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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Halozyme Therapeutics
ClinicalTrials.gov Identifier:
NCT01275131
First received: January 10, 2011
Last updated: June 26, 2014
Last verified: June 2014
  Purpose

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 Intervention Phase
Type 1 Diabetes Mellitus
Drug: Insulin aspart
Drug: Recombinant human hyaluronidase PH20 (rHuPH20)
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, 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)

Resource links provided by NLM:


Further study details as provided by Halozyme Therapeutics:

Primary Outcome Measures:
  • Early Insulin Exposure (%AUC[0-60]), Stage 1 [ Time Frame: 10 minutes predose up to 60 minutes postdose ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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:
  • Maximum Glucose Infusion Rate (GIRmax), Stage 1 [ Time Frame: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8 ] [ Designated as safety issue: No ]
    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.

  • Maximum Glucose Infusion Rate (GIRmax), Stage 3 [ Time Frame: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10 ] [ Designated as safety issue: Yes ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: Yes ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.

  • 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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 45
Study Start Date: January 2011
Study Completion Date: December 2011
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01275131

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

No publications provided

Responsible Party: Halozyme Therapeutics
ClinicalTrials.gov Identifier: NCT01275131     History of Changes
Other Study ID Numbers: HALO-117-105
Study First Received: January 10, 2011
Results First Received: June 26, 2014
Last Updated: June 26, 2014
Health Authority: United States: Food and Drug Administration

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
Autoimmune Diseases
Endocrine System Diseases
Glucose Metabolism Disorders
Immune System Diseases
Metabolic Diseases
Insulin
Insulin Aspart
Insulin, Globin Zinc
Hypoglycemic Agents
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 21, 2014