Study Design

This multicentric study involving 12 study centers was a prospective, randomized, double-blind, parallel-group (with a double-dummy active-controlled), comparative phase 3 trial (clinical trial reg. no. CTRI/2022/01/039857). The study was conducted, monitored, evaluated, and audited to comply with the International Conference on Harmonization Good Clinical Practice guidelines [17]. The study was conducted in accordance with the ethical guidelines for biomedical research on human patients by the Indian Council of Medical Research, ethical principles of the Declaration of Helsinki, and New Drugs and Clinical Trials Rules 2019. The study also received the institutional ethics committee approval at each of the 12 study sites (Supplementary material; Table S1). The master ethics approval was obtained from Institutional Ethics Committee, Maharaja Agrasen Superspecialty Hospital (IEC/APV/JAN/2022/07). Informed written consent was obtained from all the study participants. This manuscript was prepared according to CONSORT checklist (Supplementary material; Table S2).

Inclusion and Exclusion Criteria

Participants were eligible for inclusion if they were 18–65 years old (both inclusive) with the diagnosis of T2DM and were on metformin monotherapy (≥ 1500 mg/day) for a minimum of 6 weeks before screening for poor glycemic control (HbA1c ≥ 8.0% to ≤ 10.0%).

The exclusion criteria included individuals with a history of type 1 diabetes mellitus, diabetes insipidus, metabolic acidosis or diabetic ketoacidosis, bariatric surgery, or lap-band procedure within 12 months before screening, uncontrolled hypertension (systolic BP ≥ 160 mmHg and diastolic BP ≥ 100 mmHg), and any clinically significant abnormality on 12-lead electrocardiogram (ECG). Female patients with childbearing potential (who are neither surgically sterilized nor are willing to use contraceptives) were excluded. Individuals with concomitant diseases, including gastrointestinal, cardiovascular, hepatic, respiratory, and renal disorders, considered clinically relevant by the investigator or with a history of relevant chronic or acute infections were excluded.

Randomization, Blinding, and Code Breaking

The subjects who met all the inclusion criteria and did not meet any of the exclusion criteria were randomized using block randomization into one of the two arms in a 1:1 ratio. A computer-generated randomization process was used to assign patients where randomization numbers were generated using uniform distribution by a computational method. A random list was provided by the statistician and the subject was assigned to the respective treatment arm by the block randomization process. Randomized patients were simultaneously enrolled in one of the study groups as per their randomization number and were followed up in a parallel manner till completion of the study.

As this is a double-blind study, the assigned treatment arm was not known to the investigator and study staff, study subjects, contract research organization (CRO), or sponsor during the conduct of the study. To maintain double blinding, both the study drugs were indistinguishable with regards to all the physical characteristics such as size, shape, color, consistency, etc. An investigator or study team member dispensed the study medication and was responsible for performing accountability of the study medication with the compliance calculation during each follow-up visit.

During the initiation of the study, the investigator and the site study team were instructed about the unblinding procedure for any particular individual subject. Blinding should only be broken in the case of medical emergency and in the interest of subject safety where knowledge of the treatment arm is necessary. The investigator/study team member was provided with sealed envelopes containing details of the study treatment arm for that particular subject. When it is necessary to unblind the subject, the investigator/study team member notes the date, time, and reason for unblinding and record this information within the study documentation. During this procedure, the investigator/study team member also reports the occurrence of any emergency code breaks immediately to CRO/sponsor study team member. After unblinding, the subject does not receive any more study medication. The subject was withdrawn from the study immediately and follow-up visits were performed till the time adverse event resolves.

Patient Recruitment and Selection

Patients found eligible during the screening underwent a 2-week run-in period before randomization. During this period, the individuals continued on the previous medication and received a placebo. Patients who completed the run-in period were reassessed for HbA1c, fasting plasma glucose (FPG), and 2-h postprandial blood glucose (PPG) level. Patients meeting the inclusion and exclusion criteria were randomly assigned in a 1:1 ratio to either of the two treatment arms: arm X receiving the test product of FDC of dapagliflozin 10 mg + sitagliptin 100 mg + metformin hydrochloride XR 1000 mg tablets (Dapa + Sita + Met) (Exemed Pharmaceuticals; batch no. FD/DS2-M2(ER)/012) and placebo matching the product; or arm Y receiving sitagliptin phosphate tablets 100 mg and metformin hydrochloride SR tablets 1000 mg combipack (Sita + Met) (MSD Pharmaceuticals Pvt. Ltd.; batch no. 8790993A) and placebo matching the test product. All centers involved in the study used the same products. Both the drugs were administered once a day orally in the morning after breakfast around the same time every day. The minimum duration of participation of patients in the study was 84 days, and the maximum participation period was 117 days (Table 1).

Table 1 Schedule of visits during the study periodEfficacy Endpoints

The primary endpoint was the mean change in HbA1c at the end of the study compared to baseline. The secondary endpoints included the mean change in body weight, FPG, PPG, and the proportion of patients achieving target HbA1c levels (< 7.0%) at the end of the study (week 16).

Safety Endpoints

The tolerability and safety of the treatments were evaluated on the basis of the occurrence of adverse (AEs) and serious adverse events (SAEs), hypoglycemia, and laboratory abnormalities. Minor hypoglycemia episodes were defined as a capillary or plasma glucose measurement < 63 mg/dL with symptoms (with or without the need for assistance) or an asymptomatic episode with capillary or plasma glucose measurement < 63 mg/dL that does not qualify as a major hypoglycemic episode [18]. A major hypoglycemic episode was defined as a glucose value < 54 mg/dL and requiring assistance due to severe impairment in behavior or consciousness and having a prompt recovery after glucose or glucagon administration [19].

Efficacy and Safety Measurements

Glycated hemoglobin (HbA1c) and PPG were measured at screening visit (visit 1), randomization or baseline visit (visit 3/day 1), visit 6 (84 ± 2 days), and end of the study visit (visit 7/112 ± 2 days). FPG was measured at all visits except the second visit. The body mass index was recorded at all visits except the randomization visit. Physical examination, vitals, and concomitant medications were assessed and information on adverse events were obtained at all visits.

Hematological and biochemical tests were performed at the screening (visit 1) and end of the study (visit 7). Estimated glomerular filtration rate, serum creatinine, and blood urea nitrogen were performed at visit 5/week 8. A 12-lead ECG and routine urine analysis (microscopy) were performed at screening (visit 1) and end of the study (visit 7). A urine pregnancy test was conducted among women with childbearing potential at all visits except visit 2 and visit 4 (28 ± 2 days).

Evaluation of Treatment Compliance

Patients from either of the arms were administered the drug as per schedule and ensured to comply with the protocol. Records were maintained regarding the date and frequency of investigational product administration. Compliance with regimen assignment was assessed by review of each patient’s diary.

Sample Size Estimation

A sample size of 246 evaluable patients was planned in this study. This sample size was assumed to detect a mean difference of at least 0.5 between test and comparator groups in mean change of HbA1c from baseline to week 16 (at 90% power, two-sided significance level of 0.05, and standard deviation of ± 1.2). A total of 123 patients receiving FDC of dapagliflozin 10 mg + sitagliptin 100 mg + metformin hydrochloride ER 1000 mg tablets and 123 patients receiving Janumet XR CP (sitagliptin phosphate tablets 100 mg and metformin hydrochloride SR tablets 1000 mg combipack) were required. Considering a 10% dropout, we therefore enrolled 274 patients into the study.

Statistical Analysis

Statistical analysis was done using Statistical Analysis System 9.4. Continuous variables were tested using repeated measures analysis of covariance (ANCOVA) or a two-sample t test. The chi-square test was used to statistically test categorical variables. Primary and secondary efficacy endpoints were analyzed using repeated ANCOVA or two-sample t test. The primary and secondary endpoints included least square mean (LSM), standard error (SE), and 95% confidence interval (CI) for the LSM mean difference between groups. The proportion of patients achieving a therapeutic target HbA1c level was calculated using the chi-square test. All safety parameters were analyzed using descriptive statistics and two-sample t test.