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

• ClinicalTrials.gov Identifier: NCT01275131
• Recruitment Status: Completed
• First Posted: January 12, 2011
• Results First Posted: July 25, 2014
• Last Update Posted: July 25, 2014
• Sponsor: Halozyme Therapeutics
• Information provided by (Responsible Party): Halozyme Therapeutics

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Type 1 Diabetes Mellitus	Drug: Insulin aspart; Drug: Recombinant human hyaluronidase PH20 (rHuPH20)	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 45 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Basic Science
• Official Title: 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)
• Study Start Date: January 2011
• Actual Primary Completion Date: December 2011
• Actual Study Completion Date: December 2011

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Stage 1: Insulin aspart first, then insulin aspart-rHuPH20; 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; Other Name: Novolog; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20; Hylenex
Active Comparator: Stage 1: Insulin aspart-rHuPH20 first, then insulin aspart; 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; Other Name: Novolog; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20; Hylenex
Active Comparator: Stage 3: Insulin aspart first, then insulin aspart + rHuPH20; 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; Other Name: Novolog; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20; Hylenex
Active Comparator: Stage 3: Insulin aspart + rHuPH20 first, then insulin aspart; 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; Other Name: Novolog; Drug: Recombinant human hyaluronidase PH20 (rHuPH20); Other Names: PH20; Hylenex

Outcome Measures

Primary Outcome Measures :

1. Early Insulin Exposure (%AUC[0-60]), Stage 1 [ Time Frame: 10 minutes predose up to 60 minutes postdose ]
   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.
2. Early Exposure to Insulin (%AUC[0-60]), Stage 3 [ Time Frame: 10 minutes predose up to 60 minutes postdose on Days 2/7, 3/8, and 5/10 ]
   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.

Secondary Outcome Measures :

1. Maximum Glucose Infusion Rate (GIRmax), Stage 1 [ Time Frame: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 ]
   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.
2. Maximum Glucose Infusion Rate (GIRmax), Stage 3 [ Time Frame: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 ]
   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.
3. Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 1 [ Time Frame: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 ]
   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.
4. Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 [ Time Frame: 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) 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.
5. Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 [ Time Frame: 0 up to 360 minutes postdose on day 2/6 and Day 4/8 ]
   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.
6. Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 [ Time Frame: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 ]
   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.
7. Time to 50% Total Glucose Infused (50%Gtot), Stage 1 [ Time Frame: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 ]
   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.
8. Time to 50% Total Glucose Infused (50%Gtot), Stage 3 [ Time Frame: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 ]
   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.
9. Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 1 [ Time Frame: 30 minutes predose up to 360 minutes postdose on Day 2/6 and Day 4/8 ]
   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.
10. Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 [ Time Frame: 30 minutes predose up to 360 minutes postdose Days 2/7, 3/8, and 5/10 ]
    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.
11. Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 1 [ Time Frame: 10 minutes predose up to 360 minutes postdose on Day 2/6 and Day 4/8 ]
    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.
12. Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 [ Time Frame: 10 minutes predose up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. 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.
2. 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.
3. Body mass index (BMI) 18.0 to 35.0 kilograms per meter squared (kg/m^2), inclusive.
4. Glycosylated hemoglobin A1c (HbA1c) ≤10 % based on local laboratory results.
5. Fasting C-peptide <0.6 nanograms per milliliter (ng/mL).
6. Current treatment with insulin <90 units per day (U/d).
7. Routine use of continuous subcutaneous insulin infusion (CSII) as the primary route of insulin administration.
8. 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:

1. Known or suspected allergy to any component of any of the study drugs in this trial.
2. Previous enrollment in this trial (Exception: participants in Stage 1 are permitted to participate in Stage 2).
3. 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.
4. Use of any long-acting insulin injection within 72 hours of Stage 1 or Stage 3.
5. Recurrent major hypoglycemia or hypoglycemic unawareness, as judged by the Investigator.
6. Current addiction to alcohol or substances of abuse as determined by the Investigator.
7. 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.
8. 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).
9. Symptomatic gastroparesis.
10. Receipt of any investigational drug within 4 weeks of Stage 1 or Stage 2.

Contacts and Locations

Locations

United States, California

Profil Institute for Clinical Research

Chula Vista, California, United States, 91911

Sponsors and Collaborators

Halozyme Therapeutics

Investigators

• Principal Investigator: Linda Morrow, MD; Profil Institute for Clinical Research, Inc.

More Information

• Responsible Party: Halozyme Therapeutics
• ClinicalTrials.gov Identifier: NCT01275131
• Other Study ID Numbers: HALO-117-105
• First Posted: January 12, 2011
• Results First Posted: July 25, 2014
• Last Update Posted: July 25, 2014
• Last Verified: June 2014

Keywords provided by Halozyme Therapeutics:

Insulin analog; Type 1 diabetes mellitus; Pharmacokinetic; Glucodynamic; Phase 1

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Insulin Aspart; Hypoglycemic Agents; Physiological Effects of Drugs