MK0431 and Pioglitazone Co-Administration Factorial Study in Patients With Type 2 Diabetes Mellitus (0431-102 AM2)

A Multicenter, Randomized, Double-Blind Study of the Co-Administration of Sitagliptin and Pioglitazone in Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control

A study to evaluate the efficacy and safety of sitagliptin and pioglitazone co-administration in comparison with sitagliptin and pioglitazone monotherapy in patients with type 2 diabetes.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes Mellitus
• Intervention / Treatment: Drug: Sitagliptin phosphate; Drug: Matching placebo to pioglitazone; Drug: Metformin; Drug: Pioglitazone hydrochloride; Drug: Matching placebo to sitagliptin

• Study Type: Interventional
• Enrollment (Actual): 1615
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patient is highly unlikely to conceive
• Patient meets one of the 3 categories is naïve to all antihyperglycemic agent (AHA) therapies, or is non-naïve based upon the patient's current diet, medical regimen and screening A1c patient is currently not on AHA with a screening A1c >=7.5 % and =<11.0 % patient is currently on either metformin pr sulfonylurea monotherapy with a screening A1c >=7.0 % and =<9.0 %

Exclusion Criteria

• Patient has a history of type 1 diabetes mellitus or history of ketoacidosis or has C=peptide value of =<0.8 ng/mL
• Patient has previously been treated with insulin, thiazolidinedione (TZD) (rosiglitazone or pioglitazone), any Dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin, vildagliptin, or alogliptin), exenatide or has previously been in a clinical study with any DPP-4 inhibitor or incretin mimetic
• Patient is on a weight loss program and is not in the maintenance phase or has started a weight loss medication (e.g. orlistat or sibutramine) within the prior 8 weeks
• Patient has undergone surgery within the prior 30 days or has major surgery planned during the study
• Patient has a medical history of active liver disease including chronic active hepatitis B or C or symptomatic gallbladder disease including primary biliary cirrhosis
• Patient has received treatment with an investigational product within 12 weeks prior to Visit 1

Study Plan

How is the study designed?

Design Details

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

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sitagliptin 100 mg	Drug: Sitagliptin phosphate; Sitagliptin 100 mg tablet (blinded) orally once daily for 54 weeks.; Other Names: Januvia; Tesavel; Xelevia; Ristaben; Drug: Matching placebo to pioglitazone; Matching placebo to pioglitazone tablets or capsules orally once daily for 54 weeks.; Drug: Metformin; Metformin 500 mg (open-label) was to be initiated as rescue therapy to participants not meeting specific glycemic goals. The dose of metformin may have been uptitrated and adjusted, at the discretion of the investigator, up to the maximum approved dose in the country of origin.
Experimental: Pioglitazone 15 mg	Drug: Metformin; Metformin 500 mg (open-label) was to be initiated as rescue therapy to participants not meeting specific glycemic goals. The dose of metformin may have been uptitrated and adjusted, at the discretion of the investigator, up to the maximum approved dose in the country of origin.; Drug: Pioglitazone hydrochloride; Pioglitazone 15 mg, 30 mg, or 45 mg tablets or capsules (blinded) orally once daily for 54 weeks. Participants randomized to receive pioglitazone 45 mg as monotherapy or in combination with sitagliptin were to start on pioglitazone 30 mg at Week 1 and undergo uptitration to pioglitazone 45 mg at Week 4.; Other Names: Actos; Drug: Matching placebo to sitagliptin; Matching placebo to sitagliptin orally once daily for 54 weeks.
Experimental: Pioglitazone 30 mg	Drug: Metformin; Metformin 500 mg (open-label) was to be initiated as rescue therapy to participants not meeting specific glycemic goals. The dose of metformin may have been uptitrated and adjusted, at the discretion of the investigator, up to the maximum approved dose in the country of origin.; Drug: Pioglitazone hydrochloride; Pioglitazone 15 mg, 30 mg, or 45 mg tablets or capsules (blinded) orally once daily for 54 weeks. Participants randomized to receive pioglitazone 45 mg as monotherapy or in combination with sitagliptin were to start on pioglitazone 30 mg at Week 1 and undergo uptitration to pioglitazone 45 mg at Week 4.; Other Names: Actos; Drug: Matching placebo to sitagliptin; Matching placebo to sitagliptin orally once daily for 54 weeks.
Experimental: Pioglitazone 45 mg	Drug: Metformin; Metformin 500 mg (open-label) was to be initiated as rescue therapy to participants not meeting specific glycemic goals. The dose of metformin may have been uptitrated and adjusted, at the discretion of the investigator, up to the maximum approved dose in the country of origin.; Drug: Pioglitazone hydrochloride; Pioglitazone 15 mg, 30 mg, or 45 mg tablets or capsules (blinded) orally once daily for 54 weeks. Participants randomized to receive pioglitazone 45 mg as monotherapy or in combination with sitagliptin were to start on pioglitazone 30 mg at Week 1 and undergo uptitration to pioglitazone 45 mg at Week 4.; Other Names: Actos; Drug: Matching placebo to sitagliptin; Matching placebo to sitagliptin orally once daily for 54 weeks.
Experimental: Sitagliptin 100 mg/ Pioglitazone 15 mg	Drug: Sitagliptin phosphate; Sitagliptin 100 mg tablet (blinded) orally once daily for 54 weeks.; Other Names: Januvia; Tesavel; Xelevia; Ristaben; Drug: Metformin; Metformin 500 mg (open-label) was to be initiated as rescue therapy to participants not meeting specific glycemic goals. The dose of metformin may have been uptitrated and adjusted, at the discretion of the investigator, up to the maximum approved dose in the country of origin.; Drug: Pioglitazone hydrochloride; Pioglitazone 15 mg, 30 mg, or 45 mg tablets or capsules (blinded) orally once daily for 54 weeks. Participants randomized to receive pioglitazone 45 mg as monotherapy or in combination with sitagliptin were to start on pioglitazone 30 mg at Week 1 and undergo uptitration to pioglitazone 45 mg at Week 4.; Other Names: Actos
Experimental: Sitagliptin 100 mg/ Pioglitazone 30 mg	Drug: Sitagliptin phosphate; Sitagliptin 100 mg tablet (blinded) orally once daily for 54 weeks.; Other Names: Januvia; Tesavel; Xelevia; Ristaben; Drug: Metformin; Metformin 500 mg (open-label) was to be initiated as rescue therapy to participants not meeting specific glycemic goals. The dose of metformin may have been uptitrated and adjusted, at the discretion of the investigator, up to the maximum approved dose in the country of origin.; Drug: Pioglitazone hydrochloride; Pioglitazone 15 mg, 30 mg, or 45 mg tablets or capsules (blinded) orally once daily for 54 weeks. Participants randomized to receive pioglitazone 45 mg as monotherapy or in combination with sitagliptin were to start on pioglitazone 30 mg at Week 1 and undergo uptitration to pioglitazone 45 mg at Week 4.; Other Names: Actos
Experimental: Sitagliptin 100 mg/ Pioglitazone 45 mg	Drug: Sitagliptin phosphate; Sitagliptin 100 mg tablet (blinded) orally once daily for 54 weeks.; Other Names: Januvia; Tesavel; Xelevia; Ristaben; Drug: Metformin; Metformin 500 mg (open-label) was to be initiated as rescue therapy to participants not meeting specific glycemic goals. The dose of metformin may have been uptitrated and adjusted, at the discretion of the investigator, up to the maximum approved dose in the country of origin.; Drug: Pioglitazone hydrochloride; Pioglitazone 15 mg, 30 mg, or 45 mg tablets or capsules (blinded) orally once daily for 54 weeks. Participants randomized to receive pioglitazone 45 mg as monotherapy or in combination with sitagliptin were to start on pioglitazone 30 mg at Week 1 and undergo uptitration to pioglitazone 45 mg at Week 4.; Other Names: Actos

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Hemoglobin A1C (A1C) at Week 24	A1C represents the percentage of glycosylated hemoglobin.	Baseline and Week 24
Change From Baseline in A1C at Week 54	A1C represents the percentage of glycosylated hemoglobin.	Baseline and Week 54

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24		Baseline and Week 24
Change From Baseline in 2-Hour Post-meal Glucose (PMG) at Week 24	PMG was measured using the Meal Tolerance Test (MTT).	Baseline and Week 24
Change From Baseline in FPG at Week 54		Baseline and Week 54
Change From Baseline in 2-Hour PMG at Week 54	PMG was measured using the Meal Tolerance Test (MTT).	Baseline and Week 54

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Henry RR, Staels B, Fonseca VA, Chou MZ, Teng R, Golm GT, Langdon RB, Kaufman KD, Steinberg H, Goldstein BJ. Efficacy and safety of initial combination treatment with sitagliptin and pioglitazone--a factorial study. Diabetes Obes Metab. 2014 Mar;16(3):223-30. doi: 10.1111/dom.12194. Epub 2013 Aug 29.

Study record dates

Study Major Dates

• Study Start (Actual): September 5, 2008
• Primary Completion (Actual): October 26, 2010
• Study Completion (Actual): March 25, 2011

Study Registration Dates

• First Submitted: July 22, 2008
• First Submitted That Met QC Criteria: July 24, 2008
• First Posted (Estimate): July 25, 2008

Study Record Updates

• Last Update Posted (Actual): May 12, 2017
• Last Update Submitted That Met QC Criteria: April 7, 2017
• Last Verified: April 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; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Dipeptidyl-Peptidase IV Inhibitors; Metformin; Pioglitazone; Sitagliptin Phosphate
• Other Study ID Numbers: 0431-102; 2008_522 (Other Identifier: Merck Study Number)

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No