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

NCT ID: NCT01619059

Last Updated: 2016-04-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 315 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-06-30
• Study Completion Date: 2015-01-31

Brief Summary

The purpose of this study is to learn if BMS-477118 (Saxagliptin) 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.

Conditions

Type 2 Diabetes

Study Design

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

Study Groups

Arm 1: Saxagliptin+Dapagliflozin+Metformin IR

Group Type: EXPERIMENTAL

Saxagliptin

Intervention Type: DRUG

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

Dapagliflozin

Intervention Type: DRUG

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

Metformin IR

Intervention Type: DRUG

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

Arm 2: Placebo+Dapagliflozin+Metformin IR

Group Type: EXPERIMENTAL

Dapagliflozin

Intervention Type: DRUG

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

Metformin IR

Intervention Type: DRUG

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

Placebo matching with Saxagliptin

Intervention Type: DRUG

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

Interventions

Saxagliptin

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

Intervention Type: DRUG

Dapagliflozin

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

Intervention Type: DRUG

Metformin IR

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

Intervention Type: DRUG

Placebo matching with Saxagliptin

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

Intervention Type: DRUG

Other Intervention Names

Onglyza

Eligibility Criteria

Inclusion Criteria

1. Signed Written Informed Consent

a) Subjects must be willing and able to give signed and dated written informed consent.

2. Target Population

1. 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)

2. Stable metformin therapy for at least 8 weeks prior to screening visit at a dose ≥ 1500 mg per day.

3. C-peptide ≥ 1.0 ng/mL (0.34 nmol/L) at screening visit.

4. 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. See Section 3.3.3 for the definition of WOCBP.

3. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of investigational product.

4. Women must not be breastfeeding

5. Sexually active fertile men must use 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 recommended as per 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.

Note: Subjects with SBP ≥ 160mmHg and < 180mmHg or a DBP ≥ 100 mmHg and < 110mmHg will be able to enter the lead-in period, provided their hypertension treatment is adjusted as deemed appropriate by the investigator. These subjects cannot be randomized if their blood pressure remains with SBP ≥ 160 mmHg or DBP ≥ 100 mmHg measured at Day 1.

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 (see Appendix 1), unstable or acute congestive heart failure. Note: eligible patients with congestive heart failure, especially those who are on diuretic therapy, should have careful monitoring of their volumes status throughout the study.

Renal Diseases:

8. Moderate or severe impairment of renal function [defined as eGFR < 60 mL/min/1.73 m2 (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, for more than 14 days (consecutive or not) during the 12 weeks prior to screening, as well as previous participation in any DPP-4 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 saxagliptin 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 CV181-169 or MB102-129 studies specifically, do not need to wait 30 days.

3. Physical and Laboratory Test Findings

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

2. Male subjects with microscopic hematuria present at Week -18 or Week -16 AND no common cause that can be confirmed. 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 subjects 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)

3. Other central laboratory test findings:

• Abnormal free T4 values. Abnormal thyroid stimulating hormone (TSH) value at screening will be further evaluated by free T4. Subjects 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 saxagliptin and dapagliflozin Investigator Brochure, the local saxagliptin or dapagliflozin 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 saxagliptin label).

5. Sex and Reproductive Status

a) Women who are pregnant

1. Prisoners or subjects who are involuntarily incarcerated.

2. Subject who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.

• 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

Terence T. Hart, Md

Muscle Shoals, Alabama, United States

Mesa Family Medical Center

Mesa, Arizona, United States

Clinical Research Advantage Inc/Desert Clinical Research Llc

Mesa, Arizona, United States

Clinical Research Advantage, Inc

Phoenix, Arizona, United States

Clinical Research Advantage, Inc./ Stonecreek Medical Associates, Pc

Phoenix, Arizona, United States

Beach Physicians Clinical Research Corp.

Huntington Beach, California, United States

Torrance Clinical Research

Lomita, California, United States

Randall G. Shue, Do, Inc.

Los Angeles, California, United States

National Research Institute

Los Angeles, California, United States

Cassidy Medical Group/Clinical Research Advantage

Vista, California, United States

Infosphere Clinical Research, Inc.

West Hills, California, United States

New West Physicians, Pc

Golden, Colorado, United States

Southeast Clinical Research, Llc

Chiefland, Florida, United States

Clinical Therapeutics Corporation

Coral Gables, Florida, United States

Medical Research Unlimited, Llc

Hialeah, Florida, United States

University Of Florida Endocrinology & Diabetes

Jacksonville, Florida, United States

Care Partners Clinical Research, Llc

Jacksonville, Florida, United States

Clinical Research Of Miami, Inc.

Miami, Florida, United States

Clinical Research Advantage, Inc.

Evansville, Indiana, United States

Clinical Research Advantage

Evansville, Indiana, United States

Mercy Health Research

St Louis, Missouri, United States

Clinical Research Advantage, Inc.

Las Vegas, Nevada, United States

Joslin Diabetes Center Affiliate Of Snhmc

Nashua, New Hampshire, United States

N. Shore Diabetes & Endoc Assoc

New Hyde Park, New York, United States

Digiovanna Institute For Medical Education & Research

North Massapequa, New York, United States

Barat Research Group, Inc.

Charlotte, North Carolina, United States

Sterling Research Grp, Ltd.

Cincinnati, Ohio, United States

Physicians Research, Inc.

Zanesville, Ohio, United States

Tlm Medical Services

Columbia, South Carolina, United States

Family Medicine Of Sayebrook

Myrtle Beach, South Carolina, United States

Holston Medical Group

Bristol, Tennessee, United States

Vanderbilt Diabetes Center

Nashville, Tennessee, United States

Padre Coast Clinical Research

Corpus Christi, Texas, United States

Local Institution

Moncton, New Brunswick, Canada

Local Institution

St. John's, Newfoundland and Labrador, Canada

Local Institution

Halifax, Nova Scotia, Canada

Local Institution

Brampton, Ontario, Canada

Local Institution

Sarnia, Ontario, Canada

Local Institution

Montreal, Quebec, Canada

Local Institution

Québec, Quebec, Canada

Local Institution

Hradec Králové, , Czechia

Local Institution

Karlovy Vary, , Czechia

Local Institution

Prague, , Czechia

Local Institution

Balatonfüred, , Hungary

Local Institution

Budaörs, , Hungary

Local Institution

Budapest, , Hungary

Local Institution

Zalaegerszeg, , Hungary

Local Institution

Guadalajara, Jalisco, Mexico

Local Institution

Guadalajara, Jalisco, Mexico

Local Institution

Guadalajara, Jalisco, Mexico

Local Institution

Morelia, Michioacan, Mexico

Local Institution

Monterrey, Nuevo León, Mexico

Local Institution

Del. Benito Juarez, , Mexico

Local Institution

Veracruz, , Mexico

Local Institution

Bialystok, , Poland

Local Institution

Katowice, , Poland

Local Institution

Katowice, , Poland

Local Institution

Krakow, , Poland

Local Institution

Pszczyna, , Poland

Local Institution

Puławy, , Poland

Local Institution

Szczecin, , Poland

Local Institution

Warsaw, , Poland

Local Institution

Węgrów, , Poland

Local Institution

Wroclaw, , Poland

Research & Cardiovascular Corp

Ponce, , Puerto Rico

Local Institution

Brasov, Brașov County, Romania

Local Institution

Bucharest, Bucharest, Romania

Local Institution

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

Countries

United States; Canada; Czechia; Hungary; Mexico; Poland; Puerto Rico; Romania; Russia

References

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)

Matthaei S, Catrinoiu D, Celinski A, Ekholm E, Cook W, Hirshberg B, Chen H, Iqbal N, Hansen L. Randomized, Double-Blind Trial of Triple Therapy With Saxagliptin Add-on to Dapagliflozin Plus Metformin in Patients With Type 2 Diabetes. Diabetes Care. 2015 Nov;38(11):2018-24. doi: 10.2337/dc15-0811. Epub 2015 Aug 31.

Reference Type: DERIVED

PMID: 26324329 (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

2011-006323-37

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

CV181-168

Identifier Type: -

Identifier Source: org_study_id