Phase I Single Ascending Dose and Multiple Ascending Doses of Oral AFA-281 in Healthy Volunteers

Study Overview
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Brief Summary
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Phase I Part 1 (single ascending dose): Double-blind dosing will occur in healthy volunteers in 5 cohorts of 8 subjects each. Six subjects in each cohort will be randomized to receive AFA-281 and 2 subjects will be randomized to receive the matching placebo. At the end of the Part 1 study is to evaluate the safety and tolerability of AFA-281. Following completion of each cohort, bioanalytical analyses will be conducted to evaluate the pharmacokinetic profile. Phase I Part 2 (multiple dose for 14 days): Pending the results from Part 1, healthy volunteers will be administered AFA-281 for 14 consecutive days in 3 cohorts. At scheduled intervals after dosing, and at the end of the cohort's study period to evaluate the safety and tolerability of AFA-281 and the pharmacokinetic profile of AFA-281.

Detailed Description
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Phase I Part 1 (single ascending dose): Healthy volunteers will be admitted to the clinical research unit on Day -1. There will be five cohorts with 8 subjects per cohort. Five subjects per cohort will receive AFA-281 at either 20, 40, 80, 160 or 300 mg and 3 will receive placebo. Oral capsules will be administered on the morning of Day 1, following a 10-hour fast. Blood draws for assessment of Pharmacokinetic parameters will occur 0.2-1 hr pre-dose and at 0.5-, 1-, 2-, 3-, 4-, 8-, 10, 12-, 16-, 24-, 36-, 48-hr, and up to 72-hr post-dose. Vital signs will be collected at scheduled times following dosing. A 12-lead ECG will be obtained pre-dose and scheduled at 2, 4, 8, 24 hr, and 3- or 4 days post- dose. Various clinical laboratory tests will be drawn on Day -1, within 1 hr prior to dosing, and at scheduled timepoints after dosing while the volunteer is housed in the research center. Subjects of Cohorts 1 - 3 will be released following completion of blood draws and safety assessments up to 48 hours and Cohorts 4 and 5 subjects will return for 72-hour blood draws and Day 4 ECG and safety assessment. Phase I Part 2 (multiple ascending doses - 14 days): After assessment of the safety data from the single dose Phase I Part 1, healthy volunteers will be randomized into 3 cohorts with 8 subjects per cohort. Five subjects per cohort will receive AFA-281 and 3 will receive placebo. Oral capsules will be administered twice daily for 14 consecutive days. Routine clinical monitoring will occur as in Part 1. Baseline physical examination, vital signs, clinical lab tests, and ECGs will be performed prior to dosing, at scheduled intervals after dosing, and at the end of the cohort's study period to evaluate the safety and tolerability of AFA-281 and the pharmacokinetic profile of AFA-281. Reports of potential Adverse events will be elicited, and vital signs and 12-lead ECG will be measured in a similar manner to Part 1. Similarly, clinical laboratory tests will be drawn prior to and after dosing.

Official Title
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A Double-blind, Placebo-controlled, Study of the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses of Oral AFA-281 (Phase I Part 1) and Multiple Ascending Doses of Oral AFA-281 (Phase I Part 2) in Healthy Volunteers

Conditions
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Pain, Neuropathic, Pain, Inflammatory

Intervention / Treatment
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* Drug: AFA-281


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must be in good general health with no significant medical history and have no clinically significant abnormalities on physical examination at screening and/or before administration of the initial dose of study drug. Participants must have a Body Mass Index (BMI) between 18.0 and 30.0 kg/m2 inclusive. Participants must have clinical laboratory values within normal range as specified by the testing laboratory, unless deemed not clinically significant by the Investigator or delegate. Participants must have an ECG without clinically significant pathologic abnormalities. Exclusion Criteria: Participants with significant medical history or clinically significant abnormalities Participants with clinically significantly pathologic abnormalities Participants with ECG abnormalities

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Part 1: Single escalation dose Part 2: Multiple escalation doses for 14 days
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo Control<br>Double blind placebo control | Drug: AFA-281<br>* Part 1: AFA-281 will be administered as a single dose at 5 dose levels (TBD) Part 2: AFA-281 will be administered twice daily for 14 days at 3 dose levels (TBD)<br>|
| Experimental: AFA-281<br>Part 1: AFA-281 administered as an oral capsule at 5 dose levels for one day. Part 2: AFA-281 administered as an oral capsule at 3 dose levels twice daily for 14 consecutive days. Doses will be determined after completion of Part 1. | Drug: AFA-281<br>* Part 1: AFA-281 will be administered as a single dose at 5 dose levels (TBD) Part 2: AFA-281 will be administered twice daily for 14 days at 3 dose levels (TBD)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-Related Adverse Events | Number of participants with treatment-related adverse events will be assessed using CTCAE v5.0, | Predose and Up to 72 hours after dose | 
| Heart rate | Heart rate as one of vital signs will be measured | Predose and Up to 72 hours after dose | 
| Body temperature | Body temperature (0C) as one of vital signs will be measured | Predose and Up to 72 hours after dose | 
| Blood Pressure | Blood pressure as one of vital signs will be measured | Predose and Up to 72 hours after dose | 
| Electrocardiogram (ECG) | Triplicate 12-lead ECG will be measured to evaluate electrical activity of the heart | Pre-dose and up to 72 hours after dose | 
| Blood chemistry | Blood chemistry parameters will be measured | Pre-dose and up to 72 hours after dose | 
| Hematology | Hematology parameters will be measured | Pre-dose and up to 72 hours after dose | 
| Coagulation | Coagulation parameters (PT/INR, PTT) will be measured | Pre-dose and up to 72 hours after dose | 
| Urinalysis | Urinalysis parameters will be measured using dipstick and microscopic examination. | Pre-dose and up to 72 hours after dose | 
| Blood maximum plasma concentration (Cmax) of the study drug | Pharmacokinetics parameter Cmax will be measured to assess drug exposure levels in blood | Pre-dose and up to 72 hours after dose | 
| Blood study drug half-life (t1/2) | Pharmacokinetics parameter t1/2 will be measured to evaluate drug half-life in the blood | Pre-dose and up to 72 hours after dose | 
| Area under the plasma concentration versus time curve (AUC) of the study drug | Pharmacokinetics parameter AUC will be measured | Pre-dose and up to 72 hours after dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| A dose and exposure relationship | Doses of study drug and blood exposure levels will be analyzed to determine dose proportionality. | Pre-dose and up to 72 hours after dose | 
| Tmax of the major metabolite in blood | Pharmacokinetics parameter Time at which Cmax of a major metabolite appeared will be determined. | Up to 72 hours after dose | 
| Plasma Concentration (Cmax) of the major metabolite in blood | Pharmacokinetics parameter Cmax of a major metabolite will be measured. | Up to 72 hours after dose | 
| Area under the plasma concentration versus time curve (AUC) of the major metabolite in blood | Pharmacokinetics parameter AUC of a major metabolite will be measured. | Up to 72 hours after dose | 
| The major metabolite half-life (t1/2) in blood | Pharmacokinetics parameter t1//2 of a major metabolite will be measured. | Up to 72 hours after dose |