Type 2 Diabetes Mellitus
Conditions
Brief summary
To assess the effect of adding acarbose or repaglinide or gliclazide to sitagliptin plus metformin, compared to adding glimepiride, on glycemic improvements in Type 2 Diabetes Mellitus (T2DM) participants who require the addition of a third oral anti-hyperglycemic agent (OAHA) according to China Guideline for Type 2 Diabetes. The three co-primary hypotheses are that after 24 weeks of treatment in phase 2, the mean change from baseline in hemoglobin A1c (A1c) in participants receiving either (1)acarbose or (2)repaglinide or (3)gliclazide added to sitagliptin and metformin combination is non-inferior to that of participants receiving glimepiride added to sitagliptin and metformin combination. The study would be declared successful if at least one of the three primary hypotheses was met.
Detailed description
Participants coming on study will be stabilized to a standardized metformin dose: this may take about 10 weeks, and then combination therapy with metformin + sitagliptin will begin during Phase 1 (Week 0 through Week 20). If a participant has already been on a stabilized metformin dose, they will start immediately on combination therapy with metformin + sitagliptin for 20 weeks (Phase 1). In Phase 2, participants who have failed to achieve adequate glycemic control (A1c ≥ 7% and ≤ 10% at Week 16 and fasting finger stick glucose ≥130 mg/dL and ≤280 mg/dL at Week 20) will be randomized to receive add-on therapy with glimepiride, repaglinide, acarbose, or gliclazide for 24 weeks (Week 20 through Week 44).
Interventions
DRUGMetformin
Metformin, 500 mg or 850 mg oral tablets, twice or three times a day (BID or TID) for a total dose of at least 1500 mg daily; administered with food.
DRUGSitagliptin
Sitagliptin, 100 mg oral tablet, once daily (QD); administered with or without food
DRUGAcarbose
Acarbose, 50 mg oral tablets, TID (150 mg total daily dose); administered with the first bite of each main meal.
DRUGRepaglinide
Repaglinide, 0.5 mg and/or 1 mg oral tablets, TID (up to 16 mg daily); administered within 30 minutes of each meal.
DRUGGlimepiride
Glimepiride, 1 mg and/or 2 mg oral tablets, QD (up to 6 mg daily); administered before the first main meal of the day
DRUGGliclazide
Gliclazide, 30 mg oral tablets, QD or BID (30 mg to 120 mg total daily dose); administered with meal.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Has Type 2 Diabetes Mellitus; * Agrees to use an effective method of contraception or must not otherwise be at risk of becoming pregnant (female participants).
Exclusion criteria
* Has a history of type 1 diabetes mellitus or a history of ketoacidosis; * Has been treated with insulin, a dipeptidyl peptidase 4 (DPP-4) inhibitor, a Glucagon-like peptide-1 (GLP-1) mimetic or analogue before; * Is on a weight loss program (not in maintenance phase), has started a weight loss medication, or has undergone bariatric surgery within 12 months; * Has undergone a surgical procedure within 4 weeks; * Has had new or worsening signs or symptoms of coronary heart disease or congestive heart failure within past 3 months, or has acute coronary syndrome, coronary artery intervention, or stroke or transient ischemic neurological disorder; * Has a medical history of active liver disease, including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease; * Has poorly controlled hypertension; * Has severe peripheral vascular disease; * Has human immunodeficiency virus (HIV); * Has had a clinically important hematological disorder; * Routinely consumes \>2 alcoholic drinks per day or \>14 alcoholic drinks per week, or engages in binge drinking; * Has a history of intolerance or hypersensitivity or any contraindication to study medications (including sitagliptin, metformin, glimepiride, repaglinide, acarbose or gliclazide) based upon the Chinese label; * Is on or likely to require treatment with ≥2 consecutive weeks or repeated courses of pharmacologic doses of corticosteroids (other than inhaled, nasal, or topical corticosteroids); * Is pregnant or breast feeding or is expecting to conceive or donate eggs during the study, including 14 days following the last dose of study drug (female participants).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Phase 2 Baseline to Week 44 in Hemoglobin A1c (HbA1c) Levels (Phase 2) | Phase 2 Baseline (Week 20) and Week 44 | HbA1c is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Change from baseline reflects the Week 44 A1C minus baseline A1C. Baseline is defined as Visit 6/Week 20. If this measurement was unavailable, the Week 16 value was used. Change from baseline was based on the constrained longitudinal data analysis (cLDA) model including all available measurements from baseline through the last visit. The terms in the cLDA model include treatment, time in weeks (categorical), regions, and treatment-by-time interaction. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hypoglycemia Events (Phase 2) | From Week 20 through Week 44 | Hypoglycemia events represent epidsodes symptomatic of hypoglycemia (e.g., weakness, dizziness, shakiness, increased sweating, palpitations, or confusion) and/or finger stick glucose values of ≤70 mg/dL (3.9 mmol/L). The percentage of participants with hypoglycemia events was reported. |
| Percentage of Participants With a Gastrointestinal (GI) AE of Nausea (Phase 2) | From Week 20 through Week 44 | The percentage of participants with a GI AE of nausea was reported. |
| Change From Phase 2 Baseline to Week 44 in Participant Body Weight (Phase 2) | Phase 2 Baseline (Week 20), Week 44 | Change from baseline in body weight in Phase 2 was reported. Change from baseline reflects the Week 44 body weight minus baseline body weight. Baseline is defined as Visit 6/Week 20. If this measurement was unavailable, the Week 16 value was used. |
| Percentage of Participants With a GI AE of Diarrhea (Phase 2) | From Week 20 through Week 44 | The percentage of participants with a GI AE of diarrhea was reported. |
| Percentage of Participants With a GI AE of Abdominal Pain (Phase 2) | From Week 20 through Week 44 | The percentage of participants with a GI AE of abdominal pain was reported. |
| Percentage of Participants With a GI AE of Vomiting (Phase 2) | From Week 20 through Week 44 | The percentage of participants with a GI AE of vomiting was reported. |
Participant flow
Recruitment details
Adult Chinese participants (≥18 and ≤75 years of age) with a diagnosis of Type 2 Diabetes Mellitus (T2DM) and inadequate glycemic control were selected to participate in this study.
Pre-assignment details
There were 2344 participants who achieved A1C\<7% in Phase 1; they completed Phase 1 and did not enter Phase 2. Of the remaining 2589 participants, 377 participants did not meet randomization criteria to enter Phase 2.
Participants by arm
| Arm | Count |
|---|---|
| Overall Study During Phase 1, participants received sitagliptin 100 mg + metformin (Week 0 through Week 20). | 5,535 |
| Total | 5,535 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Phase 1 | Clinical Adverse Event | 80 | 0 | 0 | 0 | 0 |
| Phase 1 | Death | 2 | 0 | 0 | 0 | 0 |
| Phase 1 | Hyperglycemia (lack of efficacy) | 13 | 0 | 0 | 0 | 0 |
| Phase 1 | Laboratory Adverse Event | 16 | 0 | 0 | 0 | 0 |
| Phase 1 | Lost to Follow-up | 147 | 0 | 0 | 0 | 0 |
| Phase 1 | Physician Decision | 13 | 0 | 0 | 0 | 0 |
| Phase 1 | Protocol Violation | 118 | 0 | 0 | 0 | 0 |
| Phase 1 | Travel, moving, etc. | 30 | 0 | 0 | 0 | 0 |
| Phase 1 | Withdrawal by Subject | 218 | 0 | 0 | 0 | 0 |
| Phase 2 | Clinical Adverse Event | 0 | 10 | 10 | 6 | 11 |
| Phase 2 | Death | 0 | 0 | 1 | 0 | 0 |
| Phase 2 | Hyperglycemia (lack of efficacy) | 0 | 0 | 0 | 0 | 2 |
| Phase 2 | Laboratory Adverse Event | 0 | 1 | 0 | 1 | 1 |
| Phase 2 | Lost to Follow-up | 0 | 10 | 6 | 9 | 5 |
| Phase 2 | Physician Decision | 0 | 2 | 0 | 1 | 2 |
| Phase 2 | Protocol Violation | 0 | 19 | 19 | 13 | 9 |
| Phase 2 | Travel, moving, etc. | 0 | 2 | 3 | 3 | 5 |
| Phase 2 | Withdrawal by Subject | 0 | 8 | 6 | 15 | 12 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 53.1 Years STANDARD_DEVIATION 9.9 |
| Sex: Female, Male Female | 2240 Participants |
| Sex: Female, Male Male | 3295 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 66 / 5,527 | 3 / 551 | 33 / 545 | 20 / 550 | 48 / 549 |
| serious Total, serious adverse events | 63 / 5,527 | 11 / 551 | 9 / 545 | 10 / 550 | 8 / 549 |
Outcome results
Primary
Change From Phase 2 Baseline to Week 44 in Hemoglobin A1c (HbA1c) Levels (Phase 2)
HbA1c is blood marker used to report average blood glucose levels over prolonged periods of time and is reported as a percentage (%). Change from baseline reflects the Week 44 A1C minus baseline A1C. Baseline is defined as Visit 6/Week 20. If this measurement was unavailable, the Week 16 value was used. Change from baseline was based on the constrained longitudinal data analysis (cLDA) model including all available measurements from baseline through the last visit. The terms in the cLDA model include treatment, time in weeks (categorical), regions, and treatment-by-time interaction.
Time frame: Phase 2 Baseline (Week 20) and Week 44
Population: Per-Protocol (PP) population - excluded those participants who were identified as protocol violators and those who were non-compliant with Good Clinical Practice (GCP) requirements.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Phase 2: Metformin + Sitagliptin + Glimepiride | Change From Phase 2 Baseline to Week 44 in Hemoglobin A1c (HbA1c) Levels (Phase 2) | -0.65 Percent | 95% Confidence Interval 0.84 |
| Phase 2: Metformin + Sitagliptin + Repaglinide | Change From Phase 2 Baseline to Week 44 in Hemoglobin A1c (HbA1c) Levels (Phase 2) | -0.62 Percent | 95% Confidence Interval 0.84 |
| Phase 2: Metformin + Sitagliptin + Acarbose | Change From Phase 2 Baseline to Week 44 in Hemoglobin A1c (HbA1c) Levels (Phase 2) | -0.46 Percent | 95% Confidence Interval 0.83 |
| Phase 2: Metformin + Sitagliptin + Gliclazide | Change From Phase 2 Baseline to Week 44 in Hemoglobin A1c (HbA1c) Levels (Phase 2) | -0.69 Percent | 95% Confidence Interval 0.9 |
Comparison: Pairwise Comparison98.34% CI: [0.02, 0.36]
Comparison: Pairwise Comparison98.34% CI: [-0.15, 0.21]
Comparison: Pairwise Comparison98.34% CI: [-0.23, 0.14]
Secondary
Change From Phase 2 Baseline to Week 44 in Participant Body Weight (Phase 2)
Change from baseline in body weight in Phase 2 was reported. Change from baseline reflects the Week 44 body weight minus baseline body weight. Baseline is defined as Visit 6/Week 20. If this measurement was unavailable, the Week 16 value was used.
Time frame: Phase 2 Baseline (Week 20), Week 44
Population: All Participants as Treated (APaT) - all randomized participants who received at least one (1) dose of study treatment and were compliant with GCP requirements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 2: Metformin + Sitagliptin + Glimepiride | Change From Phase 2 Baseline to Week 44 in Participant Body Weight (Phase 2) | 0.4 kg | Standard Deviation 2.6 |
| Phase 2: Metformin + Sitagliptin + Repaglinide | Change From Phase 2 Baseline to Week 44 in Participant Body Weight (Phase 2) | 0.2 kg | Standard Deviation 2.5 |
| Phase 2: Metformin + Sitagliptin + Acarbose | Change From Phase 2 Baseline to Week 44 in Participant Body Weight (Phase 2) | -0.9 kg | Standard Deviation 2.5 |
| Phase 2: Metformin + Sitagliptin + Gliclazide | Change From Phase 2 Baseline to Week 44 in Participant Body Weight (Phase 2) | 0.2 kg | Standard Deviation 2.4 |
Secondary
Percentage of Participants With a Gastrointestinal (GI) AE of Nausea (Phase 2)
The percentage of participants with a GI AE of nausea was reported.
Time frame: From Week 20 through Week 44
Population: All Participants as Treated (APaT) - all randomized participants who received at least one (1) dose of study treatment and were compliant with GCP requirements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Metformin + Sitagliptin + Glimepiride | Percentage of Participants With a Gastrointestinal (GI) AE of Nausea (Phase 2) | 0 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Repaglinide | Percentage of Participants With a Gastrointestinal (GI) AE of Nausea (Phase 2) | 0 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Acarbose | Percentage of Participants With a Gastrointestinal (GI) AE of Nausea (Phase 2) | 0.4 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Gliclazide | Percentage of Participants With a Gastrointestinal (GI) AE of Nausea (Phase 2) | 0.2 Percentage of Participants |
Comparison: Difference in % vs. Glimepiridep-value: 0.15895% CI: [-0.3, 1.3]Miettinen & Nurminen
Comparison: Difference in % vs. Glimepiridep-value: >0.99995% CI: [-0.7, 0.7]Miettinen & Nurminen
Comparison: Difference in % vs. Glimepiridep-value: 0.31895% CI: [-0.5, 1]Miettinen & Nurminen
Secondary
Percentage of Participants With a GI AE of Abdominal Pain (Phase 2)
The percentage of participants with a GI AE of abdominal pain was reported.
Time frame: From Week 20 through Week 44
Population: All Participants as Treated (APaT) - all randomized participants who received at least one (1) dose of study treatment and were compliant with GCP requirements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Metformin + Sitagliptin + Glimepiride | Percentage of Participants With a GI AE of Abdominal Pain (Phase 2) | 0 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Repaglinide | Percentage of Participants With a GI AE of Abdominal Pain (Phase 2) | 0 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Acarbose | Percentage of Participants With a GI AE of Abdominal Pain (Phase 2) | 0.4 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Gliclazide | Percentage of Participants With a GI AE of Abdominal Pain (Phase 2) | 0.2 Percentage of Participants |
Comparison: Difference in % vs. Glimepiridep-value: 0.15895% CI: [-0.3, 1.3]Miettinen & Nurminen
Comparison: Difference in % vs. Glimepiridep-value: >0.99995% CI: [-0.7, 0.7]Miettinen & Nurminen
Comparison: Difference in % vs. Glimepiridep-value: 0.31895% CI: [-0.5, 1]Miettinen & Nurminen
Secondary
Percentage of Participants With a GI AE of Diarrhea (Phase 2)
The percentage of participants with a GI AE of diarrhea was reported.
Time frame: From Week 20 through Week 44
Population: All Participants as Treated (APaT) - all randomized participants who received at least one (1) dose of study treatment and were compliant with GCP requirements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Metformin + Sitagliptin + Glimepiride | Percentage of Participants With a GI AE of Diarrhea (Phase 2) | 0.5 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Repaglinide | Percentage of Participants With a GI AE of Diarrhea (Phase 2) | 0.4 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Acarbose | Percentage of Participants With a GI AE of Diarrhea (Phase 2) | 0.4 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Gliclazide | Percentage of Participants With a GI AE of Diarrhea (Phase 2) | 0.9 Percentage of Participants |
Comparison: Difference in % vs. Glimepiridep-value: 0.65195% CI: [-1.3, 0.8]Miettinen & Nurminen
Comparison: Difference in % vs. Glimepiridep-value: 0.6695% CI: [-1.3, 0.8]Miettinen & Nurminen
Comparison: Difference in % vs. Glimepiridep-value: 0.4895% CI: [-0.8, 1.6]Miettinen & Nurminen
Secondary
Percentage of Participants With a GI AE of Vomiting (Phase 2)
The percentage of participants with a GI AE of vomiting was reported.
Time frame: From Week 20 through Week 44
Population: All Participants as Treated (APaT) - all randomized participants who received at least one (1) dose of study treatment and were compliant with GCP requirements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Metformin + Sitagliptin + Glimepiride | Percentage of Participants With a GI AE of Vomiting (Phase 2) | 0.2 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Repaglinide | Percentage of Participants With a GI AE of Vomiting (Phase 2) | 0 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Acarbose | Percentage of Participants With a GI AE of Vomiting (Phase 2) | 0.2 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Gliclazide | Percentage of Participants With a GI AE of Vomiting (Phase 2) | 0.2 Percentage of Participants |
Comparison: Difference in % vs. Glimepiridep-value: 0.99895% CI: [-0.9, 0.9]Miettinen & Nurminen
Comparison: Difference in % vs. Glimepiridep-value: 0.31995% CI: [-1, 0.5]Miettinen & Nurminen
Comparison: Difference in % vs. Glimepiridep-value: 0.99995% CI: [-0.9, 0.9]Miettinen & Nurminen
Secondary
Percentage of Participants With Hypoglycemia Events (Phase 2)
Hypoglycemia events represent epidsodes symptomatic of hypoglycemia (e.g., weakness, dizziness, shakiness, increased sweating, palpitations, or confusion) and/or finger stick glucose values of ≤70 mg/dL (3.9 mmol/L). The percentage of participants with hypoglycemia events was reported.
Time frame: From Week 20 through Week 44
Population: All Participants as Treated (APaT) - all randomized participants who received at least one (1) dose of study treatment and were compliant with GCP requirements.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 2: Metformin + Sitagliptin + Glimepiride | Percentage of Participants With Hypoglycemia Events (Phase 2) | 8.9 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Repaglinide | Percentage of Participants With Hypoglycemia Events (Phase 2) | 6.1 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Acarbose | Percentage of Participants With Hypoglycemia Events (Phase 2) | 0.5 Percentage of Participants |
| Phase 2: Metformin + Sitagliptin + Gliclazide | Percentage of Participants With Hypoglycemia Events (Phase 2) | 3.6 Percentage of Participants |
Comparison: Difference in % vs. Glimepiridep-value: <0.00195% CI: [-11.1, -6.1]Miettinen & Nurminen
Comparison: Difference in % vs. Glimepiridep-value: 0.07295% CI: [-6.1, 0.3]Miettinen & Nurminen
Comparison: Difference in % vs. Glimepiridep-value: <0.00195% CI: [-8.3, -2.5]Miettinen & Nurminen