Type 2 Diabetes Mellitus
Conditions
Keywords
Type 2 Diabetes Mellitus, Hemoglobin A1C, glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP), dipeptidyl peptidase 4 inhibitor (DPP-4)
Brief summary
The primary objectives of this study are to determine if sitagliptin treatment is not inferior to that of glimepiride as measured by the change in baseline hemoglobin A1C (HbA1C) after 30 weeks of treatment, and if sitagliptin treatment results in a lower incidence of symptomatic hypoglycemia compared to that of glimepiride. The study will also evaluate if sitagliptin treatment, compared to glimepiride results in improvements in fasting plasma glucose (FPG) levels, and plasma lipid levels after 30 weeks of treatment. Participants will be randomized to either sitagliptin or glimepiride treatment after eligibility for study participation is determined during screening and washout study phases. Participants and study staff will not know to which treatment group they have been randomized (double-blind design). The duration of study participation will be up to 40 weeks (with 9 clinic visits). This will include a screening phase (Visit 1 to Visit 2) of 2 weeks maximum; a 6-week (Visits 2 to 3) oral antihyperglycemic agent (AHA) wash-out phase (for those who have been taking a AHA prior to the study); a placebo run-in phase (Visits 3 to 4), followed by up to 30 weeks of treatment with study medication.
Detailed description
The dose of sitagliptin will be 100 mg once daily (QD) or 50 mg QD based on the participant's estimated glomerular filtration rate (eGFR). The starting dose of glimepiride (1 mg QD) may be up-titrated as needed to optimize glycemic control over the first 18 weeks to a maximum dose of 6 mg/day, after which the dose will not be increased for the rest of the study (down-titration to avoid or control hypoglycemia is allowed).
Interventions
DRUGsitagliptin phosphate
Sitagliptin tablets, orally, at a dose of 100 mg or 50 mg QD for 30 weeks. The dose level to be administered will depend on the participant's estimated glomerular filtration rate (eGFR), calculated at Visit 3 and may be adjusted as medically indicated during the study.
DRUGGlimepiride
Glimepiride tablets, orally, starting at a dose of 1 mg QD, which may be gradually increased, as needed, to maximum dose of 6 mg QD for 30 weeks. The dose may also be decreased as medically indicated during the study.
Matching placebo tablets to sitagliptin to allow for blinding.
Matching placebo tablets to glimepiride to allow for blinding.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
65 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of type 2 diabetes mellitus
Exclusion criteria
* History of type 1 diabetes mellitus * Has undergone a surgical procedure within the prior 4 weeks. * Current participation in, or has participated, in another study with an investigational device or compound, with the prior 12 weeks, and/or is not willing to refrain from participating in any other study while participating in this study * Hypersensitivity or contraindication to any sulfonylurea (e.g., glimepiride) medication * Has been on an investigational or approved dipeptidyl peptidase-4 (DPP-4) inhibitor agent (e.g., sitagliptin, saxagliptin) * Presence of human immunodeficiency virus (HIV) * Current participation in a weight loss program or is receiving weight loss medication * History of blood disorder, certain cancers, heart, liver or kidney disease * Current or past use of recreational or illicit drugs, or a history of drug abuse or dependence, or increased alcohol consumption
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Discontinuing Study Treatment Due to An AE | Up to Week 30 | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of the treatment administered. |
| Least Squares (LS) Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 30 | Baseline and Week 30 | Participant whole blood samples were collected at baseline and Week 30 to determine the LS mean HbA1c change from baseline. HbA1c is a measure of the percentage of glycated hemoglobin in the blood and provides an indication of participant blood glucose control in the 2 to 3 months prior to the evaluation. |
| Number of Participants With an Adverse Event of Symptomatic Hypoglycemia Up to Week 30 | Up to Week 30 | Symptomatic hypoglycemia was defined as an episode with clinical symptoms attributed to hypoglycemia, without regard to glucose level. Participants were instructed to complete the Hypoglycemia Assessment Log (HAL) for any symptomatic episodes he or she believed represent hypoglycemia. If a fingerstick glucose was obtained before or shortly (i.e., within a few minutes) after treating, the value was recorded in the HAL. In addition, participants were instructed to record in the HAL any fingerstick glucose values ≤70 mg/dL (≤3.9 mmol/L) regardless of the presence of clinical symptoms. |
| Number of Participants Experiencing An Adverse Event (AE) | Up to Week 30 | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of the treatment administered. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| LS Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 30 | Baseline and Week 30 | Plasma samples were collected from participants after an overnight fast at baseline and Week 30 to determine the mean change from baseline in participant FPG. |
| Percentage of Participants With HbA1c <7.0% at Week 30 | Week 30 | Participant whole blood samples were collected at Week 30 to determine the number of participants achieving HbA1c \<7.0% at Week 30. HbA1c is a measure of the percentage of glycated hemoglobin in the blood and provides an indication of participant blood glucose control in the 2 to 3 months prior to the evaluation. |
| Percentage of Participants With HbA1c <6.5% at Week 30 | Week 30 | Participant whole blood samples were collected at Week 30 to determine the number of participants achieving HbA1c \<6.5% at Week 30. Hemoglobin A1c is a measure of the percentage of glycated hemoglobin in the blood and provides an indication of participant blood glucose control in the 2 to 3 months prior to the evaluation. |
| LS Mean Change From Baseline in Participant Body Weight at Week 30 | Baseline and Week 30 | Participants were only permitted to wear a drape gown and undergarments (no street clothes, no shoes or socks) for this evaluation. Body weight was measured after voiding (to the nearest 0.1 kg) and measurements were collected until 2 consecutive measurements did not differ by more than 0.2 kg from each other. Body weight measurements were evaluated using a standardized, calibrated digital scale and was reported in kilograms (kg) at baseline and Week 30. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Sitagliptin Sitagliptin phosphate 100 mg once daily (QD) or 50 mg QD | 241 |
| Glimepiride Glimepiride 1-6 mg QD | 239 |
| Total | 480 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 4 |
| Overall Study | Hyperglycemia Discontinuation Criteria | 5 | 5 |
| Overall Study | Lack of Efficacy | 7 | 2 |
| Overall Study | Lost to Follow-up | 1 | 7 |
| Overall Study | Non Compliance | 0 | 1 |
| Overall Study | Physician Decision | 5 | 4 |
| Overall Study | Protocol Violation | 1 | 5 |
| Overall Study | Withdrawal by Subject | 15 | 11 |
Baseline characteristics
| Characteristic | Sitagliptin | Glimepiride | Total |
|---|---|---|---|
| Age, Continuous | 70.7 years STANDARD_DEVIATION 4.8 | 70.8 years STANDARD_DEVIATION 4.9 | 70.7 years STANDARD_DEVIATION 4.8 |
| Body Weight | 76.9 kg STANDARD_DEVIATION 15.1 | 75.4 kg STANDARD_DEVIATION 16.4 | 76.0 kg STANDARD_DEVIATION 15.6 |
| Fasting Plasma Glucose (FPG) | 168.4 mg/dL STANDARD_DEVIATION 31.2 | 169.7 mg/dL STANDARD_DEVIATION 35.5 | 169.0 mg/dL STANDARD_DEVIATION 33.3 |
| Hemoglobin A1c (HbA1c) | 7.78 Percentage of HbA1c STANDARD_DEVIATION 0.7 | 7.78 Percentage of HbA1c STANDARD_DEVIATION 0.67 | 7.78 Percentage of HbA1c STANDARD_DEVIATION 0.69 |
| Sex: Female, Male Female | 130 Participants | 148 Participants | 278 Participants |
| Sex: Female, Male Male | 111 Participants | 91 Participants | 202 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 34 / 241 | 40 / 236 |
| serious Total, serious adverse events | 7 / 241 | 6 / 236 |
Outcome results
Primary
Least Squares (LS) Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 30
Participant whole blood samples were collected at baseline and Week 30 to determine the LS mean HbA1c change from baseline. HbA1c is a measure of the percentage of glycated hemoglobin in the blood and provides an indication of participant blood glucose control in the 2 to 3 months prior to the evaluation.
Time frame: Baseline and Week 30
Population: The population included all randomized participants who had a baseline HbA1c, had a HbA1c at Week 30, did not take prohibited concomitant medications, had compliance \>85%, and did not receive any incorrect study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | Least Squares (LS) Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 30 | -0.32 Percentage of HbA1c | 95% Confidence Interval 0.78 |
| Glimepiride | Least Squares (LS) Mean Change From Baseline in Hemoglobin A1c (HbA1c) at Week 30 | -0.51 Percentage of HbA1c | 95% Confidence Interval 0.89 |
95% CI: [0.03, 0.34]ANCOVA
Primary
Number of Participants Discontinuing Study Treatment Due to An AE
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of the treatment administered.
Time frame: Up to Week 30
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Number of Participants Discontinuing Study Treatment Due to An AE | 3 Participants |
| Glimepiride | Number of Participants Discontinuing Study Treatment Due to An AE | 4 Participants |
Primary
Number of Participants Experiencing An Adverse Event (AE)
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the study treatment, whether or not considered related to the use of the treatment administered.
Time frame: Up to Week 30
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Number of Participants Experiencing An Adverse Event (AE) | 118 Participants |
| Glimepiride | Number of Participants Experiencing An Adverse Event (AE) | 115 Participants |
Primary
Number of Participants With an Adverse Event of Symptomatic Hypoglycemia Up to Week 30
Symptomatic hypoglycemia was defined as an episode with clinical symptoms attributed to hypoglycemia, without regard to glucose level. Participants were instructed to complete the Hypoglycemia Assessment Log (HAL) for any symptomatic episodes he or she believed represent hypoglycemia. If a fingerstick glucose was obtained before or shortly (i.e., within a few minutes) after treating, the value was recorded in the HAL. In addition, participants were instructed to record in the HAL any fingerstick glucose values ≤70 mg/dL (≤3.9 mmol/L) regardless of the presence of clinical symptoms.
Time frame: Up to Week 30
Population: All randomized participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Number of Participants With an Adverse Event of Symptomatic Hypoglycemia Up to Week 30 | 2 Participants |
| Glimepiride | Number of Participants With an Adverse Event of Symptomatic Hypoglycemia Up to Week 30 | 11 Participants |
p-value: 0.00995% CI: [-7.5, -1.2]Miettinen & Nurminen
Secondary
LS Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 30
Plasma samples were collected from participants after an overnight fast at baseline and Week 30 to determine the mean change from baseline in participant FPG.
Time frame: Baseline and Week 30
Population: The population included all randomized participants who had a FPG value at baseline and Week 30, did not take prohibited concomitant medications, had compliance \>85%, and did not receive any incorrect study medication.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | LS Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 30 | -14.5 mg/dL | 95% Confidence Interval 39 |
| Glimepiride | LS Mean Change From Baseline in Fasting Plasma Glucose (FPG) at Week 30 | -21.2 mg/dL | 95% Confidence Interval 39.1 |
95% CI: [0.7, 12.7]ANCOVA
Secondary
LS Mean Change From Baseline in Participant Body Weight at Week 30
Participants were only permitted to wear a drape gown and undergarments (no street clothes, no shoes or socks) for this evaluation. Body weight was measured after voiding (to the nearest 0.1 kg) and measurements were collected until 2 consecutive measurements did not differ by more than 0.2 kg from each other. Body weight measurements were evaluated using a standardized, calibrated digital scale and was reported in kilograms (kg) at baseline and Week 30.
Time frame: Baseline and Week 30
Population: All randomized participants who received at least one dose of study treatment and had body weight measurements at baseline and at Week 30.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Sitagliptin | LS Mean Change From Baseline in Participant Body Weight at Week 30 | 0.4 kg | 95% Confidence Interval 3.2 |
| Glimepiride | LS Mean Change From Baseline in Participant Body Weight at Week 30 | 1.1 kg | 95% Confidence Interval 2.8 |
p-value: 0.01195% CI: [-1.3, -0.2]ANCOVA
Secondary
Percentage of Participants With HbA1c <6.5% at Week 30
Participant whole blood samples were collected at Week 30 to determine the number of participants achieving HbA1c \<6.5% at Week 30. Hemoglobin A1c is a measure of the percentage of glycated hemoglobin in the blood and provides an indication of participant blood glucose control in the 2 to 3 months prior to the evaluation.
Time frame: Week 30
Population: The population included all randomized participants who had HbA1c at baseline and Week 30, did not take prohibited concomitant medications, had compliance \>85%, and did not receive any incorrect study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percentage of Participants With HbA1c <6.5% at Week 30 | 9.1 Percentage of Participants |
| Glimepiride | Percentage of Participants With HbA1c <6.5% at Week 30 | 20.9 Percentage of Participants |
95% CI: [0.3, 0.7]Miettinen & Nurminen
Secondary
Percentage of Participants With HbA1c <7.0% at Week 30
Participant whole blood samples were collected at Week 30 to determine the number of participants achieving HbA1c \<7.0% at Week 30. HbA1c is a measure of the percentage of glycated hemoglobin in the blood and provides an indication of participant blood glucose control in the 2 to 3 months prior to the evaluation.
Time frame: Week 30
Population: The population included all randomized participants who had HbA1c at baseline and Week 30, did not take prohibited concomitant medications, had compliance \>85%, and did not receive any incorrect study medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sitagliptin | Percentage of Participants With HbA1c <7.0% at Week 30 | 33.5 Percentage of Participants |
| Glimepiride | Percentage of Participants With HbA1c <7.0% at Week 30 | 46.6 Percentage of Participants |
95% CI: [0.6, 0.9]Miettinen & Nurminen