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

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

To obtain safety and tolerability information in patients with type 1 diabetes where Dapagliflozin is added on to Insulin (for 14 days)

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Drug: Dapagliflozin; Drug: Placebo matching Dapagliflozin

Detailed Description

Study Classification : Safety, Pharmacokinetics and Pharmacodynamics

• Study Type: Interventional
• Enrollment (Actual): 171
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Chula Vista, California, United States, 91911
      • Profil Institute for Clinical Research, Inc.
    • San Diego, California, United States, 92161
      • VA San Diego Healthcare System
    • Torrance, California, United States, 90502
      • La Biomed Research Inst. At Harbor Ucla Med Ctr.
  • Florida
    • Orlando, Florida, United States, 32806
      • Compass Research Phase 1, LLC
    • Port Orange, Florida, United States, 32127
      • Progressive Medical Research
  • Kansas
    • Overland Park, Kansas, United States, 66212
      • Vince and Associates Clinical Research
  • Kentucky
    • Lexington, Kentucky, United States, 40509
      • Central Kentucky Research Associates, Inc.
  • Louisiana
    • New Orleans, Louisiana, United States, 70114
      • Louisiana Research Associates, Inc.
  • Michigan
    • Kalamazoo, Michigan, United States, 49007
      • Jasper Clinic, Inc.
  • Missouri
    • Kansas City, Missouri, United States, 64106
      • Kansas City University Of Medicine And Biosciences
  • South Dakota
    • Rapid City, South Dakota, United States, 57701
      • Regional Medical Clinic-Endocrinology
  • Texas
    • Dallas, Texas, United States, 75230
      • Dallas Diabetes & Endocrine Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change From Baseline in 7-Point Glucose Monitoring (7-PGM) at 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.	From Baseline to Day 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dapagliflozin Pharmacokinetic Parameters on Day 7 - Maximum Observed Plasma Concentration (Cmax)	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.	Day 7 (0 hr to 24 hr post dose)
Dapagliflozin Pharmacokinetic Parameters on Day 7 - Time of Maximum Observed Plasma Concentration (Tmax)	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.	Day 7 (0 hr to 24 hr post dose)
Dapagliflozin Pharmacokinetic Parameters on Day 7 - Area Under the Concentration-Time Curve in One Dosing Interval (AUC[TAU])	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.	Day 7 (0 hr to 24 hr post dose)
Dapagliflozin 3-O-glucuronide Pharmacokinetic Parameters on Day 7 - Maximum Observed Plasma Concentration (Cmax)	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.	Day 7 (0 hr to 24 hr post dose)
Dapagliflozin 3-O-glucuronide Pharmacokinetic Parameters on Day 7 - Time of Maximum Observed Plasma Concentration (Tmax)	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.	Day 7 (0 hr to 24 hr post dose)
Dapagliflozin 3-O-glucuronide Pharmacokinetic Parameters on Day 7 - Area Under the Concentration-Time Curve in One Dosing Interval (AUC[TAU])	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.	Day 7 (0 hr to 24 hr post dose)
Pharmacokinetic Parameters on Day 7 - Ratio of Metabolite (RM) to Parent AUC[TAU]	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).	Day 7 (0 hr to 24 hr post dose)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Astra Zeneca, Bristol-Myers Squibb

Publications and helpful links

General Publications

• Melin J, Tang W, Rekic D, Hamren B, Penland RC, Boulton DW, Parkinson J. Dapagliflozin Pharmacokinetics Is Similar in Adults With Type 1 and Type 2 Diabetes Mellitus. J Clin Pharmacol. 2022 Oct;62(10):1227-1235. doi: 10.1002/jcph.2062. Epub 2022 May 2.
• Henry RR, Rosenstock J, Edelman S, Mudaliar S, Chalamandaris AG, Kasichayanula S, Bogle A, Iqbal N, List J, Griffen SC. Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: a randomized, double-blind, placebo-controlled pilot study. Diabetes Care. 2015 Mar;38(3):412-9. doi: 10.2337/dc13-2955. Epub 2014 Sep 30.

Helpful Links

• MB102072_Clinical_Study_Protocol

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): October 1, 2012
• Study Completion (Actual): October 1, 2012

Study Registration Dates

• First Submitted: December 21, 2011
• First Submitted That Met QC Criteria: December 21, 2011
• First Posted (Estimate): December 23, 2011

Study Record Updates

• Last Update Posted (Actual): February 10, 2017
• Last Update Submitted That Met QC Criteria: December 20, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: MB102-072