Type 2 Diabetes Mellitus
Conditions
Brief summary
This is a study to assess the safety and efficacy of the addition of sitagliptin in Japanese participants with Type 2 diabetes mellitus (T2DM) who have inadequate glycemic control on ipragliflozin, diet, and exercise therapy. The primary hypothesis of the study is that the addition of sitagliptin once daily compared with placebo provides greater reduction in hemoglobin A1C (HbA1c) as assessed by change from baseline (Week 0) to Week 24.
Interventions
DRUGSitagliptin
50 mg tablet administered orally
DRUGPlacebo
Placebo to sitagliptin administered orally
DRUGIpragliflozin
50 mg tablet administered orally as background 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
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes mellitus * Inadequate glycemic control on diet/exercise therapy and ipragliflozin monotherapy * HbA1c ≥7.0% and ≤10.0% before study start
Exclusion criteria
* History of type 1 diabetes mellitus or a history of ketoacidosis * History of any of the following medications: thiazolidinediones (TZD) and/or insulin within 12 weeks prior to study participation, sitagliptin within 8 weeks prior to study participation. * Currently has a urinary tract infection or genital infection with subjective symptom
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in HbA1c at Week 24 | Baseline and Week 24 | HbA1c is measured as percent. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the Week 0 HbA1c percent. Statistical analysis based on a constrained longitudinal data analysis (cLDA) model with terms for treatment, time, prior use of AHAs, the interactions of treatment by time, time by prior use of AHAs, and treatment by time by prior use of AHAs with the constraint that the mean baseline is the same for both treatment groups. |
| Percentage of Participants Who Experienced at Least One Adverse Event (AE) | Up to 26 weeks | An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
| Percentage of Participants Who Discontinued Study Drug Due to an AE | Up to 24 weeks | An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 2-hr PMG at Week 24 | Baseline and Week 24 | Change from baseline in 2-hr PMG at Week 24 is defined as Week 24 2-hr PMG minus Week 0 2-hr PMG. Statistical analysis based on a cLDA model with terms for treatment, time, prior use of AHAs, the interactions of treatment by time, time by prior use of AHAs, and treatment by time by prior use of AHAs with the constraint that the mean baseline 2-hr PMG is the same for both treatment groups. |
| Change From Baseline in Glucose Total Area Under the Plasma Concentration Curve From Hour 0 to Hour 2 (AUC0-2hr) After Meal at Week 24 | Baseline and Week 24 (just before loading meal [0 min], 30 min, 60 min and 120 min) | Change from Baseline in Glucose Total AUC0-2hr after Meal at Week 24 is defined as Week 24 Glucose Total AUC0-2hr after a meal minus Week 0 Glucose Total AUC0-2hr after a meal. Statistical analysis based on a cLDA model with terms for treatment, time, prior use of AHAs, the interactions of treatment by time, time by prior use of AHAs, and treatment by time by prior use of AHAs with the constraint that the mean baseline glucose total AUC0-2hr after meal is the same for both treatment groups. |
| Change From Baseline in FPG at Week 24 | Baseline and Week 24 | Change from baseline in FPG at Week 24 is defined as Week 24 FPG minus Week 0 FPG. Statistical analysis based on a cLDA model with terms for treatment, time, prior use of AHAs, the interactions of treatment by time, time by prior use of AHAs, and treatment by time by prior use of AHAs with the constraint that the mean baseline FPG is the same for both treatment groups. |
Participant flow
Pre-assignment details
Prior to randomization, all participants received placebo for 2 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin + Ipragliflozin Sitagliptin, oral, once daily for 24 weeks plus ipragliflozin (base therapy), in addition to diet and exercise. | 70 |
| Placebo + Ipragliflozin Placebo to sitagliptin, oral, once daily for 24 weeks plus ipragliflozin (base therapy), in addition to diet and exercise. | 71 |
| Total | 141 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Placebo + Ipragliflozin | Sitagliptin + Ipragliflozin |
|---|---|---|---|
| 2-hour postmeal glucose (2-hr PMG) | 213.6 mg/dL STANDARD_DEVIATION 48.3 | 215.3 mg/dL STANDARD_DEVIATION 47 | 211.9 mg/dL STANDARD_DEVIATION 49.8 |
| Age, Continuous | 55.5 Years STANDARD_DEVIATION 10.7 | 54.0 Years STANDARD_DEVIATION 9.5 | 57.0 Years STANDARD_DEVIATION 11.6 |
| Fasting plasma glucose (FPG) | 150.0 md/dL STANDARD_DEVIATION 26.1 | 151.2 md/dL STANDARD_DEVIATION 27 | 148.8 md/dL STANDARD_DEVIATION 25.4 |
| Glucose total AUC0-2hr after meal | 418.5 mg･hr/dL STANDARD_DEVIATION 70.9 | 422.5 mg･hr/dL STANDARD_DEVIATION 68.2 | 414.4 mg･hr/dL STANDARD_DEVIATION 73.8 |
| Hemoglobin A1c (HbA1c) | 8.04 Percent STANDARD_DEVIATION 0.8 | 8.08 Percent STANDARD_DEVIATION 0.79 | 8.01 Percent STANDARD_DEVIATION 0.81 |
| Prior use of other antihyperglycemic agents (AHAs) No | 92 Participants | 46 Participants | 46 Participants |
| Prior use of other antihyperglycemic agents (AHAs) Yes | 49 Participants | 25 Participants | 24 Participants |
| Sex: Female, Male Female | 42 Participants | 26 Participants | 16 Participants |
| Sex: Female, Male Male | 99 Participants | 45 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 70 | 18 / 71 |
| serious Total, serious adverse events | 3 / 70 | 0 / 71 |
Outcome results
Primary
Change From Baseline in HbA1c at Week 24
HbA1c is measured as percent. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the Week 0 HbA1c percent. Statistical analysis based on a constrained longitudinal data analysis (cLDA) model with terms for treatment, time, prior use of AHAs, the interactions of treatment by time, time by prior use of AHAs, and treatment by time by prior use of AHAs with the constraint that the mean baseline is the same for both treatment groups.
Time frame: Baseline and Week 24
Population: All randomized participants who received at least one dose of treatment period study medication and have at least one measurement of HbA1c (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin + Ipragliflozin | Change From Baseline in HbA1c at Week 24 | -0.69 Percent |
| Placebo + Ipragliflozin | Change From Baseline in HbA1c at Week 24 | 0.14 Percent |
p-value: <0.00195% CI: [-1.05, -0.62]Constrained longitudinal data analysis
Primary
Percentage of Participants Who Discontinued Study Drug Due to an AE
An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 24 weeks
Population: All randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin + Ipragliflozin | Percentage of Participants Who Discontinued Study Drug Due to an AE | 2.9 Percentage of participants |
| Placebo + Ipragliflozin | Percentage of Participants Who Discontinued Study Drug Due to an AE | 0.0 Percentage of participants |
Primary
Percentage of Participants Who Experienced at Least One Adverse Event (AE)
An adverse event is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.
Time frame: Up to 26 weeks
Population: All randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin + Ipragliflozin | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 54.3 Percentage of participants |
| Placebo + Ipragliflozin | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 63.4 Percentage of participants |
Secondary
Change From Baseline in 2-hr PMG at Week 24
Change from baseline in 2-hr PMG at Week 24 is defined as Week 24 2-hr PMG minus Week 0 2-hr PMG. Statistical analysis based on a cLDA model with terms for treatment, time, prior use of AHAs, the interactions of treatment by time, time by prior use of AHAs, and treatment by time by prior use of AHAs with the constraint that the mean baseline 2-hr PMG is the same for both treatment groups.
Time frame: Baseline and Week 24
Population: All randomized participants who received at least one dose of treatment period study medication and have at least one measurement of 2-hr PMG (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin + Ipragliflozin | Change From Baseline in 2-hr PMG at Week 24 | -39.0 mg/dL |
| Placebo + Ipragliflozin | Change From Baseline in 2-hr PMG at Week 24 | 3.4 mg/dL |
p-value: <0.00195% CI: [-53.7, -31.2]Constrained longitudinal data analysis
Secondary
Change From Baseline in FPG at Week 24
Change from baseline in FPG at Week 24 is defined as Week 24 FPG minus Week 0 FPG. Statistical analysis based on a cLDA model with terms for treatment, time, prior use of AHAs, the interactions of treatment by time, time by prior use of AHAs, and treatment by time by prior use of AHAs with the constraint that the mean baseline FPG is the same for both treatment groups.
Time frame: Baseline and Week 24
Population: All randomized participants who received at least one dose of treatment period study medication and have at least one measurement of FPG (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin + Ipragliflozin | Change From Baseline in FPG at Week 24 | -11.8 mg/dL |
| Placebo + Ipragliflozin | Change From Baseline in FPG at Week 24 | -0.6 mg/dL |
p-value: <0.00195% CI: [-17.2, -5.2]Constrained longitudinal data analysis
Secondary
Change From Baseline in Glucose Total Area Under the Plasma Concentration Curve From Hour 0 to Hour 2 (AUC0-2hr) After Meal at Week 24
Change from Baseline in Glucose Total AUC0-2hr after Meal at Week 24 is defined as Week 24 Glucose Total AUC0-2hr after a meal minus Week 0 Glucose Total AUC0-2hr after a meal. Statistical analysis based on a cLDA model with terms for treatment, time, prior use of AHAs, the interactions of treatment by time, time by prior use of AHAs, and treatment by time by prior use of AHAs with the constraint that the mean baseline glucose total AUC0-2hr after meal is the same for both treatment groups.
Time frame: Baseline and Week 24 (just before loading meal [0 min], 30 min, 60 min and 120 min)
Population: All randomized participants who received at least one dose of treatment period study medication and have at least one measurement of glucose total AUC0-2hr after meal (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Sitagliptin + Ipragliflozin | Change From Baseline in Glucose Total Area Under the Plasma Concentration Curve From Hour 0 to Hour 2 (AUC0-2hr) After Meal at Week 24 | -65.7 mg･hr/dL |
| Placebo + Ipragliflozin | Change From Baseline in Glucose Total Area Under the Plasma Concentration Curve From Hour 0 to Hour 2 (AUC0-2hr) After Meal at Week 24 | 1.3 mg･hr/dL |
p-value: <0.00195% CI: [-84, -50]Constrained longitudinal data analysis