Eris Lifesciences Asked to Revise Phase IV Protocol for Dapagliflozin, Gliclazide, Metformin FDC
New Delhi: The Subject Expert Committee (SEC), functioning under the Central Drugs Standard Control Organisation (CDSCO), has opined that Eris Lifesciences should revise the Phase IV clinical trial protocol for its fixed-dose combination of Dapagliflozin Propanediol Monohydrate equivalent to Dapagliflozin 10/10 mg plus Gliclazide IP 60/30 mg (SR) plus Metformin Hydrochloride IP 500/500 mg (SR) film-coated bilayered tablet.
The committee recommended that the firm incorporate details of randomization of patients in both arms and expand the exclusion criteria to explicitly include patients with conditions such as diabetic foot ulcers, peripheral vascular disease, and recurrent urinary tract infections (UTIs).
In addition, the expert panel stated that the firm should submit the scientific justification for the sample size.
This came after Eris Lifesciences presented the Phase IV clinical trial protocol before the committee, in light of the condition mentioned in permission in Form CT-23 dated 25.11.2024.
Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor used in the management of type 2 diabetes mellitus. Dapagliflozin inhibits the sodium-glucose cotransporter 2 (SGLT2), which is primarily located in the proximal tubule of the nephron. SGLT2 facilitates 90% of glucose reabsorption in the kidneys and so its inhibition allows for glucose to be excreted in the urine. This excretion allows for better glycemic control and potentially weight loss in patients with type 2 diabetes mellitus.
Gliclazide is an oral antihyperglycemic agent used for the treatment of non-insulin-dependent diabetes mellitus (NIDDM). Gliclazide binds to the β cell sulfonyl urea receptor (SUR1). This binding subsequently blocks the ATP sensitive potassium channels. The binding results in closure of the channels and leads to a resulting decrease in potassium efflux, which leads to depolarization of the β cells. This opens voltage-dependent calcium channels in the β cell, resulting in calmodulin activation, which in turn leads to exocytosis of insulin-containing secretory granules.
Metformin is a biguanide antihyperglycemic used in conjunction with diet and exercise for glycemic control in type 2 diabetes mellitus. Metformin decreases blood glucose levels by decreasing hepatic glucose production (also called gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization. It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism. The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control.
After detailed deliberation, the committee made the following observations and recommendations regarding the Phase IV clinical trial protocol:
1. Firm should include details of randomization of patients in both arms.
2. Firm should include in the exclusion criteria like diabetes foot ulcer, peripheral vascular disease, recurrent UTI patients.
3. Firm should submit the scientific justification for the sample size.
In addition to the above, the expert panel recommended that the firm should submit a revised Phase IV clinical trial protocol to CDSCO for further review by the committee.
