Trial Outcomes & Findings for Randomized, Double-blind, Crossover, Pharmacokinetic (PK) and Glucodynamic (GD) Study of Continuous Subcutaneous Insulin Infusion (CSII) in Participants With Type 1 Diabetes Mellitus (T1DM) (NCT NCT01275131)

Last Updated: 2014-07-25

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, 60, 120, 150, 180, 240, 300, and 360 minutes postdose during the euglycemic clamp.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

45 participants

Primary outcome timeframe

10 minutes predose up to 60 minutes postdose

Results posted on

2014-07-25

Participant Flow

Participant milestones

Participant milestones
Measure	Stage 1: Insulin Aspart First, Then Insulin Aspart-rHuPH20 Participants first received 0.15 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4. After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart and 5-micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8.	Stage 1: Insulin Aspart-rHuPH20 First, Then Insulin Aspart Participants first received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4. After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart alone as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8.	Stage 3: Insulin Aspart First, Then Insulin Aspart + rHuPH20 Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a sham injection was administered 2.5 hr prior to the 6-hr euglycemic clamp. After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII, for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a 1.0 milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to the 6-hr euglycemic clamp.	Stage 3: Insulin Aspart + rHuPH20 First, Then Insulin Aspart Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a 1.0 milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to the 6-hr euglycemic clamp . After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII, for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a sham injection was administered 2.5 hr prior to the 6-hr euglycemic clamp.
Period 1 STARTED	11	9	13	12
Period 1 Received at Least One Dose of Study Drug	11	9	13	12
Period 1 COMPLETED	9	9	10	10
Period 1 NOT COMPLETED	2	0	3	2
5- to 14-Day Washout Period STARTED	9	9	10	10
5- to 14-Day Washout Period COMPLETED	9	9	10	10
5- to 14-Day Washout Period NOT COMPLETED	0	0	0	0
Period 2 (Crossover) STARTED	9	9	10	10
Period 2 (Crossover) COMPLETED	8	8	9	8
Period 2 (Crossover) NOT COMPLETED	1	1	1	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Stage 1: Insulin Aspart First, Then Insulin Aspart-rHuPH20 Participants first received 0.15 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4. After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart and 5-micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8.	Stage 1: Insulin Aspart-rHuPH20 First, Then Insulin Aspart Participants first received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4. After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart alone as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8.	Stage 3: Insulin Aspart First, Then Insulin Aspart + rHuPH20 Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a sham injection was administered 2.5 hr prior to the 6-hr euglycemic clamp. After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII, for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a 1.0 milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to the 6-hr euglycemic clamp.	Stage 3: Insulin Aspart + rHuPH20 First, Then Insulin Aspart Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a 1.0 milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to the 6-hr euglycemic clamp . After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII, for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a sham injection was administered 2.5 hr prior to the 6-hr euglycemic clamp.
Period 1 Withdrawal by Subject	1	0	3	2
Period 1 Physician Decision	1	0	0	0
Period 2 (Crossover) Adverse Event	0	1	0	0
Period 2 (Crossover) Withdrawal by Subject	1	0	1	2

Baseline Characteristics

Randomized, Double-blind, Crossover, Pharmacokinetic (PK) and Glucodynamic (GD) Study of Continuous Subcutaneous Insulin Infusion (CSII) in Participants With Type 1 Diabetes Mellitus (T1DM)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Stage 1: Insulin Aspart First, Then Insulin Aspart-rHuPH20 n=11 Participants Participants first received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4. After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8.	Stage 1: Insulin Aspart-rHuPH20 First, Then Insulin Aspart n=9 Participants Participants first received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4. After a 5- to 14-day washout period, participants received 0.15 U/kg insulin aspart alone as a CSII, for 4 days (Days 5-8; Period 2), including during a 6-hr euglycemic clamp on Days 6 and 8.	Stage 3: Insulin Aspart First, Then Insulin Aspart + rHuPH20 n=13 Participants Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a sham injection was administered 2.5 hr prior to the 6-hr euglycemic clamp. After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a 1.0-milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to a 6-hr euglycemic clamp.	Stage 3: Insulin Aspart + rHuPH20 First, Then Insulin Aspart n=12 Participants Participants first received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5; Period 1), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5. On Day 2 only, a 1.0-milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to the euglycemic clamp . After a 5- to 14-day washout period, participants received 0.12 U/kg insulin aspart administered as a CSII, for 5 days (Days 6-10; Period 2), including during a 6-hr euglycemic clamp on Days 7, 8, and 10. On Day 7 only, a sham injection was administered 2.5 hr prior to a 6-hr euglycemic clamp.	Total n=45 Participants Total of all reporting groups
Age, Continuous	31.3 Years STANDARD_DEVIATION 6.39 • n=93 Participants	44.6 Years STANDARD_DEVIATION 9.00 • n=4 Participants	35.5 Years STANDARD_DEVIATION 9.50 • n=27 Participants	32.3 Years STANDARD_DEVIATION 10.29 • n=483 Participants	35.44 Years STANDARD_DEVIATION 9.95 • n=36 Participants
Sex: Female, Male Female	6 Participants n=93 Participants	3 Participants n=4 Participants	7 Participants n=27 Participants	6 Participants n=483 Participants	22 Participants n=36 Participants
Sex: Female, Male Male	5 Participants n=93 Participants	6 Participants n=4 Participants	6 Participants n=27 Participants	6 Participants n=483 Participants	23 Participants n=36 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants	1 Participants n=483 Participants	2 Participants n=36 Participants
Race (NIH/OMB) White	11 Participants n=93 Participants	9 Participants n=4 Participants	11 Participants n=27 Participants	11 Participants n=483 Participants	42 Participants n=36 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	1 Participants n=27 Participants	0 Participants n=483 Participants	1 Participants n=36 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=93 Participants	1 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	2 Participants n=36 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	10 Participants n=93 Participants	8 Participants n=4 Participants	13 Participants n=27 Participants	12 Participants n=483 Participants	43 Participants n=36 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants	0 Participants n=483 Participants	0 Participants n=36 Participants
Region of Enrollment United States	11 Participants n=93 Participants	9 Participants n=4 Participants	13 Participants n=27 Participants	12 Participants n=483 Participants	45 Participants n=36 Participants

PRIMARY outcome

Timeframe: 10 minutes predose up to 60 minutes postdose

Population: Participants who completed all study periods within a given stage with evaluable early insulin exposure (%AUC\[0-60\]) data.

Outcome measures

Outcome measures
Measure	Stage 1: Insulin Aspart Alone n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Early Insulin Exposure (%AUC[0-60]), Stage 1 Stage 1, Day 2/6	20.99 Percentage of AUC(0-360) Standard Deviation 6.37	34.94 Percentage of AUC(0-360) Standard Deviation 9.48
Early Insulin Exposure (%AUC[0-60]), Stage 1 Stage 1, Day 4/8	32.83 Percentage of AUC(0-360) Standard Deviation 14.66	50.97 Percentage of AUC(0-360) Standard Deviation 13.91

PRIMARY outcome

Timeframe: 10 minutes predose up to 60 minutes postdose on Days 2/7, 3/8, and 5/10

Population: Participants who completed all periods of study within a given stage with evaluable %AUC(0-60) data.

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, 60, 120, 150, 180, 240, 300, and 360 minutes postdose during the euglycemic clamp.

Outcome measures

Outcome measures
Measure	Stage 1: Insulin Aspart Alone n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Early Exposure to Insulin (%AUC[0-60]), Stage 3 Stage 3, Day 2/7	15.70 Percentage of AUC(0-360) Standard Deviation 6.38	32.11 Percentage of AUC(0-360) Standard Deviation 10.91
Early Exposure to Insulin (%AUC[0-60]), Stage 3 Stage 3, Day 3/8	22.29 Percentage of AUC(0-360) Standard Deviation 5.43	36.39 Percentage of AUC(0-360) Standard Deviation 9.43
Early Exposure to Insulin (%AUC[0-60]), Stage 3 Stage 3, Day 5/10	27.31 Percentage of AUC(0-360) Standard Deviation 10.49	32.64 Percentage of AUC(0-360) Standard Deviation 11.32

SECONDARY outcome

Timeframe: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8

Population: Participants who completed all periods of study within a given stage with evaluable GIRmax data.

Maximum glucose infusion rates (GIRmax) for Stage1 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	Stage 1: Insulin Aspart Alone n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Maximum Glucose Infusion Rate (GIRmax), Stage 1 Stage 1, Day 4/8	11.88 Milligrams/kilogram/minute Standard Deviation 3.64	11.52 Milligrams/kilogram/minute Standard Deviation 3.67
Maximum Glucose Infusion Rate (GIRmax), Stage 1 Stage 1, Day 2/6	13.37 Milligrams/kilogram/minute Standard Deviation 4.23	12.51 Milligrams/kilogram/minute Standard Deviation 3.19

SECONDARY outcome

Timeframe: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10

Population: Participants who completed all periods of study within a given stage with evaluable GIRmax data.

Maximum glucose infusion rates (GIRmax) for Stage 3 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	Stage 1: Insulin Aspart Alone n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Maximum Glucose Infusion Rate (GIRmax), Stage 3 Stage 3, Day 2/7	9.58 Milligrams/kilogram/minute Standard Deviation 2.28	12.63 Milligrams/kilogram/minute Standard Deviation 3.88
Maximum Glucose Infusion Rate (GIRmax), Stage 3 Stage 3, Day 3/8	10.07 Milligrams/kilogram/minute Standard Deviation 3.36	12.4 Milligrams/kilogram/minute Standard Deviation 3.39
Maximum Glucose Infusion Rate (GIRmax), Stage 3 Stage 3, Day 5/10	9.97 Milligrams/kilogram/minute Standard Deviation 3.53	10.76 Milligrams/kilogram/minute Standard Deviation 3.35

SECONDARY outcome

Timeframe: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8

Population: Participants who completed all periods of study within a given stage with evaluable tGIRmax data.

Time to first occurrence of maximum glucose infusion rate (tGIRmax) for Stage 1 is 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	Stage 1: Insulin Aspart Alone n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 1 Stage 1, Day 2/6	115.38 Minutes Standard Deviation 59.21	102.38 Minutes Standard Deviation 38.28
Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 1 Stage 1, Day 4/8	92.50 Minutes Standard Deviation 24.71	84.31 Minutes Standard Deviation 25.89

SECONDARY outcome

Timeframe: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10

Population: Participants who completed all periods of study within a given stage with evaluable tGIRmax data.

Time to first occurrence of maximum glucose infusion rate (tGIRmax) for Stage 3 is 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	Stage 1: Insulin Aspart Alone n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 Stage 3, Day 2/7	127.65 Minutes Standard Deviation 60.02	78.53 Minutes Standard Deviation 27.04
Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 Stage 3, Day 3/8	135.24 Minutes Standard Deviation 73.00	79.47 Minutes Standard Deviation 42.57
Time to First Occurrence of Maximum Glucose Infusion Rate (tGIRmax), Stage 3 Stage 3, Day 5/10	117.76 Minutes Standard Deviation 75.20	79.53 Minutes Standard Deviation 42.99

SECONDARY outcome

Timeframe: 0 up to 360 minutes postdose on day 2/6 and Day 4/8

Population: Participants who completed all periods of study within a given stage with evaluable early or late tGIR50%max data.

Early and late times to 50% maximum glucose infusion rate (tGIR50%max) for Stage 1 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	Stage 1: Insulin Aspart Alone n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 Early tGIR50%max, Stage 1, Day 2/6	46.50 Minutes Standard Deviation 18.08	34.88 Minutes Standard Deviation 17.92
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 Late tGIR50%max, Stage 1, Day 2/6	162.19 Minutes Standard Deviation 56.78	158.06 Minutes Standard Deviation 52.58
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 Early tGIR50%max, Stage 1, Day 4/8	35.19 Minutes Standard Deviation 28.54	39.75 Minutes Standard Deviation 18.71
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 1 Late tGIR50%max, Stage 1, Day 4/8	132.63 Minutes Standard Deviation 47.37	114.19 Minutes Standard Deviation 29.05

SECONDARY outcome

Timeframe: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10

Population: Participants who completed all periods of study within a given stage with evaluable early and late tGIR50%max data.

Early and late time to 50% maximum glucose infusion rates (tGIR50%max) for Stage 3 studies 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	Stage 1: Insulin Aspart Alone n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 Early tGIR50%max, Stage 3, Day 2/7	58.47 Minutes Standard Deviation 17.53	31.06 Minutes Standard Deviation 20.73
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 Late tGIR50%max, Stage 3, Day 2/7	144.18 Minutes Standard Deviation 61.44	98.71 Minutes Standard Deviation 39.87
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 Early tGIR50%max, Stage 3, Day 3/8	32.59 Minutes Standard Deviation 22.88	31.53 Minutes Standard Deviation 21.27
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 Late tGIR50%max, Stage 3, Day 3/8	153.41 Minutes Standard Deviation 65.35	102.88 Minutes Standard Deviation 44.57
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 Early tGIR50%max, Stage 3, Day 5/10	27.29 Minutes Standard Deviation 18.40	28.88 Minutes Standard Deviation 21.97
Time to 50% Maximum Glucose Infusion Rate (tGIR50%Max), Stage 3 Late tGIR50%max, Stage 3, Day 5/10	136.88 Minutes Standard Deviation 73.39	110.59 Minutes Standard Deviation 55.10

SECONDARY outcome

Timeframe: 0 up to 360 minutes postdose on Day 2/6 and Day 4/8

Population: Participants who completed all periods of study within a given stage with evaluable 50%Gtot data.

Time to 50% total glucose infused (50%Gtot) is presented for Stage 1. 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	Stage 1: Insulin Aspart Alone n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Time to 50% Total Glucose Infused (50%Gtot), Stage 1 Stage 1, Day 2/6	156.13 Minutes Standard Deviation 18.70	134.94 Minutes Standard Deviation 18.28
Time to 50% Total Glucose Infused (50%Gtot), Stage 1 Stage 1, Day 4/8	137.38 Minutes Standard Deviation 22.21	115.25 Minutes Standard Deviation 14.50

SECONDARY outcome

Timeframe: 0 up to 360 minutes postdose on Days 2/7, 3/8, and 5/10

Population: Participants who completed all periods of study within a given stage with evaluable 50%Gtot data.

Time to 50% of total glucose infused (50%Gtot) is presented for Stage 3. 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	Stage 1: Insulin Aspart Alone n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Time to 50% Total Glucose Infused (50%Gtot), Stage 3 Stage 3, Day 2/7	174.59 Minutes Standard Deviation 25.86	124.18 Minutes Standard Deviation 22.03
Time to 50% Total Glucose Infused (50%Gtot), Stage 3 Stage 3, Day 3/8	154.06 Minutes Standard Deviation 24.02	120.00 Minutes Standard Deviation 17.12
Time to 50% Total Glucose Infused (50%Gtot), Stage 3 Stage 3, Day 5/10	146.59 Minutes Standard Deviation 28.63	130.18 Minutes Standard Deviation 23.54

SECONDARY outcome

Timeframe: 30 minutes predose up to 360 minutes postdose on Day 2/6 and Day 4/8

Population: Participants who completed all periods of study within a given stage with evaluable AUC(0-360) data.

Area under the glucose concentration curve for 0 to 360 minutes (AUC\[0-360\]) from Stage 1 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	Stage 1: Insulin Aspart Alone n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 1 Stage 1, Day 2/6	1978.08 Picomoles*minutes/liter Standard Deviation 631.89	1977.02 Picomoles*minutes/liter Standard Deviation 795.79
Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 1 Stage 1, Day 4/8	1598.40 Picomoles*minutes/liter Standard Deviation 546.00	1324.31 Picomoles*minutes/liter Standard Deviation 500.04

SECONDARY outcome

Timeframe: 30 minutes predose up to 360 minutes postdose Days 2/7, 3/8, and 5/10

Population: Participants who completed all periods of study within a given stage with evaluable AUC(0-360) data.

Area under the glucose concentration curve from 0 to 360 minutes (AUC\[0-360\]) for Stage 3 studies 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	Stage 1: Insulin Aspart Alone n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 Stage 3, Day 2/7	1197.60 Picomoles*minutes/liter Standard Deviation 385.44	1509.38 Picomoles*minutes/liter Standard Deviation 541.45
Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 Stage 3, Day 3/8	1368.81 Picomoles*minutes/liter Standard Deviation 424.16	1405.75 Picomoles*minutes/liter Standard Deviation 516.85
Area Under the Glucose Concentration Curve (AUC[0-360]), Stage 3 Stage 3, Day 5/10	1289.22 Picomoles*minutes/liter Standard Deviation 486.03	1369.97 Picomoles*minutes/liter Standard Deviation 462.78

SECONDARY outcome

Timeframe: 10 minutes predose up to 360 minutes postdose on Day 2/6 and Day 4/8

Population: Participants who completed all periods of study within a given stage 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\[0-360\]) for Stage 1. 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	Stage 1: Insulin Aspart Alone n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=16 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 1 Stage 1, Day 2/6	163.63 Ratio Standard Deviation 14.70	146.51 Ratio Standard Deviation 16.30
Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 1 Stage 1, Day 4/8	147.50 Ratio Standard Deviation 23.86	132.60 Ratio Standard Deviation 15.55

SECONDARY outcome

Timeframe: 10 minutes predose up to 360 minutes postdose on Days 2/7, 3/8, and 5/10

Population: Participants who completed all periods of study within a given stage 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\[0-360\]) for Stage 3. 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	Stage 1: Insulin Aspart Alone n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2	Stage 1: Insulin Aspart-rHuPH20 n=17 Participants Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) coadministered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2
Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 Stage 3, Day 2/7	180.39 ratio Standard Deviation 18.72	138.59 ratio Standard Deviation 18.41
Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 Stage 3, Day 3/8	164.65 ratio Standard Deviation 19.97	135.71 ratio Standard Deviation 17.30
Duration of Insulin Action (AUMC[0-360]/AUC[0-360]), Stage 3 Stage 3, Day 5/10	156.14 ratio Standard Deviation 26.38	145.81 ratio Standard Deviation 16.42

Adverse Events

Stage 1: Insulin Aspart

Serious events: 0 serious events

Other events: 16 other events

Deaths: 0 deaths

Stage 1: Insulin Aspart-rHuPH20

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

Stage 3: Insulin Aspart

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Stage 3: Insulin Aspart + rHuPH20

Serious events: 0 serious events

Other events: 12 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
Publication restrictions are in place

Restriction type: OTHER

Measure	Stage 1: Insulin Aspart n=20 participants at risk Participants received 0.15 units per kilogram (U/kg) insulin aspart, administered as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2.	Stage 1: Insulin Aspart-rHuPH20 n=18 participants at risk Participants received 0.15 units per kilogram (U/kg) insulin aspart and 5 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) (insulin aspart-rHuPH20) administered together as a continuous subcutaneous insulin infusion (CSII), for 4 days (Days 1-4 or 5-8), including during a 6-hour (hr) euglycemic clamp on Days 2 and 4 of Period 1 or Days 6 and 8 of Period 2.	Stage 3: Insulin Aspart n=23 participants at risk Participants received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5 or 6-10), including during a 6-hour (hr) euglycemic clamp on Days 2, 3 and 5 of Period 1 or Days 7, 8, and 10 of Period 2. On Day 2 or Day 7 only, a sham injection was administered 2.5 hr prior to the 6-hr euglycemic clamp.	Stage 3: Insulin Aspart + rHuPH20 n=22 participants at risk Participants received 0.12 units per kilogram (U/kg) insulin aspart administered as a continuous subcutaneous insulin infusion (CSII), for 5 days (Days 1-5 or 6-10), including during a 6-hour (hr) euglycemic clamp on Days 2, 3, and 5 of Period 1 or Days 7, 8, and 10 of Period 2. On Day 2 or Day 7 only, a 1-milliliter (mL) subcutaneous (SC) injection of 1.25 micrograms per milliliter (μg/mL) recombinant human hyaluronidase PH20 (rHuPH20) was administered 2.5 hr prior to the 6-hr euglycemic clamp.
Injury, poisoning and procedural complications Burns first degree	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
Metabolism and nutrition disorders Hypokalemia	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
Injury, poisoning and procedural complications Infusion related reaction	0.00% 0/20 AEs were classified by the body system affected.	5.6% 1/18 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
General disorders Injection site erythema	10.0% 2/20 • Number of events 2 AEs were classified by the body system affected.	11.1% 2/18 • Number of events 2 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
General disorders Infusion site pain	0.00% 0/20 AEs were classified by the body system affected.	11.1% 2/18 • Number of events 2 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
General disorders Injection site haemorrhage	0.00% 0/20 AEs were classified by the body system affected.	11.1% 2/18 • Number of events 2 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
General disorders Injection site pruritus	10.0% 2/20 • Number of events 4 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
General disorders Asthenia	0.00% 0/20 AEs were classified by the body system affected.	5.6% 1/18 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
General disorders Fatigue	0.00% 0/20 AEs were classified by the body system affected.	5.6% 1/18 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
General disorders Infusion site extravasation	0.00% 0/20 AEs were classified by the body system affected.	5.6% 1/18 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	9.1% 2/22 • Number of events 2 AEs were classified by the body system affected.
General disorders Infusion site haemorrhage	0.00% 0/20 AEs were classified by the body system affected.	5.6% 1/18 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
General disorders Infusion site oedema	0.00% 0/20 AEs were classified by the body system affected.	5.6% 1/18 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
General disorders Injection site inflammation	0.00% 0/20 AEs were classified by the body system affected.	5.6% 1/18 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
General disorders Injection site oedema	0.00% 0/20 AEs were classified by the body system affected.	5.6% 1/18 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Nervous system disorders Headache	35.0% 7/20 • Number of events 7 AEs were classified by the body system affected.	16.7% 3/18 • Number of events 3 AEs were classified by the body system affected.	17.4% 4/23 • Number of events 5 AEs were classified by the body system affected.	13.6% 3/22 • Number of events 3 AEs were classified by the body system affected.
Nervous system disorders Dizziness	5.0% 1/20 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
Injury, poisoning and procedural complications Incision site haemorrhage	15.0% 3/20 • Number of events 3 AEs were classified by the body system affected.	16.7% 3/18 • Number of events 3 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Injury, poisoning and procedural complications Incision site erythema	5.0% 1/20 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Gastrointestinal disorders Nausea	5.0% 1/20 • Number of events 1 AEs were classified by the body system affected.	5.6% 1/18 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	9.1% 2/22 • Number of events 2 AEs were classified by the body system affected.
Gastrointestinal disorders Abdominal pain	5.0% 1/20 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Gastrointestinal disorders Diarrhoea	5.0% 1/20 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Blood and lymphatic system disorders Anaemia	0.00% 0/20 AEs were classified by the body system affected.	5.6% 1/18 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	9.1% 2/22 • Number of events 2 AEs were classified by the body system affected.
Eye disorders Retinal haemorrhage	5.0% 1/20 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Musculoskeletal and connective tissue disorders Neck pain	5.0% 1/20 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
Respiratory, thoracic and mediastinal disorders Cough	5.0% 1/20 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Respiratory, thoracic and mediastinal disorders Nasal congestion	5.0% 1/20 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Skin and subcutaneous tissue disorders Pruritus	5.0% 1/20 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
General disorders Oedema peripheral	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
General disorders Vessel puncture site swelling	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 2 AEs were classified by the body system affected.
General disorders Injection site pain	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
General disorders Infusion site haematoma	10.0% 2/20 • Number of events 2 AEs were classified by the body system affected.	5.6% 1/18 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
General disorders Infusion site irritation	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
General disorders Infusion site pruritus	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
General disorders Infusion site thrombosis	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
General disorders Vessel puncture site pain	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
Nervous system disorders Tremor	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
Infections and infestations Infusion site infection	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
Infections and infestations Fungal infection	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Infections and infestations Hordeolum	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Infections and infestations Infusion site cellulitis	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Infections and infestations Vaginal infection	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Gastrointestinal disorders Dyspepsia	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	8.7% 2/23 • Number of events 2 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Skin and subcutaneous tissue disorders Dry skin	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	0.00% 0/23 AEs were classified by the body system affected.	4.5% 1/22 • Number of events 1 AEs were classified by the body system affected.
Skin and subcutaneous tissue disorders Ecchymosis	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/20 AEs were classified by the body system affected.	0.00% 0/18 AEs were classified by the body system affected.	4.3% 1/23 • Number of events 1 AEs were classified by the body system affected.	0.00% 0/22 AEs were classified by the body system affected.