A Phase 1, Open-label, Dose-escalation Study to Evaluate the Safety and Pharmacokinetics of a Single Intravenous Infusion of TRP-8803 (Psilocin) in Healthy Adult Participants
Tryp Therapeutics, Inc.
9 participants
Jun 28, 2024
Interventional
Conditions
Summary
Psilocin (4-Hydroxy-N,N-dimethyltryptamine) is the active form of the prodrug psilocybin (3[2(dimethylamino) ethyl]-1H-indol-4-yl] dihydrogen phosphate). Psilocybin is a natural product produced by numerous species of Psilocybe mushrooms. In humans, psilocybin is not detectable in systemic circulation or in target organs after oral administration as the phosphate group of psilocybin (a tryptamine derivative) is rapidly enzymatically cleaved to the active pharmacologic moiety psilocin . Thus, studies administering psilocybin are by default results for psilocin due to the almost immediate conversion of psilocybin to the active form psilocin. Administration of TRP8803 IV over a controlled time has potential advantages over oral administration of psilocybin such as improved control over blood levels of psilocin, faster entry into the psychedelic state, better control over the duration of the psychedelic state, and increased safety due to rapid offset of effects and avoidance of peak blood levels (Cmax) associated with oral administration. From a clinical research perspective TRP-8803 provides a mechanism to explore both the depth and duration of the psychedelic experience and how these parameters affect clinical outcomes. Infusing TRP-8803 with a bolus over the first 20 minutes (loading dose) allows attainment of Cmax in a controlled protocol and subsequent infusions for a total of 7.5, 14, or 20.5 mg over 140 minutes allows for maintenance of the psychedelic experience at a therapeutic dose. IV administration allows for the physician to control and optimize the psilocin dose.
Eligibility
Inclusion Criteria19
- Overtly healthy and medically stable in the judgment of the Principal Investigator, as determined by screening medical history, physical examination, ECG, and no clinically significant laboratory abnormality detected on routine blood tests and urinalysis.
- Male and female participants, age 18 to 55 years, inclusive, at the time of signing the ICF.
- Weight between 50kg and 120kg, inclusive; and body mass index (BMI) between 20 and 30, inclusive.
- Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
- Has adequate venous access for IV administration and for PK blood sampling.
- Contraceptive use by women and men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
- a. Women of childbearing potential (WOCBP) in sexual relationships with men must use 2 acceptable methods of contraception from 30 days prior to study screening until 30 days after completing the dose of study intervention. Ova donation is not permitted for 30 days after completing the dose of study intervention.
- b. Men must agree to avoid impregnation of women and sperm donation during and for 90 days after completing the dose of study intervention through use of an acceptable method of contraception.
- NOTE: acceptable methods of contraception include, but are not limited to, intrauterine device; injected/implanted/intravaginal/transdermal hormonal method; oral hormones plus a barrier contraception; abstinence; vasectomized sole partner; or double barrier contraception (eg, barrier method). The 2 methods of contraception cannot both be hormonal.
- WOCBP must have a negative serum pregnancy test at Screening, and negative urine pregnancy test at Baseline and on psilocin administration day (confirmed before psilocin administration). A WOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
- a. has not undergone a hysterectomy or bilateral oophorectomy, or
- b. has not been naturally postmenopausal for at least 12 consecutive months (ie, has had menses at any time in the preceding 12 consecutive months)
- Agrees to refrain from using any legal psychoactive substance (except for caffeine, described below), for the following defined time periods:
- a. Must be non- or ex-smokers (tobacco) and not use other nicotine-containing products from 90 days prior to study drug administration until participant study termination; or use less than 5 tobacco or nicotine-containing products a week by self-report and have a negative cotinine test at Screening and Dose Day (prior to dosing).
- b. Alcohol for 72 hours prior to the psilocin administration visit by self-report
- Has had no psychedelic drug use in the 3 months prior to psilocin administration visit and agrees to refrain from psychedelic drug use other than study drug during the course of the study by self-report. Psychedelic drugs include but are not limited to psilocybin, LSD, methylenedioxymethamphetamine (MDMA), and ayahuasca. If another suspected psychedelic agent is used, Sponsor must be contacted for approval.
- Agree that for 7 days before the psilocin administration day, including the morning of the dose, participant will refrain from taking any nonprescription medication, nutritional supplement, or herbal supplement except when approved by the study investigators. Exceptions will include acetaminophen, non-steroidal anti-inflammatory drugs, common doses of vitamins and minerals, and contraceptives.
- Agree that for 14 days before the study intervention administration session, participants must refrain from taking any prescription medication (except for hormonal contraceptives or hormone replacement therapy) except when approved by the Principal Investigator. No pro re nata (PRN) medications are allowed on the morning of study intervention administration.
- If the participant routinely consumes caffeinated beverages, he/she must agree to stop consuming all caffeine-containing products at least 48 hours prior to the psilocin administration day and for the period of confinement in the clinical unit.
Exclusion Criteria22
- Currently meets diagnostic criteria for any Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) psychiatric condition as assessed by the MINI.
- Prior history of primary psychotic disorder (unless substance-induced or due to a medical condition), bipolar disorder Type I or Type II, or schizophrenia, as determined by the MINI.
- Concurrent or recent (within 5 years) history of major depressive disorder, obsessive compulsive disorder, generalized anxiety disorder, panic disorder, anorexia nervosa or bulimia nervosa, overeating disorder, post traumatic stress disorder, or substance use disorder as determined by the MINI and psychiatric history.
- First degree family history of primary psychotic disorder, bipolar disorder Type I or Type II, or schizophrenia, as determined via the Family History Screen form conducted by trained staff.
- Participant has a recent history of suicide attempt (defined as an active, interrupted, or aborted attempt with the past 5 years) or reports suicidal ideation in the past 6 months as indicated by a positive response (“Yes”) to either Question 4 or Question 5 of the C-SSRS performed at the Screening Visit.
- NOTE: If a participant cannot complete the assessment, the site must document this.
- Participant has a history of alcohol abuse disorder within 1 year prior to screening or regular abuse of alcohol within 3months prior to the screening visit (defined as consistently consuming more than 10 units of alcohol per week [1 unit=150mL of wine, 360mL of beer, or 45mL of 40% alcohol]).
- Meets DSM-5 criteria for substance use disorder (other than alcohol) within the past 12 months.
- Vital signs of systolic BP >160mm Hg, diastolic BP >95mm Hg, and HR >100 bpm on 2 or more consecutive readings within 15 minutes.
- Have any of the following cardiovascular conditions: uncontrolled hypertension, coronary artery disease, congenital long QT syndrome, cardiac hypertrophy, cardiac ischemia, congestive heart failure, prior myocardial infarction, tachycardia, artificial heart valve, QTc interval >470msec (women) or >450msec (men), PR >220msec, or QRS >120msec at the Screening visit, any other clinically significant screening ECG abnormality, or any other significant cardiovascular condition at the Principal Investigator’s discretion.
- Currently under treatment for epilepsy.
- Blood chemistry test prior to study intervention administration as follows:
- a. Any liver function test with results greater than 1.5 times the ULN
- b. Estimated glomerular filtration rate (by Cockcroft & Gault) less than 60mL/min
- Currently taking (or where applicable, testing positive on urine drug test), drugs of abuse such as amphetamines, buprenorphine, benzodiazepines, cocaine, methamphetamines, MDMA/Ecstasy, morphine, methadone, oxycodone, marijuana, ethyl glucuronide, fentanyl, tramadol, and synthetic cannabinoids (K2). If urine drug test at Screening is positive, a repeat test may be conducted up until Day 1 (the end of the Screening period) at the discretion of the Principal Investigator or delegate.
- Prior adverse effects from psilocybin or other psychedelics based on self-report.
- Currently taking (within 5 half-lives of Visit 5, Dose Day) prohibited medications, including antihypertensive medications, UDP Glucuronosyltransferase Family 1 Member A9 (UGT1A9) or intestinal UDPglucuronosyltransferases 1A10 inhibitors (eg, regorafenib, rifampicin, phenytoin, eltrombopag, mefenamic acid, diflunisal, niflumic acid, sorafenib, isavuconazole, deferasiroxor, ginseng), and aldehyde or alcohol dehydrogenase inhibitors (eg, disulfiram).
- Currently (for at least 2 weeks; or at least 4 weeks for fluoxetine) taking an antidepressant.
- Participation in another concurrent clinical study or use of investigational drugs, or biologics within 5 half-lives or 30 days (whichever is longer), or investigational devices within 30 days prior to the Baseline visit (Day 1/Visit 2).
- Not suitable for study participation due to other reasons at the discretion of the study investigators.
- Women who are pregnant, lactating, or planning on becoming pregnant during the study
- Unwilling to withhold prohibited concomitant medications.
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Interventions
This is a phase 1, open-label, 3-cohort study. Participants will be prescreened for interest and eligibility and, after completion of the informed consent form, will complete screening assessments. Psilocin will be administered in the Clinical Research Unit (CRU), and participants will be kept overnight for safety observation and PK sampling. Each of the 3 cohorts will comprise 3 participants who will receive a single TRP-8803 IV infusion in an open-label fashion. At least a 1-day interval will be scheduled for psilocin administration between sequential subjects within a cohort. Participants will remain on site during the single dose IV infusion Cohort 1: 7.5 mg total psilocin (1.5 mg/20 min + 6 mg/120 min [0.05 mg/min]) Cohort 2: 14 mg total psilocin (3.0 mg/20 min + 11 mg/120 min [0.10 mg/min]) Cohort 3: 20.5 mg total psilocin (4.5 mg/20 min + 16 mg/120 min [0.15 mg/min]) In Cohort 1, participants will receive a total of 7.5 mg psilocin; Cohort 2 will receive a total of 14mg psilocin, and Cohort 3 will receive a total of 20.5mg of psilocin. The initial 20minute loading dose infusion will provide a therapeutic dose of psilocin that will be maintained by infusing either 0.05 mg/minute (min), 0.10 mg/min, or 0.15 mg/min psilocin by IV over 120 minutes. After each dose in the ascending dose study, the Safety Review Committee (SRC) will perform a PK and safety data review before advancing to the next dose. Dose escalation will stop in the unlikely event that any participant in that dose cohort exhibits an increased risk of harm to self or others, or any other sign that continuing in the study would present undue risks or has an adverse event (AE) related to the intervention such as psychosis or hypertension during the infusion. Safety will be assessed by measuring incidence of AEs and SAEs and physical examination, vital signs, ECG, clinical laboratory, suicidality findings, and Persistent Effects Questionnaire. PK will be measured at designated times predose to 24 hours postdose.
Locations(1)
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ACTRN12624000547549