Multiple Ascending Oral Dose Phase I Study With Px-102

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and tolerability of the FXR agonist Px-102 in healthy subjects after 7 days multiple oral dosing.

Detailed Description
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The study is a single-centre, double-blind, randomized, placebo-controlled, parallel group phase I study with healthy male subjects receiving ascending multiple oral oral doses of Px-102 to assess the safety and tolerability, pharmacokinetics and pharmacodynamics.

Official Title
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A Double-blind, Randomised, Placebo-controlled, Dose-escalation Study of the Safety, Tolerability and Pharmacokinetics of Increasing Multiple Oral Doses of Px-102 to Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: Px-102
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male subject of Caucasian origin 18 to 45 years of age (inclusive). Good state of health (mentally and physically) as determined by medical history, physical examination, vital signs, ECG recording and clinical lab results. BMI in between 20-29 kg/m² (inclusive); with absolute weight in between 70 to 120 kg. Total cholesterol and liver enzyme levels [alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), alkaline phosphatase (AP)] strictly within the normal ranges at screening and on Day -1. Serum triglyceride not exceeding the upper limit of normal range. HbA1c ≤ 6.5% Subject has been informed both verbally and in writing and has given written consent to participation in the study prior to start and any study-related procedure. Negative results for HIV- and Hepatitis-B and -C serology at screening. Subject (including female partners of childbearing potential) has to use a highly effective method of birth control (failure rate less than 1% per year when used consistently and correctly), e.g. implants, injectables, combined oral contra-ceptives in combination with a barrier method, some intrauterine contraceptive devices or sexual abstinence. Exclusion Criteria: Female gender Use of prescription or non-prescription drugs within 7 days (30 if the drug is a possible enzyme inducer) prior to administration of study medication. Use of drugs known to induce steatosis (e.g. valproate, amiodarone or prednisone) or to affect body weight and carbohydrate metabolism Any acute or chronic illness or clinically relevant finding at screening and at base-line examination which may jeopardize the subject's participation in the study History or presence of biliary obstruction or biliary disease, hepatic encephalopathy, advanced ascites, portal hypertension, esophageal/gastric variceal bleeding, hepatocellular carcinoma, previous liver transplantation or any other chronic liver disease Renal dysfunction, e.g. glomerular filtration rate ≤ 80 ml/min/1.73 m2 (as determined by the formula of Cockroft-Gault) Type I or II Diabetes Any clinically relevant abnormality on screening medical assessment, laboratory examination, 12-lead ECG Any clinically relevant finding in the baseline telemetry within the pre-dose evaluated observation period of at least 20 hours Marked baseline prolongation of QT/QTc interval (QTc interval > 440 ms) in the 12-lead ECG using the Fridericia method for QTc analysis Heart rate < 50 bpm. History of pathological cardiovascular symptoms or a severe cardiovascular event History of severe chronic autoimmune diseases such as severe allergy, atopic eczema, chronic dermatitis, severe psoriasis, multiple sclerosis, severe asthma, lupus or related disorders Allergies (except for mild forms of hay fever) or history of hypersensitivity reactions Smoking (regular or irregular) > 5 cigarettes (or equivalent) per day Excessive alcohol drinking (more than approximately 20 g alcohol per day), unable to refrain from alcohol drinking from 48 hours prior to dosing until the last pharmacokinetic blood sample has been withdrawn Positive test for drugs or alcohol at screening or prior to the dosing session History of alcoholism or drug/chemical/substance abuse within past 2 years Investigator deems the subject unable or unwilling to comply fully with the study protocol Has received clinical study medication within the last 30 days prior to this study Donation or loss of 400 ml or more of blood within eight (8) weeks prior to dosing Allergic to any of the active or inactive ingredients in the study medication Any other reason which the Investigator considers unsuitable for the subject to participate Any condition or previous disease leading to pruritus or itching of the skin.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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 |
| --- | --- |
| Active Comparator: Px-102<br>Px-102 drinking solution, 0.5 mg/kg, 1.0 mg/kg and 1.5 mg/kg | Drug: Px-102<br>* Px-102 drinking solution, 0.5 mg/kg, 1.0 mg/kg and 1.5 mg/kg<br>|
| Placebo Comparator: Placebo<br>Oral drinking solution | Drug: Placebo<br>* Drinking solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of Px-102 | Adverse event monitoring, laboratory values, cardiovascular monitoring. Comparison active vs. placebo | 7 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of Px-102 and metabolites | Plasma, urine and fecal concentrations (ng/mL) of Px-102 and metabolites measured by LC-MS/MS. AUC, Cmax and other pk parameters. Comparison of the pk data on day 7 vs. day 1 | Day 1: 0 min, 15 min, 30 min, 60 min, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 12 h, 22 h, 24 h; Day 5 and 6: pre-dose; Day 7: 0 min, 15 min, 30 min, 60 min, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 12 h, 22 h, 24 h, 30 h. | 
| Pharmacodynamics | Markers for FXR activation (e.G. FGF19 (pg/mL) measurement by ELISA). Comparison active vs. placebo | Pre-dose, 1, 2, 4, 8 and 10 hours after administration on Days 1 and 7; Pre-dose, 2 hours and 8 hours after administration on Days 2 to 6; at 22 hours after the last administration |