ESR-15-11293 - Saxa/Dapa, Safety and Efficacy Study

NCT02613897 | Completed Results DMC

• 1 other identifier: HSC20150742H
• Study Type: interventional
• Target: 56
• Locations: 1 country
• Sites: 1

Brief Summary

This is a 16-week, single center, randomized, double-blind, active-controlled, parallel-group, Phase 3b efficacy and safety study of simultaneous administration of saxagliptin 5 mg plus dapagliflozin 10 mg once daily (QD) compared with dapagliflozin plus placebo for saxagliptin, and placebo for saxagliptin plus placebo for dapagliflozin in patients with Type 2 diabetes who have inadequate glycemic control on metformin or metformin/sulfonylurea.

Conditions

Diabetes Mellitus, Type 2

Outcome Measures

Primary Outcomes (1)

• Change in Endogenous Glucose Production (EGP)

  All subjects received a Double-Tracer Oral Glucose Tolerance Test (OGTT) with 75g of glucose containing 14C-glucose together with intravenous primed-continuous infusion of 3(3H)-glucose for 240 minutes, at baseline (prior to) and after 16 weeks of therapy. Blood and urine samples were obtained during the OGTT to determine EGP.

  Baseline and 16 weeks

Secondary Outcomes (8)

• Change in Body Weight

  Baseline to 16 weeks

• Change in BMI

  Change from baseline to 16 weeks

• HBA1c

  Change from baseline to 16 weeks

• Mean Oral Glucose Tolerance Test (OGTT)

  Change from baseline to 16 weeks

• Change in Lipid Oxidation

  Change from baseline to 16 weeks

Study Arms (3)

DAPA/SAXA (dapagliflozin plus saxagliptin)

ACTIVE COMPARATOR

Dapagliflozin 10mg + Saxagliptin 5mg (plus standard of care treatment of metformin or metformin plus sulfonylurea).

Drug: Saxagliptin; Drug: Dapagliflozin

DAPA (Dapagliflozin plus placebo)

ACTIVE COMPARATOR

Dapagliflozin 10mg + Placebo (plus standard of care treatment of metformin or metformin plus sulfonylurea).

Drug: Dapagliflozin

PCB (Placebo plus placebo)

PLACEBO COMPARATOR

Placebo (for dapagliflozin) + placebo (for saxagliptin) (plus standard of care treatment of metformin or metformin plus sulfonylurea).

Drug: Placebo

Interventions

Saxagliptin DRUG

Saxagliptin (Onglyza™) is approved by the US FDA as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. The 5 mg dose will be used for this study as it is the dose that is routinely used in the clinic. In addition, this dose is used in the pivotal studies in the saxagliptin/dapagliflozin clinical program.

Also known as: Onglyza

DAPA/SAXA (dapagliflozin plus saxagliptin)

Dapagliflozin DRUG

Dapagliflozin (Farxiga) is approved by the FDA as an adjunct to diet and exercise to improve glycemic control in adults with T2DM. Dapagliflozin (Farxiga) is also approved in the EU as an adjunct to diet and exercise to improve glycemic control in patients with T2DM for whom metformin use is considered inappropriate due to intolerance, and in combination with other glucose-lowering medicinal products when these, in combination with diet and exercise do not provide adequate glycemic control. The 10 mg dose was chosen for this study because it has been extensively studied in Phase 3 trials and has demonstrated a favorable benefit-risk profile. In addition, this dose is the most commonly used dose in most countries.

Also known as: Farxiga

DAPA (Dapagliflozin plus placebo); DAPA/SAXA (dapagliflozin plus saxagliptin)

Placebo DRUG

Placebo

PCB (Placebo plus placebo)

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of informed consent prior to any study-specific procedures.
• Is able to read, understand, and sign the Informed Consent Forms (ICFs) and, if applicable, an Authorization to Use and Disclose Protected Health Information form (consistent with Health Insurance Portability and Accountability Act of 1996 legislation), communicate with the Investigator, and understand and comply with protocol requirements, including the use of diary and glucose meter measurements.
• Age = 18-70 years.
• Has a diagnosis of T2DM.
• Has HbA1c ≥7.5% and ≤11.0% obtained at Screening.
• Treated with a stable dose of metformin ≥1000 mg/day or stable dose of metformin (≥ 1000 mg/day) plus sulfonylurea (glipizide, ≥ 5 mg/day; glyburide, ≥ 5 mg/day; glimepiride, ≥ 4 mg/day) for at least 8 weeks prior to Screening.
• Has a BMI of 20 to 45 kg/m2 (inclusive) at Screening.
• Is male, or is female, and meets all the following criteria:
• Not pregnant or breastfeeding.
• Negative pregnancy test result at Visit 1 (Screening).
• Women of childbearing potential (WOCBP; \[including perimenopausal women who have had a menstrual period within 1 year\]) must practice and be willing to continue to practice appropriate birth control (defined as a method that results in a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as implants, injectables, hormonal contraceptives \[pills, vaginal rings, or patches\], some intrauterine contraceptive devices \[levonorgestrel-releasing or copper-T\], tubal ligation or occlusion, or a vasectomized partner) during the entire duration of the study. As applicable, all methods must be in effect prior to receiving the first dose of study medication.

You may not qualify if:

• Target Disease Exceptions
• Clinically diagnosed with Type I diabetes .
• History of diabetic ketoacidosis, hyperosmolar nonketotic coma, or corticosteroid induced Type 2 diabetes.
• Medical History and Concurrent Diseases
• History of bariatric surgery or lap-band surgery, or either procedure is planned during the time period of the study.
• History of any unstable endocrine, psychiatric, rapidly progressing, or unstable renal disease, or rheumatic disorder, as judged by the Investigator.
• Patients who, in the judgment of the Investigator, may be at risk for dehydration or volume depletion that may affect the patient's safety and/or the interpretation of efficacy or safety data.
• Has evidence of current abuse of drugs or alcohol or a history of abuse within the past 52 weeks that, in the Investigator's opinion, would cause the individual to be noncompliant.
• Cardiovascular Conditions
• Cardiovascular disease within 3 months of Screening (i.e., MI, cardiac surgery, revascularization, unstable angina, stroke, transient ischemic attack, or arrhythmia).
• Presence or history of severe congestive heart failure (New York Heart Association Class III and IV \[CCNYHA 1994\]), unstable or acute congestive heart failure, and/or known left ventricular ejection fraction of ≤40%.
• Note: Eligible patients with congestive heart failure, especially those who are on diuretic therapy, should have careful monitoring of their volume status throughout the study.
• Kidney Conditions
• Estimated (eGFR) \<60±5 mL/min/1.73 m2 or a measured serum creatinine of \>1.4 mg/dL for female patients and \>1.5 mg/dL for male patients. If the serum creatinine is ≤ 1.4 (female) or ≤ 1.5 (male) and the eGFR is ≥ 60±5 ml/min/1.73m2, the subject is eligible to participate in the study.
• Congenital renal glucosuria. Hepatic Conditions

Sponsors & Collaborators

• The University of Texas Health Science Center at San Antonio: lead
• AstraZeneca: collaborator

Study Sites (1)

The University of Texas Health Science Center at San Antonio

San Antonio, Texas, 78229, United States

Location

Related Publications (35)

• Rodbard HW, Blonde L, Braithwaite SS, Brett EM, Cobin RH, Handelsman Y, Hellman R, Jellinger PS, Jovanovic LG, Levy P, Mechanick JI, Zangeneh F; AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endocr Pract. 2007 May-Jun;13 Suppl 1:1-68. doi: 10.4158/EP.13.S1.1. No abstract available.

  PMID: 17613449 BACKGROUND

• Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011 Aug;32(4):515-31. doi: 10.1210/er.2010-0029. Epub 2011 May 23.

  PMID: 21606218 BACKGROUND

• Abdul-Ghani MA, Puckett C, Triplitt C, Maggs D, Adams J, Cersosimo E, DeFronzo RA. Initial combination therapy with metformin, pioglitazone and exenatide is more effective than sequential add-on therapy in subjects with new-onset diabetes. Results from the Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes (EDICT): a randomized trial. Diabetes Obes Metab. 2015 Mar;17(3):268-75. doi: 10.1111/dom.12417. Epub 2015 Jan 7.

  PMID: 25425451 BACKGROUND

• Ali MK, Bullard KM, Gregg EW. Achievement of goals in U.S. Diabetes Care, 1999-2010. N Engl J Med. 2013 Jul 18;369(3):287-8. doi: 10.1056/NEJMc1306652. No abstract available.

  PMID: 23863067 BACKGROUND

• Balas B, Baig MR, Watson C, Dunning BE, Ligueros-Saylan M, Wang Y, He YL, Darland C, Holst JJ, Deacon CF, Cusi K, Mari A, Foley JE, DeFronzo RA. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab. 2007 Apr;92(4):1249-55. doi: 10.1210/jc.2006-1882. Epub 2007 Jan 23.

  PMID: 17244786 BACKGROUND

• The Criteria Committee of the New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. (9th ed.). Boston: Little, Brown & Co. 1994; 253-256.

  BACKGROUND

• Centers for Disease Control and Prevention (CDC). Prevalence of overweight and obesity among adults with diagnosed diabetes--United States, 1988-1994 and 1999-2002. MMWR Morb Mortal Wkly Rep. 2004 Nov 19;53(45):1066-8.

  PMID: 15549021 BACKGROUND

• CHMP 2009 European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP). Guideline on Clinical Development of Fixed Combination Medicinal Products. CHMP/EWP/240/95 Rev. 1. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003686.pdf. Published 19 February 2009. Accessed 19 June 2014.

  BACKGROUND

• CHMP 2012 European Medicines Agency (EMA) Committee for Medicinal Products for Human Use (CHMP). Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus. CPMP/EWP/1080/00 Rev. 1. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf. Published 14 May 2012. Accessed 19 June 2014.

  BACKGROUND

• Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009 Apr;58(4):773-95. doi: 10.2337/db09-9028. No abstract available.

  PMID: 19336687 BACKGROUND

• Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011 Mar;13(3):258-67. doi: 10.1111/j.1463-1326.2010.01350.x.

  PMID: 21205122 BACKGROUND

• Dicker D. DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care. 2011 May;34 Suppl 2(Suppl 2):S276-8. doi: 10.2337/dc11-s229. No abstract available.

  PMID: 21525468 BACKGROUND

• Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86. doi: 10.1056/NEJM199309303291401.

  PMID: 8366922 BACKGROUND

• Ferrannini E, Bjorkman O, Reichard GA Jr, Pilo A, Olsson M, Wahren J, DeFronzo RA. The disposal of an oral glucose load in healthy subjects. A quantitative study. Diabetes. 1985 Jun;34(6):580-8. doi: 10.2337/diab.34.6.580.

  PMID: 3891471 BACKGROUND

• Goke B, Hershon K, Kerr D, Calle Pascual A, Schweizer A, Foley J, Shao Q, Dejager S. Efficacy and safety of vildagliptin monotherapy during 2-year treatment of drug-naive patients with type 2 diabetes: comparison with metformin. Horm Metab Res. 2008 Dec;40(12):892-5. doi: 10.1055/s-0028-1082334. Epub 2008 Aug 22.

  PMID: 18726829 BACKGROUND

• Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011 Jul;13(7):653-61. doi: 10.1111/j.1463-1326.2011.01391.x.

  PMID: 21410628 BACKGROUND

• Hansen L, Iqbal N, Ekholm E, Cook W, Hirshberg B. Postprandial dynamics of plasma glucose, insulin, and glucagon in patients with type 2 diabetes treated with saxagliptin plus dapagliflozin add-on to metformin therapy. Endocr Pract. 2014 Nov;20(11):1187-97. doi: 10.4158/EP14489.OR.

  PMID: 25370334 BACKGROUND

• Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008 Jan;31(1):81-6. doi: 10.2337/dc07-1572. Epub 2007 Oct 12.

  PMID: 17934153 BACKGROUND

• Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012 Jun;35(6):1364-79. doi: 10.2337/dc12-0413. Epub 2012 Apr 19. No abstract available.

  PMID: 22517736 BACKGROUND

• Jani R, Molina M, Matsuda M, Balas B, Chavez A, DeFronzo RA, Abdul-Ghani M. Decreased non-insulin-dependent glucose clearance contributes to the rise in fasting plasma glucose in the nondiabetic range. Diabetes Care. 2008 Feb;31(2):311-5. doi: 10.2337/dc07-1593. Epub 2007 Nov 13.

  PMID: 18000182 BACKGROUND

• Klein S, Sheard NF, Pi-Sunyer X, Daly A, Wylie-Rosett J, Kulkarni K, Clark NG; American Diabetes Association; North American Association for the Study of Obesity; American Society for Clinical Nutrition. Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies: a statement of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition. Diabetes Care. 2004 Aug;27(8):2067-73. doi: 10.2337/diacare.27.8.2067. No abstract available.

  PMID: 15277443 BACKGROUND

• Komoroski B, Vachharajani N, Boulton D, Kornhauser D, Geraldes M, Li L, Pfister M. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin Pharmacol Ther. 2009 May;85(5):520-6. doi: 10.1038/clpt.2008.251. Epub 2009 Jan 7.

  PMID: 19129748 BACKGROUND

• Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, Xiong J, Perez Z, Norton L, Abdul-Ghani MA, DeFronzo RA. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014 Feb;124(2):509-14. doi: 10.1172/JCI70704. Epub 2014 Jan 27.

  PMID: 24463448 BACKGROUND

• Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B. Management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. Update regarding the thiazolidinediones. Diabetologia. 2008 Jan;51(1):8-11. doi: 10.1007/s00125-007-0873-z. No abstract available.

  PMID: 18026926 BACKGROUND

• NHLBI 1998 National Heart, Lung, and Blood Institute (NHLBI) Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. NIH publication No. 98 4083. Available at: http://www.nhlbi.nih.gov/guidelines/obesity/ob_home.htm. Published September 1998. Accessed 19 June 2014.

  BACKGROUND

• Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med. 2011 Nov;28(11):1352-61. doi: 10.1111/j.1464-5491.2011.03387.x.

  PMID: 21781152 BACKGROUND

• Qaseem A, Vijan S, Snow V, Cross JT, Weiss KB, Owens DK; Clinical Efficacy Assessment Subcommittee of the American College of Physicians. Glycemic control and type 2 diabetes mellitus: the optimal hemoglobin A1c targets. A guidance statement from the American College of Physicians. Ann Intern Med. 2007 Sep 18;147(6):417-22. doi: 10.7326/0003-4819-147-6-200709180-00012.

  PMID: 17876024 BACKGROUND

• Rodbard HW, Jellinger PS, Davidson JA, Einhorn D, Garber AJ, Grunberger G, Handelsman Y, Horton ES, Lebovitz H, Levy P, Moghissi ES, Schwartz SS. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract. 2009 Sep-Oct;15(6):540-59. doi: 10.4158/EP.15.6.540.

  PMID: 19858063 BACKGROUND

• Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, McGuire DK, Ray KK, Leiter LA, Raz I; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013 Oct 3;369(14):1317-26. doi: 10.1056/NEJMoa1307684. Epub 2013 Sep 2.

  PMID: 23992601 BACKGROUND

• Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, Rosenzweig J, Vigersky R. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013 May;36(5):1384-95. doi: 10.2337/dc12-2480. Epub 2013 Apr 15.

  PMID: 23589542 BACKGROUND

• Sjostrand M, Iqbal N, Lu J, Hirshberg B. Saxagliptin improves glycemic control by modulating postprandial glucagon and C-peptide levels in Chinese patients with type 2 diabetes. Diabetes Res Clin Pract. 2014 Aug;105(2):185-91. doi: 10.1016/j.diabres.2014.05.006. Epub 2014 May 29.

  PMID: 24947443 BACKGROUND

• Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, Woerle HJ. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011 Jan;13(1):65-74. doi: 10.1111/j.1463-1326.2010.01326.x.

  PMID: 21114605 BACKGROUND

• Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53.

  PMID: 9742976 BACKGROUND

• Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):854-65.

  PMID: 9742977 BACKGROUND

• Qin Y, Adams J, Solis-Herrera C, Triplitt C, DeFronzo R, Cersosimo E. Clinical Parameters, Fuel Oxidation, and Glucose Kinetics in Patients With Type 2 Diabetes Treated With Dapagliflozin Plus Saxagliptin. Diabetes Care. 2020 Oct;43(10):2519-2527. doi: 10.2337/dc19-1993. Epub 2020 Jul 21.

  PMID: 32694214 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

saxagliptin; dapagliflozin

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Results Point of Contact

• Title: Yuejuan Qin
• Organization: University of Texas Health San Antonio

qiny@uthscsa.edu

210-617-5300

Study Officials

• Eugenio Cersosimo, MD

  The University of Texas Health Science Center at San Antonio

  PRINCIPAL INVESTIGATOR

• Ralph A DeFronzo, MD

  The University of Texas Health Science Center at San Antonio

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 12, 2015
• First Posted: November 25, 2015
• Study Start: January 1, 2016
• Primary Completion: June 30, 2018
• Study Completion: June 30, 2018
• Last Updated: August 14, 2019
• Results First Posted: August 14, 2019

Record last verified: 2019-06

Locations

US (1)