Study of Harmine in Healthy Subjects

Study Overview
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Brief Summary
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The present study is a phase 1 dose escalation study of harmine in healthy volunteers. The primary goal of the trial is to determine the maximum tolerated dose of harmine.

Detailed Description
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The present study is a phase 1 dose escalation study of harmine in healthy volunteers. The primary goal of the trial is to determine the maximum tolerated dose of harmine. Harmine will be administered in an open-label, dose escalation design that will use the continual reassessment method to inform the next dose to test in a subject. There will be a total of seven possible doses that include 100 mg, 200 mg, 300 mg, 500 mg, 700 mg, 900 mg and 1200 mg. Each study subject will receive a single oral dose of harmine in this single ascending dose design. On the treatment day, subjects will undergo continuous medical monitoring. All adverse events will be documented and events that qualify as dose limiting toxicities (DLTs) will be used to inform dosing for the subsequent subjects.

Official Title
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A Phase I Dose Escalation Study of Harmine in Healthy Subjects

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: Harmine Hydrochloride Capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male or female aged 18-55 years; Participants must have a level of understanding of the English language sufficient to agree to all tests and examinations required by the study and must be able to participate fully in the informed consent process; Body Mass Index (BMI) between 19 and 30; Women of childbearing potential and men must be using an acceptable method of contraception to avoid pregnancy throughout the study as judged by the investigator; Women must not be breastfeeding; Exclusion Criteria Children under the age of 18 and adults over the age of 55 due to concerns regarding neurodevelopmental and neurocognitive effects, respectively. Individuals who are underweight as defined as a BMI <19, or who are obese as defined as >30 according to the Centers for Disease Control (CDC). These criteria are in line with the goals of a phase I dose finding and pharmacokinetic study. Presence of a significant medical illness i.e., delirium, metastatic cancer, decompensated cardiac, liver or kidney failure, major surgery, stroke or myocardial infarction during the three months prior to entry; Presence of a significant neurological disease such as Parkinson's disease, primary or secondary seizure disorders, intracranial tumors, severe head trauma; neurodegenerative diseases; Presence of neurocognitive or dementing disorders; Presence or history of psychiatric disorder as diagnosed by Mini Neuropsychiatric Interview (MINI); Urine toxicology positive for illicit drugs or dis-allowed concomitant medications as per study protocol; Medications with primary central nervous system (CNS) effects are dis-allowed, including psychotropic medications, antidepressants, benzodiazepines, centrally acting hypnotic agents, and centrally acting anti-migraine therapies; Medications with primary cardiovascular effects are dis-allowed, including beta-adrenergic antagonists, ACE inhibitors, calcium channel blockers, and diuretics; Any OTC medications or herbal remedies (see concomitant medications listed above) that could interfere with the study drug, pose a risk to the subject, or contain high tyramine as outlined in the Low Tyramine Diet attachment and above in the concomitant medication summary; Any other medications that, in the opinion of the investigators, would pose a safety risk to the patient or that would interfere with the interpretation of study results; Positive pregnancy test at screen or on the morning of the treatment day in women of childbearing potential; Systolic blood pressure outside the range of 100 - 140 mmHg, diastolic blood pressure outside the range of 60 - 90 mmHg, and pulse rate at rest > 100 or < 60 bpm; History of positive tests for hepatitis B surface antigen, hepatitis C antibodies; History of HIV; Significant ECG abnormalities as follows: Heart Rate < 60 and >100 bpm PR Interval <120 and > 220 ms QRS duration < 70 and >120 ms QTC Interval (Bazett) > 450 ms

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: This study will employ the continual reassessment method (CRM) to find an MTD of Harmine. It uses a statistical model to estimate the relationship between dose and DLT risk to inform decisions on dosing. It first starts with a selected target DLT rate and a mathematical model for the relationship between dose and toxicity, the prior dose-toxicity curve. After a patient experiences a DLT or not, the dose-toxicity curve is re-fit incorporating the latest outcome. The next dose assigned is that most likely to be associated with the target toxicity level (the MTD). At every step, the next patient is assigned the dose estimated to be nearest to the MTD.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Harmine Dose<br>There will be a total of seven possible doses that include 100 mg, 200 mg, 300 mg, 500 mg, 700 mg, 900 mg and 1200 mg. Each study subject will receive a single oral dose of harmine in this single ascending dose design. | Drug: Harmine Hydrochloride Capsules<br>* capsules taken orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity (DLT) | Number of participant with DLT which is defined if have any one of the following: Patient Rated Inventory of Side Effects (PRISE): 0-51, higher scores indicate more adverse events observed Brief Psychiatric Rating Scale (BPRS): 4 - 28, higher scores indicate more symptoms of psychosis Vitals: blood pressure and heart rate will all be measured - anything outside of the following ranges will be noted: Symptomatic hypotension, or > 20% decrease in systolic blood pressure (SBP) from pre-dosing and an absolute SBP < 90; or Symptomatic hypertension, or > 20% increase in SBP or diastolic blood pressure (DBP) from predosing and absolute SBP > 170 or DBP > 95; New onset tachycardia (heart rate >100 bpm) and >20% increase from pre-dosing; or symptomatic bradycardia (heart rate <60 bpm) and > 20% decrease from pre-dosing. Signs and symptoms of cardiac ischemia, defined by acute ischemic changes on ECG with or without concomitant symptoms | end of study, at 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Analog Scale (VAS) | Visual Analog Scale (VAS) to characterize psychoactive effects of harmine in healthy adults. Full scale from 0-10, with higher scores indicating subjective states are experienced more strongly | end of study, at 18 months |