Comparison of Two Treatment Regimens (Sitagliptin Versus Liraglutide) on Participants Who Failed to Achieve Good Glucose Control on Metformin Alone (MK-0431-403)

A Phase III, Multicenter, Randomized, Open-label Clinical Trial Comparing the Efficacy and Safety of a Sitagliptin-Based Treatment Paradigm to a Liraglutide-Based Treatment Paradigm in Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Metformin Monotherapy

This study is being done to compare the effectiveness and safety of two treatment paradigms (oral sitagliptin with or without glimepiride versus liraglutide with or without increased dosing) for the treatment of participants with Type 2 Diabetes that is not adequately controlled with metformin alone. The primary hypothesis postulated that the mean change from baseline in hemoglobin A1c (A1C) in participants treated with a sitagliptin-based treatment is non-inferior to that of participants treated with a liraglutide-based

treatment.

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: sitagliptin; Drug: glimepiride; Drug: metformin; Drug: liraglutide

• Study Type: Interventional
• Enrollment (Actual): 653
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 77 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

• Type 2 diabetes mellitus.
• On stable dose of metformin monotherapy at a dose of at least 1500 mg per day for at least 12 weeks and a hemoglobin A1C ≥7.0% and ≤11.0%.
• Capable of using a liraglutide pen device.

Exclusion criteria

• History of Type 1 Diabetes mellitus.
• Use of any oral antihyperglycemic agent (AHA) besides metformin, within the prior 12 weeks of screening.
• Cardiovascular disorders within the past 3 months including acute coronary syndrome or new or worsening symptoms of coronary heart disease, coronary artery intervention, stroke, or transient ischemic neurological disorder.
• Impaired liver function.
• Impaired kidney function.
• History of malignancy or clinically important hematological disorder that requires disease-specific treatment (chemotherapy, radiation therapy, surgery) or, in the opinion of the investigator, is likely to recur during the duration of the study.
• History of leukemia, lymphoma, aplastic anemia, myeloproliferative or myelodysplastic diseases, thrombocytopenia, or malignant melanoma, regardless of the time since treatment.
• Pregnancy or breastfeeding, or intention to become pregnant or donate eggs within the projected duration of the study.
• Participation in another study with an investigational drug or device within 12 weeks prior to screening.
• History of hypersensitivity or any contraindication to sitagliptin, liraglutide, glimepiride, or metformin based upon the labels of the country of the investigational site.
• Participation in a weight loss program and not yet in maintenance phase, or starting of a weight loss medication (such as orlistat or phentermine) within the prior 8 weeks.
• Surgery within the prior 4 weeks or major surgery planned during the study.
• Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN 2).
• User of recreational or illicit drugs or recent history (within the last year) of drug abuse or increased alcohol consumption.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sitagliptin +/- glimepiride; Sitagliptin 100 mg tablet orally once daily for 26 weeks. Participants continued their stable dose of metformin >=1500 mg orally daily. Participants may have received glimepiride orally for glycemic control.	Drug: sitagliptin; 100 mg tablet, orally, once daily.; Other Names: MK-0431, Januvia®, Tesavel®, Xelevia®, Ristaben®; Drug: glimepiride; starting dose of 1 mg tablet (up-titrated as needed), once daily, as needed, after Week 12.; Other Names: Amaryl®; Drug: metformin; metformin tablets at a dose of ≥1500 mg per day; Other Names: Fortamet®, Glucophage®, Glucophage® XR, Glumetza®, Riomet®, Metgluco®, Glycoran®
Active Comparator: Liraglutide; Liraglutide subcutaneous injection once daily for 26 weeks (starting dose 0.6 mg daily up-titrated to 1.2 mg daily on Day 8). Participants continued their stable dose of metformin >=1500 mg orally daily. Participants may have had their liraglutide dose uptitrated to 1.8 mg daily for glycemic control.	Drug: metformin; metformin tablets at a dose of ≥1500 mg per day; Other Names: Fortamet®, Glucophage®, Glucophage® XR, Glumetza®, Riomet®, Metgluco®, Glycoran®; Drug: liraglutide; 0.6 mg by subcutaneous (pen) injection, once daily, on Days 1-7; up-titrated on Day 8 to 1.2 mg daily. At Week 12, dose may be increased to 1.8 mg once daily for participants who did not meet protocol-specified glycemic goals.; Other Names: Victoza®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Hemoglobin A1c (A1C)	A1C is measured as percent. Thus, this change from baseline reflects the Week 26 A1C percent minus the Week 0 A1C percent.	Baseline and Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Fasting Plasma Glucose (FPG)	Change from baseline at Week 26 is defined as Week 26 minus Week 0.	Baseline and Week 26
Percentage of Participants Reaching A1C Goal of <7.0%		Week 26
Percentage of Participants Reaching A1C Goal of <6.5%		Week 26

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Charbonnel B, Steinberg H, Eymard E, Xu L, Thakkar P, Prabhu V, Davies MJ, Engel SS. Efficacy and safety over 26 weeks of an oral treatment strategy including sitagliptin compared with an injectable treatment strategy with liraglutide in patients with type 2 diabetes mellitus inadequately controlled on metformin: a randomised clinical trial. Diabetologia. 2013 Jul;56(7):1503-11. doi: 10.1007/s00125-013-2905-1. Epub 2013 Apr 19.

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2011
• Primary Completion (Actual): February 29, 2012
• Study Completion (Actual): February 29, 2012

Study Registration Dates

• First Submitted: February 14, 2011
• First Submitted That Met QC Criteria: February 14, 2011
• First Posted (Estimate): February 15, 2011

Study Record Updates

• Last Update Posted (Actual): June 9, 2017
• Last Update Submitted That Met QC Criteria: May 9, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• 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; Anti-Arrhythmia Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Liraglutide; Metformin; Sitagliptin Phosphate; Glimepiride
• Other Study ID Numbers: 0431-403

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf

http://engagezone.msd.com/ds_documentation.php