This was a 30-week, multicenter, phase III, double-blind, double-dummy parallel-group study of once-daily dapagliflozin/linagliptin FDC compared to linagliptin single therapy in patients with inadequately controlled T2DM on metformin. The study was conducted at 16 sites across India between August 2022 and April 2023. It was in compliance with the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use‐Good Clinical Practice (ICH‐GCP) and NDCT Rule 2019. The study was approved by the institutional review board of each site. Informed consent in writing was obtained from all the study subjects.

Further, the primary objective of the study was to compare the change from baseline in HbA1c at 16 weeks between FDC of dapagliflozin 10 mg and linagliptin 5 mg (test group) versus linagliptin 5 mg alone (reference group) in patients with poorly controlled T2DM with a background of metformin monotherapy. The secondary objective was to compare the change in FPG, postprandial plasma glucose (PPG) and body weight from baseline values to week 16 between test group and the reference group. It also involved evaluating the safety and tolerability of the investigational product, FDC tablets of dapagliflozin/linagliptin 10/5 mg.

Out of the 287 patients with T2DM that were screened, 232 patients fulfilling the study selection criteria were enrolled across 16 sites in India. The inclusion criteria for the trial subjects included adult male and female patients with T2DM (age 18–65 years) with an HbA1c value between 7.5% and 10.5% (58–91 mmol/l) and an inadequate glycemic control on ≥ 1000 mg/day of metformin monotherapy for at least 28 days. The exclusion criteria included patients with known hypersensitivity to linagliptin or dapagliflozin or to any of the excipients of the investigational products; type 1 diabetes; body mass index (BMI) ≥ 40 kg/m2; FPG > 270 mg/dl; an indication of chronic kidney disease (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2); indication of liver disease (total bilirubin > 1.5 × upper limit normal (ULN), alanine transaminase (ALT)/aspartate transaminase (AST) > 2.5 × ULN, serum amylase and/or lipase > 3 × ULN).

The study duration was approximately 8 months, which included a 3-month recruitment and 5-month study period (4 weeks of screening period and 16 weeks of treatment period). Further, the study design involved a 2-week run-in period post eligibility screening of the patients. During the 14-day single-blind period, all eligible patients were shifted to linagliptin 5 mg, matching the placebo of the test product (dapagliflozin/linagliptin FDC) and previous ongoing metformin treatment. Those who failed to comply with trial procedures and take at least 80% of the total doses were excluded from the study before randomization. Post the run-in period, eligible patients (n = 232) were randomized in 1:1 ratio in parallel to receive either dapagliflozin/linagliptin 10/5 mg or linagliptin 5 mg on day 1. Figure 2 provides a graphic representation of the study design. Out of the 232 eligible patients, 225 patients (test, n = 115; reference, n = 110) completed the study and 7 patients were unable to do so. Table 1 presents causes for patient attrition.

Overall study design and plan. Out of the eligible 232 patients, 225 (test, n = 115; reference, n = 110) completed the study

The study was in compliance with ICH‐GCP guidelines and the NDCT Rule 2019 (India). It was approved by the ethics committee of all the 16 trial sites across India, that is, lnstitutional Ethics Committee Apex Hospitals, Pvt (ECR/380/Inst/RJ/2013/RR-19), Penta-Med Ethics Committee (ECR/357/Inst/MH/2013/RR-20), LPR Ethics Committee (ECR/751/Inst/MH/2015/RR-21), Shree Siddhivinayak Hospital Ethics Committee (ECR/1247/Inst/MH/2019), Ethics Committee of Trauma Care Hospital ECR/1623/Inst/MH/2021), Shrey Hospital Institutional Ethics Committee (ECR/1302/Inst/GJ/2019), Institutional Ethics Committee for Human Research Medical College and Hospital (ECR/287Inst/WB/2013/RR-19), Institutional Human Ethics Committee, Panimalar Medical College & Research Institute (ECR/1399/Inst/TN/2020), Sangini Hospital Ethics Committee (ECR/147/Inst/GJ/2013/RR-19), Institutional Ethics Committee Amrita Institute of Medical Sciences (ECR/129/Inst/KL/2013/RR-19), Ethics Committee of SMS Medical College and Attached Hospital (ECR/26/Inst/RJ/2013/RR-19), Institutional Ethics Committee Osmania Medical College (ECR/300/Inst/AP/2013/RR-19), Shree Siddhivinayak Maternity and Nursing Home Unity Campus (ECR/1247/Inst/MH/2019), Clinical Research Ethics Committee (ECR/194/Inst/WB/2013/RR-20), Institutional Ethics Committee, Meenakshi Mission Hospital and Research Centre (ECR/398/Inst/TN/2013/RR-19), and Help Hospitals Pvt. Ltd (ECR/1356/Inst/AP/2020). The study involves human subjects and informed consent was obtained from all 232 patients involved in the study.

The primary endpoint of the study was the change in HbA1c from baseline to week 16 for dapagliflozin/linagliptin 10/5 mg and linagliptin 5 mg. The secondary endpoint included changes in FPG, PPG and body weight from baseline to week 16 for the same regimen. A statistically significant reduction in primary and secondary endpoints is observed in the test group compared to the reference group.

The adverse events (AEs; coded using Medical Dictionary for Regulatory Authorities [MedDRA], version 25.0) were recorded post study drug administration and were termed treatment emergent adverse events (TEAEs). The TEAEs were categorized by system organ class (SOC) and were summarized on the basis of severity, action taken, relatedness and outcome. The incidence of TEAEs by SOCs included general disorders and administration; pain; pyrexia; infections and infestations; nasopharyngitis; upper respiratory tract infection; urinary tract infection; investigations; decreased haemoglobin; decreased platelet count; arthralgia; musculoskeletal and connective tissue; back pain; pain in extremity; nervous system disorders; headache; cough; respiratory, thoracic and mediastina. Twelve-lead ECG and haematology and urinary parameters were measured at visits 1 and 6. Biochemical parameters were measured at visits 1, 3 and 6; vital signs and a physical examination were carried out at all six visits.

Analysis for the efficacy and safety was performed by per protocol set (PPS) and intention-to-treat (ITT) analysis, respectively. The between-group difference, that is, the effect size in HbA1c change from baseline, was 0.4%, and the standard deviation (SD) was 1%. The required sample size in two groups with 15% dropout was 232; without a 15% dropout it was 196 subjects (98 in each group) (supplementary material Table S1).

The primary and secondary endpoints were analysed by an analysis of covariance (ANCOVA) model with treatment and stratification factor HbA1c level ≤ 9.0% and > 9.0% as factor and baseline as covariate. The ANCOVA model was used to derive a least-squares estimate of the treatment difference with a 95% confidence interval (CI) and a corresponding two-sided p value. Furthermore, the two-sided 95% CI for the mean change within each treatment group was calculated. A full analysis set was used to evaluate the primary and secondary efficacy endpoints. The p value derived from the ANCOVA model or 95% CI of treatment difference least-squares estimate means would be the proof of superiority.