Phase II Pharmacokinetics Study of Humalog and Humulin-R With and Without rHuPH20 in Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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Humalog and Humulin-R (recombinant human insulin) are Food and Drug Administration (FDA) approved medications for the treatment of diabetes mellitus. Recombinant human hyaluronidase PH20 (rHuPH20) is approved by the FDA for use as an aid in the absorption and dispersion of other injectable drugs. In this study, rHuPH20 will be co-administered with both Humalog and Humulin-R in order to determine if it improves the absorption of these insulins to more closely mimic the body's natural increase in insulin in response to a meal.

Detailed Description
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Participants received all 4 interventions in the same order. Dose-finding visits were conducted to identify the appropriate dose of Humalog and Humulin-R. For each Humalog dose-finding visit, a total of 24 U of rHuPH20 was injected SC per unit of Humalog, corresponding to a mass concentration of 18.2 micrograms per milliliter (μg/mL) rHuPH20 (at final concentration of 91 U/mL of Humalog). For each Humulin-R dose-finding visit, a total of 24 U of rHuPH20 was injected SC per unit of Humulin-R, corresponding to a mass concentration of 20.0 μg/mL rHuPH20 (at final concentration of 100 U/mL of Humulin-R).

Official Title
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Phase II Study Evaluating Pharmacokinetics and Postprandial Glycemic Response of Subcutaneously Injected Humalog and Humulin R With/Without Co-Injected Recombinant Human Hyaluronidase Following Liquid Meal in Type1 Diabetes Mellitus Patients

Conditions
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Type 1 Diabetes Mellitus

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


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 treated with insulin for greater than or equal to 12 months. Body mass index (BMI) 18.0 to 29.0 kilograms per meter squared (kg/m^2), inclusive. Glycosylated hemoglobin A1c (HbA1c) less than or equal to 10% based on local laboratory results. Fasting C-peptide less than 0.6 nanograms per milliliter (ng/mL). Current treatment with insulin less than 1.2 units per kilogram per day (U/kg/day). Participants 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: Known or suspected allergy to any component of any of the study drugs in this trial. Previous enrollment in this trial. A participant who has proliferative retinopathy or maculopathy, and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator. Clinically significant (as judged by the Investigator) active disease of the gastrointestinal, cardiovascular (including a history of arrhythmia or conduction delays on electrocardiogram [ECG]), hepatic, neurological, renal, genitourinary, or hematological systems, or uncontrolled hypertension (diastolic blood pressure greater than or equal to 100 millimeters of mercury [mmHg] and/or systolic blood pressure greater than or equal to 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. Clinically significant findings (as judged by the Investigator) in routine laboratory data, including anemia with hemoglobin less than lower limits of normal at screening. Use of drugs which 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. 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 milliliters [mL]) within the 9 weeks prior to first day of dosing on study. 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. Symptomatic gastroparesis. History or evidence of use of any tobacco- or nicotine-containing product within 6 months of screening or screening quantitative urine nicotine concentration >50 ng/mL. Receipt of any investigational drug within 4 weeks of first day of dosing in this study. Any condition (intrinsic or extrinsic) that in the judgment of the Investigator will interfere with trial participation or evaluation of data.

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
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First Humalog+PH20, then Humalog, Humulin-R+PH20, Humulin-R<br>Humalog + Recombinant human hyaluronidase PH20 (rHuPH20) (Intervention 1): 24 units (U) of rHuPH20 per unit of Humalog, injected subcutaneously (SC), for up to 3 visits until an appropriate dose was identified. Humalog alone (Intervention 2): a single SC injection of the appropriate identified dose of Humalog, delivered before a liquid meal. Humulin-R + rHuPH20 (Intervention 3): 24 U of rHuPH20 per unit of Humulin-R, injected SC, for up to 2 visits until an appropriate dose was identified. Humulin-R alone (Intervention 4): a single SC injection of the appropriate identified dose of Humulin-R, delivered before a liquid meal. Appropriate dose of either Humalog or Humulin-R was that at which blood glucose following a liquid meal was <160 milligrams per deciliter (mg/dL) for more than 30 minutes during the first 4 hours after injection and never fell below 60 mg/dL. All dose finding visits and interventions were separated by 3-10 days. | Drug: Humalog<br> <br> * Other names: Insulin lispro;Drug: Humulin-R<br> <br> * Other names: Recombinant human insulin;Drug: Recombinant human hyaluronidase PH20 (rHuPH20)<br> <br> * Other names: PH20;Other: Liquid meal<br> <br> * Other names: Ensure;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Insulin Concentration-time Curve for the First Hour (AUC0-60) | AUC was derived as the area under the serum insulin concentration profile from 0 to time t. Samples were taken 30, 20, and 10 minutes (mins) prior to treatment; every 3 mins from mins 0 through 15; and at 20, 30, 45, and 60 mins postdose. | Predose up to 60 minutes postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Serum Insulin Concentration (Cmax) | Cmax was determined as the maximum of all valid serum insulin concentration measurements for each measurement series. Samples were taken 30, 20, and 10 minutes (mins) prior to treatment; every 3 mins from mins 0 through 15; at 20, 30, and 45 mins; every 30 mins from mins 60 through 240; and every 60 minutes from mins 300 through 480 postdose. | Predose up to 480 minutes postdose | 
| 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, and 10 minutes (mins) prior to treatment; every 3 mins from mins 0 through 15; at 20, 30, and 45 mins; every 30 mins from mins 60 through 240; and every 60 minutes from mins 300 through 480 postdose. | Predose up to 480 minutes postdose | 
| Area Under the Blood Glucose Time-Concentration Curve Blood Glucose (AUC[BG]) | AUC(BG) values are reported for participants whose blood glucose (BG) was elevated higher than 140 milligrams per deciliter (mg/dL) within 4 hours of consuming a liquid meal. Blood samples were collected at 30, 20, 10, and within 5 minutes before; at 3, 6, 9, 12, 15, 20, 25 minutes; and every 10 minutes from minute 30 to 240 postdose. | Predose up to 4 hours after injection of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Recombinant Hyaluronidase, Type 1 Diabetes Mellitus, Humalog, Humulin R, rHuPH20, Hylenex