Safety and Efficacy of Dapagliflozin in Triple Therapy to Treat Subjects With Type 2 Diabetes
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Intervention: Dapagliflozin; Placebo matching with Dapagliflozin; Saxagliptin; Metformin immediate release (IR)
Intervention description: Tablets, Oral, 10 mg, Once daily, Up to 52 weeks; Tablets, Oral, 0 mg, Once daily, Up to 52 weeks; Tablets, Oral, 5 mg, Once daily, Up to 52 weeks; Tablets, Oral, ≥ 1500 mg, Twice daily, Up to 52 weeks
Intervention MeSH terms: Metformin; Dapagliflozin; Saxagliptin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 320.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

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.