Safety and Efficacy of Dapagliflozin as Monotherapy in Subjects With Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of this clinical research study is to learn if BMS-512148 (Dapagliflozin) can help reduce the blood sugar levels in subjects with Type 2 Diabetes who are not well controlled on diet and exercise alone. The safety of this treatment will also be studied

Official Title
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A Multicenter, Randomized, Double-Blind, Placebo Controlled, Parallel Group, Phase III 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 Mellitus

Intervention / Treatment
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* Drug: Dapagliflozin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and females, ≥18 to ≤77 years old, with type 2 diabetes mellitus Subjects must have central laboratory pre-randomization A1C ≥7.0 and ≤ 10.0% 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) >3* 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 Currently unstable or serious cardiovascular, renal, hepatic, hematological, oncological, endocrine, psychiatric, or rheumatic diseases

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: Dapagliflozin 1 mg<br>Dapagliflozin: 1 mg | Drug: Dapagliflozin<br>* Tablets, Oral, Once Daily, Up to 24 weeks<br>* Other names: Farxiga™;|
| Experimental: Dapagliflozin 2.5 mg<br>Dapagliflozin: 2.5 mg | Drug: Dapagliflozin<br>* Tablets, Oral, Once Daily, Up to 24 weeks<br>* Other names: Farxiga™;|
| Experimental: Dapagliflozin 5 mg<br>Dapagliflozin: 5 mg | Drug: Dapagliflozin<br>* Tablets, Oral, Once Daily, Up to 24 weeks<br>* Other names: Farxiga™;|
| Placebo Comparator: Placebo<br>Placebo: 0 mg | Drug: Placebo<br>* Tablets, Oral, Once Daily, Up to 24 weeks<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 (LOCF) - All Randomized 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 was determined(LOCF). HbA1c was measured as percent of hemoglobin by a central laboratory. Data after rescue medication (metformin) 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 values were obtained at enrollment, lead-in, and at Day 1, Weeks 4, 8, 12, 16, 20, and 24 in the double-blind period. | Baseline (Day 1), Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adjusted Mean Change From Baseline in Total Body Weight at Week 24 (LOCF) - Randomized Participants | Adjusted mean change in total body weight from baseline at Week 24, or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available LOCF was determined. Data after rescue medication (metformin) 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) at qualification, lead-in, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, and 24 during double-blind period. | Baseline (Day 1), Week 24 | 
| Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24 (LOCF) - Randomized Participants | Adjusted mean change in fasting plasma glucose (FPG) from baseline at Week 24 (LOCF) was determined. Data after rescue medication (metformin) was excluded from this analysis. FPG was measured as milligrams per deciliter (mg/dL) by a central laboratory at qualification, lead-in, Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, and 24 during double-blind period. 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 (Day 1), Week 24 | 
| Adjusted Mean Change From Baseline in Effect on 2-hour Post Liquid Meal Glucose at Week 24 (LOCF) - Randomized Participants | Liquid meal tolerance tests (MTTs) were scheduled to occur at Day 1 visit (MTT was to be completed 2 hours prior to first dose of treatment) and at Week 24 / End of treatment visit, or Rescue visit for participants meeting criteria for rescue due to lack of glycemic control. At Week 24, study treatment was given 1 hour before MTT was administered. Participant fasted for at least 10 hours (h) prior to both visits and abstained from tobacco, alcohol, and caffeine for 24 h prior to the MTT. The liquid meal supplement was administered over 10 minutes, starting immediately after Time 0 blood sample was drawn. Blood samples for post-liquid meal Glucose were obtained at 30, 60, 120, and 180 minutes after ingesting the liquid supplement. Glucose was measured in 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 double-blind study medication. | Baseline (Day 1), Week 24 | 
| Adjusted Percentage of Participants Achieving a Therapeutic Glycemic Response at Week 24 (LOCF) - Randomized 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 (metformin) was excluded from this analysis. HbA1c was measured as a percent of hemoglobin. | Baseline (Day 1), Week 24 | 
| Adjusted Mean Change From Baseline in Waist Circumference at Week 24 (LOCF) - Randomization Participants | Adjusted mean waist circumference values from baseline to Week 24 (or the last post-baseline measurement prior to Week 24 if no Week 24 assessment was available, last observation carried forward, (LOCF) was determined. Data after rescue medication (metformin) was excluded from this analysis. Waist circumference was measured centimeters (cm) and obtained at lead-in, Day 1, and Week 24 of the double-blind period. 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 (Day 1), Week 24 | 
| Number of Participants With Deaths, Serious AEs (SAEs), Adverse Events (AEs), 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. Baseline to last dose plus 4 days for AEs, plus 30 days for SAEs. 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 12.1. Data after rescue included for all AEs of special interest except hypoglycemia; hypoglycemia AEs were prior to 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, Including Data After Rescue - Treated Participants | Blood pressure values were obtained on Day 1, Weeks 1, 2, 4, 8, 12, 16, 20, and 24 in the double blind period, after the participant was seated for quietly for 5 minutes; the same arm (right or left) was used consistently through out the study. Measurements were taken at least 10 hours after the last ingestion of caffeine, alcohol, or nicotine. Blood pressure was 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. | Baseline (Day 1), Week 24 | 
| Mean Change From Baseline in Seated Heart Rate at Week 24 - Treated Participants | Heart rate values were obtained after the participant was seated for quietly for 5 minutes; the same arm (right or left) was used consistently through out the study. Measurements were taken at least 10 hours after the last ingestion of caffeine, alcohol, or nicotine. 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. | Baseline (Day 1), Week 24 | 
| Number of Participants With Normal or Abnormal Electrocardiogram Summary Tracing at Week 24 (LOCF) - Treated Participants | 12-Lead electrocardiograms (ECGs) were performed at Day -14 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 -14 for this parameter. | Week 24 | 
| Number of Participants With Marked Laboratory Abnormalities in 24 Week Double Blind Treatment Period - Treated Participants | Safety laboratory measurements were obtained at Day 1, Weeks 1, 2, 4, 8, 12, 20, and 24 in the double blind Period. 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 was also included. Abbreviations; Pretreatment (PreRX); grams per deciliter (g/dL); upper limit of normal (ULN); milliequivalent per liter (mEq/L); greater than (>) less than (<); Units per liter (U/L), alanine aminotransferase (ALT); aspartate aminotransferase (AST); alkaline phosphatase (ALP); 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); BUN (>60 mg/dL) or Urea >21.4 mmol/L; creatinine (>=1.5*preRX, >=2.5 mg/dL); AST and ALT >3*ULN; bilirubin >1.5*ULN; ALP >1.5*ULN. | Baseline to Week 24/end of treatment plus 4 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