Pharmacokinetic and Tolerability Study of 14 mg Single Dose of Teriflunomide in Subjects With Severe Renal Impairment

Study Overview
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Brief Summary
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Primary Objective: - To determine the effect of severe renal impairment on the pharmacokinetic profile of teriflunomide administered as a single 14 mg dose as compared to healthy subjects Secondary Objective: - To assess the tolerability of teriflunomide administered as a single 14 mg dose in subjects with severe renal impairment compared to subjects with normal renal function.

Detailed Description
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The total study duration per subject is 11-15 weeks broken down as follows: Screening: up to 3 weeks Hospitalization: 3 days (admission 1 day prior to study drug intake) Follow-up: 10 -12 weeks

Official Title
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An Open-label Pharmacokinetic and Tolerability Study of Teriflunomide Given as a Single 14 mg Dose in Subjects With Severe Renal Impairment, and in Matched Subjects With Normal Renal Function

Conditions
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Renal Impairment

Intervention / Treatment
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* Drug: Teriflunomide HMR1726
* Drug: Cholestyramine


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Subjects with renal impairment: Male subject between 18 and 75 years of age inclusive and postmenopausal female between 45 and 75 years of age inclusive. Chronic severe renal impairment as defined by Cockroft-Gault formula (creatinine clearance (CLcr) < 30mL/min, but not requiring hemodialysis). Laboratory parameters within the acceptable range for subjects with renal impairment; in particular, hepatic enzymes (ALT, AST) and bilirubin should be < 2 x upper limit of normal range and neutrophils should be within normal ranges. Matched healthy subjects: Male subject between 18 and 75 years of age inclusive and postmenopausal female between 45 and 75 years of age inclusive, matched by age. Body weight within 15% of the body weight of the subjects with renal impairment to be matched and Body Mass Index between 18.0 and 30.0 mg/kg2 inclusive. Certified as healthy by a comprehensive clinical assessment (detailed medical history and complete physical examination). Normal renal function as defined by Cockroft-Gault formula (creatinine clearance (CLcr) > 80mL/min) Laboratory parameters within the normal range, unless the Investigator considers an abnormality to be clinically irrelevant for healthy subjects; however serum creatinine, alkaline phosphatase, hepatic enzymes (AST, ALT), bilirubin (unless the subject has documented Gilbert syndrome) should not exceed the upper limit of normal range. Exclusion criteria: Subjects with renal impairment: Uncontrolled clinically relevant cardiovascular, pulmonary, gastro-intestinal, metabolic, hematological, neurological, psychiatric, systemic, ocular, gynecologic (if female) or infectious disease, or signs of acute illness. Active hepatitis, hepatic insufficiency. Acute renal failure (de novo or superimposed to pre-existing chronic renal impairment), nephrotic syndrome. Subject requiring dialysis during the study. Any significant change in chronic treatment medication within 14-days before inclusion. Any drug, which could impact by any mechanism of action, the pharmacokinetic of the investigational product. Positive reaction to Human Immunodeficiency Virus (HIV) tests: anti-HIV1 antibodies, anti-HIV2 antibodies Positive results on urine drug screen (amphetamines / methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates) unless this result is secondary to a documented medical prescription. Positive alcohol test. Man who disagrees to use a double barrier method of contraception with their partner during the study. Matched healthy subjects: Any history or presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, hematological, neurological, psychiatric, systemic, ocular, gynecologic (if female), or infectious disease, or signs of acute illness. For subjects 50 years old and below: any medication (including St John's Wort) within 14 days before inclusion, or within 5 times the elimination half-life or pharmacodynamic halflife of that drug, whichever the longest, with the exception of menopausal hormone replacement therapy. any significant change in chronic treatment medication within 14-days before inclusion. Any drug, which could impact by any mechanism of action, the pharmacokinetic of the investigational product. Positive reaction to any of the following tests: hepatitis B surface (HBs) antigen, antihepatitis C virus (anti-HCV) antibodies, HIV1 antibodies, anti-HIV2 antibodies. Positive results on urine drug screen (amphetamines / methamphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, opiates). Positive alcohol test. Man who disagrees to use a double barrier method of contraception with their partner during the study The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Severe impaired renal function<br>Subjects with severe renal impairment as defined by Cockroft-Gault formula | Drug: Teriflunomide HMR1726<br>* Pharmaceutical form:film coated tablet Route of administration: oral administration on Day 1 under fasted condition<br>Drug: Cholestyramine<br>* Pharmaceutical form:powder Route of administration: oral administration 3 times per day on Day 54 and 55<br>|
| Experimental: Normal renal function<br>Subjects with normal renal function as defined by Cockroft-Gault formula | Drug: Teriflunomide HMR1726<br>* Pharmaceutical form:film coated tablet Route of administration: oral administration on Day 1 under fasted condition<br>Drug: Cholestyramine<br>* Pharmaceutical form:powder Route of administration: oral administration 3 times per day on Day 54 and 55<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameters of Teriflunomide determined from plasma concentration (Maximum plasma concentration (Cmax), Area under the plasma concentration curve (AUClast and AUC)) |  | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical safety evaluation (AE reporting, laboratory tests (hematology, biochemistry and urinalysis), vital signs and ECG parameters) |  | Up to 12 weeks (until the end of study visit) |