Multiple Ascending Oral Dose Phase I Study With Px-102

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Px-102; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Neuss, Germany
    • FOCUS Clinical Drug Development GmbH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Px-102; Px-102 drinking solution, 0.5 mg/kg, 1.0 mg/kg and 1.5 mg/kg	Drug: Px-102; Px-102 drinking solution, 0.5 mg/kg, 1.0 mg/kg and 1.5 mg/kg
Placebo Comparator: Placebo; Oral drinking solution	Drug: Placebo; Drinking solution

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Phenex Pharmaceuticals AG
• Investigators: Study Chair: Claus Kremoser, Dr., Phenex Pharmaceuticals AG

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: November 19, 2013
• First Submitted That Met QC Criteria: November 25, 2013
• First Posted (Estimate): December 2, 2013

Study Record Updates

• Last Update Posted (Estimate): November 4, 2014
• Last Update Submitted That Met QC Criteria: November 3, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Other Study ID Numbers: PHS-Px-102-I-02