A Phase 2a, Open-label, Pilot Study to Assess the Safety and Efficacy of Oral Psilocybin (TRP-8802) Administration in Concert With Psychotherapy Among Adult Patients With Irritable Bowel Syndrome: A Randomized Delayed Treatment Control Design
Participants with IBS (all subtypes) and with no exclusionary comorbid psychiatric or medical disorders will be enrolled in the study. This study will involve a randomized waitlist control design to investigate the rapid and sustained effects of TRP-8802 following two experimental sessions in which an oral dose of TRP-8802 is administered to participants with IBS. The study will include clinician and participant ratings of depression and anxiety pre- and post-drug-session, monitor and participant ratings of subjective drug effects during and after each drug session. This study comprises approximately a 28-day screening period (Days 28 to 1). After screening and enrollment, participants will be randomized to an immediate treatment group or a delayed treatment group (waitlist control condition). Participants in the immediate treatment group will proceed directly into three weeks of baseline and preparation (Days 1 to 18), a 2-dose administration period (Days 22 and 37), integration (Days 23, 30, 38, and 45), the End of Therapy (EOT) visit (Day 52). Participants in the delayed treatment group will wait 8 weeks after enrollment before beginning the study interventions and neuroimaging assessments. As a safety precaution, participants in the delayed treatment group will be assessed weekly via telephone calls or in-person visits during the wait period (i.e., telephone assessments during post-randomization weeks 1, 2, 3, 4, 5, 6, and 7; in-person assessment during post-randomization week 8) to assess suicide risk to determine if intervention is warranted. During week 8, IBS symptoms will also be assessed. At the end of the delay period, all participants in the delayed treatment group will complete the same intervention as the participants in the immediate treatment group. Validated and commonly used assessment tools will be used to evaluate symptoms at baseline and repeatedly after each session. The weekly average of worst daily pain score and weekly stool frequency and consistency for the 7 days immediately prior to EOT visit will be assessed for change from baseline and at the 3-, 6 , and 12- month follow-up visits (Days 120, 240, 365).
⁃ Age
⁃ 1\. Participant must be 21 to 64 years of age, inclusive, at the time of signing the informed consent form.
⁃ Type of Participant and Disease Characteristics
• Participant has a body mass index (BMI) between 18.5 and 29.9
• Have a clinical diagnosis of IBS (any subtype) as defined by the Rome IV clinical criteria:
• Abdominal pain at least 4 days per month over at least 2 months associated with one or more of the following:
• i. Related to defecation ii. A change in frequency of stool iii. A change in form (appearance) of stool iv. After appropriate evaluation, the symptoms cannot be fully explained by another medical condition
• Have treatment resistant IBS (Rajagopalan 1997) by having all of the following:
∙ symptoms for more than 12 months by history
‣ received adequate explanation and reassurance for symptoms as documented by a gastroenterologist in the medical record. This means the patient's primary gastroenterologist will document that they have conducted an evaluation that is within appropriate standards of practice to exclude other medical conditions, and that in their opinion irritable bowel syndrome is the most appropriate diagnosis. The patient's primary gastroenterologist will also document that they have discussed this evaluation and diagnosis with the patient.
‣ tried at least one dietary intervention by history
‣ tried at least one pharmacologic agent for at least six weeks by history
• Have attempted a gut-brain behavior therapy for at least six weeks by history
• Concurrent psychotherapy is allowed if the type and frequency of the therapy has been stable for at least 2 months prior to screening and is expected to remain stable during participation in the study.
• Participant must not use tobacco or other nicotine containing products (e.g., vape pens) by history.
• Participant must be medically stable as determined by screening for medical problems via a personal interview and/or, a medical questionnaire, and an ECG, within 1 month of starting active intervention (performed during screening).
• Participant must agree to consume approximately the same amount of caffeine-containing beverage (e.g., coffee, tea, cola) that he/she consumes on a usual morning, before arriving at the research unit on the mornings of TRP 8802 session days. If the participant does not routinely consume caffeinated beverages, he/she must agree to not do so on the TRP 8802 session day
⁃ Participant must agree to refrain from using any psychoactive drugs, including alcoholic beverages and nicotine, within 24 hours before and after each TRP 8802 administration. The exception is caffeine.
⁃ Participant must agree to not take triptan medications (e.g., sumatriptan) within 72 hours before and after each TRP 8802 administration.
⁃ Participant must agree to not take sildenafil (Viagra®), tadalafil, or similar medications within 72 hours before and after each TRP 8802 administration.
⁃ Participant must agree to not take any pro re nata (PRN) medications on the mornings of TRP 8802 sessions.
⁃ Participant must agree that for 7 days before each TRP 8802 session, he/she will refrain from taking any nonprescription medication, cannabis, nutritional supplement, or herbal supplement except when approved by the Principal Investigator. Exceptions will be evaluated by the Principal Investigator and will include acetaminophen, non-steroidal anti-inflammatory drugs, osmotic laxatives, stimulant laxatives, secretagogues such as linaclotide and lubiprostone, birth control, thyroid hormones, and common doses of vitamins and minerals.
⁃ Participant must have at least a high school level of education or equivalent (e.g., General Educational Development \[GED\] Test).
⁃ Participant must demonstrate ability to track abdominal pain and stool frequency and consistency daily in the ePRO system.
⁃ Participant must demonstrate ability to wear watch with heart rate tracking capability for daily heart rate tracking.
⁃ Participant must be willing to attempt fMRI scan and EEG. Sex and Contraceptive/Barrier Requirements
⁃ Contraceptive use by women and men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Adequate birth control methods include intrauterine device, injected/implanted/intravaginal/transdermal hormonal method, oral hormones plus a barrier contraception, abstinence, vasectomized sole partner, or double barrier contraception. Subjects will be excluded if they cannot use highly effective birth control for any reason. If a potential subject lives in an area where local regulations preclude the use of adequate contraception (intrauterine device, injected/implanted/intravaginal/transdermal hormonal method, oral hormones plus a barrier contraception, abstinence, vasectomized sole partner, or double barrier contraception), study enrollment will not be allowed.
• If a participant is opting for abstinence as their birth control method, only true/total abstinence is permitted. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), lactational amenorrhea, and withdrawal are not acceptable. Counseling regarding the importance of maintaining abstinence, and the potential risks of exposure to a developing embryo or fetus will be provided during the preparatory sessions during the Preparation 1 session, Integration 1 session, and during Deep Phenotyping 2.
∙ Females of reproductive potential must agree to use effective birth control for the duration of active intervention (defined as the time from the Baseline \[deep phenotyping\] visit until 6 months and 3 days (for female subjects) after Deep Phenotyping/EOT visit. Female subjects must agree to not donate eggs, or participate in in vitro fertilization for the duration of the recommended contraceptive use of the trial.
∙ Sexually active male participants and/or their female partners must agree to use effective birth control for the duration of active intervention (defined as the time from the Baseline \[deep phenotyping\] visit until the 3 months and 3 days (for male subjects) after Deep Phenotyping/EOT visit of the male participant. Male participants must also agree not to donate sperm for the duration of active intervention.
⁃ Informed Consent
⁃ Participant has provided informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.