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

Type 2 Diabetes Clinical Trial

Official title:

A Multicenter, Randomized, Double-Blind, Placebo Controlled, Parallel Group, Phase 3 Trial to Evaluate the Safety and Efficacy of Triple Therapy With Saxagliptin Added to Dapagliflozin in Combination With Metformin Compared to Therapy With Placebo Added to Dapagliflozin in Combination With Metformin in Subjects With Type 2 Diabetes Who Have Inadequate Glycemic Control on Metformin and Dapagliflozin

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01619059
• Other study ID #: CV181-168
• Secondary ID: 2011-006323-37
• Status: Completed
• Phase: Phase 3
• First received: June 12, 2012
• Last updated: February 18, 2016
• Start date: June 2012
• Est. completion date: January 2015

Study information

• Verified date: February 2016
• Source: AstraZeneca
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationUnited States: Institutional Review BoardCanada: Health CanadaMexico: Federal Commission for Protection Against Health Risks
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 317
• Est. completion date: January 2015
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

6. Other Exclusion Criteria

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus, Type 2
• Type 2 Diabetes

Intervention

Drug:
• Saxagliptin
Tablets, Oral, 5 mg, Once daily, Up to 52 weeks
• Dapagliflozin
Tablets, Oral, 10 mg, Once daily, Up to 52 weeks
• Metformin IR
Tablets, Oral, = 1500mg, Twice daily, Up to 52 weeks
• Placebo matching with Saxagliptin
Tablets, Oral, 0 mg, Once daily, Up to 52 weeks

Locations

Country	Name	City	State
Canada	Local Institution	Brampton	Ontario
Canada	Local Institution	Halifax	Nova Scotia
Canada	Local Institution	Moncton	New Brunswick
Canada	Local Institution	Montreal	Quebec
Canada	Local Institution	Quebec
Canada	Local Institution	Sarnia	Ontario
Canada	Local Institution	St-john	Newfoundland and Labrador
Czech Republic	Local Institution	Hradec Kralove
Czech Republic	Local Institution	Karlovy Vary
Czech Republic	Local Institution	Praha 5
Hungary	Local Institution	Balatonfured
Hungary	Local Institution	Budaors
Hungary	Local Institution	Budapest
Hungary	Local Institution	Zalaegerszeg
Mexico	Local Institution	Del. Benito Juarez
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Guadalajara	Jalisco
Mexico	Local Institution	Monterrey	Nuevo Leon
Mexico	Local Institution	Morelia	Michioacan
Mexico	Local Institution	Veracruz
Poland	Local Institution	Bialystok
Poland	Local Institution	Katowice
Poland	Local Institution	Katowice
Poland	Local Institution	Krakow
Poland	Local Institution	Pszczyna
Poland	Local Institution	Pulawy
Poland	Local Institution	Szczecin
Poland	Local Institution	Warszawa
Poland	Local Institution	Wegrow
Poland	Local Institution	Wroclaw
Puerto Rico	Research & Cardiovascular Corp	Ponce
Romania	Local Institution	Brasov
Romania	Local Institution	Bucharest
Romania	Local Institution	Bucharest
Romania	Local Institution	Bucuresti
Romania	Local Institution	Constanta
Romania	Local Institution	Craiova
Romania	Local Institution	Galati
Romania	Local Institution	Ploiesti
Russian Federation	Local Institution	Kursk
Russian Federation	Local Institution	Moscow
Russian Federation	Local Institution	Saint-petersburg
Russian Federation	Local Institution	St. Petersburg
Russian Federation	Local Institution	St. Petersburg
Russian Federation	Local Institution	St. Petersburg
Russian Federation	Local Institution	St. Petersburg
Russian Federation	Local Institution	St.petersburg
Russian Federation	Local Institution	St.petersburg
Russian Federation	Local Institution	Yaroslaval
United States	University Of Alabama At Birmingham	Birmingham	Alabama
United States	Holston Medical Group	Bristol	Tennessee
United States	Barat Research Group, Inc.	Charlotte	North Carolina
United States	Southeast Clinical Research, Llc	Chiefland	Florida
United States	Sterling Research Grp, Ltd.	Cincinnati	Ohio
United States	Tlm Medical Services	Columbia	South Carolina
United States	Clinical Therapeutics Corporation	Coral Gables	Florida
United States	Padre Coast Clinical Research	Corpus Christi	Texas
United States	Clinical Research Advantage	Evansville	Indiana
United States	Clinical Research Advantage, Inc.	Evansville	Indiana
United States	New West Physicians, Pc	Golden	Colorado
United States	Medical Research Unlimited, Llc	Hialeah	Florida
United States	Beach Physicians Clinical Research Corp.	Huntington Beach	California
United States	Care Partners Clinical Research, Llc	Jacksonville	Florida
United States	University Of Florida Endocrinology & Diabetes	Jacksonville	Florida
United States	Clinical Research Advantage, Inc.	Las Vegas	Nevada
United States	Torrance Clinical Research	Lomita	California
United States	National Research Institute	Los Angeles	California
United States	Randall G. Shue, Do, Inc.	Los Angeles	California
United States	Clinical Research Advantage Inc/Desert Clinical Research Llc	Mesa	Arizona
United States	Mesa Family Medical Center	Mesa	Arizona
United States	Clinical Research Of Miami, Inc.	Miami	Florida
United States	Terence T. Hart, Md	Muscle Shoals	Alabama
United States	Family Medicine Of Sayebrook	Myrtle Beach	South Carolina
United States	Joslin Diabetes Center Affiliate Of Snhmc	Nashua	New Hampshire
United States	Vanderbilt Diabetes Center	Nashville	Tennessee
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	Clinical Research Advantage, Inc	Phoenix	Arizona
United States	Clinical Research Advantage, Inc./ Stonecreek Medical Associates, Pc	Phoenix	Arizona
United States	Mercy Health Research	Saint Louis	Missouri
United States	Cassidy Medical Group/Clinical Research Advantage	Vista	California
United States	Infosphere Clinical Research, Inc.	West Hills	California
United States	Physicians Research, Inc.	Zanesville	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

United States,  Canada,  Czech Republic,  Hungary,  Mexico,  Poland,  Puerto Rico,  Romania,  Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24	HbA1c was measured as percent of hemoglobin by a central laboratory. Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. HbA1c measurements were obtained at Week 24 in the double-blind period, including observations prior to rescue.	From Baseline to Week 24	No
Secondary	Adjusted Mean Change From Baseline in 2-hour Post Prandial Glucose (PPG) From a Liquid Meal Tolerance Test (MTT) at Week 24	Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. PPG measurements were obtained at Week 24 in the double-blind period, including observations prior to rescue.	From Baseline to Week 24	No
Secondary	Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24	Baseline was defined as the last assessment on or prior to the date of the first dose of the double-blind study medication. FPG measurements were obtained at Week 24 in the double-blind period, including observations prior to rescue.	From Baseline to Week 24	No
Secondary	Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])	Therapeutic glycemic response is defined as HbA1c <7.0%. Data after rescue medication was excluded from this analysis. HbA1c was measured as a percent of hemoglobin.	From Baseline to Week 24	No

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