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

Diabetes Mellitus, Type II Clinical Trial

Official title:

Effectiveness and Tolerability of Novel, Initial Triple Combination Therapy With Xigduo (Dapagliflozin Plus Metformin) and Saxagliptin vs. Conventional Stepwise add-on Therapy in Drug-naïve Patients With Type 2 Diabetes

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02946632
• Other study ID #: TRIPLE-AXEL-ESR
• Status: Not yet recruiting
• Phase: Phase 3
• First received: October 25, 2016
• Last updated: October 26, 2016
• Start date: December 2016
• Est. completion date: December 2019

Study information

• Verified date: October 2016
• Source: Korea University Anam Hospital
• Contact: SinGon Kim, MD
• Phone: 010-4191-0958
• Email: k50367[@]korea.ac.kr
• Is FDA regulated: No
• Health authority: Korea: Institutional Review BoardKorea: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Description:

ADA/EASD guideline recommends sequential treatment approach starting with metformin, and adding other classes of anti-diabetic medications if target HbA1c is not achieved. However, several clinical studies clearly showed that initial dual or triple combination therapy was more favorable in terms of glycemic control.

A DPP-4 inhibitor saxagliptin increases serum level of GLP-1, and potentiates its action of increasing glucose-dependent insulin secretion and lowering glucagon secretion. A SGLT-2 inhibitor dapagliflozin lowers hyperglycemia via blocking SGLT-2 to increase glucosuria, that is, in an insulin-independent manner. Therefore, the mechanism of action of these drugs are complimentary to that of metformin, and all of these have a low risk of hypoglycemia and weight gain.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 104
• Est. completion date: December 2019
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Diabetes Mellitus, Type II

Intervention

Drug:
• triple combination therapy
Xigduo (metformin 1000mg + dapagliflozin 10mg) saxagliptin 5mg
• Stepwise add-on therapy
metformin -> glimepirde -> sitagliptin

Locations

Country	Name	City	State
Korea, Republic of	Korea University Anam Hospital	Seoul

Sponsors (2)

Lead Sponsor	Collaborator
Korea University Anam Hospital	AstraZeneca

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (14)

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 th — View Citation

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 gl — View Citation

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 — View Citation

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. D — View Citation

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. — View Citation

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 Ass — View Citation

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. — View Citation

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. E — View Citation

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: — View Citation

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. — View Citation

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. Erratum in: Diabet — View Citation

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. — View Citation

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. — View Citation

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 sa — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	AEs/SAEs	hypoglycemia, GI trouble, urinary tract infection, genital infection, volume depletion, panreatitis, severe cutaneous events, hypersensitivity reactions); Vital signs; Collection of clinical chemistry/haematology parameters	104 weeks	Yes
Primary	Proportion of patients who met HbA1c < 6.5% without hypoglycaemia, weight gain, or discontinuation due to adverse events at 104 weeks		104 weeks	Yes
Secondary	· Proportion of patients who met HbA1c < 6.5% without hypoglycaemia, weight gain, or discontinuation due to adverse events at 52 weeks		52 weeks	Yes
Secondary	Proportion of patients who met HbA1c < 7.0% without hypoglycaemia, weight gain, or discontinuation due to adverse events at 104 weeks		104 weeks	Yes
Secondary	Change in body HbA1c from baseline to week 104		104 weeks	No
Secondary	Change in body weight from baseline to week 104		104 weeks	No
Secondary	Change in systolic blood pressure from baseline to week 104		104 weeks	No
Secondary	Changes in fat and lean mass from baseline to at 104 weeks		104 weeks	No