A Phase 4 interventional study of Commercial Hylenex® recombinant (hyaluronidase human injection) and Precommercial Hylenex recombinant (hyaluronidase human injection) in Type 1 Diabetes Mellitus, sponsored by Halozyme Therapeutics. Completed at 39 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2018-11-07.
Sponsored by Halozyme Therapeutics · Phase 4, Interventional, and Treatment
The primary objectives of this study are to compare the difference in glycosylated hemoglobin (HbA1c) from baseline to Month 6 using Hylenex recombinant preadministration in continuous subcutaneous insulin infusion (CSII) versus standard CSII and to evaluate the safety of Hylenex recombinant preadministration, including local tolerability, adverse events, and hypo- and hyperglycemia rates.
This Phase 4 study is designed to demonstrate noninferiority of pretreatment with Hylenex recombinant in the CSII setting to rapid-acting analog insulin alone with respect to glycemic control as assessed by changes in HbA1c in participants with Type 1 diabetes mellitus.
Total duration of study treatment is 24 months. However, according to the study design, the primary outcome measure is to be assessed at 6 months and an interim analysis is to be completed at 6 months for the secondary outcome measures and adverse events. Therefore, data reported in this clinical trials record is for the 6-month interim analysis.
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Exclusion Criteria:
Hylenex Formulation 1: For 6 months, participants received their regular treatment of rapid-acting continuous subcutaneous insulin infusion (CSII) (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 6-month treatment period, the participants received a pretreatment dose of the commercial form of Hylenex recombinant, delivered at 150 units (U) through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).
Drug: Commercial Hylenex® recombinant (hyaluronidase human injection) · Drug: Insulin lispro · Drug: Insulin aspart · Drug: Insulin glulisine
Hylenex Formulation 2: For 6 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 6-month treatment period, the participants received a pretreatment dose of the precommercial form of Hylenex recombinant, delivered at 150 units (U) through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).
Drug: Precommercial Hylenex recombinant (hyaluronidase human injection) · Drug: Insulin lispro · Drug: Insulin aspart · Drug: Insulin glulisine
Participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 6 months.
Drug: Insulin lispro · Drug: Insulin aspart · Drug: Insulin glulisine
Also known as: Formulation 1, Hylenex, Recombinant human hyaluronidase (rHuPH20)
Also known as: Formulation 2, Hylenex, rHuPH20
Also known as: Humalog, Lispro
Also known as: Novolog, Aspart
Also known as: Apidra, Glulisine
Change From Baseline to 6 Months in Glycosylated Hemoglobin (HbA1c)
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; 6 Months
Change From Baseline to 12 Months in HbA1c
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time frame: Baseline; 12 Months
Rates of Hypoglycemia Events (HE) to Month 6
Overall rates of hypoglycemia (defined as blood glucose ≤70 milligrams per deciliter \[mg/dL\] and \<56 mg/dL) were based on measurements after 1 month up to 6 months. A severe HE was classified as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. A nocturnal HE was classified as an event with a blood glucose of ≤70 mg/dL with start time between 2300 and 0600, inclusive. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
Time frame: After Month 1 up to Month 6
Rates of HEs to Month 12
Overall rates of hypoglycemia (defined as blood glucose ≤70 milligrams per deciliter \[mg/dL\] and \<56 mg/dL) were based on measurements after 1 month up to 12 months. A severe HE was classified as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. A nocturnal HE was classified as an event with a blood glucose of ≤70 mg/dL with start time between 2300 and 0600, inclusive. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
Time frame: After Month 1 up to Month 12
Rates of Hyperglycemia Events to Month 6
Overall rates of hyperglycemia (defined as blood glucose \>240 mg/dL and \>300 mg/dL) were based on measurements after 1 month up to 6 months. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
Time frame: After Month 1 up to Month 6
Rates of Hyperglycemia Events to Month 12
Overall rates of hyperglycemia (defined as blood glucose \>240 mg/dL and \>300 mg/dL) were based on measurements after 1 month up to 12 months. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
Time frame: After Month 1 up to Month 12
Mean Glucose Excursions at 6 Months
A 4-hour postprandial glucose excursion was measured for 3 meals after 1 month up to 6 months. For each of the 3 meals, the mealtime (breakfast, lunch, and dinner) excursions were calculated as the post-meal glucose value minus the pre-meal (for measurements taken within 15 minutes before a meal). The average of all excursions is presented. Least Squares (LS) means were calculated from ANOVA with treatment (Hylenex, standard rapid-acting insulin CSII) as a fixed effect. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
Time frame: After Month 1 up to Month 6
Mean Glucose Excursions at 12 Months
A 4-hour postprandial glucose excursion was measured for 3 meals after 1 month up to 12 months. For each of the 3 meals, the mealtime (breakfast, lunch, and dinner) excursions were calculated as the post-meal glucose value minus the pre-meal (for measurements taken within 15 minutes before a meal). The average of all excursions is presented. LS means were calculated from ANOVA with treatment (Hylenex, standard rapid-acting insulin CSII) as a fixed effect. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
Time frame: After Month 1 up to Month 12
Standard Deviation of Self-Monitoring Blood Glucose Values at 6 Months
Standard deviation of self-monitoring blood glucose values was calculated based on measurements taken within 15 minutes before a meal, 1 month and up to 6 months after study drug administration. LS means were calculated from ANOVA with treatment (Hylenex, standard rapid-acting insulin CSII) as a fixed effect. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
Time frame: After Month 1 up to Month 6
Standard Deviation of Self-Monitoring Blood Glucose Values at 12 Months
Standard deviation of self-monitoring blood glucose values was calculated based on measurements taken within 15 minutes before a meal, 1 month and up to 12 months after study drug administration. LS means were calculated from ANOVA with treatment (Hylenex, standard rapid-acting insulin CSII) as a fixed effect. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
Time frame: After Month 1 up to Month 12
Number of Participants Achieving HbA1c <7.0% and HbA1c ≤6.5% at Month 12
The number of participants achieving HbA1c goals of \<7% and ≤6.5% was calculated.
Time frame: Month 12
Change From Baseline in Body Weight to Month 12
Baseline is defined as the last measurement prior to randomization.
Time frame: Baseline; Week 2; Months 1, 2, 3, 4, 6, 9, and 12
Average of Daily Insulin Doses (Bolus, Basal, and Total)
The daily bolus insulin dose is calculated as the daily prandial (occurring before a meal) insulin dose plus the daily corrective insulin dose. Cumulative basal dosage is to generally be within 40% to 60% of the total daily dose.
Time frame: from Randomization up to Month 12
Average Carbohydrate Factor (CarbF) Values
CarbF is calculated as 2.6 \* weight (pounds) / total daily dose of insulin (grams per unit).
Time frame: Month 1 to Month 12
Average Correction Factor (CorrF) Values
CorrF is calculated as 1960 / total daily dose of insulin (milligrams/\[deciliter\*unit\]).
Time frame: Month 1 to Month 12
Average of Bolus Times Relative to Meal Times
The average meal bolus timing relative to meal time is defined as the minutes between the start time of a meal bolus and the start time of a meal.
Time frame: Month 1 to Month 12
Average Glucose, Median Glucose, and Average Daily Standard Deviation
For each participant, the following continuous glucose monitoring (CGM) parameters were calculated using CGM values recorded after Randomization up to Month 12: average glucose, median glucose, and average daily standard deviation.
Time frame: Randomization to Month 12
Time Per Day <56 Milligrams Per Deciliter (mg/dL), ≤70 mg/dL, >70 mg/dL, <140 mg/dL, ≥140 mg/dL, Outside of 71 to 180 mg/dL, and Outside of 71 to 139 mg/dL
For each participant, the following CGM parameters were calculated using CGM values recorded after Randomization up to Month 12: time per day spent in the pre-defined glucose classes.
Time frame: Randomization to Month 12
Area Per Day <56 mg/dL, ≤70 mg/dL, ≥140 mg/dL, Outside of 71 to 180 mg/dL, and Outside of 71 to 139 mg/dL
For each participant, the following continuous glucose monitoring (CGM) parameters were calculated using CGM values recorded after Randomization up to Month 12: area per day spent in the pre-defined glucose classes. The area per day for a specific glucose concentration range (e.g., \<56 mg/dL) is the sum of the area under the curve with glucose concentration falling in the specific glucose concentration range (e.g., \<56 mg/dL). For example, if the glucose stays constant at 50 mg/dL for the whole day (1,440 minutes), the area per day for glucose \< 56 mg/dL equals: 50\*1440 = 72,000 mg\*minutes/dL.
Time frame: Randomization to Month 12
Change From Baseline in Weighted Impact ADDQoL Values at Month 12
The Audit of Diabetes Dependent Quality of Life (ADDQoL) is a validated, diabetes-specific questionnaire to evaluate the participant's assessment of quality of life (QoL). Participants rated the impact of diabetes on 19 applicable domains on a scale from -3 (maximum negative impact) to +3 (maximum positive impact) and then rated the importance of those domains for their QoL on a scale from 3 (very important) to 0 (not at all important). Impact ratings were multiplied by the corresponding importance ratings to provide a weighted-impact score for each domain from -9 (maximum negative impact) to +9 (maximum positive impact).
Time frame: Baseline; Month 12
Change From Baseline in Average Weighted Impact ADDQoL Values at Month 12
The ADDQoL is a validated, diabetes-specific questionnaire to evaluate the participant's assessment of QoL. Participants rated the impact of diabetes on 19 applicable domains on a scale from -3 (maximum negative impact) to +3 (maximum positive impact) and then rated the importance of those domains for their QoL on a scale from 3 (very important) to 0 (not at all important). Impact ratings were multiplied by the corresponding importance ratings to provide a weighted-impact score for each domain from -9 (maximum negative impact) to +9 (maximum positive impact). Weighted impact scores were summed and divided by the number of applicable domains to give an overall Average Weighted Impact (AWI) score (higher values represent more positive impact). If there were less than 13 non-missing weighted-impact values, AWI was not to be calculated. Baseline is defined as the last measurement prior to randomization.
Time frame: Baseline; Month 12
Change From Baseline in DTSQs and DTSQc at Month 12
The Diabetes Treatment Satisfaction Questionnaire-status version (DTSQs) and DTSQ-change version (DTSQc) are validated tools to assess treatment satisfaction and change in treatment satisfaction after therapy changes have occurred. The scale total was computed by adding the 6 items (1, 4, 5, 6, 7, and 8) to produce the Treatment Satisfaction scale total, which has a minimum of 0 and a maximum of 36 on the DTSQs and a minimum of -18 and a maximum of 18 on the DTSQc. Higher scores represent greater satisfaction. If any of the 6 item scores were missing and the numbers of missing scores were less than the number of non-missing scores, the Treatment Satisfaction scale score was to be computed by taking the average of the existing scores and multiplying the average by 6. If there were less than 4 non-missing item scores, the Treatment Satisfaction scale score was not to be calculated. Baseline is defined as the last measurement prior to randomization.
Time frame: Baseline; Month 12
Mean Time to Change Infusion Site
Participants were asked device handling questions to provide information about the impact of the Hylenex administration procedure on everyday life and to investigate perceptions of the overall efficacy and responsiveness of their insulin program.
Time frame: Month 12
Mean Additional Time for Hylenex Pre-administration
Participants were asked device handling questions to provide information about the impact of the Hylenex administration procedure on everyday life and to investigate perceptions of the overall efficacy and responsiveness of their insulin program.
Time frame: Month 12
Number of Participants With the Indicated Responses to the Question Regarding the Difficulty of Infusion Site Change
Participants were asked device handling questions to provide information about the impact of the Hylenex administration procedure on everyday life and to investigate perceptions of the overall efficacy and responsiveness of their insulin program.
Time frame: Month 12
Number of Participants With the Indicated Responses to the Device Handling Questions
Participants were asked device handling questions to provide information about the impact of the Hylenex administration procedure on everyday life and to investigate perceptions of the overall efficacy and responsiveness of their insulin program. Question 1: Achieve excellent post meal glucose control; Question 2: Insulin responds quickly when basal rate is changed; Question 3: Insulin responds quickly when correction bolus is given.
Time frame: Month 12
Mean Times Per Week Participants Said They Were Eating to Avoid Going Low Due to Late Insulin Action
Participants were asked device handling questions to provide information about the impact of the Hylenex administration procedure on everyday life and to investigate perceptions of the overall efficacy and responsiveness of their insulin program.
Time frame: Month 12
| Milestone | Commercial Hylenex Recombinant (Formulation 1) | Precommercial Hylenex Recombinant (Formulation 2) | Standard Rapid-Acting Insulin CSII |
|---|---|---|---|
| Started | 227 | 115 | 114 |
| Received at least 1 dose of study drug | 227 | 115 | 113 |
| Completed month 6 | 194 | 106 | 103 |
| Completed | 181 | 95 | 98 |
| Not completed | 46 | 20 | 16 |
| Withdrew: Adverse event | 6 | 2 | 0 |
| Withdrew: Lost to follow-up | 6 | 2 | 2 |
| Withdrew: Protocol violation | 1 | 1 | 0 |
| Withdrew: Withdrawal by subject | 29 | 10 | 11 |
| Withdrew: Physician decision | 1 | 1 | 0 |
| Withdrew: Non compliance | 1 | 0 | 0 |
| Withdrew: Death | 1 | 0 | 1 |
| Withdrew: Other | 1 | 4 | 2 |
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
| percentage of HbA1c | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Change From Baseline to 6 Months in Glycosylated Hemoglobin (HbA1c) | -0.14 ± 0.521 | -0.18 ± 0.687 |
Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
| percentage of HbA1c | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Change From Baseline to 12 Months in HbA1c | -0.13 ± 0.590 | -0.26 ± 0.718 |
Overall rates of hypoglycemia (defined as blood glucose ≤70 milligrams per deciliter \[mg/dL\] and \<56 mg/dL) were based on measurements after 1 month up to 6 months. A severe HE was classified as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. A nocturnal HE was classified as an event with a blood glucose of ≤70 mg/dL with start time between 2300 and 0600, inclusive. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
| events per participant per month | Hylenex Recombinant | Standard Rapid-acting Insulin CSII |
|---|---|---|
| <56 mg/dL | 2.9103 | 4.1970 |
| ≤70 mg/dL | 11.6219 | 14.7112 |
| Nocturnal HEs | 1.6224 | 2.0727 |
| Severe HEs | 0.0055 | 0.0160 |
Overall rates of hypoglycemia (defined as blood glucose ≤70 milligrams per deciliter \[mg/dL\] and \<56 mg/dL) were based on measurements after 1 month up to 12 months. A severe HE was classified as an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. A nocturnal HE was classified as an event with a blood glucose of ≤70 mg/dL with start time between 2300 and 0600, inclusive. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
| events per participant per month | Hylenex Recombinant | Standard Rapid-acting Insulin CSII |
|---|---|---|
| <56 mg/dL | 2.6792 | 3.3022 |
| ≤70 mg/dL | 11.3803 | 12.3591 |
| Nocturnal HEs | 1.6754 | 1.9203 |
| Severe HEs | 0.0091 | 0.0085 |
Overall rates of hyperglycemia (defined as blood glucose \>240 mg/dL and \>300 mg/dL) were based on measurements after 1 month up to 6 months. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
| events per participant per month | Hylenex Recombinant | Standard Rapid-acting Insulin CSII |
|---|---|---|
| >240 mg/dL | 18.0422 | 18.4696 |
| >300 mg/dL | 6.4768 | 6.8155 |
Overall rates of hyperglycemia (defined as blood glucose \>240 mg/dL and \>300 mg/dL) were based on measurements after 1 month up to 12 months. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
| events per participant per month | Hylenex Recombinant | Standard Rapid-acting Insulin CSII |
|---|---|---|
| >240 mg/dL | 18.9784 | 18.2785 |
| >300 mg/dL | 7.1138 | 6.8900 |
A 4-hour postprandial glucose excursion was measured for 3 meals after 1 month up to 6 months. For each of the 3 meals, the mealtime (breakfast, lunch, and dinner) excursions were calculated as the post-meal glucose value minus the pre-meal (for measurements taken within 15 minutes before a meal). The average of all excursions is presented. Least Squares (LS) means were calculated from ANOVA with treatment (Hylenex, standard rapid-acting insulin CSII) as a fixed effect. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
| milligrams per deciliter (mg/dL) | Hylenex Recombinant | Standard Rapid-acting Insulin CSII |
|---|---|---|
| Breakfast | 17.3 ± 2.77 | 20.7 ± 4.76 |
| Lunch | 22.2 ± 2.67 | 17.9 ± 4.58 |
| Dinner | 12.6 ± 2.45 | 12.5 ± 4.18 |
| Overall | 17.1 ± 1.70 | 16.9 ± 2.91 |
A 4-hour postprandial glucose excursion was measured for 3 meals after 1 month up to 12 months. For each of the 3 meals, the mealtime (breakfast, lunch, and dinner) excursions were calculated as the post-meal glucose value minus the pre-meal (for measurements taken within 15 minutes before a meal). The average of all excursions is presented. LS means were calculated from ANOVA with treatment (Hylenex, standard rapid-acting insulin CSII) as a fixed effect. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
| milligrams per deciliter (mg/dL) | Hylenex Recombinant | Standard Rapid-acting Insulin CSII |
|---|---|---|
| Breakfast | 20.1 ± 2.36 | 24.9 ± 4.21 |
| Lunch | 22.4 ± 2.17 | 21.0 ± 3.89 |
| Dinner | 12.7 ± 2.08 | 13.8 ± 3.69 |
| Overall | 17.1 ± 1.49 | 19.7 ± 2.65 |
Standard deviation of self-monitoring blood glucose values was calculated based on measurements taken within 15 minutes before a meal, 1 month and up to 6 months after study drug administration. LS means were calculated from ANOVA with treatment (Hylenex, standard rapid-acting insulin CSII) as a fixed effect. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
| mg/dL | Hylenex Recombinant | Standard Rapid-acting Insulin CSII |
|---|---|---|
| Standard Deviation of Self-Monitoring Blood Glucose Values at 6 Months | 70.9 ± 1.09 | 72.2 ± 1.86 |
Standard deviation of self-monitoring blood glucose values was calculated based on measurements taken within 15 minutes before a meal, 1 month and up to 12 months after study drug administration. LS means were calculated from ANOVA with treatment (Hylenex, standard rapid-acting insulin CSII) as a fixed effect. Comparisons were made by pooling all of the rHuPH20 pretreatment participants (including both Formulations 1 and 2) and comparing against the standard CSII treatment arm. Formulation 1 versus Formulation 2 was compared as a supportive analysis.
| mg/dL | Hylenex Recombinant | Standard Rapid-acting Insulin CSII |
|---|---|---|
| Standard Deviation of Self-Monitoring Blood Glucose Values at 12 Months | 72.9 ± 1.04 | 72.4 ± 1.85 |
The number of participants achieving HbA1c goals of \<7% and ≤6.5% was calculated.
| Participants | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| HbA1c <7.0% | 61 | 21 |
| HbA1c ≤6.5% | 18 | 6 |
Baseline is defined as the last measurement prior to randomization.
| kilograms | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Week 2 | -0.10 ± 1.272 | 0.19 ± 1.257 |
| Month 1 | -0.11 ± 1.583 | 0.20 ± 1.696 |
| Month 2 | -0.03 ± 2.002 | 0.48 ± 1.672 |
| Month 3 | 0.16 ± 2.562 | 0.37 ± 1.858 |
| Month 4 | 0.04 ± 2.680 | 0.37 ± 2.230 |
| Month 6 | 0.60 ± 3.035 | 0.83 ± 2.287 |
| Month 9 | 0.91 ± 3.355 | 0.92 ± 3.033 |
| Month 12 | 0.61 ± 3.796 | 0.48 ± 4.078 |
The daily bolus insulin dose is calculated as the daily prandial (occurring before a meal) insulin dose plus the daily corrective insulin dose. Cumulative basal dosage is to generally be within 40% to 60% of the total daily dose.
| International units | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Daily bolus dose | 21.9 ± 0.78 | 22.9 ± 1.33 |
| Daily basal dose | 28.0 ± 0.73 | 25.7 ± 1.26 |
| Daily total dose | 49.9 ± 1.32 | 48.5 ± 2.27 |
CarbF is calculated as 2.6 \* weight (pounds) / total daily dose of insulin (grams per unit).
| grams per unit | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Average Carbohydrate Factor (CarbF) Values | 11.1 ± 0.26 | 11.0 ± 0.46 |
CorrF is calculated as 1960 / total daily dose of insulin (milligrams/\[deciliter\*unit\]).
| milligrams/(deciliter*unit) | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Average Correction Factor (CorrF) Values | 43.2 ± 1.06 | 45.3 ± 1.83 |
The average meal bolus timing relative to meal time is defined as the minutes between the start time of a meal bolus and the start time of a meal.
| minutes | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Breakfast | -2.3 ± 8.17 | -3.9 ± 7.83 |
| Lunch | -1.8 ± 6.75 | -1.6 ± 8.61 |
| Dinner | -1.7 ± 7.48 | -1.7 ± 9.19 |
| Overall | -1.9 ± 6.51 | -2.4 ± 7.86 |
For each participant, the following continuous glucose monitoring (CGM) parameters were calculated using CGM values recorded after Randomization up to Month 12: average glucose, median glucose, and average daily standard deviation.
| milliliters per deciliter | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Average glucose | 152.9 ± 1.79 | 151.9 ± 2.93 |
| Median glucose | 145.2 ± 1.80 | 143.4 ± 2.94 |
| Average daily standard deviation | 48.9 ± 0.85 | 49.7 ± 1.39 |
For each participant, the following CGM parameters were calculated using CGM values recorded after Randomization up to Month 12: time per day spent in the pre-defined glucose classes.
| minutes | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Time per day <56 mg/dL | 18.1 ± 2.40 | 20.3 ± 3.91 |
| Time per day ≤70 mg/dL | 63.0 ± 5.37 | 68.5 ± 8.77 |
| Time per day >70 mg/dL | 1358.8 ± 5.62 | 1351.9 ± 9.18 |
| Time per day <140 mg/dL | 660.3 ± 16.99 | 683.7 ± 27.74 |
| Time per day ≥140 mg/dL | 756.4 ± 17.02 | 732.5 ± 27.80 |
| Time per day outside of 71 to 180 mg/dL | 464.4 ± 15.02 | 461.7 ± 24.54 |
| Time per day outside of 71 to139 mg/dL | 819.4 ± 14.74 | 801.0 ± 24.07 |
For each participant, the following continuous glucose monitoring (CGM) parameters were calculated using CGM values recorded after Randomization up to Month 12: area per day spent in the pre-defined glucose classes. The area per day for a specific glucose concentration range (e.g., \<56 mg/dL) is the sum of the area under the curve with glucose concentration falling in the specific glucose concentration range (e.g., \<56 mg/dL). For example, if the glucose stays constant at 50 mg/dL for the whole day (1,440 minutes), the area per day for glucose \< 56 mg/dL equals: 50\*1440 = 72,000 mg\*minutes/dL.
| mg*minutes/deciliter | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Area per day <56 mg/dL | 129.7 ± 21.71 | 163.2 ± 35.45 |
| Area per day ≤70 mg/dL | 687.0 ± 77.58 | 771.7 ± 126.69 |
| Area per day ≥140 mg/dL | 42660.2 ± 1874.62 | 42317.2 ± 3061.24 |
| Area per day outside of 71 to 180 mg/dL | 20033.8 ± 1232.60 | 20411.2 ± 2012.83 |
| Area per day outside of 71 to 139 mg/dL | 43347.2 ± 1857.54 | 43089.0 ± 3033.35 |
The Audit of Diabetes Dependent Quality of Life (ADDQoL) is a validated, diabetes-specific questionnaire to evaluate the participant's assessment of quality of life (QoL). Participants rated the impact of diabetes on 19 applicable domains on a scale from -3 (maximum negative impact) to +3 (maximum positive impact) and then rated the importance of those domains for their QoL on a scale from 3 (very important) to 0 (not at all important). Impact ratings were multiplied by the corresponding importance ratings to provide a weighted-impact score for each domain from -9 (maximum negative impact) to +9 (maximum positive impact).
| score on a scale | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Leisure activities | -0.2 ± 0.14 | 0.0 ± 0.24 |
| Work life | -0.1 ± 0.15 | 0.0 ± 0.27 |
| Local or long distance travel | -0.4 ± 0.15 | -0.2 ± 0.25 |
| Vacations | 0.0 ± 0.15 | 0.2 ± 0.25 |
| Do physically | -0.1 ± 0.14 | -0.2 ± 0.23 |
| Family life | 0.2 ± 0.14 | 0.1 ± 0.23 |
| Friendships and social life | 0.3 ± 0.13 | 0.1 ± 0.22 |
| Close personal relationship | 0.1 ± 0.16 | 0.1 ± 0.27 |
| Sex life | 0.0 ± 0.14 | -0.3 ± 0.24 |
| Physical appearance | 0.1 ± 0.11 | -0.2 ± 0.19 |
| Self-confidence | 0.0 ± 0.12 | -0.1 ± 0.21 |
| Motivation | 0.0 ± 0.14 | 0.3 ± 0.24 |
| The way people in general react | 0.2 ± 0.10 | -0.1 ± 0.17 |
| Feelings about the future | -0.1 ± 0.16 | 0.3 ± 0.26 |
| Financial situation | 0.1 ± 0.14 | 0.0 ± 0.23 |
| Living situation and conditions | 0.0 ± 0.13 | -0.1 ± 0.22 |
| Depend on others | -0.1 ± 0.17 | 0.4 ± 0.28 |
| Freedom to eat | 0.0 ± 0.15 | -0.3 ± 0.25 |
| Freedom to drink | -0.2 ± 0.14 | -0.3 ± 0.23 |
The ADDQoL is a validated, diabetes-specific questionnaire to evaluate the participant's assessment of QoL. Participants rated the impact of diabetes on 19 applicable domains on a scale from -3 (maximum negative impact) to +3 (maximum positive impact) and then rated the importance of those domains for their QoL on a scale from 3 (very important) to 0 (not at all important). Impact ratings were multiplied by the corresponding importance ratings to provide a weighted-impact score for each domain from -9 (maximum negative impact) to +9 (maximum positive impact). Weighted impact scores were summed and divided by the number of applicable domains to give an overall Average Weighted Impact (AWI) score (higher values represent more positive impact). If there were less than 13 non-missing weighted-impact values, AWI was not to be calculated. Baseline is defined as the last measurement prior to randomization.
| score on a scale | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Change From Baseline in Average Weighted Impact ADDQoL Values at Month 12 | 0.0 ± 0.07 | 0.0 ± 0.12 |
The Diabetes Treatment Satisfaction Questionnaire-status version (DTSQs) and DTSQ-change version (DTSQc) are validated tools to assess treatment satisfaction and change in treatment satisfaction after therapy changes have occurred. The scale total was computed by adding the 6 items (1, 4, 5, 6, 7, and 8) to produce the Treatment Satisfaction scale total, which has a minimum of 0 and a maximum of 36 on the DTSQs and a minimum of -18 and a maximum of 18 on the DTSQc. Higher scores represent greater satisfaction. If any of the 6 item scores were missing and the numbers of missing scores were less than the number of non-missing scores, the Treatment Satisfaction scale score was to be computed by taking the average of the existing scores and multiplying the average by 6. If there were less than 4 non-missing item scores, the Treatment Satisfaction scale score was not to be calculated. Baseline is defined as the last measurement prior to randomization.
| score on a scale | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| DTSQs | 0.0 ± 0.32 | 0.0 ± 0.53 |
| DTSQc | 9.4 ± 0.40 | 9.4 ± 0.68 |
Participants were asked device handling questions to provide information about the impact of the Hylenex administration procedure on everyday life and to investigate perceptions of the overall efficacy and responsiveness of their insulin program.
| minutes | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Mean Time to Change Infusion Site | 5.7 ± 4.45 | 4.7 ± 3.68 |
Participants were asked device handling questions to provide information about the impact of the Hylenex administration procedure on everyday life and to investigate perceptions of the overall efficacy and responsiveness of their insulin program.
| minutes | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Mean Additional Time for Hylenex Pre-administration | 2.9 ± 3.96 | 3.8 ± 2.84 |
Participants were asked device handling questions to provide information about the impact of the Hylenex administration procedure on everyday life and to investigate perceptions of the overall efficacy and responsiveness of their insulin program.
| Participants | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Very easy | 143 | 49 |
| Easy | 130 | 46 |
| Difficult | 3 | 1 |
| Very difficult | 0 | 1 |
Participants were asked device handling questions to provide information about the impact of the Hylenex administration procedure on everyday life and to investigate perceptions of the overall efficacy and responsiveness of their insulin program. Question 1: Achieve excellent post meal glucose control; Question 2: Insulin responds quickly when basal rate is changed; Question 3: Insulin responds quickly when correction bolus is given.
| Participants | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Question 1 — Completely agree | 5 | 0 |
| Question 1 — Agree | 110 | 28 |
| Question 1 — Neither agree or disagree | 97 | 44 |
| Question 1 — Disagree | 59 | 22 |
| Question 1 — Completely disagree | 5 | 3 |
| Question 2 — Completely agree | 31 | 8 |
| Question 2 — Agree | 146 | 48 |
| Question 2 — Neither agree or disagree | 71 | 28 |
| Question 2 — Disagree | 25 | 12 |
| Question 2 — Completely disagree | 3 | 1 |
| Question 3 — Completely agree | 36 | 14 |
| Question 3 — Agree | 165 | 39 |
| Question 3 — Neither agree or disagree | 34 | 22 |
| Question 3 — Disagree | 38 | 20 |
| Question 3 — Completely disagree | 3 | 2 |
Participants were asked device handling questions to provide information about the impact of the Hylenex administration procedure on everyday life and to investigate perceptions of the overall efficacy and responsiveness of their insulin program.
| occurrences per week | Hylenex Recombinant | Standard Rapid-Acting Insulin CSII |
|---|---|---|
| Mean Times Per Week Participants Said They Were Eating to Avoid Going Low Due to Late Insulin Action | 2.1 ± 2.19 | 2.5 ± 2.37 |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Commercial Hylenex Recombinant (Formulation 1) | — | 11/227 (4.8%) | 174/227 (76.7%) |
| Precommercial Hylenex Recombinant (Formulation 2) | — | 10/115 (8.7%) | 84/115 (73%) |
| Standard Rapid-Acting Insulin CSII | — | 13/113 (11.5%) | 76/113 (67.3%) |
| Event | Commercial Hylenex Recombinant (Formulation 1) | Precommercial Hylenex Recombinant (Formulation 2) | Standard Rapid-Acting Insulin CSII |
|---|---|---|---|
| Coronary artery diseaseCardiac disorders | 0/227 | 0/115 | 3/113 |
| HypoglycaemiaMetabolism and nutrition disorders | 3/227 | 1/115 | 2/113 |
| Diabetic ketoacidosisMetabolism and nutrition disorders | 1/227 | 2/115 | 1/113 |
| Non-cardiac chest painGeneral disorders | 0/227 | 2/115 | 0/113 |
| MenometrorrhagiaReproductive system and breast disorders | 0/122 | 0/53 | 1/64 |
| Angina pectorisCardiac disorders | 0/227 | 0/115 | 1/113 |
| Vertigo positionalEar and labyrinth disorders | 0/227 | 0/115 | 1/113 |
| Retinal detachmentEye disorders | 0/227 | 0/115 | 1/113 |
| AppendicitisInfections and infestations | 0/227 | 1/115 | 1/113 |
| HyponatraemiaMetabolism and nutrition disorders | 0/227 | 0/115 | 1/113 |
| Event | Commercial Hylenex Recombinant (Formulation 1) | Precommercial Hylenex Recombinant (Formulation 2) | Standard Rapid-Acting Insulin CSII |
|---|---|---|---|
| Infusion site painGeneral disorders | 40/227 | 17/115 | 7/113 |
| Upper respiratory tract infectionInfections and infestations | 31/227 | 15/115 | 13/113 |
| NasopharyngitisInfections and infestations | 26/227 | 9/115 | 4/113 |
| SinusitisInfections and infestations | 12/227 | 7/115 | 8/113 |
| Infusion site erythemaGeneral disorders | 12/227 | 4/115 | 1/113 |
| NauseaGastrointestinal disorders | 9/227 | 6/115 | 2/113 |
| Urinary tract infectionInfections and infestations | 10/227 | 3/115 | 3/113 |
| DepressionPsychiatric disorders | 10/227 | 2/115 | 1/113 |
| BronchitisInfections and infestations | 5/227 | 5/115 | 3/113 |
| Gastroenteritis viralInfections and infestations | 2/227 | 5/115 | 0/113 |
All participants who received at least one dose of study drug.
| Age, Continuous(years) | Commercial Hylenex Recombinant (Formulation 1) | Precommercial Hylenex Recombinant (Formulation 2) | Standard Rapid-Acting Insulin CSII | Total |
|---|---|---|---|---|
| Mean | 47.5 ± 12.90 | 45.9 ± 13.14 | 49.7 ± 14.73 | 47.6 ± 13.47 |
| Sex: Female, Male(Participants) | Commercial Hylenex Recombinant (Formulation 1) | Precommercial Hylenex Recombinant (Formulation 2) | Standard Rapid-Acting Insulin CSII | Total |
|---|---|---|---|---|
| Female | 122 | 53 | 64 | 239 |
| Male | 105 | 62 | 49 | 216 |
| Ethnicity (NIH/OMB)(Participants) | Commercial Hylenex Recombinant (Formulation 1) | Precommercial Hylenex Recombinant (Formulation 2) | Standard Rapid-Acting Insulin CSII | Total |
|---|---|---|---|---|
| Hispanic or Latino | 10 | 7 | 5 | 22 |
| Not Hispanic or Latino | 217 | 108 | 108 | 433 |
| Unknown or Not Reported | 0 | 0 | 0 | 0 |
| Race/Ethnicity, Customized(participants) | Commercial Hylenex Recombinant (Formulation 1) | Precommercial Hylenex Recombinant (Formulation 2) | Standard Rapid-Acting Insulin CSII | Total |
|---|---|---|---|---|
| American Indian or Alaska Native | 0 | 0 | 1 | 1 |
| Asian | 3 | 0 | 2 | 5 |
| Black or African American | 8 | 3 | 2 | 13 |
| White | 216 | 112 | 107 | 435 |
| Asian Indian | 0 | 0 | 1 | 1 |
| Region of Enrollment(participants) | Commercial Hylenex Recombinant (Formulation 1) | Precommercial Hylenex Recombinant (Formulation 2) | Standard Rapid-Acting Insulin CSII | Total |
|---|---|---|---|---|
| United States | 227 | 115 | 113 | 455 |
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Halozyme Therapeutics