Pharmacokinetic and Glucodynamic Crossover Study of Subcutaneously (SC) Administered Insulin Lispro + Recombinant Human Hyaluronidase (rHuPH20) and Regular Human Insulin + rHuPH20 Compared to Insulin Lispro Alone

Study Overview
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Brief Summary
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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
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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.

Official Title
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Phase 1, Randomized, Double-Blind, Pharmacokinetic and Glucodynamic 6-Way Crossover Study of SC Administered Insulin Lispro With Recombinant Human Hyaluronidase (rHuPH20) and Regular Human Insulin With Recombinant Human Hyaluronidase (rHuPH20) Compared to Insulin Lispro Alone in Healthy Volunteers

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: Insulin Lispro
* Drug: Regular Human Insulin
* Drug: rHuPH20


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Insulin Lispro, Regular Human Insulin, rHuPH20<br>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. | Drug: Insulin Lispro<br> <br> * Other names: Humalog;Drug: Regular Human Insulin<br> <br> * Other names: Humulin R;Drug: rHuPH20<br> <br> * Other names: HYLENEX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | predose up to 30 minutes postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | predose up to 480 minutes postdose | 
| 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. | predose up to 480 minutes postdose | 
| 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. | predose up to 480 minutes postdose | 
| 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. | predose up to 240 minutes postdose | 
| 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. | first dose through 7 to 10 days after last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rHuPH20, Recombinant Human Hyaluronidase, Insulin Lispro, Regular Human Insulin