Type 2 Diabetes Mellitus
Conditions
Brief summary
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.
Interventions
DRUGSitagliptin phosphate
Sitagliptin 100 mg tablet (blinded) orally once daily for 54 weeks.
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.
Matching placebo to sitagliptin orally once daily for 54 weeks.
Matching placebo to pioglitazone tablets or capsules orally once daily for 54 weeks.
DRUGMetformin
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.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 78 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | Baseline and Week 24 | A1C represents the percentage of glycosylated hemoglobin. |
| Change From Baseline in A1C at Week 54 | Baseline and Week 54 | A1C represents the percentage of glycosylated hemoglobin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Baseline and Week 24 | PMG was measured using the Meal Tolerance Test (MTT). |
| Change From Baseline in FPG at Week 54 | Baseline and Week 54 | — |
| Change From Baseline in 2-Hour PMG at Week 54 | Baseline and Week 54 | PMG was measured using the Meal Tolerance Test (MTT). |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin 100 mg Sitagliptin 100 mg and matching placebo to pioglitazone once daily for 54 weeks. | 231 |
| Pioglitazone 15 mg Pioglitazone 15 mg and matching placebo to sitagliptin once daily for 54 weeks. | 230 |
| Pioglitazone 30 mg Pioglitazone 30 mg and matching placebo to sitagliptin once daily for 54 weeks. | 233 |
| Pioglitazone 45 mg Pioglitazone 45 mg and matching placebo to sitagliptin once daily for 54 weeks. | 230 |
| Sitagliptin 100 mg/ Pioglitazone 15 mg Sitagliptin 100 mg and pioglitazone 15 mg once daily for 54 weeks. | 230 |
| Sitagliptin 100 mg/ Pioglitazone 30 mg Sitagliptin 100 mg and pioglitazone 30 mg once daily for 54 weeks. | 231 |
| Sitagliptin 100 mg/ Pioglitazone 45 mg Sitagliptin 100 mg and pioglitazone 45 mg once daily for 54 weeks. | 230 |
| Total | 1,615 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 6 | 13 | 9 | 10 | 6 | 8 | 4 |
| Overall Study | Contraindication | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Creatinine / Creatinine clearance | 2 | 1 | 2 | 3 | 2 | 1 | 1 |
| Overall Study | Excluded medication | 0 | 1 | 1 | 0 | 0 | 0 | 1 |
| Overall Study | Hyperglycemia | 2 | 6 | 4 | 2 | 5 | 1 | 1 |
| Overall Study | Hypoglycemia | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Lack of Efficacy | 4 | 6 | 6 | 6 | 2 | 3 | 0 |
| Overall Study | Lost to Follow-up | 11 | 14 | 21 | 13 | 8 | 16 | 13 |
| Overall Study | Physician Decision | 5 | 2 | 2 | 5 | 2 | 3 | 4 |
| Overall Study | Pregnancy | 1 | 1 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Protocol Violation | 6 | 1 | 0 | 1 | 4 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 18 | 27 | 19 | 23 | 19 | 18 | 26 |
Baseline characteristics
| Characteristic | Sitagliptin 100 mg/ Pioglitazone 45 mg | Total | Pioglitazone 15 mg | Pioglitazone 30 mg | Sitagliptin 100 mg | Pioglitazone 45 mg | Sitagliptin 100 mg/ Pioglitazone 15 mg | Sitagliptin 100 mg/ Pioglitazone 30 mg |
|---|---|---|---|---|---|---|---|---|
| Age, Customized <=20 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized 21 to 30 years | 4 Participants | 35 Participants | 6 Participants | 2 Participants | 5 Participants | 5 Participants | 5 Participants | 8 Participants |
| Age, Customized 31 to 40 years | 15 Participants | 195 Participants | 39 Participants | 33 Participants | 37 Participants | 20 Participants | 17 Participants | 34 Participants |
| Age, Customized 41 to 50 years | 68 Participants | 468 Participants | 73 Participants | 60 Participants | 64 Participants | 70 Participants | 73 Participants | 60 Participants |
| Age, Customized 51 to 60 years | 87 Participants | 556 Participants | 67 Participants | 88 Participants | 83 Participants | 76 Participants | 80 Participants | 75 Participants |
| Age, Customized 61 to 70 years | 51 Participants | 307 Participants | 34 Participants | 45 Participants | 31 Participants | 53 Participants | 44 Participants | 49 Participants |
| Age, Customized >70 years | 5 Participants | 54 Participants | 11 Participants | 5 Participants | 11 Participants | 6 Participants | 11 Participants | 5 Participants |
| Sex: Female, Male Female | 95 Participants | 703 Participants | 82 Participants | 106 Participants | 95 Participants | 117 Participants | 112 Participants | 96 Participants |
| Sex: Female, Male Male | 135 Participants | 912 Participants | 148 Participants | 127 Participants | 136 Participants | 113 Participants | 118 Participants | 135 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 60 / 231 | 41 / 230 | 45 / 233 | 55 / 230 | 48 / 230 | 56 / 231 | 46 / 230 |
| serious Total, serious adverse events | 14 / 231 | 10 / 230 | 5 / 233 | 11 / 230 | 12 / 230 | 15 / 231 | 7 / 230 |
Outcome results
Primary
Change From Baseline in A1C at Week 54
A1C represents the percentage of glycosylated hemoglobin.
Time frame: Baseline and Week 54
Population: Full Analysis Set with LOCF. Reasons for exclusion included no baseline data and/or no post-baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in A1C at Week 54 | -0.93 Percent of glycosylated hemoglobin |
| Pioglitazone 15 mg | Change From Baseline in A1C at Week 54 | -0.74 Percent of glycosylated hemoglobin |
| Pioglitazone 30 mg | Change From Baseline in A1C at Week 54 | -1.16 Percent of glycosylated hemoglobin |
| Pioglitazone 45 mg | Change From Baseline in A1C at Week 54 | -1.23 Percent of glycosylated hemoglobin |
| Sitagliptin 100 mg/ Pioglitazone 15 mg | Change From Baseline in A1C at Week 54 | -1.45 Percent of glycosylated hemoglobin |
| Sitagliptin 100 mg/ Pioglitazone 30 mg | Change From Baseline in A1C at Week 54 | -1.49 Percent of glycosylated hemoglobin |
| Sitagliptin 100 mg/ Pioglitazone 45 mg | Change From Baseline in A1C at Week 54 | -1.78 Percent of glycosylated hemoglobin |
Primary
Change From Baseline in Hemoglobin A1C (A1C) at Week 24
A1C represents the percentage of glycosylated hemoglobin.
Time frame: Baseline and Week 24
Population: Full Analysis Set with last observation carried forward (LOCF). Reasons for exclusion included no baseline data and/or no post-baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -1.09 Percentage of glycosylated hemoglobin |
| Pioglitazone 15 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -0.88 Percentage of glycosylated hemoglobin |
| Pioglitazone 30 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -1.21 Percentage of glycosylated hemoglobin |
| Pioglitazone 45 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -1.20 Percentage of glycosylated hemoglobin |
| Sitagliptin 100 mg/ Pioglitazone 15 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -1.53 Percentage of glycosylated hemoglobin |
| Sitagliptin 100 mg/ Pioglitazone 30 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -1.63 Percentage of glycosylated hemoglobin |
| Sitagliptin 100 mg/ Pioglitazone 45 mg | Change From Baseline in Hemoglobin A1C (A1C) at Week 24 | -1.81 Percentage of glycosylated hemoglobin |
Secondary
Change From Baseline in 2-Hour PMG at Week 54
PMG was measured using the Meal Tolerance Test (MTT).
Time frame: Baseline and Week 54
Population: Full Analysis Set with LOCF. Reasons for exclusion included no baseline data and/or no post-baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in 2-Hour PMG at Week 54 | -37.0 mg/dL |
| Pioglitazone 15 mg | Change From Baseline in 2-Hour PMG at Week 54 | -26.7 mg/dL |
| Pioglitazone 30 mg | Change From Baseline in 2-Hour PMG at Week 54 | -46.8 mg/dL |
| Pioglitazone 45 mg | Change From Baseline in 2-Hour PMG at Week 54 | -58.2 mg/dL |
| Sitagliptin 100 mg/ Pioglitazone 15 mg | Change From Baseline in 2-Hour PMG at Week 54 | -64.7 mg/dL |
| Sitagliptin 100 mg/ Pioglitazone 30 mg | Change From Baseline in 2-Hour PMG at Week 54 | -69.7 mg/dL |
| Sitagliptin 100 mg/ Pioglitazone 45 mg | Change From Baseline in 2-Hour PMG at Week 54 | -88.2 mg/dL |
Secondary
Change From Baseline in 2-Hour Post-meal Glucose (PMG) at Week 24
PMG was measured using the Meal Tolerance Test (MTT).
Time frame: Baseline and Week 24
Population: Full Analysis Set with LOCF. Reasons for exclusion included no baseline data and/or no post-baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in 2-Hour Post-meal Glucose (PMG) at Week 24 | -51.1 mg/dL |
| Pioglitazone 15 mg | Change From Baseline in 2-Hour Post-meal Glucose (PMG) at Week 24 | -30.6 mg/dL |
| Pioglitazone 30 mg | Change From Baseline in 2-Hour Post-meal Glucose (PMG) at Week 24 | -52.5 mg/dL |
| Pioglitazone 45 mg | Change From Baseline in 2-Hour Post-meal Glucose (PMG) at Week 24 | -66.6 mg/dL |
| Sitagliptin 100 mg/ Pioglitazone 15 mg | Change From Baseline in 2-Hour Post-meal Glucose (PMG) at Week 24 | -69.2 mg/dL |
| Sitagliptin 100 mg/ Pioglitazone 30 mg | Change From Baseline in 2-Hour Post-meal Glucose (PMG) at Week 24 | -85.5 mg/dL |
| Sitagliptin 100 mg/ Pioglitazone 45 mg | Change From Baseline in 2-Hour Post-meal Glucose (PMG) at Week 24 | -93.8 mg/dL |
Secondary
Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24
Time frame: Baseline and Week 24
Population: Full Analysis Set with LOCF. Reasons for exclusion included no baseline data and/or no post-baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -24.3 mg/dL |
| Pioglitazone 15 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -19.5 mg/dL |
| Pioglitazone 30 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -29.9 mg/dL |
| Pioglitazone 45 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -37.4 mg/dL |
| Sitagliptin 100 mg/ Pioglitazone 15 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -41.0 mg/dL |
| Sitagliptin 100 mg/ Pioglitazone 30 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -46.9 mg/dL |
| Sitagliptin 100 mg/ Pioglitazone 45 mg | Change From Baseline in Fasting Plasma Glucose (FPG) at Week 24 | -52.0 mg/dL |
Secondary
Change From Baseline in FPG at Week 54
Time frame: Baseline and Week 54
Population: Full Analysis Set with LOCF. Reasons for exclusion included no baseline data and/or no post-baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in FPG at Week 54 | -13.1 mg/dL |
| Pioglitazone 15 mg | Change From Baseline in FPG at Week 54 | -10.5 mg/dL |
| Pioglitazone 30 mg | Change From Baseline in FPG at Week 54 | -24.0 mg/dL |
| Pioglitazone 45 mg | Change From Baseline in FPG at Week 54 | -33.3 mg/dL |
| Sitagliptin 100 mg/ Pioglitazone 15 mg | Change From Baseline in FPG at Week 54 | -33.9 mg/dL |
| Sitagliptin 100 mg/ Pioglitazone 30 mg | Change From Baseline in FPG at Week 54 | -37.1 mg/dL |
| Sitagliptin 100 mg/ Pioglitazone 45 mg | Change From Baseline in FPG at Week 54 | -47.8 mg/dL |