Pharmacokinetic (PK), Pharmacodynamic (PD), and Safety Study of Subcutaneously Administered Humalog® With and Without Recombinant Human Hyaluronidase (rHuPH20)and Humulin-R® With and Without rHuPH20

Study Overview
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Brief Summary
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The purpose of the study is to compare the pharmacokinetics (PK) and pharmacodynamics (PD) of Humalog (insulin lispro) or Humulin-R (recombinant human insulin) when administered as a single subcutaneous (SC) injection of 20 units (U) with or without coadministration of recombinant human hyaluronidase PH20 (rHuPH20). The study hypothesizes that the time required to reach maximum insulin concentration (tmax) when insulin is administered with rHuPH20 will be comparable or shorter than the time required without rHuPH20.

Official Title
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A Phase I, Randomized, Double-Blind Crossover Pharmacokinetic, Pharmacodynamic, and Safety Study of Subcutaneously Administered Humalog® (Insulin Lispro Injection; Rapid-Acting Insulin) With and Without Recombinant Human Hyaluronidase (rHuPH20) Versus Subcutaneously Administered Humulin R® (Regular Insulin Injection) With and Without rHuPH20

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: Humalog
* Drug: Humulin-R
* Drug: Recombinant human hyaluronidase PH20 (rHuPH20)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy male participants aged 18 to 55 years. Body mass index (BMI) 18 to 28 kilograms per meter squared (kg/m^2) and total body weight >70 kilograms (kg) (154 pounds [lb]). Willingness and ability to comply with the protocol. Vital signs within the normal range. Within 7 days before the first injection, metabolic panel results and complete blood count (CBC) within the laboratory normal reference range. Fasting plasma glucose within the normal range of 90 to 110 milligrams per deciliter (mg/dL) on the morning of the glucose clamp. Agreement not to father a child or donate sperm and to use effective contraception during the study and for at least 30 days after study completion. Willingness and ability to sign an informed consent form. Exclusion Criteria: Evidence or history of clinically significant hematologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurologic (to include history of seizures) or allergic disease, or history of hypoglycemic episodes. Known history of diabetes mellitus. Prior exposure to any insulin or insulin analogs. Known allergy to hyaluronidase or any other ingredient in HYLENEX. Known allergy to bee or vespid venom. Positive urine drug screen results. Positive human immunodeficiency virus (HIV) 1, HIV 2, hepatitis B, or hepatitis C antibody test result. Any 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, or screening urine nicotine concentration >50 nanograms per milliliter (ng/mL). Use of prescription or nonprescription drugs within 7 days or 5 half-lives, whichever was shorter, except acetaminophen at doses of less than or equal to 1 gram per day (g/day). Donation of blood in excess of 500 milliliters (mL) within 56 days before dosing. Failure to limit alcohol consumption and refrain from exercise within 48 hours before each injection. Known clinically significant intercurrent illness or other major systemic disease that would unduly risk the participant's safety or interfere with the interpretation of results. Participation in a study of any investigational drug or device 30 days before enrollment in this study. Unfitness for the study, in the investigator's opinion.

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

Sexes Eligible for Study
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Male

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

Primary Purpose: Health Services Research
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Humalog first, then Humalog + rHuPH20<br>Humalog first, then Humalog + recombinant human hyaluronidase PH20 (rHuPH20) A single subcutaneous (SC) injection of 20 units (U) Humalog on Day 1 of the study, followed by a single SC injection of 20 U Humalog + 300 U rHuPH20 after a washout period of at least 6 days | Drug: Humalog<br> <br> * Other names: Insulin lispro;Drug: Recombinant human hyaluronidase PH20 (rHuPH20)<br> <br> * Other names: HYLENEX;|
| Active Comparator: Humalog + rHuPH20 first, then Humalog<br>Humalog + recombinant human hyaluronidase PH20 (rHuPH20) first, then Humalog A single subcutaneous (SC) injection of 20 units (U) Humalog + 300 U rHuPH20 on Day 1 of the study, followed by a single SC injection of 20 U Humalog after a washout period of at least 6 days | Drug: Humalog<br> <br> * Other names: Insulin lispro;Drug: Recombinant human hyaluronidase PH20 (rHuPH20)<br> <br> * Other names: HYLENEX;|
| Active Comparator: Humulin-R first, then Humulin-R + rHuPH20<br>Humulin-R (recombinant human insulin) first, then Humulin-R + recombinant human hyaluronidase PH20 (rHuPH20) A single subcutaneous (SC) injection of 20 units (U) Humulin-R on Day 1 of the study, followed by a single SC injection of 20 U Humulin-R + 240 U rHuPH20 after a washout period of at least 6 days | Drug: Humulin-R<br> <br> * Other names: Recombinant human insulin;Drug: Recombinant human hyaluronidase PH20 (rHuPH20)<br> <br> * Other names: HYLENEX;|
| Active Comparator: Humulin-R + rHuPH20 first, then Humulin-R<br>Humulin-R (recombinant human insulin) + recombinant human hyaluronidase PH20 (rHuPH20) first, then Humulin-R A single subcutaneous (SC) injection of 20 units (U) Humulin-R + 240 U rHuPH20 on Day 1 of the study, followed by a single SC injection of 20 U Humulin-R after a washout period of at least 6 days | Drug: Humulin-R<br> <br> * Other names: Recombinant human insulin;Drug: Recombinant human hyaluronidase PH20 (rHuPH20)<br> <br> * Other names: HYLENEX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Maximum Serum Insulin Concentration (Tmax) | Time to maximum serum insulin concentration (tmax) values for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from 3 milliliter (mL) blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | 
| Maximum Serum Insulin Concentration (Cmax) | Maximum serum insulin concentration (Cmax) values for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from 3 milliliter (mL) blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | 
| Area Under the Serum Concentration-Time Curve From Time Zero to the Time Required to Reach Endogenous Plasma Glucose Levels (AUC[0-t']) | Area under the serum concentration-time curve from time zero to the time required to reach endogenous plasma glucose levels (AUC[0-t']) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from 3 milliliter (mL) blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | 
| Area Under the Concentration-Time Curve From Time 0 to Time to Reach Maximum Concentration (Tmax) for Serum Insulin With Recombinant Human Hyaluronidase PH20 (rHuPH20) (AUC[0-tmaxPH20]) | Area under the concentration-time curve from time 0 to time to reach maximum concentration (tmax) for serum insulin (Humalog or Humulin-R) with recombinant human hyaluronidase (rHuPH20) (AUC[0-tmaxPH20]) for participants who received Humalog or Humulin-R and with rHuPH20 were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment and every 3 min from min 0 through 48 for Stage 1 and, and every 3 min from min 0 through 68 for Stage 2 during the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. | Predose and up to 48 minutes postdose during Stage 1, or up to 68 minutes postdose during Stage 2 | 
| Relative Bioavailability (Area Under the Curve [AUC] for Insulin + Recombinant Human Hyaluronidase [rHuPH20] / AUC for Insulin Alone) | Relative bioavailability was determined by dividing the baseline-corrected geometric mean of the area under the curve (AUC) for insulin (ins) (Humalog or Humulin-R) with recombinant human hyaluronidase PH20 (rHuPH20) by the baseline-corrected geometric mean of the AUC for insulin alone (AUC[insulin+rHuPH20]/AUC[insulin]). Bioavailability values for participants who received Humalog or Humulin-R and rHuPH20 were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Maximum Glucose Infusion Rate (tGIR[Max]) | Time to maximal effect for glucose infusion rate (tGIR[max]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from blood samples obtained every 3 minutes during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | 
| Time to Early Half-Maximal Effect for Glucose Infusion Rate (tGIR[early50%]) | Time to early half-maximal effect for glucose infusion rate (tGIR[early50%]) for participants who were randomized to Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | 
| Time to Late Half-Maximal Effect for Glucose Infusion Rate (tGIR[late50%]) | Time to late half-maximal effect for glucose infusion rate (tGIR[late50%]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. Because the study was only 360 minutes in duration, there was not sufficient time for regular human insulin to show an effect and therefore tGIR(late50%) could not be calculated for participants receiving Humulin-R alone. | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | 
| Maximum Glucose Infusion Rate (GIR[Max]) | Maximum glucose infusion rate (GIR[max]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase PH20 (rHuPH20) were measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 through 360 throughout the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | 
| Area Under the Glucose Infusion Rate Curve From 0 to 60 Minutes After Injection (AUC[GIR{0-60}]) | The area under the curve for the glucose infusion rate from minutes (min) 0 to 60 after injection (AUC[GIR{0-60}]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 min prior to treatment and every 3 min from min 0 through 60 during the clamp procedure. Means were calculated using analysis of variance with fixed of participant, sequence within participant, treatment, and period. | Predose and up to 60 minutes postdose during Stage 1 or Stage 2 | 
| Area Under the Glucose Infusion Rate Curve From 0 to 120 Minutes After Injection (AUC[GIR{0-120}]) | The area under the glucose infusion rate curve from minutes 0 to 120 after injection (AUC[GIR{0-120}]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 minute (min) prior to treatment, every 3 min from min 0 through 60, and every 15 min from min 60 through 120 during the clamp. Means were calculated using analysis of variance with fixed effects of participant, sequence within participant, treatment, and period. | Predose and up to 120 minutes postdose during Stage 1 or Stage 2 | 
| Area Under the Glucose Infusion Rate Curve From 0 to 180 Minutes After Injection (AUC[GIR{0-180}]) | The area under the curve for the glucose infusion rate from minutes (min) 0 to 180 after injection (AUC[GIR{0-180}]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 min prior to treatment, every 3 min from min 0 through 60, and every 15 min from min 60 through 180 during the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. | Predose and up to 180 minutes postdose during Stage 1 or Stage 2 | 
| Area Under the Glucose Infusion Rate Curve From 0 to 240 Minutes After Injection (AUC[GIR{0-240}]) | The area the glucose infusion rate curve from minutes (min) 0 to 240 after injection (AUC[GIR{0-240}]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 min prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 to 240 during the clamp procedure. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. | Predose up to 240 minutes postdose during Stage 1 or Stage 2 | 
| Area Under the Glucose Infusion Rate Curve From 0 to 360 Minutes After Injection (AUC[GIR{0-360}]) | The area under glucose infusion rate curve from minutes (min) 0 to 360 after injection (AUC[GIR{0-360}]) for participants who received Humalog or Humulin-R with or without recombinant human hyaluronidase (rHuPH20) was measured from blood samples obtained during a euglycemic clamp procedure. Samples were taken 10 and 1 min prior to treatment, every 3 min from min 0 through 60, every 15 min from min 60 through 180, and every 60 min from min 180 to 360 during the clamp. Means were calculated using analysis of variance with effects of participant, sequence within participant, treatment, and period. | Predose and up to 360 minutes postdose during Stage 1 or Stage 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rHuPH20, Hyaluronidase, Insulin