Diabetes Mellitus, Type 2
Conditions
Brief summary
The purpose of this study is to test the effect of MK-0941 as add-on therapy for participants taking insulin for type 2 diabetes mellitus. The primary hypotheses of this study are that treatment with MK-0941 added to insulin will provide greater reduction in hemoglobin A1c (HbA1c) level than will placebo added to insulin at 14 weeks, and that MK-0941 will be well-tolerated at 1 or more doses that demonstrate efficacy.
Detailed description
This study is a 54-week randomized, double-blind base study with an optional 104-week extension study (MK-0941-007-11). Beginning on Week 16, participants not randomized to the maximum dose of MK-0941 could up-titrate to MK-0941 40 mg three times daily. Participants who complete the 54-week base study are eligible to enter the extension study and will remain in the treatment group to which they were assigned in the base study.
Interventions
DRUGMK-0941
MK-0941 tablets three times daily
DRUGComparator: Placebo
Matching placebo to MK-0941 three times daily
BIOLOGICALLantus
Lantus injection once daily
DRUGMetformin
Metformin ≥1500 mg/day at a stable dose for at least 6 weeks before Screening and for the duration of the study. The number of randomized participants who receive metformin will be capped at 70% of enrollment.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* has type 2 diabetes mellitus * has body mass index \>20 and \<43 kg/m\^2 * is a male, or a female who is unlikely to conceive * currently on a stable dose of insulin with or without metformin for Type 2 diabetes mellitus Extension Study Inclusion Criteria: * completed the base study either on double-blind study medication or as part of the post-treatment follow up population * had ≥85% compliance with double-blind and open-label medication during the base study double-blind treatment period
Exclusion criteria
* has any history of Type 1 diabetes mellitus or ketoacidosis * has received more that 1 week of thiazolidinedione (such as pioglitazone or rosiglitazone) therapy or injectable increatin-based therapy (such as Byetta) within the prior 8 weeks * has had ≥2 episodes during their lifetime or \>1 episode within the past year resulting in hypoglycemic seizures, comas, or unconsciousness * is on a weight loss program and is not in the maintenance phase, or patient is taking a weight loss medication (e.g., orlistat, sibutramine, rimonabant) within 8 weeks of Visit 1 * has undergone surgery within 30 days prior to Visit 1 or has planned major surgery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hemoglobin A1c (HbA1c) Level | Baseline and Weeks 14, 54, 106, and 158 | Least square means change from baseline in HbA1c. HbA1c represents the percentage of glycated hemoglobin. A negative number means reduction in HbA1c level. |
| Percentage of Participants Who Experienced at Least One Adverse Event | Entire study including 54-week study and 104-week extension | — |
| Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event | Entire study including 54-week study and 104-week extension | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving an HbA1c of <7.0% at Week 54 Who Maintain an HbA1c of <7.0% | Weeks 54, 106 and 158 | — |
| Change in the Two-hour Post Meal Glucose Level | Baseline and Weeks 14, 54, 106, and 158 | Least squares mean change from baseline in 2-hour post meal glucose level. |
| Change in the Fasting Plasma Glucose Level | Baseline and Weeks 14, 54, 106, and 158 | Least squares mean change from baseline in fasting plasma glucose. |
| Percentage of Participants Who Achieve an HbA1c of <7.0% | Weeks 106 and 158 | — |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| MK-0941 10 mg MK-0941 10 mg three times daily plus insulin once daily with or without metformin | 119 |
| MK-0941 20 mg MK-0941 20 mg three times daily plus insulin once daily with or without metformin | 117 |
| MK-0941 30 mg MK-0941 30 mg three times daily plus insulin once daily with or without metformin | 117 |
| MK-0941 40 mg MK-0941 40 mg three times daily plus insulin once daily with or without metformin | 229 |
| Placebo Placebo three times daily plus insulin once daily with or without metformin | 231 |
| Total | 813 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| 54-week Study | Adverse Event | 4 | 6 | 6 | 8 | 4 |
| 54-week Study | Creaninine/creatinine clearance | 2 | 1 | 2 | 2 | 4 |
| 54-week Study | Hyperglycemia | 0 | 0 | 1 | 0 | 1 |
| 54-week Study | Hypoglycemia | 0 | 1 | 0 | 0 | 0 |
| 54-week Study | Interruption of study medication | 0 | 0 | 1 | 0 | 0 |
| 54-week Study | Lack of Efficacy | 2 | 0 | 1 | 0 | 5 |
| 54-week Study | Lost to Follow-up | 4 | 0 | 1 | 4 | 2 |
| 54-week Study | Physician Decision | 4 | 0 | 1 | 1 | 1 |
| 54-week Study | Progressive disease | 0 | 0 | 1 | 0 | 0 |
| 54-week Study | Protocol Violation | 0 | 0 | 1 | 2 | 0 |
| 54-week Study | Reason not reported | 0 | 0 | 0 | 1 | 0 |
| 54-week Study | Study terminated by sponsor | 90 | 102 | 89 | 196 | 194 |
| 54-week Study | Withdrawal by Subject | 2 | 3 | 5 | 11 | 13 |
| Optional 104-week Extension | Study terminated by sponsor | 7 | 3 | 7 | 2 | 4 |
Baseline characteristics
| Characteristic | MK-0941 10 mg | MK-0941 20 mg | MK-0941 30 mg | MK-0941 40 mg | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Customized 26 to 71 years | 119 participants | 117 participants | 117 participants | 229 participants | 231 participants | 813 participants |
| Sex: Female, Male Female | 67 Participants | 57 Participants | 54 Participants | 123 Participants | 115 Participants | 416 Participants |
| Sex: Female, Male Male | 52 Participants | 60 Participants | 63 Participants | 106 Participants | 116 Participants | 397 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 | 74 / 119 | 75 / 117 | 78 / 117 | 120 / 229 | 101 / 231 |
| serious Total, serious adverse events | 11 / 119 | 12 / 117 | 11 / 117 | 13 / 229 | 8 / 231 |
Outcome results
Primary
Change in Hemoglobin A1c (HbA1c) Level
Least square means change from baseline in HbA1c. HbA1c represents the percentage of glycated hemoglobin. A negative number means reduction in HbA1c level.
Time frame: Baseline and Weeks 14, 54, 106, and 158
Population: Full analysis set. The additional participants added to the MK-0941 40 mg and placebo arms to enhance evaluation of safety were not included in the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| MK-0941 10 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 14 | -0.59 Percent HbA1c |
| MK-0941 10 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 54 (no participants analyzed) | NA Percent HbA1c |
| MK-0941 10 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 158 (no participants analyzed) | NA Percent HbA1c |
| MK-0941 10 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 106 (no participants analyzed) | NA Percent HbA1c |
| MK-0941 20 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 158 (no participants analyzed) | NA Percent HbA1c |
| MK-0941 20 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 106 (no participants analyzed) | NA Percent HbA1c |
| MK-0941 20 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 54 (no participants analyzed) | NA Percent HbA1c |
| MK-0941 20 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 14 | -0.72 Percent HbA1c |
| MK-0941 30 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 14 | -0.89 Percent HbA1c |
| MK-0941 30 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 54 (no participants analyzed) | NA Percent HbA1c |
| MK-0941 30 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 158 (no participants analyzed) | NA Percent HbA1c |
| MK-0941 30 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 106 (no participants analyzed) | NA Percent HbA1c |
| MK-0941 40 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 54 (no participants analyzed) | NA Percent HbA1c |
| MK-0941 40 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 106 (no participants analyzed) | NA Percent HbA1c |
| MK-0941 40 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 14 | -0.83 Percent HbA1c |
| MK-0941 40 mg | Change in Hemoglobin A1c (HbA1c) Level | Week 158 (no participants analyzed) | NA Percent HbA1c |
| Placebo | Change in Hemoglobin A1c (HbA1c) Level | Week 54 (no participants analyzed) | NA Percent HbA1c |
| Placebo | Change in Hemoglobin A1c (HbA1c) Level | Week 14 | -0.08 Percent HbA1c |
| Placebo | Change in Hemoglobin A1c (HbA1c) Level | Week 158 (no participants analyzed) | NA Percent HbA1c |
| Placebo | Change in Hemoglobin A1c (HbA1c) Level | Week 106 (no participants analyzed) | NA Percent HbA1c |
Comparison: Analysis for change from baseline to Week 14p-value: <0.00195% CI: [-0.8, -0.22]Constrained longitudinal model
Comparison: Analysis for change from baseline to Week 14p-value: <0.00195% CI: [-0.93, -0.36]Constrained longitudinal model
Comparison: Analysis for change from baseline to Week 14p-value: <0.00195% CI: [-1.1, -0.53]Contrained longitudinal model
Comparison: Analysis for change from baseline to Week 14p-value: <0.00195% CI: [-1.04, -0.46]Constrained longitudinal model
Primary
Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event
Time frame: Entire study including 54-week study and 104-week extension
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-0941 10 mg | Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event | 3.4 percentage of participants |
| MK-0941 20 mg | Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event | 5.1 percentage of participants |
| MK-0941 30 mg | Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event | 6.8 percentage of participants |
| MK-0941 40 mg | Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event | 3.1 percentage of participants |
| Placebo | Percentage of Participants Who Discontinued Study Medication Due to an Adverse Event | 1.7 percentage of participants |
Primary
Percentage of Participants Who Experienced at Least One Adverse Event
Time frame: Entire study including 54-week study and 104-week extension
Population: Full analysis set. Includes additional participants enrolled in the MK-0941 40 mg and placebo groups to enhance evaluation of the safety profile of MK-0941.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-0941 10 mg | Percentage of Participants Who Experienced at Least One Adverse Event | 80.7 percentage of participants |
| MK-0941 20 mg | Percentage of Participants Who Experienced at Least One Adverse Event | 79.5 percentage of participants |
| MK-0941 30 mg | Percentage of Participants Who Experienced at Least One Adverse Event | 80.3 percentage of participants |
| MK-0941 40 mg | Percentage of Participants Who Experienced at Least One Adverse Event | 65.5 percentage of participants |
| Placebo | Percentage of Participants Who Experienced at Least One Adverse Event | 65.4 percentage of participants |
Secondary
Change in the Fasting Plasma Glucose Level
Least squares mean change from baseline in fasting plasma glucose.
Time frame: Baseline and Weeks 14, 54, 106, and 158
Population: Full analysis set. The additional participants added to the MK-0941 40 mg and placebo arms to enhance evaluation of safety were not included in the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| MK-0941 10 mg | Change in the Fasting Plasma Glucose Level | Week 106 (no participants analyzed) | NA mg/dL |
| MK-0941 10 mg | Change in the Fasting Plasma Glucose Level | Week 54 (no participants analyzed) | NA mg/dL |
| MK-0941 10 mg | Change in the Fasting Plasma Glucose Level | Week 158 (no participants analyzed) | NA mg/dL |
| MK-0941 10 mg | Change in the Fasting Plasma Glucose Level | Week 14 | -10.0 mg/dL |
| MK-0941 20 mg | Change in the Fasting Plasma Glucose Level | Week 158 (no participants analyzed) | NA mg/dL |
| MK-0941 20 mg | Change in the Fasting Plasma Glucose Level | Week 14 | -1.5 mg/dL |
| MK-0941 20 mg | Change in the Fasting Plasma Glucose Level | Week 54 (no participants analyzed) | NA mg/dL |
| MK-0941 20 mg | Change in the Fasting Plasma Glucose Level | Week 106 (no participants analyzed) | NA mg/dL |
| MK-0941 30 mg | Change in the Fasting Plasma Glucose Level | Week 14 | -21.1 mg/dL |
| MK-0941 30 mg | Change in the Fasting Plasma Glucose Level | Week 54 (no participants analyzed) | NA mg/dL |
| MK-0941 30 mg | Change in the Fasting Plasma Glucose Level | Week 158 (no participants analyzed) | NA mg/dL |
| MK-0941 30 mg | Change in the Fasting Plasma Glucose Level | Week 106 (no participants analyzed) | NA mg/dL |
| MK-0941 40 mg | Change in the Fasting Plasma Glucose Level | Week 54 (no participants analyzed) | NA mg/dL |
| MK-0941 40 mg | Change in the Fasting Plasma Glucose Level | Week 14 | -5.0 mg/dL |
| MK-0941 40 mg | Change in the Fasting Plasma Glucose Level | Week 106 (no participants analyzed) | NA mg/dL |
| MK-0941 40 mg | Change in the Fasting Plasma Glucose Level | Week 158 (no participants analyzed) | NA mg/dL |
| Placebo | Change in the Fasting Plasma Glucose Level | Week 54 (no participants analyzed) | NA mg/dL |
| Placebo | Change in the Fasting Plasma Glucose Level | Week 14 | -11.8 mg/dL |
| Placebo | Change in the Fasting Plasma Glucose Level | Week 158 (no participants analyzed) | NA mg/dL |
| Placebo | Change in the Fasting Plasma Glucose Level | Week 106 (no participants analyzed) | NA mg/dL |
Comparison: Analysis for change from baseline to Week 14p-value: 0.79195% CI: [-11.6, 15.2]Constrained longitudinal model
Comparison: Analysis for change from baseline to Week 14p-value: 0.12195% CI: [-2.7, 23.2]Constrained longitudinal model
Comparison: Analysis for change from baseline to Week 14p-value: 0.16995% CI: [-22.6, 4]Constrained longitudinal model
Comparison: Analysis for change from baseline to Week 14p-value: 0.32195% CI: [-6.6, 20]Constrained longitudinal model
Secondary
Change in the Two-hour Post Meal Glucose Level
Least squares mean change from baseline in 2-hour post meal glucose level.
Time frame: Baseline and Weeks 14, 54, 106, and 158
Population: Full analysis set. The additional participants added to the MK-0941 40 mg and placebo arms to enhance evaluation of safety were not included in the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| MK-0941 10 mg | Change in the Two-hour Post Meal Glucose Level | Week 14 | -39.0 mg/dL |
| MK-0941 10 mg | Change in the Two-hour Post Meal Glucose Level | Week 54 (no participants analyzed) | NA mg/dL |
| MK-0941 10 mg | Change in the Two-hour Post Meal Glucose Level | Week 106 (no participants analyzed) | NA mg/dL |
| MK-0941 10 mg | Change in the Two-hour Post Meal Glucose Level | Week 158 (no participants analyzed) | NA mg/dL |
| MK-0941 20 mg | Change in the Two-hour Post Meal Glucose Level | Week 158 (no participants analyzed) | NA mg/dL |
| MK-0941 20 mg | Change in the Two-hour Post Meal Glucose Level | Week 106 (no participants analyzed) | NA mg/dL |
| MK-0941 20 mg | Change in the Two-hour Post Meal Glucose Level | Week 54 (no participants analyzed) | NA mg/dL |
| MK-0941 20 mg | Change in the Two-hour Post Meal Glucose Level | Week 14 | -29.2 mg/dL |
| MK-0941 30 mg | Change in the Two-hour Post Meal Glucose Level | Week 106 (no participants analyzed) | NA mg/dL |
| MK-0941 30 mg | Change in the Two-hour Post Meal Glucose Level | Week 54 (no participants analyzed) | NA mg/dL |
| MK-0941 30 mg | Change in the Two-hour Post Meal Glucose Level | Week 14 | -37.4 mg/dL |
| MK-0941 30 mg | Change in the Two-hour Post Meal Glucose Level | Week 158 (no participants analyzed) | NA mg/dL |
| MK-0941 40 mg | Change in the Two-hour Post Meal Glucose Level | Week 14 | -39.3 mg/dL |
| MK-0941 40 mg | Change in the Two-hour Post Meal Glucose Level | Week 106 (no participants analyzed) | NA mg/dL |
| MK-0941 40 mg | Change in the Two-hour Post Meal Glucose Level | Week 54 (no participants analyzed) | NA mg/dL |
| MK-0941 40 mg | Change in the Two-hour Post Meal Glucose Level | Week 158 (no participants analyzed) | NA mg/dL |
| Placebo | Change in the Two-hour Post Meal Glucose Level | Week 54 (no participants analyzed) | NA mg/dL |
| Placebo | Change in the Two-hour Post Meal Glucose Level | Week 14 | -2.4 mg/dL |
| Placebo | Change in the Two-hour Post Meal Glucose Level | Week 106 (no participants analyzed) | NA mg/dL |
| Placebo | Change in the Two-hour Post Meal Glucose Level | Week 158 (no participants analyzed) | NA mg/dL |
Comparison: Analysis for change from baseline to Week 14p-value: <0.00195% CI: [-55.6, -17.5]Constrained longitudial model
Comparison: Analysis for change from baseline to Week 14p-value: 0.00595% CI: [-45.4, -8.1]Constrained longitudinal model
Comparison: Analysis for change from baseline to Week 14p-value: <0.00195% CI: [-54, -16]Constrained longitudinal model
Comparison: Analysis for change from baseline to Week 14p-value: <0.00195% CI: [-55.9, -17.9]Constrained longitudinal model
Secondary
Percentage of Participants Achieving an HbA1c of <7.0% at Week 54 Who Maintain an HbA1c of <7.0%
Time frame: Weeks 54, 106 and 158
Population: Due to early termination and small numbers of participants, no efficacy analyses were performed at Weeks 106 or 158
Secondary
Percentage of Participants Who Achieve an HbA1c of <7.0%
Time frame: Weeks 106 and 158
Population: Due to early termination and small numbers of participants, no efficacy analyses were performed at Weeks 106 or 158