CONSISTENT 1: Metabolic and Safety Outcomes of Hylenex Recombinant (Hyaluronidase Human Injection) Preadministered at CSII Infusion Site in Participants With Type 1 Diabetes Mellitus (T1DM)

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.

• Commercial Hylenex® recombinant (hyaluronidase human injection) (Drug), also known as Formulation 1, Hylenex, Recombinant human hyaluronidase (rHuPH20)
• Precommercial Hylenex recombinant (hyaluronidase human injection) (Drug), also known as Formulation 2, Hylenex, rHuPH20
• Insulin lispro (Drug), also known as Humalog, Lispro
• Insulin aspart (Drug), also known as Novolog, Aspart
• Insulin glulisine (Drug), also known as Apidra, Glulisine

Primary outcomes

• Change From Baseline to 6 Months in Glycosylated Hemoglobin (HbA1c) [Baseline; 6 Months]: Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
• Change From Baseline to 12 Months in HbA1c [Baseline; 12 Months]: Change from Baseline was calculated as the post-Baseline value minus the Baseline value.

Secondary outcomes

• Rates of Hypoglycemia Events (HE) to Month 6 [After Month 1 up 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.
• Rates of HEs to Month 12 [After Month 1 up 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.
• Rates of Hyperglycemia Events to Month 6 [After Month 1 up 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.
• Rates of Hyperglycemia Events to Month 12 [After Month 1 up 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.
• Mean Glucose Excursions at 6 Months [After Month 1 up to Month 6]: 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.
• Mean Glucose Excursions at 12 Months [After Month 1 up to Month 12]: 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.
• Standard Deviation of Self-Monitoring Blood Glucose Values at 6 Months [After Month 1 up to Month 6]: 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.
• Standard Deviation of Self-Monitoring Blood Glucose Values at 12 Months [After Month 1 up to Month 12]: 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.
• Number of Participants Achieving HbA1c <7.0% and HbA1c ≤6.5% at Month 12 [Month 12]: The number of participants achieving HbA1c goals of <7% and ≤6.5% was calculated.
• Change From Baseline in Body Weight to Month 12 [Baseline; Week 2; Months 1, 2, 3, 4, 6, 9, and 12]: Baseline is defined as the last measurement prior to randomization.
• Average of Daily Insulin Doses (Bolus, Basal, and Total) [from Randomization up to Month 12]: 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.
• Average Carbohydrate Factor (CarbF) Values [Month 1 to Month 12]: CarbF is calculated as 2.6 * weight (pounds) / total daily dose of insulin (grams per unit).
• Average Correction Factor (CorrF) Values [Month 1 to Month 12]: CorrF is calculated as 1960 / total daily dose of insulin (milligrams/\[deciliter*unit\]).
• Average of Bolus Times Relative to Meal Times [Month 1 to Month 12]: 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.
• Average Glucose, Median Glucose, and Average Daily Standard Deviation [Randomization to Month 12]: 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 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 [Randomization to Month 12]: 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.
• 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 [Randomization to Month 12]: 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.
• Change From Baseline in Weighted Impact ADDQoL Values at Month 12 [Baseline; 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).
• Change From Baseline in Average Weighted Impact ADDQoL Values at Month 12 [Baseline; 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.
• Change From Baseline in DTSQs and DTSQc at Month 12 [Baseline; 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.
• Mean Time to Change Infusion Site [Month 12]: 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.
• Mean Additional Time for Hylenex Pre-administration [Month 12]: 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.
• Number of Participants With the Indicated Responses to the Question Regarding the Difficulty of Infusion Site Change [Month 12]: 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.
• Number of Participants With the Indicated Responses to the Device Handling Questions [Month 12]: 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.
• Mean Times Per Week Participants Said They Were Eating to Avoid Going Low Due to Late Insulin Action [Month 12]: 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.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Male or female of age 18 years or older with a history of T1DM for at least 12 months
2. Glycosylated hemoglobin (HbA1c) 6.5% to 9.5% (inclusive) based on central laboratory results
3. Fasting C-peptide <0.6 nanograms per milliliter (ng/mL)
4. Current use of an insulin pump compatible with available tubing for Hylenex recombinant infusion and use of an infusion set compatible with the tubing available or willingness to switch to an infusion set compatible with tubing available for infusion of Hylenex recombinant
5. Current treatment at the time of screening with insulin <300 units per day (U/day)
6. Participants who routinely use continuous glucose monitoring (CGM) (defined as average CGM use 5 or more days per week over the preceding 3 months) and those who do not routinely used CGM are both eligible for inclusion in the study. Intermittent use of CGM is also acceptable but will not be a criterion use for stratified randomization.
7. 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 this protocol.

Exclusion Criteria:

1. Type 2 diabetes
2. Known or suspected allergy to any component of any of the study drugs in this study
3. Severe proliferative retinopathy or maculopathy, and/or gastroparesis, and/or severe neuropathy, in particular autonomic neuropathy, of such severity as to impede the participant's ability to comply with protocol procedures, as judged by the Investigator
4. History of transmural myocardial infarction, congestive heart failure and uncontrolled hypertension (diastolic blood pressure \[BP\] consistently >100 millimeters of mercury \[mmHg\]) are exclusionary
5. As judged by the Investigator, clinically significant active disease of the gastrointestinal, cardiovascular (including history of stroke, history of arrhythmia, or conduction delays on electrocardiogram \[ECG\]), hepatic, neurological, renal, genitourinary, pulmonary, or hematological systems of such severity as to impede the participant's ability to comply with protocol procedures
6. History of any illness or disease that in the opinion of the Investigator might confound the results of the study 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 at screening
8. Use of drugs that may interfere with the interpretation of study results or are known to cause clinically relevant interference with hyaluronidase action, insulin action, glucose utilization, or recovery from hypoglycemia (including systemic pharmacologic corticosteroid). Use of pramlintide or a glucagon-like peptide \[GLP\]-1 receptor agonist is not exclusionary but participants using these agents will be subjected to stratified randomization. Use of aspirin (acetylsalicylic acid \[ASA\]) up to 325 milligrams (mg)/day is not exclusionary but should be noted for analysis.
9. Hypoglycemic unawareness of such severity as to impede the participant's ability to comply with protocol procedures, as judged by the Investigator.
10. Current addiction to alcohol or substance abuse as determined by the Investigator.
11. 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, and/or barrier methods). Abstinence alone is not considered an adequate contraceptive measure for the purposes of this study.
12. Mental incapacity, unwillingness, or language barriers precluding adequate understanding or cooperation in this study

Participant flow

Outcome results

• Change From Baseline to 6 Months in Glycosylated Hemoglobin (HbA1c) (Primary), Mean, percentage of HbA1c: Hylenex Recombinant -0.14 +/- 0.521; Standard Rapid-Acting Insulin CSII -0.18 +/- 0.687 (p 0.4516)
• Change From Baseline to 12 Months in HbA1c (Primary), Mean, percentage of HbA1c: Hylenex Recombinant -0.13 +/- 0.590; Standard Rapid-Acting Insulin CSII -0.26 +/- 0.718 (p 0.0711)
• Rates of Hypoglycemia Events (HE) to Month 6 (Secondary), Number, events per participant per month: Hylenex Recombinant 2.9103; Standard Rapid-acting Insulin CSII 4.1970 (p 0.0105)
• Rates of HEs to Month 12 (Secondary), Number, events per participant per month: Hylenex Recombinant 2.6792; Standard Rapid-acting Insulin CSII 3.3022 (p 0.0456)
• Rates of Hyperglycemia Events to Month 6 (Secondary), Number, events per participant per month: Hylenex Recombinant 18.0422; Standard Rapid-acting Insulin CSII 18.4696 (p 0.7292)
• Rates of Hyperglycemia Events to Month 12 (Secondary), Number, events per participant per month: Hylenex Recombinant 18.9784; Standard Rapid-acting Insulin CSII 18.2785 (p 0.5414)
• Mean Glucose Excursions at 6 Months (Secondary), Least squares mean, milligrams per deciliter (mg/dL): Hylenex Recombinant 17.3 +/- 2.77; Standard Rapid-acting Insulin CSII 20.7 +/- 4.76 (p 0.5394)
• Mean Glucose Excursions at 12 Months (Secondary), Least squares mean, milligrams per deciliter (mg/dL): Hylenex Recombinant 20.1 +/- 2.36; Standard Rapid-acting Insulin CSII 24.9 +/- 4.21 (p 0.3239)
• Standard Deviation of Self-Monitoring Blood Glucose Values at 6 Months (Secondary), Least squares mean, mg/dL: Hylenex Recombinant 70.9 +/- 1.09; Standard Rapid-acting Insulin CSII 72.2 +/- 1.86 (p 0.5260)
• Standard Deviation of Self-Monitoring Blood Glucose Values at 12 Months (Secondary), Least squares mean, mg/dL: Hylenex Recombinant 72.9 +/- 1.04; Standard Rapid-acting Insulin CSII 72.4 +/- 1.85 (p 0.8049)
• Number of Participants Achieving HbA1c <7.0% and HbA1c ≤6.5% at Month 12 (Secondary), Count of participants, Participants: Hylenex Recombinant 61; Standard Rapid-Acting Insulin CSII 21 (p 0.8955)
• Change From Baseline in Body Weight to Month 12 (Secondary), Mean, kilograms: Hylenex Recombinant -0.10 +/- 1.272; Standard Rapid-Acting Insulin CSII 0.19 +/- 1.257 (p 0.7735)
• Average of Daily Insulin Doses (Bolus, Basal, and Total) (Secondary), Least squares mean, International units: Hylenex Recombinant 21.9 +/- 0.78; Standard Rapid-Acting Insulin CSII 22.9 +/- 1.33 (p 0.4948)
• Average Carbohydrate Factor (CarbF) Values (Secondary), Least squares mean, grams per unit: Hylenex Recombinant 11.1 +/- 0.26; Standard Rapid-Acting Insulin CSII 11.0 +/- 0.46 (p 0.8778)
• Average Correction Factor (CorrF) Values (Secondary), Least squares mean, milligrams/(deciliter*unit): Hylenex Recombinant 43.2 +/- 1.06; Standard Rapid-Acting Insulin CSII 45.3 +/- 1.83 (p 0.3233)
• Average of Bolus Times Relative to Meal Times (Secondary), Mean, minutes: Hylenex Recombinant -2.3 +/- 8.17; Standard Rapid-Acting Insulin CSII -3.9 +/- 7.83
• Average Glucose, Median Glucose, and Average Daily Standard Deviation (Secondary), Least squares mean, milliliters per deciliter: Hylenex Recombinant 152.9 +/- 1.79; Standard Rapid-Acting Insulin CSII 151.9 +/- 2.93 (p 0.7708)
• 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 (Secondary), Least squares mean, minutes: Hylenex Recombinant 18.1 +/- 2.40; Standard Rapid-Acting Insulin CSII 20.3 +/- 3.91 (p 0.6252)
• 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 (Secondary), Least squares mean, mg*minutes/deciliter: Hylenex Recombinant 129.7 +/- 21.71; Standard Rapid-Acting Insulin CSII 163.2 +/- 35.45 (p 0.4216)
• Change From Baseline in Weighted Impact ADDQoL Values at Month 12 (Secondary), Least squares mean, score on a scale: Hylenex Recombinant -0.2 +/- 0.14; Standard Rapid-Acting Insulin CSII 0.0 +/- 0.24 (p 0.5246)
• 7 more outcome measures not shown.

Adverse events

Serious adverse events by term

Other adverse events by term

280 more terms not shown.

• Douglas Muchmore, MD, Study director, Halozyme Therapeutics