Type 1 Diabetes Mellitus
Conditions
Keywords
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
Brief summary
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
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.
Interventions
DRUGRapid Acting insulin with pre-treatment of rHuPH20
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.
DEVICESham injection
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.
Sponsors
Halozyme Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female participants between the ages 18 and 65 years, inclusive. 2. 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. 3. Participants with type 1 diabetes mellitus treated with insulin (multiple daily injections or continuous subcutaneous insulin infusion \[CSII\]) diagnosed ≥ 12 months prior to enrollment 4. Body mass index (BMI) 18.0 to 32.0 kilograms per meters squared (kg/m\^2) 5. HbA1c (glycated hemoglobin A1c) ≤ 10% based on local laboratory results 6. Fasting C-peptide \< 0.6 nanograms per milliliter (ng/mL) 7. Current treatment with insulin \<1.2 Units per kg per day (U/kg/day) 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 injections and assessments required in this protocol
Exclusion criteria
1. Inability to comply with study requirements as judged by the Investigator 2. Known or suspected allergy to any component of any of the study drugs in this trial 3. A participant who has proliferative retinopathy or maculopathy, severe gastroparesis, and/or severe neuropathy, in particular autonomic neuropathy, as judged by the Investigator 4. 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 5. 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) 6. 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 7. 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 8. 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 9. Recurrent major hypoglycemia or hypoglycemic unawareness, as judged by the Investigator 10. Current addiction to alcohol or substances of abuse as determined by the Investigator 11. Blood donation (\> 500 mL) within the previous 8 weeks (56 days) prior to Day -1 of Treatment Period 1 12. 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) 13. Mental incapacity, unwillingness, or language barriers precluding adequate understanding or cooperation in this study 14. Participation in any other clinical trial and receipt of any investigational drug within 4 weeks of Day -1 of Treatment Period 1 15. Any condition (intrinsic or extrinsic) that in the judgment of the Investigator will interfere with trial participation or evaluation of data 16. Positive for human immunodeficiency virus (HIV), Hepatitis C or Hepatitis B 17. Tobacco and nicotine use within 3 months prior to Day 1 of Treatment Period 1 or use during the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 0-10 hours | 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. |
| Part 3: Time to Achieve Plasma Glucose >90 mg/dL After Release of Hypoglycemic CSII Clamp | 0-12 hours | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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: Time-action Profile, Assessed by GIR in Euglycemic Participants | up to approximately 10 hours | — |
| Part 2: Plasma Glucose Concentration Over Time | up to approximately 10 hours | 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. |
| Part 2: Insulin Analog Serum Concentration as a Function of Time Following Bolus Insulin Infusion | up to approximately 10 hours | 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. |
| 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 | — |
| Part 1: Mean Residence Time (MRT) | up to approximately 22 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 | — |
Countries
United States
Participant flow
Pre-assignment details
All three parts (Parts 1, 2, and 3) of this exploratory study were to use a cross-over design that would maximize efficiency while minimizing sample size. Only Part 2 of this study was conducted; thus, all 14 participants were enrolled in Part 2 only.
Participants by arm
| Arm | Count |
|---|---|
| Hyaluronidase Human Injection/Sham Injection Participants received pretreatment of 1 milliliter (mL) hyaluronidase human injection on Day 1 of Treatment Period 1. After a 3- to 7-day washout period, participants received pretreatment of 1 mL sham injection on Day 1 of Treatment Period 2. | 7 |
| Sham Injection/Hyaluronidase Human Injection Participants received pretreatment of 1 mL sham injection on Day 1 of Treatment Period 1. After a 3- to 7-day washout period, participants received pretreatment of 1 mL hyaluronidase human injection on Day 1 of Treatment Period 2. | 7 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part 2: Treatment Period 2 (2 Days) | Intended Changes to Clamp Procedure | 1 | 0 |
Baseline characteristics
| Characteristic | Hyaluronidase Human Injection/Sham Injection | Sham Injection/Hyaluronidase Human Injection | Total |
|---|---|---|---|
| Age, Continuous | 43.6 years STANDARD_DEVIATION 8.9 | 40.4 years STANDARD_DEVIATION 14.84 | 42.0 years STANDARD_DEVIATION 11.87 |
| Race/Ethnicity, Customized White or Caucasian | 7 Participants | 7 Participants | 14 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 4 / 14 | 2 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 |
Outcome results
Primary
Part 1: Area Under the Curve (AUC) of Glucose Infusion Rate (GIR) From 0-6 Hours
Time frame: 0-6 hours
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.
Primary
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.
Time frame: 0-10 hours
Population: Safety Population: all randomized participants exposed to at least one dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hyaluronidase Human Injection/Sham Injection | Part 2: Time to Reduction in Plasma Glucose by 80 Milligrams Per Deciliter (mg/dL) Following CSII Bolus | First Intervention | 5.58 hours |
| Hyaluronidase Human Injection/Sham Injection | Part 2: Time to Reduction in Plasma Glucose by 80 Milligrams Per Deciliter (mg/dL) Following CSII Bolus | Second Intervention | 4.63 hours |
| Sham Injection/Hyaluronidase Human Injection | Part 2: Time to Reduction in Plasma Glucose by 80 Milligrams Per Deciliter (mg/dL) Following CSII Bolus | First Intervention | 5.23 hours |
| Sham Injection/Hyaluronidase Human Injection | Part 2: Time to Reduction in Plasma Glucose by 80 Milligrams Per Deciliter (mg/dL) Following CSII Bolus | Second Intervention | 5.32 hours |
Primary
Part 3: Time to Achieve Plasma Glucose >90 mg/dL After Release of Hypoglycemic CSII Clamp
Time frame: 0-12 hours
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.
Secondary
Part 1: Area Under the Curve From Time Zero to the Last Measureable Concentration (AUC0-last)
Time frame: up to approximately 22 hours
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.
Secondary
Part 1: Early Time to 50% Maximum Serum Insulin Concentration (t50%) Max
Time frame: up to approximately 22 hours
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.
Secondary
Part 1: Fractional and Absolute AUC0-1hr
Time frame: 0 to 1 hour
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.
Secondary
Part 1: Fractional and Absolute AUC2hr-end
Time frame: 2 to approximately 22 hours
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.
Secondary
Part 1: Mean Maximum Concentration (Cmax)
Time frame: up to approximately 22 hours
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.
Secondary
Part 1: Mean Residence Time (MRT)
Time frame: up to approximately 22 hours
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.
Secondary
Part 1: Time-action Profile, Assessed by GIR in Euglycemic Participants
Time frame: up to approximately 10 hours
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.
Secondary
Part 1: Time to 50% of Total AUC (AUC0-last)
Time frame: up to approximately 22 hours
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.
Secondary
Part 1: Time to Achieve Maximum Concentration (Tmax)
Time frame: up to approximately 22 hours
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.
Secondary
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.
Time frame: up to approximately 10 hours
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hyaluronidase Human Injection/Sham Injection | Part 2: Insulin Analog Serum Concentration as a Function of Time Following Bolus Insulin Infusion | First Intervention | 1341.8 picomolar |
| Hyaluronidase Human Injection/Sham Injection | Part 2: Insulin Analog Serum Concentration as a Function of Time Following Bolus Insulin Infusion | Second Intervention | 688.5 picomolar |
| Sham Injection/Hyaluronidase Human Injection | Part 2: Insulin Analog Serum Concentration as a Function of Time Following Bolus Insulin Infusion | First Intervention | 805.1 picomolar |
| Sham Injection/Hyaluronidase Human Injection | Part 2: Insulin Analog Serum Concentration as a Function of Time Following Bolus Insulin Infusion | Second Intervention | 1092.6 picomolar |
Secondary
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.
Time frame: up to approximately 10 hours
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Hyaluronidase Human Injection/Sham Injection | Part 2: Plasma Glucose Concentration Over Time | First Intervention | 299 mg/dL |
| Hyaluronidase Human Injection/Sham Injection | Part 2: Plasma Glucose Concentration Over Time | Second Intervention | 350 mg/dL |
| Sham Injection/Hyaluronidase Human Injection | Part 2: Plasma Glucose Concentration Over Time | First Intervention | 341 mg/dL |
| Sham Injection/Hyaluronidase Human Injection | Part 2: Plasma Glucose Concentration Over Time | Second Intervention | 445 mg/dL |
Secondary
Part 3: Insulin Analog Serum Concentration as a Function of Time Following Termination of Insulin Infusion
Time frame: up to approximately 12 hours
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.
Secondary
Part 3: Plasma Glucose Concentration Over Time
Time frame: up to approximately 12 hours
Population: The study was stopped early, prior to enrolling the planned 24 participants. As a result, data were not collected for analysis of this outcome measure. Only Part 2 of the study was conducted.