Clinical Trial to Evaluate the Safety and Efficacy of the Addition of Sitagliptin in Participants With Type 2 Diabetes Mellitus Receiving Acarbose Monotherapy (MK-0431-130)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01177384
• Collaborator: (none)
• Enrollment: 380
• Arms: 2
• Actual Duration (Months): 26

Study Details

Study Description

Brief Summary

This study will evaluate whether the addition of sitagliptin reduces hemoglobin A1C (A1C) more than the addition of placebo for participants with type 2 diabetes mellitus (T2DM) on a steady dose of acarbose. The primary hypothesis is that the addition of sitagliptin 100 mg once daily (q.d.) reduces A1C more than the addition of placebo in participants with T2DM with inadequate glycemic control on acarbose monotherapy.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Sitagliptin phosphate; Drug: Comparator: Placebo; Drug: Acarbose; Drug: Glimepiride	Phase 3

Detailed Description

The study includes an 8-week antihyperglycemic agent (AHA) wash-off period* (which includes a 2-week single-blind placebo run-in period) followed by a 24-week double-blind treatment period. All participants will receive open-label acarbose at a minimum dose of 50 mg three times daily (t.i.d.) during the run-in and treatment periods.

*: Wash-off only applicable to patients who were on acarbose and another AHA.

Study Design

• Study Type: Interventional
• Actual Enrollment: 380 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III, Multicenter, Randomized, Placebo-Controlled, Double-Blind Clinical Trial to Evaluate the Safety and Efficacy of the Addition of Sitagliptin in Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control on Diet/Exercise Therapy and Acarbose Monotherapy
• Actual Study Start Date: Jan 25, 2011
• Actual Primary Completion Date: Mar 25, 2013
• Actual Study Completion Date: Mar 25, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sitagliptin Sitagliptin 100 mg daily (q.d.) + acarbose (continuing the current stable dose of at least 50 mg three times daily [t.i.d.])	Drug: Sitagliptin phosphate; Sitagliptin, 100 mg tablet once daily, orally for 24 weeks; Other Names: Januvia ; Drug: Acarbose; Acarbose 50 mg or 100 mg tablet, 3 times daily, orally (continuing on the stable dose established prior to screening) for 24 weeks; Other Names: Precose ; Drug: Glimepiride; Participants not meeting specific glycemic goals during the study will use glimepiride as rescue therapy. For countries where glimepiride is not available, participants will receive a sulfonylurea marketed in that country as rescue therapy.; Other Names: Amaryl® Glimy
Placebo Comparator: Placebo Placebo q.d. + acarbose (continuing the current stable dose of at least 50 mg t.i.d.)	Drug: Comparator: Placebo; Placebo, to match sitagliptin tablet, once daily, orally for 24 weeks; Drug: Acarbose; Acarbose 50 mg or 100 mg tablet, 3 times daily, orally (continuing on the stable dose established prior to screening) for 24 weeks; Other Names: Precose ; Drug: Glimepiride; Participants not meeting specific glycemic goals during the study will use glimepiride as rescue therapy. For countries where glimepiride is not available, participants will receive a sulfonylurea marketed in that country as rescue therapy.; Other Names: Amaryl® Glimy

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Hemoglobin A1c (A1C) at Week 24 [Baseline and Week 24]

   A1C is measured as a percent. Thus, this change from baseline reflects the Week 24 A1C percent minus the Week 0 A1C percent. Efficacy analyses treated data as missing after the initiation of rescue therapy.

2. Number of Participants Who Experienced at Least One Adverse Event [Up to Week 24 + 14 Day Post-Study Follow-up]

3. Number of Participants Who Discontinued Study Drug Due to an Adverse Event [Up to 24 Weeks]

Secondary Outcome Measures

1. Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 [Baseline and Week 24]

   Change from baseline at Week 24 is defined as Week 24 FPG minus Week 0 FPG. Efficacy analyses treated data as missing after the initiation of rescue therapy.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• has T2DM and is on acarbose alone at a stable dose of at least 50 mg t.i.d.(three times a day) for at least 10 weeks or on acarbose at a stable dose of at least 50 mg t.i.d. (three times a day) for at least 10 weeks in combination with another antihyperglycemic agent (AHA)

• is at least 18 years of age (for participants in India: between 18 and 65 years of age)

• male or female who is unlikely to conceive (not of reproductive potential, or agrees to remain abstinent or use [or have partner use] acceptable birth control if of reproductive potential)

Exclusion Criteria:

• has a history of type 1 diabetes mellitus

• use of thiazolidinedione (TZD), dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, or insulin

• has the following cardiovascular disorders: acute coronary syndrome; new or worsening symptoms of coronary heart disease; coronary artery intervention; stroke or transient ischemic neurological disorder

• has liver or kidney disease

• has cancer or any clinically significant disease or disorder as judged by the Investigator

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: NCT01177384
• Other Study ID Numbers: 0431-130; 2010_543; CTRI/2011/10/002072
• First Posted: Aug 9, 2010
• Last Update Posted: Aug 16, 2018
• Last Verified: Jul 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Merck Sharp & Dohme LLC: Type 2 diabetes mellitus; T2DM
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Sitagliptin Phosphate; Glimepiride; Acarbose

Study Results

Participant Flow

Pre-assignment Detail	All participants randomized population. The participant flow module includes the second sequential randomization of a participant in the placebo group. Data for the second sequential randomization were excluded from the efficacy and safety analyses and the reason for not completed was a protocol violation.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Sitagliptin 100 mg daily (q.d.) + acarbose (continuing the current stable dose of at least 50 mg three times daily [t.i.d.])	Placebo q.d. + acarbose (continuing the current stable dose of at least 50 mg t.i.d.)
Period Title: Overall Study
STARTED	191	190
COMPLETED	177	164
NOT COMPLETED	14	26

Baseline Characteristics

Arm/Group Title	Sitagliptin	Placebo	Total
Arm/Group Description	Sitagliptin 100 mg daily (q.d.) + acarbose (continuing the current stable dose of at least 50 mg three times daily [t.i.d.])	Placebo q.d. + acarbose (continuing the current stable dose of at least 50 mg t.i.d.)	Total of all reporting groups
Overall Participants	191	189	380
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	56.5 (8.9)	57.8 (9.5)	57.1 (9.2)
Sex: Female, Male (Count of Participants)
Female	94 49.2%	92 48.7%	186 48.9%
Male	97 50.8%	97 51.3%	194 51.1%
Hemoglobin A1c (A1C) (Percent) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Percent]	8.09 (0.79)	8.08 (0.90)	8.08 (0.85)
Fasting plasma glucose (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	177.3 (37.5)	177.5 (40.2)	177.4 (38.8)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Hemoglobin A1c (A1C) at Week 24
Description	A1C is measured as a percent. Thus, this change from baseline reflects the Week 24 A1C percent minus the Week 0 A1C percent. Efficacy analyses treated data as missing after the initiation of rescue therapy.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set, all randomized participants except those who: failed to take at least 1 dose of study treatment, lacked all post-randomization data for the A1C subsequent to at least 1 dose of study treatment, or lacked baseline data for the A1C. Last observation carried forward (missing data approach).

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Sitagliptin 100 mg daily (q.d.) + acarbose (continuing the current stable dose of at least 50 mg three times daily [t.i.d.])	Placebo q.d. + acarbose (continuing the current stable dose of at least 50 mg t.i.d.)
Measure Participants	185	180
Least Squares Mean (95% Confidence Interval) [Percent]	-0.76	-0.14

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sitagliptin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	The ANCOVA model included terms for treatment and prior antihyperglycemic agent (AHA) therapy status (on acarbose monotherapy, or on acarbose in combination with other AHA(s)) and a covariate for baseline A1C.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least squares mean
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 95%; -0.79 to -0.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Description	Change from baseline at Week 24 is defined as Week 24 FPG minus Week 0 FPG. Efficacy analyses treated data as missing after the initiation of rescue therapy.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Full Analysis Set, all randomized participants except those who: failed to take at least 1 dose of study treatment, lacked all post-randomization data for the FPG subsequent to at least 1 dose of study treatment, or lacked baseline data for the FPG. Last observation carried forward (missing data approach).

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Sitagliptin 100 mg daily (q.d.) + acarbose (continuing the current stable dose of at least 50 mg three times daily [t.i.d.])	Placebo q.d. + acarbose (continuing the current stable dose of at least 50 mg t.i.d.)
Measure Participants	187	183
Least Squares Mean (95% Confidence Interval) [mg/dL]	-17.9	-3.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Sitagliptin, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	The ANCOVA model included terms for treatment and prior AHA therapy status (on acarbose monotherapy, or on acarbose in combination with other AHA(s)) and a covariate for baseline FPG.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Difference in least squares mean
	Estimated Value	-14.4
	Confidence Interval	(2-Sided) 95%; -21.8 to -7.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Number of Participants Who Experienced at Least One Adverse Event
Time Frame	Up to Week 24 + 14 Day Post-Study Follow-up

Outcome Measure Data

Analysis Population Description

All participants as treated population defined as all randomized participants who received at least one dose of study drug. Data were excluded after the initiation of rescue therapy.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Sitagliptin 100 mg daily (q.d.) + acarbose (continuing the current stable dose of at least 50 mg three times daily [t.i.d.])	Placebo q.d. + acarbose (continuing the current stable dose of at least 50 mg t.i.d.)
Measure Participants	191	189
Number [Participants]	62 32.5%	58 30.7%

4. Primary Outcome

Title	Number of Participants Who Discontinued Study Drug Due to an Adverse Event
Time Frame	Up to 24 Weeks

Outcome Measure Data

Analysis Population Description

All participants as treated population defined as all randomized participants who received at least one dose of study drug. Data were excluded after the initiation of rescue therapy.

Arm/Group Title	Sitagliptin	Placebo
Arm/Group Description	Sitagliptin 100 mg daily (q.d.) + acarbose (continuing the current stable dose of at least 50 mg three times daily [t.i.d.])	Placebo q.d. + acarbose (continuing the current stable dose of at least 50 mg t.i.d.)
Measure Participants	191	189
Number [Participants]	5 2.6%	2 1.1%

Adverse Events

Adverse Event Reporting Description	All participants as treated population. Participants received rescue therapy if they met specific glycemic goals. Serious adverse events include events that occurred either before or after receiving rescue therapy. Other adverse events only include those AEs that occurred prior to a participant receiving rescue therapy.
Arm/Group Title	Sitagliptin		Placebo
Arm/Group Description	Sitagliptin 100 mg daily (q.d.) + acarbose (continuing the current stable dose of at least 50 mg three times daily [t.i.d.])		Placebo q.d. + acarbose (continuing the current stable dose of at least 50 mg t.i.d.)
All Cause Mortality
	Sitagliptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sitagliptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/191 (5.2%)		1/189 (0.5%)
Cardiac disorders
Cardia flutter	1/191 (0.5%)	1	0/189 (0%)	0
Gastrointestinal disorders
Pancreatitis chronic	1/191 (0.5%)	1	0/189 (0%)	0
Hepatobiliary disorders
Bile duct stone	1/191 (0.5%)	1	0/189 (0%)	0
Cholecystitis	2/191 (1%)	2	0/189 (0%)	0
Infections and infestations
Gastroenteritis	1/191 (0.5%)	1	0/189 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma	0/191 (0%)	0	1/189 (0.5%)	1
Thymoma	1/191 (0.5%)	1	0/189 (0%)	0
Nervous system disorders
Cerebral infarction	1/191 (0.5%)	1	0/189 (0%)	0
Transient ischaemic attack	1/191 (0.5%)	1	0/189 (0%)	0
Renal and urinary disorders
Calculus urinary	1/191 (0.5%)	1	0/189 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/191 (0.5%)	1	0/189 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchitis chronic	1/191 (0.5%)	1	0/189 (0%)	0
Other (Not Including Serious) Adverse Events
	Sitagliptin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/191 (0%)		0/189 (0%)

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.