Diabetes Mellitus, Type 2
Conditions
Brief summary
The purpose of this two-part study is to measure how much of the study drug gets into the blood stream and how long it takes the body to get rid of it. In Part A, each participant will receive two treatments, a single dose and a single dose with continuous infusion of U-500R insulin, both administered just under the skin. Participants who complete Part A will continue into Part B where they will be assigned to 1 of 2 treatments with U-500R insulin, injected either twice or three times daily under the skin for 5-10 days. This study can last from 7-14 weeks including initial screening and follow up.
Interventions
DRUGU-500R
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Males or females with type 2 diabetes mellitus (T2DM) * Are current users of U-100, U-200 and/or U-300 insulin/analog as, basal, premixed and/or basal/bolus delivered with any injection device (pens and/or syringe/vial but excluding continuous subcutaneous infusion (CSII)/insulin pump use in the preceding 3 months), taking a total daily dose (TDD) of greater than or equal to (≥) 150 units (U) or at least one dose greater than (\>) 100 U as part of a multiple daily injection (MDI) regimen and TDD less than or equal to (≤)3.0 units per kilogram (U/kg) * Concomitant antihyperglycemic agent(s) (AHA) therapy may include: metformin (MET), dipeptidyl peptidase 4 inhibitors, pioglitazone (doses ≤30 milligrams per day (mg/day)), glucagon like peptide (GLP)-1 receptor agonists, sodium-glucose co-transporter-2 (SGLT2) inhibitors, except in combination with GLP-1 receptor agonists * Participant's antihyperglycemic agent (AHA) therapy must have been stable for ≥3 months (except for weekly GLP-1 receptor agonists which must have been stable for ≥4 months) * Have hemoglobin A1c (HbA1c) 7.5-11.5 percent (%)
Exclusion criteria
* Have type 1 diabetes mellitus (T1DM), or other types of diabetes mellitus apart from T2DM * Have known hypersensitivities or allergies to insulin, excipients contained in insulin products, or related compounds * Have used U-500R within 3 months prior to screening * Have used rosiglitazone, pramlintide, once weekly or twice daily exenatide, or other injectable or oral antihyperglycemic agent(s) not listed in the inclusion criterion; or are taking oral antidiabetic medications at doses exceeding the respective product labels * Have had a blood transfusion or severe blood loss within 3 months prior to screening or have known hemoglobinopathy, hemolytic anemia, or sickle cell anemia which may affect reliability of HbA1c measurements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Pharmacokinetics (PK): Time to Maximum Drug Concentration (Tmax) of U-500R | Period 1 and 2: -0.5, 0, 0.5, 1, 2, 3, 4, 6, 7, 8, 12, 16, 24 hours (h) post dose | Part A: Pharmacokinetics (PK): Time to Maximum Drug Concentration (Tmax) of U-500R. |
| Part B: Pharmacokinetics: Area Under the Concentration Versus Time Curve From Zero to 24 Hours Postdose (AUC[0-24]) of U-500R | Period 3: -0.5, 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose | Part B: Pharmacokinetics: Area Under the Concentration Versus Time Curve from Zero to 24 Hours Postdose (AUC\[0-24\]) of U-500R. |
| Part B: Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) of U-500R | Period 3: -0.5, 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose | Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) of U-500R. |
| Part B: Pharmacodynamics: Maximum Glucose Infusion Rate (Rmax) of U-500R | Period 3 day 1: 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18h post dose | Pharmacodynamics: Maximum Glucose Infusion Rate (Rmax) of U-500R. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Pharmacokinetics: Area Under The Concentration Versus Time Curve From Time Zero to Last Time Point With A Measurable Concentration (AUC[0-tlast]) of U-500R | Period 1 and 2: -0.5, 0, 0.5, 1, 2, 3, 4, 6, 7, 8, 12, 16, 24h post dose | Part A: Pharmacokinetics: Area Under The Concentration Versus Time Curve From Time Zero to Last Time Point With A Measurable Concentration (AUC\[0-tlast\]) of U-500R. |
| Part B: Pharmacodynamics: Time to Rmax (tRmax) of U-500R | Period 3: 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose | Part B: Pharmacodynamics: Time to Rmax (tRmax) of U-500R. |
| Part A: Pharmacodynamics (PD): Time to Rmax (tRmax) of U-500R | Period 1 and 2: 0, 0.5, 1, 2, 3, 4, 6, 7, 8, 12, 16, 24h post dose | Part A: Pharmacodynamics (PD): Time to Rmax (tRmax) of U-500R. |
| Part B: Pharmacokinetics: Time to Maximum Concentration (Tmax) of U-500R | Period 3: -0.5, 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose | Part B: Pharmacokinetics: Time to Maximum Concentration (Tmax) of U-500R. |
| Part B: Pharmacodynamics: Total Amount of Glucose Infused (Gtot) of U-500R | Period 3: 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose | Pharmacodynamics: Total Amount of Glucose Infused (Gtot) of U-500R. |
Countries
United States
Participant flow
Recruitment details
Two parts study with Part A (Periods 1 & 2) & Part B (Period 3). Part A:Participants received study drug either by subcutaneous(SC) or continuous subcutaneous insulin infusion (CSII) as per the dosing sequence. Part B: Participants received study drug via SC injection either twice daily (BID) or three times daily (TID) as per the dosing sequence.
Participants by arm
| Arm | Count |
|---|---|
| Overall Participants received 100-U of human regular U-500 insulin (U-500R) by subcutaneous (SC) injection or 4.25 U/hour U-500R basal infusion for 12 hours prior to and during the 24 hour clamp plus a 100-U of U-500R via continuous SC insulin infusion (CSII) in Part A (periods 1 & 2), and U-500R administered twice or thrice daily via SC injection in part B (period 3) as per the dosing sequence in each period. | 11 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Period 2 (Part A) | Withdrawal by Subject | 0 | 0 | 1 | 0 |
| Period 3 (Part B) | Withdrawal by Subject | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Overall |
|---|---|
| Age, Continuous | 56.2 years STANDARD_DEVIATION 7.3 |
| Body mass index | 39.63 Kilogram per square meter (kg/m^2) STANDARD_DEVIATION 8.59 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 11 | 0 / 4 | 0 / 6 |
| other Total, other adverse events | 4 / 11 | 3 / 11 | 2 / 4 | 2 / 6 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 | 0 / 4 | 0 / 6 |
Outcome results
Primary
Part A: Pharmacokinetics (PK): Time to Maximum Drug Concentration (Tmax) of U-500R
Part A: Pharmacokinetics (PK): Time to Maximum Drug Concentration (Tmax) of U-500R.
Time frame: Period 1 and 2: -0.5, 0, 0.5, 1, 2, 3, 4, 6, 7, 8, 12, 16, 24 hours (h) post dose
Population: All randomized participants who received at least one dose of study drug and had evaluable PK data in part A.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 100-U Bolus U-500R SC | Part A: Pharmacokinetics (PK): Time to Maximum Drug Concentration (Tmax) of U-500R | 6 Hours (h) |
| 100-U Bolus U-500R CSII | Part A: Pharmacokinetics (PK): Time to Maximum Drug Concentration (Tmax) of U-500R | 5 Hours (h) |
90% CI: [1.08, 1.97]Mixed Models Analysis
Primary
Part B: Pharmacodynamics: Maximum Glucose Infusion Rate (Rmax) of U-500R
Pharmacodynamics: Maximum Glucose Infusion Rate (Rmax) of U-500R.
Time frame: Period 3 day 1: 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18h post dose
Population: All randomized participants who received at least one dose of study drug and had evaluable PK data in part B.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100-U Bolus U-500R SC | Part B: Pharmacodynamics: Maximum Glucose Infusion Rate (Rmax) of U-500R | 524 Milligram per Minute (mg/min) | Geometric Coefficient of Variation 30 |
| 100-U Bolus U-500R CSII | Part B: Pharmacodynamics: Maximum Glucose Infusion Rate (Rmax) of U-500R | 588 Milligram per Minute (mg/min) | Geometric Coefficient of Variation 28 |
Primary
Part B: Pharmacokinetics: Area Under the Concentration Versus Time Curve From Zero to 24 Hours Postdose (AUC[0-24]) of U-500R
Part B: Pharmacokinetics: Area Under the Concentration Versus Time Curve from Zero to 24 Hours Postdose (AUC\[0-24\]) of U-500R.
Time frame: Period 3: -0.5, 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose
Population: All randomized participants who received at least one dose of study drug and had evaluable PK data in part B.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100-U Bolus U-500R SC | Part B: Pharmacokinetics: Area Under the Concentration Versus Time Curve From Zero to 24 Hours Postdose (AUC[0-24]) of U-500R | 7790 Picomoles hour per liter (pmol*h/L) | Geometric Coefficient of Variation 57 |
| 100-U Bolus U-500R CSII | Part B: Pharmacokinetics: Area Under the Concentration Versus Time Curve From Zero to 24 Hours Postdose (AUC[0-24]) of U-500R | 11700 Picomoles hour per liter (pmol*h/L) | Geometric Coefficient of Variation 77 |
Primary
Part B: Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) of U-500R
Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) of U-500R.
Time frame: Period 3: -0.5, 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose
Population: All randomized participants who received at least one dose of study drug and had evaluable PK data in part B.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100-U Bolus U-500R SC | Part B: Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) of U-500R | 699 Pico mole per liter (Pmol/L) | Geometric Coefficient of Variation 47 |
| 100-U Bolus U-500R CSII | Part B: Pharmacokinetics: Maximum Observed Drug Concentration (Cmax) of U-500R | 1050 Pico mole per liter (Pmol/L) | Geometric Coefficient of Variation 82 |
Secondary
Part A: Pharmacodynamics (PD): Time to Rmax (tRmax) of U-500R
Part A: Pharmacodynamics (PD): Time to Rmax (tRmax) of U-500R.
Time frame: Period 1 and 2: 0, 0.5, 1, 2, 3, 4, 6, 7, 8, 12, 16, 24h post dose
Population: All randomized participants who received at least one dose of study drug and had evaluable PD data in Part A.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 100-U Bolus U-500R SC | Part A: Pharmacodynamics (PD): Time to Rmax (tRmax) of U-500R | 8.50 Hour (h) | Geometric Coefficient of Variation 31 |
| 100-U Bolus U-500R CSII | Part A: Pharmacodynamics (PD): Time to Rmax (tRmax) of U-500R | 8.53 Hour (h) | Geometric Coefficient of Variation 35 |
90% CI: [-1.6, 2.6]
Secondary
Part A: Pharmacokinetics: Area Under The Concentration Versus Time Curve From Time Zero to Last Time Point With A Measurable Concentration (AUC[0-tlast]) of U-500R
Part A: Pharmacokinetics: Area Under The Concentration Versus Time Curve From Time Zero to Last Time Point With A Measurable Concentration (AUC\[0-tlast\]) of U-500R.
Time frame: Period 1 and 2: -0.5, 0, 0.5, 1, 2, 3, 4, 6, 7, 8, 12, 16, 24h post dose
Population: All randomized participants who received at least one dose of study drug and had evaluable PK data in Part A.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100-U Bolus U-500R SC | Part A: Pharmacokinetics: Area Under The Concentration Versus Time Curve From Time Zero to Last Time Point With A Measurable Concentration (AUC[0-tlast]) of U-500R | 5230 Picomole hours per liter (pmol^h/L) | Geometric Coefficient of Variation 35 |
| 100-U Bolus U-500R CSII | Part A: Pharmacokinetics: Area Under The Concentration Versus Time Curve From Time Zero to Last Time Point With A Measurable Concentration (AUC[0-tlast]) of U-500R | 6070 Picomole hours per liter (pmol^h/L) | Geometric Coefficient of Variation 70 |
90% CI: [0.761, 1.03]Mixed Models Analysis
Secondary
Part B: Pharmacodynamics: Time to Rmax (tRmax) of U-500R
Part B: Pharmacodynamics: Time to Rmax (tRmax) of U-500R.
Time frame: Period 3: 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose
Population: All randomized participants who received at least one dose of study drug and had evaluable PD data in part B.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100-U Bolus U-500R SC | Part B: Pharmacodynamics: Time to Rmax (tRmax) of U-500R | 12.4 Hours | Geometric Coefficient of Variation 64 |
| 100-U Bolus U-500R CSII | Part B: Pharmacodynamics: Time to Rmax (tRmax) of U-500R | 13.8 Hours | Geometric Coefficient of Variation 7 |
Secondary
Part B: Pharmacodynamics: Total Amount of Glucose Infused (Gtot) of U-500R
Pharmacodynamics: Total Amount of Glucose Infused (Gtot) of U-500R.
Time frame: Period 3: 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose
Population: All randomized participants who received at least one dose of study drug and had evaluable PK data in part B.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 100-U Bolus U-500R SC | Part B: Pharmacodynamics: Total Amount of Glucose Infused (Gtot) of U-500R | 441 Grams (g) | Geometric Coefficient of Variation 27 |
| 100-U Bolus U-500R CSII | Part B: Pharmacodynamics: Total Amount of Glucose Infused (Gtot) of U-500R | 510 Grams (g) | Geometric Coefficient of Variation 28 |
Secondary
Part B: Pharmacokinetics: Time to Maximum Concentration (Tmax) of U-500R
Part B: Pharmacokinetics: Time to Maximum Concentration (Tmax) of U-500R.
Time frame: Period 3: -0.5, 0, 0.5, 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 13, 15, 18, 24h post dose
Population: All randomized participants who received at least one dose of study drug and had evaluable PK data in part B.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 100-U Bolus U-500R SC | Part B: Pharmacokinetics: Time to Maximum Concentration (Tmax) of U-500R | 15 Hours |
| 100-U Bolus U-500R CSII | Part B: Pharmacokinetics: Time to Maximum Concentration (Tmax) of U-500R | 15 Hours |