A Multicenter, Randomized, Active-Controlled, Open-Label, Parallel-Group, Two-Arm, Phase III Study to Assess Efficacy and Safety of Fixed Dose Combination of Dapagliflozin, Glimepiride and Extended Release Metformin Hydrochloride Tablets in Comparison to Fixed Dose Combination of Metformin Hydrochloride Prolonged Release and Glimepiride Tablets in Patients with Type 2 Diabetes Mellitus
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 392
- 试验地点
- 18
- 主要终点
- Mean change in HbA1c from Baseline at the end of Week 16
研究概览
简要总结
This was a phase III, randomized, open-label, two-arm, multicenter,parallel-group, active-controlled comparative study. The study is beingconducted at total 18 geographically distributed centers in India. The studywas initiated only after the receipt of Regulatory and Ethics Committee (EC)approvals. Total 440 patients were screened to randomize 395 patients from 18geographically distributed centers in India.
The screening period was of 2 weeks. During screening period, afterobtaining the written informed consent, patients were screened by undergoingvarious assessments as mentioned in Schedule of Assessments (Appendix I).
Treatment Period
After confirming eligibility, patients were randomized into treatmentperiod. In this study, total treatment period was of 28 weeks. This 28 week oftreatment period was divided into 16 weeks of treatment period 1 and 12 weeksof treatment period 2.
Total duration wasmaximum 30 weeks
The study wasconducted as per below planned visits:
Visit 1: Screening Visit (Day -14 to Day -1)
Visit 2: Randomization/Baseline Visit (Day 1, Week 1)
Visit 3: Day 56 ± 4 (Week 8)
Visit 4: Day 84 ± 4 (Week 12)
Visit 5*: ET/EOT Visit: Day 112± 4 (Week 16)
Visit 5**: Day 112± 4 (Week 16)
Visit 6*: EOS Visit (Post-Treatment Safety Follow-up visit: Day 126± 4,(Week 18)
Visit 6**: ET/EOT Visit: Day 196 ± 4 (Week 28)
Visit 7**: EOS Visit (Post-Treatment Safety Follow-up visit: Day 210± 4,(Week 30)
Note: * is applicable for patients under treatment period 1 and ** isapplicable for treatment period 2.
Patients wereprovided with diary to record details about study drug administration, rescuemedication, and adverse events (AEs). Patients were required to bring completeddiary at each visit.
Patients whodiscontinued early from the study completed ET and post-treatment safetyfollow-up visit both considered as end of study visit.
Patients who discontinued early from the study completed ET andPost-Treatment Safety Follow-up visit. Telephonic follow-up of Visit 6 (Week18) and Visit 7 (Week 30) were also permitted if patients were unable to visitstudy center. Patients who discontinued early from the study also completedprocedure of Visit 6 (Week 18) for treatment period 1 and Visit 7 (Week 30) fortreatment period 2, two weeks after discontinuation of study medication.
Study results conclusion:
Overall, the proposed triple fixeddose combination of FDC of Dapagliflozin, Glimepiride and Extended ReleaseMetformin Hydrochloride tablets was superior in comparison to FDC of MetforminHydrochloride Prolonged Release and Glimepiride Tablets in terms of HbA1creduction at the end of Week 12 and Week 16. The proportion of patients achieving HbA1c <7.0% were higher andstatistically significant in Test arm as compared to Comparator arm atthe end of Week 12 and Week 16 demonstratingbetter glycemic control. The results of safety analysis showed that theincidence of TEAEs were comparable in all arms. Apart from the safety that isalready known for the study products, no new safety concerns were observed inthe study. Overall, the study products were safe and well tolerated.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 65.00 Year(s)（—）
- 性别
- All
入选标准
- •Patients of either gender, aged 18 to 65 years (both inclusive) and ready to give written informed consent to participate in the study at the time of screening 2) Patients with diagnosis of type 2 diabetes mellitus 3) Patients along with diet and exercise control, additionally on stable total daily dose of Glimepiride 1 mg and Metformin Sustained Release/Prolonged Release/Extended Release 1000 mg for at least 8 weeks prior to screening 4) Patients with HbA1c ≥8.0% and ≤ 11% at screening 5) Patients with BMI ≤ 45.0 kg/m2 at screening 6) Women of childbearing potential must have a negative urine pregnancy test prior to study entry and agree to use highly effective methods of contraception to prevent pregnancy from study entry till at least two weeks after the last dose of the study medication (such contraception may include hormonal birth control e.g. combined estrogen and progestogen containing [oral, intravaginal, or transdermal] or progesterone only [oral, injectable, or implantable] hormonal contraception associated with inhibition of ovulation, intrauterine devices, intrauterine hormone releasing system OR bilateral tubal occlusion, vasectomized partner, or total sexual abstinence) [Note: Women with childbearing potential are defined as: those who are not (1) surgically sterile (bilateral oophorectomy, hysterectomy, or bilateral tubal ligation) or (2) post-menopausal.
- •Post-menopausal woman will be defined as: Woman not using hormonal replacement therapy and have had at least 12 continuous months of natural (spontaneous) amenorrhea and be greater than 45 years of age.].
排除标准
- •Patients diagnosed with type 1 diabetes, diabetes insipidus, monogenic diabetes, diabetes resulting from pancreatic injury, or secondary forms of diabetes (e.g. Cushing syndrome or acromegaly-associated diabetes) 2) Patients with FBG ≥ 270 mg/dL at screening (if required, measurement can be repeated and confirmed within 7 days) 3) Patients with history of hypersensitivity to any of the study drug or to drugs of similar chemical classes (e.g. sulfonamide) or to any of its excipients 4) Patients with administration of any therapy for diabetes, other than Metformin and glimepiride during 8 weeks prior to screening 5) Patients with history of taking any weight loss medications within 3 months prior to randomization 6) Patients planning to take any anti-diabetic drugs or weight loss drugs other than study drugs or rescue medication during the study 7) Treatment with glucocorticoids equivalent to oral prednisolone ≥ 10 mg (betamethasone ≥ 1.2 mg, dexamethasone ≥ 1.5 mg, hydrocortisone ≥ 40 mg) per day within 30 days prior to randomization; topical, nasal or inhaled corticosteroids are allowed 8) Patients with history of HIV, HBV, and HCV.
- •Patients having significant renal (eGFR below 45 mL/min/1.73 m2) or hepatic impairment (AST and ALT ˃ 3 x ULN).
- •Patients taking loop diuretics within one week prior to screening or planning to take during the study 11) Patients suffering with end-stage renal disease or on dialysis 12) Any condition (e.g. infection, trauma, and surgery) which require insulin therapy at the time of screening or during the study period.
- •Short term use i.e. ≤ 7 days will be allowed 13) History of bariatric surgery (i.e. any surgery to treat obesity; for e.g. gastric banding or procedures that involve bypassing or transposing sections of the small intestine).
- •History of liposuction is allowed.
- •Patients having history of acute or chronic metabolic acidosis, including diabetic ketoacidosis and lactic acidosis, pancreatitis or hyperosmolar state (including coma) 15) Patients who are lactose intolerant 16) Patients suffering from severe urinary tract infections (e.g. urosepsis, pyelonephritis), necrotizing fasciitis of the Perineum (Fournier’s Gangrene), intravascular volume contraction and/ or female genital mycotic infections prior to 6 months from screening 17) Patients with history of myocardial infarction, coronary artery bypass surgery or percutaneous coronary intervention, stroke or transient ischemic attack prior to 6 months from screening 18) Patients with history of unstable angina prior to 3 months from screening 19) Patients with history of sustained and clinically relevant ventricular arrhythmia 20) Any of the following ECG abnormalities: Second or third degree AV block without a pacemaker, Long QT syndrome or QTc > 500 ms 21) Patients having history or currently suffering with serious allergic and hypersensitivity reactions such as anaphylaxis, angioedema and exfoliative skin conditions including Stevens-Johnson syndrome and urticaria.
- •Patients with symptomatic diarrhoea or any other medical condition which the Investigators may judge to be a risk for dehydration and hypovolemia 23) Patients with known alcohol or other substance abuse within last one year as per DSM-5 criteria.
- •Patients with NYHA class III or IV 25) Patients with uncontrolled hypertension ≥160/100 mmHg 26) Patients with inflammatory bowel disease or intestinal ulcers or chronic enteric diseases related to digestion and absorption 27) Patients with any clinically significant laboratory abnormalities/condition (e.g. immunocompromised status, malignancy, hyperthyroidism etc.) which in the opinion of Investigator would compromise the well-being of the patients or the conduct of the study, or prevent the patient from meeting or performing study requirements 28) Patients are on thyroid replacement therapy and has not been on a stable dose for at least 6 weeks prior to screening Note: Patients who meet this criterion may be re-screened after being on a stable dose of thyroid replacement therapy for at least 6 weeks.
- •Pre-planned surgery or medical procedure that would interfere with the conduct of the study 30) Employee of the Sponsor, Investigator, or study center, with direct involvement in the proposed study or other studies under the direction of that Investigator or study center, as well as family members of the employees of Sponsor or the Investigator.
- •Pregnant or lactating woman 32) Patients who has participated in another investigational study within 30 days prior to screening in this study or planning to participate during the study.
结局指标
主要结局
Mean change in HbA1c from Baseline at the end of Week 16
时间窗: Baseline to end of Week 16
次要结局
- Mean change in HbA1c from Baseline at the end of Weeks 12 and 28(Baseline to end of Weeks 12 and 28)
- Mean change in PPBG from Baseline at the end of Weeks 12, 16 and 28(Baseline to end of Weeks 12, 16 and 28)
- Mean change in FBG from Baseline at the end of Weeks 12, 16 and 28(Baseline to end of Weeks 12, 16 and 28)
- Proportion of Participants Achieving HbA1c less than 7.0% at the end of Weeks 12, 16 & 28(Weeks 12, 16 & 28)
- Mean change in bodyweight from Baseline to end of Weeks 12, 16 and 28(Baseline to end of Weeks 12, 16 and 28)
- Number of patients requiring rescue medications by Weeks 16 and 28(Weeks 16 and 28)
- Safety assessment includes TEAEs reported during the study(Week 18 & Week 30)
- Number of patients requiring hypoglycemia management by Weeks 16 and 28(Weeks 12, 16 and 28)