Safety Study of Subcutaneously-Injected Prandial INSULIN-PH20 NP Compared to Insulin Lispro Injection in Participants With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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Insulin lispro is approved by the Food and Drug Administration (FDA) 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 combined with a non-preserved (NP) formulation of regular human insulin (INSULIN-PH20 NP) will be compared to insulin lispro with respect to absorption and action of insulin.

Detailed Description
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The purpose of this study is to compare the safety and tolerability of INSULIN-PH20 NP versus insulin lispro alone.

Official Title
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A Phase II, Randomized, Open Label, 2-Way Crossover, Safety Study of Subcutaneously Injected Prandial INSULIN-PH20 NP Compared to Insulin Analog Injection in Patients With Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Insulin Lispro
* Drug: regular human insulin
* Drug: recombinant human hyaluronidase PH20
* Drug: Insulin glargine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female of age 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. Participants with Type 1 diabetes mellitus (T1DM) (per World Health Organization [WHO] criteria) treated with insulin for ≥24 months. Participants who use an insulin infusion pump for basal insulin administration must be on the device for at least 90 days prior to screening. Body mass index (BMI) 18.0 to 35.0 kilograms per square meter (kg/m^2), inclusive. Glycosylated hemoglobin A1c (HbA1c) ≤7.5 % based on central laboratory screening results. Fasting C-peptide <0.6 nanograms per milliliter (ng/mL). Participants should be in good general health based on medical history and physical examination and without medical conditions that might prevent the completion of study drug injections and assessments required in this protocol. Exclusion Criteria: Known or suspected allergy to any component of any of the study drugs in this study. Previous enrollment in this study. Participants who fail Screening may attempt to rescreen into the study. A participant who has proliferative retinopathy or maculopathy, 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 [ECG]), 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). Three attempts may be performed to measure blood pressure. History of any illness or disease that in the opinion of the Investigator might confound the results of the study or pose additional risk in administering the study drugs to the participant. As judged by the Investigator, clinically significant findings in routine laboratory data. Use of drugs (such as systemic corticosteroids) that may interfere with the interpretation of study results or are known to cause clinically relevant interference with insulin action, glucose utilization, or recovery from hypoglycemia. Recurrent severe hypoglycemia (more than 2 episodes over the last 6 months) or hypoglycemic unawareness, as judged by the Investigator. Current addiction to alcohol or substances of abuse, as determined by the Investigator. 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). Mental incapacity, unwillingness, or language barriers precluding adequate understanding or cooperation in this study. Receipt of any investigational drug within 4 weeks of Screening. Any condition (intrinsic or extrinsic) that in the judgment of the Investigator will interfere with study participation or evaluation of data. Examples would include: renal insufficiency (serum creatinine >1.5 milligrams per deciliter [mg/dL] for males or >1.4 mg/dL for females), congestive heart failure required medication treatment, and cardiac disease with New York Heart Association (NYHA) Functional Capacity of III/IV.

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

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INSULIN-PH20 NP / Insulin Lispro<br>All enrolled participants underwent a 1-month dose titration period and received 100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC) pre-meals, with doses titrated to each participant individually. Next participants were randomly assigned to 1 of 2 study treatments (Treatment A or B) for the first of two, 3-month treatment cycles. Each participant then received the second treatment for the second cycle. INSULIN-PH20 NP (Treatment A): 100 U/mL non-preserved (NP) formulation of regular human insulin with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected SC, pre-meals, doses titrated to each participant individually. Insulin Lispro (Treatment B): 100 U/mL insulin lispro, injected SC, pre-meals, doses titrated to each participant individually. Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine or maintained their usual regimen through an insulin pump. | Drug: Insulin Lispro<br> <br> * Other names: Humalog;Drug: regular human insulin<br> <br> * Other names: Humulin R;Drug: recombinant human hyaluronidase PH20<br> <br> * Other names: PH20;Drug: Insulin glargine<br> <br> * Other names: Lantus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Postprandial Glucose Excursion | A 2-hour postprandial glucose excursion was measured for 3 meals over 3 days during each treatment cycle (3 days during Week 14 of the first treatment cycle and 3 days during Week 26 of the second treatment cycle). For each of the 3 days, the mealtime (breakfast, lunch, and dinner) excursions were calculated as the post-meal glucose value minus the pre-meal value as determined by 8-point glucose monitoring. The average of all excursions over the 3 days for the corresponding treatment cycle is presented. | Week 14 and Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time Spent With Blood Glucose Value Outside a 71-139 Milligrams Per Deciliter (mg/dL) Range During Continuous Glucose Monitoring | Participants were provided a continuous glucose monitoring (CGM) device, consisting of a sensor, transmitter, and receiver. Total time the participant's blood glucose was outside the 71-139 mg/dL range during 3 days of CGM during each treatment cycle (3 days during Week 14 of the first treatment cycle and 3 days during Week 26 of the second treatment cycle) is presented. | Week 14 and Week 26 | 
| Number of Participants With Hypoglycemic Events | The number of participants with at least one hypoglycemic event (HE) reported during the entire study is presented. Additionally, the number of participants with severe HEs (those that necessitated administration of carbohydrate or glucagon, or resuscitation, by another person) is also presented. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. | Baseline through Week 29 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recombinant human hyaluronidase (rHuPH20), Insulin lispro, regular human insulin