Safety/Efficacy Study of Subcutaneously Injected Prandial... | NCT01194258

Label	Type	Description	Intervention Names
Lispro-PH20/Insulin lispro	Experimental	All enrolled participants underwent a titration period of 4 to 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. Lispro-PH20 (Treatment A): 100 U/mL insulin lispro with 5.0 micrograms per milliliter (µg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (combined: Lispro-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 Drug: Recombinant human hyaluronidase PH20 Drug: Insulin glulisine Drug: Insulin glargine
Aspart-PH20/Insulin Lispro	Experimental	All enrolled participants underwent a titration period of 4 to 6 weeks in which they received 100 U/mL insulin glulisine, injected 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. Aspart-PH20 (Treatment A): 100 U/mL insulin aspart with 5.0 µg/mL rHuPH20 (combined: Aspart-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 Drug: Insulin aspart Drug: Recombinant human hyaluronidase PH20

Name	Type	Description	Arm Group Labels	Other Names
Insulin lispro	Drug		Aspart-PH20/Insulin Lispro Lispro-PH20/Insulin lispro	Lispro Humalog

Measure	Description	Time Frame
Change From Baseline in Glycosylated Hemoglobin A1C (HbA1C) at the End of Each Treatment Period	Change in glycosylated hemoglobin A1C (HbA1C) from baseline (Week 0) to end of treatment period (Week 12 and Week 24) is presented. Data are presented by combined treatment group (Lispro-recombinant human hyaluronidase PH20 (PH20) + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin lispro from both groups). Least squares (LS) means were calculated from linear contrasts of mixed effects linear models with treatment (Lispro, Aspart), PH20 (yes, no), and treatment sequence as fixed effects and participant within treatment sequence as a random effect.	Baseline, Week 12 and Week 24

Measure	Description	Time Frame
Mean Daily Insulin Dose as Recorded During 10-Point Glucose Monitoring	Mean daily insulin dose as recorded during 10-point glucose monitoring is reported. Blood glucose values were obtained during 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) at the following timepoints: immediately prior to breakfast (fasting), 1 hour (hr) after breakfast, 2 hr after breakfast, immediately prior to lunch, 1 hr after lunch, 2 hr after lunch, immediately prior to dinner, 1 hr after dinner, 2 hr after dinner, and at 03:00. A minimum of 7 determinations were required for each day during the 3 days of 10-point glucose profiles. Prandial insulin doses were also recorded during the 10-point glucose monitoring and the mean daily insulin dose over the 3 days was calculated. Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts).

Name	Affiliation	Role
Douglas Muchmore, M.D.	Halozyme Therapeutics	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
John Muir Physician Network Clinical Research Center		Concord	California	94520	United States
Medical Group of Encino

ID	Title	Description
FG000	All Enrolled Participants	Prior to randomization, all enrolled participants underwent a titration period of 4 to 6 weeks in which they received 100 U/mL insulin glulisine, injected 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.

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change From Baseline in Glycosylated Hemoglobin A1C (HbA1C) at the End of Each Treatment Period

Change in glycosylated hemoglobin A1C (HbA1C) from baseline (Week 0) to end of treatment period (Week 12 and Week 24) is presented. Data are presented by combined treatment group (Lispro-recombinant human hyaluronidase PH20 (PH20) + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin lispro from both groups). Least squares (LS) means were calculated from linear contrasts of mixed effects linear models with treatment (Lispro, Aspart), PH20 (yes, no), and treatment sequence as fixed effects and participant within treatment sequence as a random effect.

All participants who completed both Treatment Period 1 and Treatment Period 2 with evaluable HbA1C data.

Posted

Mean

Standard Deviation

percentage of HbA1C

Baseline, Week 12 and Week 24

ID	Title	Description
OG000	Analog-PH20	100 U/mL insulin analog (insulin lispro or insulin aspart) with 5.0 µg/mL rHuPH20, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks
OG001	Insulin Lispro	100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks

Units	Counts
Participants	OG000115 OG001115

Title

Denominators

Categories

Title	Measurements
	OG000-0.48± 0.590 OG001-0.46± 0.571

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Approximately 110 participants were planned to be enrolled to allow approximately 88 participants to complete both treatment periods. Assuming a dropout rate of ≤20%, an intra-participant correlation of 0.80, a standard deviation of 1.2, and a true difference of 0, the study would have >90% power to show that either Lispro-PH20 or Aspart-PH20 (each tested separately) was non-inferior to insulin lispro alone with respect to the change from baseline in A1C at the end of each treatment period.	Mixed Models Analysis		0.3876		LS Mean difference	-0.04	Standard Error of the Mean	0.041	2-Sided	95	-0.12	0.05				Yes	Non-Inferiority or Equivalence

Secondary

Mean Daily Insulin Dose as Recorded During 10-Point Glucose Monitoring

Mean daily insulin dose as recorded during 10-point glucose monitoring is reported. Blood glucose values were obtained during 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) at the following timepoints: immediately prior to breakfast (fasting), 1 hour (hr) after breakfast, 2 hr after breakfast, immediately prior to lunch, 1 hr after lunch, 2 hr after lunch, immediately prior to dinner, 1 hr after dinner, 2 hr after dinner, and at 03:00. A minimum of 7 determinations were required for each day during the 3 days of 10-point glucose profiles. Prandial insulin doses were also recorded during the 10-point glucose monitoring and the mean daily insulin dose over the 3 days was calculated. Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin Lispro from both cohorts).

All participants who completed both Treatment Period 1 and Treatment Period 2 with evaluable insulin dosing data.

Posted

Mean

Standard Deviation

units of Insulin

Week 10 and Week 22

ID	Title	Description
OG000	Analog-PH20	100 U/mL insulin analog (insulin lispro or insulin aspart) with 5.0 µg/mL rHuPH20, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks
OG001	Insulin Lispro	100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks

Secondary

Percentage of Participants Meeting Glucose Targets at Least 2/3 of the Time

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 was recorded during non-10-point glucose monitoring was recorded. The number of participants was recorded, and the percentage of participants meeting glucose targets was calculated by 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).

Participants in Treatment Period 1 or Treatment Period 2 who received at least 1 dose of study drug and had evaluable postprandial blood glucose data.

Posted

Number

Percentage of participants

Baseline through Week 24, excluding 10-point glucose monitoring days

ID	Title	Description
OG000	Analog-PH20	100 U/mL insulin analog (insulin lispro or insulin aspart) with 5.0 µg/mL rHuPH20, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks
OG001	Insulin Lispro	100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks

Secondary

Rates of Hypoglycemia at the End of Each Treatment Period

The rate of hypoglycemia, defined as blood glucose levels ≤70 mg/dL and <56 mg/dL, was calculated based on 4 weeks of observation prior to the end of treatment period (that is, 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 groups). A summary of serious and other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.

All participants who completed both Treatment Period 1 and Treatment Period 2.

Posted

Number

Events per participant per month

Week 12 and Week 24

ID	Title	Description
OG000	Analog-PH20	100 U/mL insulin analog (insulin lispro or insulin aspart) with 5.0 µg/mL rHuPH20, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks
OG001	Insulin Lispro	100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks

Units	Counts
Participants

Secondary

Change From Baseline in Body Weight at the End of Each Treatment Period

Change from baseline in body weight at the end of each treatment period (Week 12 and Week 24) is presented. Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (Insulin lispro from both cohorts).

All participants who completed both Period 1 and Period 2 with evaluable body weight data.

Posted

Mean

Standard Deviation

pounds

Baseline, Week 12 and Week 24

ID	Title	Description
OG000	Analog-PH20	100 U/mL insulin analog (Insulin lispro or insulin aspart) with 5.0 µg/mL rHuPH20, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks
OG001	Insulin-lispro	100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks

Units	Counts
Participants	OG000

Secondary

Mean Daily PPG Excursions

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 PPG excursions during 10-point glucose monitoring for breakfast, lunch, and dinner from Treatment Period 1 or Treatment Period 2 are presented. PPG refers to the change in glucose concentration before to after a meal. Data were collected 1 and 2 hours (hr) after each meal. Data are presented by combined treatment group (Lispro-PH20 + Aspart-PH20 = Analog-PH20) and combined comparator drug (insulin lispro from both cohorts).

All participants who completed both Period 1 and Period 2 with evaluable PPG excursion data.

Posted

Mean

Standard Deviation

mg/dL

Week 10 and Week 22

ID	Title	Description
OG000	Analog-PH20	100 U/mL insulin analog (insulin lispro or insulin aspart) with 5.0 µg/mL rHuPH20, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks
OG001	Insulin Lispro	100 U/mL insulin lispro, injected SC, pre-meals, with doses titrated to each participant individually, for 12 weeks

Units	Counts

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Lymphadenopathy	Blood and lymphatic system disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG0030 events0 affected60 at risk EG0040 events0 affected62 at risk
Lymphadenopathy mediastinal	Blood and lymphatic system disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Atrial fibrillation	Cardiac disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Coronary artery disease	Cardiac disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Palpitations	Cardiac disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Cerumen impaction	Ear and labyrinth disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Vertigo positional	Ear and labyrinth disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Hypogonadism	Endocrine disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Conjunctivitis	Eye disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Retinopathy proliferative	Eye disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Vision blurred	Eye disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Chalazion	Eye disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Vitreous detachment	Eye disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0003 events3 affected132 at risk EG0010 events0 affected59 at risk EG0025 events5 affected59 at risk EG003
Nausea	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0002 events1 affected132 at risk EG0011 events1 affected59 at risk EG0023 events3 affected59 at risk EG003
Vomiting	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0022 events2 affected59 at risk EG003
Constipation	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Food poisoning	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Abdominal pain	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Colonic polyp	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Diverticulum	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Oral pain	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Toothache	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Tooth disorder	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Faeces hard	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Oedema peripheral	General disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0012 events1 affected59 at risk EG0022 events2 affected59 at risk EG003
Chest discomfort	General disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Facial pain	General disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Injection site haematoma	General disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0022 events2 affected59 at risk EG003
Injection site inflammation	General disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Non-cardiac chest pain	General disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Pain	General disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Pyrexia	General disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0002 events2 affected132 at risk EG0012 events2 affected59 at risk EG0024 events3 affected59 at risk EG003
Influenza	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0002 events2 affected132 at risk EG0012 events2 affected59 at risk EG0021 events1 affected59 at risk EG003
Upper respiratory tract infection	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0006 events6 affected132 at risk EG0014 events4 affected59 at risk EG0029 events7 affected59 at risk EG003
Gastroenteritis	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Gastroenteritis viral	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Sinusitis	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0003 events3 affected132 at risk EG0011 events1 affected59 at risk EG0022 events2 affected59 at risk EG003
Bronchitis	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Cellulitis	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Ear infection	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Acute sinusitis	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Lobar pneumonia	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Herpes zoster	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Tonsillitis	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Excoriation	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0023 events2 affected59 at risk EG003
Ligament sprain	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Muscle rupture	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Procedural pain	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Thermal burn	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Traumatic haematoma	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Contusion	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Road traffic accident	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Weight increased	Investigations	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Cardiac murmur	Investigations	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Increased appetite	Metabolism and nutrition disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Central obesity	Metabolism and nutrition disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Decreased appetite	Metabolism and nutrition disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Hypoglycaemia	Metabolism and nutrition disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Vitamin D deficiency	Metabolism and nutrition disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0002 events2 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Intervertebral disc protrusion	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Osteoarthritis	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Flank pain	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Vertebral foraminal stenosis	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Metatarsalgia	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Neck pain	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Temporomandibular joint syndrome	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Trigger finger	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Lung neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected53 at risk EG0010 events0 affected10 at risk EG0020 events0 affected10 at risk EG003
Carpal tunnel syndrome	Nervous system disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0011 events1 affected59 at risk EG0022 events2 affected59 at risk EG003
Headache	Nervous system disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0012 events2 affected59 at risk EG0020 events0 affected59 at risk EG003
Cluster headache	Nervous system disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Diabetic neuropathy	Nervous system disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Neuropathy peripheral	Nervous system disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Post herpetic neuralgia	Nervous system disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Dizziness	Nervous system disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Migraine	Nervous system disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Insomnia	Psychiatric disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0021 events1 affected59 at risk EG003
Anxiety	Psychiatric disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Delirium	Psychiatric disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Nephrolithiasis	Renal and urinary disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Dysuria	Renal and urinary disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Renal failure acute	Renal and urinary disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Erectile dysfunction	Reproductive system and breast disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected79 at risk EG0011 events1 affected38 at risk EG0020 events0 affected38 at risk EG003
Prostatitis	Reproductive system and breast disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected79 at risk EG0010 events0 affected38 at risk EG0020 events0 affected38 at risk EG003
Testicular pain	Reproductive system and breast disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected79 at risk EG0010 events0 affected38 at risk EG0020 events0 affected38 at risk EG003
Testicular swelling	Reproductive system and breast disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected79 at risk EG0010 events0 affected38 at risk EG0020 events0 affected38 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0002 events2 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0011 events1 affected59 at risk EG0021 events1 affected59 at risk EG003
Respiratory tract congestion	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Sinus congestion	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Rhinitis seasonal	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Sleep apnoea syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Dermatitis contact	Skin and subcutaneous tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Seborrhoeic dermatitis	Skin and subcutaneous tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0022 events2 affected59 at risk EG003
Blister	Skin and subcutaneous tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Acanthosis nigricans	Skin and subcutaneous tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Ingrowing nail	Skin and subcutaneous tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Hypertension	Vascular disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Flushing	Vascular disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0021 events1 affected59 at risk EG003
Peripheral arterial occlusive disease	Vascular disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003
Nasal congestion	Respiratory, thoracic and mediastinal disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Seasonal allergy	Immune system disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Depression	Psychiatric disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Anaemia	Blood and lymphatic system disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Fatigue	General disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Otitis externa	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Eye infection	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Parotitis	Infections and infestations	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Muscle strain	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0002 events2 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Skin laceration	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Joint sprain	Injury, poisoning and procedural complications	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Gout	Metabolism and nutrition disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Tendonitis	Musculoskeletal and connective tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Hyperkeratosis	Skin and subcutaneous tissue disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0011 events1 affected59 at risk EG0020 events0 affected59 at risk EG003

ID	Term
D003920	Diabetes Mellitus
D044882	Glucose Metabolism Disorders
D008659	Metabolic Diseases
D009750	Nutritional and Metabolic Diseases
D004700	Endocrine System Diseases

ID	Term
D061268	Insulin Lispro
D061267	Insulin Aspart
C479079	insulin glulisine
D000069036	Insulin Glargine

ID	Term
D061266	Insulin, Short-Acting
D061385	Insulins
D010187	Pancreatic Hormones
D036361	Peptide Hormones
D006728	Hormones
D006730	Hormones, Hormone Substitutes, and Hormone Antagonists
D010455	Peptides
D000602	Amino Acids, Peptides, and Proteins
D049528	Insulin, Long-Acting

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Titration Period	Prior to randomization, all enrolled participants underwent a titration period of 4 to 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.	2	132	34	132
EG001	Insulin Lispro (Lispro-PH20 Cohort)	Participants randomized to the Lispro-PH20 cohort. Participants received a SC injection of 100 U/mL insulin lispro alone pre-meals for 12 weeks during Treatment Period 1 or 2 of the study. Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	0	59	19	59
EG002	Lispro-PH20	Participants received a SC injection of 100 U/mL insulin lispro with 5 micrograms (μg) rHuPH20 pre-meals for 12 weeks during Treatment Period 1 or 2 of the study. Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	0	59	29	59
EG003	Insulin Lispro (Aspart-PH20 Cohort)	Participants randomized to the Aspart-PH20 cohort. Participants received a SC injection of 100 U/mL insulin lispro alone pre-meals for 12 weeks during Treatment Period 1 or 2 of the study. Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	1	60	32	60
EG004	Aspart-PH20	Participants received a SC injection of 100 U/mL insulin aspart and 5 μg rHuPH20 pre-meals for 12 weeks during Treatment Period 1 or 2 of the study. Throughout the study, participants requiring basal insulin used twice daily SC injections of 100 U/mL insulin glargine.	4	62	35	62

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Acute myocardial infarction	Cardiac disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG0030 events0 affected60 at risk EG0042 events2 affected62 at risk
Cardiac failure congestive	Cardiac disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Angina unstable	Cardiac disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Partial seizures	Nervous system disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Transient ischemic attack	Nervous system disorders	MedDRA (12.0)	Systematic Assessment	EG0000 events0 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Dyspepsia	Gastrointestinal disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003
Anaphylactic reaction	Immune system disorders	MedDRA (12.0)	Systematic Assessment	EG0001 events1 affected132 at risk EG0010 events0 affected59 at risk EG0020 events0 affected59 at risk EG003