A Multi-Center, Randomized, Double-Blind, Phase III Trial to Evaluate the Safety and Efficacy of Saxagliptin Co-administered With Dapagliflozin Compared to Saxagliptin or Dapagliflozin All Given as add-on Therapy to Metformin in Subject With Type 2 Diabetes

A Multi-Center, Randomized, Double-Blind, Active-Controlled , Parallel Group, Phase III Trial to Evaluate the Safety and Efficacy of Saxagliptin 5mg Co-administered With Dapagliflozin 5mg Compared to Saxagliptin 5mg or Dapagliflozin 5mg All Given as Add-on Therapy to Metformin inPatients With Type 2 Diabetes Who Have Inadequate Glycaemic Control on Metformin Alone

The aim of this study is to evaluate safety and efficacy of therapy with saxagliptin 5mg co-administered with dapagliflozin 5mg, compared to therapy with saxagliptin 5mg or dapagliflozin 5mg in patients who are inadequately controlled on ≥1500mg/day of metformin monotherapy.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus; Inadequate Glycaemic Control
• Intervention / Treatment: Drug: Dapagliflozin; Drug: Saxagliptin; Drug: Placebo for Saxagliptin; Drug: Placebo for Dapagliflozin

• Study Type: Interventional
• Enrollment (Actual): 905
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • New Brunswick
    • Moncton, New Brunswick, Canada, E1G 1A7
      • Research Site
  • Nova Scotia
    • Bridgewater, Nova Scotia, Canada, B4V 3N2
      • Research Site
  • Ontario
    • Brampton, Ontario, Canada, L7A 3P1
      • Research Site
    • Etobicoke, Ontario, Canada, M9W 4L6
      • Research Site
    • London, Ontario, Canada, N5W 6A2
      • Research Site
    • Scarborough, Ontario, Canada, M1P 2T7
      • Research Site
    • Sudbury, Ontario, Canada, P3E 6C3
      • Research Site
    • Toronto, Ontario, Canada, M3J 2C5
      • Research Site
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Research Site
    • Levis, Quebec, Canada, G6W 0M5
      • Research Site
    • Mirabel, Quebec, Canada, J7J 2K8
      • Research Site
    • Pointe-Claire, Quebec, Canada, H9R 3J1
      • Research Site
    • Saint-Marc-des-Carrieres, Quebec, Canada, G0A 4B0
      • Research Site
• Czechia
  • Ceske Budejovice, Czechia, 370 01
    • Research Site
  • Chrudim III, Czechia, 537 01
    • Research Site
  • Jilove u Prahy, Czechia, 254 01
    • Research Site
  • Ostrava, Czechia, 710 00
    • Research Site
  • Pardubice, Czechia, 530 02
    • Research Site
  • Plzen, Czechia, 301 66
    • Research Site
  • Praha - Klanovice, Czechia, 190 14
    • Research Site
  • Praha 10, Czechia, 100 00
    • Research Site
  • Praha 4, Czechia, 140 46
    • Research Site
  • Praha 4, Czechia, 149 00
    • Research Site
  • Praha 8, Czechia, 181 00
    • Research Site
  • Uherske Hradiste, Czechia, 686 01
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• Germany
  • Berlin, Germany, 10787
    • Research Site
  • Bünde, Germany, 32257
    • Research Site
  • Essen, Germany, 45359
    • Research Site
  • Giengen, Germany, 89537
    • Research Site
  • Grossheirath, Germany, 96269
    • Research Site
  • Hof, Germany, 95030
    • Research Site
  • Hohenmölsen, Germany, 06679
    • Research Site
  • Karlsruhe, Germany, 76199
    • Research Site
  • Lichtenfels, Germany, 96215
    • Research Site
  • Meine, Germany, 38527
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  • Münster, Germany, 48153
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  • Rehburg Loccum, Germany, 31547
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  • Stolberg, Germany, 52222
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  • Villingen-Schwenningen, Germany, 78048
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• Mexico
  • Guadalajara, Mexico, 44670
    • Research Site
  • Guadalajara, Mexico, 44160
    • Research Site
  • Guadalajara, Mexico, 44600
    • Research Site
  • Mexico, Mexico, 03800
    • Research Site
  • Monterrey, Mexico, 64460
    • Research Site
  • Monterrey, Mexico, 64465
    • Research Site
  • Zapopan, Mexico, 45116
    • Research Site
• Russian Federation
  • Arkhangelsk, Russian Federation, 163001
    • Research Site
  • Ekaterinburg, Russian Federation, 620039
    • Research Site
  • Ekaterinburg, Russian Federation, 620219
    • Research Site
  • Izhevsk, Russian Federation, 426063
    • Research Site
  • Kazan, Russian Federation, 420008
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  • Moscow, Russian Federation, 119991
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  • Moscow, Russian Federation, 127473
    • Research Site
  • Perm, Russian Federation, 6144090
    • Research Site
  • Perm, Russian Federation, 614056
    • Research Site
  • Rostov-on-Don, Russian Federation, 344022
    • Research Site
  • Saint Petersburg, Russian Federation, 196601
    • Research Site
  • Saint-Petersburg, Russian Federation, 196143
    • Research Site
  • St.Petersburg, Russian Federation, 198013
    • Research Site
  • Tver, Russian Federation, 170036
    • Research Site
  • Ufa, Russian Federation, 450071
    • Research Site
  • Vladikavkaz, Russian Federation, 362007
    • Research Site
• United States
  • Alabama
    • Saraland, Alabama, United States, 36571
      • Research Site
  • California
    • Fresno, California, United States, 93702
      • Research Site
    • Harbor City, California, United States, 90710
      • Research Site
    • Hawaiian Gardens, California, United States, 90716
      • Research Site
    • Lancaster, California, United States, 93534
      • Research Site
    • Los Angeles, California, United States, 90057
      • Research Site
    • Montclair, California, United States, 91763
      • Research Site
    • Pomona, California, United States, 91767
      • Research Site
    • Spring Valley, California, United States, 91978
      • Research Site
    • Vallejo, California, United States, 94592
      • Research Site
  • Colorado
    • Denver, Colorado, United States, 80220
      • Research Site
    • Northglenn, Colorado, United States, 80234
      • Research Site
    • Wheat Ridge, Colorado, United States, 80033
      • Research Site
  • Connecticut
    • Waterbury, Connecticut, United States, 06708
      • Research Site
  • Florida
    • Cooper City, Florida, United States, 33024
      • Research Site
    • Doral, Florida, United States, 33166
      • Research Site
    • Hialeah, Florida, United States, 33012
      • Research Site
    • Miami, Florida, United States, 33186
      • Research Site
    • Miami, Florida, United States, 33176
      • Research Site
    • Miami Lakes, Florida, United States, 33016
      • Research Site
  • Georgia
    • Buford, Georgia, United States, 30518
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60607
      • Research Site
    • Hazel Crest, Illinois, United States, 60429
      • Research Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70115
      • Research Site
    • Zachary, Louisiana, United States, 70791
      • Research Site
  • Mississippi
    • Biloxi, Mississippi, United States, 39531
      • Research Site
  • Missouri
    • Florissant, Missouri, United States, 63031
      • Research Site
  • New York
    • Albany, New York, United States, 12203
      • Research Site
    • Bronx, New York, United States, 10459
      • Research Site
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Research Site
    • Mooresville, North Carolina, United States, 28117
      • Research Site
  • North Dakota
    • Fargo, North Dakota, United States, 58103
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43201
      • Research Site
    • Maumee, Ohio, United States, 43537
      • Research Site
  • Rhode Island
    • East Providence, Rhode Island, United States, 02914
      • Research Site
  • South Carolina
    • West Columbia, South Carolina, United States, 29169
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75230
      • Research Site
    • Dallas, Texas, United States, 75208
      • Research Site
    • El Paso, Texas, United States, 79935
      • Research Site
    • Fort Worth, Texas, United States, 76132
      • Research Site
    • Houston, Texas, United States, 77004
      • Research Site
    • Houston, Texas, United States, 77036
      • Research Site
    • Houston, Texas, United States, 77040
      • Research Site
    • Odessa, Texas, United States, 79761
      • Research Site
    • Sugar Land, Texas, United States, 77479
      • Research Site
    • Waco, Texas, United States, 76710
      • Research Site
  • Utah
    • Salt Lake City, Utah, United States, 84102
      • Research Site
  • Virginia
    • Norfolk, Virginia, United States, 23510
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 130 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Patients aged ≥18 years old at time of informed consent;
2. Patients with Type 2 diabetes mellitus (T2DM) defined as HbA1C≥7.5% to ≤10.0% at screening visit;
3. Stable metformin therapy for at least 8 weeks prior to enrolment at a dose of ≥1500mg per day;
4. BMI ≤45.0kg/m2 at Enrolment visit;
5. Fasting Plasma Glucose (FPG) ≤ 270mg/dl(15.0mmol/L) at the enrolment visit;
6. For Females Only: Women of childbearing potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study and for at least 4 weeks after the last dose of study medication in such a manner that the risk of pregnancy is minimized.

Exclusion Criteria:

1. History of diabetes insipidus, Type 1 diabetes or Latent Autoimmune Diabetes of Adults, diabetic ketoacidosis or hyperosmolar nonketotic coma and 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 3 months prior to Enrolment (Visit 1), or other signs and symptoms.
2. History of pancreatitis.
3. Administration of any antihyperglycaemic therapy, other than metformin, for more than 14 days (consecutive or not) during the 8 weeks prior to enrolment
4. Any use of DPP-4 inhibitor or SGLT-2 inhibitor within 8 weeks prior to enrolment.
5. Significant hepatic disease, including, but not limited to, chronic active hepatitis and/or severe hepatic insufficiency and/or significant abnormal liver function, including patients with Alanine transaminase (ALT) and/or Aspartate transaminase (AST) ≥3x ULN (Upper Limit of Normal)and/or Total Bilirubin ≥2.0x ULN. History of severe hepatobiliary disease or hepatotoxicity with any medication. Positive serologic evidence of current infectious liver disease, including patients who are known to be positive for Hepatitis viral antibody ImmunoglobulinM (IgM), Hepatitis B surface antigen, and Hepatitis C virus antibody.
6. Moderate or severe impairment of renal function [defined as Estimated Glomerular Filtration Rate (eGFR) <60milliLitre/min/1.73 m2 (estimated by Modification in Diet and Renal Disease (MDRD)) or serum creatinine ≥1.5mg/dL in males or ≥1.4mg/dL in females]. Conditions of congenital renal glucosuria, history of unstable or rapidly progressing renal disease.
7. History of any clinically significant disease or disorder which, in the opinion of the investigator, may put the patient at risk because of participation in the study, may influence the results, or may limit the patient's ability to participate in or complete the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Saxagliptin+Dapagliflozin+Metformin; 5 mg Tablets, Oral, Once daily, 24 weeks for Saxagliptin and Dapagliflozin	Drug: Dapagliflozin; 5mg, orally, Green, plain, diamond-shaped, film-coated tablet; Other Names: Forxiga; Drug: Saxagliptin; 5mg, orally, Plain, yellow, biconvex, round, film-coated tablet; Other Names: Onglyza™
Active Comparator: Dapagliflozin+Saxagliptin placebo+Metformin; 5 mg Tablets, Oral, Once daily, 24 weeks for Dapagliflozin and Saxagliptin Placebo	Drug: Dapagliflozin; 5mg, orally, Green, plain, diamond-shaped, film-coated tablet; Other Names: Forxiga; Drug: Placebo for Saxagliptin; Does not contain active ingredient, orally, Plain, yellow, biconvex, round, film-coated tablet
Active Comparator: Saxagliptin+Dapagliflozin placebo+metformin; 5 mg Tablets, Oral, Once daily, 24 weeks for Saxagliptin and Dapagliflozin placebo	Drug: Saxagliptin; 5mg, orally, Plain, yellow, biconvex, round, film-coated tablet; Other Names: Onglyza™; Drug: Placebo for Dapagliflozin; Does not contain active ingredient, orally, Green, plain, diamond-shaped, film-coated tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in HbA1c at Week 24	To demonstrate the superiority of the change from baseline HbA1c achieved with the co-administered saxagliptin 5 mg and dapagliflozin 5 mg to either agent individually after 24 weeks. Results were presented for the modified full analysis set. Note: Baseline was defined as the last assessment on or prior to the date of the first dose of the study medication.	Baseline and week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of Participants Achieving HbA1c <7.0% at 24 Weeks	To demonstrate the effect of the co-administered saxagliptin 5 mg and dapagliflozin 5 mg to either agent individually on proportion of participants achieving therapeutic glycaemic response after 24 weeks. Therapeutic glycaemic response was defined as an HbA1c value at Week 24 <7.0% irrespective of whether participant received rescue medication. Risk difference for each treatment was calculated as adjusted response rate. Participants who did not had an HbA1c measurement at Week 24 were regarded as non-responders. Results were presented for the modified full analysis set.	Baseline and week 24
Change in Fasting Plasma Glucose at 24 Weeks	To demonstrate the effect of the co-administered saxagliptin 5 mg and dapagliflozin 5mg to either agent individually on fasting plasma glucose after 24 weeks. Results were presented for the modified full analysis set.	Baseline and week 24
Change in Total Body Weight at 24 Weeks	To demonstrate the effect of the co-administered saxagliptin 5 mg and dapagliflozin 5 mg to saxagliptin 5 mg on total body weight after 24 weeks. Results were presented for the modified full analysis set.	Baseline and week 24

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• d1683c00005 csp Redacted
• D1683C00005 SAP redacted

Study record dates

Study Major Dates

• Study Start (Actual): February 26, 2016
• Primary Completion (Actual): July 15, 2017
• Study Completion (Actual): July 15, 2017

Study Registration Dates

• First Submitted: February 10, 2016
• First Submitted That Met QC Criteria: February 10, 2016
• First Posted (Estimate): February 12, 2016

Study Record Updates

• Last Update Posted (Actual): October 10, 2018
• Last Update Submitted That Met QC Criteria: September 10, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: metformin; Diabetes Mellitus Type 2,; saxagliptin,; dapagliflozin,
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Dapagliflozin; Saxagliptin
• Other Study ID Numbers: D1683C00005