A 26-week, placebo- and pioglitazone-controlled, dose-ranging study of rivoglitazone, a novel thiazolidinedione for the treatment of type 2 diabetes

Abstract

Objective:

To examine the efficacy and general safety of rivoglitazone, a novel thiazolidinedione, as a treatment for type 2 diabetes in a dose-ranging study over a period of up to 6 months.

Research design and methods:

A 26-week, randomized, double-blind, double-dummy, placebo- and active comparator (pioglitazone 45 mg)-controlled study designed to evaluate the efficacy and safety of once-daily rivoglitazone 1, 2, or 3 mg in subjects with type 2 diabetes. The study was conducted in adults with type 2 diabetes (glycated hemoglobin [HbA_1c] ≥7.0% and <10.5%) who were either naïve to prior antidiabetes drug treatment or discontinued pre-study antidiabetes medications and were switched to study medication. A total of 441 subjects were randomized, using an equal allocation schedule to one of five treatment arms, including placebo. The primary efficacy measurement was the change in HbA_1c from baseline to week 26 in the intent-to-treat population (last observation carried forward), for drug treatments minus placebo (placebo-subtracted).

Clinical Trial Registration:

Trial registration: ClinicalTrials.gov identifier: NCT00143520.

Results:

The incidence of early discontinuations was >50%, with most cases being related to a lack of efficacy (highest on placebo) or adverse experiences (highest on rivoglitazone 3 mg). Rivoglitazone 1, 2, and 3 mg and pioglitazone 45 mg were more effective than placebo in reducing HbA_1c from baseline to week 26 (placebo-subtracted change from baseline: −0.55% [p = 0.0034], −0.99% [p < 0.0001], −1.10% [p < 0.0001], and −0.59% [p = 0.0016], respectively). In general, all treatments were safe. The most common drug-related adverse events reported with rivoglitazone were peripheral edema and weight gain; incidences increased with dose and were higher with rivoglitazone 2 and 3 mg than with pioglitazone or rivoglitazone 1 mg.

Conclusions:

Rivoglitazone is a potent thiazolidinedione agent with demonstrated glycemic benefits over a 6-month period in subjects with type 2 diabetes. Once-daily doses of 1, 2, and 3 mg rivoglitazone demonstrated HbA_1c reduction similar or superior to those observed for pioglitazone 45 mg. Limitations in generalizing from this study include a modest sample size and a high rate of discontinuation prior to the last scheduled visit.

Key words::

• Glycemic control
• Pioglitazone
• Rivoglitazone
• Thiazolidinedione
• Type 2 diabetes mellitus

Transparency

Declaration of funding

This study was funded by Daiichi Sankyo, Inc. and was registered with ClinicalTrials.gov (NCT00143520).

Declaration of financial/other relationships

J.R. has served on advisory boards and received honoraria or consulting fees from Amylin, Eli Lilly & Co., Daiichi Sankyo, Inc., GlaxoSmithKline, Johnson & Johnson, MannKind, Novartis, Novo Nordisk, Pfizer, Roche, sanofi-aventis, and Takeda Pharmaceuticals. J.R. has also received research grants from Amylin, AstraZeneca, Bristol-Myers Squibb, Eli Lilly & Co., Daiichi Sankyo, Inc., GlaxoSmithKline, Johnson & Johnson, MannKind, Merck, Novartis, Novo Nordisk, Pfizer, sanofi-aventis, and Takeda Pharmaceuticals. R.B.G. has served on advisory boards and received honoraria or consulting fees from Abbott Laboratories, AstraZeneca, Eli Lilly & Co., Merck, Pfizer, Schering-Plough, and Takeda Pharmaceuticals; has been a speaker for and received honoraria from AstraZeneca, Abbott Laboratories, Eli Lilly & Co., KOS, Merck, Pfizer, Schering-Plough, and Takeda Pharmaceuticals, and has also received research grants from AstraZeneca, Daiichi Sankyo, Inc., KOS, Merck, Novo Nordisk, and Pfizer. K.E.T., H.S.C., D.M., J.T., and A.C.W. are employees of Daiichi Sankyo, Inc.

Peer reviewers may receive honoraria for their review work with CMRO. Peer Reviewer 1 has disclosed that he/she has received honoraria from Takeda, GlaxoSmithKline, Bayer and Eli Lilly. Peer Reviewer 2 has disclosed no relevant financial relationships.

Acknowledgments

The authors acknowledge the investigators who participated in this study. The authors also acknowledge Soamnauth Misir, PharmD, of Daiichi Sankyo, Inc. who provided a critical review of the manuscript. Editorial assistance for the preparation of the manuscript was provided by Karen Stauffer, PhD, of inScience Communications.

Previously presented at the 68th Annual American Diabetes Association Scientific Sessions; San Francisco, CA, June 2008.