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

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ClinicalTrials.gov Identifier: NCT01296412
Recruitment Status : Completed
First Posted : February 15, 2011
Results First Posted : March 15, 2013
Last Update Posted : June 9, 2017
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Diabetes Mellitus, Type 2
Interventions Drug: sitagliptin
Drug: liraglutide
Drug: glimepiride
Drug: metformin
Enrollment 653
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Sitagliptin +/- Glimepiride Liraglutide
Hide Arm/Group Description Sitagliptin 100 mg tablet once daily for 26 weeks. Participants continued their stable dose of metformin >=1500 mg orally daily. Participants may have received glimepiride for glycemic control. 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.
Period Title: Overall Study
Started 326 327
Completed 275 257
Not Completed 51 70
Reason Not Completed
Adverse Event             8             29
Lack of Efficacy             1             0
Lost to Follow-up             10             7
Non-compliance with study drug             1             2
Other reason not specified             20             15
Physician Decision             1             3
Pregnancy             0             1
Withdrawal by Subject             10             13
Arm/Group Title Sitagliptin +/- Glimepiride Liraglutide Total
Hide Arm/Group Description Sitagliptin 100 mg tablet once daily for 26 weeks. Participants continued their stable dose of metformin >=1500 mg orally daily. Participants may have received glimepiride for glycemic control. 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. Total of all reporting groups
Overall Number of Baseline Participants 326 327 653
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 326 participants 327 participants 653 participants
56.9  (10.0) 57.6  (10.8) 57.3  (10.4)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 326 participants 327 participants 653 participants
Female
148
  45.4%
147
  45.0%
295
  45.2%
Male
178
  54.6%
180
  55.0%
358
  54.8%
Hemoglobin A1c (A1C)   [1] 
Mean (Standard Deviation)
Unit of measure:  Percent
Number Analyzed 326 participants 327 participants 653 participants
8.2  (1.1) 8.1  (0.9) 8.2  (1.0)
[1]
Measure Description: A1C baseline values are presented for participants with data: Sitagliptin + metformin, n=325; liraglutide + metformin, n= 325; total population, n=650
Fasting Plasma Glucose   [1] 
Mean (Standard Deviation)
Unit of measure:  mg/dL
Number Analyzed 326 participants 327 participants 653 participants
174.1  (43.7) 172.9  (40.8) 173.5  (42.3)
[1]
Measure Description: FPG baseline values are presented for participants with data: Sitagliptin + metformin, n=325; liraglutide + metformin, n= 325; total population, n=650
1.Primary Outcome
Title Change From Baseline in Hemoglobin A1c (A1C)
Hide Description A1C is measured as percent. Thus, this change from baseline reflects the Week 26 A1C percent minus the Week 0 A1C percent.
Time Frame Baseline and Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol population defined as participants who had a measurement at baseline and a measurement after at least 24 weeks (i.e., 168 days) of treatment, and did not have any major protocol violations.
Arm/Group Title Sitagliptin +/- Glimepiride Liraglutide
Hide Arm/Group Description:
Sitagliptin 100 mg tablet once daily for 26 weeks. Participants continued their stable dose of metformin >=1500 mg orally daily. Participants may have received glimepiride for glycemic control.
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.
Overall Number of Participants Analyzed 269 253
Least Squares Mean (95% Confidence Interval)
Unit of Measure: percent
-1.32
(-1.42 to -1.23)
-1.42
(-1.51 to -1.32)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin +/- Glimepiride, Liraglutide
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The sitagliptin-based treatment paradigm was to be declared non-inferior to the liraglutide-based treatment paradigm in lowering A1C at Week 26 if the upper bound of 95% confidence intervals of between group difference was less than the non-inferiority margin of 0.4%.
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANCOVA
Comments The ANCOVA model included a term for treatment paradigm and a covariate for baseline value.
Method of Estimation Estimation Parameter Difference in least squares mean
Estimated Value 0.09
Confidence Interval (2-Sided) 95%
-0.05 to 0.23
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Change From Baseline in Fasting Plasma Glucose (FPG)
Hide Description Change from baseline at Week 26 is defined as Week 26 minus Week 0.
Time Frame Baseline and Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol population defined as participants who had a measurement at baseline and a measurement after at least 24 weeks (i.e., 168 days) of treatment, and did not have any major protocol violations.
Arm/Group Title Sitagliptin +/- Glimepiride Liraglutide
Hide Arm/Group Description:
Sitagliptin 100 mg tablet once daily for 26 weeks. Participants continued their stable dose of metformin >=1500 mg orally daily. Participants may have received glimepiride for glycemic control.
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.
Overall Number of Participants Analyzed 269 252
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mg/dL
-33.7
(-37.5 to -29.9)
-39.6
(-43.6 to -35.7)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin +/- Glimepiride, Liraglutide
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANCOVA
Comments The ANCOVA model included a term for treatment paradigm and a covariate for baseline value.
Method of Estimation Estimation Parameter Difference in least squares mean
Estimated Value 5.9
Confidence Interval (2-Sided) 95%
0.5 to 11.4
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percentage of Participants Reaching A1C Goal of <7.0%
Hide Description [Not Specified]
Time Frame Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol population defined as participants who had a measurement at baseline and a measurement after at least 24 weeks (i.e., 168 days) of treatment, and did not have any major protocol violations.
Arm/Group Title Sitagliptin +/- Glimepiride Liraglutide
Hide Arm/Group Description:
Sitagliptin 100 mg tablet once daily for 26 weeks. Participants continued their stable dose of metformin >=1500 mg orally daily. Participants may have received glimepiride for glycemic control.
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.
Overall Number of Participants Analyzed 269 253
Measure Type: Number
Unit of Measure: percentage of participants
62.8 72.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin +/- Glimepiride, Liraglutide
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Miettinen & Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percent
Estimated Value -9.5
Confidence Interval (2-Sided) 95%
-17.4 to -1.5
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Percentage of Participants Reaching A1C Goal of <6.5%
Hide Description [Not Specified]
Time Frame Week 26
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol population defined as participants who had a measurement at baseline and a measurement after at least 24 weeks (i.e., 168 days) of treatment, and did not have any major protocol violations.
Arm/Group Title Sitagliptin +/- Glimepiride Liraglutide
Hide Arm/Group Description:
Sitagliptin 100 mg tablet once daily for 26 weeks. Participants continued their stable dose of metformin >=1500 mg orally daily. Participants may have received glimepiride for glycemic control.
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.
Overall Number of Participants Analyzed 269 253
Measure Type: Number
Unit of Measure: percentage of participants
33.8 38.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sitagliptin +/- Glimepiride, Liraglutide
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Miettinen & Nurminen
Comments [Not Specified]
Method of Estimation Estimation Parameter Difference in percent
Estimated Value -4.5
Confidence Interval (2-Sided) 95%
-12.7 to 3.7
Estimation Comments [Not Specified]
Time Frame [Not Specified]
Adverse Event Reporting Description Safety analyses were performed on the all participants as treated population (defined as participants who received at least 1 dose of study therapy). Participants were included in the reporting group corresponding to the actual study treatment received. Three participants randomized to therapy did not receive any study therapy.
 
Arm/Group Title Sitagliptin +/- Glimepiride Liraglutide
Hide Arm/Group Description Sitagliptin 100 mg tablet once daily for 26 weeks. Participants continued their stable dose of metformin >=1500 mg orally daily. Participants may have received glimepiride for glycemic control. 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.
All-Cause Mortality
Sitagliptin +/- Glimepiride Liraglutide
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Sitagliptin +/- Glimepiride Liraglutide
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   17/326 (5.21%)      12/324 (3.70%)    
Cardiac disorders     
Atrial fibrillation  1/326 (0.31%)  1 0/324 (0.00%)  0
Coronary artery disease  1/326 (0.31%)  1 0/324 (0.00%)  0
Myocardial infarction  1/326 (0.31%)  1 0/324 (0.00%)  0
Gastrointestinal disorders     
Inguinal hernia  1/326 (0.31%)  1 0/324 (0.00%)  0
General disorders     
Accidental death  1/326 (0.31%)  1 0/324 (0.00%)  0
Non-cardiac chest pain  1/326 (0.31%)  1 1/324 (0.31%)  1
Infections and infestations     
Cellulitis  1/326 (0.31%)  1 0/324 (0.00%)  0
Cholecystitis infective  1/326 (0.31%)  1 0/324 (0.00%)  0
Injury, poisoning and procedural complications     
Craniocerebral injury  1/326 (0.31%)  1 0/324 (0.00%)  0
Rib fracture  1/326 (0.31%)  1 0/324 (0.00%)  0
Road traffic accident  2/326 (0.61%)  2 0/324 (0.00%)  0
Spinal compression fracture  1/326 (0.31%)  1 0/324 (0.00%)  0
Sternal fracture  1/326 (0.31%)  1 0/324 (0.00%)  0
Subcutaneous hematoma  1/326 (0.31%)  1 0/324 (0.00%)  0
Investigations     
Prostatic specific antigen increased  0/326 (0.00%)  0 1/324 (0.31%)  1
Metabolism and nutrition disorders     
Hypoglycaemia  1/326 (0.31%)  1 0/324 (0.00%)  0
Musculoskeletal and connective tissue disorders     
Muscle haemorrhage  1/326 (0.31%)  1 0/324 (0.00%)  0
Osteoarthritis  0/326 (0.00%)  0 1/324 (0.31%)  1
Spinal column stenosis  0/326 (0.00%)  0 1/324 (0.31%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Breast cancer  0/326 (0.00%)  0 1/324 (0.31%)  1
Malignant melanoma stage I  1/326 (0.31%)  1 0/324 (0.00%)  0
Prostate cancer  0/326 (0.00%)  0 1/324 (0.31%)  1
Squamous cell carcinoma  1/326 (0.31%)  1 0/324 (0.00%)  0
Nervous system disorders     
Encephalopathy  0/326 (0.00%)  0 1/324 (0.31%)  1
Sciatica  0/326 (0.00%)  0 1/324 (0.31%)  2
Transient ischaemic attack  0/326 (0.00%)  0 1/324 (0.31%)  1
Renal and urinary disorders     
Ureteric stenosis  1/326 (0.31%)  1 0/324 (0.00%)  0
Urinary tract obstruction  1/326 (0.31%)  1 0/324 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Bronchitis chronic  1/326 (0.31%)  1 0/324 (0.00%)  0
Chronic obstructive pulmonary disease  1/326 (0.31%)  1 1/324 (0.31%)  1
Emphysema  1/326 (0.31%)  1 0/324 (0.00%)  0
Skin and subcutaneous tissue disorders     
Angioedema  0/326 (0.00%)  0 1/324 (0.31%)  1
Dermatitis allergic  0/326 (0.00%)  0 1/324 (0.31%)  1
Vascular disorders     
Blue toe syndrome  1/326 (0.31%)  1 0/324 (0.00%)  0
Peripheral ischaemia  1/326 (0.31%)  1 0/324 (0.00%)  0
1
Term from vocabulary, MedDRA (14.1)
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Sitagliptin +/- Glimepiride Liraglutide
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   58/326 (17.79%)      97/324 (29.94%)    
Gastrointestinal disorders     
Diarrhoea  7/326 (2.15%)  9 35/324 (10.80%)  42
Nausea  10/326 (3.07%)  13 63/324 (19.44%)  73
Vomiting  6/326 (1.84%)  10 21/324 (6.48%)  25
Metabolism and nutrition disorders     
Decreased appetite  4/326 (1.23%)  4 21/324 (6.48%)  21
Hypoglycaemia  41/326 (12.58%)  89 15/324 (4.63%)  31
1
Term from vocabulary, MedDRA (14.1)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Senior Vice President, Global Clinical Development
Organization: Merck Sharp & Dohme Corp
Phone: 1-800-672-6372
EMail: ClinicalTrialsDisclosure@merck.com
Layout table for additonal information
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01296412    
Other Study ID Numbers: 0431-403
First Submitted: February 14, 2011
First Posted: February 15, 2011
Results First Submitted: February 5, 2013
Results First Posted: March 15, 2013
Last Update Posted: June 9, 2017