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)

• Sponsor: Halozyme Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01848990
• Collaborator: (none)
• Enrollment: 456
• Locations: 39
• Arms: 3
• Duration (Months): 18
• Patients Per Site: 11.7
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Type 1 Diabetes Mellitus	Drug: Commercial Hylenex® recombinant (hyaluronidase human injection); Drug: Precommercial Hylenex recombinant (hyaluronidase human injection); Drug: Insulin lispro; Drug: Insulin aspart; Drug: Insulin glulisine	Phase 4

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 456 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: CONtinuous Subcutaneous Insulin Infusion STudy ENrolling Type 1 (CONSISTENT 1): Evaluation of Metabolic Outcomes and Safety of Hylenex Recombinant (Hyaluronidase Human Injection) Used as a Preadministration Infusion Site Treatment in Subjects With Type 1 Diabetes (T1DM) Using Continuous Subcutaneous Insulin Infusion (CSII)
• Study Start Date: Mar 1, 2013
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Sep 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Commercial Hylenex Recombinant (Formulation 1) 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); Other Names: Formulation 1 Hylenex Recombinant human hyaluronidase (rHuPH20) ; Drug: Insulin lispro; Other Names: Humalog Lispro ; Drug: Insulin aspart; Other Names: Novolog Aspart ; Drug: Insulin glulisine; Other Names: Apidra Glulisine
Experimental: Precommercial Hylenex Recombinant (Formulation 2) 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); Other Names: Formulation 2 Hylenex rHuPH20 ; Drug: Insulin lispro; Other Names: Humalog Lispro ; Drug: Insulin aspart; Other Names: Novolog Aspart ; Drug: Insulin glulisine; Other Names: Apidra Glulisine
Active Comparator: Standard Rapid-Acting Insulin CSII Participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 6 months.	Drug: Insulin lispro; Other Names: Humalog Lispro ; Drug: Insulin aspart; Other Names: Novolog Aspart ; Drug: Insulin glulisine; Other Names: Apidra Glulisine

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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).

13. Average Correction Factor (CorrF) Values [Month 1 to Month 12]

    CorrF is calculated as 1960 / total daily dose of insulin (milligrams/[deciliter*unit]).

14. 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.

15. 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.

16. 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.

17. 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.

18. 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).

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Concord	California	United States	94520
2	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Encino	California	United States	91436
3	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Escondido	California	United States	92026
4	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Greenbrae	California	United States	94904
5	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	La Jolla	California	United States	92037
6	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	San Mateo	California	United States	94401
7	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Aurora	Colorado	United States	80045
8	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Hollywood	Florida	United States	33021
9	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Miami	Florida	United States	33136
10	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Miami	Florida	United States	33156
11	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Atlanta	Georgia	United States	30318
12	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Roswell	Georgia	United States	30076
13	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Idaho Falls	Idaho	United States	83404
14	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Des Moines	Iowa	United States	50314
15	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Wichita	Kansas	United States	67226
16	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Lexington	Kentucky	United States	40503
17	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Hyattsville	Maryland	United States	20782
18	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Rockville	Maryland	United States	20852
19	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Detroit	Michigan	United States	48202
20	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Minneapolis	Minnesota	United States	55416
21	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Butte	Montana	United States	59701
22	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Henderson	Nevada	United States	89052
23	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Las Vegas	Nevada	United States	89148
24	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	New Hyde Park	New York	United States	11042
25	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Asheville	North Carolina	United States	28803
26	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Durham	North Carolina	United States	27713
27	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Morehead City	North Carolina	United States	28557
28	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Cincinnati	Ohio	United States	45219
29	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Portland	Oregon	United States	97210
30	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Bartlett	Tennessee	United States	38133
31	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Chattanooga	Tennessee	United States	37411
32	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Austin	Texas	United States	78731
33	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Dallas	Texas	United States	75231
34	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Round Rock	Texas	United States	78681
35	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	San Antonio	Texas	United States	78258
36	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Olympia	Washington	United States	98502
37	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Renton	Washington	United States	98057
38	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Seattle	Washington	United States	98105
39	For additional information regarding investigative sites for this trial, call [phone] 8 AM to 5 PM Mon-Fri Pacific Standard Time	Madison	Wisconsin	United States	53717

Sponsors and Collaborators

• Halozyme Therapeutics

Investigators

• Study Director: Douglas Muchmore, MD, Halozyme Therapeutics

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Halozyme Therapeutics
• ClinicalTrials.gov Identifier: NCT01848990
• Other Study ID Numbers: Halo-117-403
• First Posted: May 8, 2013
• Last Update Posted: Nov 7, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by Halozyme Therapeutics: Type 1 Diabetes Mellitus; Sub Cutaneous Insulin Infusion; Rapid Acting Analog Insulin; Hylenex; Halozyme; Phase 4
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin; Insulin, Globin Zinc; Insulin Aspart; Insulin Lispro; Insulin glulisine

Study Results

Participant Flow

Arm/Group Title	Commercial Hylenex Recombinant (Formulation 1)	Precommercial Hylenex Recombinant (Formulation 2)	Standard Rapid-Acting Insulin CSII
Arm/Group Description	Hylenex Formulation 1: For 12 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 12-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).	Hylenex Formulation 2: For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of the precommercial form of Hylenex recombinant, delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Period Title: Overall Study
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

Baseline Characteristics

Arm/Group Title	Commercial Hylenex Recombinant (Formulation 1)	Precommercial Hylenex Recombinant (Formulation 2)	Standard Rapid-Acting Insulin CSII	Total
Arm/Group Description	Hylenex Formulation 1: For 12 months, participants received their regular treatment of rapid-acting continuous CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of the commercial form of Hylenex recombinant, delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Hylenex Formulation 2: For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of the precommercial form of Hylenex recombinant, delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.	Total of all reporting groups
Overall Participants	227	115	113	455
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.5 (12.90)	45.9 (13.14)	49.7 (14.73)	47.6 (13.47)
Sex: Female, Male (Count of Participants)
Female	122 53.7%	53 46.1%	64 56.6%	239 52.5%
Male	105 46.3%	62 53.9%	49 43.4%	216 47.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	10 4.4%	7 6.1%	5 4.4%	22 4.8%
Not Hispanic or Latino	217 95.6%	108 93.9%	108 95.6%	433 95.2%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
American Indian or Alaska Native	0 0%	0 0%	1 0.9%	1 0.2%
Asian	3 1.3%	0 0%	2 1.8%	5 1.1%
Black or African American	8 3.5%	3 2.6%	2 1.8%	13 2.9%
White	216 95.2%	112 97.4%	107 94.7%	435 95.6%
Asian Indian	0 0%	0 0%	1 0.9%	1 0.2%
Region of Enrollment (participants) [Number]
United States	227 100%	115 100%	113 100%	455 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to 6 Months in Glycosylated Hemoglobin (HbA1c)
Description	Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame	Baseline; 6 Months

Outcome Measure Data

Analysis Population Description

Participants who received at least one dose of study drug and had evaluable HbA1c data. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	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 Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 6 months.
Measure Participants	296	103
Mean (Standard Deviation) [percentage of HbA1c]	-0.14 (0.521)	-0.18 (0.687)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments	Sample size calculated based on approximately 400 participants (Pt) being enrolled. No more than 10% dropout rate at 6 months allowed at least 270 Hylenex and 90 standard CSII Pt to reach primary metabolic endpoint evaluation. Assuming HbA1c standard deviation of 0.7% and population difference of 0% between treatments, Pt reaching primary efficacy endpoint would provide >90% power to demonstrate HbA1c noninferiority at margin of 0.4% using confidence bound from 2-tailed 95% confidence interval.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	If the upper bound of the 95% CI for the treatment difference ≤0.40, it is concluded that Hylenex recombinant preadministration is noninferior to standard CSII.
Statistical Test of Hypothesis	p-Value	0.4516
	Comments
	Method	ANOVA
	Comments	Analysis of variance (ANOVA) with treatment (Hylenex, standard rapid-acting insulin CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

2. Primary Outcome

Title	Change From Baseline to 12 Months in HbA1c
Description	Change from Baseline was calculated as the post-Baseline value minus the Baseline value.
Time Frame	Baseline; 12 Months

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all randomized participants (par.). Comparisons were made by pooling all rHuPH20 pretreatment par. (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. Only par. with available data were analyzed.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	268	95
Mean (Standard Deviation) [percentage of HbA1c]	-0.13 (0.590)	-0.26 (0.718)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments	Sample size calculated based on approximately 400 Pt being enrolled. No more than 10% dropout rate at 6 months allowed at least 270 Hylenex and 90 standard CSII Pt to reach primary metabolic endpoint evaluation. Assuming HbA1c standard deviation of 0.7% and population difference of 0% between treatments, Pt reaching primary efficacy endpoint would provide >90% power to demonstrate HbA1c noninferiority at margin of 0.4% using confidence bound from 2-tailed 95% confidence interval.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	If the upper bound of the 95% CI for the treatment difference ≤0.40, it is concluded that Hylenex recombinant preadministration is noninferior to standard CSII.
Statistical Test of Hypothesis	p-Value	0.0711
	Comments
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, standard rapid-acting insulin CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.28
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

3. Secondary Outcome

Title	Rates of Hypoglycemia Events (HE) to Month 6
Description	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

Outcome Measure Data

Analysis Population Description

Primary Self-Monitoring of Blood Glucose (SMBG) Analysis Population: all randomized participants who received study treatment and had SMBG data up to Month 6. Only participants with available data were analyzed. The "Number Analyzed" reflects the number of participants with at least one event.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-acting Insulin CSII
Arm/Group Description	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 Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 6 months.
Measure Participants	184	63
<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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.0105
	Comments	SMBG <56 mg/dL
	Method	negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.69
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex/Standard CSII

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.0130
	Comments	SMBG <=70 mg/dL
	Method	negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.79
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex/Standard CSII

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.0511
	Comments	Nocturnal HEs
	Method	negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.78
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex/Standard CSII

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.1176
	Comments	Severe HEs
	Method	negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.34
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex/Standard CSII

4. Secondary Outcome

Title	Rates of HEs to Month 12
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. The "Number Analyzed" reflects the number of participants with at least one event.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	342	114
<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

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.0456
	Comments	SMBG <56 mg/dL
	Method	negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.81
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex/Standard CSII

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.2322
	Comments	SMBG <=70 mg/dL
	Method	negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.92
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex/Standard CSII

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.1365
	Comments	Nocturnal HEs
	Method	negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.87
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex/Standard CSII

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.8909
	Comments	Severe HEs
	Method	negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	1.07
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex/Standard CSII

5. Secondary Outcome

Title	Rates of Hyperglycemia Events to Month 6
Description	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

Outcome Measure Data

Analysis Population Description

Primary SMBG Analysis Population. Only participants with available data were analyzed. The "Number Analyzed" reflects the number of participants with at least one event.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-acting Insulin CSII
Arm/Group Description	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 Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 6 months.
Measure Participants	298	103
>240 mg/dL	18.0422	18.4696
>300 mg/dL	6.4768	6.8155

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.7292
	Comments	SMBG >240 mg/dL
	Method	negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.98
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex/Standard CSII

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.5895
	Comments	SMBG >300 mg/dL
	Method	negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	0.95
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex/Standard CSII

6. Secondary Outcome

Title	Rates of Hyperglycemia Events to Month 12
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. The "Number Analyzed" reflects the number of participants with at least one event.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	342	114
>240 mg/dL	18.9784	18.2785
>300 mg/dL	7.1138	6.8900

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.5414
	Comments	SMBG >240 mg/dL
	Method	negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	1.04
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex/Standard CSII

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.7110
	Comments	SMBG >300 mg/dL
	Method	negative binomial model
	Comments
Method of Estimation	Estimation Parameter	rate ratio
	Estimated Value	1.03
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex/Standard CSII

7. Secondary Outcome

Title	Mean Glucose Excursions at 6 Months
Description	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

Outcome Measure Data

Analysis Population Description

Primary SMBG Analysis Population. Only participants with available data were analyzed.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-acting Insulin CSII
Arm/Group Description	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 Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 6 months.
Measure Participants	184	63
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.5394
	Comments	Breakfast
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-3.4
	Confidence Interval	(2-Sided) 95%; -14.2 to 7.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.4151
	Comments	Lunch
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	4.3
	Confidence Interval	(2-Sided) 95%; -6.1 to 14.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.9930
	Comments	Dinner
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -9.5 to 9.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.9410
	Comments	Overall
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -6.4 to 6.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

8. Secondary Outcome

Title	Mean Glucose Excursions at 12 Months
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	200	63
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.3239
	Comments	Breakfast
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-4.8
	Confidence Interval	(2-Sided) 95%; -14.3 to 4.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.7540
	Comments	Lunch
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; -7.4 to 10.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.7904
	Comments	Dinner
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -9.5 to 7.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.4016
	Comments	Overall
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-2.6
	Confidence Interval	(2-Sided) 95%; -8.5 to 3.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

9. Secondary Outcome

Title	Standard Deviation of Self-Monitoring Blood Glucose Values at 6 Months
Description	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

Outcome Measure Data

Analysis Population Description

Primary SMBG Analysis Population. Only participants with available data were analyzed.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-acting Insulin CSII
Arm/Group Description	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 Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 6 months.
Measure Participants	184	63
Least Squares Mean (Standard Error) [mg/dL]	70.9 (1.09)	72.2 (1.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.5260
	Comments
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-1.4
	Confidence Interval	(2-Sided) 95%; -5.6 to 2.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

10. Secondary Outcome

Title	Standard Deviation of Self-Monitoring Blood Glucose Values at 12 Months
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	200	63
Least Squares Mean (Standard Error) [mg/dL]	72.9 (1.04)	72.4 (1.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.8049
	Comments
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.5
	Confidence Interval	(2-Sided) 95%; -3.7 to 4.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

11. Secondary Outcome

Title	Number of Participants Achieving HbA1c <7.0% and HbA1c ≤6.5% at Month 12
Description	The number of participants achieving HbA1c goals of <7% and ≤6.5% was calculated.
Time Frame	Month 12

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	268	95
HbA1c <7.0%	61 26.9%	21 18.3%
HbA1c ≤6.5%	18 7.9%	6 5.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.8955
	Comments	HbA1c <7.0%
	Method	Chi-squared
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.8926
	Comments	HbA1c ≤6.5%
	Method	Chi-squared
	Comments

12. Secondary Outcome

Title	Change From Baseline in Body Weight to Month 12
Description	Baseline is defined as the last measurement prior to randomization.
Time Frame	Baseline; Week 2; Months 1, 2, 3, 4, 6, 9, and 12

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	342	114
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.7735
	Comments
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.13
	Confidence Interval	(2-Sided) 95%; -0.76 to 1.03
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

13. Secondary Outcome

Title	Average of Daily Insulin Doses (Bolus, Basal, and Total)
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	327	111
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.4948
	Comments	Daily bolus dose
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -4.1 to 2.0
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.1099
	Comments	Daily basal dose
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	2.3
	Confidence Interval	(2-Sided) 95%; -0.5 to 5.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.5830
	Comments	Daily total dose
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	1.4
	Confidence Interval	(2-Sided) 95%; -3.7 to 6.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

14. Secondary Outcome

Title	Average Carbohydrate Factor (CarbF) Values
Description	CarbF is calculated as 2.6 * weight (pounds) / total daily dose of insulin (grams per unit).
Time Frame	Month 1 to Month 12

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	304	100
Least Squares Mean (Standard Error) [grams per unit]	11.1 (0.26)	11.0 (0.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.8778
	Comments
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -1.0 to 1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

15. Secondary Outcome

Title	Average Correction Factor (CorrF) Values
Description	CorrF is calculated as 1960 / total daily dose of insulin (milligrams/[deciliter*unit]).
Time Frame	Month 1 to Month 12

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	299	101
Least Squares Mean (Standard Error) [milligrams/(deciliter*unit)]	43.2 (1.06)	45.3 (1.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.3233
	Comments
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-2.1
	Confidence Interval	(2-Sided) 95%; -6.3 to 2.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

16. Secondary Outcome

Title	Average of Bolus Times Relative to Meal Times
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	342	114
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)

17. Secondary Outcome

Title	Average Glucose, Median Glucose, and Average Daily Standard Deviation
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	80	30
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.7708
	Comments	Average glucose
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	1.0
	Confidence Interval	(2-Sided) 95%; -5.8 to 7.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.6058
	Comments	Median glucose
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	1.8
	Confidence Interval	(2-Sided) 95%; -5.0 to 8.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.6571
	Comments	Average daily standard deviation
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -4.0 to 2.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

18. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	80	30
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.6252
	Comments	Time per day <56 mg/dL
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-2.2
	Confidence Interval	(2-Sided) 95%; -11.3 to 6.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.5929
	Comments	Time per day ≤70 mg/dL
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-5.5
	Confidence Interval	(2-Sided) 95%; -25.9 to 14.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.5207
	Comments	Time per day >70 mg/dL
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	6.9
	Confidence Interval	(2-Sided) 95%; -14.4 to 28.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.4754
	Comments	Time per day <140 mg/dL
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-23.3
	Confidence Interval	(2-Sided) 95%; -87.8 to 41.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.4644
	Comments	Time per day ≥140 mg/dL
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	23.9
	Confidence Interval	(2-Sided) 95%; -40.7 to 88.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.9232
	Comments	Time per day outside of 71 to 180 mg/dL
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	2.8
	Confidence Interval	(2-Sided) 95%; -54.2 to 59.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.5151
	Comments	Time per day outside of 71 to 139 mg/dL
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	18.4
	Confidence Interval	(2-Sided) 95%; -37.5 to 74.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

19. Secondary Outcome

Title	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
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	80	30
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.4216
	Comments	Area per day <56 mg/dL
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-33.5
	Confidence Interval	(2-Sided) 95%; -115.9 to 48.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.5697
	Comments	Area per day ≤70 mg/dL
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-84.7
	Confidence Interval	(2-Sided) 95%; -379.2 to 209.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.9241
	Comments	Area per day ≥140 mg/dL
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	342.9
	Confidence Interval	(2-Sided) 95%; -6772.3 to 7458.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.9232
	Comments	Area per day outside of 71 to 180 mg/dL
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	2.8
	Confidence Interval	(2-Sided) 95%; -54.2 to 59.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.9423
	Comments	Area per day outside of 71 to 139 mg/dL
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	258.2
	Confidence Interval	(2-Sided) 95%; -6792.2 to 7308.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Least squares mean treatment difference (Hylenex minus Standard CSII)

20. Secondary Outcome

Title	Change From Baseline in Weighted Impact ADDQoL Values at Month 12
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	342	114
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)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.5246
	Comments	Leisure activities
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.7 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.6380
	Comments	Work life
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.8 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.5719
	Comments	Local or long distance travel
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.7 to 0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.4052
	Comments	Vacations
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-0.2
	Confidence Interval	(2-Sided) 95%; -0.8 to 0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.7240
	Comments	Do physically
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.6876
	Comments	Family life
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.6478
	Comments	Friendships and social life
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.9744
	Comments	Close personal relationship
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.6 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.3177
	Comments	Sex life
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.2087
	Comments	Physical appearance
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 11

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.7907
	Comments	Self-confidence
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 12

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.3444
	Comments	Motivation
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 95%; -0.8 to 0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 13

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.2175
	Comments	The way people in general react
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.2
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 14

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.2062
	Comments	Feelings about the future
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-0.4
	Confidence Interval	(2-Sided) 95%; -1.0 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 15

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.8762
	Comments	Financial situation
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 16

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.8900
	Comments	Living situation and conditions
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.5 to 0.5
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 17

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.1367
	Comments	Depend on others
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	-0.5
	Confidence Interval	(2-Sided) 95%; -1.1 to 0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 18

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.3144
	Comments	Freedom to eat
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 19

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.6869
	Comments	Freedom to drink
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

21. Secondary Outcome

Title	Change From Baseline in Average Weighted Impact ADDQoL Values at Month 12
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	265	95
Least Squares Mean (Standard Error) [score on a scale]	0.0 (0.07)	0.0 (0.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.9901
	Comments
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -0.3 to 0.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

22. Secondary Outcome

Title	Change From Baseline in DTSQs and DTSQc at Month 12
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	342	114
DTSQs	0.0 (0.32)	0.0 (0.53)
DTSQc	9.4 (0.40)	9.4 (0.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.9081
	Comments	DTSQs
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -1.1 to 1.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Hylenex Recombinant, Standard Rapid-Acting Insulin CSII
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	prespecific non-inferiority margin of 0.4%
Statistical Test of Hypothesis	p-Value	0.9840
	Comments	DTSQc
	Method	ANOVA
	Comments	ANOVA with treatment (Hylenex, Standard CSII) as a fixed effect
Method of Estimation	Estimation Parameter	least squares mean treatment difference
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -1.5 to 1.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hylenex minus Standard CSII

23. Secondary Outcome

Title	Mean Time to Change Infusion Site
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	276	97
Mean (Standard Deviation) [minutes]	5.7 (4.45)	4.7 (3.68)

24. Secondary Outcome

Title	Mean Additional Time for Hylenex Pre-administration
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	276	37
Mean (Standard Deviation) [minutes]	2.9 (3.96)	3.8 (2.84)

25. Secondary Outcome

Title	Number of Participants With the Indicated Responses to the Question Regarding the Difficulty of Infusion Site Change
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	276	97
Very easy	143 63%	49 42.6%
Easy	130 57.3%	46 40%
Difficult	3 1.3%	1 0.9%
Very difficult	0 0%	1 0.9%

26. Secondary Outcome

Title	Number of Participants With the Indicated Responses to the Device Handling Questions
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	276	97
Completely agree	5 2.2%	0 0%
Agree	110 48.5%	28 24.3%
Neither agree or disagree	97 42.7%	44 38.3%
Disagree	59 26%	22 19.1%
Completely disagree	5 2.2%	3 2.6%
Completely agree	31 13.7%	8 7%
Agree	146 64.3%	48 41.7%
Neither agree or disagree	71 31.3%	28 24.3%
Disagree	25 11%	12 10.4%
Completely disagree	3 1.3%	1 0.9%
Completely agree	36 15.9%	14 12.2%
Agree	165 72.7%	39 33.9%
Neither agree or disagree	34 15%	22 19.1%
Disagree	38 16.7%	20 17.4%
Completely disagree	3 1.3%	2 1.7%

27. Secondary Outcome

Title	Mean Times Per Week Participants Said They Were Eating to Avoid Going Low Due to Late Insulin Action
Description	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

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with available data were analyzed. 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.

Arm/Group Title	Hylenex Recombinant	Standard Rapid-Acting Insulin CSII
Arm/Group Description	For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of Hylenex recombinant (either Formulation 1 or Formulation 2), delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).	Participants received their regular treatment of rapid-acting insulin CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
Measure Participants	275	97
Mean (Standard Deviation) [occurrences per week]	2.1 (2.19)	2.5 (2.37)

Adverse Events

Arm/Group Title	Commercial Hylenex Recombinant (Formulation 1)		Precommercial Hylenex Recombinant (Formulation 2)		Standard Rapid-Acting Insulin CSII
Arm/Group Description	Hylenex Formulation 1: For 12 months, participants received their regular treatment of rapid-acting continuous CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of the commercial form of Hylenex recombinant, delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).		Hylenex Formulation 2: For 12 months, participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine). Additionally, during this 12-month treatment period, the participants received a pretreatment dose of the precommercial form of Hylenex recombinant, delivered at 150 U through their insulin infusion cannula each time they changed infusion sets (every 2 to 3 days).		Participants received their regular treatment of rapid-acting CSII (for example, insulin lispro, insulin aspart, and insulin glulisine) for 12 months.
All Cause Mortality
	Commercial Hylenex Recombinant (Formulation 1)		Precommercial Hylenex Recombinant (Formulation 2)		Standard Rapid-Acting Insulin CSII
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Commercial Hylenex Recombinant (Formulation 1)		Precommercial Hylenex Recombinant (Formulation 2)		Standard Rapid-Acting Insulin CSII
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/227 (4.8%)		10/115 (8.7%)		13/113 (11.5%)
Cardiac disorders
Angina pectoris	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Coronary artery disease	0/227 (0%)		0/115 (0%)		3/113 (2.7%)
Acute myocardial infarction	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Ear and labyrinth disorders
Vertigo positional	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Eye disorders
Retinal detachment	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Gastrointestinal disorders
Oesophagitis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
General disorders
Chest pain	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Non-cardiac chest pain	0/227 (0%)		2/115 (1.7%)		0/113 (0%)
Infections and infestations
Appendicitis	0/227 (0%)		1/115 (0.9%)		1/113 (0.9%)
Viral infection	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Abscess limb	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Cellulitis	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Influenza	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Postoperative wound infection	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Injury, poisoning and procedural complications
Spinal fracture	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Procedural pain	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Metabolism and nutrition disorders
Diabetic ketoacidosis	1/227 (0.4%)		2/115 (1.7%)		1/113 (0.9%)
Hypoglycaemia	3/227 (1.3%)		1/115 (0.9%)		2/113 (1.8%)
Hyponatraemia	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Dehydration	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Musculoskeletal and connective tissue disorders
Flank pain	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Nervous system disorders
Convulsion	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Stiff person syndrome	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Syncope	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Transient ischaemic attack	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Renal and urinary disorders
Nephrolithiasis	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Reproductive system and breast disorders
Pelvic floor muscle weakness	1/122 (0.8%)		0/53 (0%)		0/64 (0%)
Menometrorrhagia	0/122 (0%)		0/53 (0%)		1/64 (1.6%)
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Pleural effusion	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Dyspnoea	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Vascular disorders
Arteriosclerosis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Other (Not Including Serious) Adverse Events
	Commercial Hylenex Recombinant (Formulation 1)		Precommercial Hylenex Recombinant (Formulation 2)		Standard Rapid-Acting Insulin CSII
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	174/227 (76.7%)		84/115 (73%)		76/113 (67.3%)
Blood and lymphatic system disorders
Anaemia	3/227 (1.3%)		1/115 (0.9%)		0/113 (0%)
Iron deficiency anaemia	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Cardiac disorders
Atrial fibrillation	0/227 (0%)		0/115 (0%)		2/113 (1.8%)
Coronary artery disease	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Palpitations	2/227 (0.9%)		0/115 (0%)		1/113 (0.9%)
Bradycardia	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Tachycardia	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Ear and labyrinth disorders
Tinnitus	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Vertigo	1/227 (0.4%)		2/115 (1.7%)		1/113 (0.9%)
Ear pain	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Eustachian tube dysfunction	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Otorrhoea	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Endocrine disorders
Goitre	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Hypogonadism	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Hypothyroidism	0/227 (0%)		1/115 (0.9%)		1/113 (0.9%)
Eye disorders
Angle closure glaucoma	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Cataract	0/227 (0%)		1/115 (0.9%)		1/113 (0.9%)
Conjunctivitis	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Diabetic retinopathy	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Dry eye	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Eye discharge	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Macular oedema	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Retinal haemorrhage	3/227 (1.3%)		0/115 (0%)		0/113 (0%)
Vitreous floaters	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Eye haemorrhage	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Vitreous haemorrhage	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Keratitis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Gastrointestinal disorders
Abdominal discomfort	4/227 (1.8%)		0/115 (0%)		0/113 (0%)
Abdominal distention	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Abdominal pain	2/227 (0.9%)		1/115 (0.9%)		1/113 (0.9%)
Abdominal pain upper	3/227 (1.3%)		0/115 (0%)		3/113 (2.7%)
Colitis ulcerative	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Constipation	1/227 (0.4%)		1/115 (0.9%)		1/113 (0.9%)
Dental caries	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Diarrhoea	6/227 (2.6%)		2/115 (1.7%)		0/113 (0%)
Dyspepsia	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Gastritis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Gastrooesophageal reflux disease	2/227 (0.9%)		2/115 (1.7%)		1/113 (0.9%)
Impaired gastric emptying	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Irritable bowel syndrome	1/227 (0.4%)		1/115 (0.9%)		1/113 (0.9%)
Melaena	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Nausea	9/227 (4%)		6/115 (5.2%)		2/113 (1.8%)
Periodontal disease	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Toothache	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Upper gastrointestinal haemorrhage	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Vomiting	6/227 (2.6%)		1/115 (0.9%)		2/113 (1.8%)
Oesophagitis	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Coeliac disease	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Gastric ulcer	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Oesophageal ulcer	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Tooth impacted	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
General disorders
Application site erythema	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Chest discomfort	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Fatigue	3/227 (1.3%)		2/115 (1.7%)		1/113 (0.9%)
Feeling hot	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Infusion site bruising	5/227 (2.2%)		3/115 (2.6%)		0/113 (0%)
Infusion site discomfort	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Infusion site erythema	12/227 (5.3%)		4/115 (3.5%)		1/113 (0.9%)
Infusion site haematoma	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Infusion site haemorrhage	5/227 (2.2%)		2/115 (1.7%)		0/113 (0%)
Infusion site induration	4/227 (1.8%)		0/115 (0%)		0/113 (0%)
Infusion site oedema	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Infusion site pain	40/227 (17.6%)		17/115 (14.8%)		7/113 (6.2%)
Infusion site paraesthesia	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Infusion site pruritus	4/227 (1.8%)		2/115 (1.7%)		0/113 (0%)
Infusion site scar	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Infusion site rash	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Infusion site reaction	1/227 (0.4%)		1/115 (0.9%)		1/113 (0.9%)
Infusion site warmth	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Injection site pain	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Injury associated with device	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Localised oedema	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Non-cardiac chest pain	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Oedema peripheral	3/227 (1.3%)		2/115 (1.7%)		1/113 (0.9%)
Pyrexia	1/227 (0.4%)		1/115 (0.9%)		1/113 (0.9%)
Chest pain	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Hunger	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Hepatobiliary disorders
Cholecystitis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Biliary colic	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Cholestasis	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Immune system disorders
Drug hypersensitivity	3/227 (1.3%)		0/115 (0%)		0/113 (0%)
Hypersensitivity	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Seasonal allergy	2/227 (0.9%)		1/115 (0.9%)		0/113 (0%)
Allergy to chemicals	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Allergy to metals	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Sarcoidosis	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Infections and infestations
Abscess oral	0/227 (0%)		1/115 (0.9%)		1/113 (0.9%)
Acute sinusitis	0/227 (0%)		0/115 (0%)		2/113 (1.8%)
Atypical pneumonia	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Bacterial infection	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Bronchitis	5/227 (2.2%)		5/115 (4.3%)		3/113 (2.7%)
Cellulitis	2/227 (0.9%)		0/115 (0%)		1/113 (0.9%)
Cystitis	3/227 (1.3%)		1/115 (0.9%)		1/113 (0.9%)
Ear infection	5/227 (2.2%)		1/115 (0.9%)		4/113 (3.5%)
Eye infection	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Gastroenteritis	4/227 (1.8%)		4/115 (3.5%)		1/113 (0.9%)
Gastroenteritis viral	2/227 (0.9%)		5/115 (4.3%)		0/113 (0%)
Influenza	6/227 (2.6%)		4/115 (3.5%)		2/113 (1.8%)
Infusion site infection	2/227 (0.9%)		1/115 (0.9%)		1/113 (0.9%)
Kidney infection	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Laryngitis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Localised infection	2/227 (0.9%)		1/115 (0.9%)		2/113 (1.8%)
Lower respiratory tract infection	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Nail infection	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Nasopharyngitis	26/227 (11.5%)		9/115 (7.8%)		4/113 (3.5%)
Oral herpes	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Oral infection	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Otitis media	1/227 (0.4%)		1/115 (0.9%)		1/113 (0.9%)
Paronychia	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Pharyngitis	1/227 (0.4%)		0/115 (0%)		2/113 (1.8%)
Pharyngitis streptococcal	1/227 (0.4%)		1/115 (0.9%)		2/113 (1.8%)
Pneumonia	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Respiratory tract infection	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Respiratory tract infection viral	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Rhinovirus infection	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Sialoadenitis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Sinusitis	12/227 (5.3%)		7/115 (6.1%)		8/113 (7.1%)
Skin infection	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Tinea pedis	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Tooth abscess	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Tooth infection	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Upper respiratory tract infection	31/227 (13.7%)		15/115 (13%)		13/113 (11.5%)
Urinary tract infection	10/227 (4.4%)		3/115 (2.6%)		3/113 (2.7%)
Varicella	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Vulvovaginal mycotic infection	0/227 (0%)		2/115 (1.7%)		1/113 (0.9%)
Abscess limb	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Bronchitis viral	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Enteritis infectious	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Eye infection viral	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Fungal infection	0/227 (0%)		1/115 (0.9%)		1/113 (0.9%)
Gastrointestinal infection	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Gastrointestinal viral infection	3/227 (1.3%)		1/115 (0.9%)		0/113 (0%)
H1N1 Influenza	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Herpes zoster	0/227 (0%)		0/115 (0%)		2/113 (1.8%)
Hordeolum	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Infectious mononucleosis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Mastoiditis	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Mycobacteriuim abscessus infection	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Oral candidiasis	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Pilonidal cyst	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Rhinitis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Staphylococcal skin infection	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Tonsillitis	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Viral upper respiratory tract infection	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Candidiasis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Injury, poisoning and procedural complications
Animal bite	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Arthropod bite	1/227 (0.4%)		1/115 (0.9%)		2/113 (1.8%)
Concussion	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Corneal abrasion	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Epicondylitis	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Excoriation	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Foot fracture	4/227 (1.8%)		0/115 (0%)		1/113 (0.9%)
Foreign body in eye	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Hand fracture	0/227 (0%)		0/115 (0%)		2/113 (1.8%)
Incision cite erythema	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Joint injury	3/227 (1.3%)		0/115 (0%)		1/113 (0.9%)
Laceration	1/227 (0.4%)		2/115 (1.7%)		3/113 (2.7%)
Ligament rupture	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Ligament sprain	4/227 (1.8%)		1/115 (0.9%)		1/113 (0.9%)
Lumbar vertebral fracture	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Meniscus injury	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Muscle rupture	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Muscle strain	2/227 (0.9%)		1/115 (0.9%)		1/113 (0.9%)
Procedural pain	3/227 (1.3%)		0/115 (0%)		0/113 (0%)
Road traffic accident	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Scar	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Skeletal injury	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Stress fracture	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Tendon rupture	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Thermal burn	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Tooth fracture	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Traumatic haematoma	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Upper limb fracture	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Wrist fracture	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Contusion	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Fall	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Fascial rupture	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Foreign body	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Joint dislocation	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Limb injury	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Radius fracture	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Rib fracture	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Ulna fracture	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Investigations
Aspartate aminotransferase increased	0/227 (0%)		0/115 (0%)		2/113 (1.8%)
Blood alkaline phosphatase increased	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Blood glucose increased	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Blood potassium increased	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Blood triglycerides increased	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Fibrin D dimer increased	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Glycosylated haemoglobin increased	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Liver function test abnormal	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Urine ketone body present	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Weight decreased	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Alanine aminotransferase increased	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Blood bilirubin increased	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Carotid bruit	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Metabolism and nutrition disorders
Dehydration	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Diabetic ketoacidosis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Hyperglycaemia	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Hyperlipidaemia	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Hypocalcaemia	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Hyponatraemia	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Vitamin D deficiency	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Abnormal loss of weight	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Decreased appetite	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Hypokalaemia	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Tetany	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/227 (1.8%)		3/115 (2.6%)		0/113 (0%)
Back pain	6/227 (2.6%)		3/115 (2.6%)		0/113 (0%)
Bursitis	2/227 (0.9%)		0/115 (0%)		1/113 (0.9%)
Costochondritis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Dupuytren's contracture	1/227 (0.4%)		0/115 (0%)		2/113 (1.8%)
Fibromyalgia	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Flank pain	1/227 (0.4%)		2/115 (1.7%)		1/113 (0.9%)
Intervertebral disc protrusion	4/227 (1.8%)		1/115 (0.9%)		0/113 (0%)
Joint range of motion decreased	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Joint swelling	3/227 (1.3%)		0/115 (0%)		0/113 (0%)
Muscle atrophy	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Muscle spasms	3/227 (1.3%)		2/115 (1.7%)		1/113 (0.9%)
Musculoskeletal chest pain	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Musculoskeletal pain	4/227 (1.8%)		1/115 (0.9%)		1/113 (0.9%)
Myalgia	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Neck pain	4/227 (1.8%)		0/115 (0%)		0/113 (0%)
Osteoarthritis	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Pain in extremity	2/227 (0.9%)		2/115 (1.7%)		4/113 (3.5%)
Periarthritis	3/227 (1.3%)		0/115 (0%)		0/113 (0%)
Plantar fasciitis	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Spondylitis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Tendonitis	1/227 (0.4%)		1/115 (0.9%)		1/113 (0.9%)
Trigger finger	3/227 (1.3%)		2/115 (1.7%)		0/113 (0%)
Bunion	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Exostosis	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Intervertebral disc degeneration	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Muscular weakness	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Rotator cuff syndrome	0/227 (0%)		0/115 (0%)		2/113 (1.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign neoplasm of skin	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Seborrhoeic keratosis	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Skin papilloma	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Basal cell carcinoma	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Knuckle pads	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Morton's neuroma	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Nervous system disorders
Carpal tunnel syndrome	4/227 (1.8%)		0/115 (0%)		1/113 (0.9%)
Burning sensation	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Cervicobrachial syndrome	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Decreased vibratory sense	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Headache	6/227 (2.6%)		2/115 (1.7%)		4/113 (3.5%)
Hypoaesthesia	2/227 (0.9%)		0/115 (0%)		2/113 (1.8%)
Loss of consciousness	0/227 (0%)		0/115 (0%)		2/113 (1.8%)
Migraine	1/227 (0.4%)		1/115 (0.9%)		1/113 (0.9%)
Nerve compression	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Neuropathy peripheral	3/227 (1.3%)		0/115 (0%)		0/113 (0%)
Paraesthesia	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Reflexes abnormal	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Sinus headache	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Syncope	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Tension headache	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Convulsion	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Amnesia	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Cerebrovascular accident	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Dizziness	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Neuralgia	0/227 (0%)		1/115 (0.9%)		1/113 (0.9%)
Psychiatric disorders
Anxiety	2/227 (0.9%)		2/115 (1.7%)		2/113 (1.8%)
Attention deficit/hyperactivity disorder	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Depression	10/227 (4.4%)		2/115 (1.7%)		1/113 (0.9%)
Insomnia	3/227 (1.3%)		1/115 (0.9%)		0/113 (0%)
Libido decreased	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Post-traumatic stress disorder	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Binge eating	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Panic attack	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Renal and urinary disorders
Nephrolithiasis	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Haematuria	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Proteinuria	0/227 (0%)		1/115 (0.9%)		1/113 (0.9%)
Pyelocaliectasis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Pyuria	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Renal failure acute	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Stress urinary incontinence	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Urethral pain	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Urinary retention	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Calculus bladder	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Cystitis noninfective	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Reproductive system and breast disorders
Bartholin's cyst	0/122 (0%)		1/53 (1.9%)		0/64 (0%)
Breast inflammation	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Breast pain	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Breast tenderness	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Dysmenorrhoea	1/122 (0.8%)		0/53 (0%)		1/64 (1.6%)
Fibrocystic breast disease	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Menstruation irregular	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Pelvic floor muscle weakness	1/122 (0.8%)		0/53 (0%)		0/64 (0%)
Postmenopausal haemorrhage	0/122 (0%)		0/53 (0%)		1/64 (1.6%)
Uterine polyp	0/122 (0%)		1/53 (1.9%)		1/64 (1.6%)
Erectile dysfunction	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Menorrhagia	0/227 (0%)		2/115 (1.7%)		0/113 (0%)
Vulvovaginal pruritus	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Respiratory, thoracic and mediastinal disorders
Allergic sinusitis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Asthma	3/227 (1.3%)		1/115 (0.9%)		0/113 (0%)
Atelectasis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Cough	6/227 (2.6%)		5/115 (4.3%)		4/113 (3.5%)
Dyspnoea exertional	1/227 (0.4%)		1/115 (0.9%)		1/113 (0.9%)
Epistaxis	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Nasal congestion	2/227 (0.9%)		4/115 (3.5%)		0/113 (0%)
Nasal septum deviation	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Oropharyngeal pain	2/227 (0.9%)		2/115 (1.7%)		0/113 (0%)
Paranasal sinus hypersecretion	1/227 (0.4%)		1/115 (0.9%)		2/113 (1.8%)
Respiratory tract congestion	2/227 (0.9%)		3/115 (2.6%)		1/113 (0.9%)
Sinus congestion	3/227 (1.3%)		3/115 (2.6%)		3/113 (2.7%)
Upper respiratory tract congestion	2/227 (0.9%)		1/115 (0.9%)		0/113 (0%)
Upper-airway cough syndrome	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Skin and subcutaneous tissue disorders
Acne	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Actinic keratosis	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Blister	2/227 (0.9%)		0/115 (0%)		0/113 (0%)
Chronic spontaneous urticaria	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Dermal cyst	1/227 (0.4%)		0/115 (0%)		1/113 (0.9%)
Dermatitis contact	4/227 (1.8%)		0/115 (0%)		2/113 (1.8%)
Dry skin	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Erythema	6/227 (2.6%)		0/115 (0%)		0/113 (0%)
Hyperhidrosis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Hyperkeratosis	1/227 (0.4%)		1/115 (0.9%)		0/113 (0%)
Ingrowing Nail	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Lipohypertrophy	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Onychomadesis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Pruritus	3/227 (1.3%)		0/115 (0%)		1/113 (0.9%)
Rash	5/227 (2.2%)		1/115 (0.9%)		0/113 (0%)
Rash erythematous	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Rash maculo-papular	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Scab	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Seborrhoeic dermatitis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Skin mass	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Skin ulcer	0/227 (0%)		1/115 (0.9%)		1/113 (0.9%)
Urticaria	0/227 (0%)		1/115 (0.9%)		1/113 (0.9%)
Dermatitis	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Eczema	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Scar pain	0/227 (0%)		1/115 (0.9%)		0/113 (0%)
Skin irritation	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Stasis dermatitis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Social circumstances
Menopause	1/122 (0.8%)		0/53 (0%)		0/64 (0%)
Surgical and medical procedures
Wisdom teeth removal	0/227 (0%)		0/115 (0%)		1/113 (0.9%)
Vascular disorders
Aortic arteriosclerosis	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Hypertension	4/227 (1.8%)		1/115 (0.9%)		2/113 (1.8%)
Hypotension	1/227 (0.4%)		0/115 (0%)		0/113 (0%)
Varicose vein	0/227 (0%)		0/115 (0%)		1/113 (0.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

All information obtained as a result of this study or during the conduct of this study will be regarded as confidential. The Investigator agrees to use the information for the purpose of carrying out this study and for no other purpose, unless written permission from the sponsor (Halozyme) is obtained.