Type 1 Diabetes Mellitus
Conditions
Keywords
Type 1 Diabetes, Continuous Subcutaneous Insulin Infusion (CSII)
Brief summary
The purpose of this study is to evaluate consistency of accelerated insulin absorption and onset-of-action and shortened duration of action for bolus insulin infusions after pretreatment with 150 units (U) of Hylenex® (recombinant human hyaluronidase PH20 \[rHuPH20\]) injection at the time of infusion set insertion compared to sham injection.
Interventions
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. Males or females 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. 2. Non-smoking participants with Type 1 diabetes mellitus (T1DM) treated with insulin for ≥12 months. Nonsmoking means abstinence from cigarettes and cigars for 3 months and negative cotinine screening tests at screening. 3. Body mass index (BMI) 18.0 to 35.0 kilograms per meter squared (kg/m²), inclusive. 4. Glycosylated hemoglobin A1c (HbA1c) ≤10% based on local laboratory results. 5. Fasting connecting peptide of insulin (C-peptide) \<0.6 nanograms per milliliter (ng/mL). 6. Current treatment with insulin \<90 units per day (U/d). 7. Current use of rapid acting insulin analog. 8. Routine use of CSII as the primary route of insulin administration for at least 3 months prior to screening 9. 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 infusions and assessments required in the study protocol.
Exclusion criteria
1. Known or suspected allergy to any component of any of the study drugs in this study. 2. Previous enrollment in this study. 3. Use of drugs 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. Participants taking maintenance doses of blood thinners (for example, coumadin or heparin) will be excluded. 4. Use of any long-acting insulin injection within 72 hours of Study Day 1; participants will continue to refrain from use throughout the duration of the study (Phases I and II). 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 the Screening Visit(s) in this study. 8. Pregnancy, breastfeeding, 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 Study Day 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early Insulin Exposure (%AUC[0-60]) | 10 minutes predose; 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose on Days 1 and 4 | 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, and 60 minutes postdose during a euglycemic clamp. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax) | 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4 | 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) | 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4 | Early and late tGIR50%max 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) | 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4 | 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]) | 30 minutes and 10 minutes predose; 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4 | Area under the glucose concentration curve from 0 to 360 minutes (AUC\[0-360\]) 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]) | 10 minutes predose; 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4 | 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\[0-360\]). AUCM is the total area under the first moment curve. First moment curve is obtained by plotting concentration-time versus time. It can be used to measure how long a drug stays in the body. 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. |
| Time to 50% Total Glucose Infused (50%Gtot) | 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Enrolled Participants All participants enrolled in the study. | 25 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Phase 1 | Protocol Violation | 1 | 0 |
| Phase 1 | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | All Enrolled Participants |
|---|---|
| Age, Continuous | 31.6 years STANDARD_DEVIATION 9.13 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 23 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 23 Participants |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 13 / 24 | 9 / 23 |
| serious Total, serious adverse events | 0 / 24 | 0 / 23 |
Outcome results
Primary
Early Insulin Exposure (%AUC[0-60])
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, and 60 minutes postdose during a euglycemic clamp.
Time frame: 10 minutes predose; 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose on Days 1 and 4
Population: Participants who completed both phases of the study and with evaluable %AUC(0-60) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Aspart or Lispro)-rHuPH20 | Early Insulin Exposure (%AUC[0-60]) | Day 1 | 33.53 percentage of AUC(0-60) | Standard Deviation 11.81 |
| Insulin (Aspart or Lispro)-rHuPH20 | Early Insulin Exposure (%AUC[0-60]) | Day 4 | 39.45 percentage of AUC(0-60) | Standard Deviation 9.72 |
| Insulin (Aspart or Lispro)-Sham | Early Insulin Exposure (%AUC[0-60]) | Day 1 | 17.85 percentage of AUC(0-60) | Standard Deviation 8.24 |
| Insulin (Aspart or Lispro)-Sham | Early Insulin Exposure (%AUC[0-60]) | Day 4 | 33.52 percentage of AUC(0-60) | Standard Deviation 10.78 |
p-value: <0.000190% CI: [1.71, 2.71]Mixed Models Analysis
p-value: <0.000190% CI: [2.08, 3.29]Mixed Models Analysis
Secondary
Area Under the Glucose Concentration Curve (AUC[0-360])
Area under the glucose concentration curve from 0 to 360 minutes (AUC\[0-360\]) 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.
Time frame: 30 minutes and 10 minutes predose; 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4
Population: Participants who completed both phases of the study and with evaluable AUC(0-360) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Aspart or Lispro)-rHuPH20 | Area Under the Glucose Concentration Curve (AUC[0-360]) | Day 1 | 1312.41 picomoles*minutes/liter | Standard Deviation 627.33 |
| Insulin (Aspart or Lispro)-rHuPH20 | Area Under the Glucose Concentration Curve (AUC[0-360]) | Day 4 | 1063.77 picomoles*minutes/liter | Standard Deviation 500.06 |
| Insulin (Aspart or Lispro)-Sham | Area Under the Glucose Concentration Curve (AUC[0-360]) | Day 1 | 1199.54 picomoles*minutes/liter | Standard Deviation 535.8 |
| Insulin (Aspart or Lispro)-Sham | Area Under the Glucose Concentration Curve (AUC[0-360]) | Day 4 | 1139.65 picomoles*minutes/liter | Standard Deviation 414.94 |
Secondary
Duration of Insulin Action (AUMC[0-360]/AUC[0-360])
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\[0-360\]). AUCM is the total area under the first moment curve. First moment curve is obtained by plotting concentration-time versus time. It can be used to measure how long a drug stays in the body. 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.
Time frame: 10 minutes predose; 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4
Population: Participants who completed both phases of the study and with evaluable AUMC(0-360)/AUC(0-360) data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Aspart or Lispro)-rHuPH20 | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]) | Day 1 | 119.02 ratio | Standard Deviation 21.18 |
| Insulin (Aspart or Lispro)-rHuPH20 | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]) | Day 4 | 111.25 ratio | Standard Deviation 20.59 |
| Insulin (Aspart or Lispro)-Sham | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]) | Day 1 | 154.03 ratio | Standard Deviation 27.58 |
| Insulin (Aspart or Lispro)-Sham | Duration of Insulin Action (AUMC[0-360]/AUC[0-360]) | Day 4 | 120.57 ratio | Standard Deviation 20.85 |
Secondary
Maximum Glucose Infusion Rate (GIRmax)
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 frame: 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4
Population: Participants who completed both phases of the study and with evaluable GIRmax data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Aspart or Lispro)-rHuPH20 | Maximum Glucose Infusion Rate (GIRmax) | Day 1 | 13.47 milligrams/kilogram/minute | Standard Deviation 5.46 |
| Insulin (Aspart or Lispro)-rHuPH20 | Maximum Glucose Infusion Rate (GIRmax) | Day 4 | 10.75 milligrams/kilogram/minute | Standard Deviation 3.73 |
| Insulin (Aspart or Lispro)-Sham | Maximum Glucose Infusion Rate (GIRmax) | Day 1 | 11.14 milligrams/kilogram/minute | Standard Deviation 4.21 |
| Insulin (Aspart or Lispro)-Sham | Maximum Glucose Infusion Rate (GIRmax) | Day 4 | 11.83 milligrams/kilogram/minute | Standard Deviation 3.26 |
Secondary
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max)
Early and late tGIR50%max 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 frame: 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4
Population: Participants who completed both phases of the study and with evaluable early and late tGIR50%max data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Aspart or Lispro)-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) | Early tGIR50%, Day 1 | 40.33 minutes | Standard Deviation 20.13 |
| Insulin (Aspart or Lispro)-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) | Late tGIR50%, Day 1 | 114.52 minutes | Standard Deviation 54.33 |
| Insulin (Aspart or Lispro)-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) | Early tGIR50%, Day 4 | 32.57 minutes | Standard Deviation 14.5 |
| Insulin (Aspart or Lispro)-rHuPH20 | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) | Late tGIR50%, Day 4 | 113.24 minutes | Standard Deviation 48.72 |
| Insulin (Aspart or Lispro)-Sham | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) | Late tGIR50%, Day 4 | 126.71 minutes | Standard Deviation 50.37 |
| Insulin (Aspart or Lispro)-Sham | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) | Early tGIR50%, Day 1 | 54.67 minutes | Standard Deviation 33.97 |
| Insulin (Aspart or Lispro)-Sham | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) | Early tGIR50%, Day 4 | 39.67 minutes | Standard Deviation 15.51 |
| Insulin (Aspart or Lispro)-Sham | Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) | Late tGIR50%, Day 1 | 152.14 minutes | Standard Deviation 61 |
Secondary
Time to 50% Total Glucose Infused (50%Gtot)
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 frame: 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4
Population: Participants who completed both phases of the study and with evaluable 50%Gtot data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Aspart or Lispro)-rHuPH20 | Time to 50% Total Glucose Infused (50%Gtot) | Day 1 | 40.33 minutes | Standard Deviation 20.13 |
| Insulin (Aspart or Lispro)-rHuPH20 | Time to 50% Total Glucose Infused (50%Gtot) | Day 4 | 54.67 minutes | Standard Deviation 54.67 |
| Insulin (Aspart or Lispro)-Sham | Time to 50% Total Glucose Infused (50%Gtot) | Day 1 | 32.57 minutes | Standard Deviation 14.5 |
| Insulin (Aspart or Lispro)-Sham | Time to 50% Total Glucose Infused (50%Gtot) | Day 4 | 39.67 minutes | Standard Deviation 15.51 |
Secondary
Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax)
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 frame: 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4
Population: Participants who completed both phases of the study and with evaluable tGIRmax data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Insulin (Aspart or Lispro)-rHuPH20 | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax) | Day 1 | 78.95 minutes | Standard Deviation 37.16 |
| Insulin (Aspart or Lispro)-rHuPH20 | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax) | Day 4 | 81.86 minutes | Standard Deviation 45.99 |
| Insulin (Aspart or Lispro)-Sham | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax) | Day 1 | 132.62 minutes | Standard Deviation 55.07 |
| Insulin (Aspart or Lispro)-Sham | Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax) | Day 4 | 97.38 minutes | Standard Deviation 47.31 |