Diabetes Mellitus, Type 2
Conditions
Brief summary
The purpose of this clinical study is to determine the safety and efficacy of an investigational drug in patients with type 2 diabetes mellitus.
Interventions
Phase A: Sitagliptin 100 mg once a day for 24 weeks. Phase B: Sitagliptin 100 mg once a day for 80 weeks.
DRUGSitagliptin
Phase A: Sitagliptin 200 mg once a day for 24 weeks. Phase B: Sitagliptin 200 mg once a day for 80 weeks.
DRUGPlacebo
Phase A: Placebo matching Sitagliptin 100 mg once a day for 24 weeks. Phase B: Sitagliptin 100 mg once a day for 80 weeks.
DRUGMetformin - Rescue
Phase A: Patients not meeting specific glycemic goals will receive open-label metformin as 500 mg, 850 mg, and 1000 mg oral tablets titrated at the discretion of the investigator. Phase B: These patients will not initiate Phase B double-blind medication.
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 75 Years
Healthy volunteers
No
Inclusion criteria
* Patients with type 2 diabetes mellitus * Patient is not pregnant or breastfeeding * Male or female patient unlikely to conceive * Patient not on an antihyperglycemic drug
Exclusion criteria
* Patient has history of type 1 diabetes mellitus * Patient has history of ketoacidosis * Patient requires insulin within 8 weeks prior to start of study * Patient on weight loss program and is not in maintenance phase * Patient taking weight loss medication within 8 weeks prior to start of study * Patient on or likely to require = 14 days or repeated courses of corticosteroids * Patient taking immunosuppressive/immunomodulating medication * Patient taking digoxin or other cardiac medication * Patient has undergone surgical general anesthesia within 30 days prior to start of study * Patient taking investigational drug within 8 weeks prior to start of study * Patient is diagnosed with liver disease * Patient has chronic myopathy, progressive neurological/neuromuscular disorder * Patient has with severe cardiac conditions within the last 6 months * Patient is Human immunodeficiency virus (HIV) positive * Patient has hematological disorder * Patient has history of malignancy * Patient has history of alcohol or drug abuse within the past 3 years
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in A1C at Week 24 | Weeks 0-24 | A1C is measured as a percent. Thus, this change from baseline reflects the Week 24 A1C percent minus the Week 0 A1C percent. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in FPG at Week 24 | Weeks 0-24 | Change from baseline at Week 24 is defined as Week 24 FPG minus Week 0 FPG. |
| Change From Baseline in 2-hour Post-meal Glucose (2-hr PMG) at Week 24 | Weeks 0-24 | Change from baseline at Week 24 is defined as Week 24 2-hr PMG minus Week 0 2-hr PMG. |
| Change From Baseline in A1C at Week 104 | Weeks 0-104 | A1C is measured as a percent. Thus, this change from baseline reflects the Week 104 A1C percent minus the Week 0 A1C percent. |
| Change From Baseline in FPG at Week 104 | Weeks 0-104 | Change from baseline at Week 104 is defined as Week 104 FPG minus Week 0 FPG. |
| Change From Baseline in 2-hr PMG at Week 104 | Weeks 0-104 | Change from baseline at Week 104 is defined as Week 104 2-hr PMG minus Week 0 2-hr PMG. |
Participant flow
Recruitment details
First Patient In: 08-Jul-2004; Last Patient Last Visit: 07-Feb-2007; One hundred eleven medical clinics worldwide (56 in the United States and Puerto Rico, 16 in 6 countries in Europe and 39 in 11 countries in the rest of the world).
Pre-assignment details
Patients 18-75 years not on an antihyperglycemic agent (AHA) or on oral single AHA or low-dose combination therapy were eligible to participate. Following a screening diet/exercise period of variable duration, patients with hemoglobin A1c (A1C) 7-10% were eligible to enter a 2-week placebo run-in/wash-off period prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin 100 mg The Sitagliptin 100 mg/100 mg group includes data from patients randomized to receive treatment with oral tablets of sitagliptin 100 mg q.d. (once daily) for up to 104 weeks (including the 24-week Phase A study period and 80-week Phase B study period). | 238 |
| Sitagliptin 200 mg The Sitagliptin 200 mg/200 mg group includes data from patients randomized to receive treatment with oral tablets of sitagliptin 200 mg q.d. for up to 104 weeks (including the 24-week Phase A study period and 80-week Phase B study period). | 250 |
| Placebo The Placebo group includes data from patients randomized to receive treatment with oral tablets of sitagliptin-matching placebo tablets once daily during the 24-week Phase A study period followed by oral tablets of sitagliptin 100 or 200 mg q.d. during the 80-week Phase B study period. | 253 |
| Total | 741 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 10 | 10 | 3 | 6 |
| Overall Study | Lack of Efficacy | 82 | 80 | 39 | 29 |
| Overall Study | Lost to Follow-up | 8 | 6 | 5 | 5 |
| Overall Study | Other | 0 | 0 | 1 | 0 |
| Overall Study | Patient moved | 3 | 2 | 1 | 0 |
| Overall Study | Patient was non-compliant | 3 | 1 | 0 | 0 |
| Overall Study | Protocol specified discontinuation | 35 | 33 | 33 | 26 |
| Overall Study | Protocol Violation | 4 | 8 | 3 | 6 |
| Overall Study | Recommendation of Primary Care Physician | 0 | 0 | 0 | 1 |
| Overall Study | Site terminated | 0 | 2 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 16 | 27 | 11 | 12 |
Baseline characteristics
| Characteristic | Sitagliptin 100 mg | Sitagliptin 200 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 53.4 years STANDARD_DEVIATION 9.5 | 54.9 years STANDARD_DEVIATION 10.1 | 54.3 years STANDARD_DEVIATION 10.1 | 54.2 years STANDARD_DEVIATION 9.9 |
| Fasting Plasma Glucose (FPG) | 170.7 mg/dL STANDARD_DEVIATION 43 | 174.2 mg/dL STANDARD_DEVIATION 46.2 | 176.1 mg/dL STANDARD_DEVIATION 41.8 | 173.7 mg/dL STANDARD_DEVIATION 43.7 |
| Hemoglobin A1c (A1C) | 8.0 Percent STANDARD_DEVIATION 0.9 | 8.1 Percent STANDARD_DEVIATION 0.9 | 8.0 Percent STANDARD_DEVIATION 0.8 | 8.0 Percent STANDARD_DEVIATION 0.9 |
| Race/Ethnicity, Customized Asian | 32 participants | 37 participants | 34 participants | 103 participants |
| Race/Ethnicity, Customized Black | 10 participants | 12 participants | 16 participants | 38 participants |
| Race/Ethnicity, Customized Hispanic | 58 participants | 53 participants | 64 participants | 175 participants |
| Race/Ethnicity, Customized Other | 16 participants | 16 participants | 12 participants | 44 participants |
| Race/Ethnicity, Customized White | 122 participants | 132 participants | 127 participants | 381 participants |
| Sex: Female, Male Female | 102 Participants | 133 Participants | 123 Participants | 358 Participants |
| Sex: Female, Male Male | 136 Participants | 117 Participants | 130 Participants | 383 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 127 / 238 | 137 / 250 | 70 / 130 | 65 / 123 |
| serious Total, serious adverse events | 24 / 238 | 25 / 250 | 10 / 130 | 13 / 123 |
Outcome results
Primary
Change From Baseline in A1C at 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.
Time frame: Weeks 0-24
Population: The all-patients-treated population included all patients with at least one dose of double-blind study therapy, and with a baseline value and ≥1 post-baseline value for this outcome. Data following glycemic rescue were treated as missing. Missing data were handled using the last observation carrying forward method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in A1C at Week 24 | -0.61 Percent |
| Sitagliptin 200 mg | Change From Baseline in A1C at Week 24 | -0.76 Percent |
| Placebo | Change From Baseline in A1C at Week 24 | 0.18 Percent |
p-value: <0.00195% CI: [-0.96, -0.62]ANCOVA
p-value: <0.00195% CI: [-1.11, -0.77]ANCOVA
Secondary
Change From Baseline in 2-hour Post-meal Glucose (2-hr PMG) at Week 24
Change from baseline at Week 24 is defined as Week 24 2-hr PMG minus Week 0 2-hr PMG.
Time frame: Weeks 0-24
Population: The all-patients-treated population included all patients with at least one dose of double-blind study therapy, and with a baseline value and ≥1 post-baseline value for this outcome. Data following glycemic rescue were treated as missing. Missing data were handled using the last observation carrying forward method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in 2-hour Post-meal Glucose (2-hr PMG) at Week 24 | -48.9 mg/dL |
| Sitagliptin 200 mg | Change From Baseline in 2-hour Post-meal Glucose (2-hr PMG) at Week 24 | -56.3 mg/dL |
| Placebo | Change From Baseline in 2-hour Post-meal Glucose (2-hr PMG) at Week 24 | -2.2 mg/dL |
p-value: <0.00195% CI: [-59.4, -34.1]ANCOVA
p-value: <0.00195% CI: [-66.7, -41.6]ANCOVA
Secondary
Change From Baseline in 2-hr PMG at Week 104
Change from baseline at Week 104 is defined as Week 104 2-hr PMG minus Week 0 2-hr PMG.
Time frame: Weeks 0-104
Population: The all-patients-treated population for Week 104, included all patients with at least one dose of double-blind study therapy after Week 24, and with a baseline value and ≥1 post-baseline value for this outcome. Data following glycemic rescue were treated as missing. Missing data were handled using the last observation carrying forward method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in 2-hr PMG at Week 104 | -30.5 mg/dL |
| Sitagliptin 200 mg | Change From Baseline in 2-hr PMG at Week 104 | -41.5 mg/dL |
| Placebo | Change From Baseline in 2-hr PMG at Week 104 | -38.3 mg/dL |
| Placebo/Sitagliptin 200 mg | Change From Baseline in 2-hr PMG at Week 104 | -35.5 mg/dL |
Secondary
Change From Baseline in A1C at Week 104
A1C is measured as a percent. Thus, this change from baseline reflects the Week 104 A1C percent minus the Week 0 A1C percent.
Time frame: Weeks 0-104
Population: The all-patients-treated population for Week 104 included all patients with at least one dose of double-blind study therapy after Week 24, and with a baseline value and ≥1 post-baseline value for this outcome. Data following glycemic rescue were treated as missing. Missing data were handled using the last observation carrying forward method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in A1C at Week 104 | -0.27 Percent |
| Sitagliptin 200 mg | Change From Baseline in A1C at Week 104 | -0.40 Percent |
| Placebo | Change From Baseline in A1C at Week 104 | -0.32 Percent |
| Placebo/Sitagliptin 200 mg | Change From Baseline in A1C at Week 104 | -0.34 Percent |
Secondary
Change From Baseline in FPG at Week 104
Change from baseline at Week 104 is defined as Week 104 FPG minus Week 0 FPG.
Time frame: Weeks 0-104
Population: The all-patients-treated population for Week 104, included all patients with at least one dose of double-blind study therapy after Week 24, and with a baseline value and ≥1 post-baseline value for this outcome. Data following glycemic rescue were treated as missing. Missing data were handled using the last observation carrying forward method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in FPG at Week 104 | -1.8 mg/dL |
| Sitagliptin 200 mg | Change From Baseline in FPG at Week 104 | -5.7 mg/dL |
| Placebo | Change From Baseline in FPG at Week 104 | -4.1 mg/dL |
| Placebo/Sitagliptin 200 mg | Change From Baseline in FPG at Week 104 | -4.1 mg/dL |
Secondary
Change From Baseline in FPG at Week 24
Change from baseline at Week 24 is defined as Week 24 FPG minus Week 0 FPG.
Time frame: Weeks 0-24
Population: The all-patients-treated population included all patients with at least one dose of double-blind study therapy, and with a baseline value and ≥1 post-baseline value for this outcome. Data following glycemic rescue were treated as missing. Missing data were handled using the last observation carrying forward method.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin 100 mg | Change From Baseline in FPG at Week 24 | -12.4 mg/dL |
| Sitagliptin 200 mg | Change From Baseline in FPG at Week 24 | -16.6 mg/dL |
| Placebo | Change From Baseline in FPG at Week 24 | 4.7 mg/dL |
p-value: <0.00195% CI: [-24.1, -10.1]ANCOVA
p-value: <0.00195% CI: [-28.2, -14.4]ANCOVA