Clinical trial NCT01619059: Safety and Efficacy of Saxagliptin in Triple Therapy to Treat Subjects With Type 2 Diabetes
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Type 2 Diabetes
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2012-06-14
Enrollment: 315
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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
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.

Primary outcomes:
measure: Adjusted Mean Change From Baseline in Hemoglobin A1C (HbA1c) at Week 24
timeFrame: From Baseline to Week 24
Secondary outcomes:
measure: Adjusted Mean Change From Baseline in 2-hour Post Prandial Glucose (PPG) From a Liquid Meal Tolerance Test (MTT) at Week 24
timeFrame: From Baseline to Week 24
measure: Adjusted Mean Change From Baseline in Fasting Plasma Glucose at Week 24
timeFrame: From Baseline to Week 24
measure: Percentage of Participants Achieving a Therapeutic Glycemic Response (Hemoglobin A1c [HbA1C]) <7.0% at Week 24 (Last Observation Carried Forward [LOCF])
timeFrame: From Baseline to Week 24
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University Of Alabama At Birmingham
state: Alabama
city: Muscle Shoals
country: United States
facility: Terence T. Hart, Md
state: Alabama
city: Mesa
country: United States
facility: Mesa Family Medical Center
state: Arizona
city: Mesa
country: United States
facility: Clinical Research Advantage Inc/Desert Clinical Research Llc
state: Arizona
city: Phoenix
country: United States
facility: Clinical Research Advantage, Inc
state: Arizona
city: Phoenix
country: United States
facility: Clinical Research Advantage, Inc./ Stonecreek Medical Associates, Pc
state: Arizona
city: Huntington Beach
country: United States
facility: Beach Physicians Clinical Research Corp.
state: California
city: Lomita
country: United States
facility: Torrance Clinical Research
state: California
city: Los Angeles
country: United States
facility: Randall G. Shue, Do, Inc.
state: California
city: Los Angeles
country: United States
facility: National Research Institute
state: California
city: Vista
country: United States
facility: Cassidy Medical Group/Clinical Research Advantage
state: California
city: West Hills
country: United States
facility: Infosphere Clinical Research, Inc.
state: California
city: Golden
country: United States
facility: New West Physicians, Pc
state: Colorado
city: Chiefland
country: United States
facility: Southeast Clinical Research, Llc
state: Florida
city: Coral Gables
country: United States
facility: Clinical Therapeutics Corporation
state: Florida
city: Hialeah
country: United States
facility: Medical Research Unlimited, Llc
state: Florida
city: Jacksonville
country: United States
facility: University Of Florida Endocrinology & Diabetes
state: Florida
city: Jacksonville
country: United States
facility: Care Partners Clinical Research, Llc
state: Florida
city: Miami
country: United States
facility: Clinical Research Of Miami, Inc.
state: Florida
city: Evansville
country: United States
facility: Clinical Research Advantage, Inc.
state: Indiana
city: Evansville
country: United States
facility: Clinical Research Advantage
state: Indiana
city: Saint Louis
country: United States
facility: Mercy Health Research
state: Missouri
city: Las Vegas
country: United States
facility: Clinical Research Advantage, Inc.
state: Nevada
city: Nashua
country: United States
facility: Joslin Diabetes Center Affiliate Of Snhmc
state: New Hampshire
city: New Hyde Park
country: United States
facility: N. Shore Diabetes & Endoc Assoc
state: New York
city: North Massapequa
country: United States
facility: Digiovanna Institute For Medical Education & Research
state: New York
city: Charlotte
country: United States
facility: Barat Research Group, Inc.
state: North Carolina
city: Cincinnati
country: United States
facility: Sterling Research Grp, Ltd.
state: Ohio
city: Zanesville
country: United States
facility: Physicians Research, Inc.
state: Ohio
city: Columbia
country: United States
facility: Tlm Medical Services
state: South Carolina
city: Myrtle Beach
country: United States
facility: Family Medicine Of Sayebrook
state: South Carolina
city: Bristol
country: United States
facility: Holston Medical Group
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Diabetes Center
state: Tennessee
city: Corpus Christi
country: United States
facility: Padre Coast Clinical Research
state: Texas
city: Moncton
country: Canada
facility: Local Institution
state: New Brunswick
city: St-john
country: Canada
facility: Local Institution
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: Local Institution
state: Nova Scotia
city: Brampton
country: Canada
facility: Local Institution
state: Ontario
city: Sarnia
country: Canada
facility: Local Institution
state: Ontario
city: Montreal
country: Canada
facility: Local Institution
state: Quebec
city: Quebec
country: Canada
facility: Local Institution
city: Hradec Kralove
country: Czech Republic
facility: Local Institution
city: Karlovy Vary
country: Czech Republic
facility: Local Institution
city: Praha 5
country: Czech Republic
facility: Local Institution
city: Balatonfured
country: Hungary
facility: Local Institution
city: Budaors
country: Hungary
facility: Local Institution
city: Budapest
country: Hungary
facility: Local Institution
city: Zalaegerszeg
country: Hungary
facility: Local Institution
city: Guadalajara
country: Mexico
facility: Local Institution
state: Jalisco
city: Guadalajara
country: Mexico
facility: Local Institution
state: Jalisco
city: Guadalajara
country: Mexico
facility: Local Institution
state: Jalisco
city: Morelia
country: Mexico
facility: Local Institution
state: Michioacan
city: Monterrey
country: Mexico
facility: Local Institution
state: Nuevo Leon
city: Del. Benito Juarez
country: Mexico
facility: Local Institution
city: Veracruz
country: Mexico
facility: Local Institution
city: Bialystok
country: Poland
facility: Local Institution
city: Katowice
country: Poland
facility: Local Institution
city: Katowice
country: Poland
facility: Local Institution
city: Krakow
country: Poland
facility: Local Institution
city: Pszczyna
country: Poland
facility: Local Institution
city: Pulawy
country: Poland
facility: Local Institution
city: Szczecin
country: Poland
facility: Local Institution
city: Warszawa
country: Poland
facility: Local Institution
city: Wegrow
country: Poland
facility: Local Institution
city: Wroclaw
country: Poland
facility: Local Institution
city: Ponce
country: Puerto Rico
facility: Research & Cardiovascular Corp
city: Brasov
country: Romania
facility: Local Institution
city: Bucharest
country: Romania
facility: Local Institution
city: Bucharest
country: Romania
facility: Local Institution
city: Bucuresti
country: Romania
facility: Local Institution
city: Constanta
country: Romania
facility: Local Institution
city: Craiova
country: Romania
facility: Local Institution
city: Galati
country: Romania
facility: Local Institution
city: Ploiesti
country: Romania
facility: Local Institution
city: Kursk
country: Russian Federation
facility: Local Institution
city: Moscow
country: Russian Federation
facility: Local Institution
city: Saint-petersburg
country: Russian Federation
facility: Local Institution
city: St. Petersburg
country: Russian Federation
facility: Local Institution
city: St. Petersburg
country: Russian Federation
facility: Local Institution
city: St. Petersburg
country: Russian Federation
facility: Local Institution
city: St. Petersburg
country: Russian Federation
facility: Local Institution
city: St.petersburg
country: Russian Federation
facility: Local Institution
city: St.petersburg
country: Russian Federation
facility: Local Institution
city: Yaroslaval
country: Russian Federation
facility: Local Institution
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.