Multiple Ascending Dose Study of TMP-301 in Healthy Subjects

Study Overview
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Brief Summary
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A PHASE 1, RANDOMIZED, PLACEBO CONTROLLED, MULTIPLE ASCENDING DOSE (MAD) STUDY TO EVALUATE THE SAFETY, TOLERABILITY, AND PHARMACOKINETICS OF TMP-301 IN HEALTHY SUBJECTS.

Detailed Description
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This study will be a randomized, double-blind, placebo controlled, fixed sequence, MAD study. The study will be conducted in a single clinical research unit (CRU). The study will consist of up to 4 cohorts. Subjects will only participate in 1 cohort. Screening will occur within approximately 28 days prior to the first scheduled study drug administration. Subjects who meet all inclusion criteria and none of the exclusion criteria and who consent to participation will be admitted to the CRU for baseline evaluations prior to dosing. Subjects will be fasted overnight for 10 hours prior to the morning dose, followed by a 2 hour fast. Subjects are fasted for 2 hours prior to dosing and 2 hours following the evening dose for the cohort 1 (50 mg bid). Subjects will be discharged from the CRU on Day 18. Subjects will return to the CRU on Day 25 for a follow-up visit and EOS procedures. Caffeine (100 mg) will be included as probe CYP1A2 substrate in cohort 2 and subsequent cohorts. The maximum duration of subject participation, including Screening, will be approximately 53 days. Subjects who terminate the study early will perform follow-up procedures at the time of Early Termination.

Official Title
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A Phase 1, Randomized, Placebo-Controlled, Multiple Ascending Dose (MAD) Study To Evaluate The Safety, Tolerability, and Pharmacokinetics of TMP-301 in Healthy Subjects

Conditions
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Cocaine Use Disorder, Substance Use Disorders, Healthy Volunteers

Intervention / Treatment
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* Drug: TMP-301
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provision of signed and dated informed consent form (ICF) Stated willingness to comply with all study procedures and availability for the duration of the study Healthy adult male or female If male, meets one of the following criteria: a) Is able to procreate and agrees to use one of the accepted contraceptive regimens and not to donate sperm from the first study drug administration to at least 90 days after the follow-up visit. An acceptable method of contraception includes one of the following: Abstinence from heterosexual intercourse, or Male condom with spermicide or male condom with a vaginal spermicide (gel, foam, or suppository); or b) Is unable to procreate; defined as surgically sterile (ie, has undergone a vasectomy at least 180 days prior to the first study drug administration) If female, meets one of the following criteria: (1) Physiological postmenopausal status, defined as the following: a) absence of menses for at least 12 months prior to the first study drug administration (without an alternative medical condition); and b) Follicle stimulating hormone (FSH) levels ≥ 40 mIU/mL at Screening; Or (2) Surgical postmenopausal status, defined as the following: a) bilateral oophorectomy, salpingectomy, or tubal ligation; hysterectomy Aged at least 18 years but not older than 59 years, inclusive, at the time of informed consent Body mass index (BMI) within 18.5 kg/m2 to 32.0 kg/m2, inclusively Minimum body weight of at least 50.0 kg Non- or ex smoker (An ex smoker is defined as someone who completely stopped using nicotine products for at least 90 days prior to the first study drug administration) Must be willing to abstain from drinking coffee or caffeine containing beverages during the study, except where part of the study procedures Has supine blood pressure and pulse rate within the following ranges after 5 minutes rest: systolic blood pressure 90 to 140 mmHg, diastolic blood pressure 50 to 90 mmHg, and pulse rate 45 to 90 bpm at Screening and on Day -1 Have no clinically significant diseases captured in the medical history or evidence of clinically significant findings on the physical examination (including vital signs) and/or ECG, as determined by an Investigator Has clinical laboratory test results within the reference ranges of the testing laboratory, with the exception of results outside the reference ranges that are deemed not clinically significant by the Investigator (or designee) at Screening and check-in * Exclusion Criteria: Female who is lactating Female who is pregnant according to the pregnancy test at Screening or prior to the first study drug administration Female using the following systemic contraceptives: oral, patch or vaginal ring, in the 28 days prior to the first study drug administration and during the study Female using hormone replacement therapy in the 28 days prior to the first study drug administration and during the study Female using the following systemic contraceptives: injections or implant, or hormone releasing intrauterine device in the 13 weeks prior to the first study drug administration and during the study Drinking excessive amounts of tea, coffee, chocolate, and/or beverage or eating food containing caffeine (> 2 cups/day) Use of tobacco or nicotine containing products (including but not limited to; cigarettes, electronic cigarettes, pipes, cigars, chewing tobacco, nicotine patch, or nicotine gum) within 90 days prior to the first study drug administration and the inability to abstain from nicotine containing products until the follow-up visit. Past or current history of any mental, behavioral, or neurodevelopmental disorder as defined by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) or significant risk of developing a psychosis (assessed by PRIME screen) or a personal history of psychotic symptoms (hallucinations or delusions) with or without a formal psychiatric diagnosis. Subjects with family history of significant mental, behavioral, or neurodevelopmental disorders unless determined by the Investigator (or designee) and agreed by the Medical Monitor to be non-clinically significant (NCS) will be excluded. History or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, hematological, pulmonary, gastrointestinal, neurological, respiratory, or endocrine disorder, unless determined by the Investigator (or designee) and agreed by the Medical Monitor to be NCS Active or history of cardiovascular or cerebrovascular disease, including hypertension, angina, ischemic heart disease, transient ischemic attacks, bundle branch block, evidence of myocardial ischemia, stroke, and peripheral arterial disease sufficient to cause symptoms and/or require therapy to maintain stable status History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee) Active neoplastic disease or history of any neoplastic disease within 5 years of Screening (except for basal or squamous cell carcinoma of the skin or carcinoma in situ that has been definitely treated with standard of care) Active infection (eg, sepsis, pneumonia, abscess) or a serious infection (eg, resulting in hospitalization or requiring parenteral antibiotic treatment) within 6 weeks prior to dosing History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (uncomplicated appendectomy and hernia repair will be allowed) Any of the following at Screening and/or prior to the first study drug administration: QT interval corrected for heart rate using Fridericia's method (QTcF) > 450 ms confirmed by repeat measurement QRS duration > 110 ms confirmed by confirmed by repeat measurement PR interval > 220 ms confirmed by repeat measurement Findings which would make QTc measurements difficult or QTc data uninterpretable History of additional risk factors for torsades de pointe (eg, heart failure, hypokalemia, family history of long QT syndrome) Maintenance therapy with any drug or significant history of drug dependency or alcohol abuse (> 3 units of alcohol per day, intake of excessive alcohol, acute or chronic) Positive test result for alcohol, cotinine, and/or drugs of abuse at Screening or prior to the first drug administration Positive screening results to HIV Ag/Ab combo, hepatitis B surface antigen or hepatitis C virus tests Any other clinically significant abnormalities in laboratory test results at Screening that would, in the opinion of an Investigator, increase the subject's risk of participation, jeopardize complete participation in the study, or compromise interpretation of study data Intake of an IP in the 28 days prior to the first study drug administration Use of any prescription drugs in the 28 days prior to the first study drug administration, that in the opinion of an Investigator would put into question the status of the participant as healthy Use of St. John's wort in the 28 days prior to the first study drug administration and during the study Consumption of any foods or beverages which alter CYP1A2 activity, e.g., barbecued food or cruciferous vegetables, such as broccoli and cauliflower, within 14 days prior to (first) check-in (a list of prohibited foods will be provided to subjects) Consumption of any foods or beverages containing Seville-type oranges, grapefruit, or poppy seeds within 7 days prior to (first) check-in Receipt of blood products within 2 months prior to check-in Donation of 1 unit of blood to American Red Cross or equivalent organization or donation of over 500 mL of blood in the 56 days prior to the first study drug administration Donation of plasma in the 7 days prior to the first study drug administration Poor peripheral venous access History or significant hypersensitivity to TMP301 or any related products (including excipients of the formulations) as well as severe hypersensitivity reactions (like angioedema) to any drugs Subjects who, in the opinion of the Investigator (or designee; including input from subjects' general practitioner, as applicable), should not participate in this study Subject hospitalized for any reason in a period of 30 days before the start of the study Subjects who are investigational site staff members or directly involved in the conduct of the study and their family members or subjects who are employed by the Sponsor

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 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
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: sequential assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Active TMP-301<br>Cohort 1= 50mg, capsules form, one capsule - two times per day - total 100mg/day; Cohort 2= 50mg, capsule form, 1 capsules - one time per day- total 50mg/day Cohort 3= 50mg, capsule form, 2 capsules - one time per day- total 100mg/day; Cohort 4 = Dose Titration: 50mg, capsule form, 1 capsules - one time per day - total 50 mg/day - on Days 1-7; and 50 mg, capsule form, 2 capsules - one time per day - total 100mg/day - on Days 8-14; Each cohort duration is 14 days of dosing | Drug: TMP-301<br>* Multiple ascending dose active<br>|
| Placebo Comparator: Placebo<br>Cohort 1= Placebo, capsules form, one capsule - two times per day; Cohort 2= Placebo, capsule form, 1 capsules - one time per day; Cohort 3= Placebo, capsule form, 2 capsules - one time per day; Cohort 4 = Dose Titration: Placebo, capsule form, 1 capsules - one time per day - on Days 1-7; and Placebo, capsule form, 2 capsules - one time per day - on Days 8-14; Each cohort duration is 14 days of dosing | Drug: Placebo<br>* Multiple ascending dose comparator<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Occurence of Adverse Events, spontaneously reported and identified through clinical laboratory tests, vital sign measurements, ECG, physical exams and psychiatric assessments. | Within each cohort from screening to end of the follow up period up to 25 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma levels TMP 301 | Repeated collections on Day 1, intermittent samples from Day 2 through Day 13, repeated collections on Day 14, and intermittent samples during washout | Within each cohort from screening to end of the follow up period up to 25 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CUD, drug abuse, drug addiction, cocaine use disorder, cocaine dependance, TMP-301, cocaine use