Evaluation of Psilocybin- and Midazolam-Assisted Psychotherapy on Atherosclerotic Plaque Regression in Patients with Ischemic Heart Disease
- Trial ID
- 2024-517902-27-00
- Protocol
- RAFAEL
- Sponsor
- Psyon s.r.o.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to demonstrate the **regression** of atherosclerotic plaque volume in patients with **Ischemic Heart Disease**. This will be assessed by comparing baseline and follow-up invasive coronary artery disease examinations conducted 12 months apart. Patients will be treated with standard hypolipidemic therapy to achieve target LDL cholesterol levels and will be randomized to receive either psilocybin-assisted psychotherapy or midazolam-assisted psychotherapy as a negative control. The clinical relevance of this objective lies in its potential to establish psilocybin-assisted psychotherapy as an effective intervention for reducing atherosclerotic plaque volume, which could lead to improved cardiovascular outcomes.
Secondary objectives include: - Evaluating the change in the composition of atherosclerotic plaques between the initial and follow-up invasive coronary artery examinations performed 12 months apart. - Assessing the reduction in the incidence of the highest-risk phenotype, thin-cap fibroatheroma (TCFA), between initial and follow-up invasive coronary artery angiography conducted 12 months apart. - Utilizing optical coherence tomography to measure the increase in fibrous cap thickness between baseline and follow-up invasive coronary artery angiography performed 12 months apart.
Participants
The clinical trial involves participants diagnosed with **Ischemic Heart Disease**, specifically those with stable coronary artery disease and a history of myocardial infarction. The study population includes both men and women aged 18 to 75 years. Participants are required to have a coronary finding of stenosis on one of the major coronary arteries, with specific criteria regarding the diameter and narrowing of the artery. The trial population was selected based on their cognitive ability to understand study information and complete questionnaires. Participants of childbearing age must adhere to prescribed contraceptive methods during the trial. The sponsor has not provided information regarding the total number of participants. The trial includes both male and female subjects and considers vulnerable populations. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **psilocybin**-assisted psychotherapy in the regression of atherosclerotic plaque volume in patients with **ischemic heart disease**. This is a Phase IV, randomized, double-blind, controlled trial comparing psilocybin with **midazolam** as a negative control. The trial aims to demonstrate a reduction in plaque volume over a 12-month period, with primary endpoints assessed through selective coronarography, intravascular ultrasound, virtual histology, and optical coherence tomography. Secondary endpoints include changes in plaque composition and fibrous cap thickness, hypothesizing that psilocybin may reduce chronic stress and inflammation.
Participants will be involved in the study for approximately 12 months, with the trial expected to conclude by the end of 2027. The study will commence with a screening visit to confirm eligibility based on criteria such as age, diagnosis of stable coronary artery disease, and cognitive ability to understand study information. Following randomization, participants will undergo baseline assessments and receive either psilocybin or midazolam in hard capsule form, administered orally. The maximum daily dose for psilocybin is 25 mg, while for midazolam, it is 5 mg, with both treatments lasting a single day.
Study visits will include follow-up assessments at regular intervals to monitor safety and efficacy, with the primary endpoint evaluation occurring 12 months after the initial treatment. The end-of-study visit will involve comprehensive assessments to determine the final outcomes. Participants may be withdrawn from the study if they experience adverse effects, fail to adhere to the protocol, or withdraw consent. The trial will ensure that all participants use effective contraceptive methods during the study and for three days post-treatment to prevent pregnancy.
Treatment
The clinical trial involves the administration of **psilocybine**, a chemical compound known for its psychoactive properties. The experimental medication is provided in the form of a hard capsule, with each capsule containing a maximum daily dose of 25 mg. The route of administration is oral, and the treatment period is limited to a single day. Psilocybine is utilized in this study to assess its potential effects on the regression of atherosclerotic plaque volume in patients with coronary artery disease. The compound is chemically synthesized and is not formulated for pediatric use.
In addition to the experimental treatment, the study employs **midazolam** as a comparator treatment. Midazolam is also administered in the form of a hard capsule, with a maximum daily dose of 5 mg. Similar to psilocybine, midazolam is administered orally and is used for a single day. Midazolam serves as a negative control in the study, providing a basis for comparison against the effects of psilocybine-assisted psychotherapy. This compound is also of chemical origin and is not intended for pediatric use.
Both treatments are monitored for participant compliance, ensuring adherence to the dosing schedule. The trial aims to evaluate the efficacy of psilocybine in achieving a reduction in atherosclerotic plaque volume, with midazolam serving as a control to validate the findings. The study is conducted under the auspices of the Narodni Ustav Dusevniho Zdravi, with both substances being chemically synthesized and authorized for use in this clinical setting.
Efficacy
Efficacy in this clinical trial will be assessed by evaluating the regression of atherosclerotic plaque volume in patients with coronary artery disease. The primary endpoint involves the assessment of plaque volume 12 months after treatment with either **psilocybin**- or midazolam-assisted psychotherapy. This evaluation will be conducted using selective coronarography, intravascular ultrasound (IVUS), virtual histology (IVUS-VH), and optical coherence tomography (OCT). These methods will provide detailed imaging and analysis of the coronary arteries to determine changes in plaque volume.
Secondary endpoints include changes in the composition of atherosclerotic plaques, reduction in the incidence of thin-cap fibroatheroma (TCFA), and an increase in fibrous cap thickness. These parameters will be measured between the initial and follow-up invasive coronary artery examinations, performed 12 months apart. The hypothesis is that psilocybin-assisted psychotherapy will reduce chronic stress, contributing to a decrease in chronic inflammation and necrotic tissue within the plaques. Optical coherence tomography will be used to measure the increase in fibrous cap thickness, which is expected to occur as chronic inflammation is reduced, leading to the breakdown of fibrous tissue by degradative enzymes released from macrophages.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Men and women aged 18-80.
- Diagnosis of stable ischemic heart disease (I25.9).
- A coronary finding of stenosis on one of the major coronary arteries of at least 2.5 mm in diameter with narrowing that does not exceed 50 % of the reference diameter and is on the native artery without previous intervention.
- Patient's cognitive ability to fully understand CT information and study questionnaires.
- Participants of childbearing age or with preserved fertility must agree to use prescribed contraceptive methods throughout the clinical trial..The following methods of contraception are required: (a) Women - we require at least one of the highly effective conception protection methods listed below: Combined (estrogen and progesterone) hormonal contraceptives (oral, transdermal, or intravaginal); Progesterone hormonal contraceptives (oral, transdermal, or intravaginal); Intrauterine device (IUD); Intrauterine Hormone Releasing System (IUS); Bilateral fallopian tube closure; Bilateral interruption of fallopian tubes in a partner; Sexual abstinence. (b) Men - use of at least an adequate barrier contraceptive method (condom) or sexual abstinence from the signing of the informed consent until 48 hours after administration of the study medication (study visit F4).
Exclusion Criteria
- Severe neurological disease of the CNS. In case of suspicion of such disease, the CNS imaging (CT/MR) must be negative.
- Any other serious psychiatric illness based on psychiatric examination
- Stable treatment with antidepressants / thymostabilisers / antipsychotics in a non-hypnotic indication (doses must not achieve the antidepressant, antipsychotic or thymostabilising effect as per SPC).
- Renal insufficiency with creatinine clearance < 0.6 ml/s
- Presence of suicidal ideation or suicidal behavior based on the C-SSRS version Lifetime/Recent (L/R) or C-SSRS version since last visit (SLV), specifically, a "yes" response to question 4 and 5 in the past 6 months and/or any "yes" response to suicidal behavior questions in the past 6 months and/or clinical examination
- Current or history of alcohol or drug dependence F1X.X. unless at least 2 years of abstinence can be demonstrated
- Other inappropriateness of the patient's classification based on the clinical judgment of the examining physician
- Known intolerance or allergy to psilocybin or midazolam
- Pregnancy or breastfeeding
- Hepatic dysfunction with GGT, AST, ALT values > 5 times the upper limit of normal, total bilirubin > 50 μmol/l
- Cardiovascular instability in the sense of uncorrected hypertension (baseline BP ≥ 140/95 mm Hg - mean of 3 measurements), manifest heart failure NYHA II or more, left ventricular ejection fraction < 50%, history of ventricular tachycardia except reperfusion arrhythmias, atrial fibrillation with resting ventricular rate > 100 beats/min (mean of 3 measurements)
- Severe thrombocytopenia < 50 x 10^9/l, resistant to replacement
- Anatomical findings not allowing IVUS and OCT examination. i.e. tortuous coronary artery, markedly calcified stenosis.
- Myasthenia gravis
- Epilepsy including a history of isolated epileptic seizures
- Known paraneoplastic syndrome or ectopic hormone production by the primary tumour, which could include hypercalcemia, Cushing's syndrome, hypoglycaemia, SIADH, or carcinoid syndrome.
- Sleep apnoea syndrome
- Status post aortocoronary bypass with a functional graft to the artery of interest
- Diabetes mellitus on insulin or corrected with oral antidiabetic agents if there is a history of clinically significant hypoglycaemia.
- Prior myocardial infarction less than 6 weeks ago with full revascularization
- Prior stroke and/or TIA less than 6 months ago
- Clinically significant peripheral vascular disease (acute venous thrombosis, chronic venous insufficiency at the stage of tibial ulceration, lower extremity ischemic disease at the stage of defects)
- Focal neurological findings
- Pulmonary disease with a reduction in vital capacity to lower than 75% of appropriate values, or FEV1 < 1,5 l
- Psychoterapy initiated less than 3 months prior to the start of the RAFAEL study
- Patient's condition does not allow compliance with concomitant therapy
- Inability to orally administer study medication in capsule form
- Untreated or incompletely compensated hyperthyroidism
- Use of psilocybin or another serotonergic psychedelic in the past 12 months
- Any current or history of psychotic illness from the diagnosis F2X.X
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Czechia | Recruiting | 14 Oct 2024 | 60 |
Sites & Investigators
Research sites
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Midazolam 1 mg | Comparator | CAPSULE, HARD | ORAL USE | 5 | 1 | PRD13496562 |
Psilocybine 5 mg | Test | CAPSULE, HARD | ORAL USE | 25 | 1 | PRD13494807 |