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

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

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.

Study Overview

• Status: Completed
• Conditions: Renal Impairment
• Intervention / Treatment: Drug: Teriflunomide HMR1726; Drug: Cholestyramine

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany
    • Sanofi-Aventis Administrative Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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)

Collaborators and Investigators

• Sponsor: Sanofi

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): February 1, 2011
• Study Completion (Actual): March 1, 2011

Study Registration Dates

• First Submitted: November 9, 2010
• First Submitted That Met QC Criteria: November 10, 2010
• First Posted (Estimate): November 11, 2010

Study Record Updates

• Last Update Posted (Estimate): March 1, 2012
• Last Update Submitted That Met QC Criteria: February 28, 2012
• Last Verified: February 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Kidney Diseases; Urologic Diseases; Renal Insufficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites; Immunosuppressive Agents; Immunologic Factors; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Teriflunomide; Cholestyramine Resin
• Other Study ID Numbers: POP11432; 2010-022354-16 (EudraCT Number); U1111-1117-6723 (Other Identifier: UTN)