Type 2 Diabetes Mellitus
Conditions
Brief summary
The primary purpose of this study is to compare the effect of a double dose of a study drug known as insulin peglispro to a double dose of insulin glargine in participants who have type 2 diabetes. Participants will be treated with study insulin daily, in two 4-week study periods. Each participant will receive insulin peglispro during one treatment period and insulin glargine during the other treatment period.
Interventions
Administered SQ
DRUGInsulin Glargine
Administered SQ
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Have type 2 diabetes mellitus (T2DM), based on the World Health Organization (WHO) classification, for ≥1 year. * Use any type of basal insulin (except degludec), including once-or twice-daily human insulin neutral protamine Hagedom (NPH), insulin detemir, or insulin glargine. * Have hemoglobin A1c (HbA1c) levels ≤9.0% according to local laboratory testing at screening. * Have body mass index (BMI) ≤40.0 kilograms/square meter (kg/m\^2). * Have been treated with stable doses of insulin for at least 30 days before screening with: * Basal insulin with daily doses ±30% of mean during the last 4 weeks. * Doses of a basal insulin must be between 0.3 unit/kg/day and 1 unit/kg/day. * If on metformin, thiazolidinediones (TZDs), sodium glucose co-transporter 2 (SGLT-2) inhibitors, or dipeptidyl peptidase (DPP4) inhibitors, must be on stable doses for the last 30 days.
Exclusion criteria
* Are using prandial, self-mixed, or premixed insulin. Participants using prandial insulin may be switched to everyday (qd) glargine if investigator judges that the participant will still meet fasting glucose requirements for randomization. * Are using insulin pump therapy. * Have excessive insulin resistance: Defined as \>1.0 unit/kg/day as baseline treatment. * If being treated with sulfonylureas (SUs) before screening, then must have SUs washed out between screening and randomization. * Use any of these concomitant medications: morphine, codeine, antidiuretics, glucagon-like peptide-1 (GLP-1) receptor agonists (for example, exenatide, exenatide once weekly, lixisenatide or liraglutide), or pramlintide, used concurrently or within 90 days before screening. * Have hypoglycemia unawareness, defined as confirmed by laboratory test results or by historical episodes of hypoglycemia \<54 mg/dL (3.0 mmol/L) without symptoms. * Have fasting hypertriglyceridemia \>400 mg/dL (\>4.5 mmol/L) at screening, as determined by the local laboratory. * Have had any episode of severe hypoglycemia (defined by requiring assistance due to neurologically disabling hypoglycemia) within 6 months before entry into the study. * Have had 2 or more emergency room visits or hospitalizations due to poor glucose control in the past 6 months. * Have had a previous clinically significant episode of ketoacidosis as determined by the investigator (ketone bodies at fasting and without acidosis is acceptable) in the past 6 months. * Have history of renal transplantation, are currently receiving renal dialysis, or have estimated Glomerular Filtration Rate (eGFR) \<60 milliliters/minute. * Have obvious clinical signs or symptoms of liver disease (excluding nonalcoholic fatty liver disease), acute or chronic hepatitis, nonalcoholic steatohepatitis, or elevated liver enzyme measurements. * Have active or untreated malignancy, have been in remission from clinically significant malignancy (other than basal cell or squamous cell skin cancer) for less than 5 years, or are at increased risk for developing cancer or a recurrence of cancer in the opinion of the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinically Significant Hypoglycemia | Predose to 84 Hours Post Double Dose | The percentage was calculated by dividing the number of participants with clinically significant hypoglycemia events defined as blood glucose \<54 milligrams per deciliter (mg/dL) (3.0 millimole per liter \[mmol/L\]) or symptoms of severe hypoglycemia by the total number of participants analyzed, multiplied by 100. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Hypoglycemia | Predose to 12 Hours Post Double Dose and 84 Hours Post Double Dose | The percentage was calculated by dividing the number of participants with hypoglycemia events defined as blood glucose ≤70 mg/dL (3.9 mmol/L) by the total number of participants analyzed, multiplied by 100. |
| Nadir Glucose | Predose to 84 Hours Post Double Dose | Nadir glucose was defined as the lowest blood glucose for a participant with blood glucose ≤70 mg/dL (3.9 mmol/L). Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor. |
| Time to the Nadir Glucose | Predose to 84 Hours Post Double Dose | Nadir glucose was defined as the lowest blood glucose for a participant with blood glucose ≤70 mg/dL (3.9 mmol/L). The average time was calculated by dividing the sum of time from double dose to the nadir glucose for participants with blood glucose ≤70 mg/dL (3.9 mmol/L) by the number of participants with blood glucose ≤70 mg/dL (3.9 mmol/L) during the first 84 hours after the double dose. |
| Duration of Glucose ≤70 mg/dL | Predose to 84 Hours Post Double Dose | The duration in minutes of each hypoglycemia episode with glucose ≤70 mg/dL (3.9 mmol/L) was calculated from start time to end time. The duration for a participant was the sum of the durations over the multiple hypoglycemia episodes. LS means were calculated using an MMRM analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor. |
| Percentage of Participants With Clinically Significant Hypoglycemia 12 Hours Post Double Dose | Predose to 12 Hours Post Double Dose | The percentage was calculated by dividing the number of participants with clinically significant hypoglycemia events defined as blood glucose \<54 mg/dL (3.0 mmol/L) or symptoms of severe hypoglycemia by the total number of participants analyzed, multiplied by 100. |
| Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) | Preprandial to 3 Hours Postprandial during the day following the standard dose | Glucose AUC within 3 hours after each meal assessed by the AUC of glucose from preprandial to 3 hours postprandial. LS means were calculated using an MMRM analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor. |
| Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) Excursion | Preprandial to 3 Hours Postprandial during the day following the standard dose | Glucose AUC excursion within 3 hours after each meal assessed by the AUC of adjusted glucose (= observed glucose - preprandial glucose) from preprandial to 3 hours postprandial. LS means were calculated using an MMRM analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor. |
| Beta Cell Function | 0-30 minutes during the meal tolerance test on the day following the standard dose | Beta cell function assessed by the change between pre meal tolerance test and 30 minutes post meal tolerance test in C-peptide corrected insulin/Glucose (ΔC-peptide corrected insulin/ΔGlucose). LS means were calculated using an MMRM analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor. |
| Fasting Blood Glucose | Day 1, Day 2, and Day 3 Following Double Dose | Fasting blood glucose (FBG) was measured by self-monitored blood glucose. LS means were calculated by MMRM analysis with fixed effects of treatment, dosing day, sequence, period, interaction of treatment and dosing day, baseline basal insulin dose stratification factor, and baseline FBG. |
Countries
Germany, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Insulin Peglispro/Insulin Glargine Standard dose of insulin peglispro administered subcutaneously (SQ) once daily for 4 weeks in the first study period. Double dose of insulin peglispro administered once, SQ on day 3 of the inpatient stay.
Standard dose of insulin glargine administered subcutaneously (SQ) once daily for 4 weeks in the second study period. Double dose of insulin glargine administered once, SQ on day 3 of the inpatient stay. | 34 |
| Insulin Glargine/Insulin Peglispro Standard dose of insulin glargine administered subcutaneously (SQ) once daily for 4 weeks in the first study period. Double dose of insulin glargine administered once, SQ on day 3 of the inpatient stay.
Standard dose of insulin peglispro administered subcutaneously (SQ) once daily for 4 weeks in the second study period. Double dose of insulin peglispro administered once, SQ on day 3 of the inpatient stay. | 34 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Study Period 1 | Physician Decision | 1 | 0 |
| Study Period 1 | Withdrawal by Subject | 0 | 4 |
| Study Period 2 (Crossover) | Adverse Event | 0 | 1 |
| Study Period 2 (Crossover) | Physician Decision | 2 | 0 |
Baseline characteristics
| Characteristic | Insulin Peglispro/Insulin Glargine | Total | Insulin Glargine/Insulin Peglispro |
|---|---|---|---|
| Age, Continuous | 57.82 years STANDARD_DEVIATION 8.06 | 57.78 years STANDARD_DEVIATION 6.99 | 57.74 years STANDARD_DEVIATION 5.86 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants | 9 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 30 Participants | 59 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 32 Participants | 66 Participants | 34 Participants |
| Region of Enrollment Germany | 29 Participants | 58 Participants | 29 Participants |
| Region of Enrollment United States | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Female | 10 Participants | 20 Participants | 10 Participants |
| Sex: Female, Male Male | 24 Participants | 48 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 31 / 64 | 26 / 67 |
| serious Total, serious adverse events | 2 / 64 | 1 / 67 |
Outcome results
Primary
Percentage of Participants With Clinically Significant Hypoglycemia
The percentage was calculated by dividing the number of participants with clinically significant hypoglycemia events defined as blood glucose \<54 milligrams per deciliter (mg/dL) (3.0 millimole per liter \[mmol/L\]) or symptoms of severe hypoglycemia by the total number of participants analyzed, multiplied by 100.
Time frame: Predose to 84 Hours Post Double Dose
Population: All randomized participants who received the double dose of study drug and had evaluable hypoglycemia data were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Peglispro | Percentage of Participants With Clinically Significant Hypoglycemia | 6.6 percentage of participants |
| Insulin Glargine | Percentage of Participants With Clinically Significant Hypoglycemia | 35.5 percentage of participants |
Secondary
Beta Cell Function
Beta cell function assessed by the change between pre meal tolerance test and 30 minutes post meal tolerance test in C-peptide corrected insulin/Glucose (ΔC-peptide corrected insulin/ΔGlucose). LS means were calculated using an MMRM analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor.
Time frame: 0-30 minutes during the meal tolerance test on the day following the standard dose
Population: All randomized participants who received at least one dose of study drug and had evaluable ΔC-peptide data were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Peglispro | Beta Cell Function | 88.65 mmol/L | Standard Error 8.43 |
| Insulin Glargine | Beta Cell Function | 103.62 mmol/L | Standard Error 8.32 |
Secondary
Duration of Glucose ≤70 mg/dL
The duration in minutes of each hypoglycemia episode with glucose ≤70 mg/dL (3.9 mmol/L) was calculated from start time to end time. The duration for a participant was the sum of the durations over the multiple hypoglycemia episodes. LS means were calculated using an MMRM analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor.
Time frame: Predose to 84 Hours Post Double Dose
Population: All randomized participants who received the double dose of study drug and had evaluable hypoglycemia data were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Peglispro | Duration of Glucose ≤70 mg/dL | 95.28 Minutes per participant | Standard Error 37.57 |
| Insulin Glargine | Duration of Glucose ≤70 mg/dL | 362.26 Minutes per participant | Standard Error 37.26 |
Secondary
Fasting Blood Glucose
Fasting blood glucose (FBG) was measured by self-monitored blood glucose. LS means were calculated by MMRM analysis with fixed effects of treatment, dosing day, sequence, period, interaction of treatment and dosing day, baseline basal insulin dose stratification factor, and baseline FBG.
Time frame: Day 1, Day 2, and Day 3 Following Double Dose
Population: All randomized participants who received the double dose of study drug and had evaluable fasting blood glucose data were included in the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Peglispro | Fasting Blood Glucose | Day 1 | 102.03 mg/dL | Standard Error 2.9 |
| Insulin Peglispro | Fasting Blood Glucose | Day 2 | 100.94 mg/dL | Standard Error 2.92 |
| Insulin Peglispro | Fasting Blood Glucose | Day 3 | 102.18 mg/dL | Standard Error 2.99 |
| Insulin Glargine | Fasting Blood Glucose | Day 1 | 85.61 mg/dL | Standard Error 2.87 |
| Insulin Glargine | Fasting Blood Glucose | Day 2 | 86.16 mg/dL | Standard Error 2.91 |
| Insulin Glargine | Fasting Blood Glucose | Day 3 | 86.27 mg/dL | Standard Error 3 |
Secondary
Nadir Glucose
Nadir glucose was defined as the lowest blood glucose for a participant with blood glucose ≤70 mg/dL (3.9 mmol/L). Least Squares (LS) means were calculated using a mixed model repeated measures (MMRM) analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor.
Time frame: Predose to 84 Hours Post Double Dose
Population: All randomized participants who received the double dose of study drug and had blood glucose ≤70 mg/dL (3.9 mmol/L) during the first 84 hours after the double dose were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Insulin Peglispro | Nadir Glucose | 61.70 mg/dL | Standard Error 1.36 |
| Insulin Glargine | Nadir Glucose | 55.93 mg/dL | Standard Error 0.97 |
Secondary
Percentage of Participants With Clinically Significant Hypoglycemia 12 Hours Post Double Dose
The percentage was calculated by dividing the number of participants with clinically significant hypoglycemia events defined as blood glucose \<54 mg/dL (3.0 mmol/L) or symptoms of severe hypoglycemia by the total number of participants analyzed, multiplied by 100.
Time frame: Predose to 12 Hours Post Double Dose
Population: All randomized participants who received the double dose of study drug and had evaluable hypoglycemia data were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Peglispro | Percentage of Participants With Clinically Significant Hypoglycemia 12 Hours Post Double Dose | 1.6 percentage of participants |
| Insulin Glargine | Percentage of Participants With Clinically Significant Hypoglycemia 12 Hours Post Double Dose | 22.6 percentage of participants |
Secondary
Percentage of Participants With Hypoglycemia
The percentage was calculated by dividing the number of participants with hypoglycemia events defined as blood glucose ≤70 mg/dL (3.9 mmol/L) by the total number of participants analyzed, multiplied by 100.
Time frame: Predose to 12 Hours Post Double Dose and 84 Hours Post Double Dose
Population: All randomized participants who received the double dose of study drug and had evaluable hypoglycemia data were included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Insulin Peglispro | Percentage of Participants With Hypoglycemia | 12 Hours Post Double Dose | 19.7 percentage of participants |
| Insulin Peglispro | Percentage of Participants With Hypoglycemia | 84 Hours Post Double Dose | 42.6 percentage of participants |
| Insulin Glargine | Percentage of Participants With Hypoglycemia | 12 Hours Post Double Dose | 64.5 percentage of participants |
| Insulin Glargine | Percentage of Participants With Hypoglycemia | 84 Hours Post Double Dose | 82.3 percentage of participants |
Secondary
Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC)
Glucose AUC within 3 hours after each meal assessed by the AUC of glucose from preprandial to 3 hours postprandial. LS means were calculated using an MMRM analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor.
Time frame: Preprandial to 3 Hours Postprandial during the day following the standard dose
Population: All randomized participants who received at least one dose of study drug and had evaluable glucose data were included in the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Peglispro | Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) | Breakfast | 633.50 mg/dL*h | Standard Error 15.59 |
| Insulin Peglispro | Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) | Lunch | 566.00 mg/dL*h | Standard Error 19.92 |
| Insulin Peglispro | Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) | Dinner | 564.68 mg/dL*h | Standard Error 15.95 |
| Insulin Glargine | Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) | Breakfast | 568.64 mg/dL*h | Standard Error 15.51 |
| Insulin Glargine | Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) | Lunch | 568.20 mg/dL*h | Standard Error 19.84 |
| Insulin Glargine | Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) | Dinner | 577.46 mg/dL*h | Standard Error 15.95 |
Secondary
Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) Excursion
Glucose AUC excursion within 3 hours after each meal assessed by the AUC of adjusted glucose (= observed glucose - preprandial glucose) from preprandial to 3 hours postprandial. LS means were calculated using an MMRM analysis including the following fixed effects: treatment, period, sequence, and baseline basal insulin dose stratification factor.
Time frame: Preprandial to 3 Hours Postprandial during the day following the standard dose
Population: All randomized participants who received at least one dose of study drug and had evaluable glucose data were included in the analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Peglispro | Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) Excursion | Breakfast | 266.33 mg/dL*h | Standard Error 12.04 |
| Insulin Peglispro | Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) Excursion | Lunch | -2.38 mg/dL*h | Standard Error 11.42 |
| Insulin Peglispro | Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) Excursion | Dinner | 134.40 mg/dL*h | Standard Error 10.2 |
| Insulin Glargine | Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) Excursion | Breakfast | 270.32 mg/dL*h | Standard Error 11.98 |
| Insulin Glargine | Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) Excursion | Lunch | 36.92 mg/dL*h | Standard Error 11.34 |
| Insulin Glargine | Pharmacodynamics: Three-Hour Postprandial Glucose Area Under the Concentration Time Curve (AUC) Excursion | Dinner | 150.23 mg/dL*h | Standard Error 10.2 |
Secondary
Time to the Nadir Glucose
Nadir glucose was defined as the lowest blood glucose for a participant with blood glucose ≤70 mg/dL (3.9 mmol/L). The average time was calculated by dividing the sum of time from double dose to the nadir glucose for participants with blood glucose ≤70 mg/dL (3.9 mmol/L) by the number of participants with blood glucose ≤70 mg/dL (3.9 mmol/L) during the first 84 hours after the double dose.
Time frame: Predose to 84 Hours Post Double Dose
Population: All randomized participants who received the double dose of study drug and had blood glucose ≤70 mg/dL (3.9 mmol/L) during the first 84 hours after the double dose were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Peglispro | Time to the Nadir Glucose | 35.92 hours | Standard Deviation 26.37 |
| Insulin Glargine | Time to the Nadir Glucose | 28.15 hours | Standard Deviation 23.46 |