Clinical trial NCT05526430: Study of Harmine in Healthy Subjects
Official title: A Phase I Dose Escalation Study of Harmine in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Diabetes Mellitus
Lead sponsor: Icahn School of Medicine at Mount Sinai
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2022-09-02
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SEQUENTIAL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicity (DLT)
timeFrame: 24 hours
measure: Maximum Tolerated Dose (MTD) of Oral Harmine HCl Based on Dose Limiting Toxicity (DLT)
timeFrame: 24 hours
Secondary outcomes:
measure: Visual Analog Scale (VAS) - Nausea
timeFrame: baseline, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7 8, and 24 hours
measure: Visual Analog Scale (VAS) - Hunger
timeFrame: baseline, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7 8, and 24 hours
measure: Visual Analog Scale (VAS) - Feeling High/Intoxicated
timeFrame: baseline, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7 8, and 24 hours
measure: Visual Analog Scale (VAS) - Drowsiness
timeFrame: baseline, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7 8, and 24 hours
measure: Visual Analog Scale (VAS) - Anxiety
timeFrame: baseline, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7 8, and 24 hours
measure: Visual Analog Scale (VAS) - Depressed Mood
timeFrame: baseline, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7 8, and 24 hours
measure: Visual Analog Scale (VAS) - Happy Mood
timeFrame: baseline, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7 8, and 24 hours
measure: Visual Analog Scale (VAS) - Excitement
timeFrame: baseline, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7 8, and 24 hours
measure: Visual Analog Scale (VAS) - Feeling of Control
timeFrame: baseline, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7 8, and 24 hours
measure: Visual Analog Scale (VAS) - Vividness of Image
timeFrame: baseline, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7 8, and 24 hours
measure: Profile of Mood States Bipolar Scale (POMS-Bi): Composed-Anxious Scale
timeFrame: Baseline, 2, 6, 7, 8, and 24 hours
measure: Profile of Mood States Bipolar Scale (POMS-Bi): Agreeable-Hostile Scale
timeFrame: Baseline, 2, 6, 7, 8, and 24 hours
measure: Profile of Mood States Bipolar Scale (POMS-Bi): Elated-Depression Scale
timeFrame: Baseline, 2, 6, 7, 8, and 24 hours
measure: Profile of Mood States Bipolar Scale (POMS-Bi): Confident-Unsure Scale
timeFrame: Baseline, 2, 6, 7, 8, and 24 hours
measure: Profile of Mood States Bipolar Scale (POMS-Bi): Energetic-Tired Scale
timeFrame: Baseline, 2, 6, 7, 8, and 24 hours
measure: Profile of Mood States Bipolar Scale (POMS-Bi): Clearheaded-Confused Scale
timeFrame: Baseline, 2, 6, 7, 8, and 24 hours
measure: Perceived Stress Scale (PSS)
timeFrame: 24 hours
measure: Patient Rated Inventory of Side Effects (PRISE)
timeFrame: 24 hours
measure: Brief Psychiatric Rating Scale (BPRS)
timeFrame: Baseline, 2, 6, 7, 8, and 24 hours
measure: Columbia Suicide Severity Rating Scale (C-SSRS)
timeFrame: 24 hours
Other outcomes:
Locations:
city: New York
country: United States
facility: Depression and Anxiety Center
state: New York
Study officials:
affiliation: Icahn School of Medicine at Mount Sinai
name: James Murrough, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: