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BMS - Safety, Pharmacokinetics (PK) and Pharmacodynamics (PD) of Dapagliflozin in Type 1 Diabetes

This study has been completed.
Sponsor:
Collaborator:
Astra Zeneca, Bristol-Myers Squibb
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01498185
First received: December 21, 2011
Last updated: December 20, 2016
Last verified: December 2016
  Purpose
To obtain safety and tolerability information in patients with type 1 diabetes where Dapagliflozin is added on to Insulin (for 14 days)

Condition Intervention Phase
Type 1 Diabetes Mellitus Drug: Dapagliflozin Drug: Placebo matching Dapagliflozin Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-controlled, Parallel Group, Phase 2 Trial to Explore the Safety, Pharmacokinetics and Pharmacodynamics of Dapagliflozin as an Add-on to Insulin Therapy in Subjects With Type 1 Diabetes Mellitus

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Mean Change From Baseline in 7-Point Glucose Monitoring (7-PGM) at Day 7 [ Time Frame: 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:
  • Dapagliflozin Pharmacokinetic Parameters on Day 7 - Maximum Observed Plasma Concentration (Cmax) [ Time Frame: 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) [ Time Frame: 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 Pharmacokinetic Parameters on Day 7 - Area Under the Concentration-Time Curve in One Dosing Interval (AUC[TAU]) [ Time Frame: 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) [ Time Frame: 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 3-O-glucuronide Pharmacokinetic Parameters on Day 7 - Time of Maximum Observed Plasma Concentration (Tmax) [ Time Frame: 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]) [ Time Frame: 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.

  • Pharmacokinetic Parameters on Day 7 - Ratio of Metabolite (RM) to Parent AUC[TAU] [ Time Frame: 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).


Enrollment: 171
Study Start Date: February 2012
Study Completion Date: October 2012
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1: Dapagliflozin (1 mg) Drug: Dapagliflozin
Tablets, Oral, 1 mg, Once daily, 14 days
Experimental: Arm 2: Dapagliflozin (2.5 mg) Drug: Dapagliflozin
Tablets, Oral, 1 mg, Once daily, 14 days
Experimental: Arm 3: Dapagliflozin (5 mg) Drug: Dapagliflozin
Tablets, Oral, 1 mg, Once daily, 14 days
Experimental: Arm 4: Dapagliflozin (10 mg) Drug: Dapagliflozin
Tablets, Oral, 1 mg, Once daily, 14 days
Experimental: Arm 5: Placebo matching Dapagliflozin Drug: Placebo matching Dapagliflozin
Tablets, Oral, 0 mg, Once daily, 14 days

Detailed Description:
Study Classification : Safety, Pharmacokinetics and Pharmacodynamics
  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01498185

Locations
United States, California
Profil Institute For Clinical Research, Inc.
Chula Vista, California, United States, 91911
Va San Diego Healthcare System
San Diego, California, United States, 92161
La Biomed Research Inst. At Harbor Ucla Med Ctr.
Torrance, California, United States, 90502
United States, Florida
Compass Research Phase 1, Llc
Orlando, Florida, United States, 32806
Progressive Medical Research
Port Orange, Florida, United States, 32127
United States, Kansas
Vince And Associates Clinical Research
Overland Park, Kansas, United States, 66212
United States, Kentucky
Central Kentucky Research Associates, Inc.
Lexington, Kentucky, United States, 40509
United States, Louisiana
Louisiana Research Associates, Inc.
New Orleans, Louisiana, United States, 70114
United States, Michigan
Jasper Clinic, Inc.
Kalamazoo, Michigan, United States, 49007
United States, Missouri
Kansas City University Of Medicine And Biosciences
Kansas City, Missouri, United States, 64106
United States, South Dakota
Regional Medical Clinic-Endocrinology
Rapid City, South Dakota, United States, 57701
United States, Texas
Dallas Diabetes & Endocrine Center
Dallas, Texas, United States, 75230
Sponsors and Collaborators
AstraZeneca
Astra Zeneca, Bristol-Myers Squibb
Investigators
Study Director: Bristol-Myers Squibb Bristol-Myers Squibb
  More Information

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01498185     History of Changes
Other Study ID Numbers: MB102-072
Study First Received: December 21, 2011
Results First Received: October 7, 2016
Last Updated: December 20, 2016

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases

ClinicalTrials.gov processed this record on September 21, 2017