Clinical trial NCT01646320: Safety and Efficacy of Dapagliflozin in Triple Therapy to Treat Subjects With Type 2 Diabetes
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2012-07-20
Enrollment: 320
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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.

Primary outcomes:
measure: Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24
timeFrame: From Baseline to Week 24
Secondary outcomes:
measure: Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24
timeFrame: From Baseline to Week 24
measure: Adjusted Mean Change From Baseline in 120-minute Postprandial Glucose (PPG) at Week 24
timeFrame: From Baseline to Week 24
measure: Adjusted Mean Change From Baseline in Body Weight at Week 24
timeFrame: From baseline to Week 24
measure: Percentage of Subjects Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])
timeFrame: From baseline to week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University Of Alabama At Birmingham
state: Alabama
city: Mesa
country: United States
facility: Clinical Research Advantage Inc/Desert Clinical Research Llc
state: Arizona
city: Phoenix
country: United States
facility: Clinical Research Advantage, Inc.
state: Arizona
city: Phoenix
country: United States
facility: Elite Clinical Studies, Llc
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Clinical Research
state: Arkansas
city: Lomita
country: United States
facility: Torrance Clinical Research Institute Inc.
state: California
city: Los Angeles
country: United States
facility: Randall G. Shue, Do, Inc.
state: California
city: Los Angeles
country: United States
facility: National Research Institute
state: California
city: Northridge
country: United States
facility: Diabetes Medical Center Of California
state: California
city: Vista
country: United States
facility: Cassidy Medical Group/Clinical Research Advantage
state: California
city: Hialeah
country: United States
facility: Palm Springs Research Institute
state: Florida
city: Kissimmee
country: United States
facility: Fpa Clinical Research
state: Florida
city: Miami
country: United States
facility: International Research Associates, Llc
state: Florida
city: Orlando
country: United States
facility: Omega Research Consultants, Llc
state: Florida
city: Oviedo
country: United States
facility: Compass Research East, Llc
state: Florida
city: Palm Harbor
country: United States
facility: Palm Harbor Medical Associates
state: Florida
city: Chicago
country: United States
facility: Cedar Crosse Research Center
state: Illinois
city: Evansville
country: United States
facility: Clinical Research Advantage
state: Indiana
city: Battle Creek
country: United States
facility: Associated Internal Medicine Specialists
state: Michigan
city: Rolling Fork
country: United States
facility: Jackson Clinic
state: Mississippi
city: Trenton
country: United States
facility: Premier Research
state: New Jersey
city: Charlotte
country: United States
facility: Metrolina Internal Medicine
state: North Carolina
city: Cincinnati
country: United States
facility: Sterling Research Grp, Ltd.
state: Ohio
city: Houston
country: United States
facility: Endocrine Associates
state: Texas
city: San Antonio
country: United States
facility: Sam Clinical Research Center
state: Texas
city: Virginia Beach
country: United States
facility: Tidewater Integrated Medical Research
state: Virginia
city: Broumov
country: Czech Republic
facility: Local Institution
city: Pardubice
country: Czech Republic
facility: Local Institution
city: Praha 10
country: Czech Republic
facility: Local Institution
city: Praha 4
country: Czech Republic
facility: Local Institution
city: Pribram V
country: Czech Republic
facility: Local Institution
city: Guadalajara
country: Mexico
facility: Local Institution
state: Jalisco
city: Zapopan
country: Mexico
facility: Local Institution
state: Jalisco
city: Zapopan
country: Mexico
facility: Local Institution
state: Jalisco
city: Monterrey
country: Mexico
facility: Local Institution
state: Nuevo Leon
city: Monterrey
country: Mexico
facility: Local Institution
state: Nuevo Leon
city: Aguascalientes
country: Mexico
facility: Local Institution
city: Bialystok
country: Poland
facility: Local Institution
city: Krakow
country: Poland
facility: Local Institution
city: Ruda Slaska
country: Poland
facility: Local Institution
city: Warszawa
country: Poland
facility: Local Institution
city: Warszawa
country: Poland
facility: Local Institution
city: Warszawa
country: Poland
facility: Local Institution
city: Zory
country: Poland
facility: Local Institution
city: San Juan
country: Puerto Rico
facility: Clinical Research Puerto Rico
city: Bucharest
country: Romania
facility: Local Institution
city: Bucharest
country: Romania
facility: Local Institution
city: Constanta
country: Romania
facility: Local Institution
city: Craiova
country: Romania
facility: Local Institution
city: Galati
country: Romania
facility: Local Institution
city: Ploiesti
country: Romania
facility: Local Institution
city: Kursk
country: Russian Federation
facility: Local Institution
city: Moscow
country: Russian Federation
facility: Local Institution
city: Saint-petersburg
country: Russian Federation
facility: Local Institution
city: St. Petersburg
country: Russian Federation
facility: Local Institution
city: St. Petersburg
country: Russian Federation
facility: Local Institution
city: St. Petersburg
country: Russian Federation
facility: Local Institution
city: St. Petersburg
country: Russian Federation
facility: Local Institution
city: St.petersburg
country: Russian Federation
facility: Local Institution
city: St.petersburg
country: Russian Federation
facility: Local Institution
city: Yaroslaval
country: Russian Federation
facility: Local Institution
city: Portsmouth
country: United Kingdom
facility: Local Institution
state: Hants
city: Newport
country: United Kingdom
facility: Local Institution
state: Isle of Wight
city: Liverpool
country: United Kingdom
facility: Local Institution
state: Merseyside
city: Chippenham
country: United Kingdom
facility: Local Institution
state: Wiltshire
city: Bedfordshire
country: United Kingdom
facility: Local Institution
city: London
country: United Kingdom
facility: Local Institution
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: Mathieu C, Catrinoiu D, Ranetti AE, Johnsson E, Hansen L, Chen H, Garcia-Sanchez R, Iqbal N, Celinski A. Characterization of the Open-Label Lead-In Period of Two Randomized Controlled Phase 3 Trials Evaluating Dapagliflozin, Saxagliptin, and Metformin in Type 2 Diabetes. Diabetes Ther. 2018 Aug;9(4):1703-1711. doi: 10.1007/s13300-018-0445-x. Epub 2018 May 25.
citation: Mathieu C, Ranetti AE, Li D, Ekholm E, Cook W, Hirshberg B, Chen H, Hansen L, Iqbal N. Randomized, Double-Blind, Phase 3 Trial of Triple Therapy With Dapagliflozin Add-on to Saxagliptin Plus Metformin in Type 2 Diabetes. Diabetes Care. 2015 Nov;38(11):2009-17. doi: 10.2337/dc15-0779. Epub 2015 Aug 5.