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

NCT ID: NCT01646320

Last Updated: 2016-06-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 320 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-09-30
• Study Completion Date: 2015-02-28

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.

Conditions

Type 2 Diabetes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Arm1: Dapagliflozin (10 mg) + Saxagliptin + Metformin IR

Group Type: EXPERIMENTAL

Dapagliflozin

Intervention Type: DRUG

Tablets, Oral, 10 mg, Once daily, Up to 52 weeks

Saxagliptin

Intervention Type: DRUG

Tablets, Oral, 5 mg, Once daily, Up to 52 weeks

Metformin immediate release (IR)

Intervention Type: DRUG

Tablets, Oral, ≥ 1500 mg, Twice daily, Up to 52 weeks

Arm 2: Placebo + Saxagliptin + Metformin IR

Group Type: EXPERIMENTAL

Placebo matching with Dapagliflozin

Intervention Type: DRUG

Tablets, Oral, 0 mg, Once daily, Up to 52 weeks

Saxagliptin

Intervention Type: DRUG

Tablets, Oral, 5 mg, Once daily, Up to 52 weeks

Metformin immediate release (IR)

Intervention Type: DRUG

Tablets, Oral, ≥ 1500 mg, Twice daily, Up to 52 weeks

Interventions

Dapagliflozin

Tablets, Oral, 10 mg, Once daily, Up to 52 weeks

Intervention Type: DRUG

Placebo matching with Dapagliflozin

Tablets, Oral, 0 mg, Once daily, Up to 52 weeks

Intervention Type: DRUG

Saxagliptin

Tablets, Oral, 5 mg, Once daily, Up to 52 weeks

Intervention Type: DRUG

Metformin immediate release (IR)

Tablets, Oral, ≥ 1500 mg, Twice daily, Up to 52 weeks

Intervention Type: DRUG

Other Intervention Names

Onglyza

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.

• 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.

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

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AstraZeneca

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Bristol-Myers Squibb

Role: STUDY_DIRECTOR

Bristol-Myers Squibb

Locations

University Of Alabama At Birmingham

Birmingham, Alabama, United States

Clinical Research Advantage Inc/Desert Clinical Research Llc

Mesa, Arizona, United States

Clinical Research Advantage, Inc.

Phoenix, Arizona, United States

Elite Clinical Studies, Llc

Phoenix, Arizona, United States

Arkansas Clinical Research

Little Rock, Arkansas, United States

Torrance Clinical Research Institute Inc.

Lomita, California, United States

Randall G. Shue, Do, Inc.

Los Angeles, California, United States

National Research Institute

Los Angeles, California, United States

Diabetes Medical Center Of California

Northridge, California, United States

Cassidy Medical Group/Clinical Research Advantage

Vista, California, United States

Palm Springs Research Institute

Hialeah, Florida, United States

Fpa Clinical Research

Kissimmee, Florida, United States

International Research Associates, Llc

Miami, Florida, United States

Omega Research Consultants, Llc

Orlando, Florida, United States

Compass Research East, Llc

Oviedo, Florida, United States

Palm Harbor Medical Associates

Palm Harbor, Florida, United States

Cedar Crosse Research Center

Chicago, Illinois, United States

Clinical Research Advantage

Evansville, Indiana, United States

Associated Internal Medicine Specialists

Battle Creek, Michigan, United States

Jackson Clinic

Rolling Fork, Mississippi, United States

Premier Research

Trenton, New Jersey, United States

Metrolina Internal Medicine

Charlotte, North Carolina, United States

Sterling Research Grp, Ltd.

Cincinnati, Ohio, United States

Endocrine Associates

Houston, Texas, United States

Sam Clinical Research Center

San Antonio, Texas, United States

Tidewater Integrated Medical Research

Virginia Beach, Virginia, United States

Local Institution

Broumov, , Czechia

Local Institution

Pardubice, , Czechia

Local Institution

Prague, , Czechia

Local Institution

Prague, , Czechia

Local Institution

Pribram V, , Czechia

Local Institution

Aguascalientes, Aguascalientes, Mexico

Local Institution

Guadalajara, Jalisco, Mexico

Local Institution

Zapopan, Jalisco, Mexico

Local Institution

Zapopan, Jalisco, Mexico

Local Institution

Monterrey, Nuevo León, Mexico

Local Institution

Monterrey, Nuevo León, Mexico

Local Institution

Bialystok, , Poland

Local Institution

Krakow, , Poland

Local Institution

Ruda Śląska, , Poland

Local Institution

Warsaw, , Poland

Local Institution

Warsaw, , Poland

Local Institution

Warsaw, , Poland

Local Institution

Żory, , Poland

Clinical Research Puerto Rico

San Juan, , Puerto Rico

Local Institution

Bucharest, Bucharest, Romania

Local Institution

Bucharest, , Romania

Local Institution

Constanța, , Romania

Local Institution

Craiova, , Romania

Local Institution

Galati, , Romania

Local Institution

Ploieşti, , Romania

Local Institution

Kursk, , Russia

Local Institution

Moscow, , Russia

Local Institution

Saint Petersburg, , Russia

Local Institution

Saint Petersburg, , Russia

Local Institution

Saint Petersburg, , Russia

Local Institution

Saint Petersburg, , Russia

Local Institution

Saint Petersburg, , Russia

Local Institution

Saint Petersburg, , Russia

Local Institution

Yaroslaval, , Russia

Local Institution

Portsmouth, Hants, United Kingdom

Local Institution

Newport, Isle of Wight, United Kingdom

Local Institution

Liverpool, Merseyside, United Kingdom

Local Institution

Chippenham, Wiltshire, United Kingdom

Local Institution

Bedfordshire, , United Kingdom

Local Institution

London, , United Kingdom

Countries

United States; Czechia; Mexico; Poland; Puerto Rico; Romania; Russia; United Kingdom

References

Natale P, Tunnicliffe DJ, Toyama T, Palmer SC, Saglimbene VM, Ruospo M, Gargano L, Stallone G, Gesualdo L, Strippoli GF. Sodium-glucose co-transporter protein 2 (SGLT2) inhibitors for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev. 2024 May 21;5(5):CD015588. doi: 10.1002/14651858.CD015588.pub2.

Reference Type: DERIVED

PMID: 38770818 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29802530 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 26246458 (View on PubMed)

Related Links

http://www.bms.com/studyconnect/Pages/home.aspx

BMS clinical trial educational resource

http://www.bms.com/clinical_trials/Pages/Investigator_Inquiry_form.aspx

Investigator Inquiry form

Other Identifiers

2011-006324-20

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

MB102-129

Identifier Type: -

Identifier Source: org_study_id