Type 1 Diabetes Mellitus
Conditions
Brief summary
The purpose of this study is to assess the safety, pharmacokinetics, and pharmacodynamics of MK-1293 compared with a basal insulin (EU-Lantus™) in participants with Type 1 Diabetes. The primary hypotheses are that the duration of action, pharmacodynamic profile, and pharmacokinetic profile of MK-1293 and the comparator basal insulin are similar.
Interventions
DRUGMK-1293
MK-1293 0.4 units/kg administered subcutaneously
DRUGEU-Lantus™
EU-Lantus™ 0.4 units/kg administered subcutaneously
DRUGNovolog™
Participants will receive an intravenous infusion of insulin aspart (Novolog™ or other rapid-acting insulin analog) for several hours prior to MK-1293 or EU-Lantus™ dosing in each dosing period to meet basal insulin requirements
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Has type 1 diabetes mellitus diagnosed at least 12 months before screening * Subject to investigator discretion, is on a stable dose of insulin for at least 2 weeks before screening * Has a total daily insulin dose \<=1.2 units/kg * Has a screening hemoglobin A1c \<9.5% * Has a body mass index \>18.0 and \<=30.0 kg/m\^2 * Has a weight \>=50 kg * Female participant of reproductive potential has a serum beta-human chorionic gonadotropin level consistent with the nongravid state and agrees to use (and/or have her partner use) 2 acceptable methods of birth control until 2 weeks after the last dose of study drug * Postmenopausal female participant is without menses for \>=1 year * Surgically sterile female participant status is post hysterectomy, oophorectomy, or tubal ligation * Has not used nicotine or nicotine-containing products for at least 3 months before study start or smokes less than 10 cigarettes per day and is willing to abstain during the trial
Exclusion criteria
* Has a history of clinically significant gastrointestinal, cardiovascular, hematological, hepatic, immunological, renal, respiratory, genitourinary, or major neurological abnormalities or disease * Has a history of clinically significant endocrine abnormalities or diseases except type 1 diabetes mellitus * Has had any severe hypoglycemic episodes associated with hypoglycemic seizures, comas, or unconsciousness within the past 3 months * Has a history of diabetic ketoacidosis within the past 6 months * Has a history of significant multiple or severe allergies, anaphylactic reaction, or significant intolerability to drugs or food * Has a history of hypersensitivity to pharmacologic insulins * Is positive for hepatitis B surface antigen, hepatitis C, or Human Immunodeficiency Virus * Has had major surgery or donated or lost 1 unit of blood within 4 weeks before screening * Unable to refrain from use of any medication or herbal remedy from 2 weeks prior to the first dose of study drug to until the posttrial visit. Some medications are permitted and may be discussed with the investigators * Vaccination within 12 weeks of start of study participation * Consumes \>3 glasses of alcoholic beverages per day. Participants consuming 4 glasses of alcoholic beverages may be enrolled at the discretion of the investigator. * Consumes \>6 servings of caffeinated beverages per day * Is a regular user of any illicit drugs or has a history of drug abuse (including alcohol) within approximately 1 year * Is on a carbohydrate-restricted diet (\<100 grams carbohydrate per day); participants who are on a carbohydrate-restricted diet may be included if they agree to a diet consisting of \>=100 grams of carbohydrate daily throughout the study * Has a personal or family history of hypercoagulability or thromboembolic disease * Has used systemic glucocorticoids within 3 months of screening or anticipates treatment with systemic glucocorticoids during study participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| M1 Glargine Metabolite Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve (AUC0-24) | Up to 24 hours postdose | M1 glargine is the dominant circulating glargine-derived insulin metabolite after subcutaneous injection and it is pharmacologically active. AUC0-24 is a measure of the total amount of drug in the plasma from the dose to Hour 24. Analysis was performed on log scale with results back transformed to the original scale |
| PD: Area Under the Glucose Infusion Rate Versus Time Curve Over the Second 12 Hours After Dosing (GIR-AUC12-24hr) | From 12 to 24 hours postdose | The area under the glucose infusion rate curve from hours 12 to 24 after injection (AUC\[GIR{12-24}\]) for participants who received either MK-1293 or Lantus™ administered subcutaneously on Day 1 in 2 out of 4 study periods in a replicate crossover design was measured from blood samples obtained during a euglycemic clamp procedure. |
| PD: Maximum Glucose Infusion Rate (GIRmax) | Up to 30 hours postdose | Maximum glucose infusion rate (GIR\[max\]) based on smoothed data for participants who received either MK-1293 or EU-Lantus™ administered subcutaneously on Day 1 in 2 out of 4 study periods in a replicate crossover design was measured from blood samples obtained during a euglycemic clamp procedure. |
| M1 Glargine Metabolite PK: Maximum Plasma Concentration (Cmax) | Up to 24 hours postdose | M1 glargine is the dominant circulating glargine-derived insulin metabolite after subcutaneous injection and it is pharmacologically active. Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Analysis was performed on log scale with results back transformed to original scale. |
| Comparison of MK-1293 and EU-Approved Lantus Duration of Pharmacodynamic Action During a 30-Hour Euglycemic Clamp Study | Up to 30 hours postdose | Duration of Action (DOA) is defined as the length of time from dosing to End of Action. End of Action is defined as the time point at which plasma glucose has been above 150 mg/dL for 30 minutes and no glucose has been infused for 30 minutes. Median and max below are reported for the length of clamp duration (i.e. 30 hours). |
| PD: Area Under the Glucose Infusion Rate Versus Time Curve Over 24 Hours After Dosing (GIR-AUC0-24hr) | Up to 24 hours postdose | The area under the glucose infusion rate curve from hours 0 to 24 after injection (AUC\[GIR{0-24}\]) for participants who received either MK-1293 or EU-Lantus™ administered subcutaneously on Day 1 in 2 out of 4 study periods in a replicate crossover design was measured from blood samples obtained during a euglycemic clamp procedure. |
| PD: Area Under the Glucose Infusion Rate Versus Time Curve Over the First 12 Hours After Dosing (GIR-AUC0-12hr) | Up to 12 hours postdose | The area under the glucose infusion rate curve from hours 0 to 12 after injection (AUC\[GIR{0-12}\]) for participants who received either MK-1293 or EU-Lantus™ administered subcutaneously on Day 1 in 2 out of 4 study periods in a replicate crossover design was measured from blood samples obtained during a euglycemic clamp procedure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| M1 Glargine Metabolite PK: Area Under the Plasma Concentration Versus Time Curve Over the Second 12 Hours After Dosing (AUC12-24) | From 12 to 24 hours postdose | M1 glargine is the dominant circulating glargine-derived insulin metabolite after subcutaneous injection and it is pharmacologically active. AUC12-24 is a measure of the total amount of drug in the plasma from Hour 12 to Hour 24. Analysis was performed on log scale with results back transformed to original scale. |
| M1 Glargine Metabolite PK: Area Under the Plasma Concentration Versus Time Curve Over the First 12 Hours After Dosing (AUC0-12) | Up to 12 hours postdose | M1 glargine is the dominant circulating glargine-derived insulin metabolite after subcutaneous injection and it is pharmacologically active. AUC0-12 is a measure of the total amount of drug in the plasma from the dose to Hour 12. Analysis was performed on log scale with results back transformed to original scale. |
Participant flow
Recruitment details
Male and female participants with Type I diabetes mellitus between the ages of 18 and 65 years (inclusive) were enrolled in this trial in 1 clinical site in the United States.
Participants by arm
| Arm | Count |
|---|---|
| All Participants MK-1293 or EU-Lantus™ 0.4 units/kg administered subcutaneously on Day 1 in 2 out of 4 study periods in a replicate crossover design with a minimum of 7 days between each treatment period | 76 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1 | Withdrawal by Subject | 0 | 2 |
| Period 2 | Protocol Violation | 1 | 0 |
| Period 2 | Withdrawal by Subject | 0 | 2 |
| Period 3 | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 33.4 Years STANDARD_DEVIATION 11.7 |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 60 / 74 | 56 / 76 |
| serious Total, serious adverse events | 0 / 74 | 0 / 76 |
Outcome results
Primary
Comparison of MK-1293 and EU-Approved Lantus Duration of Pharmacodynamic Action During a 30-Hour Euglycemic Clamp Study
Duration of Action (DOA) is defined as the length of time from dosing to End of Action. End of Action is defined as the time point at which plasma glucose has been above 150 mg/dL for 30 minutes and no glucose has been infused for 30 minutes. Median and max below are reported for the length of clamp duration (i.e. 30 hours).
Time frame: Up to 30 hours postdose
Population: The Per-Protocol population consists of 75 participants, including the 70 with complete data across all 4 treatment periods and 5 participants with partial data. One participant was not included in the PP population due to a medical issue. All available data from 5 of the participants who discontinued the study were included in the analyses.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MK-1293 | Comparison of MK-1293 and EU-Approved Lantus Duration of Pharmacodynamic Action During a 30-Hour Euglycemic Clamp Study | 30 Hours |
| EU-Lantus™ | Comparison of MK-1293 and EU-Approved Lantus Duration of Pharmacodynamic Action During a 30-Hour Euglycemic Clamp Study | 30 Hours |
Comparison: Because numerous participants did not achieve End of Action within the 30-hour clamp timeframe, the pre-specified hypothesis of similarity with regard to mean DOA could not be tested and a survival analysis approach was undertaken. The hazard rate is a measure of the instantaneous risk of reaching End of Action at time t given End of Action has not been met up until time t, with the hazard ratio being an estimate of the relative difference in hazard rates between treatments.95% CI: [0.72, 1.59]
Primary
M1 Glargine Metabolite Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve (AUC0-24)
M1 glargine is the dominant circulating glargine-derived insulin metabolite after subcutaneous injection and it is pharmacologically active. AUC0-24 is a measure of the total amount of drug in the plasma from the dose to Hour 24. Analysis was performed on log scale with results back transformed to the original scale
Time frame: Up to 24 hours postdose
Population: The Per-Protocol population consists of 75 participants, including the 70 with complete data across all 4 treatment periods and 5 participants with partial data. One participant was not included in the PP population due to a medical issue. All available data from 5 of the participants who discontinued the study were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MK-1293 | M1 Glargine Metabolite Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve (AUC0-24) | 6530 pg∙hr/mL |
| EU-Lantus™ | M1 Glargine Metabolite Pharmacokinetics (PK): Area Under the Plasma Concentration Versus Time Curve (AUC0-24) | 6763 pg∙hr/mL |
90% CI: [0.91, 1.02]
Primary
M1 Glargine Metabolite PK: Maximum Plasma Concentration (Cmax)
M1 glargine is the dominant circulating glargine-derived insulin metabolite after subcutaneous injection and it is pharmacologically active. Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Analysis was performed on log scale with results back transformed to original scale.
Time frame: Up to 24 hours postdose
Population: The Per-Protocol population consists of 75 participants, including the 70 with complete data across all 4 treatment periods and 5 participants with partial data. One participant was not included in the PP population due to a medical issue. All available data from 5 of the participants who discontinued the study were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MK-1293 | M1 Glargine Metabolite PK: Maximum Plasma Concentration (Cmax) | 372 pg/mL |
| EU-Lantus™ | M1 Glargine Metabolite PK: Maximum Plasma Concentration (Cmax) | 382 pg/mL |
90% CI: [0.93, 1.03]
Primary
PD: Area Under the Glucose Infusion Rate Versus Time Curve Over 24 Hours After Dosing (GIR-AUC0-24hr)
The area under the glucose infusion rate curve from hours 0 to 24 after injection (AUC\[GIR{0-24}\]) for participants who received either MK-1293 or EU-Lantus™ administered subcutaneously on Day 1 in 2 out of 4 study periods in a replicate crossover design was measured from blood samples obtained during a euglycemic clamp procedure.
Time frame: Up to 24 hours postdose
Population: The Per-Protocol population included 70 participants with complete data and 5 participants with partial data. One participant was not included in the PP population due to a medical issue. Data from 5 discontinued participants were included in the analyses; data from 1 participant was not (incomplete clamp data, only out to 18.5 hours).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MK-1293 | PD: Area Under the Glucose Infusion Rate Versus Time Curve Over 24 Hours After Dosing (GIR-AUC0-24hr) | 1470.07 mg/kg |
| EU-Lantus™ | PD: Area Under the Glucose Infusion Rate Versus Time Curve Over 24 Hours After Dosing (GIR-AUC0-24hr) | 1554.53 mg/kg |
95% CI: [0.88, 1.01]
Primary
PD: Area Under the Glucose Infusion Rate Versus Time Curve Over the First 12 Hours After Dosing (GIR-AUC0-12hr)
The area under the glucose infusion rate curve from hours 0 to 12 after injection (AUC\[GIR{0-12}\]) for participants who received either MK-1293 or EU-Lantus™ administered subcutaneously on Day 1 in 2 out of 4 study periods in a replicate crossover design was measured from blood samples obtained during a euglycemic clamp procedure.
Time frame: Up to 12 hours postdose
Population: The Per-Protocol population consists of 75 participants, including the 70 with complete data across all 4 treatment periods and 5 participants with partial data. One participant was not included in the PP population due to a medical issue. All available data from 5 of the participants who discontinued the study were included in the analyses.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MK-1293 | PD: Area Under the Glucose Infusion Rate Versus Time Curve Over the First 12 Hours After Dosing (GIR-AUC0-12hr) | 659.38 mg/kg |
| EU-Lantus™ | PD: Area Under the Glucose Infusion Rate Versus Time Curve Over the First 12 Hours After Dosing (GIR-AUC0-12hr) | 736.31 mg/kg |
95% CI: [0.81, 0.99]
Primary
PD: Area Under the Glucose Infusion Rate Versus Time Curve Over the Second 12 Hours After Dosing (GIR-AUC12-24hr)
The area under the glucose infusion rate curve from hours 12 to 24 after injection (AUC\[GIR{12-24}\]) for participants who received either MK-1293 or Lantus™ administered subcutaneously on Day 1 in 2 out of 4 study periods in a replicate crossover design was measured from blood samples obtained during a euglycemic clamp procedure.
Time frame: From 12 to 24 hours postdose
Population: The Per-Protocol population included 70 participants with complete data and 5 participants with partial data. One participant was not included in the PP population due to a medical issue. Data from 5 discontinued participants were included in the analyses; data from 1 participant was not (incomplete clamp data, only out to 18.5 hours).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MK-1293 | PD: Area Under the Glucose Infusion Rate Versus Time Curve Over the Second 12 Hours After Dosing (GIR-AUC12-24hr) | 811.43 mg/kg |
| EU-Lantus™ | PD: Area Under the Glucose Infusion Rate Versus Time Curve Over the Second 12 Hours After Dosing (GIR-AUC12-24hr) | 818.20 mg/kg |
95% CI: [0.92, 1.06]
Primary
PD: Maximum Glucose Infusion Rate (GIRmax)
Maximum glucose infusion rate (GIR\[max\]) based on smoothed data for participants who received either MK-1293 or EU-Lantus™ administered subcutaneously on Day 1 in 2 out of 4 study periods in a replicate crossover design was measured from blood samples obtained during a euglycemic clamp procedure.
Time frame: Up to 30 hours postdose
Population: The Per-Protocol population included 70 participants with complete data and 5 participants with partial data. One participant was not included in the PP population due to a medical issue. Data from 5 discontinued participants were included in the analyses; data from 1 participant was not (incomplete clamp data, only out to 18.5 hours).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| MK-1293 | PD: Maximum Glucose Infusion Rate (GIRmax) | 2.34 mg/kg/min |
| EU-Lantus™ | PD: Maximum Glucose Infusion Rate (GIRmax) | 2.43 mg/kg/min |
95% CI: [0.91, 1.02]
Secondary
M1 Glargine Metabolite PK: Area Under the Plasma Concentration Versus Time Curve Over the First 12 Hours After Dosing (AUC0-12)
M1 glargine is the dominant circulating glargine-derived insulin metabolite after subcutaneous injection and it is pharmacologically active. AUC0-12 is a measure of the total amount of drug in the plasma from the dose to Hour 12. Analysis was performed on log scale with results back transformed to original scale.
Time frame: Up to 12 hours postdose
Population: The Per-Protocol population consists of 75 participants, including the 70 with complete data across all 4 treatment periods and 5 participants with partial data. One participant was not included in the PP population due to a medical issue. All available data from 5 of the participants who discontinued the study were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MK-1293 | M1 Glargine Metabolite PK: Area Under the Plasma Concentration Versus Time Curve Over the First 12 Hours After Dosing (AUC0-12) | 2981 pg∙hr/mL |
| EU-Lantus™ | M1 Glargine Metabolite PK: Area Under the Plasma Concentration Versus Time Curve Over the First 12 Hours After Dosing (AUC0-12) | 3251 pg∙hr/mL |
90% CI: [0.86, 0.97]
Secondary
M1 Glargine Metabolite PK: Area Under the Plasma Concentration Versus Time Curve Over the Second 12 Hours After Dosing (AUC12-24)
M1 glargine is the dominant circulating glargine-derived insulin metabolite after subcutaneous injection and it is pharmacologically active. AUC12-24 is a measure of the total amount of drug in the plasma from Hour 12 to Hour 24. Analysis was performed on log scale with results back transformed to original scale.
Time frame: From 12 to 24 hours postdose
Population: The Per-Protocol population consists of 75 participants, including the 70 with complete data across all 4 treatment periods and 5 participants with partial data. One participant was not included in the PP population due to a medical issue. All available data from 5 of the participants who discontinued the study were included in the analyses.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| MK-1293 | M1 Glargine Metabolite PK: Area Under the Plasma Concentration Versus Time Curve Over the Second 12 Hours After Dosing (AUC12-24) | 3510 pg∙hr/mL |
| EU-Lantus™ | M1 Glargine Metabolite PK: Area Under the Plasma Concentration Versus Time Curve Over the Second 12 Hours After Dosing (AUC12-24) | 3522 pg∙hr/mL |
90% CI: [0.95, 1.04]