A Study of Continuous Subcutaneous Insulin Infusion (CSII) Pump Function in Subjects With Type 1 Diabetes With Recombinant Human Hyaluronidase (rHuPH20)

Study Overview
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Brief Summary
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The goal of this study is to determine if Hylenex recombinant leads to changes in the insulin time-action profiles and glucose responses when preadministered in the setting of continuous subcutaneous insulin infusion (CSII) compared to CSII without Hylenex recombinant (sham injection).

Detailed Description
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There is a recognized need for more rapid insulin action than is available from current rapid-acting analog products. In addition, current products have inconstant absorption and action profiles over the course of infusion set life. Previous human studies of prandial insulin preparations have used co-mixtures of rHuPH20 (study drug) with insulin delivered to study participants by subcutaneous injection and have demonstrated acceleration of insulin absorption and action. CSII has been used clinically for the treatment of diabetes over the last three decades, and a previous study using a co-mixture of rHuPH20 during CSII showed that the combination resulted in a more consistent and ultrafast profile of insulin absorption and action across infusion set use as compared to rapid analog insulin alone.

Official Title
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A Phase 4, Double Blind, Single Center, Randomized, Cross-Over Study of Continuous Subcutaneous Insulin Infusion (CSII) Pump Functionality in Subjects With Type 1 Diabetes Comparing Pretreatment vs. No Pretreatment With Recombinant Human Hyaluronidase (rHuPH20)

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: Rapid Acting insulin with pre-treatment of rHuPH20
* Device: Sham injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female participants between the ages 18 and 65 years, inclusive. Females of child-bearing potential must agree to use a standard and effective means of birth control for the duration of the study. Adequate contraceptive measures include oral or injectable contraceptives, sterilization, intra-uterine device (IUD), barrier methods, or abstinence. Participants with type 1 diabetes mellitus treated with insulin (multiple daily injections or continuous subcutaneous insulin infusion [CSII]) diagnosed ≥ 12 months prior to enrollment Body mass index (BMI) 18.0 to 32.0 kilograms per meters squared (kg/m^2) HbA1c (glycated hemoglobin A1c) ≤ 10% based on local laboratory results Fasting C-peptide < 0.6 nanograms per milliliter (ng/mL) Current treatment with insulin <1.2 Units per kg per day (U/kg/day) 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 injections and assessments required in this protocol Exclusion Criteria: Inability to comply with study requirements as judged by the Investigator Known or suspected allergy to any component of any of the study drugs in this trial A participant who has proliferative retinopathy or maculopathy, severe gastroparesis, and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator As judged by the Investigator, clinically significant active disease of the gastrointestinal, cardiovascular (including a history of arrhythmia or conduction delays on electrocardiogram), hepatic, neurological, renal, genitourinary, or hematological systems As judged by the Investigator, uncontrolled hypertension (diastolic blood pressure ≥ 100 millimeters of mercury [mmHg] and/or systolic blood pressure ≥ 160 mmHg after 5 minutes in the supine position) History of any illness or disease that in the opinion of the Investigator might confound the results of the trial or pose additional risk in administering the study drugs to the participant As judged by the Investigator, clinically significant findings in routine laboratory data. Anemia with hemoglobin less than lower limits of normal at screening is specifically exclusionary 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, or drugs not permitted according to Hylenex recombinant package insert 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 (> 500 mL) within the previous 8 weeks (56 days) prior to Day -1 of Treatment Period 1 Pregnancy, breast-feeding, the intention of becoming pregnant, or not using adequate contraceptive measures (adequate contraceptive measures consist of sterilization, IUD, oral or injectable contraceptives, or barrier methods) Mental incapacity, unwillingness, or language barriers precluding adequate understanding or cooperation in this study Participation in any other clinical trial and receipt of any investigational drug within 4 weeks of Day -1 of Treatment Period 1 Any condition (intrinsic or extrinsic) that in the judgment of the Investigator will interfere with trial participation or evaluation of data Positive for human immunodeficiency virus (HIV), Hepatitis C or Hepatitis B Tobacco and nicotine use within 3 months prior to Day 1 of Treatment Period 1 or use during the study

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hylenex recombinant<br>Comparing the preadministration of Hylenex recombinant in the setting of continuous subcutaneous insulin infusion (CSII). | Drug: Rapid Acting insulin with pre-treatment of rHuPH20<br>* Hylenex recombinant will be administered via infusion sets and insulin pumps. These will be compatible with component tubing system attached to the insulin infusion site and will be placed in the lower abdominal area.<br>* Other names: Hylenex;|
| Sham Comparator: Sham Injection<br>Comparing the preadministration of a sham injection in the setting of CSII. | Device: Sham injection<br>* A sham injection will be administered via infusion sets and insulin pumps. These will be compatible with component tubing system attached to the insulin infusion site and will be placed in the lower abdominal area.<br>* Other names: placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Area Under the Curve (AUC) of Glucose Infusion Rate (GIR) From 0-6 Hours |  | 0-6 hours | 
| Part 2: Time to Reduction in Plasma Glucose by 80 Milligrams Per Deciliter (mg/dL) Following CSII Bolus | Time to reduction is reported as the maximum time it took for any participant receiving each treatment sequence to achieve a reduction in plasma glucose by 80 mg/dL. During the course of the study, it became difficult to establish a stable hyperglycemic plateau with a target glucose level of 220 mg/dL, even after adjusting several operational parameters. The study was stopped early, prior to enrolling the planned 24 participants for Part 2. Thus, analysis for this endpoint was not conducted. Raw data (as a maximum) are reported. | 0-10 hours | 
| Part 3: Time to Achieve Plasma Glucose >90 mg/dL After Release of Hypoglycemic CSII Clamp |  | 0-12 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Time-action Profile, Assessed by GIR in Euglycemic Participants |  | up to approximately 10 hours | 
| Part 1: Mean Maximum Concentration (Cmax) |  | up to approximately 22 hours | 
| Part 1: Time to Achieve Maximum Concentration (Tmax) |  | up to approximately 22 hours | 
| Part 1: Early Time to 50% Maximum Serum Insulin Concentration (t50%) Max |  | up to approximately 22 hours | 
| Part 1: Time to 50% of Total AUC (AUC0-last) |  | up to approximately 22 hours | 
| Part 1: Fractional and Absolute AUC0-1hr |  | 0 to 1 hour | 
| Part 1: Fractional and Absolute AUC2hr-end |  | 2 to approximately 22 hours | 
| Part 1: Area Under the Curve From Time Zero to the Last Measureable Concentration (AUC0-last) |  | up to approximately 22 hours | 
| Part 1: Mean Residence Time (MRT) |  | up to approximately 22 hours | 
| Part 2: Plasma Glucose Concentration Over Time | Plasma glucose concentration over time is reported as the maximum concentration for any participant receiving each treatment sequence. During the course of the study, it became difficult to establish a stable hyperglycemic plateau with a target glucose level of 220 mg/dL, even after adjusting several operational parameters. The study was stopped early, prior to enrolling the planned 24 participants for Part 2. Thus, analysis for this endpoint was not conducted. Raw data (as a maximum) are reported. | up to approximately 10 hours | 
| Part 2: Insulin Analog Serum Concentration as a Function of Time Following Bolus Insulin Infusion | Insulin analog serum concentration is reported as the maximum concentration for any participant receiving each treatment sequence. During the course of the study, it became difficult to establish a stable hyperglycemic plateau with a target glucose level of 220 mg/dL, even after adjusting several operational parameters. The study was stopped early, prior to enrolling the planned 24 participants for Part 2. Thus, analysis for this endpoint was not conducted. Raw data (as a maximum) are reported. | up to approximately 10 hours | 
| Part 3: Plasma Glucose Concentration Over Time |  | up to approximately 12 hours | 
| Part 3: Insulin Analog Serum Concentration as a Function of Time Following Termination of Insulin Infusion |  | up to approximately 12 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Type 1 Diabetes Mellitus, Type 1 Diabetes, T1DM, Continuous Subcutaneous Insulin Infusion (CSII), CSII, Insulin pump, Insulin, rHuPH20, Hylenex, recombinant human hyaluronidase (rHuPH20), Recombinant hyaluronidase