Treatment Differences Between Canagliflozin and Placebo in Insulin Secretion in Subjects With Type 2 Diabetes Mellitus (T2DM)
The purpose of this study is to assess changes from baseline in insulin sensitivity, hepatic fat content and beta cell function after approximately 24-25 weeks of treatment with canagliflozin compared to placebo in participants with type 2 diabetes mellitus (T2DM) with inadequate glycemic (blood sugar) control on metformin monotherapy or on combination therapy with metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor.
Diabetes Mellitus, Type 2
Drug: Canagliflozin, 100 mg
Drug: Canagliflozin, 300 mg
|Study Design:||Allocation: Randomized
Endpoint Classification: Pharmacokinetics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
|Official Title:||A Double-Blind, Placebo-Controlled, Randomized, Parallel Groups, Multicenter Study to Investigate the Effects of Canagliflozin on Insulin Sensitivity, Hepatic Fat Content and Beta Cell Function in Subjects With Type 2 Diabetes Mellitus|
- Change from baseline in hepatic insulin sensitivity [ Time Frame: Baseline, 25 weeks ] [ Designated as safety issue: No ]
- Change from baseline in peripheral tissue insulin sensitivity [ Time Frame: Baseline, 25 weeks ] [ Designated as safety issue: No ]
- Change from baseline in liver fat content, determined using magnetic resonance spectroscopy (MRS) [ Time Frame: Baseline, 25 weeks ] [ Designated as safety issue: No ]
- Change from baseline in insulin secretion rate (ISR) during mixed-meal tolerance test (MMTT) [ Time Frame: Baseline, 25 weeks ] [ Designated as safety issue: No ]
- Change from baseline in beta-cell glucose sensitivity, determined as a slope of ISR vs. plasma glucose concentration during MMTT [ Time Frame: Baseline, 25 weeks ] [ Designated as safety issue: No ]
- Changes from baseline in substrate oxidation and energy production rates during MMTT and euglycemic clamp [ Time Frame: Baseline, 25 weeks ] [ Designated as safety issue: No ]
- Changes from baseline in insulin clearance during MMTT and euglycemic clamp [ Time Frame: Baseline, 25 weeks ] [ Designated as safety issue: No ]
- Change from baseline in suppression of free fatty acids (FFAs) during euglycemic clamp [ Time Frame: Baseline, 25 weeks ] [ Designated as safety issue: No ]
- Changes from baseline in basal and postprandial plasma glucagon, FFAs and β-hydroxybutyrate during MMTT [ Time Frame: Baseline, 25 weeks ] [ Designated as safety issue: No ]
- Change from baseline in renal threshold for glucose (RTG), estimated using an MMTT-based method [ Time Frame: Baseline, 25 weeks ] [ Designated as safety issue: No ]
|Study Start Date:||July 2014|
|Estimated Study Completion Date:||December 2015|
|Estimated Primary Completion Date:||February 2015 (Final data collection date for primary outcome measure)|
Experimental: Canagliflozin (JNJ-28431754)
Each patient will receive canagliflozin 100 mg once daily during the first 4 weeks of the 25 weeks double-blind period, then the dose may be increased to 300 mg once daily, till the end of the period.
Drug: Canagliflozin, 100 mg
One 100 mg capsule taken orally (by mouth) once dailyDrug: Canagliflozin, 300 mg
One 300 mg capsule taken orally (by mouth) once daily
Placebo Comparator: Placebo
One placebo capsule taken orally (by mouth) once daily for approximately 28 days during the Pre-Treatment Run-In and the Baseline Periods, then during double-blind study for 178 days (approximately 24-25 weeks).
One placebo capsule (inactive medication) once daily.
This is a double-blind (neither physician nor participants knows the treatment that the participant receives), randomized (the study medication is assigned by chance), placebo-controlled (an inactive substance is compared with a medication to test whether the medication has a real effect in a clinical study), parallel-groups study which will be conducted at 2 clinical research centers (CRC) in the US. Approximately 56 participants, ages 25-70 years, with T2DM inadequately controlled on either metformin monotherapy or combination therapy with metformin and a DPP-4 inhibitor, will be enrolled. The study has 3 phases: pre-treatment, double-blind treatment, and post-treatment.
Pre-Treatment Phase will consist of a screening visit (Week -5), 14 days Single- Blind Placebo Run-in period, followed by 14 days of Single-Blind Placebo Baseline Period, during which participants will be randomized (1:1) to one of 2 treatment groups, either canagliflozin or placebo. Double-Blind Treatment Phase begins on Day 1, and ends at approximately Week 25, during which participants will be assessed at least biweekly at outpatient visits or by telephone contact. Canagliflozin treatment will be initiated at 100 mg/day, with up-titration to 300 mg/day, consistent with the approved INVOKANA® US Prescribing Information 2013. During post-treatment phase, a follow-up visit will occur within approximately 28 days after the last dose of study drug.
At baseline and after 24 weeks of treatment with canagliflozin, hepatic and peripheral insulin sensitivity will be assessed using tracer labeled euglycemic clamp technique; hepatic fat content will be determined using 1H nuclear magnetic resonance spectroscopy (MRS); beta cell function (insulin secretion rate and beta cell glucose sensitivity) will be assessed during mixed meal tolerance test (MMTT); substrate oxidation and energy production rates will be measured using indirect calorimetry during euglycemic clamp and MMTT.
During the study, participants will remain on their stable dose regimens of metformin or combination metformin DPP-4 inhibitor therapy, unless the investigator considers dose modification to be medically necessary. The total study duration for each participant participating in this study will be up to approximately 34 weeks.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02009488
|Contact: This study is not yet recruiting patients. Please check back for future recruiting sites, or email||JNJ.CT@sylogent.com|
|United States, California|
|Not yet recruiting|
|San Diego, La Jolla, California, United States|
|United States, Florida|
|Not yet recruiting|
|Gainesville, Florida, United States|
|Study Director:||Janssen Research & Development, LLC Clinical Trial||Janssen Research & Development, LLC|