A Study of the Safety, Tolerability, Pharmacokinetics and Food Effect After Single and Multiple Ascending Oral Doses

Study Overview
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Brief Summary
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This is a Phase I Healthy volunteer study with the primary objective to evaluate the safety and pharmacokinetics profile of AX-158. The first part will evaluate single ascending dose administrations. A substudy will be performed as well to evaluate possible impact of food on drug exposure if administered under fasted or fed state. The second part will evaluate multiple ascending dose over 10 days of dosing in fed or fast state depending on the results of the substudy food effect on AX-158.

Detailed Description
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This is a phase I, randomised, double-blind , placebo controlled study to investigate the safety, tolerability, and PK of AX-158 in healthy male participants following single (Part A) and multiple (Part C) ascending doses including food effect (Part B).The study will be conducted in three parts (Part A, Part B and Part C). Part A will enrol 8 participants per cohort randomised (3 :1) to receive AX-158 (6 participants) or placebo (2 participants). Part A will follow a single ascending dose (SAD) design with all participants receiving one dose of AX-158 (or placebo) in the fasted state. Part B (Food Effect) will be conducted in 8 participants in a cross-over manner; each participant will receive AX-158 in the fed and fasted state. Part C will enrol 8 participants per cohort randomised to (3 :1) to receive AX-158 (6 participants) or placebo (2 participants). Part C will follow a multiple ascending dose (MAD) design with participants receiving AX-158 (or placebo) once daily for 10 consecutive days, in a fed or fasted state (depending on the outcome of the Part B (Food Effect).

Official Title
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A Randomised, Double-blind, Placebo-controlled, Study of the Safety, Tolerability, and Pharmacokinetics of AX-158 Following Administration of Single and, Multiple Ascending Oral Doses and Food Effect Sub-study in Healthy Male Volunteers

Conditions
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Autoimmune Diseases

Intervention / Treatment
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* Drug: AX-158


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy Male participant, between 18 and 50 years of age, inclusive. Male participant (and partner of childbearing potential) willing to use a highly effective method of contraception in addition to a condom, if applicable (unless anatomically sterile or where abstaining from sexual intercourse is in line with the preferred and usual lifestyle of the participant) from first dose until 4 months after last dose of Investigational Medicinal Product (IMP). Participant with a body mass index (BMI) of 18-30kg/m2. BMI = body weight (kg) / [height (m)]2. Total serum bilirubin, alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 x upper limit of normal (ULN). If total bilirubin is above the upper limit of normal and is then fractionated, direct bilirubin must be within normal limits. Total serum Testosterone levels 2 x above the lower limit of the normal range within 28 days before the first dose administration of the IMP. Participant with a negative urinary drugs of abuse (DOA) screen (including alcohol) test results, determined within 28 days before the first dose administration of the IMP (N.B.: A positive test result may be repeated at the Investigator's discretion). Participant with negative human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg)) and hepatitis C virus antibody (HCV Ab) test results at Screening. No clinically significant abnormalities in 12-lead electrocardiogram (ECG) determined within 28 days before first dose of IMP including a QRS interval > 120ms, PR interval > 220ms and QTcF > 450ms. No clinically significant abnormalities in vital signs (e.g., blood pressure/pulse rate, respiration rate and oral temperature) determined within 28 days before first dose of IMP. Participant must be available to complete the study (including all follow-up visits). Participant must satisfy an Investigator about his fitness to participate in the study. Participant must provide written informed consent to participate in the study. Participants with a negative COVID-19 PCR test on admission. Exclusion Criteria: A clinically significant history of gastrointestinal disorder likely to influence IMP absorption. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 28 days or 5 half-lives (whichever is longer) prior to the first dose of IMP. Occasional use of paracetamol will be allowed. Evidence of renal, hepatic, central nervous system, respiratory, cardiovascular, or metabolic dysfunction. Clinically significant history of previous allergy / sensitivity to AX-158 or any of the excipients contained within the IMP. Participant with history of autoimmune disease, cardiac disease, kidney disease or any food intolerance. Participants with clinically significant abnormal test results for serum biochemistry, haematology and/or urine analyses within 28 days before the first dose administration of the IMP A clinically significant history of drug or alcohol abuse (defined as the consumption of more than 14 units [for male and female participants] of alcohol a week) within the past two years. Inability to communicate well with the Investigators (i.e., language problem, poor mental development, or impaired cerebral function). Participation in a New Chemical Entity (NCE) clinical study within the previous 3 months or five half-lives, whichever is longer, or a marketed drug clinical study within the 30 days or five half-lives, whichever is longer, before the first dose of IMP. (Washout period between studies is defined as the period of time elapsed between the last dose of the previous study and the first dose of the next study). Donation of 450 milliliters or more blood within the 3 months before the first dose of IMP. Vegans, vegetarians, or other dietary restrictions (e.g., restrictions for medical, religious, or cultural reasons, etc), which would prevent participants from consuming a high-fat breakfast or standardised meal. Users of nicotine products i.e., current smokers or ex-smokers who have smoked within the 6 months prior to screening or users of cigarette replacements (i.e., e-cigarettes, nicotine patches or gums). Participants who have received a COVID-19 vaccine injection within 28 days prior to the first dose of IMP.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A-Drug (AX-158 or Placebo)<br>AX-158 oral single or placebo (single ascending dose). | Drug: AX-158<br>* Oral administrations of AX-158<br>* Other names: Placebo;|
| Experimental: Part B-Drug (AX-158)<br>AX-158 oral single dose with and without food | Drug: AX-158<br>* Oral administrations of AX-158<br>* Other names: Placebo;|
| Experimental: Part C-Drug (AX-158 and Placebo)<br>AX-158 oral or placebo daily dose for 10 days (multiple ascending dose). | Drug: AX-158<br>* Oral administrations of AX-158<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | The number and severity of adverse events that can be related to treatment with single and multiple doses of ARTAX | Up to 10 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The pharmacokinetics (PK) of single and multiple dose administration of ARTAX in volunteers | Maximal plasma concentration (Cmax) | Up to 10 days | 
| Total Plasma Drug Exposure of a single and multiple dose administration of ARTAX in volunteers | Measurement of the area under the curve (AUC) at day 1 and day 10 in plasma | Up to 10 days | 
| Comparison of the single dose and multiple dose elimination of ARTAX | Determination of the half-life (T1/2) for single and multiple doses of ARTAX | Up to 10 days | 
| Total Plasma Drug Exposure of single dose administration of ARTAX under fasting and fed conditions in volunteers | Measurement of the area under the curve (AUC) after single dose administration of ARTAX after an overnight fast or after a high fat breakfast | Three days |