Trial Outcomes & Findings for Randomized, Double Blind, 2 Way Crossover Study of CSII With, Versus Without, Pretreatment With Human Hyaluronidase (NCT NCT01526733)

Last Updated: 2019-02-26

Results Overview

Early insulin exposure, defined as the percentage of total insulin exposure (area under the insulin concentration curve \[AUC{0 360}\]) that occurs within the first hour following bolus dose of insulin during the 2 euglycemic clamps is presented. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose during a euglycemic clamp.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

25 participants

Primary outcome timeframe

10 minutes predose; 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose on Days 1 and 4

Results posted on

2019-02-26

Participant Flow

Participant milestones

Participant milestones
Measure	Insulin-rHuPH20, Then Insulin-sham In Phase I, participants received 0.15 units per kilogram (U/kg) insulin (either insulin aspart or insulin lispro) as a continuous subcutaneous insulin infusion (CSII) for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 milliliter (mL) (150 U) injection of recombinant human hyaluronidase PH20 (rHuPH20). In Phase II, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with a sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Phase I and II were separated by a washout period of 5 to 21 days.	Insulin-sham, Then Insulin-rHuPH20 In Phase I, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with a sham injection administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. In Phase II, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Phase I and Phase II were separated by a washout period of 5 to 21 days.
Phase 1 STARTED	12	13
Phase 1 Received at Least 1 Dose of Study Drug	12	13
Phase 1 COMPLETED	10	12
Phase 1 NOT COMPLETED	2	1
Washout Period of 5 to 21 Days STARTED	10	12
Washout Period of 5 to 21 Days COMPLETED	10	12
Washout Period of 5 to 21 Days NOT COMPLETED	0	0
Phase 2 STARTED	10	12
Phase 2 COMPLETED	10	12
Phase 2 NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Insulin-rHuPH20, Then Insulin-sham In Phase I, participants received 0.15 units per kilogram (U/kg) insulin (either insulin aspart or insulin lispro) as a continuous subcutaneous insulin infusion (CSII) for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 milliliter (mL) (150 U) injection of recombinant human hyaluronidase PH20 (rHuPH20). In Phase II, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with a sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Phase I and II were separated by a washout period of 5 to 21 days.	Insulin-sham, Then Insulin-rHuPH20 In Phase I, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with a sham injection administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. In Phase II, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Phase I and Phase II were separated by a washout period of 5 to 21 days.
Phase 1 Protocol Violation	1	0
Phase 1 Withdrawal by Subject	1	1

Baseline Characteristics

Randomized, Double Blind, 2 Way Crossover Study of CSII With, Versus Without, Pretreatment With Human Hyaluronidase

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	All Enrolled Participants n=25 Participants All participants enrolled in the study.
Age, Continuous	31.6 years STANDARD_DEVIATION 9.13 • n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants
Sex: Female, Male Male	11 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	2 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	23 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	23 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment United States	25 participants n=5 Participants

PRIMARY outcome

Timeframe: 10 minutes predose; 0, 5, 10, 15, 20, 30, 45, and 60 minutes postdose on Days 1 and 4

Population: Participants who completed both phases of the study and with evaluable %AUC(0-60) data.

Outcome measures

Outcome measures
Measure	Insulin (Aspart or Lispro)-rHuPH20 n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	Insulin (Aspart or Lispro)-Sham n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Early Insulin Exposure (%AUC[0-60]) Day 1	33.53 percentage of AUC(0-60) Standard Deviation 11.81	17.85 percentage of AUC(0-60) Standard Deviation 8.24
Early Insulin Exposure (%AUC[0-60]) Day 4	39.45 percentage of AUC(0-60) Standard Deviation 9.72	33.52 percentage of AUC(0-60) Standard Deviation 10.78

SECONDARY outcome

Timeframe: 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

Population: Participants who completed both phases of the study and with evaluable GIRmax data.

Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Outcome measures

Outcome measures
Measure	Insulin (Aspart or Lispro)-rHuPH20 n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	Insulin (Aspart or Lispro)-Sham n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Maximum Glucose Infusion Rate (GIRmax) Day 1	13.47 milligrams/kilogram/minute Standard Deviation 5.46	11.14 milligrams/kilogram/minute Standard Deviation 4.21
Maximum Glucose Infusion Rate (GIRmax) Day 4	10.75 milligrams/kilogram/minute Standard Deviation 3.73	11.83 milligrams/kilogram/minute Standard Deviation 3.26

SECONDARY outcome

Timeframe: 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

Population: Participants who completed both phases of the study and with evaluable tGIRmax data.

Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Outcome measures

Outcome measures
Measure	Insulin (Aspart or Lispro)-rHuPH20 n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	Insulin (Aspart or Lispro)-Sham n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax) Day 4	81.86 minutes Standard Deviation 45.99	97.38 minutes Standard Deviation 47.31
Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax) Day 1	78.95 minutes Standard Deviation 37.16	132.62 minutes Standard Deviation 55.07

SECONDARY outcome

Timeframe: 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

Population: Participants who completed both phases of the study and with evaluable early and late tGIR50%max data.

Early and late tGIR50%max are presented. Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Outcome measures

Outcome measures
Measure	Insulin (Aspart or Lispro)-rHuPH20 n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	Insulin (Aspart or Lispro)-Sham n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) Early tGIR50%, Day 1	40.33 minutes Standard Deviation 20.13	54.67 minutes Standard Deviation 33.97
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) Late tGIR50%, Day 1	114.52 minutes Standard Deviation 54.33	152.14 minutes Standard Deviation 61.00
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) Early tGIR50%, Day 4	32.57 minutes Standard Deviation 14.50	39.67 minutes Standard Deviation 15.51
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max) Late tGIR50%, Day 4	113.24 minutes Standard Deviation 48.72	126.71 minutes Standard Deviation 50.37

SECONDARY outcome

Timeframe: 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

Population: Participants who completed both phases of the study and with evaluable 50%Gtot data.

Blood samples were collected at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Outcome measures

Outcome measures
Measure	Insulin (Aspart or Lispro)-rHuPH20 n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	Insulin (Aspart or Lispro)-Sham n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Time to 50% Total Glucose Infused (50%Gtot) Day 1	40.33 minutes Standard Deviation 20.13	32.57 minutes Standard Deviation 14.50
Time to 50% Total Glucose Infused (50%Gtot) Day 4	54.67 minutes Standard Deviation 54.67	39.67 minutes Standard Deviation 15.51

SECONDARY outcome

Timeframe: 30 minutes and 10 minutes predose; 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

Population: Participants who completed both phases of the study and with evaluable AUC(0-360) data.

Area under the glucose concentration curve from 0 to 360 minutes (AUC\[0-360\]) is presented. Blood samples were collected 30 and 10 minutes prior to insulin bolus and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Outcome measures

Outcome measures
Measure	Insulin (Aspart or Lispro)-rHuPH20 n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	Insulin (Aspart or Lispro)-Sham n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Area Under the Glucose Concentration Curve (AUC[0-360]) Day 4	1063.77 picomoles*minutes/liter Standard Deviation 500.06	1139.65 picomoles*minutes/liter Standard Deviation 414.94
Area Under the Glucose Concentration Curve (AUC[0-360]) Day 1	1312.41 picomoles*minutes/liter Standard Deviation 627.33	1199.54 picomoles*minutes/liter Standard Deviation 535.80

SECONDARY outcome

Timeframe: 10 minutes predose; 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose on Days 1 and 4

Population: Participants who completed both phases of the study and with evaluable AUMC(0-360)/AUC(0-360) data.

Duration of insulin action was calculated by dividing the area under the first moment curve (AUMC\[0-360\]) by the area under the concentration versus time curve (AUC\[0-360\]). AUCM is the total area under the first moment curve. First moment curve is obtained by plotting concentration-time versus time. It can be used to measure how long a drug stays in the body. Blood samples were collected 10 minutes predose and at 0, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 300, and 360 minutes postdose during a euglycemic clamp.

Outcome measures

Outcome measures
Measure	Insulin (Aspart or Lispro)-rHuPH20 n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	Insulin (Aspart or Lispro)-Sham n=21 Participants In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Duration of Insulin Action (AUMC[0-360]/AUC[0-360]) Day 4	111.25 ratio Standard Deviation 20.59	120.57 ratio Standard Deviation 20.85
Duration of Insulin Action (AUMC[0-360]/AUC[0-360]) Day 1	119.02 ratio Standard Deviation 21.18	154.03 ratio Standard Deviation 27.58

Adverse Events

Insulin (Aspart or Lispro)-rHuPH20

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Insulin (Aspart or Lispro)-Sham

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Vice President, Endocrinology Clinical Development

Halozyme Therapeutics, Inc

Phone: 858-794-8889

Results disclosure agreements

Principal investigator is a sponsor employee 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 prior written permission from the Sponsor (Halozyme) is obtained.
Publication restrictions are in place

Restriction type: OTHER

Measure	Insulin (Aspart or Lispro)-rHuPH20 n=24 participants at risk In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days. Prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16, participants received a 1 mL (150 U) injection of rHuPH20. Each Phase was separated by a washout period of 5 to 21 days.	Insulin (Aspart or Lispro)-Sham n=23 participants at risk In Phase I or Phase II of the study, participants received 0.15 U/kg insulin (either insulin aspart or insulin lispro) as a CSII for 16 days, with sham injections administered prior to outpatient euglycemic clamps on Days 1 and 4 and prior to outpatient meal test procedures on Days 7, 10, 13, and 16. Each Phase was separated by a washout period of 5 to 21 days.
Blood and lymphatic system disorders Anaemia	8.3% 2/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	17.4% 4/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Gastrointestinal disorders Nausea	8.3% 2/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	4.3% 1/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Gastrointestinal disorders Vomiting	8.3% 2/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	0.00% 0/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Gastrointestinal disorders Constipation	4.2% 1/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	0.00% 0/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
General disorders Injection site pain	12.5% 3/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	4.3% 1/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
General disorders Injection site pruritus	4.2% 1/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	8.7% 2/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
General disorders Injection site haemorrhage	4.2% 1/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	0.00% 0/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
General disorders Injection site haematoma	4.2% 1/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	0.00% 0/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
General disorders Injection site induration	4.2% 1/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	0.00% 0/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
General disorders Injection site inflammation	0.00% 0/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	4.3% 1/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
General disorders Tenderness	0.00% 0/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	4.3% 1/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Infections and infestations Upper respiratory tract infection	4.2% 1/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	4.3% 1/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Injury, poisoning and procedural complications Clavicle fracture	0.00% 0/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	4.3% 1/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Injury, poisoning and procedural complications Sunburn	4.2% 1/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	0.00% 0/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Nervous system disorders Headache	8.3% 2/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	13.0% 3/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Musculoskeletal and connective tissue disorders Neck pain	0.00% 0/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	4.3% 1/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Respiratory, thoracic and mediastinal disorders Cough	4.2% 1/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	0.00% 0/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Respiratory, thoracic and mediastinal disorders Dysphonia	4.2% 1/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	0.00% 0/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	4.2% 1/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	0.00% 0/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.
Skin and subcutaneous tissue disorders Ecchymosis	4.2% 1/24 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.	0.00% 0/23 Insulin was not considered a study drug for safety assessments and causality assessments were done for rHuPH20 only.