Effectiveness & Tolerability of Novel, Initial Triple Combination Therapy vs Conventional Therapy in Type 2 Diabetes

NCT02946632 | Unknown Phase 3 DMC

• 1 other identifier: TRIPLE-AXEL-ESR
• Study Type: interventional
• Target: 104
• Locations: 1 country
• Sites: 1

Brief Summary

In this study, the investigators will assess the efficacy and tolerability of a novel, initial triple combination therapy with metformin, saxaglipitin, and dapagliflozin, compared to conventional stepwise add-on therapy in drug-naïve patients with recently onset type 2 diabetes.

Conditions

Diabetes Mellitus, Type II

Outcome Measures

Primary Outcomes (1)

• Proportion of patients who met HbA1c < 6.5% without hypoglycaemia, weight gain, or discontinuation due to adverse events at 104 weeks

  104 weeks

Secondary Outcomes (6)

• ∙ Proportion of patients who met HbA1c < 6.5% without hypoglycaemia, weight gain, or discontinuation due to adverse events at 52 weeks

  52 weeks

• Proportion of patients who met HbA1c < 7.0% without hypoglycaemia, weight gain, or discontinuation due to adverse events at 104 weeks

  104 weeks

• Change in body HbA1c from baseline to week 104

  104 weeks

• Change in body weight from baseline to week 104

  104 weeks

• Change in systolic blood pressure from baseline to week 104

  104 weeks

Other Outcomes (1)

• AEs/SAEs

  104 weeks

Study Arms (2)

Triple combination therapy group

EXPERIMENTAL

Xigduo (metformin 1000mg + dapagliflozin 10mg), saxagliptin 5mg once daily for 104 weeks

Drug: triple combination therapy

Stepwise add-on therapy group

ACTIVE COMPARATOR

* Participants were started on metformin 1000mg once daily after screening \& assignment * At each visits, FPG and HbA1c are measured. Sequential add-on therapy regimen is described

Drug: Stepwise add-on therapy

Interventions

triple combination therapy DRUG

Xigduo (metformin 1000mg + dapagliflozin 10mg) saxagliptin 5mg

Also known as: metformin 1000mg, dapagliflozin 10mg, saxagliptin 5mg

Triple combination therapy group

Stepwise add-on therapy DRUG

metformin -\> glimepirde -\> sitagliptin

Also known as: Metformin, Glimepiride, Sitagliptin

Stepwise add-on therapy group

Eligibility Criteria

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

You may qualify if:

• Drug-naïve patients with type 2 diabetes by American Diabetes Association criteria
• HbA1c ≥ 8%, \< 10.5% at screening
• Age ≥ 18 years, \< 65 years
• Body mass index (BMI) ≥ 23 kg/m2, \< 35 kg/m2
• Estimated GFR (eGFR) ≥ 60 ml/min/1.73m2

You may not qualify if:

• Uncontrolled hyperglycemia \> 270 mg/dl after an overnight fast
• Diabetic ketoacidosis
• Type 1 diabetes
• Confirmed cardiovascular disease (acute coronary syndrome, stroke, or transient ischemic attack) within 3 months of screening
• Congestive heart failure (New York Heart Association functional class IV)
• severe hepatic dysfunction (serum levels of either AST, ALT, or alkaline phosphatase above 3 x upper limit of normal (ULN))
• alcohol abuse within the 3 months prior to informed consent that would interfere with trial participation or any ongoing condition leading to a decreased compliance to study procedures or study drug intake
• pregnant women, women with potential of pregnancy not using adequate contraception method as evaluated by the investigator, lactating women
• use of systemic glucocorticoid

Sponsors & Collaborators

• Korea University Anam Hospital: lead
• AstraZeneca: collaborator

Study Sites (1)

Korea University Anam Hospital

Seoul, South Korea

Location

Related Publications (15)

• Klein R, Klein BE, Moss SE. Relation of glycemic control to diabetic microvascular complications in diabetes mellitus. Ann Intern Med. 1996 Jan 1;124(1 Pt 2):90-6. doi: 10.7326/0003-4819-124-1_part_2-199601011-00003.

  PMID: 8554220 RESULT

• Moss SE, Klein R, Klein BE, Meuer SM. The association of glycemia and cause-specific mortality in a diabetic population. Arch Intern Med. 1994 Nov 14;154(21):2473-9.

  PMID: 7979844 RESULT

• 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 RESULT

• Action to Control Cardiovascular Risk in Diabetes Study Group; Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2545-59. doi: 10.1056/NEJMoa0802743. Epub 2008 Jun 6.

  PMID: 18539917 RESULT

• ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560-72. doi: 10.1056/NEJMoa0802987. Epub 2008 Jun 6.

  PMID: 18539916 RESULT

• Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008 Oct 9;359(15):1577-89. doi: 10.1056/NEJMoa0806470. Epub 2008 Sep 10.

  PMID: 18784090 RESULT

• 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 RESULT

• Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, Dagogo-Jack S, Davidson MB, Einhorn D, Garvey WT, Grunberger G, Handelsman Y, Hirsch IB, Jellinger PS, McGill JB, Mechanick JI, Rosenblit PD, Umpierrez GE, Davidson MH. American Association of Clinical Endocrinologists' comprehensive diabetes management algorithm 2013 consensus statement--executive summary. Endocr Pract. 2013 May-Jun;19(3):536-57. doi: 10.4158/EP13176.CS. No abstract available.

  PMID: 23816937 RESULT

• 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 RESULT

• 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 RESULT

• Lewin A, DeFronzo RA, Patel S, Liu D, Kaste R, Woerle HJ, Broedl UC. Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care. 2015 Mar;38(3):394-402. doi: 10.2337/dc14-2365. Epub 2015 Jan 29.

  PMID: 25633662 RESULT

• Rosenstock J, Hansen L, Zee P, Li Y, Cook W, Hirshberg B, Iqbal N. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care. 2015 Mar;38(3):376-83. doi: 10.2337/dc14-1142. Epub 2014 Oct 28.

  PMID: 25352655 RESULT

• Augeri DJ, Robl JA, Betebenner DA, Magnin DR, Khanna A, Robertson JG, Wang A, Simpkins LM, Taunk P, Huang Q, Han SP, Abboa-Offei B, Cap M, Xin L, Tao L, Tozzo E, Welzel GE, Egan DM, Marcinkeviciene J, Chang SY, Biller SA, Kirby MS, Parker RA, Hamann LG. Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005 Jul 28;48(15):5025-37. doi: 10.1021/jm050261p.

  PMID: 16033281 RESULT

• List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009 Apr;32(4):650-7. doi: 10.2337/dc08-1863. Epub 2008 Dec 29.

  PMID: 19114612 RESULT

• Kim NH, Lim S, Kwak SH, Moon MK, Moon JS, Lee YH, Cho HC, Lee J, Kim SG. Efficacy and tolerability of novel triple combination therapy in drug-naive patients with type 2 diabetes from the TRIPLE-AXEL trial: protocol for an open-label randomised controlled trial. BMJ Open. 2018 Sep 24;8(9):e022448. doi: 10.1136/bmjopen-2018-022448.

  PMID: 30249630 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Metformin; dapagliflozin; saxagliptin; glimepiride; Sitagliptin Phosphate

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Biguanides; Guanidines; Amidines; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines

Study Officials

• SinGon Kim, MD

  'Korea University Anam Hospital' in Seoul, Korea

  PRINCIPAL INVESTIGATOR

Central Study Contacts

SinGon Kim, MD

CONTACT

010-4191-0958; k50367@korea.ac.kr

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: October 25, 2016
• First Posted: October 27, 2016
• Study Start: December 1, 2016
• Primary Completion: December 1, 2019
• Study Completion: December 1, 2019
• Last Updated: October 27, 2016

Record last verified: 2016-10

Locations

KR (1)