Sitagliptin (MK-0431) vs. Placebo in Patients With Inadequate Glycemic Control on Metformin With Pioglitazone (MK-0431-128)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00885352
• Collaborator: (none)
• Enrollment: 313
• Arms: 2
• Actual Duration (Months): 18.9

Study Details

Study Description

Brief Summary

This study will examine the safety and efficacy of the addition of sitagliptin (MK-0431) compared to placebo in patients with type 2 diabetes mellitus with inadequate glycemic control who are taking pioglitazone and metformin.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Sitagliptin; Drug: Comparator: Placebo; Drug: Pioglitazone; Drug: Metformin; Drug: Glipizide	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 313 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized, Placebo-Controlled Clinical Trial to Study the Safety and Efficacy of the Addition of Sitagliptin (MK-0431) in Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Combination Therapy With Metformin and Pioglitazone
• Actual Study Start Date: Apr 15, 2009
• Actual Primary Completion Date: Nov 10, 2010
• Actual Study Completion Date: Nov 10, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sitagliptin Sitagliptin 100 mg tablet orally once daily for 26 weeks.	Drug: Sitagliptin; Sitagliptin 100 mg tablet orally once daily for 26 weeks.; Other Names: Januvia MK-0431 ; Drug: Pioglitazone; Participants taking 30 mg or more pioglitazone oral tablet(s) daily at screening in combination with metformin will enter a 4-week dose-stable period followed by a 2-week single-blind run-in and a 26-week treatment period. Participants taking 4 mg or more rosiglitazone oral tablet(s) daily at screening in combination with metformin were to be switched to a corresponding dose of pioglitazone prior to starting a 4-week dose-stable period. Participants who are taking less than 30 mg/day or no pioglitazone at screening will be titrated to a stable dose of at least 30 mg pioglitazone once daily over a maximum of 4 weeks followed by a dose-stable period of 10 weeks, a 2-week single-blind placebo run-in, and a 26-week treatment period. Total treatment with pioglitazone will be up to 42 weeks.; Other Names: Actos ; Drug: Metformin; Participants taking 1500 mg or more metformin oral tablet(s) and at least 30 mg pioglitazone or 4 mg rosiglitazone daily at screening will enter a 4-week dose-stable period followed by a 2-week single-blind placebo run-in, and a 26-week treatment period. Participants who are taking less than 1500 mg/day metformin at screening will be titrated to a stable dose of at least 1500 mg metformin once daily over a maximum of 4 weeks followed by a dose-stable period of 10 weeks, a 2-week single-blind placebo run-in, and a 26-week treatment period. Total treatment with metformin will be up to 42 weeks.; Other Names: Glucophage ; Drug: Glipizide; Participants not meeting specific glycemic controls during the 26-week treatment period will use glipizide oral tablets as rescue therapy. In countries where glipizide is not available, participants will receive a sulfonylurea marketed in that country.; Other Names: Glucotrol
Placebo Comparator: Placebo Placebo to sitagliptin orally once daily for 26 weeks.	Drug: Comparator: Placebo; Placebo to sitagliptin 100 mg tablet orally once daily for 26 weeks.; Drug: Pioglitazone; Participants taking 30 mg or more pioglitazone oral tablet(s) daily at screening in combination with metformin will enter a 4-week dose-stable period followed by a 2-week single-blind run-in and a 26-week treatment period. Participants taking 4 mg or more rosiglitazone oral tablet(s) daily at screening in combination with metformin were to be switched to a corresponding dose of pioglitazone prior to starting a 4-week dose-stable period. Participants who are taking less than 30 mg/day or no pioglitazone at screening will be titrated to a stable dose of at least 30 mg pioglitazone once daily over a maximum of 4 weeks followed by a dose-stable period of 10 weeks, a 2-week single-blind placebo run-in, and a 26-week treatment period. Total treatment with pioglitazone will be up to 42 weeks.; Other Names: Actos ; Drug: Metformin; Participants taking 1500 mg or more metformin oral tablet(s) and at least 30 mg pioglitazone or 4 mg rosiglitazone daily at screening will enter a 4-week dose-stable period followed by a 2-week single-blind placebo run-in, and a 26-week treatment period. Participants who are taking less than 1500 mg/day metformin at screening will be titrated to a stable dose of at least 1500 mg metformin once daily over a maximum of 4 weeks followed by a dose-stable period of 10 weeks, a 2-week single-blind placebo run-in, and a 26-week treatment period. Total treatment with metformin will be up to 42 weeks.; Other Names: Glucophage ; Drug: Glipizide; Participants not meeting specific glycemic controls during the 26-week treatment period will use glipizide oral tablets as rescue therapy. In countries where glipizide is not available, participants will receive a sulfonylurea marketed in that country.; Other Names: Glucotrol

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Hemoglobin A1c (A1C) at Week 26 [Baseline and Week 26]

   Change from baseline reflects the Week 26 value minus the baseline value. A1C represents the percentage of glycosylated hemoglobin.

Secondary Outcome Measures

1. Change From Baseline in 2-Hour Post-Meal Glucose (PMG) at Week 26 [Baseline and Week 26]

   Change from baseline reflects the Week 26 value minus the baseline value.

2. Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26 [Baseline and Week 26]

   Change from baseline reflects the Week 26 value minus the baseline value.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 78 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• has type 2 diabetes and is at least 18 years of age and no older than 78 years of age

• is male or is a female who is unlikely to conceive children

• is on stable doses of a peroxisome proliferator-activated receptor gamma agonist and metformin OR metformin and a sulfonylurea agent

Exclusion Criteria:

• has type 1 diabetes

• has taken a dipeptidyl peptidase (DPP-4) inhibitor or a glucagon-like peptide-1 (GLP-1) analogue

• is on a weight loss program that is not in the maintenance phase or has started a weight loss medication within 8 weeks of screening

• has had surgery within 30 days of screening or has major surgery planned during the study

• is on or is likely to require treatment with corticosteroids for more than 2 weeks

• has a history of active liver disease, including hepatitis B or C, cirrhosis, or gallbladder disease

• is human immunodeficiency virus (HIV) positive

• has congestive heart failure, or has had new or worsening symptoms of coronary heart disease within 3 months prior to screening

• has had acute coronary syndrome, coronary artery intervention, or stroke within 3 months of screening

• has severe active peripheral vascular disease

• has a history of cancer or blood disorder

• is pregnant or breast feeding

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Monitor, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT00885352
• Other Study ID Numbers: 0431-128; 2009_577
• First Posted: Apr 21, 2009
• Last Update Posted: May 23, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Metformin; Pioglitazone; Sitagliptin Phosphate; Glipizide

Study Results

Participant Flow

Pre-assignment Detail	Lab abnormalities (the reason for discontinuation cited below) included creatinine, creatinine clearance, and estimated glomerular filtration rate.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Sitagliptin 100 mg once daily	Placebo to sitagliptin once daily
Period Title: Overall Study
STARTED	157	156
COMPLETED	149	136
NOT COMPLETED	8	20

Baseline Characteristics

Arm/Group Title	Sitagliptin	Placebo	Total
Arm/Group Description	Sitagliptin 100 mg once daily	Placebo to sitagliptin once daily	Total of all reporting groups
Overall Participants	157	156	313
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.7 (8.7)	56.4 (9.4)	56.1 (9.0)
Sex: Female, Male (Count of Participants)
Female	60 38.2%	58 37.2%	118 37.7%
Male	97 61.8%	98 62.8%	195 62.3%
Hemoglobin A1c (A1C) (Percent of gylcosylated hemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent of gylcosylated hemoglobin]	8.8 (1.0)	8.7 (1.0)	8.7 (1.0)
2-hour post-meal glucose (PMG) (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	275.5 (66.4)	266.0 (62.4)	270.8 (64.5)
Fasting plasma glucose (FPG) (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	179.3 (44.3)	173.6 (38.9)	176.5 (41.7)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Hemoglobin A1c (A1C) at Week 26
Description	Change from baseline reflects the Week 26 value minus the baseline value. A1C represents the percentage of glycosylated hemoglobin.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set excluded participants without baseline or post-baseline data. Full analysis set with last observation carried forward.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Sitagliptin 100 mg once daily	Placebo to sitagliptin once daily
Measure Participants	152	153
Least Squares Mean (95% Confidence Interval) [Percent of glycosylated hemoglobin]	-1.15 (0.93)	-0.40 (1.00)

2. Secondary Outcome

Title	Change From Baseline in 2-Hour Post-Meal Glucose (PMG) at Week 26
Description	Change from baseline reflects the Week 26 value minus the baseline value.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set excluded participants without baseline or post-baseline data. Full analysis set with last observation carried forward.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Sitagliptin 100 mg once daily	Placebo to sitagliptin once daily
Measure Participants	141	135
Least Squares Mean (95% Confidence Interval) [mg/dL]	-54.4 (64.4)	-14.7 (59.6)

3. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG) at Week 26
Description	Change from baseline reflects the Week 26 value minus the baseline value.
Time Frame	Baseline and Week 26

Outcome Measure Data

Analysis Population Description

Full analysis set excluded participants without baseline or post-baseline data. Full analysis set with last observation carried forward.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Sitagliptin 100 mg once daily	Placebo to sitagliptin once daily
Measure Participants	155	153
Least Squares Mean (95% Confidence Interval) [mg/dL]	-20.3 (49.5)	-2.8 (41.6)

Adverse Events

Time Frame	Weeks 0 to 26
Adverse Event Reporting Description	Participants received glycemic rescue medication if they met specific glycemic goals. Serious adverse events include events that occurred either before or after receiving rescue medication. Other adverse events only include those AEs that occurred prior to a participant receiving rescue medication.
Arm/Group Title	Sitagliptin 100 mg		Placebo
Arm/Group Description	Sitagliptin 100 mg once daily		Placebo to sitagliptin once daily
All Cause Mortality
	Sitagliptin 100 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sitagliptin 100 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/157 (1.9%)		6/156 (3.8%)
Cardiac disorders
Cardiac arrest	0/157 (0%)	0	1/156 (0.6%)	1
Gastrointestinal disorders
Gastric ulcer haemorrhage	0/157 (0%)	0	1/156 (0.6%)	1
Peritonitis	0/157 (0%)	0	1/156 (0.6%)	1
General disorders
Chest discomfort	1/157 (0.6%)	1	0/156 (0%)	0
Infections and infestations
Appendicitis	0/157 (0%)	0	1/156 (0.6%)	1
Dengue fever	0/157 (0%)	0	1/156 (0.6%)	1
Injury, poisoning and procedural complications
Cartilage injury	0/157 (0%)	0	1/156 (0.6%)	1
Patella fracture	0/157 (0%)	0	1/156 (0.6%)	1
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/157 (0%)	0	1/156 (0.6%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	1/157 (0.6%)	1	0/156 (0%)	0
Renal and urinary disorders
Renal colic	1/157 (0.6%)	1	0/156 (0%)	0
Other (Not Including Serious) Adverse Events
	Sitagliptin 100 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/157 (14%)		20/156 (12.8%)
Infections and infestations
Upper respiratory tract infection	13/157 (8.3%)	13	14/156 (9%)	15
Metabolism and nutrition disorders
Hypoglycaemia	10/157 (6.4%)	23	7/156 (4.5%)	16

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the sponsor as confidential must be deleted prior to submission.