Randomized, Double-blind, Crossover, Pharmacokinetic (PK) and Glucodynamic (GD) Study of Continuous Subcutaneous Insulin Infusion (CSII) in Participants With Type 1 Diabetes Mellitus (T1DM)

Study Overview
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Brief Summary
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The purpose of this study is to determine if recombinant human hyaluronidase PH20 (rHuPH20) will change the exposure and action of approved insulin analogs when given by continuous subcutaneous insulin infusion (CSII) in participants with Type 1 diabetes mellitus (T1DM). This study is divided into Stage 1, 2, and 3. Stage 3 was started chronologically before Stage 2 and, prior to performing Stage 2, the Sponsor made the decision to terminate Stage 2. Stage 2 was not initiated due to a strategic business decision and termination was not based on safety or efficacy concerns. No participants were enrolled in Stage 2.

Official Title
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Randomized, Double-Blind, Pharmacokinetic (PK) and Glucodynamic (GD) Crossover Study of Continuous Subcutaneous Insulin Infusion (CSII) of Rapid Acting Insulin Analogs With and Without Recombinant Human Hyaluronidase (rHuPH20)

Conditions
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Type 1 Diabetes Mellitus

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged 18 to 65 years, inclusive. Females of child-bearing potential must use a standard and effective means of birth control for the duration of the study. Non-smoking participants with Type 1 diabetes mellitus (T1DM) treated with insulin for greater than or equal to 12 months. Non-smoking means abstinence from cigarettes and cigars for 3 months and negative cotinine screening tests. Body mass index (BMI) 18.0 to 35.0 kilograms per meter squared (kg/m^2), inclusive. Glycosylated hemoglobin A1c (HbA1c) ≤10 % based on local laboratory results. Fasting C-peptide <0.6 nanograms per milliliter (ng/mL). Current treatment with insulin <90 units per day (U/d). Routine use of continuous subcutaneous insulin infusion (CSII) as the primary route of insulin administration. Participant should be in good general health based on medical history and physical examination, without medical conditions that might prevent the completion of study drug infusions and assessments required in this protocol. Exclusion Criteria: Known or suspected allergy to any component of any of the study drugs in this trial. Previous enrollment in this trial (Exception: participants in Stage 1 are permitted to participate in Stage 2). Use of drugs that may interfere with the interpretation of trial results or are known to cause clinically relevant interference with insulin action, glucose utilization, or recovery from hypoglycemia. Participants taking maintenance doses of blood thinners (eg, Coumadin or heparin) will be excluded. Use of any long-acting insulin injection within 72 hours of Stage 1 or Stage 3. Recurrent major hypoglycemia or hypoglycemic unawareness, as judged by the Investigator. Current addiction to alcohol or substances of abuse as determined by the Investigator. Blood donation or phlebotomy (>500 milliliters [mL]) within the previous 8 weeks of Screening. This applies both to new participants and to participants who have participated in Stage 1 and who wish to continue in Stage 2. Pregnancy, breast-feeding, the intention of becoming pregnant, or not using adequate contraceptive measures (adequate contraceptive measures consist of sterilization, intra-uterine device [IUD], oral or injectable contraceptives, or barrier methods). Symptomatic gastroparesis. Receipt of any investigational drug within 4 weeks of Stage 1 or Stage 2.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Stage 1: Insulin aspart first, then insulin aspart-rHuPH20<br>Participants first received 0.15 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4. After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8. | Drug: Insulin aspart<br> <br> * Other names: Novolog;Drug: Recombinant human hyaluronidase PH20 (rHuPH20)<br> <br> * Other names: Hylenex;|
| Active Comparator: Stage 1: Insulin aspart-rHuPH20 first, then insulin aspart<br>Participants first received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4. After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart alone as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8. | Drug: Insulin aspart<br> <br> * Other names: Novolog;Drug: Recombinant human hyaluronidase PH20 (rHuPH20)<br> <br> * Other names: Hylenex;|
| Active Comparator: Stage 3: Insulin aspart first, then insulin aspart + rHuPH20<br>Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a sham injection was administered 2.5 hr prior to the 6-hr euglycemic clamp. After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII, for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a 1.0-milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to the 6-hr euglycemic clamp. | Drug: Insulin aspart<br> <br> * Other names: Novolog;Drug: Recombinant human hyaluronidase PH20 (rHuPH20)<br> <br> * Other names: Hylenex;|
| Active Comparator: Stage 3: Insulin aspart + rHuPH20 first, then insulin aspart<br>Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6- hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a 1.0-milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to the euglycemic clamp . After a 5- to 14- day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII, for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a sham injection was administered 2.5 hr prior to the 6-hour euglycemic clamp. | Drug: Insulin aspart<br> <br> * Other names: Novolog;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 |
| --- | --- | --- |
| Early Insulin Exposure (%AUC[0-60]), Stage 1 | Early insulin exposure, defined as the percentage of total insulin exposure (area under the insulin concentration curve [AUC{0-360}]) that occurs within the first hour following bolus dose of insulin during the 2 euglycemic clamps is presented. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 120, 150, 180, 240, 300, and 360 minutes postdose during the euglycemic clamp. | 10 minutes predose up to 60 minutes postdose | 
| Early Exposure to Insulin (%AUC[0-60]), Stage 3 | Early insulin exposure, defined as the percentage of total insulin exposure (area under the insulin concentration curve [AUC{0-360}) that occurs within the first hour following bolus dose of insulin during the 2 euglycemic clamps is presented. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 120, 150, 180, 240, 300, and 360 minutes postdose during the euglycemic clamp. | 10 minutes predose up to 60 minutes postdose on Days 2/7, 3/8, and 5/10 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Glucose Infusion Rate (GIRmax), Stage 1 | Maximum glucose infusion rates (GIRmax) for Stage1 are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. | 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 | 
| Maximum Glucose Infusion Rate (GIRmax), Stage 3 | Maximum glucose infusion rates (GIRmax) for Stage 3 are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. | 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 | 
| Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 1 | Time to first occurrence of maximum glucose infusion rate (tGIRmax) for Stage 1 is presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. | 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 | 
| Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 | Time to first occurrence of maximum glucose infusion rate (tGIRmax) for Stage 3 is presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. | 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 | 
| Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 | Early and late times to 50% maximum glucose infusion rate (tGIR50%max) for Stage 1 are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. | 0 up to 360 minutes postdose on day 2/6 and Day 4/8 | 
| Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 | Early and late time to 50% maximum glucose infusion rates (tGIR50%max) for Stage 3 studies are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. | 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 | 
| Time to 50% Total Glucose Infused (50%Gtot), Stage 1 | Time to 50% total glucose infused (50%Gtot) is presented for Stage 1. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. | 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 | 
| Time to 50% Total Glucose Infused (50%Gtot), Stage 3 | Time to 50% of total glucose infused (50%Gtot) is presented for Stage 3. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. | 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 | 
| Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 1 | Area under the glucose concentration curve for 0 to 360 minutes (AUC[0-360]) from Stage 1 is presented. Blood samples were collected 30 and 10 minutes prior to insulin bolus and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. | 30 minutes predose up to 360 minutes postdose on Day 2/6 and Day 4/8 | 
| Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 | Area under the glucose concentration curve from 0 to 360 minutes (AUC[0-360]) for Stage 3 studies is presented. Blood samples were collected 30 and 10 minutes prior to insulin bolus and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. | 30 minutes predose up to 360 minutes postdose Days 2/7, 3/8, and 5/10 | 
| Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 1 | Duration of insulin action was calculated by dividing the area under the first moment curve (AUMC[0-360]) by the area under the concentration versus time curve (AUC[0-360]) for Stage 1. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. | 10 minutes predose up to 360 minutes postdose on Day 2/6 and Day 4/8 | 
| Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 | Duration of insulin action was calculated by dividing the area under the first moment curve (AUMC[0-360]) by the area under the concentration versus time curve (AUC[0-360]) for Stage 3. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp. | 10 minutes predose up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Insulin analog, Type 1 diabetes mellitus, Pharmacokinetic, Glucodynamic