Study of Sitagliptin for the Treatment of Type 2 Diabetes Mellitus With Inadequate Glycemic Control on Insulin (MK-0431-260)

A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Study the Safety and Insulin-Sparing Efficacy of the Addition of Sitagliptin in Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Insulin Alone or in Combination With Metformin

The purpose of this study is to examine the insulin-sparing effect of sitagliptin 100 mg once-daily compared with placebo over 24 weeks in participants with type 2 diabetes mellitus who have inadequate glycemic control on insulin alone or in combination with metformin. The primary hypothesis of this study is that after 24 weeks, sitagliptin reduces the dose of insulin relative to placebo.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Sitagliptin; Biological: Insulin Glargine; Drug: Metformin; Drug: Comparator: Placebo

• Study Type: Interventional
• Enrollment (Actual): 660
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• has type 2 diabetes mellitus

• has one of the following criteria:

  • diagnosed with diabetes after age 40 years and insulin therapy was initiated at least 3 years following diagnosis
  • if diagnosed with diabetes under age 40 years or insulin started earlier than 3 years after diagnosis, has a fasting C-peptide greater than 0.7 ng/mL
• must be at least 18 years of age and less than or equal to 80 years of age (for participants in India: must be at least 18 years of age and less than or equal to 65 years of age)
• on a stable regimen of insulin for at least 10 weeks with or without metformin (at least 1500 mg/day) and/or sulfonylurea for at least 10 weeks
• is highly unlikely to become pregnant (not of reproductive potential or agrees to remain abstinent or use (or have their partner use) an acceptable method of birth control during the study and for 14 days after the last dose of study medication

Exclusion Criteria:

• has been treated with a dipeptidyl peptidase IV (DPP-4) inhibitor, a thiazolidinedione (TZD), or a glucagon-like peptide-1 (GLP-1) mimetic or analogue, within the past 12 weeks
• currently on treatment with daily use (one or more injections per day) of a

pre-prandial short-acting or rapid-acting insulin alone or as part of a basal/bolus insulin regimen

• has symptomatic hyperglycemia that requires immediate initiation, adjustment, or addition of antihyperglycemic therapy
• has a history of 2 or more episodes of hypoglycemia resulting in seizure,

coma, or loss of consciousness, - or - has had recurrent (≥3 times per week) episodes of hypoglycemia over the past 8 weeks

• has a history of ketoacidosis
• is not appropriate for or does not agree to target a fasting glucose of 72-100 mg/dL [4.0-5.6 mmol/L]
• is on or likely to require treatment with corticosteroids
• has undergone a surgical procedure within 4 weeks or has planned major surgery during the study
• is currently being treated for hyperthyroidism or is on thyroid hormone

therapy and has not been on a stable dose for at least 6 weeks

• has a history of active liver disease (other than non-alcoholic hepatic

steatosis)

• has had new or worsening signs or symptoms of coronary heart disease or

congestive heart failure within the past 3 months, or has any of the following

disorders within the past 3 months:

• acute coronary syndrome
• coronary artery intervention

• stroke or transient ischemic neurological disorder

  • has a systolic blood pressure greater than 160 mm Hg or a diastolic blood pressure greater than 90 mm Hg
  • has human immunodeficiency virus (HIV)
  • has severe peripheral vascular disease
  • has a clinically important hematological disorder
  • has a history of malignancy that is less than 5 years from study start, except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer
  • has a positive urine pregnancy test
  • is pregnant or breast-feeding, or is expecting to conceive or donate eggs

during the study

• a user of recreational or illicit drugs or has had a recent history of drug abuse

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sitagliptin; Sitagliptin 100 mg once daily	Drug: Sitagliptin; Sitagliptin 100 mg tablet once daily for 24 weeks; Other Names: Januvia; Biological: Insulin Glargine; Participants on insulin glargine or another insulin regimen for at least 10 weeks prior to screening will continue or switch to open-label insulin glargine once-daily in the evening for the duration of the study.; Drug: Metformin; Participants on metformin oral tablet(s) at a dose of at least 1500 mg/day for at least 10 weeks prior to screening will continue receiving metformin at their current dose for the duration of the study.; Other Names: Glucophage
Placebo Comparator: Placebo; Placebo to sitagliptin once daily	Biological: Insulin Glargine; Participants on insulin glargine or another insulin regimen for at least 10 weeks prior to screening will continue or switch to open-label insulin glargine once-daily in the evening for the duration of the study.; Drug: Metformin; Participants on metformin oral tablet(s) at a dose of at least 1500 mg/day for at least 10 weeks prior to screening will continue receiving metformin at their current dose for the duration of the study.; Other Names: Glucophage; Drug: Comparator: Placebo; Placebo to sitagliptin once daily for 24 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Daily Insulin Dose at Week 24	Change in daily insulin dose following 24 weeks of therapy (i.e., daily insulin dose at Week 24 minus daily insulin dose at baseline)	Baseline and Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Hemoglobin A1c (A1C) at Week 24	A1C is measured as the percentage of glycosylated hemoglobin. Change in A1C following 24 weeks of therapy (i.e., A1C at Week 24 minus A1C at baseline)	Baseline and Week 24
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24	Change in FPG (before breakfast) following 24 weeks of therapy (i.e., FPG at Week 24 minus FPG at baseline)	Baseline and Week 24
Percent of Participants Achieving Fasting Glucose Target at Any Time During the Study	The fasting glucose target was defined as 3 consecutive days with a fingerstick glucose of 72 to 100 mg/dL (4.0 - 5.6 mmol/L).	Up to 24 weeks
Time to Achieve the Fasting Glucose Target	Fasting glucose target 3 consecutive days with a fingerstick glucose of 72 to 100 mg/dL (4.0 - 5.6 mmol/L). This analysis was the Kaplan-Meier estimated 50th percentile of time (days) to first attainment of target.	Up to 24 weeks

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Mathieu C, Shankar RR, Lorber D, Umpierrez G, Wu F, Xu L, Golm GT, Latham M, Kaufman KD, Engel SS. A Randomized Clinical Trial to Evaluate the Efficacy and Safety of Co-Administration of Sitagliptin with Intensively Titrated Insulin Glargine. Diabetes Ther. 2015 Jun;6(2):127-42. doi: 10.1007/s13300-015-0105-3. Epub 2015 Mar 28.

Study record dates

Study Major Dates

• Study Start (Actual): January 13, 2012
• Primary Completion (Actual): June 6, 2013
• Study Completion (Actual): June 7, 2013

Study Registration Dates

• First Submitted: October 27, 2011
• First Submitted That Met QC Criteria: October 28, 2011
• First Posted (Estimate): October 31, 2011

Study Record Updates

• Last Update Posted (Actual): August 17, 2018
• Last Update Submitted That Met QC Criteria: July 20, 2018
• Last Verified: July 1, 2018

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; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Insulin Glargine; Sitagliptin Phosphate
• Other Study ID Numbers: 0431-260

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf

Study Data/Documents

1. CSR Synopsis