Type 2 Diabetes Mellitus
Conditions
Brief summary
This is a study to assess the safety and efficacy of the addition of ipragliflozin once daily in Japanese participants with Type 2 diabetes mellitus (T2DM) who have inadequate glycemic control on sitagliptin, diet, and exercise therapy. The primary hypothesis for this study is that the addition of ipragliflozin compared with placebo provides greater reduction in hemoglobin A1C (HbA1c) as assessed by change from baseline at Week 24.
Interventions
DRUGIpragliflozin
50 mg tablet administered orally
DRUGPlacebo
Placebo to ipragliflozin tablet administered orally
DRUGSitagliptin
Background medication; 50 mg tablet administered orally
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 sitagliptin 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 and sodium glucose cotransporter 2 (SGLT2) inhibitors anytime * 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, treatment by time by prior use of AHAs, and baseline eGFR value with the constraint that the mean baseline HbA1c 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 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, treatment by time by prior use of AHAs, and baseline eGFR value with the constraint that the mean baseline FPG is the same for both treatment groups. |
| 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, treatment by time by prior use of AHAs, and baseline eGFR value with the constraint that the mean baseline 2-hr PMG is the same for both treatment groups. |
| Change From Baseline in Glucose Total AUC0-2hr After Meal at Week 24 | Baseline and Week 24 (just before the 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, and baseline eGFR value with the constraint that the mean baseline glucose total AUC0-2hr after meal is the same for both treatment groups. |
| Change From Baseline in Body Weight at Week 24 | Baseline and Week 24 | Change from baseline in body weight at Week 24 is defined as Week 24 body weight minus Week 0 body weight. 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, and baseline eGFR value with the constraint that the mean baseline body weight 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 |
|---|---|
| Ipragliflozin + Sitagliptin Ipragliflozin once daily for 24 weeks in addition to sitagliptin, diet, and exercise. | 73 |
| Placebo + Sitagliptin Placebo to ipragliflozin once daily for 24 weeks in addition to sitagliptin, diet, and exercise. | 70 |
| Total | 143 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Ipragliflozin + Sitagliptin | Placebo + Sitagliptin | Total |
|---|---|---|---|
| 2-hour Post-Meal Glucose (2-hr PMG) | 225.3 mg/dL STANDARD_DEVIATION 59.9 | 231.5 mg/dL STANDARD_DEVIATION 48.9 | 228.3 mg/dL STANDARD_DEVIATION 54.7 |
| Age, Continuous | 61.0 Years STANDARD_DEVIATION 9.1 | 60.0 Years STANDARD_DEVIATION 10.4 | 60.5 Years STANDARD_DEVIATION 9.7 |
| Body Weight | 69.8 kg STANDARD_DEVIATION 11.7 | 70.1 kg STANDARD_DEVIATION 11.1 | 69.9 kg STANDARD_DEVIATION 11.4 |
| Estimated Glomerular Filtration Rate (eGFR) | 82.0 mL/min/1.73m^2 STANDARD_DEVIATION 13.5 | 83.4 mL/min/1.73m^2 STANDARD_DEVIATION 16.7 | 82.7 mL/min/1.73m^2 STANDARD_DEVIATION 15.1 |
| Fasting Plasma Glucose (FPG) | 158.0 mg/dL STANDARD_DEVIATION 33.2 | 163.0 mg/dL STANDARD_DEVIATION 26.2 | 160.5 mg/dL STANDARD_DEVIATION 30 |
| Glucose Total Area Under the Plasma Concentration Curve from Hour 0 to Hour 2 (AUC0-2hr) after Meal | 429.4 mg･hr/dL STANDARD_DEVIATION 86.3 | 443.4 mg･hr/dL STANDARD_DEVIATION 67 | 436.2 mg･hr/dL STANDARD_DEVIATION 77.5 |
| HbA1c | 8.05 Percent STANDARD_DEVIATION 0.83 | 7.99 Percent STANDARD_DEVIATION 0.62 | 8.02 Percent STANDARD_DEVIATION 0.73 |
| Prior use of other antihyperglycemic agents (AHAs) No | 42 Participants | 40 Participants | 82 Participants |
| Prior use of other antihyperglycemic agents (AHAs) Yes | 31 Participants | 30 Participants | 61 Participants |
| Sex: Female, Male Female | 19 Participants | 17 Participants | 36 Participants |
| Sex: Female, Male Male | 54 Participants | 53 Participants | 107 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 12 / 73 | 15 / 70 |
| serious Total, serious adverse events | 2 / 73 | 4 / 70 |
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, treatment by time by prior use of AHAs, and baseline eGFR value with the constraint that the mean baseline HbA1c 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) |
|---|---|---|
| Ipragliflozin + Sitagliptin | Change From Baseline in HbA1c at Week 24 | -0.84 Percent |
| Placebo + Sitagliptin | Change From Baseline in HbA1c at Week 24 | -0.07 Percent |
p-value: <0.00195% CI: [-0.98, -0.57]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) |
|---|---|---|
| Ipragliflozin + Sitagliptin | Percentage of Participants Who Discontinued Study Drug Due to an AE | 2.7 Percentage of participants |
| Placebo + Sitagliptin | Percentage of Participants Who Discontinued Study Drug Due to an AE | 5.7 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) |
|---|---|---|
| Ipragliflozin + Sitagliptin | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 50.7 Percentage of participants |
| Placebo + Sitagliptin | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 65.7 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, treatment by time by prior use of AHAs, and baseline eGFR value 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) |
|---|---|---|
| Ipragliflozin + Sitagliptin | Change From Baseline in 2-hr PMG at Week 24 | -52.4 mg/dL |
| Placebo + Sitagliptin | Change From Baseline in 2-hr PMG at Week 24 | -3.8 mg/dL |
p-value: <0.00195% CI: [-59.6, -37.5]Constrained longitudinal data analysis
Secondary
Change From Baseline in Body Weight at Week 24
Change from baseline in body weight at Week 24 is defined as Week 24 body weight minus Week 0 body weight. 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, and baseline eGFR value with the constraint that the mean baseline body weight 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 body weight after meal (baseline or post-baseline).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Ipragliflozin + Sitagliptin | Change From Baseline in Body Weight at Week 24 | -2.4 kg |
| Placebo + Sitagliptin | Change From Baseline in Body Weight at Week 24 | -0.6 kg |
p-value: <0.00195% CI: [-2.5, -1.1]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, treatment by time by prior use of AHAs, and baseline eGFR value 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) |
|---|---|---|
| Ipragliflozin + Sitagliptin | Change From Baseline in FPG at Week 24 | -30.3 mg/dL |
| Placebo + Sitagliptin | Change From Baseline in FPG at Week 24 | -2.1 mg/dL |
p-value: <0.00195% CI: [-34.8, -21.5]Constrained longitudinal data analysis
Secondary
Change From Baseline in Glucose Total 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, and baseline eGFR value 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 the 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) |
|---|---|---|
| Ipragliflozin + Sitagliptin | Change From Baseline in Glucose Total AUC0-2hr After Meal at Week 24 | -86.9 mg･hr/dL |
| Placebo + Sitagliptin | Change From Baseline in Glucose Total AUC0-2hr After Meal at Week 24 | -2.3 mg･hr/dL |
p-value: <0.00195% CI: [-102.6, -66.6]Constrained longitudinal data analysis