BMS - Safety, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Dapagliflozin in Type 1 Diabetes
- Conditions
- Type 1 Diabetes Mellitus
- Interventions
- Registration Number
- NCT01498185
- Lead Sponsor
- AstraZeneca
- Brief Summary
To obtain safety and tolerability information in patients with type 1 diabetes where Dapagliflozin is added on to Insulin (for 14 days)
- Detailed Description
Study Classification : Safety, Pharmacokinetics and Pharmacodynamics
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 171
- Type 1 diabetes with central lab Glycosylated hemoglobin (A1C) ≥ 7.0% and ≤ 10.0%
- Insulin use for at least 12 months and initiation immediately after diagnosis of diabetes
- Method of Insulin administration [multiple daily injections (MDI) or continuous subcutaneous Insulin infusion (CSII)] stable ≥ 3 months
- Stable basal Insulin dose ≥ 2 weeks
- Ages 18 to 65 years
- Central laboratory C-peptide value of < 0.7 ng/mL
- Body mass index (BMI) 18.5 to 35.0 kg/m2
- History of type 2 diabetes mellitus (T2DM), maturity onset diabetes of young (MODY), pancreatic surgery or chronic pancreatitis
- Oral hypoglycemic agents
- History of diabetes ketoacidosis (DKA) within 24 weeks
- History of hospital admission for glycemic control within 6 months
- Frequent episodes of hypoglycemia (2 unexplained within 3 months) or hypoglycemic unawareness
- Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) or Serum total bilirubin > 2X Upper limit of normal (ULN)
- Abnormal Free T4 [if screening Thyroid Stimulating Hormone (TSH) abnormal]
- Estimated glomerular filtration rate (eGFR) Modification of Diet in Renal Disease (MDRD) formula ≤ 60 mL/min/1.73m2
- Cardiovascular (CV)/Vascular Diseases within 6 months
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 1: Dapagliflozin (1 mg) Dapagliflozin - Arm 3: Dapagliflozin (5 mg) Dapagliflozin - Arm 4: Dapagliflozin (10 mg) Dapagliflozin - Arm 5: Placebo matching Dapagliflozin Placebo matching Dapagliflozin - Arm 2: Dapagliflozin (2.5 mg) Dapagliflozin -
- Primary Outcome Measures
Name Time Method Mean Change From Baseline in 7-Point Glucose Monitoring (7-PGM) at Day 7 From Baseline to Day 7 7-PGM was measured as milligrams per deciliter (mg/dL) by a central laboratory. Baseline was defined as the assessment on Day -1, prior to the start date and time of the first dose of the double-blind study medication. 7-PGM included the average of all available glucose values before and 2-hour (hr) after each meal (breakfast, lunch, dinner) as well as bedtime. Measurements were on Day -1, and Day 7 in the double-blind period.
- Secondary Outcome Measures
Name Time Method Dapagliflozin Pharmacokinetic Parameters on Day 7 - Area Under the Concentration-Time Curve in One Dosing Interval (AUC[TAU]) Day 7 (0 hr to 24 hr post dose) Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The concentrations below the lower limit of quantitation (\<LLOQ) were set as "missing" for the calculation of PK parameters as well as summary statistics. AUC\[TAU\], was calculated by a mixture of logand linear-trapezoidal summations.
Dapagliflozin Pharmacokinetic Parameters on Day 7 - Maximum Observed Plasma Concentration (Cmax) Day 7 (0 hr to 24 hr post dose) Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The Cmax was recorded directly from experimental observations.
Dapagliflozin Pharmacokinetic Parameters on Day 7 - Time of Maximum Observed Plasma Concentration (Tmax) Day 7 (0 hr to 24 hr post dose) Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The Tmax was recorded directly from experimental observations.
Dapagliflozin 3-O-glucuronide Pharmacokinetic Parameters on Day 7 - Time of Maximum Observed Plasma Concentration (Tmax) Day 7 (0 hr to 24 hr post dose) Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The Tmax was recorded directly from experimental observations.
Dapagliflozin 3-O-glucuronide Pharmacokinetic Parameters on Day 7 - Area Under the Concentration-Time Curve in One Dosing Interval (AUC[TAU]) Day 7 (0 hr to 24 hr post dose) Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The concentrations below the lower limit of quantitation (\<LLOQ) were set as "missing" for the calculation of PK parameters as well as summary statistics. AUC\[TAU\], was calculated by a mixture of logand linear-trapezoidal summations.
Dapagliflozin 3-O-glucuronide Pharmacokinetic Parameters on Day 7 - Maximum Observed Plasma Concentration (Cmax) Day 7 (0 hr to 24 hr post dose) Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The Cmax was recorded directly from experimental observations.
Pharmacokinetic Parameters on Day 7 - Ratio of Metabolite (RM) to Parent AUC[TAU] Day 7 (0 hr to 24 hr post dose) Serial blood samples were collected predose 0 hr, and hr 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 in the double-blind period. Individual subject PK parameter values were derived by non-compartmental methods by a validated PK analysis program, Kinetica®. Actual sampling times were used for PK calculations and nominal times were used for generation of mean plasma concentration-time plots and summaries. Pre-dose sample collection times were changed from negative numbers (based on elapsed time to dose) to zero for the purpose of calculating PK parameters. The concentrations below the lower limit of quantitation (\<LLOQ) were set as "missing" for the calculation of PK parameters as well as summary statistics. MR was calculated as the ratio of metabolite to parent AUC(TAU), corrected for molecular weights of dapagliflozin and dapagliflozin 3-O-glucuronide (408.82 and 584.99, respectively).
Trial Locations
- Locations (12)
La Biomed Research Inst. At Harbor Ucla Med Ctr.
🇺🇸Torrance, California, United States
Va San Diego Healthcare System
🇺🇸San Diego, California, United States
Vince And Associates Clinical Research
🇺🇸Overland Park, Kansas, United States
Central Kentucky Research Associates, Inc.
🇺🇸Lexington, Kentucky, United States
Jasper Clinic, Inc.
🇺🇸Kalamazoo, Michigan, United States
Profil Institute For Clinical Research, Inc.
🇺🇸Chula Vista, California, United States
Compass Research Phase 1, Llc
🇺🇸Orlando, Florida, United States
Progressive Medical Research
🇺🇸Port Orange, Florida, United States
Kansas City University Of Medicine And Biosciences
🇺🇸Kansas City, Missouri, United States
Dallas Diabetes & Endocrine Center
🇺🇸Dallas, Texas, United States
Louisiana Research Associates, Inc.
🇺🇸New Orleans, Louisiana, United States
Regional Medical Clinic-Endocrinology
🇺🇸Rapid City, South Dakota, United States