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



Status:Completed
Conditions:Diabetes
Therapuetic Areas:Endocrinology
Healthy:No
Age Range:18 - Any
Updated:4/21/2016
Start Date:September 2012
End Date:February 2015

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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

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.

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.

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.
We found this trial at
27
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2010 Wilshire Boulevard
Los Angeles, California 90057
213-413-2500
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1720 2nd Ave S
Birmingham, Alabama 35233
(205) 934-4011 
University of Alabama at Birmingham The University of Alabama at Birmingham (UAB) traces its roots...
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