Type 1 Diabetes Mellitus
Conditions
Keywords
Recombinant Hyaluronidase, Type 1 Diabetes Mellitus, Humalog, Humulin R, rHuPH20, Hylenex
Brief summary
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
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).
Interventions
Sponsors
Halozyme Therapeutics
Study design
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Insulin Concentration-time Curve for the First Hour (AUC0-60) | Predose up to 60 minutes postdose | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Serum Insulin Concentration (Cmax) | Predose up to 480 minutes postdose | 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. |
| Time to Maximum Serum Insulin Concentration (Tmax) | Predose up to 480 minutes postdose | 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. |
| Area Under the Blood Glucose Time-Concentration Curve Blood Glucose (AUC[BG]) | Predose up to 4 hours after injection of study drug | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Overall Study Humalog+recombinant human hyaluronidase PH20 (rHuPH20): Up to 3 dose-finding (DF) visits (each visit separated by 3-10 days \[d\]) until an appropriate dose of Humalog was identified. For each DF visit, a total of 24 units (U) of rHuPH20 was injected subcutaneously (SC) per unit of Humalog, corresponding to a mass concentration (conc) of 18.2 micrograms per milliliter (μg/mL) rHuPH20 (at final conc of 91 U/mL of Humalog)
Humalog alone: After a 3-10 d washout (wo), a single SC injection of the appropriate identified dose of Humalog was delivered
Humulin-R+rHuPH20: After a 3-10 d wo, up to 2 DF visits (both visits separated by 3-10 d) until an appropriate dose of Humulin-R was identified. For each DF visit, a total of 24 U of rHuPH20 was injected SC per unit of Humulin-R, corresponding to a mass conc of 20.0 μg/mL rHuPH20 (at final conc of 100 U/mL of Humulin-R)
Humulin-R alone: After a 3-10 d wo, a single SC injection of the appropriate identified dose of Humulin-R was delivered | 22 |
| Total | 22 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Intervention 4 | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Overall Study |
|---|---|
| Age, Continuous | 40.7 years STANDARD_DEVIATION 10.73 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment United States | 22 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 14 / 22 | 15 / 22 | 18 / 22 | 18 / 21 |
| serious Total, serious adverse events | 0 / 22 | 0 / 22 | 0 / 22 | 0 / 21 |
Outcome results
Primary
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.
Time frame: Predose up to 60 minutes postdose
Population: Participants who received at least one dose of Humalog alone, Humalog + rHuPH20, Humulin-R + rHuPH20, or Humulin-R alone with evaluable AUC0-60 data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Humalog + rHuPH20 | Area Under the Insulin Concentration-time Curve for the First Hour (AUC0-60) | 12346.67 nanomole*minute per liter (nmol*min/L) | Standard Deviation 4996.79 |
| Humalog Alone | Area Under the Insulin Concentration-time Curve for the First Hour (AUC0-60) | 8297.62 nanomole*minute per liter (nmol*min/L) | Standard Deviation 3670.03 |
| Humulin-R + rHuPH20 | Area Under the Insulin Concentration-time Curve for the First Hour (AUC0-60) | 11607.65 nanomole*minute per liter (nmol*min/L) | Standard Deviation 6770.61 |
| Humulin-R Alone | Area Under the Insulin Concentration-time Curve for the First Hour (AUC0-60) | 4331.76 nanomole*minute per liter (nmol*min/L) | Standard Deviation 3068.1 |
Comparison: Due to the exploratory nature of this study, the sample size is not based on a formal calculation.p-value: 0.0011ANOVA
Comparison: Due to the exploratory nature of this study, the sample size is not based on a formal calculation.p-value: <0.0001ANOVA
Secondary
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.
Time frame: Predose up to 4 hours after injection of study drug
Population: Participants who received at least one dose of Humalog alone, Humalog + rHuPH20, Humulin-R + rHuPH20, or Humulin-R alone with evaluable AUC(BG) data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Humalog + rHuPH20 | Area Under the Blood Glucose Time-Concentration Curve Blood Glucose (AUC[BG]) | 111 minutes*milligrams per deciliter |
| Humalog Alone | Area Under the Blood Glucose Time-Concentration Curve Blood Glucose (AUC[BG]) | 526 minutes*milligrams per deciliter |
| Humulin-R + rHuPH20 | Area Under the Blood Glucose Time-Concentration Curve Blood Glucose (AUC[BG]) | 181 minutes*milligrams per deciliter |
| Humulin-R Alone | Area Under the Blood Glucose Time-Concentration Curve Blood Glucose (AUC[BG]) | 1,238 minutes*milligrams per deciliter |
Secondary
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.
Time frame: Predose up to 480 minutes postdose
Population: Participants who received at least one dose of Humalog alone, Humalog + rHuPH20, Humulin-R + rHuPH20, or Humulin-R alone with evaluable Cmax data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Humalog + rHuPH20 | Maximum Serum Insulin Concentration (Cmax) | 307.67 Picomoles per liter (pmol/L) | Standard Deviation 125.73 |
| Humalog Alone | Maximum Serum Insulin Concentration (Cmax) | 226.38 Picomoles per liter (pmol/L) | Standard Deviation 85.51 |
| Humulin-R + rHuPH20 | Maximum Serum Insulin Concentration (Cmax) | 285.88 Picomoles per liter (pmol/L) | Standard Deviation 139.54 |
| Humulin-R Alone | Maximum Serum Insulin Concentration (Cmax) | 165.05 Picomoles per liter (pmol/L) | Standard Deviation 68.98 |
Comparison: Due to the exploratory nature of this study, the sample size is not based on a formal calculation.p-value: 0.0057ANOVA
Comparison: Due to the exploratory nature of this study, the sample size is not based on a formal calculation.p-value: <0.0001ANOVA
Secondary
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.
Time frame: Predose up to 480 minutes postdose
Population: Participants who received at least one dose of Humalog alone, Humalog + rHuPH20, Humulin-R + rHuPH20, or Humulin-R alone with evaluable tmax data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Humalog + rHuPH20 | Time to Maximum Serum Insulin Concentration (Tmax) | 30.24 minutes | Standard Deviation 8.73 |
| Humalog Alone | Time to Maximum Serum Insulin Concentration (Tmax) | 48.57 minutes | Standard Deviation 13.34 |
| Humulin-R + rHuPH20 | Time to Maximum Serum Insulin Concentration (Tmax) | 57.06 minutes | Standard Deviation 30.83 |
| Humulin-R Alone | Time to Maximum Serum Insulin Concentration (Tmax) | 116.76 minutes | Standard Deviation 65.02 |
Comparison: Due to the exploratory nature of this study, the sample size is not based on a formal calculation.p-value: <0.0001ANOVA
Comparison: Due to the exploratory nature of this study, the sample size is not based on a formal calculation.p-value: 0.0018ANOVA