CTRI/2022/06/043249 [Registered on: 14/06/2022] Trial Registered Prospectively
Last Modified On:
17/07/2023
Post Graduate Thesis
No
Type of Trial
Interventional
Type of Study
Drug
Study Design
Randomized, Parallel Group, Active Controlled Trial
Public Title of Study
Study to Assess Efficacy and Safety of Combination of Dapagliflozin, Glimepiride and Metformin Hydrochloride Tablets in Comparison to Glimepiride and Metformin Hydrochloride as Separate Tablets in Patients With Diabetes Mellitus
Scientific Title of Study
A Multicenter, Randomized, Open-Label, Parallel-Group, Four-Arm, Phase III, Active Controlled Comparative Study to Assess Efficacy and Safety of Fixed Dose Combination of Dapagliflozin, Glimepiride and Metformin Hydrochloride Tablets in Comparison to Co-administration of Glimepiride and Metformin Hydrochloride Tablets in Patients With Type 2 Diabetes Mellitus
Trial Acronym
Secondary IDs if Any
Secondary ID
Identifier
ICR/21/015 version 1.0 dated 14/Oct/2021
Protocol Number
Details of Principal Investigator or overall Trial Coordinator (multi-center study) Modification(s)
Name
Dr Pravin Ghadge
Designation
AVP and Head-India Clinical Research
Affiliation
Sun Pharma Laboratories Limited
Address
Sun House, Plot No. 201 B/1, Western Express Highway,
Goregaon (E), Mumbai-400063, Maharashtra, India
Ground Floor ,Room No-003,
Department of General Medicine, BGS Global Institute of Medical Sciences,
#67,BGS Health and Education City, Uttarahalli Road, Kengeri, Bengaluru-560060
Bangalore KARNATAKA
Near Airport, Jalna Road, Aurangabad- 431007, Maharashtra, India Aurangabad MAHARASHTRA
9579268780
drsandipgofne@gmail.com
Dr Shendkar Kaustubh Vijay
Global Hospital and Research Institute
Global Hospital and Research Institute, Ground floor, OPD No. 9, Department of Diabetology, 577/2, off Sinhgad Road,near Dattawadi, Pune, Maharashtra 411030 Pune MAHARASHTRA
9763060606
kaustubhshendkar@gmail.com
Dr Vishal Kumar Gupta
GSVM Medical College
Room No.11,Ground floor, Post Graduate Department of Medicine, Swaroop Nagar, Kanpur, U.P India-208002 Kanpur Nagar UTTAR PRADESH
8765172558
drvkguptagsvm@gmail.com
Dr Lomte Nilesh Keshavrao
Hormone Care
Room No.02, Hormone Care, 2nd Floor, Oberoi Chambers, Besides Hotel Amarpreet, Jalna Road, Aurangabad-431005 Aurangabad MAHARASHTRA
8652225827
enileshlomte@gmail.com
Dr Amit Bhaskar
Janta Hospital
OPD ward, Ground floor, Near Water Head tank,Amara-Akhari Bypass,Chunar Road, Varanasi- Uttar Pradesh 221011 Varanasi UTTAR PRADESH
9580210470
dramitbhaskar@gmail.com
Dr Sandeep Gupta
M.V. Hospitals
Research Center Floor, 314/30, mirza mandi, Chowk, Lucknow, Uttar Pradesh 266024 Lucknow UTTAR PRADESH
0522-2258215
sandeepkumar.gupta@rediffmail.com
Dr Prabhat Kumar Sharma
Maharaja Agrasen Superspeciality Hospital
Department of General Medicine, OPD floor, Central Spine, Agrasen aspatal marg, Sector-7, vidyadhar nagar, Jaipur, Rajasthan, 302039 Jaipur RAJASTHAN
8118877284
pksharma.clinical@gmail.com
Dr Manish Kumar Singh
Maya Hospital & Maternity Centre
Department of General Medicine 343 E Block, Panki Kanpur, UP, 208020 Kanpur Nagar UTTAR PRADESH
07007592197
drmanishkumar820@gmail.com
Dr Animesh Maiti
Medical College and Hospital, Kolkata
Medical College and Hospital , Department of Endocrinology, 88 College, Street Kolkata 700073, West Bengal, India Kolkata WEST BENGAL
09830936076
animeshmaiti73@gmail.com
Dr Chikkalingaiah Siddegowda
Medstar Speciality Hospital
Medstar Speciality Hospital, #641/17/1/3, Kodigehalli Main Road, Sahakarnagar, Bangalore 560092, Karnataka, India Bangalore KARNATAKA
9844004187
medstarclinicalresearch@gmail.com
Dr Jitendra Shukla
Moti lal Nehru Medical College
Moti lal Nehru Medical College, Department of Medicine, OPD Floor, Room No :01, George Town Civil Lines Prayagraj 211002 Allahabad UTTAR PRADESH
7007590702
drjeetendramln@gmail.com
Dr Arjun Baidya
Nil Ratan Sircar Medical College and Hospital,
Nil Ratan Sircar Medical College and Hospital, Department of Endocrinology, 138,AJC Bose Road, Kolkata -700014, West Bengal, India Kolkata WEST BENGAL
S. P. Medical College & A.G of Hospitals Bikaner PBM Hospital
Research room, near medicine
ICU, Department of medicine,
SP Medical College & AG of Hospitals Bikaner BM hospital, Bikaner, Rajasthan 334001
Bikaner RAJASTHAN
9414604192
drsurendrakumar@rediffmail.com
Dr Prakash Kurmi
Shivam Hospital
C/4 STYANARAYAN SOC, Jashoda Nagar Cross Rd, near GOR NO KUVO, Ahmedabad, Gujarat 382445 Ahmadabad GUJARAT
09825047692
drprakash_kurmi@theshivamhospital.in
Dr Gupta Hemant Ramsharan
Sir J.J. Group of Hospitals
OPD No 20, Department of Medicine, OPD Building, Grant Govt. Medical College and Sir J.J. Group of Hospitals, Byculla, Mumbai 400008. Mumbai MAHARASHTRA
9870456888
drhemantgupta@hotmail.com
Dr Sunil Kumar Mahavar
SMS Hospital
Department of Medicine, Ground Floor, Dhanvantri OPD Block Jaipur-302004 Jaipur RAJASTHAN
0946059469
drsunilmahavar09@gmail.com
Dr Aravind GN
Victoria Hospital
Department of General Medicine, OPD Floor, K R Road, Fort, Bangalore - 560002 Bangalore KARNATAKA
(1) ICD-10 Condition: E119||Type 2 diabetes mellitus without complications,
Intervention / Comparator Agent
Type
Name
Details
Intervention
Dapagliflozin,
Glimepiride and
Metformin
Hydrochloride Tablets (Test arm 1)
FDC of Dapagliflozin,
Glimepiride and
Metformin
Hydrochloride (5 mg, 1
mg and 500 mg) tablet to
be taken BID in treatment period 1 (16 weeks). FDC of Dapagliflozin,
Glimepiride and
Metformin
Hydrochloride (5 mg, 2
mg and 500 mg) Tablet
to be taken BID in treatment period 2 (12 weeks)
Intervention
Dapagliflozin, Glimepiride
and Metformin Hydrochloride
Tablets (Test arm 2)
FDC of Dapagliflozin,
Glimepiride and Metformin
Hydrochloride (5 mg, 1 mg
and 1000 mg) tablet to be
taken BID in treatment period 1 (16 weeks) and FDC of Dapagliflozin,
Glimepiride and
Metformin
Hydrochloride (5 mg, 2
mg and 1000 mg) Tablet
to be taken BID in Treatment period 2 (12 weeks)
Comparator Agent
Metformin Hydrochloride Tablets IP and Glimepiride tablets IP 1 mg (Comparator arm 1)
One tablet of Metformin
Hydrochloride 500 mg BID (Total
dose of Metformin 1000 mg) and One
tablet of Glimepiride 1 mg to be taken
BID in treatment period 1 (16 weeks) and One tablet of Metformin
Hydrochloride 500 mg BID (Total
dose of Metformin 1000 mg) and One
tablet of Glimepiride 2 mg to be
taken BID in treatment period 2 (12 weeks).
Comparator Agent
Metformin Hydrochloride Tablets IP and Glimepiride tablets IP 1 mg (Comparator arm 2)
Two tablets of Metformin
Hydrochloride 500 mg BID (Total
dose of Metformin 2000 mg) and
One tablet of Glimepiride 1 mg to
be taken BID in treatment period 1 (16 weeks) and Two tablets of Metformin
Hydrochloride 500 mg BID (Total dose
of Metformin 2000 mg) and One tablet
of Glimepiride 2 mg to be taken BID in treatment period 2 (12 weeks)
Inclusion Criteria
Age From
18.00 Year(s)
Age To
65.00 Year(s)
Gender
Both
Details
1) 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
2 mg and Metformin 1000 mg to 2000 mg (both inclusive) for at least 8 weeks prior to screening
4) Patients with HbA1c ≥ 8.0% and ≤ 11% at screening and randomization
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
ExclusionCriteria
Details
1) 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) and randomization
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 screening
6) Patients planning to take any anti-diabetic drugs (other than study drugs or rescue medication) or
weight loss drugs 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 screening;
topical, nasal or inhaled corticosteroids are allowed
8) Patients with history of HIV, HBV, and HCV
9) Patients having significant renal impairment eGFR below 45 mL/min/1.73 m2 or end-stage renal
disease or on dialysis) or hepatic impairment (AST and ALT ˃ 3 x ULN) at screening.
10) Patients taking loop diuretics within one week prior to screening or planning to take during the
study.
11) Any condition (e.g. infection, trauma, and surgery) which requires insulin therapy at the time of
screening or during the study period. Short term use i.e. ≤ 7 days will be allowed.
12) History of bariatric surgery (i.e. any surgery to treat obesity; e.g. gastric banding or procedures that
involve bypassing or transposing sections of the small intestine). History of liposuction will be
allowed.
13) Patients having history of acute or chronic metabolic acidosis, including diabetic ketoacidosis and
lactic acidosis, pancreatitis or hyperosmolar state (including coma)
14) Patients who are lactose intolerant
15) 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
16) 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
17) Patients with history of unstable angina prior to 3 months from screening
18) Patients with history of sustained and clinically relevant ventricular arrhythmia
19) Any of the following ECG abnormalities at screening: Second or third degree AV block without a pacemaker, Long QT syndrome or QTc greater than 500 ms,
20) 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
21) Patients with symptomatic diarrhoea or any other medical condition which the Investigators may
judge to be a risk for dehydration and hypovolemia
22) Patients with known alcohol or other substance abuse within last one year as per DSM-5 criteria
23) Patients with NYHA class III or IV heart failure
24) Patients with uncontrolled hypertension ≥160/100 mmHg at screening and randomization
25) Patients with inflammatory bowel disease or intestinal ulcers or chronic enteric diseases related to
digestion and absorption
26) 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 patient or the conduct of the study, or prevent
the patient from meeting or performing study requirements.
27) 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.
28) Pre-planned surgery or medical procedure that would interfere with the conduct of the study
29) 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.
30) Pregnant or lactating woman
31) Patients who have participated in another investigational study within 30 days prior to screening in
this study or planning to participate during the study
Method of Generating Random Sequence
Permuted block randomization, fixed
Method of Concealment
Not Applicable
Blinding/Masking
Not Applicable
Primary Outcome
Outcome
TimePoints
Mean change in HbA1c from Baseline at the end of Week 16
Baseline, at the end of Week 16
Secondary Outcome
Outcome
TimePoints
Mean change in HbA1c from Baseline at the end of Weeks 12 and 28
Baseline, at the end of Weeks 12 and 28
Mean change in PPBG from Baseline at the end of Weeks 12, 16 and 28
Baseline, at the end of Weeks 12 and 28
Mean change in FBG from Baseline at the end of Weeks 12, 16 and 28
Baseline, at the end of Weeks 12 and 28
Proportion of Participants Achieving HbA1c 7.0% at the end of Weeks 12, 16 and 28
Weeks 12, 16 and 28
Mean change in bodyweight from Baseline at the end of Weeks 12, 16 and 28
Baseline, at the end of Weeks 12 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
till end of study
Number of patients requiring hypoglycemia management by Weeks 16 and 28
Weeks 16 and 28
Target Sample Size
Total Sample Size="536" Sample Size from India="536" Final Enrollment numbers achieved (Total)= "536" Final Enrollment numbers achieved (India)="536"
This was a phase III, randomized, open-label, four-arm, multicenter, parallel-group, active-controlled comparative study. In this study, the total treatment period was 28 weeks (maximum). The 28-week of treatment period was divided into treatment period 1(16 weeks) and treatment period 2 (12 weeks).
The study was conducted at approximately 21 number of centers in India, having qualified Investigators. The study will be initiated only after the receipt of Regulatory and EC approval. A total of 536 patients were randomized from 21 geographically distributed centers in India.
*Screening period was maximum up to 1 week, however, patients who were eligible at screening visit immediately entered run-in period. After confirming the eligibility, patients were randomized by allotting the randomization number. Of 536 patients, 134 each in test arm 1 and test arm 2 of FDC of Dapagliflozin, Glimepiride and Metformin Hydrochloride Tablets BID, 134 each in Comparator arm 1 and comparator arm 2.
Of 536 patients, 134 each in test arm 1 and test arm 2 of FDC of Dapagliflozin, Glimepiride and Metformin Hydrochloride Tablets BID, 134 each in Comparator arm 1 and comparator arm 2.
The study treatment period was 28 weeks, which consisted of treatment period 1 (16 weeks) and treatment period 2 (12 weeks).
During the study, assessments were performed as mentioned in Schedule of Assessment. At the end of Week 16, based on HbA1c level, patients entered treatment period 2. For patients who were not eligible had EOS visit at Week 18
in comparison to co-administration of dual therapies (Metformin Hydrochloride and Glimepiride tablets
Mean change in HbA1c from baseline to end of Week 16 was statistically significant in FDC of Dapagliflozin, Glimepiride and Metformin Hydrochloride tablets BID (test arm 1 and test arm 2) compared to co-administration of Metformin Hydrochloride and Glimepiride tablets IP BID (comparator arm 1 and comparator arm 2). The proportion of patients achieving HbA1c <7.0% were higher and statistically significant in FDC of Dapagliflozin, Glimepiride and Metformin Hydrochloride tablets arm as compared to co-administration of Metformin Hydrochloride and Glimepiride tablets arm at the end of Week 16 demonstrating better glycaemic control. The results of safety analysis showed that the incidence of TEAEs were comparable in all arms. Apart from the safety that is already known for the study products, no new safety concerns were observed in the study. Overall, the study products were safe and well tolerated.