A Phase III Study of BMS-512148 (Dapagliflozin) in Patients With Type 2 Diabetes Who Are Not Well Controlled With Diet and Exercise

Study Overview
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Brief Summary
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The purpose of this clinical research study is to determine whether dapagliflozin can improve (decrease) blood glucose values in patients with Type 2 diabetes who have never been treated with medication or have been taking medication for less than 24 weeks since their original diabetes diagnosis. The safety of this treatment will also be studied.

Detailed Description
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All eligible participants will receive single-blind placebo medication during the 2-week lead-in period. All participants may receive additional open-label treatment with metformin, 500-2000 mg, as needed for rescue, based on protocol specific criteria.

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Dapagliflozin as Monotherapy in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control With Diet and Exercise

Conditions
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Type 2 Diabetes

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Dapagliflozin placebo
* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria Males and females, aged 18 to 77 years Type 2 diabetes with inadequate glycemic control, defined as: Group 1, hemoglobin A1c (HbA1c) ≥7% and ≤10%; Group 2, HbA1c ≥10.1% and ≤12.0% Drug naive, defined as never having received prescription medications for diabetes, having received prescription medications for diabetes for <24 weeks since the original diagnosis C-peptide ≥1.0 ng/mL at enrollment Body Mass Index ≤ 45.0 kg/m^2 at enrollment Key Exclusion Criteria Urine albumin:creatinine ratio >1,800 mg/g Aspartate aminotransferase >3*upper limit of normal (ULN) Alanine aminotransferase >3*ULN Serum total bilirubin >2*ULN Serum creatinine ≥1.5 mg/dL for men; ≥1.4 mg/dLfor women Calcium value outside of the central laboratory normal reference range Positive hepatitis B surface antigen Positive anti-hepatitis C virus antibody Hemoglobin ≤11 g/dL for men; hemoglobin ≤10 g/dL for women Creatine kinase >3*ULN Abnormal free T4 values History of diabetes insipidus Symptoms of poorly controlled diabetes, including marked polyuria and polydipsia with greater than 10% weight loss in the 3 months prior to enrollment History of diabetic ketoacidosis or hyperosmolar nonketotic coma Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg Any of the following within 6 months of enrollment: Myocardial infarction, cardiac surgery or revascularization, unstable angina, unstable congestive heart failure (CHF), CHF New York Heart Association Class III or IV status, transient ischemic attack or significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia History of unstable or rapidly progressing renal disease Conditions of congenital renal glucosuria Significant hepatic disease, including chronic active hepatitis and/or severe hepatic insufficiency Documented history of hepatotoxicity with any medication Documented history of severe hepatobiliary disease History of hemoglobinopathy, with the exception of sickle cell trait, thalassemia minor, or chronic or recurrent hemolysis Donation of blood or blood products to a blood bank, blood transfusion, or participation in a clinical study requiring withdrawal of >400 mL of blood during the 6 weeks prior to enrollment Malignancy (with the exception of treated basal cell or treated squamous cell carcinoma) within 5 years of enrollment visit Known immunocompromised status, including individuals who had undergone organ transplantation or who had positive HIV results Administration of any antidiabetic therapy for more than 14 days (consecutive or not) during the 12 weeks prior to enrollment Administration of any antidiabetic therapy, other than any previously specified, at any dose, at any time during the 4 weeks prior to enrollment Replacement or chronic systemic corticosteroid therapy, defined as any dose of systemic corticosteroid taken for >4 weeks within 3 months prior to enrollment History of bariatric surgery or lap-band procedure Administration of sibutramine, phentermine, orlistat, rimonabant, benzphetamine, diethylpropion, methamphetamine, and/or phendimetrazine, within 30 days of enrollment

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Dapagliflozin, 2.5 mg AM<br>Participants with hemoglobin A1c (HbA1c) ≥7% and ≤10% at enrollment received dapagliflozin tablets, 2.5 mg, once each morning for up to 102 weeks. | Drug: Dapagliflozin<br>* Tablets; oral; 2.5, 5.0, or 10 mg; once daily in the morning or evening for up to 102 weeks<br>* Other names: BMS-512148;Drug: Metformin<br> <br> * Other names: Tablets, 500-2000 mg, orally as needed in any arm for rescue, based on protocol specific criteria;|
| Experimental: Group 1: Dapagliflozin, 10 mg AM<br>Participants with HbA1c ≥7% and ≤10% at enrollment received dapagliflozin tablets, 10 mg, once each morning for up to 102 weeks. | Drug: Dapagliflozin<br>* Tablets; oral; 2.5, 5.0, or 10 mg; once daily in the morning or evening for up to 102 weeks<br>* Other names: BMS-512148;Drug: Metformin<br> <br> * Other names: Tablets, 500-2000 mg, orally as needed in any arm for rescue, based on protocol specific criteria;|
| Experimental: Group 1: Dapagliflozin 2.5 mg PM<br>Participants with HbA1c ≥7% and ≤10% at enrollment received dapagliflozin tablets, 2.5 mg, once each evening for up to 102 weeks. | Drug: Dapagliflozin<br>* Tablets; oral; 2.5, 5.0, or 10 mg; once daily in the morning or evening for up to 102 weeks<br>* Other names: BMS-512148;Drug: Metformin<br> <br> * Other names: Tablets, 500-2000 mg, orally as needed in any arm for rescue, based on protocol specific criteria;|
| Experimental: Group 1: Dapagliflozin, 5 mg PM<br>Participants with HbA1c ≥7% and ≤10% at enrollment received dapagliflozin tablets, 5 mg, once each evening for up to 102 weeks. | Drug: Dapagliflozin<br>* Tablets; oral; 2.5, 5.0, or 10 mg; once daily in the morning or evening for up to 102 weeks<br>* Other names: BMS-512148;Drug: Metformin<br> <br> * Other names: Tablets, 500-2000 mg, orally as needed in any arm for rescue, based on protocol specific criteria;|
| Experimental: Group 1: Dapagliflozin, 10 mg PM<br>Participants with HbA1c ≥7% and ≤10% at enrollment received dapagliflozin tablets, 10 mg, once each evening for up to 102 weeks. | Drug: Dapagliflozin<br>* Tablets; oral; 2.5, 5.0, or 10 mg; once daily in the morning or evening for up to 102 weeks<br>* Other names: BMS-512148;Drug: Metformin<br> <br> * Other names: Tablets, 500-2000 mg, orally as needed in any arm for rescue, based on protocol specific criteria;|
| Experimental: Group 2: Dapagliflozin, 5 mg AM<br>Participants with HbA1c ≥10.1% and ≤12% at enrollment received dapagliflozin tablets, 5 mg, once each morning for up to 102 weeks. | Drug: Dapagliflozin<br>* Tablets; oral; 2.5, 5.0, or 10 mg; once daily in the morning or evening for up to 102 weeks<br>* Other names: BMS-512148;Drug: Metformin<br> <br> * Other names: Tablets, 500-2000 mg, orally as needed in any arm for rescue, based on protocol specific criteria;|
| Experimental: Group 2: Dapagliflozin, 10 mg AM<br>Participants with HbA1c ≥10.1% and ≤12% at enrollment received dapagliflozin tablets, 5 mg, once each morning for up to 102 weeks. | Drug: Dapagliflozin<br>* Tablets; oral; 2.5, 5.0, or 10 mg; once daily in the morning or evening for up to 102 weeks<br>* Other names: BMS-512148;Drug: Metformin<br> <br> * Other names: Tablets, 500-2000 mg, orally as needed in any arm for rescue, based on protocol specific criteria;|
| Experimental: Group 1: Dapagliflozin placebo AM & PM<br>Participants with HbA1c ≥7% and ≤10% at enrollment received dapagliflozin placebo once each morning and evening for up to 102 weeks. | Drug: Dapagliflozin placebo<br>* Tablets, oral, 0 mg, once daily in the morning or evening for up to 102 weeks<br>Drug: Metformin<br> <br> * Other names: Tablets, 500-2000 mg, orally as needed in any arm for rescue, based on protocol specific criteria;|
| Experimental: Group 1: Dapaglifozon, 5 mg AM<br>Participants with (HbA1c ≥7% and ≤10% at enrollment received dapagliflozin tablets, 5 mg, once each morning for up to 102 weeks. | Drug: Dapagliflozin<br>* Tablets; oral; 2.5, 5.0, or 10 mg; once daily in the morning or evening for up to 102 weeks<br>* Other names: BMS-512148;Drug: Metformin<br> <br> * Other names: Tablets, 500-2000 mg, orally as needed in any arm for rescue, based on protocol specific criteria;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline to Week 24 in Hemoglobin A1C (HbA1c) (Last Observation Carried Forward [LOCF]): Group 1 | HbA1c was measured 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. If no Week 24 assessment was available, the last postbaseline measurement prior to Week 24 was used. For rescued participants, measurements obtained after initiation of rescue medication were not considered in calculating the primary endpoint. Evening dosing groups were summarized as exploratory endpoints. | Baseline to Week 24 (end of Short-term Period) | 
| Adjusted Mean Change From Baseline to Week 24 in Hemoglobin A1c (HbA1c) (Last Observation Carried Forward [LOCF]): Group 2 | HbA1c was measured 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. If no Week 24 assessment was available, the last postbaseline measurement prior to Week 24 was used. For rescued participants, measurements obtained after initiation of rescue medication were not considered in calculating the primary endpoint. Group 2 (patients with enrollment baseline HbA1c >10% and ≤2%) was considered an exploratory group, included to obtain initial efficacy and safety data for these patients. No comparator arm was included. | Baseline to Week 24 (end of Short-term Period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline to Week 24 in Fasting Plasma Glucose Levels (Last Observation Carried Forward [LOCF]): Group 1 | Secondary endpoints were tested using a sequential testing procedure and are presented in hierarchical order. Because the primary focus of the entire dapagliflozin program was on morning dosing in a population with HbA1c ≥7% and ≤10%, only data on AM dosing were summarized in secondary efficacy analyses. Data after rescue medication were 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. If no Week 24 assessment was available, glucose levels were recorded from the last postbaseline measurement prior to Week 24. For rescued participants, measurements obtained after initiation of rescue medication was not considered in calculating the endpoint. | Baseline to Week 24 (end of Short-term Period) | 
| Adjusted Mean Change From Baseline to Week 24 in Fasting Plasma Glucose Levels (Last Observation Carried Forward [LOCF]): Group 2 | Group 2 was an exploratory group, included to obtain initial efficacy and safety data. No comparator arm was included. Secondary endpoints were tested using a sequential testing procedure and are presented in hierarchical order. Data after rescue medication were 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. If no Week 24 assessment was available, glucose levels were recorded from the last postbaseline measurement prior to Week 24. For rescued participants, measurements obtained after initiation of rescue medication was not considered in calculating the endpoint. | Baseline to Week 24 (end of Short-term Period) | 
| Adjusted Mean Change in Total Body Weight at Week 24 (Last Observation Carried Forward [LOCF]): Group 1 | Secondary endpoints were tested using a sequential testing procedure and are presented in hierarchical order. Because the primary focus of the entire dapagliflozin program was on morning dosing in a population with HbA1c ≥7% and ≤10%, only data on AM dosing were summarized. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline 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. | From Baseline to Week 24 (end of Short-term Period) | 
| Adjusted Mean Change in Total Body Weight at Week 24 (Last Observation Carried Forward [LOCF]): Group 2 | Secondary endpoints were tested using a sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline 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.Group 2 (patients with enrollment baseline HbA1c >10% and ≤2%) was considered an exploratory group, included to obtain initial efficacy and safety data for these patients. No comparator arm was included. | From Baseline to Week 24 (end of Short-term Period) | 
| Adjusted Mean Change From Baseline in Fasting Plasma Glucose Levels at Week 1 (Last Observation Carried Forward [LOCF]): Group 1 | Secondary endpoints were tested using a sequential testing procedure and are presented in hierarchical order. Because the primary focus of the entire dapagliflozin program was on morning dosing in a population with HbA1c ≥7% and ≤10%, only data on AM dosing were summarized. Data after rescue medication was excluded from this analysis. Fasting plasma glucose was measured 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. | Baseline to Week 1 (end of Short-term Period) | 
| Adjusted Mean Change From Baseline in Fasting Plasma Glucose Levels at Week 1 (Last Observation Carried Forward [LOCF]): Group 2 | Secondary endpoints were tested using a sequential testing procedure and are presented in hierarchical order. Because the primary focus of the entire dapagliflozin program was on morning dosing in a population with HbA1c ≥7% and ≤10%, only data on AM dosing were summarized. Data after rescue medication was excluded from this analysis. Fasting plasma glucose was measured 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. | Baseline to Week 1 | 
| Adjusted Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1c] <7.0%) at Week 24 (Last Observation Carried Forward [LOCF]) | Secondary endpoints were tested using a sequential testing procedure and are presented in hierarchical order. Therapeutic glycemic response is defined as HbA1c <7.0%. Data after rescue medication was excluded from this analysis. If no Week 24 assessment was available, HbA1c was recorded from the last postbaseline measurement prior to Week 24. Group 2 (patients with enrollment baseline HbA1c >10% and ≤2%) was considered an exploratory group, included to obtain initial efficacy and safety data for these patients. No comparator arm was included. Thus, only key safety and efficacy analyses were performed for Group 2. | Baseline to Week 24 (end of Short-term Period) | 
| Adjusted Mean Change From Baseline to Week 24 in Hemoglobin A1c (HbA1c) in Patients With Baseline HbA1c ≥9.0% (Last Observation Carried Forward [LOCF]) | Secondary endpoints were tested using a sequential testing procedure and are presented in hierarchical order. If no Week 24 assessment was available, HbA1c was recorded from the last postbaseline measurement prior to Week 24. HbA1c was measured as % of hemoglobin by a central laboratory. The population included randomized patients who received treatment and had baseline HbA1c >9.0%. Data after rescue medication were excluded from this analysis. Baseline was defined as the last assessment prior to the start date and time of the first dose of double-blind study drug. In cases where time of the first dose or 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 drug. Group 2 (patients with enrollment baseline HbA1c >10% and ≤2%) was considered exploratory, included to obtain initial data. No comparator arm was included. Thus, only key safety and efficacy analyses were performed in Group 2. | Baseline to Week 24 (end of Short-term Period) | 
| Adjusted Mean Change From Baseline in Hemoglobin A1c (HbA1c) in Participants With Baseline Body Mass Index (BMI) ≥27 kg/m^2 (Last Observation Carried Forward [LOCF]) | Secondary endpoints were tested using a sequential testing procedure and are presented in hierarchical order. If no Week 24 assessment was available, HbA1c was recorded from the last postbaseline measurement prior to Week 24. 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. Group 2 (patients with enrollment baseline HbA1c >10% and ≤2%) was considered an exploratory group, included to obtain initial efficacy and safety data for these patients. No comparator arm was included. Thus, only key safety and efficacy analyses were performed for Group 2. | Baseline to Week 24 (end of Short-term Period) | 
| Adjusted Percentage of Participants Who Achieved Hemoglobin A1c [HbA1c] ≤6.5% (Last Observation Carried Forward [LOCF]) | Secondary endpoints were tested using a sequential testing procedure and are presented in hierarchical order. If no Week 24 assessment was available, HbA1c was recorded from the last postbaseline measurement prior to Week 24. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. Group 2 (patients with enrollment baseline HbA1c >10% and ≤2%) was considered an exploratory group, included to obtain initial efficacy and safety data for these patients. No comparator arm was included. Thus, only key safety and efficacy analyses were performed for Group 2. | Baseline to Week 24 (end of Short-term Period) | 
| Adjusted Mean Change From Baseline to Week 24 in Total Body Weight in Patients With Baseline Body Mass Index ≥27 kg/m^2 (Last Observation Carried Forward) | Secondary endpoints were tested using sequential testing procedure and are presented in hierarchical order. Adjusted mean change from baseline in total body weight at Week 24 (or the last postbaseline 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. Group 2 (patients with enrollment baseline HbA1c >10% and ≤2%) was considered an exploratory group, included to obtain initial efficacy and safety data for these patients. No comparator arm was included. Thus, only key safety and efficacy analyses were performed for Group 2. | Baseline to Week 24 (end of Short-term Period) | 
| Number of Participants With Adverse Events (AE), Hypoglycemia, Related AEs, Death as Outcome, Related Serious AEs (SAEs), SAEs and AEs Leading to Discontinuation, and Hypoglycemia Leading to Discontinuation (Short-term + Long-term Periods) | 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. Related=having certain, probable, possible, or missing relationship to study drug. Includes non-SAEs and hypoglycemia with onset on or after the first date/time of double-blind treatment and on or prior to the last day of short-term plus long-term treatment plus 4 days. Includes SAEs with onset on or after the first date/time of double-blind treatment and on or prior to the last day of short-term plus long-term treatment plus 30 days. | Day 1 to Week 102 (end of Long-term Period) + 30 days | 
| Number of Participants With Laboratory Test Results Meeting the Criteria for Marked Laboratory Abnormality (Short-term and Long-term Periods) | Baseline was defined as the last assessment prior to the start of the first dose of the double-blind study medication. Data included from baseline up to and including the last day of treatment plus 4 days. Data after rescue were also included. ULN=upper limit of normal; preRX=pretreatment. Phosphorus, inorganic (high) defined as >=5.6 mg/dL for ages 17-65 years or >=5.1 mg/dL for ages >=66. | Baseline to Week 102 (end of Long-term Period) | 
| Number of Participants With Elevated Levels of Liver Enzymes on Laboratory Test Results (Short-term and Long-term Periods) | Data after rescue was included. AST=aspartate aminotransferase; ALT=alanine aminotransferase; ALP=alkaline phosphatase. Group 2 (patients with enrollment baseline HbA1c >10% and ≤2%) was considered an exploratory group, included to obtain initial efficacy and safety data for these patients. No comparator arm was included. Thus, only key safety and efficacy analyses were performed for Group 2. | Day 1 to Week 102 (end of Long-term Period) | 
| Number of Participants With Changes From Baseline in Electrocardiogram (ECG) Findings (Last Observation Carried Forward {LOCF]) | 12-Lead ECGs were performed at entry into lead-in period Day -7 visit and Week 24/end of treatment visit (LOCF) on participants who were supine. ECGs were assessed by the investigator. Baseline was Day -7 for this parameter, and data after rescue were included.The Week 102 value is the last observation, regardless of rescue prior to Week 102 if no Week 102 measurement was available. Group 2 (patients with enrollment baseline HbA1c >10% and ≤2%) was considered an exploratory group, included to obtain initial efficacy and safety data for these patients. No comparator arm was included. Thus, only key safety and efficacy analyses were performed for Group 2. | Baseline to Week 24 (end of Short-term Period) |