Diabetes Mellitus
Conditions
Keywords
rHuPH20, Recombinant Human Hyaluronidase, Insulin Lispro, Regular Human Insulin
Brief summary
Insulin lispro and regular human insulin are Food and Drug Administration (FDA)-approved medications for the treatment of diabetes mellitus. Recombinant human hyaluronidase (rHuPH20) is approved by the FDA as an aid to the absorption and dispersion of other injectable drugs. In this study, rHuPH20 will be co-administered with both insulin lispro and regular human insulin in order to determine if it improves the absorption of these insulins to more closely mimic the body's natural increase in insulin in response to a meal.
Detailed description
The purpose of this study is to compare the pharmacokinetics (absorption, distribution, breakdown and elimination) of regular human insulin + recombinant human hyaluronidase (rHuPH20) versus insulin lispro alone, and to compare the pharmacokinetics of insulin lispro + rHuPH20 versus insulin lispro alone. The effects of regular human insulin + rHuPH20, insulin lispro + rHuPH20, and insulin lispro alone on the body will be evaluated by blood glucose measurements and by calculating the rate at which a glucose solution is infused to maintain blood glucose within a certain range. The safety and tolerability of insulin lispro with and without rHuPH20 and regular human insulin with rHuPH20 will be studied. The study drugs will be administered by subcutaneous (under the skin) injection.
Interventions
Sponsors
Halozyme Therapeutics
Study design
Intervention model
CROSSOVER
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy participants between the ages of 18 and 55 years, inclusive. (Healthy is defined as no clinically relevant abnormalities.) * Body mass index (BMI) between 18-27 kilograms per meter squared (kg/m\^2), inclusive. * Total body weight \>65 kilograms (kg) (143 pounds \[lb\]) for men and \>46 kg (101 lb) for women. * Decision making capacity and willingness to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures including adequate venous access. * Vital signs (blood pressure, pulse rate, body temperature) within normal range or, if out of range, assessed by the Principal Investigator (PI) as not clinically significant (NCS). * Fasting blood glucose level \<100 milligrams per deciliter (mg/dL) at screening. * A negative serum pregnancy test (if female of childbearing potential). * Female participants of childbearing potential must agree to be practicing effective birth control or abstinence currently and agree to continue to do so for the duration of their time on study. * Signed, written Institutional Review Board (IRB)-approved informed consent.
Exclusion criteria
* Evidence or history of clinically significant hematological, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, oncologic, or neurologic (to include history of seizures) disease; hypoglycemic episodes; intercurrent illness (such as influenza); or allergic disease (including severe drug allergies, but excluding untreated, asymptomatic, seasonal allergies at time of dosing). Clinical significance to be determined by the PI. * As judged by the Investigator, clinically significant findings in routine laboratory data. (Anemia with hematocrit less than 33% at screening is specifically exclusionary.) * Known history of diabetes mellitus (type 1 or type 2) or gestational diabetes. * Known allergy to hyaluronidase or any other ingredient in the study drug. * Positive human immunodeficiency virus (HIV 1) antibody test, hepatitis B (anti-hepatitis B surface antigen \[anti-HBsAg\]) or hepatitis C (anti-hepatitis C virus \[anti-HCV\]) antibody test. * History or evidence of alcohol or drug abuse. * History or evidence of use of any tobacco or nicotine-containing product within 6 months of screening and a screening qualitative urine nicotine test. * Use of drugs that may interfere with the interpretation of trial results or are known to cause clinically relevant interference with insulin action or glucose utilization. * Donation of blood in excess of 500 milliliters (mL) within 56 days before dosing. * Participation in a study of any investigational drug or device 30 days before enrollment in this study. * The participant is unfit for the study in the opinion of the Investigator. * Women who are pregnant or breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intra-participant Variability in Percent of Total Area Under the Plasma Insulin Concentration-Versus-Time Curve Attained by Time T (%AUC[0-T]) | predose up to 30 minutes postdose | Blood samples were taken 30, 20, 10 minutes (mins) prior to each injection; every 3 mins (from 0 to 15 mins); and every 5 mins (from 15 to 30 mins) after each injection. The percent coefficient of variation (CV%) was calculated as 100\*(standard deviation/mean). The intra-participant CV% was calculated directly from the 2 replications of each treatment. The CV% for percentage of total AUC is reported from 0 to 30 minutes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Early and Late 50% Maximum Serum Insulin Concentration (t[50%Max]) | predose up to 480 minutes postdose | Blood samples were taken 30, 20, 10 minutes (mins) prior to each injection; every 3 mins (from 0 to 15 mins); every 5 mins (from 15 to 30 mins); every 15 mins (from 30 to 90 mins); every 30 mins (from 90 to 240 mins); and every 60 mins (from 240 to 480 mins) after each injection. |
| Peak Serum Insulin Concentration (Cmax) | predose up to 480 minutes postdose | Cmax was determined as the maximum of all valid serum insulin concentration measurements for each measurement series. Blood samples were taken 30, 20, 10 minutes (mins) prior to each injection; every 3 mins (from 0 to 15 mins); every 5 mins (from 15 to 30 mins); every 15 mins (from 30 to 90 mins); every 30 mins (from 90 to 240 mins); and every 60 mins (from 240 to 480 mins) after each injection. |
| Time to Percentage of Total Glucose Infused | predose up to 480 minutes postdose | Blood samples were taken 30, 20, 10 minutes (mins) prior to each injection; every 3 mins (from 0 to 15 mins); every 5 mins (from 15 to 30 mins); every 15 mins (from 30 to 90 mins); every 30 mins (from 90 to 240 mins); and every 60 mins (from 240 to 480 mins) after each injection. Time to 25%, 50%, and 75% of total glucose infused are summarized. |
| Percentage of Total Glucose Infused | predose up to 240 minutes postdose | Blood samples were taken 30, 20, 10 minutes (mins) prior to each injection; every 3 mins (from 0 to 15 mins); every 5 mins (from 15 to 30 mins); every 15 mins (from 30 to 90 mins); and every 30 mins (from 90 to 240 mins) after each injection. Percentage of total glucose infused from 0 to 4 hours is summarized. |
| Number of Treatment Emergent Adverse Events (TEAEs) Related to Study Drug | first dose through 7 to 10 days after last dose | The number of TEAEs related to study drug (as determined by the Investigator) are summarized. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Participants All participants were randomized to 1 of 6 treatment sequences (ABC, ACB, BAC, BCA, CAB, or CBA), each of which was comprised of the same 3 interventions (A, B, and C).
Intervention A: a single, subcutaneous (SC) injection of 0.15 units per kilogram (U/kg) insulin lispro with 3.75 nanograms per kilogram (ng/kg) recombinant human hyaluronidase (rHuPH20)
Intervention B: a single, SC injection of 0.15 U/kg regular human insulin (RHI) with 3.75 ng/kg rHuPH20
Intervention C: a single, SC injection of 0.15 U/kg insulin lispro alone
There was a washout period of 3 to 14 days between interventions.
The treatment sequence (ABC, ACB, BAC, BCA, CAB, or CBA) was repeated once so that each participant received up to 6 injections. | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Washout 1 (3 to 14 Days) | Withdrawal by Subject | 0 | 1 | 0 | 0 | 0 | 0 |
| Washout 2 (3 to 14 Days) | Protocol Violation | 0 | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 35.9 years STANDARD_DEVIATION 9.24 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 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 | 19 Participants |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 22 | 4 / 20 | 9 / 21 |
| serious Total, serious adverse events | 0 / 22 | 0 / 20 | 0 / 21 |
Outcome results
Primary
Intra-participant Variability in Percent of Total Area Under the Plasma Insulin Concentration-Versus-Time Curve Attained by Time T (%AUC[0-T])
Blood samples were taken 30, 20, 10 minutes (mins) prior to each injection; every 3 mins (from 0 to 15 mins); and every 5 mins (from 15 to 30 mins) after each injection. The percent coefficient of variation (CV%) was calculated as 100\*(standard deviation/mean). The intra-participant CV% was calculated directly from the 2 replications of each treatment. The CV% for percentage of total AUC is reported from 0 to 30 minutes.
Time frame: predose up to 30 minutes postdose
Population: Participants who completed all study visits and had evaluable %AUC(0-t) data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Lispro + rHuPH20 | Intra-participant Variability in Percent of Total Area Under the Plasma Insulin Concentration-Versus-Time Curve Attained by Time T (%AUC[0-T]) | 14.04 percentage of coefficient of variance | Standard Deviation 11.12 |
| Regular Human Insulin + rHuPH20 | Intra-participant Variability in Percent of Total Area Under the Plasma Insulin Concentration-Versus-Time Curve Attained by Time T (%AUC[0-T]) | 23.81 percentage of coefficient of variance | Standard Deviation 12.43 |
| Insulin Lispro Alone | Intra-participant Variability in Percent of Total Area Under the Plasma Insulin Concentration-Versus-Time Curve Attained by Time T (%AUC[0-T]) | 40.51 percentage of coefficient of variance | Standard Deviation 24.3 |
p-value: <0.000190% CI: [18.22, 34.71]Mixed Models Analysis
p-value: 0.001590% CI: [8.45, 24.94]Mixed Models Analysis
Secondary
Number of Treatment Emergent Adverse Events (TEAEs) Related to Study Drug
The number of TEAEs related to study drug (as determined by the Investigator) are summarized. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Time frame: first dose through 7 to 10 days after last dose
Population: Participants who received at least one dose of study drug (insulin lispro, regular human insulin, or recombinant human hyaluronidase \[rHuPH20\]).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Insulin Lispro + rHuPH20 | Number of Treatment Emergent Adverse Events (TEAEs) Related to Study Drug | 1 events |
| Regular Human Insulin + rHuPH20 | Number of Treatment Emergent Adverse Events (TEAEs) Related to Study Drug | 0 events |
| Insulin Lispro Alone | Number of Treatment Emergent Adverse Events (TEAEs) Related to Study Drug | 3 events |
Secondary
Peak Serum Insulin Concentration (Cmax)
Cmax was determined as the maximum of all valid serum insulin concentration measurements for each measurement series. Blood samples were taken 30, 20, 10 minutes (mins) prior to each injection; every 3 mins (from 0 to 15 mins); every 5 mins (from 15 to 30 mins); every 15 mins (from 30 to 90 mins); every 30 mins (from 90 to 240 mins); and every 60 mins (from 240 to 480 mins) after each injection.
Time frame: predose up to 480 minutes postdose
Population: Participants who completed all study visits and had evaluable Cmax data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Lispro + rHuPH20 | Peak Serum Insulin Concentration (Cmax) | 782.85 picomoles per liter (pmol/L) | Standard Deviation 199.84 |
| Regular Human Insulin + rHuPH20 | Peak Serum Insulin Concentration (Cmax) | 561.93 picomoles per liter (pmol/L) | Standard Deviation 141.88 |
| Insulin Lispro Alone | Peak Serum Insulin Concentration (Cmax) | 482.40 picomoles per liter (pmol/L) | Standard Deviation 119.5 |
Secondary
Percentage of Total Glucose Infused
Blood samples were taken 30, 20, 10 minutes (mins) prior to each injection; every 3 mins (from 0 to 15 mins); every 5 mins (from 15 to 30 mins); every 15 mins (from 30 to 90 mins); and every 30 mins (from 90 to 240 mins) after each injection. Percentage of total glucose infused from 0 to 4 hours is summarized.
Time frame: predose up to 240 minutes postdose
Population: Participants who completed all study visits and had evaluable glucose infusion data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Insulin Lispro + rHuPH20 | Percentage of Total Glucose Infused | 88.70 percentage of total glucose infused | Standard Deviation 9.04 |
| Regular Human Insulin + rHuPH20 | Percentage of Total Glucose Infused | 85.17 percentage of total glucose infused | Standard Deviation 7.89 |
| Insulin Lispro Alone | Percentage of Total Glucose Infused | 79.81 percentage of total glucose infused | Standard Deviation 11.27 |
Secondary
Time to Early and Late 50% Maximum Serum Insulin Concentration (t[50%Max])
Blood samples were taken 30, 20, 10 minutes (mins) prior to each injection; every 3 mins (from 0 to 15 mins); every 5 mins (from 15 to 30 mins); every 15 mins (from 30 to 90 mins); every 30 mins (from 90 to 240 mins); and every 60 mins (from 240 to 480 mins) after each injection.
Time frame: predose up to 480 minutes postdose
Population: Participants who completed all study visits and had evaluable t(50%max) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Lispro + rHuPH20 | Time to Early and Late 50% Maximum Serum Insulin Concentration (t[50%Max]) | early t(50%max) | 14.14 minutes | Standard Deviation 3.01 |
| Insulin Lispro + rHuPH20 | Time to Early and Late 50% Maximum Serum Insulin Concentration (t[50%Max]) | late t(50%max) | 88.14 minutes | Standard Deviation 16.96 |
| Regular Human Insulin + rHuPH20 | Time to Early and Late 50% Maximum Serum Insulin Concentration (t[50%Max]) | early t(50%max) | 21.52 minutes | Standard Deviation 4.95 |
| Regular Human Insulin + rHuPH20 | Time to Early and Late 50% Maximum Serum Insulin Concentration (t[50%Max]) | late t(50%max) | 136.67 minutes | Standard Deviation 27.16 |
| Insulin Lispro Alone | Time to Early and Late 50% Maximum Serum Insulin Concentration (t[50%Max]) | early t(50%max) | 24.73 minutes | Standard Deviation 5.16 |
| Insulin Lispro Alone | Time to Early and Late 50% Maximum Serum Insulin Concentration (t[50%Max]) | late t(50%max) | 144.43 minutes | Standard Deviation 31.79 |
Secondary
Time to Percentage of Total Glucose Infused
Blood samples were taken 30, 20, 10 minutes (mins) prior to each injection; every 3 mins (from 0 to 15 mins); every 5 mins (from 15 to 30 mins); every 15 mins (from 30 to 90 mins); every 30 mins (from 90 to 240 mins); and every 60 mins (from 240 to 480 mins) after each injection. Time to 25%, 50%, and 75% of total glucose infused are summarized.
Time frame: predose up to 480 minutes postdose
Population: Participants who completed all study visits and had evaluable glucose infusion data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin Lispro + rHuPH20 | Time to Percentage of Total Glucose Infused | 50% | 118.95 minutes | Standard Deviation 22.93 |
| Insulin Lispro + rHuPH20 | Time to Percentage of Total Glucose Infused | 25% | 72.38 minutes | Standard Deviation 12.5 |
| Insulin Lispro + rHuPH20 | Time to Percentage of Total Glucose Infused | 75% | 179.23 minutes | Standard Deviation 40.73 |
| Regular Human Insulin + rHuPH20 | Time to Percentage of Total Glucose Infused | 50% | 142.55 minutes | Standard Deviation 21.31 |
| Regular Human Insulin + rHuPH20 | Time to Percentage of Total Glucose Infused | 25% | 91.58 minutes | Standard Deviation 15.85 |
| Regular Human Insulin + rHuPH20 | Time to Percentage of Total Glucose Infused | 75% | 203.15 minutes | Standard Deviation 31.12 |
| Insulin Lispro Alone | Time to Percentage of Total Glucose Infused | 25% | 99.13 minutes | Standard Deviation 19.26 |
| Insulin Lispro Alone | Time to Percentage of Total Glucose Infused | 75% | 222.48 minutes | Standard Deviation 44.44 |
| Insulin Lispro Alone | Time to Percentage of Total Glucose Infused | 50% | 156.83 minutes | Standard Deviation 30.36 |