Pragmatic Trial of Psilocybin Therapy in Palliative Care

Study Overview
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Brief Summary
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This multicenter, triple-blind, phase 2, randomized controlled trial will evaluate the efficacy and safety of psilocybin therapy compared to an active control in treating demoralization in adults near the end of life (≤2 years life expectancy).

Detailed Description
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After providing written informed consent, participants deemed eligible for this trial will be randomized to a brief course of talk therapy plus 1 dose of oral psilocybin vs the same brief course of talk therapy plus 1 dose of oral ketamine (the active control). Participants' degree of demoralization and other clinical outcomes (e.g., depression, anxiety) will be assessed at 1, 2, and 5 weeks after the study drug administration. After completing the study, participants will have the option of being told which study drug they took (aka, unblinded); those who were randomized to the active control will be offered another brief course of talk therapy plus 1 dose of oral psilocybin, and the same sequence of outcome assessments.

Official Title
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Pragmatic Trial of Psilocybin Therapy in Palliative Care (PT2PC): A Multicenter Triple-blind Phase 2 Randomized Controlled Trial of Psilocybin Therapy for Demoralized Adults Near the End of Life

Conditions
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Demoralization

Intervention / Treatment
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* Drug: Psilocybin
* Drug: Ketamine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18 years and older Has the capacity to consent to research Is currently a patient in a study-engaged clinical site Has a life-threatening illness and a life expectancy of ≤2 years Has moderate-to-severe demoralization Ability to take oral medication (capsules and liquid) Exclusion Criteria: General Treatment with another investigational drug or intervention within 1 month of signing Informed Consent Form (ICF) If deemed by clinical judgment of the study investigators to be unsafe for undergoing the intervention Neurological Cognitive impairment sufficient to impede the ability to complete study tasks History of intracranial hemorrhage Recent embolic stroke Recent seizure Current intracranial mass Advanced stage of a neurologic disease that elevates risk for psychosis Cardiovascular Uncontrolled hypertension Clinically significant cardiac disease Respiratory Severe pulmonary disease Supplemental oxygen requirement Gastrointestinal Current intractable nausea/vomiting/diarrhea Recent, clinically significant GI bleed Markedly abnormal liver function tests Endocrine, Renal, and Reproductive Pregnancy or lactation Severe renal insufficiency Unstable insulin-dependent diabetes mellitus Prohibited Medications Antipsychotics Antidepressants (with exceptions) Dopamine agonists Drugs known to have adverse interactions with psilocybin or ketamine

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Parallel with optional Crossover for the control arm
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Psilocybin<br>A single moderate-to-high dose of oral psilocybin, plus 4-5 sessions of a brief, existential psychotherapy. | Drug: Psilocybin<br>* Psilocybin, [3-[2-(dimethylamino)ethyl]-1H-indol-4-yl] dihydrogen phosphate.<br>* Other names: Hallucinogen;|
| Active Comparator: Ketamine<br>A single low-to-moderate dose of oral liquid ketamine, plus 4-5 sessions of a brief, existential psychotherapy. | Drug: Ketamine<br>* ketamine hydrochloride injection, for intravenous or intramuscular use, contains ketamine, a nonbarbiturate general anesthetic and has a molecular formula of C13H16ClNO•HCl and a molecular weight of 274.19. The chemical name for ketamine hydrochloride is (±)-2-(o-Chlorophenyl)-2-(methylamino)cyclohexanone hydrochloride.<br>* Other names: Ketalar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline on 16-item Demoralization Scale - II (DS-II) at Week 5 | The DS-II is a validated, patient-reported outcome assessing demoralization with a 2-week recall period. Possible scores range 0-32 with higher scores indicating a greater degree of demoralization. | Baseline and Week 5 | 
| Change from Baseline on 16-item Demoralization Scale - II (DS-II) at Week 2 | The DS-II is a validated, patient-reported outcome assessing demoralization with a 2-week recall period. Possible scores range 0-32 with higher scores indicating a greater degree of demoralization. | Baseline and Week 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Odds of improvement from Baseline on Clinical Global Impression scale (CGI-I) for demoralization at Week 5. | The CGI-I is a widely used and validated assessment of global clinical improvement. Possible scores range 0=Not assessed, 1=Very much improved, to 7=Very much worse. The CGI-I has been adapted here for assessing improvement in demoralization. | Baseline and Week 5 | 
| Odds of improvement from Baseline on Clinical Global Impression scale (CGI-I) for demoralization at Week 2. | The CGI-I is a widely used and validated clinician-rated assessment of global clinical improvement. Possible scores range 0=Not assessed, 1=Very much improved, to 7=Very much worse. The CGI-I has been adapted here for assessing improvement in demoralization. | Baseline and Week 2 | 
| Odds of meeting criteria for demoralization on the Diagnostic Criteria for Psychosomatic Research-Revised (DCPR-R) at Week 5. | The DCPR-R is a validated clinician-rated assessment of various psychosomatic conditions, including demoralization, which is rated as Present or Absent with a 1-month recall period. | Week 5 | 
| Odds of meeting criteria for demoralization on the Diagnostic Criteria for Psychosomatic Research-Revised (DCPR-R) at Week 2. | The DCPR-R is a validated clinician-rated assessment of various psychosomatic conditions, including demoralization, which is rated as Present or Absent with a 1-month recall period. | Week 2 | 
| Change from Baseline on GRID Hamilton Rating Scale for Depression 6-item (GRID-HAMD-6) at Week 5. | The GRID-HAMD-6 is a validated, clinician-rated measure of the core symptoms of major depression. Possible scores range 0-4 with higher scores indicating a greater degree of depressed mood. | Baseline and Week 5 | 
| Change from Baseline on GRID Hamilton Rating Scale for Depression 6-item (GRID-HAMD-6) at Week 2. | The GRID-HAMD-6 is a validated, clinician-rated measure of the core symptoms of major depression. Possible scores range 0-4 with higher scores indicating a greater degree of depressed mood. | Baseline and Week 2 | 
| Change from Baseline on Patient Health Questionnaire-9 (PHQ-9) at Week 5. | The PHQ-9 is a validated, patient-reported outcome assessing depression symptom severity with a 2-week recall period. Possible scores range 0-27 with higher scores indicating worse depression. | Baseline and Week 5 | 
| Change from Baseline on Patient Health Questionnaire-9 (PHQ-9) at Week 2. | The PHQ-9 is a validated, patient-reported outcome assessing depression symptom severity with a 2-week recall period. Possible scores range 0-27 with higher scores indicating worse depression. | Baseline and Week 2 | 
| Change from Baseline on Generalized Anxiety Disorder-7 (GAD-7) at Week 5. | The GAD-7 is a validated, patient-reported outcome assessing the severity of generalized anxiety disorder (GAD) symptoms with a 2-week recall period. Possible scores range 0-21 with higher scores indicating greater severity of symptoms of GAD. | Baseline and Week 5 | 
| Change from Baseline on Generalized Anxiety Disorder-7 (GAD-7) at Week 2. | The GAD-7 is a validated, patient-reported outcome assessing the severity of generalized anxiety disorder (GAD) symptoms with a 2-week recall period. Possible scores range 0-21 with higher scores indicating greater severity of symptoms of GAD. | Baseline and Week 2 | 
| Change from Baseline on Functional Assessment of Chronic Illness Therapy-Palliative Care 14-item scale (FACIT-Pal-14) at Week 5. | The FACIT-Pal-14 is a validated, patient-reported outcome assessing quality of life in palliative care patients with a 7-day recall period. Possible scores range 0-56 with higher scores indicating a better quality of life. | Baseline and Week 5 | 
| Change from Baseline on Functional Assessment of Chronic Illness Therapy-Palliative Care 14-item scale (FACIT-Pal-14) at Week 2. | The FACIT-Pal-14 is a validated, patient-reported outcome assessing quality of life in palliative care patients with a 7-day recall period. Possible scores range 0-56 with higher scores indicating a better quality of life. | Baseline and Week 2 | 
| Change from Baseline on Functional Assessment of Chronic Illness Therapy-Spiritual Well-being 12-item scale (FACIT-Sp-12) at Week 5. | The FACIT-Sp-12 is a validated, patient-reported outcome assessing spiritual well-being with a 7-day recall period. Scores range 0-48 with a higher score indicating better spiritual well-being. | Baseline and Week 5 | 
| Change from Baseline on Functional Assessment of Chronic Illness Therapy-Spiritual Well-being 12-item scale (FACIT-Sp-12) at Week 2. | The FACIT-Sp-12 is a validated, patient-reported outcome assessing spiritual well-being with a 7-day recall period. Scores range 0-48 with a higher score indicating better spiritual well-being. | Baseline and Week 2 | 
| Change from Baseline on Hopelessness Assessment in Illness Questionnaire (HAI) at Week 5. | The HAI is a validated patient-reported measure of hopelessness in terminally ill cancer patients. Scores range 0-16 with higher scores indicating higher levels of hopelessness. | Baseline and Week 5 | 
| Change from Baseline on Hopelessness Assessment in Illness Questionnaire (HAI) at Week 2. | The HAI is a validated patient-reported measure of hopelessness in terminally ill cancer patients. Scores range 0-16 with higher scores indicating higher levels of hopelessness. | Baseline and Week 2 | 
| Relative risks for treatment-related, clinically significant adverse events | Relative risks for treatment-related serious adverse events, unexpected adverse events, common adverse events, and adverse events of special interest | Through study completion (up to 4 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Palliative Care, Serious Medical Illness, Life-threatening Condition, Advanced and Progressive Illness