Clinical trial NCT05913752: A First in Human Study of CMND-100 in Healthy and Alcohol Use Disorder (AUD) Subjects
Official title: A Phase I/II Single and Multiple Dose Tolerability, Safety and Pharmacokinetic Study of CMND-100 in Healthy Volunteers and Subjects With Binge Drinking/ Alcohol Use Disorder (AUD)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Alcohol Use Disorder
Lead sponsor: Clearmind Medicine Inc.
Sponsor class: INDUSTRY
First posted: 2023-06-22
Enrollment: 84
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Single and repeated doses of CMND-100. Parts A and B are open-label, non-controlled parts, in which HVs and subjects with binge drinking/AUD respectively will be treated with single, ascending dose cohorts of CMND-100, for evaluation of tolerability, safety and PK/PD. Parts C and D are randomized, double-blind, placebo-controlled parts, in which HVs and subjects with binge drinking/AUD respectively will be treated with repeated doses of CMND-100, for evaluation of safety, PK/PD and preliminary efficacy.
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to find the tolerable dose and characterize the safety and pharmacokinetics/ pharmacodynamics (PK/PD) of single and repeated dose of CMND-100 in Healthy Volunteers (HV) and Subjects with Binge Drinking/Alcohol Use Disorder (AUD).

The secondary objective of this study is to preliminarily evaluate the efficacy of CMND-100 in reduction of drinking patterns and craving in subjects with binge drinking or/and moderate to severe AUD.

Detailed description: This is a Phase I/II, four-parts study (Parts A to D) in HVs and subjects with binge drinking/AUD, evaluating the tolerability, safety, and pharmacokinetics/ pharmacodynamics (PK/PD) of single and repeated doses of CMND-100. Parts A and B are open-label, non-controlled parts, in which HVs and subjects with binge drinking/AUD respectively will be treated with single, ascending dose cohorts of CMND-100, for evaluation of tolerability, safety and PK/PD. Parts C and D are randomized, double-blind, placebo-controlled part, in which HVs and subjects with binge drinking/AUD respectively will be treated with repeated doses of CMND-100, for evaluation of safety, PK/PD and preliminary efficacy. Below is a short description of each part of the study.

* Part A - Single dose (\~ 24) HVs: At least four consecutive ascending dose cohorts (20 mg, 40, 80 and 160mg) will be included in this part of the study in accordance with a pre-defined dose escalating scheme (see Section 5.2). In each cohort, 6 HVs will receive a single dose of investigation medicine product (CMND-100) with the first cohort starting with the lowest dose of 20 mg. Once dosed, the subjects will be sampled for PK for 24 hours following dosing and will be monitored for drug effects with a physical examination at the end of 24 hours after dosing and daily monitored for safety for a period of 1 week following dosing. Assuming no serious adverse reactions (as defined in Section 11.1) or limiting toxicity (grade 2 and higher) in up to 2 subjects, as defined in Section 5.2) are observed in this dose level, then the next 6 subjects are treated with the next escalated dose, in accordance with a pre-defined dose escalating scheme. The information gathered in this part of the study will be reviewed by the DSMB and guide the doses to be studied in Parts B, C and D of this study.
* Part B - Single dose (\~12) subjects with binge drinking/AUD: Once Part A has been completed and data analyzed and approved by the DSMB, Part B will be initiated and will consist of enrolling subjects with binge drinking/AUD in at least 2 consecutive ascending single dose cohorts using the highest tolerable doses found in Part A. The first cohort will start with the lower ascending dose. Six subjects will be dosed and sampled for PK for 24 hours following dosing and will be monitored for drug effects with a physical examination at the end of 24 hours after dosing and daily monitored for safety for a period of 1 week following dosing. Assuming no serious adverse reactions (as defined in Section 11.1) or limiting toxicity (grade 2 and higher in up to 2 subjects, as defined in Section 5.2) are observed in this dose level, then the next 6 subjects are treated with the next escalated dose. For any grade 2 or higher toxicity in more of two subjects refer to Section 5.2. At the end of this part, real time PK data from the dose cohorts will be collected and analyzed and this information together with the safety information gathered in this part of the study and the data observed in Part A will be reviewed by the DSMB and will guide the dose to be studied in Part D of this study.
* Part C - Multiple dose (18) HVs: Once Part A has been completed, the data analyzed and approved by the DSMB, Part C will be initiated. This part will consist of a repeated-dose cohort based on the higher tolerable dose found in Part A. HVs will be randomized into either the treatment or the placebo arm at a ratio of 2:1 (12 subjects treated with the investigation product and 6 subjects receiving placebo) and will receive the drug/placebo at a daily basis for a total of 10 consecutive days. Each subject will be sampled for PK for 24 hours after first and last dosing and will be daily monitored for drug effects and safety throughout the study period and until 1 week after the last dosing. Real time PK data will be collected, and results analyzed (as defined in Section 5.2). The PK and safety information gathered from in this part of the study will be evaluated by the DSMB and will guide the dose to be studied in Part D of this study.
* Part D - Multiple dose (18) subjects with binge drinking/AUD: Once Part B and Part C has been completed, the data analyzed and approved by the DSMB, Part D will be initiated. This part will consist of a repeated-dose cohort, based on the higher tolerable dose found in Part C and considering the dose effects found in Part B. Subjects will be randomized into either the treatment or the placebo arm at a ratio of 2:1 (12 subjects treated with the investigation product and 6 subjects receiving placebo) and will receive the drug/placebo at a daily basis for a total of 10 consecutive days. Each subject will be sampled for PK for 24 hours after first and last dosing and will be daily monitored for drug effects and safety throughout the study period and until 1 week after the last dosing. The PK and safety information gathered from in this part of the study will be evaluated by the DSMB.

Eligibility criteria: Inclusion Criteria:

All Subjects

* Signed informed consent prior to any study-related procedures,
* Subjects understand the nature and the procedures related with the study design of the trial and accept to fulfill all activities related to this trial,
* Subjects 18 to 60 years of age,
* Body mass index between 18 and 35 kg/m2,
* No (history of) clinically significant conditions and/or concomitant medications which in the opinion of the investigator could endanger the safety of the subject or impact the validity of the study results,
* Male subjects who wish use condoms for the duration of the study and for a suitable time period after the last drug dose (e.g., 5 half-lives),
* Female subjects who are not pregnant or breast-feeding or who do not wish to become pregnant during the period of the clinical study and for three months later,
* Female subjects of childbearing potential (less than 24 months after the last menstrual cycle) who use adequate contraceptive methods. Adequate contraceptive methods may include any approved method of birth control such as combined estrogen and progestogen containing hormonal contraception, associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intra-uterine devices, condoms, abstinence or vasectomized partner. Contraception should be maintained until study end.

Additional Criteria for AUD Subjects

* Non-treatment seeking subjects who report heavy binge drinking (i.e. at least i.e. ≥ 5 standard drinks in a day for men or ≥ 4 standard drinks in a day for women) in at least 5 days in the last month prior to screening OR:
* Treatment seeking subjects with AUD meeting DSM-5 criteria as assessed by SCID and:
* Consumed at least 4 binge drinking days (i.e. ≥ 5 standard drinks in a day for men or ≥ 4 standard drinks in a day for women) in the month prior to screening.
* A desire to reduce or stop drinking.
* Stable housing in the 3 months prior to randomization with no foreseeable risk to lose this in the 3 months after screening,
* Agree to abstain from new/additional psychotropic medications, except for benzodiazepines as rescue medication prescribed by the PI or a stable dose of psychotropic medications in the 1 months prior to randomization with the intention to continue this medication during the study.

Exclusion Criteria All Subjects

* The subject has a clinically significant history of a disease or a disorder that could interfere with the interpretation of the results or could increase the risk to the subject all according to the opinion of the PI.
* Subjects with symptoms of alcohol withdrawal or intoxication at time of screening.
* Subjects with history of seizures or epilepsy,
* Subjects with moderate to severe symptoms of alcohol withdrawal or intoxication at time of screening.
* Subjects positive to HIV at screening,
* Current or past history of Major Depressive Disorder (MDD) (within past 1 years), Bipolar Disorder, Schizophrenia, suicidal ideation (within past 2 years) or suicide attempts in the past 2 years. Individuals suffering from depressed mood who do not meet current criteria for MDD can be included in this trial,
* Uncontrolled inter-current illness (i.e., active infection),
* Clinically significant abnormal vital signs (e.g., systolic blood pressure ≥139 mmHg, diastolic blood pressure ≥90 mmHg, heart rate \>90 beats per minute) at separate three measures before dosing,
* Clinically significant abnormal ECG parameters, including subjects with QTc greater than 450 msec,
* Clinically significant abnormal liver functions (ALT and AST), higher than three times the normal amount, clinically significant abnormal Hb,
* Subjects using concomitant medications such as antipsychotic and mood stabilizing medications (including SSRIs such as Fluoxetine and Paroxetine, SNRIs and trazodone), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), vitamins, herbal and/or mineral supplements, dietary supplements (and/or grapefruit juice), and enzyme altering agents (rifampin, barbiturates, phenothiazines, cimetidine, etc.) or any other medications that may have significant interaction with the study medication, within 2 weeks prior to the study and until the entire duration of study treatment,
* Subjects taking OCT1 and OCT2 substrates,
* Received an experimental drug or used an experimental medical device within 1 month or within a period \<5 times the drug's half-life for small molecules, or 3 months for biologics, whichever is longer, before the study drug is administered for the first time,
* Subjects which are in a depression state co-morbidity who take anti depressive drugs on a regular basis,
* Donated blood within 90 days or plasma within 30 days of study dosing,
* Any self-reported current use of drugs such as cocaine, amphetamines, opioids, or barbiturates and/or a positive urine screen for the drugs of abuse just mentioned,
* Any subject who may not be able to fulfill the study requirements per the investigator's clinical judgement.

Additional Criteria for Healthy Subjects

* Subject has a history of drug/substance or alcohol use disorder within 2 years before screening, except for cannabis and nicotine use disorders,
* Subject is unable to abstain from ingesting alcohol for 72 hours prior to dosing.
* Subjects who are symptomatic or requiring ongoing treatment for any mood disorder/event.

Primary outcomes:
measure: Safety as Adverse Events Profile
timeFrame: up to 31 days
measure: Tmax
timeFrame: up to 31 days
measure: Cmax
timeFrame: up to 31 days
measure: AUC0-∞
timeFrame: up to 31 days
measure: t1/2
timeFrame: up to 31 days
measure: Cl
timeFrame: up to 31 days
measure: Vd
timeFrame: up to 31 days
Secondary outcomes:
measure: Part D only - Alcohol craving assessment using the Visual Analogue Scale of Craving (VAS)
timeFrame: Change from pre-dose to Day 5 and Days 10 and 17
measure: Part D only - Assessment of craving for alcohol using the Penn Alcohol Craving Scale (PACS)
timeFrame: The change from pre-dose to Day 5 and Days 10 and 17 of the total score will be evaluated.
Other outcomes:
measure: Assessment of subjective level of sleepiness using the Karolisnka Sleepiness Scale (KSS). (Exploratory Endpoint - 1)
timeFrame: change from pre-dose to Day 5 and Days 10 and 17
measure: Assessment of depression symptoms using the Beck Depression Inventory (BDI-II) (Exploratory Endpoint - 2)
timeFrame: The change from pre-dose to Day 5 and Days 10 and 17
measure: Evaluation of alcohol consumption using Alcohol Timeline Follow-Back (TLFB) (Exploratory Endpoint - 3)
timeFrame: The change from pre-dose to post-dose Day 5 and Days 10 and 17
measure: Detection of alcohol abuse using alcohol use blood marker gamma-glutamyl transferase (GGT)
timeFrame: The change from pre-dose to post-dose Day 5 and Days 10 and 17
measure: Measurement of chronic alcohol intake using Carbohydrate-deficient transferrin (CDT)
timeFrame: The change from pre-dose to post-dose Day 5 and Days 10 and 17
Locations:
city: New Haven
country: United States
facility: Connecticut Mental Health Center
state: Connecticut
city: Baltimore
country: United States
facility: Johns Hopkins Bayview Medical Center
state: Maryland
city: Ramat Gan
country: Israel
facility: The Sophie and Abram Stuchynski Israeli Alzheimer Medical Center
Study officials:
References: