Safety and Efficacy of Dapagliflozin in Triple Therapy to Treat Subjects With Type 2 Diabetes

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT01646320
First received: July 18, 2012
Last updated: March 9, 2016
Last verified: March 2016
  Purpose
The purpose of this study is to learn if BMS-512148 (Dapagliflozin) as part of a triple combination therapy can improve (decrease) hemoglobin A1c in patients with type 2 diabetes after 24 weeks of treatment compared to a 2 drug oral antidiabetic therapy. The safety of this treatment will also be studied.

Condition Intervention Phase
Type 2 Diabetes
Drug: Dapagliflozin
Drug: Placebo matching with Dapagliflozin
Drug: Saxagliptin
Drug: Metformin immediate release (IR)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Therapy With Dapagliflozin Added to Saxagliptin in Combination With Metformin Compared to Therapy With Placebo Added to Saxagliptin in Combination With Metformin in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control on Metformin and Saxagliptin

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24 [ Time Frame: From Baseline to Week 24 ] [ Designated as safety issue: No ]
    HbA1c was measured as percent of hemoglobin 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. HbA1c measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 6, 12, 18, and 24 in the double-blind period.


Secondary Outcome Measures:
  • Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24 [ Time Frame: From Baseline to Week 24 ] [ Designated as safety issue: No ]
    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. FPG measurements were obtained during the qualification and lead-in periods and on Day 1 and Weeks 6, 12, 18, and 24 in the double-blind period

  • Adjusted Mean Change From Baseline in 120-minute Postprandial Glucose (PPG) at Week 24 [ Time Frame: From Baseline to Week 24 ] [ Designated as safety issue: No ]
    2-hour postprandial glucose (PPG) from a liquid meal tolerance test (2-h MTT) Subject must be fasted for at least 8 hrs prior to the MTT.

  • Adjusted Mean Change From Baseline in Body Weight at Week 24 [ Time Frame: From baseline to Week 24 ] [ Designated as safety issue: No ]
    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. Body weights were measured during the qualification and lead-in periods and on Day 1 and Weeks 6, 12, 18, and 24 in the double-blind period.

  • Percentage of Subjects Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF]) [ Time Frame: From baseline to week 24 ] [ Designated as safety issue: No ]
    Percent adjusted for baseline HbA1c. Therapeutic glycemic response is defined as HbA1c <7.0%. Data after rescue medication was excluded from this analysis.


Enrollment: 320
Study Start Date: September 2012
Study Completion Date: February 2015
Primary Completion Date: August 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm1: Dapagliflozin (10 mg) + Saxagliptin + Metformin IR Drug: Dapagliflozin
Tablets, Oral, 10 mg, Once daily, Up to 52 weeks
Drug: Saxagliptin
Tablets, Oral, 5 mg, Once daily, Up to 52 weeks
Other Name: Onglyza
Drug: Metformin immediate release (IR)
Tablets, Oral, ≥ 1500 mg, Twice daily, Up to 52 weeks
Experimental: Arm 2: Placebo + Saxagliptin + Metformin IR Drug: Placebo matching with Dapagliflozin
Tablets, Oral, 0 mg, Once daily, Up to 52 weeks
Drug: Saxagliptin
Tablets, Oral, 5 mg, Once daily, Up to 52 weeks
Other Name: Onglyza
Drug: Metformin immediate release (IR)
Tablets, Oral, ≥ 1500 mg, Twice daily, Up to 52 weeks

Detailed Description:
Prior to randomization, all eligible subjects will receive open-label treatment with Saxagliptin 5mg and Metformin IR during the 16-week open-label treatment period.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria

  1. Signed Written Informed Consent

    1. Subjects must be willing and able to give signed and dated written informed consent.
  2. Target Population

    For inclusion into Stratum A:

    i) Subjects with T2DM with inadequate glycemic control, defined as central laboratory HbA1c ≥ 8.0 and ≤ 11.5% obtained at the screening visit (ie Week -18 visit), on stable metformin therapy alone for at least 8 weeks prior to screening visit at a dose ≥ 1500 mg per day

    For inclusion into Stratum B:

    ii) Subjects with T2DM with inadequate glycemic control, and HbA1c ≥ 7.5 and ≤ 10.5% obtained at the screening visit and on stable metformin therapy at a dose ≥ 1500 mg per day AND a DPP4 inhibitor at the maximum approved dose for at least 8 weeks prior to screening visit.

    b) C-peptide ≥ 1.0 ng/mL (0.34 nmol/L) at screening visit. c) BMI ≤ 45.0 kg/m2 at the screening visit.

  3. Age and Reproductive Status

    1. Men and women, aged ≥ 18 years old at time of screening visit.
    2. Women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized.
    3. WOCBP must have a negative serum or urine pregnancy test within 24 hours prior to the start of investigational product.
    4. Women must not be breastfeeding
    5. Sexually active fertile men must use highly effective birth control if their partners are WOCBP.

Exclusion Criteria

  1. Target Disease Exceptions

    1. History of diabetes insipidus
    2. Symptoms of poorly controlled diabetes that would preclude participation in this trial including but not limited to marked polyuria and polydipsia with greater than 10% weight loss during the three months prior to screening, or other signs and symptoms.
    3. History of diabetic ketoacidosis or hyperosmolar nonketotic coma.
  2. Medical History and Concurrent Diseases

    1. History of bariatric surgery or lap-band procedure within 12 months prior to screening.
    2. Any unstable endocrine, psychiatric or rheumatic disorders as judged by the Investigator.
    3. Subject who, in the judgment of the investigator, may be at risk for dehydration or volume depletion that may affect the interpretation of efficacy or safety data and concomitant use of loop diuretics in countries where this is not recognized in the Dapagliflozin label.
    4. Subject is currently abusing alcohol or other drugs or has done so within the last 6 months.

      Acute Vascular Event:

    5. Uncontrolled hypertension defined as systolic blood pressure (SBP) ≥ 160 mmHg and/or diastolic blood pressure (DBP) ≥ 100 mmHg.
    6. Cardiovascular Disease within 3 months of the screening visit [ie myocardial infarction, cardiac surgery or revascularization (CABG/PTCA), unstable angina, stroke or transient ischemic attack (TIA)].
    7. Congestive heart failure as New York Association (NYHA) class IV, unstable or acute congestive heart failure.

      Renal Diseases:

    8. Moderate or severe impairment of renal function [defined as eGFR < 60 mL/min/1.73m2 (estimated by MDRD) or serum creatinine (Scr) ≥ 1.5 mg/dL in males or ≥ 1.4 mg/dL in females.]
    9. Conditions of congenital renal glucosuria

      Hepatic Diseases:

    10. Significant hepatic disease, including, but not limited to, chronic active hepatitis and/or severe hepatic insufficiency, including subjects with ALT and/or AST > 3x ULN and or Total Bilirubin > 2.5 x ULN.

      Hematological and Oncological Disease/Conditions:

    11. History of hemoglobinopathy, with the exception of sickle cell trait (SA) or thalassemia minor; or chronic or recurrent hemolysis.
    12. Malignancy within 5 years of the screening visit (with the exception of treated basal cell or treated squamous cell carcinoma)
    13. Known immunocompromised status, including but not limited to, individuals who have undergone organ transplantation or who are positive for the human immunodeficiency virus.
    14. 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 months prior to the screening visit.

      Prohibited treatment and therapies:

    15. Administration of any antihyperglycemic therapy, other than metformin and DPP4's, for more than 14 days (consecutive or not) during the 12 weeks prior to screening, as well as previous exposure to DPP4 or SGLT-2 inhibitor in any DPP4 or SGLT-2 inhibitor trial is an exclusion criterion.
    16. Current treatment with potent cytochrome P450 3A4/5 inhibitors (in countries where dose adjustment would be required by the dapagliflozin label).
    17. Administration of any other investigational drug or participation in any interventional clinical studies within 30 days of planned screening to this study. Subjects who failed to satisfy all eligibility criteria at screening and did not enter the lead-in or open-label period in CV181-168 or CV181-169 studies specifically, do not need to wait 30 days.
  3. Physical and Laboratory Test Findings

    a) Hemoglobin ≤ 11.0 g/dL (110 g/L) for men; hemoglobin ≤ 10.0 g/dL (100 g/L) for women

    b) Presence of hematuria:

    i) For male subjects being considered for Stratum A: microscopic hematuria present at Week -18 or Week -16 AND no common cause that can be confirmed is exclusionary. Male subjects with a confirmed common cause can be entered into the open-label phase with a documented negative result for hematuria microscopic urinalysis performed by the central laboratory.

    ii) For male subjects being considered for Stratum B: microscopic hematuria present at Week -10 or Week -8 AND no common cause that can be confirmed is exclusionary. Male subjects with a confirmed common cause can be entered into the open-label phase with a documented negative result for hematuria microscopic urinalysis performed by the central laboratory.

    NOTE: Female sub}ects with hematuria can be entered into the open-label phase and be randomized, but should be investigated according to local standards and best clinical practices. (See Appendix 3)

    c) Other central laboratory test findings:

    − Abnormal free T4 values. Abnormal thyroid stimulating hormone (TSH) value at screening will be further evaluated by free T4. Sub}ects with abnormal free T4 values will be excluded.

    • Positive for hepatitis B surface antigen
    • Positive for anti-hepatitis C virus antibody
  4. Allergies and Adverse Drug Reaction

    a) Subjects who have contraindications to therapy as outlined in the dapagliflozin and saxagliptin Investigator Brochure, the local dapagliflozin or saxagliptin package insert or the local metformin package insert, including current treatment with potent cytochrome P450 3A4/5 inhibitors (in countries where dose adjustment would be required by the local Onglyza (saxagliptin) label.

  5. Sex and Reproductive Status

    a) Women who are pregnant

  6. Other Exclusion Criteria

    1. Prisoners or subjects who are involuntarily incarcerated
    2. Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
    3. Subjects on a commercial weight loss program with ongoing weight loss, or on an intensive exercise program.
    4. Employee of BMS, AstraZeneca (AZ), or their relatives.
    5. Subject with any condition which, in the judgment of the Investigator, may render the subject unable to complete the study or which may pose a significant risk to the subject.
    6. Subject is a participating investigator, study coordinator, employee of an investigator or immediate family member of any of the aforementioned.

      Open Label Treatment Period

      Note: Enrollment of subjects into the open-label (Stratum A) treatment period, beginning eee -16 of the study with HbA1c values at the lower bound (≥ 8.0% and ≤ 9.0%) and Enrollment of subjects into the open-label (Stratum B) eee -8, of the study with HbA1c values at the lower bound (≥ 7.5% and ≤ 8.5%) will be limited to approximately 50% of the total number of subjects randomized.

      • For subject in Stratum A:

      • At Week -10 and Week -2 a FPG qualification check will be performed. Subjects with a central laboratory FPG value meeting > 270 mg/dL will be scheduled for a follow-up visit (within 3 - 5 days) to obtain a second central laboratory FPG value. If the mean of the originally scheduled central laboratory FPG and the repeat central laboratory FPG value is > 270 mg/dL, the subject cannot be randomized and must be discontinued.

        • For subjects in Stratum B:
      • At Week -2 a FPG qualification check will be performed. Subjects with a central laboratory FPG value meeting > 270 mg/dL will be scheduled for a follow-up visit (within 3 - 5 days) to obtain a second central laboratory FPG value. If the mean of the originally scheduled central laboratory FPG and the repeat central laboratory FPG value is > 270 mg/dL, the subject cannot be randomized and must be discontinued

      Double Blind Treatment Period

      Inclusion criteria:

      • For Stratum A AND Stratum B:

      − Subjects with T2DM with inadequate glycemic control, defined as central laboratory HbA1c ≥ 7.0 and ≤ 10.5% obtained at the Week -2 visit of the open-label treatment period.

  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: NCT01646320

  Hide Study Locations
Locations
United States, Alabama
University Of Alabama At Birmingham
Birmingham, Alabama, United States, 35294
United States, Arizona
Clinical Research Advantage Inc/Desert Clinical Research Llc
Mesa, Arizona, United States, 85213
Clinical Research Advantage, Inc.
Phoenix, Arizona, United States, 85018
Elite Clinical Studies, Llc
Phoenix, Arizona, United States, 85018
United States, Arkansas
Arkansas Clinical Research
Little Rock, Arkansas, United States, 72205
United States, California
Torrance Clinical Research Institute Inc.
Lomita, California, United States, 90717
National Research Institute
Los Angeles, California, United States, 90057
Randall G. Shue, Do, Inc.
Los Angeles, California, United States, 90023
Diabetes Medical Center Of California
Northridge, California, United States, 91325
Cassidy Medical Group/Clinical Research Advantage
Vista, California, United States, 92083
United States, Florida
Palm Springs Research Institute
Hialeah, Florida, United States, 33012
Fpa Clinical Research
Kissimmee, Florida, United States, 34741
International Research Associates, Llc
Miami, Florida, United States, 33183
Omega Research Consultants, Llc
Orlando, Florida, United States, 32804
Compass Research East, Llc
Oviedo, Florida, United States, 32765
Palm Harbor Medical Associates
Palm Harbor, Florida, United States, 34684
United States, Illinois
Cedar Crosse Research Center
Chicago, Illinois, United States, 60607
United States, Indiana
Clinical Research Advantage
Evansville, Indiana, United States, 47714
United States, Michigan
Associated Internal Medicine Specialists
Battle Creek, Michigan, United States, 49015
United States, Mississippi
Jackson Clinic
Rolling Fork, Mississippi, United States, 39159
United States, New Jersey
Premier Research
Trenton, New Jersey, United States, 08611
United States, North Carolina
Metrolina Internal Medicine
Charlotte, North Carolina, United States, 28204
United States, Ohio
Sterling Research Grp, Ltd.
Cincinnati, Ohio, United States, 45246
United States, Texas
Endocrine Associates
Houston, Texas, United States, 77004
Sam Clinical Research Center
San Antonio, Texas, United States, 78229
United States, Virginia
Tidewater Integrated Medical Research
Virginia Beach, Virginia, United States, 23454
Czech Republic
Local Institution
Broumov, Czech Republic, 550 01
Local Institution
Pardubice, Czech Republic, 530 02
Local Institution
Praha 10, Czech Republic, 100 00
Local Institution
Praha 4, Czech Republic, 149 00
Local Institution
Pribram V, Czech Republic, 261 95
Mexico
Local Institution
Guadalajara, Jalisco, Mexico, 44670
Local Institution
Zapopan, Jalisco, Mexico, 45116
Local Institution
Zapopan, Jalisco, Mexico, 45200
Local Institution
Monterrey, Nuevo Leon, Mexico, 64060
Local Institution
Monterrey, Nuevo Leon, Mexico, 64460
Local Institution
Aguascalientes, Mexico, 20127
Poland
Local Institution
Bialystok, Poland, 15-435
Local Institution
Krakow, Poland, 30-015
Local Institution
Ruda Slaska, Poland, 41-709
Local Institution
Warszawa, Poland, 00-465
Local Institution
Warszawa, Poland, 01-868
Local Institution
Warszawa, Poland, 03-003
Local Institution
Zory, Poland, 44-240
Puerto Rico
Clinical Research Puerto Rico
San Juan, Puerto Rico, 00909
Romania
Local Institution
Bucharest, Romania, 010825
Local Institution
Bucharest, Romania, 070208
Local Institution
Constanta, Romania, 900591
Local Institution
Craiova, Romania, 200349
Local Institution
Galati, Romania, 800098
Local Institution
Ploiesti, Romania, 100097
Russian Federation
Local Institution
Kursk, Russian Federation, 305035
Local Institution
Moscow, Russian Federation, 119034
Local Institution
Saint-petersburg, Russian Federation, 194044
Local Institution
St. Petersburg, Russian Federation, 197136
Local Institution
St. Petersburg, Russian Federation, 194156
Local Institution
St. Petersburg, Russian Federation, 195257
Local Institution
St. Petersburg, Russian Federation, 194044
Local Institution
St.petersburg, Russian Federation, 195112
Local Institution
St.petersburg, Russian Federation, 197022
Local Institution
Yaroslaval, Russian Federation, 150062
United Kingdom
Local Institution
Portsmouth, Hants, United Kingdom, PO3 6LY
Local Institution
Newport, Isle of Wight, United Kingdom, PO30 5TG
Local Institution
Liverpool, Merseyside, United Kingdom, L7 8XP
Local Institution
Chippenham, Wiltshire, United Kingdom, SN15 1HP
Local Institution
Bedfordshire, United Kingdom, SG19 3JR
Local Institution
London, United Kingdom, W6 7HY
Sponsors and Collaborators
AstraZeneca
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: NCT01646320     History of Changes
Other Study ID Numbers: MB102-129  2011-006324-20 
Study First Received: July 18, 2012
Results First Received: March 9, 2016
Last Updated: March 9, 2016
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board
Canada: Health Canada
Mexico: Federal Commission for Protection Against Health Risks

Additional relevant MeSH terms:
Diabetes Mellitus, Type 2
Diabetes Mellitus
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Metformin
Saxagliptin
Dipeptidyl-Peptidase IV Inhibitors
Enzyme Inhibitors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Hypoglycemic Agents
Incretins
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protease Inhibitors

ClinicalTrials.gov processed this record on May 02, 2016