Evaluation of Psilocybine, Ketamine Hydrochloride, and Midazolam in Treating Depression Comorbid with Cancer: A Randomized Double-Blind Clinical Trial
- Trial ID
- 2024-517747-31-00
- Protocol
- PSIKET_002CZE
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is the **evaluation** of the effectiveness of **psilocybin** in treating depression comorbid with cancer over a period of 4 weeks (day 28) following its administration. This is compared to the effects of **ketamine** and **midazolam**. This objective is clinically relevant as it aims to identify a rapid antidepressant strategy for patients with depression associated with oncological conditions, potentially improving their mental health outcomes during cancer treatment.
Secondary objectives include:
- Evaluation of the onset and duration of the antidepressant effect of psilocybin and ketamine.
- Assessment of the rate of onset of the antidepressant effect during the Substance Session using the BECK self-rating scale.
- Comparison of the effects of psilocybin and ketamine on quality of life, well-being, and their potential mediators, as well as on nonspecific anxiety.
- Investigation of the effect of psilocybin and ketamine on patients' subjective perception of life values, existential distress, and pain.
- Evaluation of potential mediators of clinical response and comparison of the antidepressant effect depending on the use of standard antidepressants during the trial.
- Assessment of the antidepressant effect in the open-label part of the study and the quality of the blinding of the study medication.
- Evaluation of the safety and tolerability of psilocybin in patients with comorbid depression.
Participants
The clinical trial involves a study population comprising **men and women** aged 18 to 75 years, diagnosed with **depressive disorder comorbid with cancer**. The trial does not specify the total number of participants, as the sponsor has not provided this information. Participants were selected based on their diagnosis of a depressive syndrome comorbid with an oncological disease, which is either at an advanced stage, has a poor prognosis, is currently progressing, shows recurrence, or is in a controlled phase for at least six months. The trial includes individuals who have not used standard antidepressants or have used them without achieving satisfactory results, as well as those who have undergone psychosocial interventions without satisfactory outcomes. Participants must have the cognitive ability to understand the clinical trial information and questionnaires. A secured caregiver is required to accompany the participant during the trial. Participants of childbearing age must agree to use prescribed methods of contraception. The trial includes both male and female subjects and considers a vulnerable population due to the nature of the comorbid conditions.
Plans and Procedures
The clinical trial is designed to evaluate the **effectiveness** of **psilocybin** in treating depressive disorder comorbid with cancer. This study is a randomized, double-blind, controlled trial with the possibility of entering an open extension phase. The trial involves three active substances: psilocybin, **ketamine hydrochloride**, and **midazolam**, administered in hard capsule form via oral use. The primary objective is to assess the antidepressant effects of psilocybin compared to ketamine and midazolam over a period of 4 weeks, with the primary endpoint being the reduction in depression symptoms as measured by the MADRS scale.
The trial is expected to last until July 2026, with participant recruitment having commenced in July 2022. Participants will be involved in the study for a maximum of 24 weeks, with the treatment period for each substance being 1 day. The study includes several key visits: an initial screening visit to determine eligibility, followed by multiple follow-up visits to monitor progress and assess outcomes. These follow-up visits are scheduled at day 1, day 4, 1 week, 4 weeks, 8 weeks, 16 weeks, and 24 weeks post-administration of the study medication. The end-of-study visit will occur at the conclusion of the participant's involvement, or earlier if necessary.
Inclusion criteria for the study require participants to be between 18 and 75 years of age, with a confirmed diagnosis of depressive disorder comorbid with an oncological disease. Participants must have a caregiver available throughout the trial and agree to use prescribed methods of contraception. Exclusion criteria are not specified in the provided data. Conditions that may lead to early termination from the study include adverse events or non-compliance with study protocols. The trial will assess both primary and secondary endpoints, including the rate of onset and duration of antidepressant effects, quality of life, and safety, using various scales such as the BECK, FACIT, HAM-A, and others.
Treatment
The clinical trial involves the administration of three distinct **experimental medications** in the form of hard capsules, each containing a different active substance. The primary experimental medication is **psilocybine**, which is administered orally. The maximum daily dose is 20 mg, with a total dose not exceeding 20 mg over a treatment period of one day. Psilocybine is a chemical substance, and its role in the trial is to evaluate its effectiveness in treating depression comorbid with cancer.
The first comparator treatment in the study is **ketamine hydrochloride**, also administered in the form of hard capsules for oral use. The maximum daily dose for ketamine hydrochloride is 200 mg, with a total dose not exceeding 200 mg over a one-day treatment period. Ketamine hydrochloride serves as a comparator to assess its efficacy relative to psilocybine in the context of the trial's objectives.
The second comparator treatment is **midazolam**, which is also provided as hard capsules for oral administration. The maximum daily dose of midazolam is 5 mg, with a total dose not exceeding 5 mg over a one-day treatment period. Midazolam acts as a control substance in the trial, allowing for the evaluation of psilocybine's effectiveness against a standard treatment.
All medications are administered orally, and the trial ensures that the dosing schedules are adhered to strictly. Participant compliance is monitored throughout the study to ensure accurate and reliable results. The trial is designed to assess the rapid antidepressant response of psilocybine in patients with depression comorbid with cancer, compared to the effects of ketamine hydrochloride and midazolam.
Efficacy
The efficacy of **psilocybin** in treating depression comorbid with cancer will be assessed in a randomized double-blind clinical trial. The primary endpoint for evaluating efficacy is the comparison of psilocybin with the antidepressant ketamine and the control substance midazolam using the Montgomery-Åsberg Depression Rating Scale (MADRS). Response is defined as a reduction of 50% or more in the MADRS total score from baseline, while remission is defined as a MADRS score of 10 or less. Baseline measurements are taken at Preparation Session 1, which occurs 9 to 7 days prior to the administration of the study medication.
Secondary endpoints include the assessment of the rate of onset and duration of substance use using both the MADRS objective scale and the BECK self-report scale. These assessments will be conducted at multiple timepoints: 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 the administration of the study medication. Additionally, the effect of psilocybin and ketamine on the patient's quality of life and well-being will be evaluated using the FACIT scale and its sub-scales at 1 week, 4 weeks, and 24 weeks post-administration.
Further efficacy assessments will include changes in scores on the Hamilton Anxiety Rating Scale (HAM-A) and the State-Trait Anxiety Inventory (STAI) at specified intervals. The PEQ scale will be used to evaluate existential distress, including subjective attitudes towards life, perceived hopelessness, and demoralization. The pain visual analogue scale (VAS) will be employed to monitor changes in pain perception. The subjective 5D-ASCs and MEQ scales will assess the intensity of acute psychological effects during sessions with psilocybin, ketamine, and midazolam, reflecting the main psychological dimensions of intoxication that may affect therapeutic antidepressant response.
The study will also compare the antidepressant effect in patients taking standard antidepressants (AD-plus group) versus those not taking them (AD-free group), hypothesizing a more pronounced effect in the AD-plus group. In the open-label part of the study, only psilocybin and ketamine will be compared, without the administration of midazolam. The quality of blinding in the double-blind part of the study will be monitored using the BQQ Questionnaire, with evaluations conducted independently of the participant, therapist, and co-therapist.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Men and women aged 18‒75 years
- 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
- 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.
- The patient's cognitive ability to fully understand the information about CT and the study questionnaires.
- 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.
- 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
- 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.
- Myocardial infarction less than 6 months ago
- A stroke and/or TIA less than 6 months ago
- 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)
- Dyspnea of any etiology higher than NYHA II, acute respiratory failure or severe respiratory insufficiency, sleep apnea syndrome
- Severe thrombocytopenia < 30 x 10 9/l, resistant to substitution
- Neurological foci findings
- Impossibility of oral administration of the study medication in the form of capsules
- Estimated patient survival time less than 4 months
- The patient's condition does not allow compliance with the rules of concomitant treatment (see chapters 6.5 and 6.6 of the protocol)
- Known intolerance or allergy to psilocybin, ketamine, midazolam or other drugs from the benzodiazepine group
- Pregnancy or breastfeeding
- Liver dysfunction with GGT, AST, ALT values > 5x upper limit of normal, total bilirubin > 50 μmol/l
- 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)
- Myasthenia gravis
- Epilepsy incl. history of isolated epileptic seizures
- Renal insufficiency with a GFR value of less than 0.66 ml/s/1.73 m2 according to CKD-EPI (creatinine)
- 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
- Diabetes mellitus on insulin or corrected with oral antidiabetic drugs, if there is a history of clinically significant hypoglycemia
- Glaucoma
- Untreated or imperfectly compensated hyperthyroidism
- Any current or anamnestic psychotic illness from the range of diagnoses F2x.x
- Current or anamnestic bipolar affective disorder F31.x and manic phase F30.x
- Current major depressive episode with psychotic symptoms F32.3 and F33.3
- 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
- Organic mental disorders including symptomatic F00.x-F09.x
- 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)
- 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
- Undergoing electroconvulsive therapy less than 3 months ago
- First-degree relative of a patient suffering from schizophrenia, other psychotic disorder (unless caused by a substance or medical condition)
- Inappropriateness of patient inclusion based on the clinical judgment of the examining physician
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Recruiting | 22 Jul 2022 | 60 |