Study of Dapagliflozin in Combination With Metformin XR to Initiate the Treatment of Type 2 Diabetes

Study Overview
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Brief Summary
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The primary purpose of this study is to compare the change from baseline in hemoglobin A1C achieved with dapagliflozin 10 mg in combination with metformin XR as compared with metformin XR monotherapy and compared with Dapagliflozin monotherapy, after 24 weeks of oral administration of double-blind treatment. The safety of treatment with dapagliflozin will also be assessed in this study

Official Title
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A Multicenter, Randomized, Double-Blind, Active Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Dapagliflozin 10 mg in Combination With Metformin as Initial Therapy as Compared With Dapagliflozin 10 mg Monotherapy and Metformin Monotherapy in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Metformin XR
* Drug: Metformin XR
* Drug: dapagliflozin matching Placebo
* Drug: metformin HCl Modified Release matching Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Treatment naive males and females, >= 18 years old and <= 77 years old, with type 2 diabetes mellitus Subjects must have central laboratory pre-randomization hemoglobin A1C >= 7.5 and <= 12.0% C-peptide >= 1.0 ng/mL (0.34 nmol/L) Body Mass Index <= 45 kg/m2 Must be able to perform self monitoring of blood glucose Exclusion Criteria: aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3X*upper limit of normal (ULN) Serum Total bilirubin >2 mg/dL (34.2 µmol/L) Creatinine kinase >3*ULN Serum creatinine >= 1.50 mg/dL (133 µmol/L) for male subjects, >= 1.40 mg/dL (124 µmol/L) for female subjects Calcium value outside of the central laboratory normal reference range Currently unstable or serious cardiovascular, renal, hepatic, hematological, oncological, endocrine, psychiatric, or rheumatic diseases Urine albumin:creatinine ratio (UACR) >1800 mg/g (203.4 mg/mmol Cr) Severe uncontrolled hypertension defined as systolic blood pressure (SBP) >=180 mmHg and/or diastolic blood pressure (DBP) >=110 mmHg Hemoglobin >=11.0 g/dL (110 g/L) for men; hemoglobin >=10.0 g/dL (100 g/L) for women Positive for hepatitis B surface antigen Positive for anti-hepatitis C virus antibody History of diabetes insipidus History of diabetic ketoacidosis or hyperosmolar nonketotic coma Symptoms of poorly controlled diabetes that would preclude participation in this trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 77 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin + Metformin XR<br>Dapagliflozin: Tablets, Oral, 10 mg, once daily, 24 weeks Metformin XR: Tablets, Oral, up to 2000 mg, once daily, 24 weeks | Drug: Dapagliflozin<br>* Tablets, Oral, 10 mg, once daily, 24 weeks<br>* Other names: Farxiga™;Drug: Metformin XR<br>* Tablets, Oral, up to 2000 mg, once daily, 24 weeks<br>* Other names: Glucophage®;|
| Experimental: Dapagliflozin + Placebo<br>Dapagliflozin: Tablets, Oral, 10 mg, once daily, 24 weeks. Placebo: Metformin HCl Modified Release matching placebo tablets, once daily, 24 weeks. | Drug: Dapagliflozin<br>* Tablets, Oral, 10 mg, once daily, 24 weeks<br>* Other names: Farxiga™;Drug: metformin HCl Modified Release matching Placebo<br>* Tablets<br>|
| Active Comparator: Metformin XR + Placebo<br>Metformin XR: Tablets, Oral, 500 mg up to 2000 mg, once daily 24 weeks Placebo: Dapagliflozin matching placebo tablets once daily, 24 weeks | Drug: Metformin XR<br>* Tablets, Oral, 500 mg up to 2000 mg, once daily 24 weeks<br>* Other names: Glucophage®;Drug: dapagliflozin matching Placebo<br>* Tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 24 (Last Observation Carried Forward) - Randomized Treated Participants | Adjusted mean change in HbA1c from baseline at Week 24 (or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available, ie, last observation carried forward (LOCF) was determined. HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained during the Qualification and Lead-In Periods and on Day 1 and Weeks 4, 8, 12, 16, 20, and 24 in the Double-Blind Period. | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 (LOCF) - Randomized, Treated Participants | Data after rescue medication was excluded from this analysis. FPG was measured as milligrams per deciliter (mg/dL) by a central laboratory. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained during the Qualification and Lead-In Periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of the Double-Blind Period. | Week 24 | 
| Percent Adjusted for Baseline HbA1c of Participants Achieving a Therapeutic Glycemic Response at Week 24 (LOCF) - Randomized, Treated Participants | Therapeutic glycemic response was defined as HbA1c less than 7.0%. n=Number of participants with HBA1c less than (<) 7 % at Week 24, last observation carried forward (LOCF) while N=number of randomized participants with non-missing baseline and Week 24 (LOCF) values. Percent=n/N and was adjusted for Baseline HbA1c. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. | Week 24 | 
| Adjusted Mean Change From Baseline in HbA1C at Week 24 (LOCF) in Participants Whose Baseline HbA1C Category ≥9.0% | HbA1c was measured as percent of hemoglobin by a central laboratory. The population included those randomized, treated participants whose Baseline HbA1c was greater than, equal to (>=) 9.0%. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. | Week 24 | 
| The Adjusted Mean Change From Baseline in Total Body Weight at Week 24 (LOCF) - Randomized, Treated Participants | Adjusted mean change from baseline in total body weight at Week 24 (or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available was determined. Data after rescue medication was excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. Body weight was measured in kilograms (kg). Body weight measurements were obtained during the Qualification and Lead-In Periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of the Double-Blind Period. | Week 24 | 
| Number of Participants With Adverse Events (AEs), Serious AEs (SAEs), Discontinuation Due to AEs, During the 12 Week Double Blind Period, Including Data After Rescue - All Treated Participants | Medical Dictionary for Regulatory Activities (MedDRA), version 12.1 AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug as per the investigator. Events captured from baseline to last dose plus 4 days for AEs, plus 30 days for SAEs during the Double Blind 12 Week Period. Data after rescue included. | Day 1 of Double Blind Period to end of Week 24 Plus 30 days | 
| Number of Participants With Adverse Events of Special Interest During the 12 Week Double Blind Period - All Treated Participants | Participants with AEs of hypoglycemia, cardiac/vascular disorders, renal impairment or failure, volume depletion (hypotension/dehydration/hypovolemia), fractures, urinary stones, and other reports suggestive of genital infection or urinary tract infection (UTI) were summarized using MedDRA version 13.0. Data after rescue included for all special AEs except hypoglycemia (excluded data after rescue). Major hypoglycemic episode: symptomatic requiring 3rd party assistance due to severe impairment in consciousness or behavior with a glucose value < 54 mg/dL and prompt recovery after glucose/glucagon; Minor: either symptomatic with glucose measurement < 63 mg/dL, regardless of need for 3rd party assistance, or asymptomatic with glucose < 63 mg/dL that does not qualify as major; Other: suggestive but not meeting criteria for major or minor. | Baseline to last dose plus 4 days in 12 Week Double Blind Period | 
| Mean Change From Baseline in Seated Systolic and Diastolic Blood Pressure at Week 24 - Treated Participants | Measurements were taken during the Qualification and Lead-In Periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 in the Double Blind Period. Blood pressure values were obtained: after the participant was seated quietly for 5 minutes; at least 8 hours after the last ingestion of caffeine, alcohol, or nicotine; and in the same arm (right or left) consistently through out the study. Systolic and Diastolic pressures were measured in millimeters of mercury (mmHg). Data after rescue were also included. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. | Week 24 | 
| Mean Change From Baseline in Seated Heart Rate at Week 24 - Randomized, Treated Participants | Measurements were taken during the Qualification and Lead-In Periods and on Day 1 and Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 in the Double Blind Period. Heart rate values were obtained: after the participant was seated quietly for 5 minutes; at least 8 hours after the last ingestion of caffeine, alcohol, or nicotine; and in the same arm (right or left) consistently throughout the study. Heart rate was measured in beats per minute (bpm). Data after rescue were also included. Baseline was defined as the last assessment prior to the start date and time of the first dose of the double-blind study medication. In cases where time of the first dose or time of the assessment was not available, baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. | Week 24 | 
| Number of Participants With Normal or Abnormal Electrocardiogram Summary Tracing at Week 24 (LOCF) - Randomized, Treated Participants | 12-Lead electrocardiograms (ECGs) were performed at entry into Lead-In Period Day -7 visit and Week 24/End of treatment visit (last observation carried forward) on participants who were supine. ECGs were assessed by the investigator. Baseline (BL) was Day -7 for this parameter. Data after rescue included. | Week 24 | 
| Number of Participants With Marked Laboratory Abnormalities (Not Including Liver Function) in 24 Week Double Blind Treatment Period, Including Data After Rescue - Randomized, Treated Participants | Laboratory samples: Qualification and Lead-In Periods, Day 1, Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 of Double-Blind Period. Baseline (BL)=last assessment prior to start of first dose of double-blind study medication. Data after rescue included. Pretreatment (PreRX); grams per deciliter (g/dL); upper limit of normal (ULN); milliequivalent per liter (mEq/L); Units per liter (U/L), blood urea nitrogen (BUN). Marked abnormality Low (High) defined: hemoglobin <6 (>18 females or >20 males) g/dL; hematocrit <20% ( >55% females or >60% males); creatinine (>=1.5*preRX, >=2.5 mg/dL); glucose <54 (>350) mg/dL; creatine kinase (>5*ULN);calcium <7.5 (>=1 mg/dL from ULN and >= 0.5mg/dL from PreRX); sodium <130 or < 120 male/female (>150 mEq/L; potassium <=2.5 (>=6.0) mEq/L; bicarbonate <= 13 mEq/L; inorganic phosphorus: <=1.8 if age 17-65 or <=2.1 if age >=66, (>=5.6 if age 17-65 or >=5.1) mg/dL if age >=66; albumin <=2 (>6) g/dL; urine albumin(alb) / creatinine (creat) ratio (>1800 mg/g) | Baseline to Week 24/end of treatment plus 4 days | 
| Number of Participants With Marked Laboratory Abnormalities in Liver Function in 24 Week Double Blind Treatment Period, Including Data After Rescue - Randomized, Treated Participants | Safety laboratory measurements were obtained during the Qualification and Lead-In Periods and on Day 1 of the Double-Blind Period and at Weeks 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24. BL was defined as the last assessment prior to the start of the first dose of the double-blind study medication. Data included from BL up to and including the last day of treatment plus 30 days. Liver function abnormality criteria: FDA Guidance for Industry: Premarketing Clinical Evaluation (July 2009). Data after rescue was also included. Abbreviations: Pretreatment (PreRX), upper limit of normal (ULN); greater than (>) less than (<); Units per liter (U/L), alanine aminotransferase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP). Marked abnormality Low (High) defined: ALP, AST and ALT (>3*ULN); bilirubin (>2*ULN if PreRX <= ULN; >3*ULN if PreRX > ULN); AST or ALT plus (+) bilirubin elevation: AST or ALT >3*ULN and bilirubin >1.5*ULN within 14 days on or after ALT elevation. | Baseline to Week 24/end of treatment plus 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes Mellitus, Type 2, Diabetes Mellitus, Endocrine System Diseases, Glucose Metabolism Disorders, Metabolic Diseases, Metformin, Dapagliflozin, Hypoglycemic Agents, Pharmacologic Actions, Physiological Effects of Drugs