory failure or severe respiratory insufficiency, sleep apnea syndrome
6. Severe thrombocytopenia < 30 x 10 9/l, resistant to substitution
7. Neurological foci findings
8. Impossibility of oral administration of the study medication in the form of capsules
9. Estimated patient survival time less than 4 months
10. The patient's condition does not allow compliance with the rules of concomitant treatment (see chapters 6.5 and 6.6 of the protocol)
11. Known intolerance or allergy to psilocybin, ketamine, midazolam or other drugs from the benzodiazepine group
12. Pregnancy or breastfeeding
13. Liver dysfunction with GGT, AST, ALT values ​​> 5x upper limit of normal, total bilirubin > 50 μmol/l
14. Cardiovascular instability in the sense of uncorrected hypertension (initial BP values ​​≥ 140/90 mm Hg – average value of 3 measurements), angina pectoris, heart failure or pre-existing clinically significant changes in the ECG (significant conduction disturbances, significant arrhythmias) or tachycardia (initial values ​​≥ 100 beats/min – average value from 3 measurements)
15. Myasthenia gravis
16. Epilepsy incl. history of isolated epileptic seizures
17. Renal insufficiency with a GFR value of less than 0.66 ml/s/1.73 m2 according to CKD-EPI (creatinine)
18. Known paraneoplastic syndrome or ectopic production of hormones by the primary tumor, within which hypercalcemia, Cushing's syndrome, hypoglycemia, SIADH or carcinoid syndrome could occur
19. Diabetes mellitus on insulin or corrected with oral antidiabetic drugs, if there is a history of clinically significant hypoglycemia
20. Glaucoma
21. Untreated or imperfectly compensated hyperthyroidism
22. Any current or anamnestic psychotic illness from the range of diagnoses F2x.x
23. Current or anamnestic bipolar affective disorder F31.x and manic phase F30.x
24. Current major depressive episode with psychotic symptoms F32.3 and F33.3
25. Presence of suicidal ideation/behavior on the C-SSRS Lifetime/Recent (L/R) version (specifically, a “yes” answer to question 5 in the past 1 month and/or any “yes” answer to the suicidal behavior questions in the past 3 months) and /or based on clinical examination
26. Organic mental disorders including symptomatic F00.x-F09.x
27. Psychotic disorders caused by the use of addictive substances (F10.x – F19.x), dissociative disorder (F44.x), eating disorders (F50.x), emotionally unstable, or borderline disorder (F60.3)
28. Current or anamnestic alcohol or drug addiction F1x.x. (except opioids and medicinal cannabis used in accordance with the controlled treatment of the underlying disease), if abstinence for at least 2 years cannot be proven
29. Undergoing electroconvulsive therapy less than 3 months ago
30. First-degree relative of a patient suffering from schizophrenia, other psychotic disorder (unless caused by a substance or medical condition)
31. Inappropriateness of patient inclusion based on the clinical judgment of the examining physician

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The effectiveness of psilocybin will be evaluated by comparison with the antidepressant ketamine and midazolam using the MADRS scale. Response and remission will be evaluated. Baseline is defined as the score obtained at Preparation Session 1 (9 - 7 days) prior to study medication administration. Response is defined as ≥ 50% reduction in MADRS total score from baseline, and remission is defined as ≤10 MADRS

Secondary endpoints 11

1. The rate of onset and duration of substance use will be assessed using the MADRS objective scale and the BECK self-report scale as change scores on day 1, day 4, 1 week (day 7), 4 weeks (day 28), 8 weeks (day 56 ), 16 weeks (day 112) and 24 weeks (day 224) from administration of study medication compared to baseline.
2. The BECK self-rating scale, which is administered before the administration of the study medication at the beginning of the day and after the administration of the study medication at the end of the day
3. The effect of psilocybin and ketamine on the patient's subjectively perceived quality of life and well-being will be assessed as a change in the score on the FACIT scale and its sub-scales 1 week (day 7), 4 weeks (day 28) and 24 weeks (day 224) from administration of study medication versus baseline.
4. Efficacy will be assessed as change in HAM-A objective scale and STAI self-report scores at day 1, day 4, 1 week (day 7), 4 weeks (day 28), 8 weeks (day 56), 16. weeks (112th day) and 24 weeks (224th day) from administration of study medication compared to baseline.
5. PEQ scale will be assessed 4 weeks (day 28) and 24 weeks (day 224) after administration of the study medication and will be evaluated as a change from baseline. The effect of psilocybin on existential distress including patients' subjective attitude towards life (LAP-R), subjectively perceived hopelessness (HAI) and demoralization (DS) will be assessed as change in scores on the respective scales at 1 week (day 7), 4 weeks (day 28 ) and 24 weeks (day 224) from administration of study medication.
6. This effect will be monitored using a pain visual analogue scale (VAS) at day 1, 1 week (day 7), 4 weeks (day 28) and 24 weeks (day 224) of study medication administration versus baseline.
7. Evaluation of the antidepressant effect of psilocybin and ketamine depending on the intensity of acute psychological effects during a session with the substance. Acute effects will be assessed by the patient at the end of the day after each session with psilocybin, ketamine and midazolam using the subjective 5D-ASCs and MEQ scales, which reflect the main psychological dimensions of intoxication affecting therapeutic antidepressant response.
8. The antidepressant effect will be compared in patients taking standard antidepressants during the clinical trial (AD-plus group) versus a group of patients not taking antidepressants (AD-free). We hypothesize that the clinical effect of psilocybin will be more pronounced in the AD-plus group than in the AD-free group.
9. Evaluation of the antidepressant effect in the open-label part of the study will correspond to the primary (2.2), secondary (2.3) and exploratory (2.3) objectives, with the evaluation not being blinded and only psilocybin and ketamine being compared (midazolam will not be administered).
10. The quality of the blinding of the study medication in the double-blind part of the study will be monitored using the BQQ Questionnaire. The estimate of administered study medication will be determined independently of the participant, therapist and co-therapist. The questionnaire will be filled in 4 weeks (day 28) from the administration of the study medication, at the end of Integration Session 3 after evaluation by an independent evaluator.
11. Safety will be assessed by changes in vital signs (blood pressure [BP], heart rate [TF]) during drug sessions, the BPRS scale, and suicidal ideation/behavior scores assessed by the C-SSRS, version Since Last Visit (SLV) at the end of the session with the substance, based on monitoring the incidence of adverse events throughout the study and further evaluating the persistent psychotropic effects of psilocybin using the PSQ scale 1 day after administration of the study medication.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Narodni Ustav Dusevniho Zdravi

Sponsor organisation

Narodni Ustav Dusevniho Zdravi

Address

Topolova 748

City

Klecany

Postcode

250 67

Country

Czechia

Scientific contact point

Organisation

Narodni Ustav Dusevniho Zdravi

Contact name

Jiří Horáček

Public contact point

Organisation

Narodni Ustav Dusevniho Zdravi

Contact name

Nikola Leca

Third parties 1

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 26 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications