Safety/Efficacy Study of Subcutaneously Injected Prandial Insulins Compared to Insulin Lispro Alone in Participants With Type 1 Diabetes Mellitus

• Sponsor: Halozyme Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01194245
• Collaborator: (none)
• Enrollment: 135
• Locations: 19
• Arms: 2
• Duration (Months): 12
• Patients Per Site: 7.1
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of the study is to compare Humalog (Insulin lispro)-recombinant human hyaluronidase (rHuPH20) or Novolog (Insulin aspart)-rHuPH20 to Humalog (Insulin lispro) for the treatment of Type 1 Diabetes Mellitus (T1DM) in basal-bolus therapy.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: Insulin lispro; Drug: recombinant human hyaluronidase PH20; Drug: Insulin aspart; Drug: Insulin glulisine; Drug: Insulin glargine	Phase 2

Detailed Description

Criteria for randomization into the study included 1) fasting blood glucose and predinner glucose values in the range of 70 to 140 milligrams per deciliter (mg/dL) approximately 60% of the time for 7 days prior to randomization 2) 90 minute or 2-hour postprandial blood glucose <220 mg/dL approximately 70% of the time for 7 days prior to randomization and 3) successfully completed 3 days of 10-point glucose monitoring and have at least 4 self-monitored blood glucose values on all non-10-point monitoring days. Participants that did not meet 1 or more of these criteria during a 4- to 6-week Titration Period were not randomized.

Study Design

• Study Type: Interventional
• Actual Enrollment: 135 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Randomized, Double Blind, 2-Way Crossover Safety and Efficacy Study of Subcutaneously Injected Prandial Insulins: Lispro-PH20 or Aspart-PH20 Compared to Insulin Lispro (Humalog®) in Patients With Type 1 Diabetes
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Lispro-PH20 / Insulin Lispro All enrolled participants underwent a titration period of 4-6 weeks in which they received 100 units per milliliter (U/mL) insulin glulisine, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually. Next participants were randomly assigned to 1 of 2 study treatments (Treatment A or B) for the first of two, 3-month treatment cycles. Each participant then received the second treatment for the second cycle with no washout period. Lispro-PH20 (Treatment A): 100 U/mL insulin lispro with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected SC, pre-meals, with doses titrated to each participant individually Insulin Lispro (Treatment B): 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	Drug: Insulin lispro; Other Names: Humalog ; Drug: recombinant human hyaluronidase PH20; Other Names: Hylenex rHuPH20 PH20 ; Drug: Insulin glulisine; Other Names: Apidra ; Drug: Insulin glargine; Other Names: Lantus
Experimental: Aspart-PH20 / Insulin Lispro All enrolled participants underwent a titration period of 4-6 weeks in which they received 100 units per milliliter (U/mL) insulin glulisine, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually. Next participants were randomly assigned to 1 of 2 study treatments (Treatment A or B) for the first of two, 3-month treatment cycles. Each participant then received the second treatment for the second cycle with no washout period. Aspart-PH20 (Treatment A): 100 U/mL insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected SC, pre-meals, with doses titrated to each participant individually Insulin Lispro (Treatment B): 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	Drug: Insulin lispro; Other Names: Humalog ; Drug: recombinant human hyaluronidase PH20; Other Names: Hylenex rHuPH20 PH20 ; Drug: Insulin aspart; Drug: Insulin glulisine; Other Names: Apidra ; Drug: Insulin glargine; Other Names: Lantus

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Glycosylated Hemoglobin A1C (HbA1c) at the End of Each Treatment Period [Baseline, Week 12 and Week 24]

   Glycosylated hemoglobin A1C (HBA1c) levels were measured at baseline (Week 0) and at the end of each treatment period (Week 12 and Week 24). Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts). Least Squares (LS) means were calculated from mixed effects linear models with treatment (Lispro, Aspart), recombinant human hyaluronidase PH20 (rHuPH20; yes, no), and treatment sequence as fixed effects and participant within treatment sequence as a random effect.

Secondary Outcome Measures

1. Mean Daily Insulin Dose [Week 10 and Week 22]

   Prandial insulin doses were recorded during 10-point glucose monitoring for a total of 3 days during each treatment period (3 days during Week 10 of Treatment Period 1 and 3 days during Week 22 of Treatment Period 2). The mean daily insulin dose over the 3 days during each treatment period is presented. Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts).

2. Percentage of Participants Meeting Glucose Targets [Baseline through Week 24, excluding 10-point glucose monitoring days]

   Participants were instructed to monitor their blood glucose levels a minimum of 4 times per day on all non-10-point glucose monitoring days. The number of participants meeting 90-minute postprandial plasma glucose (PPG) targets of <140 and <180 milligrams per deciliter (mg/dL) for at least 2/3 of values during non-10-point glucose monitoring days was recorded. The percentage was calculated by dividing the number of participants with values meeting the specified target at least 2/3 of the time by the total number of participants analyzed, multiplied by 100. Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts).

3. Rates of Hypoglycemia at the End of Each Treatment Period [Week 12 and Week 24]

   Overall rates of hypoglycemia (blood glucose ≤70 milligrams per deciliter [mg/dL] and <56 mg/dL) were calculated based on 4 weeks of observation for each treatment period. Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts). A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.

4. Change From Baseline in Body Weight at the End of Each Treatment Period [Baseline, Week 12 and Week 24]

   Body weight was measured at baseline (Week 0) and at the end of each treatment period (Week 12 and Week 24). Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts).

5. Mean Daily Postprandial Glucose (PPG) Excursions [Week 10 and Week 22]

   Participants performed 10-point glucose monitoring for a total of 3 days during each treatment period (3 days during Week 10 of Treatment Period 1 and 3 days during Week 22 of Treatment Period 2). Mean daily postprandial plasma glucose (PPG) excursions (referring to the change in blood glucose levels from before to after a meal) during 10-point glucose monitoring for breakfast, lunch, and dinner are presented. Data were collected 1 and 2 hours (hr) after each meal for 3 days and the means of each excursion are presented.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Males or females aged ≥18 years

• Type 1 Diabetes Mellitus (T1DM) treated with insulin for ≥12 months

• Body mass index (BMI) 18.0 to 40.0 kilograms per square meter (kg/m^2).

• Hemoglobin A1C (HbA1C) level 6.7% to 8.2%, inclusive

• Fasting C-peptide <0.6 nanograms per milliliter (ng/mL)

• Willingness to use twice daily (BID) insulin glargine as basal insulin for the duration of the study

• Willingness to avoid use of an insulin infusion pump or unblinded continuous glucose monitoring (CGM) during the study

Exclusion Criteria:

• Known or suspected allergy to any component of any of the study drugs

• Use of pramlintide within 30 days of Screening

• Use of drugs during the study or within 30 days of Screening (such as corticosteroids or antimetabolites) that could interfere with the interpretation of study results or are known to cause clinically relevant interference with insulin action, glucose utilization, or recovery from hypoglycemia

• Recurrent severe hypoglycemia (more than 2 episodes over the last 6 months) or hypoglycemic unawareness, as judged by the Investigator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	AMCR Institute, Inc.	Escondido	California	United States	92026
2	Scripps Whittier Diabetes Institute	La Jolla	California	United States	92037
3	Mills-Peninsula Health Services	San Mateo	California	United States	94401
4	Barbara Davis Center for Childhood Diabetes	Aurora	Colorado	United States	80045
5	Center for Diabetes and Endocrine Care	Hollywood	Florida	United States	33021
6	Diabetes Research Institute	Miami	Florida	United States	33136
7	Rocky Mountain Diabetes and Osteoporosis Center	Idaho Falls	Idaho	United States	83404
8	Mid-America Diabetes Associates	Wichita	Kansas	United States	67211
9	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
10	Medstar Research Institute	Hyattsville	Maryland	United States	20782
11	Henry Ford Health System	Detroit	Michigan	United States	48202
12	International Diabetes Center	Minneapolis	Minnesota	United States	55416
13	Mercury Street Medical	Butte	Montana	United States	59701
14	Desert Endocrinology	Henderson	Nevada	United States	89052
15	UT Southwestern Medical Center at Dallas	Dallas	Texas	United States	75390
16	Texas Diabetes and Endocrinology	Round Rock	Texas	United States	78681
17	Cetero Research-San Antonio	San Antonio	Texas	United States	78229
18	West Olympia Internal Medicine	Olympia	Washington	United States	98502
19	University of Washington School of Medicine	Seattle	Washington	United States	98105

Sponsors and Collaborators

• Halozyme Therapeutics

Investigators

• Study Director: Douglas Muchmore, M.D., Halozyme Therapeutics

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Halozyme Therapeutics
• ClinicalTrials.gov Identifier: NCT01194245
• Other Study ID Numbers: HALO-117-205
• First Posted: Sep 2, 2010
• Last Update Posted: Feb 26, 2019
• Last Verified: Feb 1, 2019

• Keywords provided by Halozyme Therapeutics: Type 1 diabetes
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin; Insulin, Globin Zinc; Insulin Glargine; Insulin Aspart; Insulin Lispro; Insulin glulisine

Study Results

Participant Flow

Pre-assignment Detail	The study included an open-label titration period of at least 4 weeks and up to 6 weeks prior to randomization at Week 0.

Arm/Group Title	All Enrolled Participants	Lispro-PH20 First, Then Insulin Lispro	Insulin Lispro First, Then Lispro-PH20	Aspart-PH20 First, Then Insulin Lispro	Insulin Lispro First, Then Aspart-PH20
Arm/Group Description	Prior to randomization, all enrolled participants underwent a titration period of 4-6 weeks in which they received 100 units per milliliter (U/mL) insulin glulisine, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually. Participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	Following a titration period of 4 to 6 weeks, participants were randomly assigned to Treatment A for the first 3-month treatment cycle, followed by Treatment B for the second 3-month treatment cycle. Lispro-PH20 (Treatment A): 100 units per milliliter (U/mL) insulin lispro with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually Insulin Lispro (Treatment B): 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	Following a titration period of 4 to 6 weeks, participants were randomly assigned to Treatment B for the first 3-month treatment cycle, followed by Treatment A for the second 3-month treatment cycle. Insulin Lispro (Treatment B): 100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually Lispro-PH20 (Treatment A): 100 U/mL insulin lispro with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected SC, pre-meals, with doses titrated to each participant individually Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	Following a titration period of 4 to 6 weeks, participants were randomly assigned to Treatment A for the first 3-month treatment cycle, followed by Treatment B for the second 3-month treatment cycle. Aspart-PH20 (Treatment A): 100 units per milliliter (U/mL) insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually Insulin Lispro (Treatment B): 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	Following a titration period of 4 to 6 weeks, participants were randomly assigned to Treatment B for the first 3-month treatment cycle, followed by Treatment A for the second 3-month treatment cycle. Insulin Lispro (Treatment B): 100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually Aspart-PH20 (Treatment A): 100 U/mL insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected SC, pre-meals, with doses titrated to each participant individually Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.
Period Title: Titration Period (4 to 6 Weeks)
STARTED	135	0	0	0	0
COMPLETED	117	0	0	0	0
NOT COMPLETED	18	0	0	0	0
Period Title: Titration Period (4 to 6 Weeks)
STARTED	0	29	28	30	30
Received at Least 1 Dose of Study Drug	0	29	28	30	30
COMPLETED	0	29	27	29	28
NOT COMPLETED	0	0	1	1	2
Period Title: Titration Period (4 to 6 Weeks)
STARTED	0	29	27	29	28
COMPLETED	0	29	27	29	28
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Non-randomized Participants	Lispro-PH20 First, Then Insulin Lispro	Insulin Lispro First, Then Lispro-PH20	Aspart-PH20 First, Then Insulin Lispro	Insulin Lispro First, Then Aspart-PH20	Total
Arm/Group Description	Participants underwent a titration period of 4-6 weeks in which they received 100 units per milliliter (U/mL) insulin glulisine, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually. Participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine. Participants did not complete the titration period or did not meet one or more randomization criteria and, therefore, were not randomized.	Following a titration period of 4 to 6 weeks, participants were randomly assigned to Treatment A for the first 3-month treatment cycle, followed by Treatment B for the second 3-month treatment cycle. Lispro-PH20 (Treatment A): 100 units per milliliter (U/mL) insulin lispro with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually Insulin Lispro (Treatment B): 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	Following a titration period of 4 to 6 weeks, participants were randomly assigned to Treatment B for the first 3-month treatment cycle, followed by Treatment A for the second 3-month treatment cycle. Insulin Lispro (Treatment B): 100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually Lispro-PH20 (Treatment A): 100 U/mL insulin lispro with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected SC, pre-meals, with doses titrated to each participant individually Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	Following a titration period of 4 to 6 weeks, participants were randomly assigned to Treatment A for the first 3-month treatment cycle, followed by Treatment B for the second 3-month treatment cycle. Aspart-PH20 (Treatment A): 100 units per milliliter (U/mL) insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually Insulin Lispro (Treatment B): 100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	Following a titration period of 4 to 6 weeks, participants were randomly assigned to Treatment B for the first 3-month treatment cycle, followed by Treatment A for the second 3-month treatment cycle. Insulin Lispro (Treatment B): 100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually Aspart-PH20 (Treatment A): 100 U/mL insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected SC, pre-meals, with doses titrated to each participant individually Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	Total of all reporting groups
Overall Participants	18	29	28	30	30	135
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	34.8 (11.71)	44.6 (14.56)	45.7 (14.94)	42.8 (14.13)	42.5 (14.70)	42.6 (14.41)
Sex: Female, Male (Count of Participants)
Female	6 33.3%	13 44.8%	13 46.4%	14 46.7%	15 50%	61 45.2%
Male	12 66.7%	16 55.2%	15 53.6%	16 53.3%	15 50%	74 54.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 5.6%	0 0%	0 0%	0 0%	0 0%	1 0.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	1 3.6%	0 0%	2 6.7%	3 2.2%
White	17 94.4%	27 93.1%	27 96.4%	30 100%	28 93.3%	129 95.6%
More than one race	0 0%	2 6.9%	0 0%	0 0%	0 0%	2 1.5%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 22.2%	1 3.4%	2 7.1%	2 6.7%	1 3.3%	10 7.4%
Not Hispanic or Latino	14 77.8%	28 96.6%	26 92.9%	28 93.3%	29 96.7%	125 92.6%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	18 100%	29 100%	28 100%	30 100%	30 100%	135 100%

Outcome Measures

1. Secondary Outcome

Title	Mean Daily Insulin Dose
Description	Prandial insulin doses were recorded during 10-point glucose monitoring for a total of 3 days during each treatment period (3 days during Week 10 of Treatment Period 1 and 3 days during Week 22 of Treatment Period 2). The mean daily insulin dose over the 3 days during each treatment period is presented. Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts).
Time Frame	Week 10 and Week 22

Outcome Measure Data

Analysis Population Description

Participants who completed both Treatment Period 1 and Treatment Period 2 and had evaluable insulin dose data.

Arm/Group Title	Analog-PH20	Insulin Lispro
Arm/Group Description	100 units per milliliter (U/mL) insulin lispro or insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (SC), pre-meals, for 12 weeks, with doses titrated to each participant individually	100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, for 12 weeks, with doses titrated to each participant individually
Measure Participants	102	105
Mean (Standard Deviation) [units (U)]	54.28 (27.071)	56.05 (27.243)

2. Secondary Outcome

Title	Percentage of Participants Meeting Glucose Targets
Description	Participants were instructed to monitor their blood glucose levels a minimum of 4 times per day on all non-10-point glucose monitoring days. The number of participants meeting 90-minute postprandial plasma glucose (PPG) targets of <140 and <180 milligrams per deciliter (mg/dL) for at least 2/3 of values during non-10-point glucose monitoring days was recorded. The percentage was calculated by dividing the number of participants with values meeting the specified target at least 2/3 of the time by the total number of participants analyzed, multiplied by 100. Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts).
Time Frame	Baseline through Week 24, excluding 10-point glucose monitoring days

Outcome Measure Data

Analysis Population Description

Participants who completed both Treatment Period 1 and Treatment Period 2 and had evaluable postprandial glucose data.

Arm/Group Title	Analog-PH20	Insulin Lispro
Arm/Group Description	100 units per milliliter (U/mL) insulin lispro or insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (SC), pre-meals, for 12 weeks, with doses titrated to each participant individually	100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, for 12 weeks, with doses titrated to each participant individually
Measure Participants	113	113
PPG <140 mg/dL for all meals	15.0 83.3%	8.8 30.3%
PPG <140 mg/dL for breakfast	21.4 118.9%	10.6 36.6%
PPG <180 mg/dL for all meals	69.9 388.3%	59.3 204.5%
PPG <180 mg/dL for breakfast	70.5 391.7%	54.0 186.2%

3. Secondary Outcome

Title	Rates of Hypoglycemia at the End of Each Treatment Period
Description	Overall rates of hypoglycemia (blood glucose ≤70 milligrams per deciliter [mg/dL] and <56 mg/dL) were calculated based on 4 weeks of observation for each treatment period. Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts). A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Time Frame	Week 12 and Week 24

Outcome Measure Data

Analysis Population Description

Participants who completed both Treatment Period 1 and Treatment Period 2.

Arm/Group Title	Analog-PH20	Insulin Lispro
Arm/Group Description	100 units per milliliter (U/mL) insulin lispro or insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (SC), pre-meals, for 12 weeks, with doses titrated to each participant individually	100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, for 12 weeks, with doses titrated to each participant individually
Measure Participants	113	113
≤70 mg/dL	18.96	19.91
<56 mg/dL	7.50	8.05

4. Primary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin A1C (HbA1c) at the End of Each Treatment Period
Description	Glycosylated hemoglobin A1C (HBA1c) levels were measured at baseline (Week 0) and at the end of each treatment period (Week 12 and Week 24). Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts). Least Squares (LS) means were calculated from mixed effects linear models with treatment (Lispro, Aspart), recombinant human hyaluronidase PH20 (rHuPH20; yes, no), and treatment sequence as fixed effects and participant within treatment sequence as a random effect.
Time Frame	Baseline, Week 12 and Week 24

Outcome Measure Data

Analysis Population Description

Participants who completed both Treatment Period 1 and Treatment Period 2 and had evaluable hemoglobin A1C data.

Arm/Group Title	Analog-PH20	Insulin Lispro
Arm/Group Description	100 units per milliliter (U/mL) insulin lispro or insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (SC), pre-meals, for 12 weeks, with doses titrated to each participant individually	100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, for 12 weeks, with doses titrated to each participant individually
Measure Participants	111	110
Mean (Standard Deviation) [percentage of hemoglobin A1C]	-0.14 (0.415)	-0.19 (0.440)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Analog-PH20, Insulin Lispro
	Comments	Approximately 110 participants were to be enrolled, allowing approximately 88 participants to complete both treatment periods (44 for each investigational drug). Assuming a dropout rate of no more than 20%, intra-participant correlation of 0.80, standard deviation of 1.2, and a true difference of 0, the study would have a greater than 90% power to show that Analog-PH20 was non-inferior to insulin lispro alone with respect to the change from baseline in A1C at the end of each treatment period.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	Non-inferiority would be supported if the upper limit of the two-sided 95% confidence interval for the difference between Analog-PH20 and the comparator (insulin lispro) did not exceed 0.40.
Statistical Test of Hypothesis	p-Value	0.2878
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS Means Difference
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline in Body Weight at the End of Each Treatment Period
Description	Body weight was measured at baseline (Week 0) and at the end of each treatment period (Week 12 and Week 24). Data is presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts).
Time Frame	Baseline, Week 12 and Week 24

Outcome Measure Data

Analysis Population Description

Participants who completed both Treatment Period 1 and Treatment Period 2 and had evaluable body weight data.

Arm/Group Title	Analog-PH20	Insulin Lispro
Arm/Group Description	100 units per milliliter (U/mL) insulin lispro or insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (SC), pre-meals, for 12 weeks, with doses titrated to each participant individually	100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, for 12 weeks, with doses titrated to each participant individually
Measure Participants	113	113
Mean (Standard Deviation) [pounds (lbs)]	-0.25 (5.702)	0.10 (4.601)

6. Secondary Outcome

Title	Mean Daily Postprandial Glucose (PPG) Excursions
Description	Participants performed 10-point glucose monitoring for a total of 3 days during each treatment period (3 days during Week 10 of Treatment Period 1 and 3 days during Week 22 of Treatment Period 2). Mean daily postprandial plasma glucose (PPG) excursions (referring to the change in blood glucose levels from before to after a meal) during 10-point glucose monitoring for breakfast, lunch, and dinner are presented. Data were collected 1 and 2 hours (hr) after each meal for 3 days and the means of each excursion are presented.
Time Frame	Week 10 and Week 22

Outcome Measure Data

Analysis Population Description

Participants who completed both Treatment Period 1 and Treatment Period 2 and had evaluable postprandial glucose (PPG) excursion data.

Arm/Group Title	Analog-PH20	Insulin Lispro
Arm/Group Description	100 units per milliliter (U/mL) insulin lispro or insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (SC), pre-meals, for 12 weeks, with doses titrated to each participant individually	100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, for 12 weeks, with doses titrated to each participant individually
Measure Participants	102	106
1-hr breakfast excursion	18.85 (48.348)	27.46 (43.938)
2-hr breakfast excursion	-5.63 (52.657)	7.08 (56.997)
1-hr lunch excursion	16.26 (46.524)	26.25 (39.070)
2-hr lunch excursion	10.68 (53.787)	20.77 (47.005)
1-hr dinner excursion	-0.31 (41.368)	4.47 (52.986)
2-hr dinner excursion	-5.13 (46.956)	-5.16 (54.309)

Adverse Events

Adverse Event Reporting Description	Adverse event data were collected in the Intent-to-Treat (ITT) analysis set, defined as all participants who received at least one injection of study drug during a treatment period and had any efficacy endpoint data collected.
Arm/Group Title	Titration Period (All Enrolled Participants)		Lispro-PH20 Treatment Period		Insulin Lispro (Lispro-PH20 Cohort) Treatment Period		Aspart-PH20 Treatment Period		Insulin Lispro (Aspart-PH20 Cohort) Treatment Period
Arm/Group Description	Prior to randomization, all enrolled participants underwent a titration period of 4-6 weeks in which they received 100 units per milliliter (U/mL) insulin glulisine, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually. Participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.		100 units per milliliter (U/mL) insulin lispro with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually Participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.		Participants were randomized to the Lispro-PH20 cohort. 100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually Participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.		100 units per milliliter (U/mL) insulin aspart with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually Participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.		Participants were randomized to the Aspart-PH20 cohort. 100 units per milliliter (U/mL) insulin lispro, injected subcutaneously (SC), pre-meals, with doses titrated to each participant individually Participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.
All Cause Mortality
	Titration Period (All Enrolled Participants)		Lispro-PH20 Treatment Period		Insulin Lispro (Lispro-PH20 Cohort) Treatment Period		Aspart-PH20 Treatment Period		Insulin Lispro (Aspart-PH20 Cohort) Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Titration Period (All Enrolled Participants)		Lispro-PH20 Treatment Period		Insulin Lispro (Lispro-PH20 Cohort) Treatment Period		Aspart-PH20 Treatment Period		Insulin Lispro (Aspart-PH20 Cohort) Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/135 (1.5%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		1/59 (1.7%)
Cardiac disorders
Pericarditis	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Metabolism and nutrition disorders
Hypoglycaemia	1/135 (0.7%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		1/59 (1.7%)
Other (Not Including Serious) Adverse Events
	Titration Period (All Enrolled Participants)		Lispro-PH20 Treatment Period		Insulin Lispro (Lispro-PH20 Cohort) Treatment Period		Aspart-PH20 Treatment Period		Insulin Lispro (Aspart-PH20 Cohort) Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	48/135 (35.6%)		34/56 (60.7%)		29/57 (50.9%)		27/58 (46.6%)		30/59 (50.8%)
Blood and lymphatic system disorders
Anaemia	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Cardiac disorders
Bradycardia	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Palpitations	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Pericarditis	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Ear and labyrinth disorders
Ear pain	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Endocrine disorders
Goitre	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Eye disorders
Astigmatism	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Conjunctivitis allergic	0/135 (0%)		1/56 (1.8%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Gastrointestinal disorders
Abdominal discomfort	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Abdominal pain upper	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Constipation	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Diarrhoea	3/135 (2.2%)		2/56 (3.6%)		1/57 (1.8%)		1/58 (1.7%)		0/59 (0%)
Dysphagia	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Food poisoning	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Irritable bowel syndrome	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Nausea	2/135 (1.5%)		1/56 (1.8%)		0/57 (0%)		1/58 (1.7%)		3/59 (5.1%)
Oesophageal obstruction	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Oesophageal spasm	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Oral pain	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Stomatitis	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Toothache	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Vomiting	2/135 (1.5%)		1/56 (1.8%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
General disorders
Asthenia	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Chest discomfort	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Chills	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Fatigue	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Influenza like illness	2/135 (1.5%)		2/56 (3.6%)		2/57 (3.5%)		0/58 (0%)		1/59 (1.7%)
Injection site erythema	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Injection site haematoma	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Injection site pain	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Injection site pruritus	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Injection site rash	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Injection site urticaria	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Non-cardiac chest pain	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Oedema peripheral	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Pain	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Pyrexia	2/135 (1.5%)		1/56 (1.8%)		3/57 (5.3%)		0/58 (0%)		0/59 (0%)
Immune system disorders
Allergy to animal	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Infections and infestations
Bronchitis	0/135 (0%)		2/56 (3.6%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Candidiasis	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Conjunctivitis infective	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Cystitis	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Ear infection	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Fungal infection	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Gastroenteritis	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		1/58 (1.7%)		1/59 (1.7%)
Gastroenteritis viral	1/135 (0.7%)		1/56 (1.8%)		2/57 (3.5%)		2/58 (3.4%)		3/59 (5.1%)
Gastrointestinal viral infection	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		2/59 (3.4%)
Herpes zoster	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Influenza	3/135 (2.2%)		2/56 (3.6%)		2/57 (3.5%)		1/58 (1.7%)		0/59 (0%)
Injection site infection	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Laryngitis	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Localised infection	1/135 (0.7%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Lower respiratory tract infection	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Nasopharyngitis	8/135 (5.9%)		8/56 (14.3%)		8/57 (14%)		8/58 (13.8%)		6/59 (10.2%)
Oral herpes	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Pharyngitis	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Pharyngitis streptococcal	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Respiratory tract infection viral	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Sinusitis	5/135 (3.7%)		2/56 (3.6%)		3/57 (5.3%)		5/58 (8.6%)		2/59 (3.4%)
Tinea pedis	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Upper respiratory tract infection	8/135 (5.9%)		7/56 (12.5%)		3/57 (5.3%)		2/58 (3.4%)		3/59 (5.1%)
Urinary tract infection	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		2/58 (3.4%)		0/59 (0%)
Viral infection	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Viral upper respiratory tract infection	2/135 (1.5%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Injury, poisoning and procedural complications
Fall	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Fibula fracture	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Joint sprain	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		1/59 (1.7%)
Ligament rupture	0/135 (0%)		1/56 (1.8%)		1/57 (1.8%)		0/58 (0%)		1/59 (1.7%)
Procedural pain	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Road traffic accident	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Skin laceration	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Stress fracture	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Synovial rupture	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Thermal burn	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Tooth fracture	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Investigations
Weight increased	3/135 (2.2%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	0/135 (0%)		2/56 (3.6%)		1/57 (1.8%)		0/58 (0%)		1/59 (1.7%)
Hypoglycaemia	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Hypokalaemia	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/135 (0.7%)		0/56 (0%)		1/57 (1.8%)		1/58 (1.7%)		1/59 (1.7%)
Back pain	2/135 (1.5%)		2/56 (3.6%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Facet joint syndrome	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Intervertebral disc disorder	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Joint swelling	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Musculoskeletal discomfort	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Musculoskeletal pain	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Myalgia	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		1/59 (1.7%)
Neck pain	0/135 (0%)		1/56 (1.8%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Osteoarthritis	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Pain in extremity	2/135 (1.5%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Plantar fasciitis	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Spinal osteoarthritis	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Spondylolisthesis	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Synovial cyst	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Trochanteric syndrome	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Nervous system disorders
Diabetic neuropathy	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Dizziness	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Headache	2/135 (1.5%)		1/56 (1.8%)		1/57 (1.8%)		4/58 (6.9%)		1/59 (1.7%)
Lethargy	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Paraesthesia	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Psychiatric disorders
Anxiety	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Depression	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Stress	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		1/59 (1.7%)
Renal and urinary disorders
Dysuria	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Nephrolithiasis	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Nocturia	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Urine flow decreased	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Reproductive system and breast disorders
Dysmenorrhoea	0/61 (0%)		0/26 (0%)		1/26 (3.8%)		0/28 (0%)		0/29 (0%)
Gynaecomastia	0/61 (0%)		0/26 (0%)		0/26 (0%)		0/28 (0%)		1/29 (3.4%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Cough	0/135 (0%)		0/56 (0%)		0/57 (0%)		3/58 (5.2%)		0/59 (0%)
Nasal congestion	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		1/59 (1.7%)
Nasal polyps	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Oropharyngeal pain	2/135 (1.5%)		0/56 (0%)		1/57 (1.8%)		1/58 (1.7%)		0/59 (0%)
Paranasal sinus hypersecretion	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Productive cough	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Respiratory tract congestion	0/135 (0%)		1/56 (1.8%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Rhinitis allergic	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Rhinitis seasonal	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Sinus congestion	1/135 (0.7%)		1/56 (1.8%)		2/57 (3.5%)		1/58 (1.7%)		1/59 (1.7%)
Upper respiratory tract congestion	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Skin and subcutaneous tissue disorders
Alopecia	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Dermatitis	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Dermatitis allergic	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		1/59 (1.7%)
Dry skin	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Eczema asteatotic	0/135 (0%)		0/56 (0%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Hyperhidrosis	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Hyperkeratosis	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Rash	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Skin discolouration	0/135 (0%)		1/56 (1.8%)		0/57 (0%)		0/58 (0%)		0/59 (0%)
Stasis dermatitis	0/135 (0%)		0/56 (0%)		0/57 (0%)		1/58 (1.7%)		0/59 (0%)
Urticaria	0/135 (0%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		1/59 (1.7%)
Social circumstances
Stress at work	0/135 (0%)		1/56 (1.8%)		1/57 (1.8%)		0/58 (0%)		0/59 (0%)
Vascular disorders
Hypertension	1/135 (0.7%)		0/56 (0%)		0/57 (0%)		0/58 (0%)		0/59 (0%)

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.