A First in Human Study of CMND-100 in Healthy and Alcohol Use Disorder (AUD) Subjects

Study Overview
=================
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 and AUD subjects. The secondary objective of this study is to preliminarily evaluate the efficacy of CMND-100 in reduction of drinking patterns and craving in individuals with moderate to severe AUD.

Detailed Description
-----------------
This is a Phase I/II, three-parts study (Parts A, B and C) in healthy and AUD subjects, 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 healthy and AUD subjects will be treated with single, ascending dose cohorts of CMND-100, for evaluation of tolerability, safety and PK/PD. Part C is a randomized, double-blind, placebo-controlled part, in which AUD subjects will be treated with repeated ascending dose cohorts 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 (total of up to 30 healthy subjects): At least four consecutive ascending dose cohorts (starting dose of 20 mg/kg) will be included in this part of the study, in accordance with a pre-defined dose escalating scheme. In each cohort, 3 healthy subjects will receive a single dose of investigational medicinal product (CMND-100) with the first cohort starting with the lowest dose of 20 mg/kg. Once dosed, the subjects will be sampled for PK for 24 hours following dosing and will be monitored for safety for a period of 1 week following dosing. If no serious adverse reactions or limiting toxicity (grade 3 and higher) are observed in this dose level, then the next 3 subjects are treated with the next escalated dose. Any toxicity seen will be handled according to the pre-defined dose escalating scheme. The information gathered from all dose cohorts studied in this part of the study will guide the range of doses to be studied in Part B of this study. Part B (a total of up to 18 AUD subjects): Once Part A has been completed and data analysed and approved by the DSMB, Part B will be initiated and will consist of enrolling AUD subjects in at least 2 consecutive ascending single dose cohorts using the tolerable dose found in Part A. The first cohort will start with the lower ascending dose, in accordance with a pre-defined dose escalation scheme. Three subjects will be dosed and sampled for PK for 24 hours following dosing and will be monitored for safety for a period of 1 week following dosing. If no serious adverse reactions or limiting toxicity (grade 3 and higher) are observed in this dose level, then the next 3 subjects are treated with the next escalated dose. Any toxicity seen will be handled according to the pre-defined dose escalating scheme. The information gathered from the dose cohorts studied in this part of the study will guide the range of doses to be studied in Part C of this study. Part C (total of up to 36 AUD subjects): Once Part B has been completed, the data analysed and approved by the DSMB, Part C will be initiated. This part will consist of two repeated-dose cohorts, considering the tolerable doses found in Part B, starting with the lower dose. In each cohort, up to 18 AUD 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 monitored for safety for a period of 1 week following last dosing. Once all subjects in the lower dose cohort will be enrolled and monitored throughout the study period, and assuming no serious adverse reactions or limiting toxicity (grade 3 and higher) will be observed, the Investigator will be allowed to start the next dose cohort. If any serious adverse reaction or grade 3 toxicity and higher will be reported, the Data Safety Monitoring Board (DSMB) should be consulted and its approval to start the next cohort will be required.

Official Title
-----------------
A Phase I/II Single and Multiple Dose Tolerability, Safety and Pharmacokinetic Study of CMND-100 in Healthy Volunteers and Alcohol Use Disorder (AUD) Subjects

Conditions
-----------------
Alcohol Use Disorder

Intervention / Treatment
-----------------
* Drug: CMND-100


Participation Criteria
=================
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, Normal vital signs (temperature, heart rate and blood pressure) at screening (heart rate in the range of 50-90, diastolic blood pressure of 50-85 and systolic blood pressure of 90-145), Normal or clinical insignificant 12-lead ECG according to PI, 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 Treatment seeking subjects with moderate/severe AUD, meeting DSM-5 criteria and: Consumed at least 4 heavy drinking days (For men: Heavy Drinking Days (HDD): ≥ 5 standard drinks/day; for women: HDD: ≥ 4 standard drinks/day) 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 moderate or severe withdraw symptoms. Current or past history of Major Depressive Disorder (within past 1 years), Bipolar Disorder, Schizophrenia, suicidal ideation (within past 2 years) or suicide attempts. Individuals suffering from depressed mood who do not meet current criteria for Major Depressive Disorder (MDD) can be included in this trial, Uncontrolled inter-current illness (i.e., active infection), 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, 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 or alcohol abuse within 2 years before screening, Subject is unable to abstain from ingesting alcohol for 72 hours prior to dosing.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Single and repeated doses of CMND-100. Parts A and B are open-label, non-controlled parts, in which healthy (Part A) and AUD subjects (Part B) will be treated with single, ascending dose cohorts of CMND-100. Part C is a randomized, double-blind, placebo-controlled part, in which AUD subjects will be treated with repeated ascending dose cohorts of CMND-100
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Healthy Subjects - Part A<br>Up to 30 healthy subjects in four consecutive ascending dose cohorts - starting dose of 20 mg/kg. Subjects will be sampled for PK for 24 hours following dosing and will be monitored for safety for a period of 1 week The investigational product CMND-100 consists of gelatin capsules, each containing the active ingredient (either 20 or 60 mg) 5-methoxy-2-aminoindane (MEAI) and excipients (stabilizers). MEAI is a psychoactive compound of the aminoindane class | Drug: CMND-100<br>* The investigational product CMND-100 consists of gelatin capsules, each containing the active ingredient (either 20 or 60 mg) 5-methoxy-2-aminoindane (MEAI) and excipients (stabilizers). MEAI is a psychoactive compound of the aminoindane class<br>* Other names: MEAI;|
| Other: AUD Subjects - Part B<br>Up to 36 AUD subjects in at least 2 consecutive ascending single dose cohorts using the tolerable dose found in Part A. The first cohort will start with the lowest ascending dose, in accordance with a pre-defined dose escalation scheme (see Section 5.2). Three subjects will be dosed and sampled for PK for 24 hours following dosing and will be monitored for safety for a period of 1 week | Drug: CMND-100<br>* The investigational product CMND-100 consists of gelatin capsules, each containing the active ingredient (either 20 or 60 mg) 5-methoxy-2-aminoindane (MEAI) and excipients (stabilizers). MEAI is a psychoactive compound of the aminoindane class<br>* Other names: MEAI;|
| Placebo Comparator: AUD Subjects - Part C<br>Up to 18 AUD subjects in at least 2 consecutive ascending single dose cohorts using the tolerable dose found in Part A. The first cohort will start with the lowest ascending dose, in accordance with a pre-defined dose escalation scheme (see Section 5.2). Three subjects will be dosed and sampled for PK for 24 hours following dosing and will be monitored for safety for a period of 1 week | Drug: CMND-100<br>* The investigational product CMND-100 consists of gelatin capsules, each containing the active ingredient (either 20 or 60 mg) 5-methoxy-2-aminoindane (MEAI) and excipients (stabilizers). MEAI is a psychoactive compound of the aminoindane class<br>* Other names: MEAI;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as Adverse Events Profile | Incidence of adverse events and classification in terms of severity, causality and outcome | up to 31 days | 
| Tmax | Time to maximum plasma concentration | up to 31 days | 
| Cmax | Maximum plasma concentration | up to 31 days | 
| AUC0-∞ | Area under the concentration-time curve from 0 minutes extrapolated to infinity | up to 31 days | 
| t1/2 | Terminal elimination phase half-life expressed in time units | up to 31 days | 
| Cl | The volume of plasma cleared of the drug per unit time | up to 31 days | 
| Vd | The volume in which a drug is distributed | up to 31 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part C only - Alcohol craving assessment using the Visual Analogue Scale of Craving (VAS) | VAS was adapted from the Alcohol Craving Questionnaire (ACQ) - Assessment of craving for alcohol based on a 10-point VAS response to the questions How strong is your craving for alcohol now where 1 indicates not at all and 10 indicates the most I've ever felt. | Change from pre-dose to Day 5 and Days 10 and 17 | 
| Part C only - Assessment of craving for alcohol using the Penn Alcohol Craving Scale (PACS) | PACS is a questionnaire that includes 5 questions where each question is scored 0 to 6, ranging from the lowest craving-related response (0) to the highest craving-related response (6). | The change from pre-dose to Day 5 and Days 10 and 17 of the total score will be evaluated. |