Dalong Zhu1, Shenglian Gan2, Yu Liu3, Jianhua Ma4, Xiaolin Dong5, Weihong Song6, Jiao'e Zeng7, Guixia Wang8, Wenjuan Zhao9, Qiu Zhang10, Yukun Li11, Hui Fang12, Xiaofeng Lv13, Yongquan Shi14, Haoming Tian15, Linong Ji16, Xin Gao17, Lihui Zhang18, Yuqian Bao19, Minxiang Lei20, Ling Li21, Longyi Zeng22, Xiaoying Li17, Xinghua Hou23, Yu Zhao23, Tianxin Hu23, Xiaoyun Ge23, Guiyu Zhao23, Yongguo Li23, Yi Zhang23, Li Chen24. 1. Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. 2. The First People's Hospital of Changde City, Changde, China. 3. The Second Hospital of Jilin University, Changchun, China. 4. Nanjing First Hospital, Nanjing Medical University, Nanjing, China. 5. Jinan Central Hospital, Jinan, China. 6. Chenzhou No 1 People's Hospital, Chenzhou, China. 7. Jingzhou Central Hospital, Jingzhou, China; The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 8. The First Hospital of Jilin University, Changchun, China. 9. The Affiliated Hospital of Qingdao University, Qingdao, China. 10. The First Affiliated Hospital of Anhui Medical University, Hefei, China. 11. The Third Hospital of Hebei Medical University, Shijiazhuang, China. 12. Tangshan Gongren Hospital, Tangshan, China. 13. Army General Hospital of the People's Liberation Army, Beijing, China. 14. Shanghai Changzheng Hospital, Shanghai, China. 15. West China Hospital, West China School of Medicine, Sichuan University, Chengdu, China. 16. Peking University People's Hospital, Beijing, China. 17. Zhongshan Hospital, Fudan University, Shanghai, China. 18. The Second Hospital of Hebei Medical University, Shijiazhuang, China. 19. Shanghai Sixth People's Hospital Affiliated with Shanghai Jiao Tong University, Shanghai, China. 20. Xiangya Hospital Central South University, Changsha, China. 21. Shengjing Hospital of China Medical University, Shenyang, China. 22. The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 23. Hua Medicine, Shanghai, China. 24. Hua Medicine, Shanghai, China. Electronic address: lichen@huamedicine.com.
Abstract
BACKGROUND: Glucokinase acts as a glucose sensor in the pancreas and a glucose processor in the liver, and has a central role in glucose homoeostasis. Dorzagliatin is a new, dual-acting, allosteric glucokinase activator that targets both pancreatic and hepatic glucokinases. Dorzagliatin has good pharmacokinetic and pharmacodynamic properties in humans, and provides effective 24-h glycaemic control and improves glucose sensitivity in patients with type 2 diabetes. We aimed to assess the efficacy and safety of dorzagliatin monotherapy at different doses in Chinese patients with type 2 diabetes. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 2 study, we randomly assigned (1:1:1:1:1) patients to receive oral placebo or one of four doses of oral dorzagliatin (75 mg once a day, 100 mg once a day, 50 mg twice a day, or 75 mg twice a day) using permuted-block randomisation, with a block size of ten and without stratification. Eligible patients were men or non-fertile women (aged 40-75 years) with type 2 diabetes who had a BMI of 19·0-30·0 kg/m2, were on a diet and exercise regimen, and were previously untreated or treated withmetformin or α-glucosidase inhibitor monotherapy. The study started with a 4-week placebo run-in period followed by a 12-week treatment period. The primary endpoint was the change in HbA1c from baseline to week 12, which was assessed in all patients who received at least one dose of study drug and had both baseline and at least one post-baseline HbA1c value. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02561338. FINDINGS: Between Sept 29, 2015, and Aug 17, 2016, we randomly assigned 258 patients to one of the five study groups. At the end of 12 weeks, the least squares mean change in HbA1c from baseline was -0·35% (95% CI -0·60 to -0·10) in the placebo group, -0·39% (-0·64 to -0·14) in the 75 mg once daily group, -0·65% (-0·92 to -0·38) in the 100 mg once daily group, -0·79% (-1·06 to -0·52) in the 50 mg twice daily group, and -1·12% (-1·39 to -0·86) in the 75 mg twice daily group. Compared with the placebo group, the change in HbA1c between baseline and 12 weeks was significant in the 50 mg twice daily (p=0·0104) and the 75 mg twice daily (p<0·0001) groups. The number of adverse events was similar between the treatment groups and the placebo group. There were no reports of drug-related serious adverse events or severe hypoglycaemia. INTERPRETATION: Dorzagliatin had a beneficial effect on glycaemic control and was safe and well tolerated over 12 weeks in Chinese patients with type 2 diabetes. FUNDING: Hua Medicine, National Major Scientific and Technological Special Project for Significant New Drugs Development, Shanghai Science and Technology Innovation Action Project, Shanghai Pudong District Science and Technology Innovation Action Project, and Shanghai Municipal Commission of Economy and Informatisation Innovation Action Project.
RCT Entities:
BACKGROUND:Glucokinase acts as a glucose sensor in the pancreas and a glucose processor in the liver, and has a central role in glucose homoeostasis. Dorzagliatin is a new, dual-acting, allosteric glucokinase activator that targets both pancreatic and hepatic glucokinases. Dorzagliatin has good pharmacokinetic and pharmacodynamic properties in humans, and provides effective 24-h glycaemic control and improves glucose sensitivity in patients with type 2 diabetes. We aimed to assess the efficacy and safety of dorzagliatin monotherapy at different doses in Chinese patients with type 2 diabetes. METHODS: In this multicentre, randomised, double-blind, placebo-controlled, phase 2 study, we randomly assigned (1:1:1:1:1) patients to receive oral placebo or one of four doses of oral dorzagliatin (75 mg once a day, 100 mg once a day, 50 mg twice a day, or 75 mg twice a day) using permuted-block randomisation, with a block size of ten and without stratification. Eligible patients were men or non-fertile women (aged 40-75 years) with type 2 diabetes who had a BMI of 19·0-30·0 kg/m2, were on a diet and exercise regimen, and were previously untreated or treated with metformin or α-glucosidase inhibitor monotherapy. The study started with a 4-week placebo run-in period followed by a 12-week treatment period. The primary endpoint was the change in HbA1c from baseline to week 12, which was assessed in all patients who received at least one dose of study drug and had both baseline and at least one post-baseline HbA1c value. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02561338. FINDINGS: Between Sept 29, 2015, and Aug 17, 2016, we randomly assigned 258 patients to one of the five study groups. At the end of 12 weeks, the least squares mean change in HbA1c from baseline was -0·35% (95% CI -0·60 to -0·10) in the placebo group, -0·39% (-0·64 to -0·14) in the 75 mg once daily group, -0·65% (-0·92 to -0·38) in the 100 mg once daily group, -0·79% (-1·06 to -0·52) in the 50 mg twice daily group, and -1·12% (-1·39 to -0·86) in the 75 mg twice daily group. Compared with the placebo group, the change in HbA1c between baseline and 12 weeks was significant in the 50 mg twice daily (p=0·0104) and the 75 mg twice daily (p<0·0001) groups. The number of adverse events was similar between the treatment groups and the placebo group. There were no reports of drug-related serious adverse events or severe hypoglycaemia. INTERPRETATION:Dorzagliatin had a beneficial effect on glycaemic control and was safe and well tolerated over 12 weeks in Chinese patients with type 2 diabetes. FUNDING: Hua Medicine, National Major Scientific and Technological Special Project for Significant New Drugs Development, Shanghai Science and Technology Innovation Action Project, Shanghai Pudong District Science and Technology Innovation Action Project, and Shanghai Municipal Commission of Economy and Informatisation Innovation Action Project.
Authors: Konstantinos A Toulis; Krishnarajah Nirantharakumar; Chrysa Pourzitaki; Anthony H Barnett; Abd A Tahrani Journal: Drugs Date: 2020-04 Impact factor: 9.546
Authors: Mei-Ling Yang; Sheryl Horstman; Renelle Gee; Perrin Guyer; TuKiet T Lam; Jean Kanyo; Ana L Perdigoto; Cate Speake; Carla J Greenbaum; Aïsha Callebaut; Lut Overbergh; Richard G Kibbey; Kevan C Herold; Eddie A James; Mark J Mamula Journal: Nat Commun Date: 2022-04-06 Impact factor: 17.694