A Study of ALS-4 in Healthy Adults Subjects

Study Overview
=================
Brief Summary
-----------------
A Phase I trial to evaluate the safety, tolerability and Pharmacokinetics of ALS-4 (IM032) in a single ascending dose (SAD) and multiple ascending dose (MAD) in healthy adult subjects.

Detailed Description
-----------------
This is a randomized, double-blind, placebo-controlled, first-in-human (FIH) study of ALS-4 (IM032) in healthy male and non-pregnant, non-lactating female volunteers. The study will consist of two phases: SAD and MAD. The study will evaluate the safety, tolerability and pharmacokinetic (PK) in 6 planned SAD cohorts (5 dose levels, and 1 cohort to evaluate for a potential food or circadian effect) with sentinel design (n=8 per cohort, total randomized 6 active: 2 placebo; sentinel design not applicable when a cohort with the same or a higher drug exposure has already been evaluated) and 3 planned MAD cohorts with sentinel design (n=8 per cohort, total randomized 6 active: 2 placebo).

Official Title
-----------------
A Phase I, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Doses of ALS-4 (IM032) Administered Orally to Healthy Volunteers

Conditions
-----------------
Healthy Subject

Intervention / Treatment
-----------------
* Drug: ALS-4
* Drug: Placebo
* Drug: ALS-4
* Drug: ALS-4
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy, non-smoking male and female volunteers (18-60 years inclusive at the time of informed consent.) Body mass index (BMI) within 18.5 - 33.0 kg/m2 inclusive and weight >50 kg. Healthy, according to the medical history, ECG, vital signs, laboratory results and physical examination as determined by the PI/Sub-Investigator. QTc interval < 440 milliseconds for males and < 460 milliseconds for females, unless deemed otherwise by the PI/Sub-Investigator Systolic blood pressure between 95-140 mmHg, inclusive, and diastolic blood pressure between 55-90 mmHg, inclusive, and heart rate between 55-100 bpm, inclusive, unless deemed otherwise by the PI/Sub-Investigator. Clinical laboratory values within the most recent acceptable laboratory test range, and/or values are deemed by the PI/Sub-Investigator as Not Clinically Significant. Ability to comprehend and be informed of the nature of the study, as assessed by staff. Capable of giving written informed consent prior to any study related procedure. Must be able to communicate effectively with clinic staff. Availability to volunteer for the entire study duration and willing to adhere to all protocol requirements. Agree not to have a tattoo or body piercing until the end of the study. Subject agree to avoid pregnancy and use an acceptable highly effective method of contraception from at least 30 days prior to the study until at least 30 days after the last study procedure (IM032 or placebo). Exclusion Criteria: Known history or presence of any clinically significant hepatic, renal/genitourinary, gastrointestinal, cardiovascular, cerebrovascular, pulmonary, endocrine, immunological, musculoskeletal, neurological, psychiatric, dermatological or hematological disease or condition unless determined as not clinically significant by the PI/Sub-Investigator. Clinically significant history or presence of any clinically significant gastrointestinal pathology (e.g., chronic diarrhea, inflammatory bowel disease), unresolved gastrointestinal symptoms (e.g., diarrhea, vomiting), or other conditions known to interfere with the absorption, distribution, metabolism or excretion of the drug experienced within 7 days prior to first study drug administration, as determined by the PI/Sub-Investigator. Presence of any clinically significant illness within 30 days prior to first dosing, as determined by the PI/Sub-Investigator. Presence of any significant physical or organ abnormality as determined by the PI/Sub-Investigator. A known history or positive test result for human immunodeficiency virus (HIV), chronic Hepatitis B surface antigen, or Hepatitis C. A positive test result for drugs of abuse (marijuana, amphetamines, barbiturates, cocaine, opiates, phencyclidine and benzodiazepines), alcohol test and cotinine. Positive pregnancy test for female subjects. Known history or presence of Food allergies and/or presence of any dietary restrictions unless deemed by the - - PI/Sub-I as Not Clinically Significant or Severe allergic reactions Intolerance to and/or difficulty with blood sampling through venipuncture. Individuals who have donated, in the days prior to first study drug administration: 50-499 mL of blood in the previous 30 days; or 500 mL or more in the previous 56 days; or donation of plasma by plasmapheresis within 7 days prior to first study drug administration. Individuals who have participated in another clinical trial or who received an investigational drug within 30 days or 5-half-lives prior to first study drug administration. Use of any enzyme-modifying drugs and/or other products, including strong inhibitors of cytochrome P450 (CYP) enzymes (e.g., cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and HIV antivirals) and strong inducers of CYP enzymes (e.g., barbiturates, carbamazepine, glucocorticoids, phenytoin, St. John´s Wort, and rifampicin) in the previous 30 days before first study drug administration. Use of any monoamine oxidase (MAO) inhibitors (e.g., phenelzine, tranylcypromine) within 30 days prior to first study drug administration. Use of any prescription medication within 14 days prior to first study drug administration (except for accepted methods of contraception). Use of any over-the-counter medications (including oral multivitamins, herbal and/or dietary supplements) within 14 days prior to first study drug administration (except for accepted methods of contraception). Consumption of food or beverages containing grapefruit and/or pomelo within 10 days prior to first study drug administration. Consumption of food or beverages containing caffeine/methylxanthines, poppy seeds and/or alcohol within 48 hours before dosing. Individuals having undergone any major surgery within 6 months prior to the start of the study, unless deemed otherwise by PI/Sub-Investigator. Have any other conditions that, in the opinion of the Investigator or Sponsor, would make the subject unsuitable for inclusion, or could interfere with the subject participating in or completing the study. Have had a tattoo or body piercing within 30 days prior to first study drug administration.

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A1 (Single dose): Cohort A: ALS-4 25mg<br>Single dose of ALS-4 or placebo before Breakfast | Drug: ALS-4<br>* Single dose of ALS-4 before Breakfast<br>* Other names: IM032;Drug: Placebo<br>* Single dose of placebo before Breakfast<br>|
| Experimental: Part A1 (Single dose): Cohort B: ALS-4 50mg<br>Single dose of ALS-4 or placebo before Breakfast | Drug: ALS-4<br>* Single dose of ALS-4 before Breakfast<br>* Other names: IM032;Drug: Placebo<br>* Single dose of placebo before Breakfast<br>|
| Experimental: Part A1 (Single dose): Cohort C: ALS-4 100mg<br>Single dose of ALS-4 or placebo before Breakfast | Drug: ALS-4<br>* Single dose of ALS-4 before Breakfast<br>* Other names: IM032;Drug: Placebo<br>* Single dose of placebo before Breakfast<br>|
| Experimental: Part A1 (Single dose): Cohort D: ALS-4 200mg<br>Single dose of ALS-4 or placebo before Breakfast | Drug: ALS-4<br>* Single dose of ALS-4 before Breakfast<br>* Other names: IM032;Drug: Placebo<br>* Single dose of placebo before Breakfast<br>|
| Experimental: Part A1 (Single dose): Cohort E: ALS-4 300mg<br>Single dose of ALS-4 or placebo before Breakfast | Drug: ALS-4<br>* Single dose of ALS-4 before Breakfast<br>* Other names: IM032;Drug: Placebo<br>* Single dose of placebo before Breakfast<br>|
| Experimental: Part A2 (Single dose): Cohort F: ALS-4 50mg<br>Dose three separate times in crossover fashion: (1) fasted morning dose; (2) fed morning dose; (3) fasted evening dose | Drug: Placebo<br>* Single dose of placebo before Breakfast<br>Drug: ALS-4<br>* Dose three separate times in crossover fashion: (1) fasted morning dose; (2) fed morning dose; (3) fasted evening dose<br>* Other names: IM032;|
| Experimental: Part B (Multiple dose): Cohort AA: ALS-4 50mg<br>Multiple dose of ALS-4 or placebo up to two times daily | Drug: ALS-4<br>* Multiple dose of ALS-4 up to two times daily<br>* Other names: IM032;Drug: Placebo<br>* Multiple dose of placebo up to two times daily<br>|
| Experimental: Part B (Multiple dose): Cohort BB: ALS-4 100mg<br>Multiple dose of ALS-4 or placebo up to two times daily | Drug: ALS-4<br>* Multiple dose of ALS-4 up to two times daily<br>* Other names: IM032;Drug: Placebo<br>* Multiple dose of placebo up to two times daily<br>|
| Experimental: Part B (Multiple dose): Cohort CC: ALS-4 200mg<br>Multiple dose of ALS-4 or placebo up to two times daily | Drug: ALS-4<br>* Multiple dose of ALS-4 up to two times daily<br>* Other names: IM032;Drug: Placebo<br>* Multiple dose of placebo up to two times daily<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse Events | An adverse event is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the Study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. | Up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration-time curve from time-zero extrapolated to infinite time (AUCinf) |  | Up to 24 hours post dose | 
| Area under the plasma concentration vs time curve from time 0 to the time of the last measurable concentration, or last sampling time t (AUCt) |  | Up to 24 hours post dose | 
| Time of maximum observed plasma concentration (Cmax) |  | Up to 24 hours post dose | 
| Time of maximum plasma concentration (Tmax) |  | Up to 24 hours post dose | 
| Terminal elimination rate constant (λz) |  | Up to 24 hours post dose | 
| Terminal elimination half-life(T1/2) |  | Up to 24 hours post dose | 
| Plasma concentration at the end of the dosing interval at steady state on Day 14 (Ctau) |  | Up to 24 hours post dose | 
| Minimum steady-state plasma concentration during a dosage interval on Day 14 (Cmin) |  | Up to 24 hours post dose | 
| Maximum plasma concentration during a dosage interval (x = 1 or 14) (Cmax, Day x) |  | Up to 24 hours post dose | 
| Area under the plasma concentration-time curve during a dosage interval on Day x (x = 1 or 14) (AUC12, Day x) |  | Up to 24 hours post dose | 
| Accumulation ratio from Cmax from Day 1 to Day 14 (AR(Cmax)) |  | Up to 24 hours post dose | 
| Accumulation ratio from AUC from Day 1 to Day 14 (AR(AUC)) |  | Up to 24 hours post dose | 
| Time until maximum plasma concentration reached on Day x (x = 1 or 14) (Tmax,Day x) |  | Up to 24 hours post dose |