A Pharmacokinetic and Glucodynamic Study of Subcutaneously Administered Insulin Analogs With rHuPH20 Compared to Insulin Analogs Alone

Study Overview
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Brief Summary
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This is a single-center, Phase 1, randomized, double-blind, 6-way crossover study to determine insulin pharmacokinetics, insulin glucodynamics, safety, and tolerability of subcutaneously administered dose(s) of insulin lispro + recombinant human hyaluronidase PH20 (rHuPH20), insulin lispro alone, insulin glulisine + rHuPH20, insulin glulisine alone, insulin aspart + rHuPH20, and insulin aspart alone.

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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Recombinant human hyaluronidase PH20 (rHuPH20)
* Drug: Insulin lispro
* Drug: Insulin glulisine
* Drug: Insulin aspart


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 [BP], pulse rate, body temperature) within normal range or, if out of range, assessed by the Principal Investigator as not clinically significant. 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 practice 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 Principal Investigator. 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, hepatitis B, or hepatitis C 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 prior to screening and a screening qualitative urine nicotine test. Use of drugs that may interfere with the interpretation of study results or are known to cause clinically relevant interference with insulin action or glucose utilization. Blood donation or high volume phlebotomy, for example, >100 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

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lispro+PH20, Lispro, Glulis+PH20, Glulis, Aspart+PH20, Aspart<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). Each intervention was separated by a 3- to 14-day washout. Intervention A: Participants received a single, subcutaneous (SC) injection of 95 units per milliliter (U/mL) Lispro + 5 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20 (PH20) and a single, SC injection of 95 U/mL Lispro alone 3 to 14 days apart. Intervention B: Participants received a single, SC injection of 95 U/mL Glulisine (Glulis) + 5 µg/mL PH20 and a single, SC injection of 95 U/mL Glulis alone 3 to 14 days apart. Intervention C: Participants received a single, SC injection of 95 U/mL Aspart + 5 µg/mL PH20 and a single, SC injection of 95 U/mL Aspart alone 3 to 14 days apart. | Drug: Recombinant human hyaluronidase PH20 (rHuPH20)<br> <br> * Other names: PH20;Drug: Insulin lispro<br> <br> * Other names: Lispro;Drug: Insulin glulisine<br> <br> * Other names: Glulisine;Drug: Insulin aspart<br> <br> * Other names: Aspart;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-time Curve for Serum Insulin From Time 0 to 60 Minutes (AUC0-60) | Area under the concentration (AUC)-time curve was derived as the area under the serum insulin concentration profile from 0 to 60 minutes. Blood samples were taken 30, 20, and 10 minutes (mins) prior to each injection; every 3 mins (from 0 to 15 mins); and at 20, 25, 30, 45, and 60 mins after each injection. | Predose up to 60 minutes postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Maximum Serum Insulin Concentration (Tmax) | Tmax was determined as the timepoint where the maximum of all valid concentration measurements for each measurement series was observed. 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 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 | 
| Time to Maximum Glucose Infusion Rate (tGIR[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 | 
| Percentage of Total Area Under the Concentration-time Curve for Serum Insulin Attained by Time t (AUC0-t) | Percentage of total area under the concentration (AUC)-time curve at 15, 30, 60, 120 minutes after injection was measured. 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 at 90 and 120 mins after each injection. | Predose up to 120 minutes postdose | 
| Time to Percentage of Total Insulin Exposure | Time to 10% and 50% of total insulin exposure was measured. 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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insulin, recombinant human hyaluronidase, Healthy volunteers