Diabetes Mellitus
Conditions
Keywords
Diabetes Mellitus, Diabetes Mellitus, Type 2, Glucose Metabolism Disorders, Metabolic Diseases, Endocrine System Diseases, Metformin, Hypoglycemic Agents, Pharmacologic Actions, Therapeutic Uses
Brief summary
This study will examine the safety and efficacy of once-weekly omarigliptin in participants 18 to \<45 years of age with Type 2 diabetes mellitus and inadequate glycemic control. The study hypothesis is that treatment with omarigliptin compared with placebo provides greater reduction in hemoglobin A1c (A1C) in participants after 24 weeks.
Interventions
DRUGOmarigliptin
Omarigliptin 25 mg capsule administered orally once weekly
Matching placebo to omarigliptin 25 mg capsule administered orally once weekly
DRUGMetformin
Open-label metformin (dosed daily according to the country-specific product label) was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited.
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 44 Years
Healthy volunteers
No
Inclusion criteria
* Has type 2 diabetes mellitus * Currently not on an antihyperglycemic agent (AHA) for at least the past 12 weeks and has not been treated with omarigliptin at any time prior to study participation * Participant is one of the following: 1. Male 2. Female who is not of reproductive potential 3. Female of reproductive potential who agrees to remain abstinent from heterosexual activity or use (or have her partner use) 2 acceptable methods of contraception to prevent pregnancy during the study and for 21 days after the last dose of study drug
Exclusion criteria
* History of type 1 diabetes mellitus or a history of ketoacidosis * History of hypersensitivity to dipeptidyl-peptidase-4 (DPP-4) inhibitor * Currently participating in or has participated in a clinical trial in the past 12 weeks * Is on a weight loss program and not in the maintenance phase; has been on a weight loss medication in the past 6 months; or has undergone bariatric surgery within 12 months prior to study participation * Has undergone a surgical procedure within 4 weeks of study participation or has planned major surgery during the study * Is on or likely to require treatment for ≥14 consecutive days or repeated courses of pharmacologic doses of corticosteroids * Is currently being treated for hyperthyroidism or is on thyroid replacement therapy and has not been on a stable dose for at least 6 weeks * Is expecting to undergo hormonal therapy in preparation to donate eggs during the study, including 21 days following the last dose of study drug * History of active liver disease (other than non-alcoholic hepatic steatosis) including chronic active hepatitis B or C, primary biliary cirrhosis, or symptomatic gallbladder disease * Has human immunodeficiency virus (HIV) * Has had new or worsening coronary heart disease or congestive heart failure within the past 3 months, or has any of the following disorders within the past 3 months: 1. Acute coronary syndrome 2. Coronary artery intervention 3. Stroke or transient ischemic neurological disorder * Has poorly controlled hypertension * History of malignancy ≤5 years prior to study participation, except for basal cell or squamous cell skin cancer or in situ cervical cancer * Has a hematological disorder (such as aplastic anemia, myeloproliferative or myelodysplastic syndromes, thrombocytopenia) * Has a positive urine pregnancy test * Pregnant or breastfeeding, or is expecting to conceive during the study, including 21 days following the last dose of study drug * User of recreational or illicit drugs or has had a recent history of drug abuse. Routinely consumes \>2 alcoholic drinks per day or \>14 alcoholic drinks per week, or engages in binge drinking. * Has donated blood products or has had a phlebotomy (\>300 mL) within 8 weeks of study participation, or intends to donate blood products during the study or has received, or is anticipated to receive, blood products within 12 weeks of study participation or during the study * Has a clinically significant electrocardiogram abnormality
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in A1C at Week 24 | Baseline and Week 24 | A1C (%) is used to report average blood glucose levels over prolonged periods of time. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. |
| Percentage of Participants Who Experienced at Least One Adverse Event (AE) | Up to Week 27 | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Data presented exclude data following the initiation of glycemic rescue. The safety database was analyzed in a standard fashion in the all participants as treated (APaT) population for all participants who took at least one dose of study medication. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above). |
| Percentage of Participants Who Discontinued Study Drug Due to an AE | Up to Week 24 | An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Data presented exclude data following the initiation of glycemic rescue. The safety database was analyzed in a standard fashion in the APaT population for all participants who took at least one dose of study medication. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Attaining A1C Glycemic Goals of <6.5% (48 mmol/Mol) at Week 24 | Week 24 | Percentage of participants was estimated using standard multiple imputation techniques (cLDA). Within-group CIs were calculated via the Wilson score method. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. |
| Change From Baseline in 2-hr PMG at Week 24 | Baseline and Week 24 | Blood glucose was measured 120 minutes from start of meal. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. |
| Percentage of Participants Who Required Glycemic Rescue by Week 24 | Up to Week 24 | Participants exceeding pre-specified glycemic thresholds after starting the double-blind treatment period may have received rescue therapy (per protocol) with open-label metformin initiated by the investigator. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above). |
| Change in Baseline in FPG at Week 24 | Baseline and Week 24 | Blood glucose was measured on a fasting basis. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. |
| Percentage of Participants Attaining A1C Glycemic Goals of <7.0% at Week 24 | Week 24 | Percentage of participants was estimated using standard multiple imputation techniques (constrained longitudinal data analysis \[cLDA\] model). Within-group confidence intervals (CIs) were calculated via the Wilson score method. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Omarigliptin 25 mg Omarigliptin 25 mg, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited. | 102 |
| Placebo Placebo to omarigliptin, once weekly, for 24 weeks. Open-label metformin daily was to be initiated for participants meeting protocol-specified glycemic criteria, but was otherwise prohibited. | 101 |
| Total | 203 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Study site terminated by sponsor | 1 | 1 |
| Overall Study | Withdrawal by Subject | 6 | 4 |
Baseline characteristics
| Characteristic | Omarigliptin 25 mg | Total | Placebo |
|---|---|---|---|
| 2-hour post-meal glucose (2-hr PMG) | 204.9 mg/dL STANDARD_DEVIATION 55.1 | 211.2 mg/dL STANDARD_DEVIATION 62 | 217.3 mg/dL STANDARD_DEVIATION 67.7 |
| Age, Continuous | 38.8 Years STANDARD_DEVIATION 4.7 | 39.2 Years STANDARD_DEVIATION 4.6 | 39.5 Years STANDARD_DEVIATION 4.5 |
| Fasting plasma glucose (FPG) | 164.0 mg/dL STANDARD_DEVIATION 38.9 | 165.9 mg/dL STANDARD_DEVIATION 39.7 | 167.8 mg/dL STANDARD_DEVIATION 40.6 |
| Hemoglobin A1c (A1C) | 7.9 Percent STANDARD_DEVIATION 0.8 | 8.0 Percent STANDARD_DEVIATION 0.8 | 8.1 Percent STANDARD_DEVIATION 0.9 |
| Sex: Female, Male Female | 35 Participants | 76 Participants | 41 Participants |
| Sex: Female, Male Male | 67 Participants | 127 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 102 | 7 / 101 |
| serious Total, serious adverse events | 1 / 102 | 3 / 101 |
Outcome results
Primary
Change From Baseline in A1C at Week 24
A1C (%) is used to report average blood glucose levels over prolonged periods of time. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.
Time frame: Baseline and Week 24
Population: Full analysis set (FAS) population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Omarigliptin 25 mg | Change From Baseline in A1C at Week 24 | -0.33 Percent |
| Placebo | Change From Baseline in A1C at Week 24 | -0.45 Percent |
p-value: 0.53595% CI: [-0.26, 0.49]Constrained longitudinal data analysis
Primary
Percentage of Participants Who Discontinued Study Drug Due to an AE
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Data presented exclude data following the initiation of glycemic rescue. The safety database was analyzed in a standard fashion in the APaT population for all participants who took at least one dose of study medication. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above).
Time frame: Up to Week 24
Population: APaT population included all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Omarigliptin 25 mg | Percentage of Participants Who Discontinued Study Drug Due to an AE | 0.0 Percentage of participants |
| Placebo | Percentage of Participants Who Discontinued Study Drug Due to an AE | 2.0 Percentage of participants |
Primary
Percentage of Participants Who Experienced at Least One Adverse Event (AE)
An AE is defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it is considered related to the medical treatment or procedure, that occurs during the course of the study. Data presented exclude data following the initiation of glycemic rescue. The safety database was analyzed in a standard fashion in the all participants as treated (APaT) population for all participants who took at least one dose of study medication. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above).
Time frame: Up to Week 27
Population: APaT population included all randomized participants who received at least one dose of study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Omarigliptin 25 mg | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 39.2 Percentage of participants |
| Placebo | Percentage of Participants Who Experienced at Least One Adverse Event (AE) | 39.6 Percentage of participants |
95% CI: [-13.8, 13]
Secondary
Change From Baseline in 2-hr PMG at Week 24
Blood glucose was measured 120 minutes from start of meal. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.
Time frame: Baseline and Week 24
Population: FAS population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Omarigliptin 25 mg | Change From Baseline in 2-hr PMG at Week 24 | -11.3 mg/dL |
| Placebo | Change From Baseline in 2-hr PMG at Week 24 | -15.5 mg/dL |
p-value: 0.68595% CI: [-16.1, 24.4]Constrained longitudinal data analysis
Secondary
Change in Baseline in FPG at Week 24
Blood glucose was measured on a fasting basis. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.
Time frame: Baseline and Week 24
Population: FAS population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Omarigliptin 25 mg | Change in Baseline in FPG at Week 24 | -5.0 mg/dL |
| Placebo | Change in Baseline in FPG at Week 24 | -1.3 mg/dL |
p-value: 0.58695% CI: [-17.1, 9.7]Constrained longitudinal data analysis
Secondary
Percentage of Participants Attaining A1C Glycemic Goals of <6.5% (48 mmol/Mol) at Week 24
Percentage of participants was estimated using standard multiple imputation techniques (cLDA). Within-group CIs were calculated via the Wilson score method. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.
Time frame: Week 24
Population: FAS population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Omarigliptin 25 mg | Percentage of Participants Attaining A1C Glycemic Goals of <6.5% (48 mmol/Mol) at Week 24 | 21.7 Percentage of participants |
| Placebo | Percentage of Participants Attaining A1C Glycemic Goals of <6.5% (48 mmol/Mol) at Week 24 | 17.6 Percentage of participants |
95% CI: [-7.4, 15.5]Mietinnen and Nurminen
Secondary
Percentage of Participants Attaining A1C Glycemic Goals of <7.0% at Week 24
Percentage of participants was estimated using standard multiple imputation techniques (constrained longitudinal data analysis \[cLDA\] model). Within-group confidence intervals (CIs) were calculated via the Wilson score method. The unexpected absence of a treatment effect in this study led to investigations that included measurement of metformin levels in available samples collected for future research during the study. Of the 92 participants with samples who had not been rescued with metformin, 57% (25/44) in the placebo group and 29% (14/48) in the omarigliptin group had detectable metformin, indicating the use of metformin that was prohibited by the protocol. The use of metformin prohibited by the protocol was without investigator knowledge and is a confounding factor impacting the ability to draw any conclusions regarding the efficacy results from this study.
Time frame: Week 24
Population: FAS population comprised all participants who received at least one dose of study treatment and had a baseline measurement or a post-randomization measurement for the analysis endpoint.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Omarigliptin 25 mg | Percentage of Participants Attaining A1C Glycemic Goals of <7.0% at Week 24 | 33.5 Percentage of participants |
| Placebo | Percentage of Participants Attaining A1C Glycemic Goals of <7.0% at Week 24 | 34.0 Percentage of participants |
95% CI: [-14, 13.1]Mietinnen and Nurminen
Secondary
Percentage of Participants Who Required Glycemic Rescue by Week 24
Participants exceeding pre-specified glycemic thresholds after starting the double-blind treatment period may have received rescue therapy (per protocol) with open-label metformin initiated by the investigator. This analysis may have been confounded by the use of metformin prohibited by the protocol (see efficacy results description above).
Time frame: Up to Week 24
Population: All randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Omarigliptin 25 mg | Percentage of Participants Who Required Glycemic Rescue by Week 24 | 10.8 Percentage of participants |
| Placebo | Percentage of Participants Who Required Glycemic Rescue by Week 24 | 12.9 Percentage of participants |