A Study of Canagliflozin in Study Participants With Various Degrees of Impaired Hepatic (Liver) Function

An Open-Label Study to Evaluate the Pharmacokinetics of a Single Oral Dose of 300 mg JNJ-28431754 (Canagliflozin) in Subjects With Various Degrees of Impaired Hepatic Function Compared With Subjects With Normal Hepatic Function

The purpose of the study is to determine the concentration of canagliflozin in blood and urine samples after the administration of canagliflozin to study participants with mild or moderate hepatic (liver) impairment compared with study participants with normal hepatic function.

Study Overview

• Status: Completed
• Conditions: Hepatic Insufficiency; Healthy
• Intervention / Treatment: Drug: Canagliflozin

Detailed Description

This is an open-label (both study participant and investigator will know the name of the assigned treatment), pharmacokinetic (the study of how drugs are absorbed in the body, how they are distributed within the body, and how they are removed from the body over time) study of canagliflozin in adult study participants with mild or moderate hepatic (liver) impairment compared to study participants with normal hepatic function. Approximately 24 study participants who meet entry criteria for the study will be classified into 1 of 3 hepatic function groups: Group 1 (8 study participants with normal hepatic function), Group 2 (8 study participants with mild hepatic impairment) and Group 3 (8 study participants with moderate hepatic impairment). The group allocation is based on the Child-Pugh score, an assessment of 5 clinical measures that is used to characterize the degree of hepatic impairment. At least 3 men and 3 women will be enrolled in each group and the 3 groups will be balanced with respect to an average age and body weight. Study participants will be required to stay overnight at the study center for 5 nights to receive study drug and have study procedures and safety assessments performed. All study participants will be administered a single 300-mg oral (by mouth) dose of canagliflozin after fasting (not eating food) for a period of at least 10 hours. After study drug administration, study participants will be provided with standardized meals (breakfast, lunch, and dinner). Blood and urine samples for analyses of canagliflozin and metabolites (M7 and M5) will be collected from study participants at specified time points up to 120 hours (blood) and 48 hours (urine) after study drug administration. After discharge from the study center, study participants will be required to return to the study center for 3 outpatient visits to have study procedures and safety assessments performed. Study participants will be monitored for safety during the study by evaluating adverse events reported and results from clinical laboratory tests, 12-lead electrocardiograms (ECGs), vital sign measurements, and physical examinations. On Day 1 of the study, a single 300 mg dose of canagliflozin will be orally administered to study participants after a fasting period of at least 10 hours followed 10 minutes later by a standardized breakfast that must be eaten within 30 minutes. Study participants are to remain standing or sitting for the first 4 hours after dosing. At 2 hours after dosing (but not earlier) all study participants must drink 1 glass of water; drinking of water is allowed from then onwards.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Orlando, Florida, United States
  • Tennessee
    • Knoxville, Tennessee, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All study participants must have a body mass index (ie, a measure of one's weight in relation to height) between 18 and 33 kg/m2 (inclusive)
• Study participants with normal hepatic function must have blood pressure at screening and before study drug administration between 90 and 160 mmHg systolic, inclusive, and 55 and 100 mmHg diastolic, inclusive
• Study participants with normal hepatic function should be comparable to the groups with hepatic impairment with respect to mean (average) age (range of +/- 15 years) and mean weight (range of +/- 25%)
• Study participants with mild or moderate hepatic impairment must be otherwise in acceptable clinical condition on the basis results from prestudy assessments, have a total Child-Pugh score of 5 or 6 (mild hepatic impairment) or a score of between 7 and 9, inclusive (moderate hepatic impairment)
• In study participants with mild or moderate hepatic impairment, concomitant therapy to treat underlying disease states or medical conditions related to hepatic insufficiency are allowed

Exclusion Criteria:

• Study participants with normal hepatic function who have a history of or current medical illness deemed clinically significant by the investigator, use of any prescription or nonprescription medication, except for acetaminophen, oral contraceptives and hormonal replacement therapy within 14 days before the study drug administration, and have a positive test for drugs of abuse before study drug administration
• Study participants with mild or moderate hepatic impairment who have a positive test for drugs of abuse, have severe ascites or pleural effusion (accumulation of fluid in the abdomen and lungs, respectively), have a score of 3 or 4 for hepatic encephalopathy
• have acute exacerbation (worsening) of liver disease, as indicated by worsening clinical signs of hepatic impairment, or by an increase in total bilirubin (a liver function test) or prothrombin time (ie, the time it takes blood to clot) of more than 50% in the 3 months prior to study entry

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 001; Canagliflozin One 300-mg dose of canagliflozin on Day 1	Drug: Canagliflozin; One 300-mg dose of canagliflozin on Day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Plasma concentrations of canagliflozin to evaluate protocol-specified pharmacokinetic parameters	At protocol-specified time points before and after dosing on Day 1 through Day 6
Urine concentrations of canagliflozin to evaluate protocol-specified pharmacokinetic parameters	At protocol-specified time points after dosing on Day 1 through Day 3

Secondary Outcome Measures

Outcome Measure	Time Frame
Plasma concentrations of canagliflozin metabolites, (M5 and M7 to evaluate protocol-specified pharmacokinetic parameters	At protocol-specified time points before and after dosing on Day 1 through Day 6
Urine concentrations of canagliflozin metabolites (M5 and M7) to evaluate protocol-specified pharmacokinetic parameters	At protocol-specified time points after dosing on Day 1 through Day 3
Adverse events reported	From Screening (up to 23 days prior to dosing) to 7 to 10 days after Day 6 or at the time of early withdrawal from the study.
Vital signs measurements and results from electrocardiograms	From Screening (up to 23 days prior to dosing) to 7 to 10 days after Day 6 or at the time of early withdrawal from the study.
Physical examination findings	From Screening (up to 23 days prior to dosing) to 7 to 10 days after Day 6 or at the time of early withdrawal from the study.
Laboratory test results	From Screening (up to 23 days prior to dosing) to 7 to 10 days after Day 6 or at the time of early withdrawal from the study.

Collaborators and Investigators

• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Publications and helpful links

General Publications

• Devineni D, Curtin CR, Marbury TC, Smith W, Vaccaro N, Wexler D, Vandebosch A, Rusch S, Stieltjes H, Wajs E. Effect of hepatic or renal impairment on the pharmacokinetics of canagliflozin, a sodium glucose co-transporter 2 inhibitor. Clin Ther. 2015 Mar 1;37(3):610-628.e4. doi: 10.1016/j.clinthera.2014.12.013. Epub 2015 Feb 3.

Helpful Links

• An Open-label Study to Evaluate the Pharmacokinetics of a Single Oral Dose of 300 mg JNJ-28431754 (Canagliflozin) in Subjects With Various Degrees of Impaired Hepatic Function Compared With Subjects With Normal Hepatic Function

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: August 19, 2010
• First Submitted That Met QC Criteria: August 19, 2010
• First Posted (Estimate): August 23, 2010

Study Record Updates

• Last Update Posted (Estimate): May 29, 2013
• Last Update Submitted That Met QC Criteria: May 27, 2013
• Last Verified: May 1, 2013

More Information

Terms related to this study

• Keywords: Pharmacokinetic; Canagliflozin; Hepatic impairment; JNJ-28431754; Liver diseases; Normal hepatic function
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Liver Failure; Hepatic Insufficiency; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Canagliflozin
• Other Study ID Numbers: CR017227