Efficacy and Safety of the Peroxisome Proliferator-Activated Receptor Pan-Agonist Chiglitazar in Patients with Type 2 Diabetes (CMAP): A 24 Week, Multicentre, Randomised, Double-Blind, Placebo-Controlled Phase 3 Superiority Trial

Background: Chiglitazar is a novel PPARα/γ/δ pan-agonist with moderate transcriptional activities. Phase 2 studies demonstrated that chiglitazar had significant effects on glycemic control and lipid modulation in patients with type 2 diabetes. The current CMAP study aimed to assess the efficacy and safety of chiglitazar compared with placebo in type 2 diabetes patients who had not previously received anti-diabetic treatment. Methods: This study was a double-blind and placebo-controlled phase 3 trial conducted at 26 centres in China. Eligible patients were 18-70 years old, type 2 diabetes with HbA1c ≥7*5% and ≤10*0% and without previous anti-diabetic treatment. Patients were randomly assigned to receive chiglitazar 32 mg or 48 mg, or placebo once daily. The primary endpoint was change in HbA1c at week 24 with superiority of chiglitazar to placebo. Findings: Between June 17, 2014, and Oct 13, 2016, 535 patients were randomly assigned to receive chiglitazar 32 mg (n=167), 48 mg (n=166), or placebo (n=202). In the primary LOCF analysis in the full-analysispopulation, both chiglitazar doses were superior to placebo for HbA1c reduction at week 24, with the mean differences between chiglitazar 32 mg or 48 mg versus placebo were -0*87% [95% CI -1*10 to -0*65] or -1*05% [- 1*29 to -0*81], respectively. Overall frequency of adverse events and study discontinuation attributable to adverse events were similar among groups. Serious adverse events were reported for seven (3%) in the placebo group, four (2%) in the chiglitazar 32 mg group, and eight (5%) in the chiglitazar 48 mg group. A small increased mild edema events and body weight gain was reported in the chiglitazar dose groups. Interpretation: The PPAR pan-agonist chiglitazar had significant and clinically relevant improvements in glycaemic control in patients with type 2 diabetes, with no unexpected safety findings. Trial Registration: This study is registered with clinicaltrials.gov number NCT02121717. Funding Statement: Chipscreen Biosciences. This study was partly supported by grants from Chinese National and Provincial Major Project for New Drug Innovation (National: 2008ZX09101-002, 2013ZX09401301; Provincial: 2011A080501010) and Shenzhen Municipal Major Project (2010-1746). Declaration of Interests: ZN, HC, DP, HY and XL are employees of Chipscreen Biosciences Ltd. The other authors declare no competing interests. Ethics Approval Statement: The study complied with the Declaration of Helsinki and Good Clinical Practice guidelines, and was approved by institutional review boards and independent ethics committees for participating centers. All participants provided written informed consent.