Safety, Tolerability and Pharmacokinetics of AM1476 in Healthy Subjects

Study Overview
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Brief Summary
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This is a First in Human (FIH), double-blind, randomised, placebo-controlled study designed to evaluate safety, tolerability and PK of single and multiple ascending oral doses of AM1476 in healthy subjects.

Detailed Description
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Part A (SAD); In the SAD part of the study, single oral doses of AM1476 will be administered in up to 9 sequential groups, each consisting of 8 subjects randomised to recieve either AM1476 or placebo in a 3:1 ratio. The first 2 subjects in each group will be dosed in a sentinel fashion, 1 subject will receive AM1476 and the other will receive placebo as randomised. The SAD part incorporating a 2-period crossover arm for a food-effect evaluation in 2 groups. Part B (MAD); The MAD part of the study will explore multiple ascending dosing of AM1476 for 10 days. AM1476 will be administered in up to 6 sequential groups, each consisting of 8 subjects randomised to recieve either AM1476 or placebo in a 3:1 ratio.

Official Title
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AM1476 - A Phase I, Double-blind, Placebo-controlled, Single- and Multiple-oral Dose, Safety, Tolerability, and Pharmacokinetic Study in Healthy Subjects

Conditions
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Safety, Tolerability

Intervention / Treatment
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* Drug: AM1476
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, of any race, between 18 and 60 years of age, inclusive. A body mass index (BMI) between 18.0 and 32.0 kg/m2, inclusive. In good health, determined by no clinically significant findings from medical history, physical examination, 12-lead ECG, vital signs measurements, and clinical laboratory evaluations (congenital non-haemolytic hyperbilirubinemia [eg, suspicion of Gilbert's syndrome based on total and direct bilirubin] is not acceptable) at Screening and/or Check-in (Day -1) as assessed by the Investigator (or designee). Females will not be pregnant or lactating, and females of childbearing potential and males will agree to use contraception as detailed in Appendix 4. Able to comprehend and willing to sign an ICF and to abide by the study restrictions. Exclusion Criteria Significant history or clinical manifestation of any metabolic, allergic, dermatological, hepatic, renal, haematological, pulmonary, cardiovascular, gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as determined by the Investigator (or designee). History of significant hypersensitivity, intolerance, or allergy to any drug compound, food, or other substance, unless approved by the Investigator (or designee). 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 observed in at least 2 of 3 ECG measurements performed: QTcF > 450 msec. QRS duration > 110 msec. PR interval > 220 msec. findings which would make QTc measurements difficult or QTc data uninterpretable. Any history of additional risk factors for torsades de pointes (eg, heart failure, hypokalaemia, family history of long QT syndrome). Any history or current controlled or uncontrolled hypertension or systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg confirmed by repeat measurement. History of alcoholism or drug/chemical abuse within 2 years prior to Check-in (Day -1). Alcohol consumption of > 21 units per week for males and > 14 units per week for females. One unit of alcohol equals ½ pint (285 mL) of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits. Positive alcohol breath test result or positive urine drug screen (confirmed by repeat) at Screening or Check-in (Day -1). Positive hepatitis panel and/or positive human immunodeficiency virus test (Appendix 2). Participation in a clinical study involving administration of an investigational drug (new chemical entity) in the past 90 days prior to dosing. Use or intend to use any medications/products known to alter drug absorption, metabolism, or elimination processes, including St. John's Wort, within 30 days prior to dosing, unless deemed acceptable by the Investigator (or designee). Use or intend to use any prescription medications/products other than hormone replacement therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives within 14 days prior to dosing, unless deemed acceptable by the Investigator (or designee). Use or intend to use slow release medications/products considered to still be active within 14 days prior to Check-in (Day -1), unless deemed acceptable by the Investigator (or designee). Use or intend to use any non-prescription medications/products including vitamins, minerals, and phytotherapeutic/herbal/plant-derived preparations within 7 days prior to Check-in (Day -1), unless deemed acceptable by the Investigator (or designee). Use of tobacco- or nicotine-containing products within 3 months prior to Check-in (Day -1) or positive cotinine at Screening or Check-in (Day -1). Ingestion of poppy seeds, Seville orange, or grapefruit-containing foods or beverages within 7 days prior to Check-in (Day -1). Subjects who are vegetarians, vegans, or are unable to consume the high-fat breakfast (subjects who will participate in a food-effect evaluation [planned to be Group A3] only). Receipt of blood products within 2 months prior to Check-in (Day -1). Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening. Poor peripheral venous access. Have previously completed or withdrawn from this study or any other study investigating AM1476, and have previously received AM1476. Subjects who are not willing to minimise or avoid exposure to natural or artificial sunlight (tanning beds or UVA/B treatment) following administration of study drug until 2 weeks after the last dose. Subjects who, in the opinion of the Investigator (or designee), should not participate in this study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Parallel Assignment
Interventional Model Description: Part A (SAD) Within each group, subjects will be randomised in a 3:1 ratio to receive either AM1476 (n=6) or placebo (n=2). The first 2 subjects in each group will be dosed in a sentinel fashion; 1 subject will receive AM1476 and the other will receive placebo as randomised. Part B (MAD) Within each group, subjects will be randomised in a 3:1 ratio to receive either AM1476 (n=6) or placebo (n=2).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A, Group 1: AM1476 1 mg<br>Part A, Group 1: AM1476 1 mg capsule, orally once on Day 1 in fasted state | Drug: AM1476<br>* AM1476 Capsules<br>|
| Experimental: Part A, Group 2: AM1476 5 mg<br>Part A, Group 2: AM1476 5 mg capsule, orally once on Days 1 in fasted state | Drug: AM1476<br>* AM1476 Capsules<br>|
| Experimental: Part A, Group 3: AM1476 25 mg<br>Part A, Group 3: AM1476 25 mg capsule, orally once on Days 1 in fasted state | Drug: AM1476<br>* AM1476 Capsules<br>|
| Experimental: Part A, Group 4: AM1476 125 mg<br>Part A, Group 4: AM1476 125 mg capsule, orally once on Days 1 in fasted state | Drug: AM1476<br>* AM1476 Capsules<br>|
| Experimental: Part A, Group 5: AM1476 375 mg<br>Part A, Group 5: AM1476 375 mg capsule, orally once on Days 1 in fasted state | Drug: AM1476<br>* AM1476 Capsules<br>|
| Experimental: Part A, Group 6: AM1476 650 mg<br>Part A, Group 6: AM1476 650 mg capsule, orally once on Days 1 in fasted state | Drug: AM1476<br>* AM1476 Capsules<br>|
| Experimental: Part A, Group 7: AM1476 950 mg<br>Part A, Group 7: AM1476 950 mg capsule, orally once on Days 1 in fasted state | Drug: AM1476<br>* AM1476 Capsules<br>|
| Experimental: Part A, Group 8: AM1476 1500 mg<br>Part A, Group 8: AM1476 1500 mg capsule, orally once on Days 1 in fasted state | Drug: AM1476<br>* AM1476 Capsules<br>|
| Experimental: Part A, Group 9: AM1476 2400 mg<br>Part A, Group 9: AM1476 2400 mg capsule, orally once on Days 1 in fasted state | Drug: AM1476<br>* AM1476 Capsules<br>|
| Placebo Comparator: Part A, Groups 1 to 9: Placebo<br>Part A, Groups 1 to 9: AM1476 placebo-matching capsule, orally once on Days 1 in fasted state | Drug: Placebo<br>* Placebo Capsules<br>|
| Experimental: Part B, Group 1: AM1476 100 mg QD<br>Part B, Group 1: AM1476 100 mg capsule, orally once on Days 1-10 in fasted state | Drug: AM1476<br>* AM1476 Capsules<br>|
| Experimental: Part B, Group 2: AM1476 375 mg BID<br>Part B, Group 2: AM1476 375 mg capsule, orally twice on Days 1-9 and once on Days 10 in fasted state | Drug: AM1476<br>* AM1476 Capsules<br>|
| Experimental: Part B, Group 3: AM1476 500 mg BID<br>Part B, Group 3: AM1476 500 mg capsule, orally twice on Days 1-9 and once on Days 10 in fasted state | Drug: AM1476<br>* AM1476 Capsules<br>|
| Placebo Comparator: Part B, Groups 1 to 3: Placebo<br>Part B, Groups 1 to 3: AM1476 placebo-matching capsule, orally once or twice on Days 1-10 in fasted state | Drug: Placebo<br>* Placebo Capsules<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, including abnormal laboratory events | Frequency, severity and seriousness of adverse events (AEs) including physical examination, safety laboratory parameters, vitals signs, body temperature and ECGs will be analyzed. | Through study completion, an average of 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | maximum plasma concentration | SAD: From pre-dose to up to 48 hours post-dose; MAD: From pre-dose to 24 hours post first dose and 48 hours post last dose | 
| Tmax | time to Cmax | SAD: From pre-dose to up to 48 hours post-dose; MAD: From pre-dose to 24 hours post first dose and 48 hours post last dose | 
| T½ | terminal half-life | SAD: From pre-dose to up to 48 hours post-dose; MAD: From pre-dose to 24 hours post first dose and 48 hours post last dose | 
| AUC0-t | area under the curve from time 0 to time t | SAD: From pre-dose to up to 48 hours post-dose; MAD: From pre-dose to 12/24 hours post first dose and 48 hours post last dose | 
| CL/F | apparent total clearance | SAD: From pre-dose to up to 48 hours post-dose; MAD: From pre-dose to 12/24 hours post first dose and 48 hours post last dose | 
| Vz/F | apparent volume of distribution during the terminal phase | SAD: From pre-dose to up to 48 hours post-dose; MAD: From pre-dose to 12/24 hours post first dose and 48 hours post last dose |