Table 14.3.1.1.1 Summary of Adverse Events by Enrollment ......Table 14.3.1.3 Adverse Events by...

Protocol: NICHD-2011-HTN01 – HTN-Lisinopril PK Data Lock: May 5, 2014 DRAFT (v1.0) CONFIDENTIAL

Table 14.3.1.1.1 Summary of Adverse Events by Enrollment Group

Safety Population: IC1

1

30-59 ml/min per 1.73m >60 ml/min per 1.73m

0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Number of Events/Participants

Number of Adverse Events 1 0 3 5 6 15

Participants with at least one AE

1 (33.3%) 0 2 (66.7%) 2 (40.0%) 2 (66.7%) 7 (46.7%)

Number of SAEs 0 0 0 1 0 1

Participants with at least one SAE

0 0 0 1 (20.0%) 0 1 (6.7%)

Severity (All AEs)

Mild 1 0 3 4 4 12

Moderate 0 0 0 1 2 3

Highest Severity Per Participant

Mild 1 (33.3%) 0 2 (66.7%) 1 (20.0%) 0 4 (26.7%)

Moderate 0 0 0 1 (20.0%) 2 (66.7%) 3 (20.0%)

Relationship (All AEs)

Not related 1 0 1 3 5 10

Related 0 0 2 2 1 5

Strongest Relationship Per Participant

Not related 1 (33.3%) 0 1 (33.3%) 1 (20.0%) 1 (33.3%) 4 (26.7%)

Related 0 0 1 (33.3%) 1 (20.0%) 1 (33.3%) 3 (20.0%)

Severity (All SAEs)




2


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Mild 0 0 0 1 0 1

Relationship (All SAEs)

Not related 0 0 0 1 0 1




1


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Number of Events/Participants

Number of Adverse Events 1 6 4 1 12

Participants with at least one AE 1 (50.0%) 1 (50.0%) 2 (40.0%) 1 (50.0%) 5 (45.5%)

Severity (All AEs)

Mild 1 5 4 0 10

Moderate 0 1 0 1 2

Highest Severity Per Participant

Mild 1 (50.0%) 0 2 (40.0%) 0 3 (27.3%)

Moderate 0 1 (50.0%) 0 1 (50.0%) 2 (18.2%)

Relationship (All AEs)

Not related 1 6 4 1 12

Strongest Relationship Per Participant

Not related 1 (50.0%) 1 (50.0%) 2 (40.0%) 1 (50.0%) 5 (45.5%)


Table 14.3.1.2.1 Adverse Events by System Organ Class, Preferred Term and Enrollment Group

Safety Population

1


0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=3) 0.1 mg/kg/day

(N=8) 0.2 mg/kg/day

(N=7) 0.4 mg/kg/day

(N=3) Total

(N=26)

System Organ Class Preferred Term

Participants with Event

N (%)

Total Events

N


N (%)

Total Events

N


N (%)

Total Events

N


N (%)

Total Events

N


N (%)

Total Events

N


N (%)

Total Events

N

Blood and lymphatic system disorders

1 (20%) 1 0 0 0 0 0 0 0 0 1 (3.8%) 1

Anaemia 1 (20%) 1 0 0 0 0 0 0 0 0 1 (3.8%) 1

Gastrointestinal disorders

0

0

1 (33.3%)

5

1 (12.5%)

2

2 (28.6%)

2

1 (33.3%)

1

5 (19.2%)

10

Abdominal pain upper 0 0 1 (33.3%) 2 1 (12.5%) 1 0 0 0 0 2 (7.7%) 3

Diarrhoea 0 0 1 (33.3%) 1 0 0 1 (14.3%) 1 0 0 2 (7.7%) 2

Nausea 0 0 0 0 1 (12.5%) 1 1 (14.3%) 1 0 0 2 (7.7%) 2

Retching 0 0 1 (33.3%) 2 0 0 0 0 0 0 1 (3.8%) 2

Vomiting 0 0 0 0 0 0 0 0 1 (33.3%) 1 1 (3.8%) 1

General disorders and administration site conditions

0

0

0

0

2 (25%)

3

0

0

0

0

2 (7.7%)

3

Infusion site extravasation

0 0 0 0 1 (12.5%) 1 0 0 0 0 1 (3.8%) 1

Infusion site pain 0 0 0 0 1 (12.5%) 1 0 0 0 0 1 (3.8%) 1

Infusion site pruritus 0 0 0 0 1 (12.5%) 1 0 0 0 0 1 (3.8%) 1

Infections and infestations

0

0

0

0

0

0

2 (28.6%)

2

0

0

2 (7.7%)

2

Gastroenteritis 0 0 0 0 0 0 1 (14.3%) 1 0 0 1 (3.8%) 1

Otitis externa 0 0 0 0 0 0 1 (14.3%) 1 0 0 1 (3.8%) 1


Table 14.3.1.2.1 Adverse Events by System Organ Class, Preferred Term and Enrollment Group

Safety Population

2


0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=3) 0.1 mg/kg/day

(N=8) 0.2 mg/kg/day

(N=7) 0.4 mg/kg/day

(N=3) Total

(N=26)

System Organ Class Preferred Term


N (%)

Total Events

N


N (%)

Total Events

N


N (%)

Total Events

N


N (%)

Total Events

N


N (%)

Total Events

N


N (%)

Total Events

N

Injury, poisoning and procedural complications

1 (20%)

1

0

0

0

0

0

0

1 (33.3%)

1

2 (7.7%)

2

Arthropod sting 1 (20%) 1 0 0 0 0 0 0 0 0 1 (3.8%) 1

Upper limb fracture 0 0 0 0 0 0 0 0 1 (33.3%) 1 1 (3.8%) 1

Investigations

0

0

0

0

0

0

0

0

2 (66.7%)

4

2 (7.7%)

4

Glomerular filtration rate decreased

0 0 0 0 0 0 0 0 1 (33.3%) 1 1 (3.8%) 1

Haemoglobin decreased

0 0 0 0 0 0 0 0 1 (33.3%) 1 1 (3.8%) 1

Immunoglobulins abnormal

0 0 0 0 0 0 0 0 1 (33.3%) 1 1 (3.8%) 1

Neutrophil count decreased

0 0 0 0 0 0 0 0 1 (33.3%) 1 1 (3.8%) 1

Nervous system disorders

0

0

1 (33.3%)

1

1 (12.5%)

1

1 (14.3%)

2

0

0

3 (11.5%)

4

Dizziness 0 0 0 0 0 0 1 (14.3%) 2 0 0 1 (3.8%) 2

Headache 0 0 1 (33.3%) 1 1 (12.5%) 1 0 0 0 0 2 (7.7%) 2

Skin and subcutaneous tissue disorders

0

0

0

0

1 (12.5%)

1

0

0

0

0

1 (3.8%)

1

Rash 0 0 0 0 1 (12.5%) 1 0 0 0 0 1 (3.8%) 1


Table 14.3.1.3 Adverse Events by System Organ Class, Preferred Term, Severity and by Enrollment Group

Safety Population

Note: The percentages are based on the total number of participants in each treatment group or total.

Participants are counted once at each System Organ Class and Preferred Term levels using the highest severity. 1


System Organ Class Preferred Term Severity

0.1 mg/kg/day (N=5)

0.2 mg/kg/day (N=3)

0.1 mg/kg/day (N=8)

0.2 mg/kg/day (N=7)

0.4 mg/kg/day (N=3)

Total (N=26)

Blood and lymphatic system disorders Mild 1 (20.0%) 0 0 0 0 1 (3.8%)

Anaemia Mild 1 (20.0%) 0 0 0 0 1 (3.8%)

Gastrointestinal disorders Mild 0 0 1 (12.5%) 1 (14.3%) 0 2 (7.7%)

Moderate 0 1 (33.3%) 0 1 (14.3%) 1 (33.3%) 3 (11.5%)

Abdominal pain upper Mild 0 1 (33.3%) 1 (12.5%) 0 0 2 (7.7%)

Diarrhoea Mild 0 1 (33.3%) 0 0 0 1 (3.8%)

Moderate 0 0 0 1 (14.3%) 0 1 (3.8%)

Nausea Mild 0 0 1 (12.5%) 1 (14.3%) 0 2 (7.7%)

Retching Moderate 0 1 (33.3%) 0 0 0 1 (3.8%)

Vomiting Moderate 0 0 0 0 1 (33.3%) 1 (3.8%)

General disorders and administration site conditions Mild 0 0 2 (25.0%) 0 0 2 (7.7%)

Infusion site extravasation Mild 0 0 1 (12.5%) 0 0 1 (3.8%)

Infusion site pain Mild 0 0 1 (12.5%) 0 0 1 (3.8%)

Infusion site pruritus Mild 0 0 1 (12.5%) 0 0 1 (3.8%)

Infections and infestations Mild 0 0 0 2 (28.6%) 0 2 (7.7%)

Gastroenteritis Mild 0 0 0 1 (14.3%) 0 1 (3.8%)

Otitis externa Mild 0 0 0 1 (14.3%) 0 1 (3.8%)

Injury, poisoning and procedural complications Mild 1 (20.0%) 0 0 0 1 (33.3%) 2 (7.7%)

Arthropod sting Mild 1 (20.0%) 0 0 0 0 1 (3.8%)


Table 14.3.1.3 Adverse Events by System Organ Class, Preferred Term, Severity and by Enrollment Group

Safety Population


Participants are counted once at each System Organ Class and Preferred Term levels using the highest severity. 2


System Organ Class Preferred Term Severity

0.1 mg/kg/day (N=5)

0.2 mg/kg/day (N=3)

0.1 mg/kg/day (N=8)

0.2 mg/kg/day (N=7)

0.4 mg/kg/day (N=3)

Total (N=26)

Upper limb fracture Mild 0 0 0 0 1 (33.3%) 1 (3.8%)

Investigations Mild 0 0 0 0 1 (33.3%) 1 (3.8%)

Moderate 0 0 0 0 1 (33.3%) 1 (3.8%)

Glomerular filtration rate decreased Moderate 0 0 0 0 1 (33.3%) 1 (3.8%)

Haemoglobin decreased Mild 0 0 0 0 1 (33.3%) 1 (3.8%)

Immunoglobulins abnormal Mild 0 0 0 0 1 (33.3%) 1 (3.8%)

Neutrophil count decreased Mild 0 0 0 0 1 (33.3%) 1 (3.8%)

Nervous system disorders Mild 0 1 (33.3%) 1 (12.5%) 0 0 2 (7.7%)

Moderate 0 0 0 1 (14.3%) 0 1 (3.8%)

Dizziness Moderate 0 0 0 1 (14.3%) 0 1 (3.8%)

Headache Mild 0 1 (33.3%) 1 (12.5%) 0 0 2 (7.7%)

Skin and subcutaneous tissue disorders Mild 0 0 1 (12.5%) 0 0 1 (3.8%)

Rash Mild 0 0 1 (12.5%) 0 0 1 (3.8%)


Table 14.3.1.4 Adverse Events by System Organ Class, Preferred Term, Relationship to Study Medication and by Enrollment Group

Safety Population


Participants are counted once at each System Organ Class and Preferred Term levels using the closest relationship to study drug. 1


System Organ Class Preferred Term Relationship

0.1 mg/kg/day (N=5)

0.2 mg/kg/day (N=3)

0.1 mg/kg/day (N=8)

0.2 mg/kg/day (N=7)

0.4 mg/kg/day (N=3)

Total (N=26)

Blood and lymphatic system disorders Not related 1 (20.0%) 0 0 0 0 1 (3.8%)

Anaemia Not related 1 (20.0%) 0 0 0 0 1 (3.8%)

Gastrointestinal disorders Not related 0 1 (33.3%) 0 1 (14.3%) 1 (33.3%) 3 (11.5%)

Related 0 0 1 (12.5%) 1 (14.3%) 0 2 (7.7%)

Abdominal pain upper Not related 0 1 (33.3%) 0 0 0 1 (3.8%)

Related 0 0 1 (12.5%) 0 0 1 (3.8%)

Diarrhoea Not related 0 1 (33.3%) 0 1 (14.3%) 0 2 (7.7%)

Nausea Related 0 0 1 (12.5%) 1 (14.3%) 0 2 (7.7%)

Retching Not related 0 1 (33.3%) 0 0 0 1 (3.8%)

Vomiting Not related 0 0 0 0 1 (33.3%) 1 (3.8%)

General disorders and administration site conditions Not related 0 0 2 (25.0%) 0 0 2 (7.7%)

Infusion site extravasation Not related 0 0 1 (12.5%) 0 0 1 (3.8%)

Infusion site pain Not related 0 0 1 (12.5%) 0 0 1 (3.8%)

Infusion site pruritus Not related 0 0 1 (12.5%) 0 0 1 (3.8%)

Infections and infestations Not related 0 0 0 2 (28.6%) 0 2 (7.7%)

Gastroenteritis Not related 0 0 0 1 (14.3%) 0 1 (3.8%)

Otitis externa Not related 0 0 0 1 (14.3%) 0 1 (3.8%)

Injury, poisoning and procedural complications Not related 1 (20.0%) 0 0 0 1 (33.3%) 2 (7.7%)

Arthropod sting Not related 1 (20.0%) 0 0 0 0 1 (3.8%)


Table 14.3.1.4 Adverse Events by System Organ Class, Preferred Term, Relationship to Study Medication and by Enrollment Group

Safety Population


Participants are counted once at each System Organ Class and Preferred Term levels using the closest relationship to study drug. 2


System Organ Class Preferred Term Relationship

0.1 mg/kg/day (N=5)

0.2 mg/kg/day (N=3)

0.1 mg/kg/day (N=8)

0.2 mg/kg/day (N=7)

0.4 mg/kg/day (N=3)

Total (N=26)

Upper limb fracture Not related 0 0 0 0 1 (33.3%) 1 (3.8%)

Investigations Not related 0 0 0 0 1 (33.3%) 1 (3.8%)

Related 0 0 0 0 1 (33.3%) 1 (3.8%)

Glomerular filtration rate decreased Related 0 0 0 0 1 (33.3%) 1 (3.8%)

Haemoglobin decreased Not related 0 0 0 0 1 (33.3%) 1 (3.8%)

Immunoglobulins abnormal Not related 0 0 0 0 1 (33.3%) 1 (3.8%)

Neutrophil count decreased Not related 0 0 0 0 1 (33.3%) 1 (3.8%)

Nervous system disorders Not related 0 1 (33.3%) 1 (12.5%) 0 0 2 (7.7%)

Related 0 0 0 1 (14.3%) 0 1 (3.8%)

Dizziness Related 0 0 0 1 (14.3%) 0 1 (3.8%)

Headache Not related 0 1 (33.3%) 1 (12.5%) 0 0 2 (7.7%)

Skin and subcutaneous tissue disorders Not related 0 0 1 (12.5%) 0 0 1 (3.8%)

Rash Not related 0 0 1 (12.5%) 0 0 1 (3.8%)


Table 14.3.1.5 Adverse Events Listed by Most Frequent Preferred Term and by Enrollment Group

Safety Population

Events that occurred in 5% or more participants are included.

1


0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=3) 0.1 mg/kg/day

(N=8) 0.2 mg/kg/day

(N=7) 0.4 mg/kg/day

(N=3) Total

(N=26)

System Organ Class

Preferred Term


N (%)

Total Events

N


N (%)

Total Events

N


N (%)

Total Events

N


N (%)

Total Events

N


N (%)

Total Events

N


N (%)

Total Events

N


Abdominal pain upper

0 0 1 (33.3%) 2 1 (12.5%) 1 0 0 0 0 2 (7.7%) 3


Diarrhoea 0 0 1 (33.3%) 1 0 0 1 (14.3%) 1 0 0 2 (7.7%) 2

Nervous system disorders

Headache 0 0 1 (33.3%) 1 1 (12.5%) 1 0 0 0 0 2 (7.7%) 2


Nausea 0 0 0 0 1 (12.5%) 1 1 (14.3%) 1 0 0 2 (7.7%) 2


Table 14.3.2.1.1 Summary of Clinical Laboratory Measurements by Enrollment Group: Hematology

Safety Population - IC1

Note:1 95% Non-parametric Confidence Interval for median

Baseline measurement defined as closest measurement before first dose administration. Post-dose value calculated as last value while the participant was on study drug (PK visit if completed and interim otherwise).

1

30 – 59 ml/min per 1.73m² >60 ml/min per 1.73m²

0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Hematocrit (%)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 40.5 (3.7) 41.3 41.6 (2.4) 37.2 (3.9) 38.4 (4.5) 39.3 (3.7)

Median (Min, Max) 41.6 (36.4, 43.5) 41.3 (41.3, 41.3) 41.0 (39.6, 44.3) 39.0 (31.0, 40.2) 39.4 (33.4, 42.3) 40.0 (31.0, 44.3)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 38.5 (2.8) 43.7 38.9 (3.1) 35.8 (2.1) 38.6 (6.4) 38.0 (3.4)

Median (Min, Max) 39.1 (35.4, 41.0) 43.7 (43.7, 43.7) 39.8 (35.4, 41.5) 34.8 (33.7, 38.8) 38.6 (34.1, 43.1) 38.0 (33.7, 43.7)

Change from Baseline

N 3 1 3 5 2 14

Mean (SD) -2.0 (0.9) 2.4 -2.7 (4.1) -1.4 (2.6) -2.3 (4.3) -1.7 (2.8)

Median (Min, Max) -2.5 (-2.5, -1.0) 2.4 (2.4, 2.4) -4.5 (-5.6, 1.9) -1.4 (-4.2, 2.7) -2.3 (-5.3, 0.8) -2.0 (-5.6, 2.7)

95% CI for Median 1 (-4.2, 1.9)

Percentage Change

N 3 1 3 5 2 14

Mean (SD) -4.8 (1.8) 5.8 -6.3 (9.8) -3.3 (7.3) -5.8 (10.8) -4.0 (7.1)

Median (Min, Max) -5.8 (-6.0, -2.7) 5.8 (5.8, 5.8) -10.2 (-13.7, 4.8) -3.9 (-10.8, 8.7) -5.8 (-13.5, 1.9) -4.8 (-13.7, 8.7)

Participant with at least one newly emergent abnormal finding

0 0 0 0 0 0






2


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Hemoglobin (g/dL)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 13.4 (1.0) 14.5 13.4 (1.0) 12.4 (1.3) 13.2 (1.9) 13.1 (1.3)

Median (Min, Max) 13.8 (12.3, 14.2) 14.5 (14.5, 14.5) 13.6 (12.3, 14.3) 12.9 (10.7, 13.9) 13.2 (11.3, 15.0) 13.2 (10.7, 15.0)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 12.9 (0.8) 15.1 12.3 (1.3) 11.7 (1.0) 12.4 (1.7) 12.4 (1.3)

Median (Min, Max) 13.3 (12.0, 13.3) 15.1 (15.1, 15.1) 12.6 (10.9, 13.4) 11.3 (10.9, 13.1) 12.4 (11.2, 13.6) 12.5 (10.9, 15.1)


N 3 1 3 5 2 14

Mean (SD) -0.6 (0.3) 0.6 -1.1 (0.8) -0.7 (0.9) -1.7 (0.4) -0.8 (0.8)

Median (Min, Max) -0.5 (-0.9, -0.3) 0.6 (0.6, 0.6) -1.4 (-1.7, -0.2) -0.6 (-2.0, 0.6) -1.7 (-2.0, -1.4) -0.7 (-2.0, 0.6)

95% CI for Median 1 (-1.4, -0.2)

Percentage Change

N 3 1 3 5 2 14

Mean (SD) -4.1 (2.0) 4.1 -8.3 (5.9) -5.1 (7.5) -12.2 (4.1) -5.9 (6.4)

Median (Min, Max) -3.6 (-6.3, -2.4) 4.1 (4.1, 4.1) -11.4 (-11.9, -1.5) -5.2 (-15.5, 5.6) -12.2 (-15.2, -9.3) -5.5 (-15.5, 5.6)


0 1 (100.0%) 1 (33.3%) 1 (20.0%) 1 (33.3%) 4 (26.7%)






3


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Platelets (103/µL)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 247.7 (66.4) 280.0 304.7 (127.6) 279.8 (74.3) 269.7 (67.1) 276.3 (74.4)

Median (Min, Max) 216.0 (203.0, 324.0) 280.0 (280.0, 280.0) 253.0 (211.0, 450.0) 249.0 (206.0, 392.0) 235.0 (227.0, 347.0) 249.0 (203.0, 450.0)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 262.7 (67.6) 250.0 226.7 (62.6) 266.2 (80.2) 258.0 (66.5) 254.6 (62.2)

Median (Min, Max) 267.0 (193.0, 328.0) 250.0 (250.0, 250.0) 213.0 (172.0, 295.0) 262.0 (168.0, 362.0) 258.0 (211.0, 305.0) 256.0 (168.0, 362.0)


N 3 1 3 5 2 14

Mean (SD) 15.0 (32.0) -30.0 -78.0 (174.4) -13.6 (85.7) -29.0 (18.4) -24.6 (90.5)

Median (Min, Max) 4.0 (-10.0, 51.0) -30.0 (-30.0, -30.0) 2.0 (-278.0, 42.0) -38.0 (-130.0, 91.0) -29.0 (-42.0, -16.0) -13.0 (-278.0, 91.0)

95% CI for Median 1 (-38.0, 47.0)

Percentage Change

N 3 1 3 5 2 14

Mean (SD) 6.6 (15.0) -10.7 -14.7 (41.5) -2.7 (28.9) -9.6 (3.6) -4.8 (24.9)

Median (Min, Max) 1.2 (-4.9, 23.6) -10.7 (-10.7, -10.7) 1.0 (-61.8, 16.6) -15.3 (-33.2, 38.4) -9.6 (-12.1, -7.0) -6.0 (-61.8, 38.4)


0 0 0 1 (20.0%) 0 1 (6.7%)






4


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

WBC (103/µL)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 6.9 (2.9) 5.3 8.7 (3.2) 7.7 (2.4) 6.6 (1.4) 7.3 (2.4)

Median (Min, Max) 8.4 (3.5, 8.7) 5.3 (5.3, 5.3) 7.5 (6.2, 12.3) 7.9 (3.8, 9.9) 6.9 (5.1, 7.9) 7.5 (3.5, 12.3)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 7.7 (1.9) 4.4 9.0 (2.5) 5.7 (1.8) 4.8 (0.9) 6.6 (2.3)

Median (Min, Max) 7.7 (5.8, 9.6) 4.4 (4.4, 4.4) 8.2 (7.0, 11.8) 5.4 (3.9, 8.5) 4.8 (4.2, 5.4) 6.1 (3.9, 11.8)


N 3 1 3 5 2 14

Mean (SD) 0.8 (3.5) -0.9 0.3 (0.7) -2.0 (2.1) -1.7 (2.8) -0.8 (2.3)

Median (Min, Max) 1.2 (-2.9, 4.2) -0.9 (-0.9, -0.9) 0.7 (-0.5, 0.8) -1.5 (-5.2, 0.1) -1.7 (-3.7, 0.3) -0.7 (-5.2, 4.2)

95% CI for Median 1 (-2.6, 0.8)

Percentage Change

N 3 1 3 5 2 14

Mean (SD) 33.6 (78.0) -16.2 5.9 (9.2) -22.0 (22.0) -20.1 (37.5) -3.4 (41.6)

Median (Min, Max) 14.3 (-32.9, 119.4) -16.2 (-16.2, -16.2) 8.8 (-4.4, 13.2) -14.7 (-54.5, 2.6) -20.1 (-46.6, 6.5) -7.8 (-54.5, 119.4)


0 0 0 1 (20.0%) 0 1 (6.7%)






1


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Hematocrit (%)

Pre-dose value

N 2 2 4 2 10

Mean (SD) 33.1 (2.1) 37.2 (7.1) 40.8 (4.3) 33.8 (0.2) 37.1 (4.9)

Median (Min, Max) 33.1 (31.6, 34.5) 37.2 (32.2, 42.2) 41.6 (35.8, 44.4) 33.8 (33.6, 33.9) 35.2 (31.6, 44.4)

Post-dose value

N 2 2 4 1 9

Mean (SD) 30.8 (4.5) 36.8 (10.1) 41.0 (1.3) 31.9 36.8 (6.0)

Median (Min, Max) 30.8 (27.6, 34.0) 36.8 (29.6, 43.9) 40.8 (39.6, 42.6) 31.9 (31.9, 31.9) 39.6 (27.6, 43.9)


N 2 2 3 1 8

Mean (SD) -2.3 (2.5) -0.5 (3.0) -1.6 (4.8) -1.7 -1.5 (3.0)

Median (Min, Max) -2.3 (-4.0, -0.5) -0.5 (-2.6, 1.7) -4.0 (-4.8, 3.9) -1.7 (-1.7, -1.7) -2.2 (-4.8, 3.9)

95% CI for Median 1 (-4.0, 3.9)

Percentage Change

N 2 2 3 1 8

Mean (SD) -7.1 (7.9) -2.0 (8.6) -3.3 (11.6) -5.1 -4.1 (7.9)

Median (Min, Max) -7.1 (-12.7, -1.4) -2.0 (-8.1, 4.0) -9.0 (-10.8, 10.1) -5.1 (-5.1, -5.1) -6.6 (-12.7, 10.1)


0 1 (50.0%) 0 1 (50.0%) 2 (18.2%)






2


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Hemoglobin (g/dL)

Pre-dose value

N 2 2 4 2 10

Mean (SD) 11.1 (0.8) 12.4 (1.8) 13.4 (1.6) 11.2 (0.0) 12.3 (1.6)

Median (Min, Max) 11.1 (10.5, 11.7) 12.4 (11.1, 13.6) 13.8 (11.3, 14.8) 11.2 (11.2, 11.2) 11.5 (10.5, 14.8)

Post-dose value

N 2 2 4 1 9

Mean (SD) 10.2 (1.6) 11.7 (2.6) 13.3 (0.3) 10.8 12.0 (1.8)

Median (Min, Max) 10.2 (9.1, 11.3) 11.7 (9.8, 13.5) 13.3 (13.1, 13.7) 10.8 (10.8, 10.8) 13.1 (9.1, 13.7)


N 2 2 3 1 8

Mean (SD) -0.9 (0.7) -0.7 (0.8) -0.9 (1.0) -0.4 -0.8 (0.7)

Median (Min, Max) -0.9 (-1.4, -0.4) -0.7 (-1.3, -0.1) -1.3 (-1.7, 0.2) -0.4 (-0.4, -0.4) -0.9 (-1.7, 0.2)

95% CI for Median 1 (-1.4, 0.2)

Percentage Change

N 2 2 3 1 8

Mean (SD) -8.4 (7.0) -6.2 (7.8) -6.3 (6.9) -3.6 -6.5 (5.6)

Median (Min, Max) -8.4 (-13.3, -3.4) -6.2 (-11.7, -0.7) -9.0 (-11.5, 1.5) -3.6 (-3.6, -3.6) -6.3 (-13.3, 1.5)


0 0 0 0 0






3


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Platelets (103/µL)

Pre-dose value

N 2 2 4 2 10

Mean (SD) 276.5 (53.0) 259.0 (19.8) 327.5 (101.8) 264.0 (19.8) 290.9 (69.9)

Median (Min, Max) 276.5 (239.0, 314.0) 259.0 (245.0, 273.0) 293.5 (247.0, 476.0) 264.0 (250.0, 278.0) 275.5 (239.0, 476.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 223.5 (13.4) 248.0 (4.2) 201.3 (46.0) 244.0 221.3 (35.5)

Median (Min, Max) 223.5 (214.0, 233.0) 248.0 (245.0, 251.0) 211.0 (139.0, 244.0) 244.0 (244.0, 244.0) 233.0 (139.0, 251.0)


N 2 2 3 1 8

Mean (SD) -53.0 (39.6) -11.0 (15.6) -56.0 (53.0) -34.0 -41.3 (38.2)

Median (Min, Max) -53.0 (-81.0, -25.0) -11.0 (-22.0, 0.0) -56.0 (-109.0, -3.0) -34.0 (-34.0, -34.0) -29.5 (-109.0, 0.0)

95% CI for Median 1 (-81.0, 0.0)

Percentage Change

N 2 2 3 1 8

Mean (SD) -18.1 (10.8) -4.0 (5.7) -18.9 (17.3) -12.2 -14.2 (12.3)

Median (Min, Max) -18.1 (-25.8, -10.5) -4.0 (-8.1, 0.0) -19.9 (-35.7, -1.2) -12.2 (-12.2, -12.2) -11.4 (-35.7, 0.0)


0 0 0 0 0






4


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

WBC (103/µL)

Pre-dose value

N 2 2 4 2 10

Mean (SD) 8.9 (0.8) 4.4 (1.3) 7.9 (0.9) 8.8 (0.3) 7.6 (1.9)

Median (Min, Max) 8.9 (8.3, 9.4) 4.4 (3.5, 5.3) 8.2 (6.6, 8.7) 8.8 (8.6, 9.0) 8.3 (3.5, 9.4)

Post-dose value

N 2 2 4 1 9

Mean (SD) 7.3 (1.6) 4.2 (0.7) 6.3 (1.5) 6.3 6.1 (1.6)

Median (Min, Max) 7.3 (6.2, 8.4) 4.2 (3.7, 4.7) 6.6 (4.2, 7.6) 6.3 (6.3, 6.3) 6.2 (3.7, 8.4)


N 2 2 3 1 8

Mean (SD) -1.5 (2.3) -0.2 (0.6) -0.7 (1.5) -2.3 -1.0 (1.4)

Median (Min, Max) -1.5 (-3.2, 0.1) -0.2 (-0.6, 0.2) -0.3 (-2.3, 0.6) -2.3 (-2.3, -2.3) -0.5 (-3.2, 0.6)

95% CI for Median 1 (-2.3, 0.6)

Percentage Change

N 2 2 3 1 8

Mean (SD) -16.0 (25.0) -2.4 (11.8) -7.5 (18.8) -27.0 -10.8 (16.8)

Median (Min, Max) -16.0 (-33.6, 1.7) -2.4 (-10.7, 6.0) -4.2 (-27.7, 9.5) -27.0 (-27.0, -27.0) -7.5 (-33.6, 9.5)


0 1 (50.0%) 0 0 1 (9.1%)


Table 14.3.2.2.1 Summary of Clinical Laboratory Measurements by Enrollment Group: Differential



Baseline measurement defined as closest measurement before first dose administration. Post-dose value calculated as last value while the participant was on study drug (PK visit if completed and interim otherwise). Percentage change not calculated when pre-dose value equals to 0.

1

30 – 59 ml/min per

1.73m² >60 ml/min per 1.73m²

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5)

0.4 mg/kg/day

(N=3) Total

(N=15)

Bands (%)

Pre-dose value

N 0 0 0 0 1 1

Mean (SD) 0.0 0.0

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)

Post-dose value

N 1 0 2 2 0 5

Mean (SD) 0.0 0.0 (0.0) 0.0 (0.0) 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0 0






2


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Basophils (%)

Pre-dose value

N 3 1 3 4 2 13

Mean (SD) 0.1 (0.2) 0.7 0.3 (0.2) 0.2 (0.3) 0.6 (0.4) 0.3 (0.3)

Median (Min, Max) 0.0 (0.0, 0.3) 0.7 (0.7, 0.7) 0.3 (0.1, 0.5) 0.2 (0.0, 0.6) 0.6 (0.3, 0.8) 0.3 (0.0, 0.8)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 0.1 (0.2) 0.0 0.3 (0.6) 0.6 (0.5) 0.5 (0.7) 0.4 (0.5)

Median (Min, Max) 0.0 (0.0, 0.4) 0.0 (0.0, 0.0) 0.0 (0.0, 1.0) 1.0 (0.0, 1.0) 0.5 (0.0, 1.0) 0.0 (0.0, 1.0)


N 3 1 3 4 1 12

Mean (SD) 0.0 (0.1) -0.7 0.0 (0.4) 0.3 (0.8) -0.8 -0.0 (0.6)

Median (Min, Max) 0.0 (0.0, 0.1) -0.7 (-0.7, -0.7) -0.1 (-0.3, 0.5) 0.4 (-0.6, 1.0) -0.8 (-0.8, -0.8) -0.1 (-0.8, 1.0)

95% CI for Median 1 (-0.6, 0.5)

Percentage Change

N 1 1 3 2 1 8

Mean (SD) 33.3 -100.0 -33.3 (115.5) -100.0 (0.0) -100.0 -58.3 (79.2)

Median (Min, Max) 33.3 (33.3, 33.3) -100.0 (-100.0, -100.0) -100.0 (-100.0, 100.0) -100.0 (-100.0, -100.0) -100.0 (-100.0, -100.0) -100.0 (-100.0, 100.0)


0 0 0 1 (20.0%) 0 1 (6.7%)






3


1.73m² >60 ml/min per 1.73m²

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5)

0.4 mg/kg/day

(N=3) Total

(N=15)

Blasts (%)

Pre-dose value

N 0 0 0 0 1 1

Mean (SD) 0.0 0.0

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)

Post-dose value

N 1 0 2 2 0 5

Mean (SD) 0.0 0.0 (0.0) 0.0 (0.0) 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0 0






4


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Eosinophils (%)

Pre-dose value

N 3 1 3 4 3 14

Mean (SD) 1.2 (0.7) 5.2 2.4 (1.7) 1.6 (1.5) 3.1 (1.7) 2.3 (1.6)

Median (Min, Max) 1.0 (0.7, 2.0) 5.2 (5.2, 5.2) 2.1 (0.9, 4.3) 1.7 (0.0, 3.0) 2.2 (2.0, 5.0) 2.1 (0.0, 5.2)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 2.2 (2.4) 3.0 2.0 (1.0) 5.8 (4.5) 5.0 (2.8) 3.9 (3.3)

Median (Min, Max) 1.0 (0.7, 5.0) 3.0 (3.0, 3.0) 2.0 (1.0, 3.0) 6.0 (1.0, 13.0) 5.0 (3.0, 7.0) 3.0 (0.7, 13.0)


N 3 1 3 4 2 13

Mean (SD) 1.0 (2.6) -2.2 -0.4 (0.8) 2.4 (1.0) 1.4 (0.8) 0.9 (1.9)

Median (Min, Max) 0.0 (-1.0, 4.0) -2.2 (-2.2, -2.2) -0.1 (-1.3, 0.1) 2.7 (1.0, 3.2) 1.4 (0.8, 2.0) 0.8 (-2.2, 4.0)

95% CI for Median 1 (-1.0, 3.0)

Percentage Change

N 3 1 3 3 2 12

Mean (SD) 116.7 (246.6) -42.3 -8.0 (20.9) 204.8 (169.2) 38.2 (2.6) 81.2 (157.3)

Median (Min, Max) 0.0 (-50.0, 400.0) -42.3 (-42.3, -42.3) -4.8 (-30.2, 11.1) 114.3 (100.0, 400.0) 38.2 (36.4, 40.0) 23.7 (-50.0, 400.0)


0 0 0 1 (20.0%) 1 (33.3%) 2 (13.3%)






5


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Lymphocytes (%)

Pre-dose value

N 3 1 3 4 3 14

Mean (SD) 19.6 (17.0) 31.8 44.4 (8.3) 31.6 (11.0) 40.1 (25.0) 33.6 (16.2)

Median (Min, Max) 12.8 (7.0, 39.0) 31.8 (31.8, 31.8) 43.1 (36.8, 53.2) 31.2 (21.0, 43.0) 42.6 (14.0, 63.8) 37.9 (7.0, 63.8)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 17.7 (5.5) 24.0 48.0 (4.0) 42.4 (7.8) 53.5 (12.0) 38.6 (14.6)

Median (Min, Max) 18.0 (12.0, 23.0) 24.0 (24.0, 24.0) 48.0 (44.0, 52.0) 46.0 (30.0, 50.0) 53.5 (45.0, 62.0) 44.5 (12.0, 62.0)


N 3 1 3 4 2 13

Mean (SD) -1.9 (18.5) -7.8 3.6 (6.6) 8.9 (11.7) 14.6 (23.2) 4.8 (13.8)

Median (Min, Max) -0.8 (-21.0, 16.0) -7.8 (-7.8, -7.8) 0.9 (-1.2, 11.2) 6.8 (-3.0, 25.0) 14.6 (-1.8, 31.0) 0.9 (-21.0, 31.0)

95% CI for Median 1 (-3.0, 16.0)

Percentage Change

N 3 1 3 4 2 13

Mean (SD) 56.2 (151.2) -24.5 10.1 (17.8) 39.6 (55.0) 109.3 (158.6) 42.4 (90.2)

Median (Min, Max) -6.3 (-53.8, 228.6) -24.5 (-24.5, -24.5) 2.1 (-2.3, 30.4) 23.1 (-7.0, 119.0) 109.3 (-2.8, 221.4) 2.1 (-53.8, 228.6)


3 (100.0%) 1 (100.0%) 2 (66.7%) 0 0 6 (40.0%)






6


1.73m² >60 ml/min per 1.73m²

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5)

0.4 mg/kg/day

(N=3) Total

(N=15)

Metamyelocytes (%)

Pre-dose value

N 0 0 0 0 1 1

Mean (SD) 0.0 0.0

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)

Post-dose value

N 1 0 2 2 0 5

Mean (SD) 0.0 0.0 (0.0) 0.0 (0.0) 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0 0






7


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Monocytes (%)

Pre-dose value

N 3 1 3 4 2 13

Mean (SD) 9.0 (5.6) 5.6 6.1 (1.0) 5.8 (1.7) 8.9 (1.2) 7.1 (2.9)

Median (Min, Max) 8.1 (4.0, 15.0) 5.6 (5.6, 5.6) 5.9 (5.2, 7.2) 5.6 (4.0, 8.0) 8.9 (8.0, 9.7) 5.9 (4.0, 15.0)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 5.6 (1.5) 12.0 6.3 (1.5) 7.6 (2.3) 6.5 (0.7) 7.1 (2.2)

Median (Min, Max) 6.0 (4.0, 6.9) 12.0 (12.0, 12.0) 6.0 (5.0, 8.0) 8.0 (4.0, 10.0) 6.5 (6.0, 7.0) 7.0 (4.0, 12.0)


N 3 1 3 4 1 12

Mean (SD) -3.4 (6.8) 6.4 0.2 (2.2) 1.2 (1.1) -1.0 0.1 (4.1)

Median (Min, Max) -1.2 (-11.0, 2.0) 6.4 (6.4, 6.4) 0.8 (-2.2, 2.1) 1.1 (0.0, 2.6) -1.0 (-1.0, -1.0) 0.9 (-11.0, 6.4)

95% CI for Median 1 (-1.2, 2.1)

Percentage Change

N 3 1 3 4 1 12

Mean (SD) -12.7 (61.7) 114.3 6.8 (33.9) 20.3 (20.4) -12.5 13.8 (47.1)

Median (Min, Max) -14.8 (-73.3, 50.0) 114.3 (114.3, 114.3) 15.4 (-30.6, 35.6) 16.6 (0.0, 48.1) -12.5 (-12.5, -12.5) 13.9 (-73.3, 114.3)


0 0 0 1 (20.0%) 0 1 (6.7%)






8


1.73m² >60 ml/min per 1.73m²

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5)

0.4 mg/kg/day

(N=3) Total

(N=15)

Myelocytes (%)

Pre-dose value

N 0 0 0 0 1 1

Mean (SD) 0.0 0.0

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)

Post-dose value

N 1 0 2 2 0 5

Mean (SD) 0.0 0.0 (0.0) 0.0 (0.0) 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0 0






9


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Neutrophils (%)

Pre-dose value

N 2 1 1 3 2 9

Mean (SD) 61.6 (23.4) 56.3 48.7 64.3 (13.4) 35.2 (14.1) 54.6 (16.9)

Median (Min, Max) 61.6 (45.0, 78.1) 56.3 (56.3, 56.3) 48.7 (48.7, 48.7) 69.8 (49.0, 74.0) 35.2 (25.2, 45.1) 49.0 (25.2, 78.1)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 74.0 (5.6) 62.0 43.3 (5.9) 44.0 (12.1) 34.0 (9.9) 50.1 (16.4)

Median (Min, Max) 73.0 (69.0, 80.0) 62.0 (62.0, 62.0) 41.0 (39.0, 50.0) 47.0 (27.0, 59.0) 34.0 (27.0, 41.0) 48.0 (27.0, 80.0)


N 2 1 1 3 1 8

Mean (SD) 15.0 (18.5) 5.7 1.3 -15.6 (8.1) 1.8 -1.0 (15.5)

Median (Min, Max) 15.0 (1.9, 28.0) 5.7 (5.7, 5.7) 1.3 (1.3, 1.3) -11.0 (-25.0, -10.8) 1.8 (1.8, 1.8) 1.6 (-25.0, 28.0)

95% CI for Median 1 (-11.0, 28.0)

Percentage Change

N 2 1 1 3 1 8

Mean (SD) 32.3 (42.3) 10.1 2.7 -23.9 (9.2) 7.1 1.6 (29.0)

Median (Min, Max) 32.3 (2.4, 62.2) 10.1 (10.1, 10.1) 2.7 (2.7, 2.7) -22.5 (-33.8, -15.5) 7.1 (7.1, 7.1) 2.6 (-33.8, 62.2)


2 (66.7%) 0 0 1 (20.0%) 1 (33.3%) 4 (26.7%)






10


1.73m² >60 ml/min per 1.73m²

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5)

0.4 mg/kg/day

(N=3) Total

(N=15)

Nucleated RBC (%)

Pre-dose value

N 0 0 1 0 1 2

Mean (SD) 2.3 0.0 1.2 (1.6)

Median (Min, Max) 2.3 (2.3, 2.3) 0.0 (0.0, 0.0) 1.2 (0.0, 2.3)

Post-dose value

N 1 0 2 2 0 5

Mean (SD) 0.0 0.0 (0.0) 0.0 (0.0) 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


N 0 0 1 0 0 1

Mean (SD) -2.3 -2.3

Median (Min, Max) -2.3 (-2.3, -2.3) -2.3 (-2.3, -2.3)

95% CI for Median 1 (., .)

Percentage Change

N 0 0 1 0 0 1

Mean (SD) -100.0 -100.0

Median (Min, Max) -100.0 (-100.0, -100.0) -100.0 (-100.0, -100.0)


0 0 0 0 0 0






11


1.73m² >60 ml/min per 1.73m²

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5)

0.4 mg/kg/day

(N=3) Total

(N=15)

Plasma cells (%)

Pre-dose value

N 0 0 0 0 1 1

Mean (SD) 0.0 0.0

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)

Post-dose value

N 1 0 2 2 0 5

Mean (SD) 0.0 0.0 (0.0) 0.0 (0.0) 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0 0






12


1.73m² >60 ml/min per 1.73m²

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5)

0.4 mg/kg/day

(N=3) Total

(N=15)

Promyelocytes (%)

Pre-dose value

N 0 0 0 0 1 1

Mean (SD) 0.0 0.0

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)

Post-dose value

N 1 0 2 2 0 5

Mean (SD) 0.0 0.0 (0.0) 0.0 (0.0) 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0 0






1


0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2)

0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Bands (%)

Post-dose value

N 1 1 1 1 4

Mean (SD) 0.0 0.0 0.0 0.0 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0






2


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Basophils (%)

Pre-dose value

N 2 2 3 2 9

Mean (SD) 0.3 (0.1) 0.9 (0.2) 0.3 (0.5) 0.2 (0.2) 0.4 (0.4)

Median (Min, Max) 0.3 (0.2, 0.3) 0.9 (0.7, 1.0) 0.0 (0.0, 0.9) 0.2 (0.0, 0.3) 0.3 (0.0, 1.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 0.0 (0.0) 0.5 (0.7) 0.3 (0.5) 0.0 0.2 (0.4)

Median (Min, Max) 0.0 (0.0, 0.0) 0.5 (0.0, 1.0) 0.0 (0.0, 1.0) 0.0 (0.0, 0.0) 0.0 (0.0, 1.0)


N 2 2 3 1 8

Mean (SD) -0.3 (0.1) -0.4 (0.5) 0.0 (0.1) 0.0 -0.1 (0.3)

Median (Min, Max) -0.3 (-0.3, -0.2) -0.4 (-0.7, 0.0) 0.0 (0.0, 0.1) 0.0 (0.0, 0.0) 0.0 (-0.7, 0.1)

95% CI for Median 1 (-0.3, 0.1)

Percentage Change

N 2 2 1 0 5

Mean (SD) -100.0 (0.0) -50.0 (70.7) 11.1 -57.8 (57.9)

Median (Min, Max) -100.0 (-100.0, -100.0) -50.0 (-100.0, 0.0) 11.1 (11.1, 11.1) -100.0 (-100.0, 11.1)


0 0 0 0 0






3


0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2)

0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Blasts (%)

Post-dose value

N 1 1 1 1 4

Mean (SD) 0.0 0.0 0.0 0.0 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0






4


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Eosinophils (%)

Pre-dose value

N 2 2 3 2 9

Mean (SD) 2.8 (0.4) 3.2 (1.1) 2.0 (1.0) 2.0 (1.4) 2.4 (1.0)

Median (Min, Max) 2.8 (2.5, 3.1) 3.2 (2.4, 4.0) 2.0 (1.0, 3.0) 2.0 (1.0, 3.0) 2.5 (1.0, 4.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 1.0 (0.0) 5.5 (4.9) 2.0 (0.8) 1.0 2.4 (2.6)

Median (Min, Max) 1.0 (1.0, 1.0) 5.5 (2.0, 9.0) 2.0 (1.0, 3.0) 1.0 (1.0, 1.0) 2.0 (1.0, 9.0)


N 2 2 3 1 8

Mean (SD) -1.8 (0.4) 2.3 (3.8) -0.3 (0.6) 0.0 0.0 (2.2)

Median (Min, Max) -1.8 (-2.1, -1.5) 2.3 (-0.4, 5.0) 0.0 (-1.0, 0.0) 0.0 (0.0, 0.0) -0.2 (-2.1, 5.0)

95% CI for Median 1 (-1.5, 5.0)

Percentage Change

N 2 2 3 1 8

Mean (SD) -63.9 (5.5) 54.2 (100.2) -11.1 (19.2) 0.0 -6.6 (59.6)

Median (Min, Max) -63.9 (-67.7, -60.0) 54.2 (-16.7, 125.0) 0.0 (-33.3, 0.0) 0.0 (0.0, 0.0) -8.3 (-67.7, 125.0)


0 0 0 0 0






5


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Lymphocytes (%)

Pre-dose value

N 2 2 4 2 10

Mean (SD) 27.0 (6.2) 40.7 (17.9) 31.3 (6.5) 33.4 (6.2) 32.7 (9.0)

Median (Min, Max) 27.0 (22.6, 31.3) 40.7 (28.0, 53.3) 30.0 (25.0, 40.0) 33.4 (29.0, 37.8) 30.2 (22.6, 53.3)

Post-dose value

N 2 2 4 1 9

Mean (SD) 29.5 (12.0) 37.5 (14.8) 35.0 (6.2) 52.0 36.2 (10.2)

Median (Min, Max) 29.5 (21.0, 38.0) 37.5 (27.0, 48.0) 35.5 (27.0, 42.0) 52.0 (52.0, 52.0) 36.0 (21.0, 52.0)


N 2 2 3 1 8

Mean (SD) 2.6 (5.9) -3.2 (3.0) 2.7 (13.6) 23.0 3.7 (11.2)

Median (Min, Max) 2.6 (-1.6, 6.7) -3.2 (-5.3, -1.0) 10.0 (-13.0, 11.0) 23.0 (23.0, 23.0) 2.9 (-13.0, 23.0)

95% CI for Median 1 (-5.3, 23.0)

Percentage Change

N 2 2 3 1 8

Mean (SD) 7.2 (20.1) -6.8 (4.5) 14.3 (41.0) 79.3 15.4 (35.8)

Median (Min, Max) 7.2 (-7.1, 21.4) -6.8 (-9.9, -3.6) 31.3 (-32.5, 44.0) 79.3 (79.3, 79.3) 8.9 (-32.5, 79.3)


0 1 (50.0%) 0 1 (50.0%) 2 (18.2%)






6


0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2)

0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Metamyelocytes (%)

Post-dose value

N 1 1 1 1 4

Mean (SD) 0.0 0.0 0.0 0.0 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0






7


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Monocytes (%)

Pre-dose value

N 2 2 4 2 10

Mean (SD) 5.7 (1.8) 6.7 (0.5) 7.9 (5.4) 4.9 (2.7) 6.6 (3.5)

Median (Min, Max) 5.7 (4.4, 7.0) 6.7 (6.3, 7.0) 7.2 (2.0, 15.0) 4.9 (3.0, 6.8) 6.6 (2.0, 15.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 7.5 (2.1) 7.0 (8.5) 5.5 (3.1) 4.0 6.1 (3.8)

Median (Min, Max) 7.5 (6.0, 9.0) 7.0 (1.0, 13.0) 5.5 (2.0, 9.0) 4.0 (4.0, 4.0) 6.0 (1.0, 13.0)


N 2 2 3 1 8

Mean (SD) 1.8 (0.3) 0.4 (9.0) -1.1 (1.2) 1.0 0.2 (3.7)

Median (Min, Max) 1.8 (1.6, 2.0) 0.4 (-6.0, 6.7) -1.0 (-2.4, 0.0) 1.0 (1.0, 1.0) 0.5 (-6.0, 6.7)

95% CI for Median 1 (-2.4, 6.7)

Percentage Change

N 2 2 3 1 8

Mean (SD) 32.5 (5.5) 10.3 (135.8) -16.7 (19.1) 33.3 8.6 (57.2)

Median (Min, Max) 32.5 (28.6, 36.4) 10.3 (-85.7, 106.3) -12.5 (-37.5, 0.0) 33.3 (33.3, 33.3) 14.3 (-85.7, 106.3)


0 0 0 0 0






8


0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2)

0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Myelocytes (%)

Post-dose value

N 1 1 1 1 4

Mean (SD) 0.0 0.0 0.0 0.0 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0






9


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Neutrophils (%)

Pre-dose value

N 2 1 2 2 7

Mean (SD) 64.1 (3.7) 61.0 60.5 (16.3) 59.5 (10.6) 61.3 (8.3)

Median (Min, Max) 64.1 (61.5, 66.7) 61.0 (61.0, 61.0) 60.5 (49.0, 72.0) 59.5 (52.0, 67.0) 61.5 (49.0, 72.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 61.5 (10.6) 50.0 (17.0) 57.3 (6.2) 44.0 55.1 (9.9)

Median (Min, Max) 61.5 (54.0, 69.0) 50.0 (38.0, 62.0) 56.5 (52.0, 64.0) 44.0 (44.0, 44.0) 54.0 (38.0, 69.0)


N 2 1 2 1 6

Mean (SD) -2.6 (6.9) 1.0 2.0 (18.4) -23.0 -3.9 (13.0)

Median (Min, Max) -2.6 (-7.5, 2.3) 1.0 (1.0, 1.0) 2.0 (-11.0, 15.0) -23.0 (-23.0, -23.0) -3.3 (-23.0, 15.0)

95% CI for Median 1 (-23.0, 15.0)

Percentage Change

N 2 1 2 1 6

Mean (SD) -4.4 (11.1) 1.6 7.7 (32.4) -34.3 -4.4 (21.9)

Median (Min, Max) -4.4 (-12.2, 3.4) 1.6 (1.6, 1.6) 7.7 (-15.3, 30.6) -34.3 (-34.3, -34.3) -5.3 (-34.3, 30.6)


1 (50.0%) 0 1 (20.0%) 0 2 (18.2%)






10


0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2)

0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Nucleated RBC (%)

Post-dose value

N 1 1 1 1 4

Mean (SD) 0.0 0.0 0.0 0.0 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0






11


0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2)

0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Plasma cells (%)

Post-dose value

N 1 1 1 1 4

Mean (SD) 0.0 0.0 0.0 0.0 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0






12


0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2)

0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Promyelocytes (%)

Post-dose value

N 1 1 1 1 4

Mean (SD) 0.0 0.0 0.0 0.0 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0


Table 14.3.2.3.1 Summary of Clinical Laboratory Measurements by Enrollment Group: Chemistry




1


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Albumin (g/dL)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 4.3 (0.4) 4.4 4.4 (0.2) 4.4 (0.1) 4.5 (0.1) 4.4 (0.2)

Median (Min, Max) 4.5 (3.9, 4.6) 4.4 (4.4, 4.4) 4.4 (4.2, 4.5) 4.4 (4.3, 4.5) 4.5 (4.4, 4.6) 4.4 (3.9, 4.6)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 4.2 (0.2) 4.2 4.3 (0.3) 4.3 (0.2) 4.3 (0.1) 4.3 (0.2)

Median (Min, Max) 4.1 (4.1, 4.5) 4.2 (4.2, 4.2) 4.5 (4.0, 4.5) 4.2 (4.0, 4.6) 4.3 (4.2, 4.4) 4.2 (4.0, 4.6)


N 3 1 3 5 2 14

Mean (SD) -0.1 (0.3) -0.2 -0.0 (0.2) -0.1 (0.3) -0.3 (0.1) -0.1 (0.2)

Median (Min, Max) -0.1 (-0.4, 0.2) -0.2 (-0.2, -0.2) 0.0 (-0.2, 0.1) -0.2 (-0.3, 0.3) -0.3 (-0.3, -0.2) -0.2 (-0.4, 0.3)

95% CI for Median 1 (-0.3, 0.1)

Percentage Change

N 3 1 3 5 2 14

Mean (SD) -2.0 (7.0) -4.6 -0.8 (3.6) -3.1 (5.8) -5.5 (1.6) -2.8 (4.7)

Median (Min, Max) -2.2 (-8.9, 5.1) -4.6 (-4.5, -4.5) 0.0 (-4.8, 2.3) -4.6 (-7.0, 7.0) -5.5 (-6.7, -4.3) -4.5 (-8.9, 7.0)


0 0 0 0 0 0






2


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Alkaline phosphatase (U/L)

Pre-dose value

N 3 1 1 4 3 12

Mean (SD) 234.0 (138.0) 146.0 228.0 129.5 (54.8) 131.7 (119.4) 165.8 (96.6)

Median (Min, Max) 164.0 (145.0, 393.0) 146.0 (146.0, 146.0) 228.0 (228.0, 228.0) 138.0 (57.0, 185.0) 162.0 (0.0, 233.0) 158.0 (0.0, 393.0)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 210.7 (106.0) 158.0 165.3 (73.7) 130.4 (47.7) 174.5 (68.6) 163.4 (67.7)

Median (Min, Max) 164.0 (136.0, 332.0) 158.0 (158.0, 158.0) 154.0 (98.0, 244.0) 137.0 (60.0, 181.0) 174.5 (126.0, 223.0) 156.0 (60.0, 332.0)


N 3 1 1 4 2 11

Mean (SD) -23.3 (32.9) 12.0 16.0 -11.8 (10.5) 58.0 (96.2) 2.5 (45.8)

Median (Min, Max) -9.0 (-61.0, 0.0) 12.0 (12.0, 12.0) 16.0 (16.0, 16.0) -14.5 (-21.0, 3.0) 58.0 (-10.0, 126.0) -9.0 (-61.0, 126.0)

95% CI for Median 1 (-17.0, 16.0)

Percentage Change

N 3 1 1 4 1 10

Mean (SD) -7.2 (7.8) 8.2 7.0 -6.7 (8.0) -4.3 -3.8 (8.5)

Median (Min, Max) -6.2 (-15.5, 0.0) 8.2 (8.2, 8.2) 7.0 (7.0, 7.0) -10.4 (-11.4, 5.3) -4.3 (-4.3, -4.3) -5.3 (-15.5, 8.2)


0 0 0 1 (20.0%) 0 1 (6.7%)






3


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

ALT (U/L)

Pre-dose value

N 3 1 1 5 3 13

Mean (SD) 49.3 (42.1) 18.0 10.0 19.2 (7.1) 10.0 (10.0) 23.2 (23.8)

Median (Min, Max) 52.0 (6.0, 90.0) 18.0 (18.0, 18.0) 10.0 (10.0, 10.0) 21.0 (7.0, 25.0) 10.0 (0.0, 20.0) 20.0 (0.0, 90.0)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 34.0 (23.5) 12.0 11.3 (2.9) 16.2 (9.6) 9.0 (2.8) 17.6 (14.2)

Median (Min, Max) 45.0 (7.0, 50.0) 12.0 (12.0, 12.0) 13.0 (8.0, 13.0) 12.0 (7.0, 28.0) 9.0 (7.0, 11.0) 12.0 (7.0, 50.0)


N 3 1 1 5 2 12

Mean (SD) -15.3 (21.7) -6.0 -2.0 -3.0 (8.9) 4.0 (9.9) -5.1 (13.0)

Median (Min, Max) -7.0 (-40.0, 1.0) -6.0 (-6.0, -6.0) -2.0 (-2.0, -2.0) 0.0 (-16.0, 5.0) 4.0 (-3.0, 11.0) -2.5 (-40.0, 11.0)

95% CI for Median 1 (-8.0, 4.0)

Percentage Change

N 3 1 1 5 1 11

Mean (SD) -13.8 (30.6) -33.3 -20.0 -12.6 (37.9) -30.0 -17.1 (28.6)

Median (Min, Max) -13.5 (-44.4, 16.7) -33.3 (-33.3, -33.3) -20.0 (-20.0, -20.0) 0.0 (-64.0, 21.7) -30.0 (-30.0, -30.0) -20.0 (-64.0, 21.7)


0 0 0 0 0 0






4


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

AST (U/L)

Pre-dose value

N 3 1 1 5 3 13

Mean (SD) 44.0 (42.3) 23.0 35.0 24.0 (8.6) 16.7 (14.7) 27.7 (21.6)

Median (Min, Max) 28.0 (12.0, 92.0) 23.0 (23.0, 23.0) 35.0 (35.0, 35.0) 25.0 (11.0, 33.0) 22.0 (0.0, 28.0) 25.0 (0.0, 92.0)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 30.3 (23.6) 17.0 19.0 (2.0) 20.6 (6.4) 19.5 (0.7) 21.9 (11.0)

Median (Min, Max) 28.0 (8.0, 55.0) 17.0 (17.0, 17.0) 19.0 (17.0, 21.0) 21.0 (12.0, 30.0) 19.5 (19.0, 20.0) 19.5 (8.0, 55.0)


N 3 1 1 5 2 12

Mean (SD) -13.7 (20.3) -6.0 -14.0 -3.4 (4.7) 8.5 (16.3) -5.1 (13.0)

Median (Min, Max) -4.0 (-37.0, 0.0) -6.0 (-6.0, -6.0) -14.0 (-14.0, -14.0) -3.0 (-11.0, 1.0) 8.5 (-3.0, 20.0) -3.5 (-37.0, 20.0)

95% CI for Median 1 (-11.0, 0.0)

Percentage Change

N 3 1 1 5 1 11

Mean (SD) -24.5 (21.5) -26.1 -40.0 -10.5 (17.4) -13.6 -18.7 (17.6)

Median (Min, Max) -33.3 (-40.2, 0.0) -26.1 (-26.1, -26.1) -40.0 (-40.0, -40.0) -9.1 (-36.7, 9.1) -13.6 (-13.6, -13.6) -16.0 (-40.2, 9.1)


0 0 0 0 0 0






5


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Bicarbonate (mEq/L)

Pre-dose value

N 3 1 3 4 3 14

Mean (SD) 21.0 (1.0) 22.0 23.7 (1.2) 22.3 (3.9) 22.7 (0.6) 22.4 (2.2)

Median (Min, Max) 21.0 (20.0, 22.0) 22.0 (22.0, 22.0) 23.0 (23.0, 25.0) 21.5 (19.0, 27.0) 23.0 (22.0, 23.0) 22.5 (19.0, 27.0)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 20.0 (2.6) 22.0 21.3 (1.5) 20.4 (2.7) 20.7 (3.1) 20.7 (2.3)

Median (Min, Max) 21.0 (17.0, 22.0) 22.0 (22.0, 22.0) 21.0 (20.0, 23.0) 20.0 (17.0, 24.0) 20.0 (18.0, 24.0) 21.0 (17.0, 24.0)


N 3 1 3 4 3 14

Mean (SD) -1.0 (1.7) 0.0 -2.3 (2.5) -1.5 (4.4) -2.0 (3.6) -1.6 (2.9)

Median (Min, Max) 0.0 (-3.0, 0.0) 0.0 (0.0, 0.0) -2.0 (-5.0, 0.0) -1.0 (-7.0, 3.0) -3.0 (-5.0, 2.0) -1.0 (-7.0, 3.0)

95% CI for Median 1 (-3.0, 1.0)

Percentage Change

N 3 1 3 4 3 14

Mean (SD) -5.0 (8.7) 0.0 -9.6 (10.0) -4.8 (19.7) -8.6 (15.9) -6.3 (12.8)

Median (Min, Max) 0.0 (-15.0, 0.0) 0.0 (0.0, 0.0) -8.7 (-20.0, 0.0) -2.9 (-29.2, 15.8) -13.0 (-21.7, 9.1) -4.4 (-29.2, 15.8)


0 0 0 1 (20.0%) 1 (33.3%) 2 (13.3%)






6


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5)

0.4 mg/kg/day

(N=3) Total

(N=15)

Bilirubin, direct (mg/dL)

Pre-dose value

N 1 1 0 4 3 9

Mean (SD) 0.2 0.3 0.1 (0.1) 0.1 (0.1) 0.1 (0.1)

Median (Min, Max) 0.2 (0.2, 0.2) 0.3 (0.3, 0.3) 0.1 (0.0, 0.2) 0.2 (0.0, 0.2) 0.2 (0.0, 0.3)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 0.2 (0.1) 0.2 0.2 (0.0) 0.2 (0.0) 0.2 (0.0) 0.2 (0.0)

Median (Min, Max) 0.2 (0.1, 0.2) 0.2 (0.2, 0.2) 0.2 (0.2, 0.2) 0.2 (0.2, 0.2) 0.2 (0.2, 0.2) 0.2 (0.1, 0.2)


N 1 1 0 4 2 8

Mean (SD) 0.0 -0.1 0.1 (0.1) 0.1 (0.1) 0.1 (0.1)

Median (Min, Max) 0.0 (0.0, 0.0) -0.1 (-0.1, -0.1) 0.1 (0.0, 0.2) 0.1 (0.0, 0.2) 0.0 (-0.1, 0.2)

95% CI for Median 1 (0.0, 0.2)

Percentage Change

N 1 1 0 2 1 5

Mean (SD) 0.0 -33.3 0.0 (0.0) 0.0 -6.7 (14.9)

Median (Min, Max) 0.0 (0.0, 0.0) -33.3 (-33.3, -33.3) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (-33.3, 0.0)


0 0 0 0 0 0






7


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Bilirubin, total (mg/dL)

Pre-dose value

N 3 1 1 5 3 13

Mean (SD) 0.4 (0.1) 0.4 0.7 0.3 (0.1) 0.1 (0.1) 0.3 (0.2)

Median (Min, Max) 0.4 (0.3, 0.4) 0.4 (0.4, 0.4) 0.7 (0.7, 0.7) 0.3 (0.2, 0.5) 0.2 (0.0, 0.2) 0.3 (0.0, 0.7)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 0.2 (0.2) 0.2 0.2 (0.2) 0.1 (0.1) 0.1 (0.0) 0.2 (0.1)

Median (Min, Max) 0.2 (0.1, 0.4) 0.2 (0.2, 0.2) 0.1 (0.1, 0.4) 0.1 (0.1, 0.2) 0.1 (0.1, 0.1) 0.1 (0.1, 0.4)


N 3 1 1 5 2 12

Mean (SD) -0.1 (0.2) -0.2 -0.3 -0.2 (0.2) 0.0 (0.1) -0.1 (0.1)

Median (Min, Max) -0.1 (-0.3, 0.0) -0.2 (-0.2, -0.2) -0.3 (-0.3, -0.3) -0.1 (-0.4, 0.0) 0.0 (-0.1, 0.1) -0.1 (-0.4, 0.1)

95% CI for Median 1 (-0.3, 0.0)

Percentage Change

N 3 1 1 5 1 11

Mean (SD) -36.1 (37.6) -50.0 -42.9 -46.0 (31.1) -50.0 -43.7 (26.4)

Median (Min, Max) -33.3 (-75.0, 0.0) -50.0 (-50.0, -50.0) -42.9 (-42.9, -42.9) -50.0 (-80.0, 0.0) -50.0 (-50.0, -50.0) -50.0 (-80.0, 0.0)


0 0 0 0 0 0






8


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Blood urea nitrogen (BUN) (mg/dL)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 28.3 (3.1) 16.0 14.7 (2.1) 14.4 (4.7) 13.7 (4.5) 17.2 (6.7)

Median (Min, Max) 29.0 (25.0, 31.0) 16.0 (16.0, 16.0) 14.0 (13.0, 17.0) 14.0 (9.0, 22.0) 14.0 (9.0, 18.0) 14.0 (9.0, 31.0)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 33.3 (2.9) 17.0 19.3 (4.0) 11.8 (1.3) 15.7 (4.0) 18.7 (8.5)

Median (Min, Max) 35.0 (30.0, 35.0) 17.0 (17.0, 17.0) 20.0 (15.0, 23.0) 12.0 (10.0, 13.0) 18.0 (11.0, 18.0) 17.0 (10.0, 35.0)


N 3 1 3 5 3 15

Mean (SD) 5.0 (1.0) 1.0 4.7 (4.7) -2.6 (4.4) 2.0 (2.0) 1.5 (4.5)

Median (Min, Max) 5.0 (4.0, 6.0) 1.0 (1.0, 1.0) 3.0 (1.0, 10.0) -2.0 (-9.0, 3.0) 2.0 (0.0, 4.0) 2.0 (-9.0, 10.0)

95% CI for Median 1 (-1.0, 4.0)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) 17.9 (4.3) 6.3 33.9 (37.6) -11.7 (28.3) 16.9 (15.0) 10.2 (28.0)

Median (Min, Max) 20.0 (12.9, 20.7) 6.3 (6.3, 6.3) 17.7 (7.1, 76.9) -15.4 (-40.9, 33.3) 22.2 (0.0, 28.6) 12.9 (-40.9, 76.9)


0 0 2 (66.7%) 0 0 2 (13.3%)






9


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5)

0.4 mg/kg/day

(N=3) Total

(N=15)

Calcium (mg/dL)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 10.0 (0.5) 9.8 10.2 (0.2) 9.5 (0.4) 9.7 (0.3) 9.8 (0.4)

Median (Min, Max) 10.1 (9.5, 10.4) 9.8 (9.8, 9.8) 10.2 (10.0, 10.3) 9.4 (9.1, 10.0) 9.8 (9.4, 9.9) 9.8 (9.1, 10.4)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 9.9 (0.1) 10.4 9.9 (0.2) 9.5 (0.5) 9.8 (0.2) 9.8 (0.4)

Median (Min, Max) 9.9 (9.8, 10.0) 10.4 (10.4, 10.4) 10.0 (9.7, 10.1) 9.4 (9.0, 10.2) 9.9 (9.6, 10.0) 9.9 (9.0, 10.4)


N 3 1 3 5 3 15

Mean (SD) -0.1 (0.5) 0.6 -0.2 (0.3) 0.0 (0.3) 0.1 (0.1) 0.0 (0.3)

Median (Min, Max) -0.3 (-0.5, 0.5) 0.6 (0.6, 0.6) -0.3 (-0.5, 0.1) 0.0 (-0.3, 0.3) 0.2 (0.0, 0.2) 0.0 (-0.5, 0.6)

95% CI for Median 1 (-0.3, 0.2)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) -0.8 (5.4) 6.1 -2.3 (3.0) -0.0 (2.7) 1.4 (1.2) 0.1 (3.5)

Median (Min, Max) -3.0 (-4.8, 5.3) 6.1 (6.1, 6.1) -2.9 (-4.9, 1.0) 0.0 (-3.2, 3.3) 2.0 (0.0, 2.1) 0.0 (-4.9, 6.1)


0 0 0 0 0 0






10


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Chloride (mEq/L)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 105.3 (2.1) 103.0 102.0 (3.5) 103.2 (2.3) 101.7 (1.5) 103.1 (2.4)

Median (Min, Max) 106.0 (103.0, 107.0) 103.0 (103.0, 103.0) 104.0 (98.0, 104.0) 104.0 (100.0, 106.0) 102.0 (100.0, 103.0) 103.0 (98.0, 107.0)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 105.0 (2.6) 102.0 102.7 (1.5) 103.2 (3.1) 103.7 (2.1) 103.5 (2.4)

Median (Min, Max) 104.0 (103.0, 108.0) 102.0 (102.0, 102.0) 103.0 (101.0, 104.0) 103.0 (100.0, 108.0) 103.0 (102.0, 106.0) 103.0 (100.0, 108.0)


N 3 1 3 5 3 15

Mean (SD) -0.3 (1.5) -1.0 0.7 (4.0) 0.0 (1.2) 2.0 (3.5) 0.4 (2.4)

Median (Min, Max) 0.0 (-2.0, 1.0) -1.0 (-1.0, -1.0) 0.0 (-3.0, 5.0) 0.0 (-1.0, 2.0) 0.0 (0.0, 6.0) 0.0 (-3.0, 6.0)

95% CI for Median 1 (-1.0, 1.0)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) -0.3 (1.4) -1.0 0.7 (4.0) -0.0 (1.2) 2.0 (3.5) 0.4 (2.4)

Median (Min, Max) 0.0 (-1.9, 0.9) -1.0 (-1.0, -1.0) 0.0 (-2.9, 5.1) 0.0 (-1.0, 1.9) 0.0 (0.0, 6.0) 0.0 (-2.9, 6.0)


0 0 0 0 0 0






11


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Cholesterol (mg/dL)

Pre-dose value

N 1 1 1 4 3 10

Mean (SD) 72.0 163.0 131.0 177.8 (31.2) 141.3 (127.6) 150.1 (71.0)

Median (Min, Max) 72.0 (72.0, 72.0) 163.0 (163.0, 163.0) 131.0 (131.0, 131.0) 165.5 (156.0, 224.0) 176.0 (0.0, 248.0) 164.0 (0.0, 248.0)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 162.3 (69.5) 155.0 149.0 (21.0) 168.8 (40.2) 178.5 (4.9) 163.6 (37.5)

Median (Min, Max) 162.0 (93.0, 232.0) 155.0 (155.0, 155.0) 158.0 (125.0, 164.0) 163.0 (122.0, 229.0) 178.5 (175.0, 182.0) 162.5 (93.0, 232.0)


N 1 1 1 4 2 9

Mean (SD) 21.0 -8.0 -6.0 -12.3 (17.1) 54.5 (170.4) 7.4 (67.5)

Median (Min, Max) 21.0 (21.0, 21.0) -8.0 (-8.0, -8.0) -6.0 (-6.0, -6.0) -10.0 (-34.0, 5.0) 54.5 (-66.0, 175.0) -6.0 (-66.0, 175.0)

95% CI for Median 1 (-34.0, 21.0)

Percentage Change

N 1 1 1 4 1 8

Mean (SD) 29.2 -4.9 -4.6 -7.9 (10.6) -26.6 -4.8 (16.9)

Median (Min, Max) 29.2 (29.2, 29.2) -4.9 (-4.9, -4.9) -4.6 (-4.6, -4.6) -6.1 (-21.8, 2.2) -26.6 (-26.6, -26.6) -4.7 (-26.6, 29.2)


1 (33.3%) 0 0 0 1 (33.3%) 2 (13.3%)






12


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Creatinine (mg/dL)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 1.8 (0.6) 1.3 0.7 (0.1) 0.8 (0.2) 0.6 (0.2) 1.0 (0.5)

Median (Min, Max) 2.0 (1.1, 2.3) 1.3 (1.3, 1.3) 0.7 (0.6, 0.8) 0.8 (0.6, 1.0) 0.6 (0.4, 0.8) 0.8 (0.4, 2.3)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 1.6 (0.4) 1.2 0.7 (0.1) 0.8 (0.2) 0.7 (0.2) 1.0 (0.4)

Median (Min, Max) 1.8 (1.1, 1.8) 1.2 (1.2, 1.2) 0.7 (0.6, 0.8) 0.8 (0.7, 1.1) 0.8 (0.5, 0.8) 0.8 (0.5, 1.8)


N 3 1 3 5 3 15

Mean (SD) -0.2 (0.3) -0.1 0.0 (0.0) 0.0 (0.1) 0.1 (0.1) -0.0 (0.2)

Median (Min, Max) -0.2 (-0.5, 0.0) -0.1 (-0.1, -0.1) 0.0 (0.0, 0.0) 0.1 (-0.1, 0.1) 0.1 (-0.0, 0.2) 0.0 (-0.5, 0.2)

95% CI for Median 1 (-0.1, 0.1)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) -8.6 (12.3) -7.7 4.4 (1.3) 3.8 (8.5) 13.2 (15.7) 2.6 (11.7)

Median (Min, Max) -8.5 (-20.9, 3.8) -7.7 (-7.7, -7.7) 5.1 (2.9, 5.3) 7.8 (-7.2, 13.2) 16.3 (-3.8, 27.1) 3.8 (-20.9, 27.1)


0 0 0 0 2 (66.7%) 2 (13.3%)






13


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Glucose (mg/dL)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 79.3 (8.5) 109.0 92.0 (9.6) 96.6 (12.2) 101.3 (11.0) 94.0 (12.7)

Median (Min, Max) 76.0 (73.0, 89.0) 109.0 (109.0, 109.0) 96.0 (81.0, 99.0) 94.0 (84.0, 117.0) 105.0 (89.0, 110.0) 94.0 (73.0, 117.0)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 85.0 (10.4) 113.0 84.0 (8.7) 92.2 (18.7) 85.0 (3.6) 89.1 (13.6)

Median (Min, Max) 90.0 (73.0, 92.0) 113.0 (113.0, 113.0) 88.0 (74.0, 90.0) 91.0 (74.0, 122.0) 84.0 (82.0, 89.0) 89.0 (73.0, 122.0)


N 3 1 3 5 3 15

Mean (SD) 5.7 (7.4) 4.0 -8.0 (2.6) -4.4 (23.6) -16.3 (11.5) -4.9 (15.7)

Median (Min, Max) 3.0 (0.0, 14.0) 4.0 (4.0, 4.0) -7.0 (-11.0, -6.0) -2.0 (-38.0, 28.0) -16.0 (-28.0, -5.0) -5.0 (-38.0, 28.0)

95% CI for Median 1 (-11.0, 3.0)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) 7.3 (9.8) 3.7 -8.7 (2.4) -3.4 (22.5) -15.4 (9.9) -4.2 (15.4)

Median (Min, Max) 3.4 (0.0, 18.4) 3.7 (3.7, 3.7) -8.6 (-11.1, -6.3) -2.2 (-32.5, 29.8) -15.2 (-25.5, -5.6) -5.6 (-32.5, 29.8)


0 1 (100.0%) 0 0 0 1 (6.7%)






14


0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Phosphorus (mg/dL)

Pre-dose value

N 2 1 2 4 3 12

Mean (SD) 3.7 (0.1) 4.2 4.7 (0.4) 4.3 (0.7) 4.3 (0.3) 4.3 (0.5)

Median (Min, Max) 3.7 (3.6, 3.7) 4.2 (4.2, 4.2) 4.7 (4.4, 5.0) 4.4 (3.7, 4.9) 4.5 (4.0, 4.5) 4.3 (3.6, 5.0)

Post-dose value

N 0 0 0 0 1 1

Mean (SD) 5.0 5.0

Median (Min, Max) 5.0 (5.0, 5.0) 5.0 (5.0, 5.0)


N 0 0 0 0 1 1

Mean (SD) 1.0 1.0

Median (Min, Max) 1.0 (1.0, 1.0) 1.0 (1.0, 1.0)


Percentage Change

N 0 0 0 0 1 1

Mean (SD) 25.0 25.0

Median (Min, Max) 25.0 (25.0, 25.0) 25.0 (25.0, 25.0)


0 0 0 0 0 0






15


0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Potassium (mEq/L)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 4.8 (0.4) 4.1 4.1 (0.4) 4.3 (0.3) 4.2 (0.8) 4.3 (0.5)

Median (Min, Max) 4.9 (4.3, 5.1) 4.1 (4.1, 4.1) 4.2 (3.6, 4.4) 4.2 (4.0, 4.8) 4.5 (3.3, 4.9) 4.3 (3.3, 5.1)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 5.0 (0.5) 4.3 4.3 (0.5) 3.9 (0.5) 4.5 (0.5) 4.4 (0.6)

Median (Min, Max) 4.8 (4.6, 5.6) 4.3 (4.3, 4.3) 4.3 (3.9, 4.8) 3.6 (3.5, 4.6) 4.6 (4.0, 5.0) 4.3 (3.5, 5.6)


N 3 1 3 5 3 15

Mean (SD) 0.2 (0.3) 0.2 0.3 (0.2) -0.4 (0.6) 0.3 (0.5) 0.1 (0.5)

Median (Min, Max) 0.3 (-0.1, 0.5) 0.2 (0.2, 0.2) 0.3 (0.1, 0.4) -0.4 (-1.3, 0.4) 0.5 (-0.3, 0.7) 0.2 (-1.3, 0.7)

95% CI for Median 1 (-0.3, 0.4)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) 4.9 (6.2) 4.9 6.6 (3.7) -8.0 (13.3) 8.7 (13.8) 1.7 (11.7)

Median (Min, Max) 7.0 (-2.0, 9.8) 4.9 (4.9, 4.9) 8.3 (2.4, 9.1) -10.0 (-27.1, 9.5) 11.1 (-6.1, 21.2) 4.9 (-27.1, 21.2)


1 (33.3%) 0 0 0 0 1 (6.7%)






16


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Protein, total (g/d)

Pre-dose value

N 3 1 2 4 3 13

Mean (SD) 7.3 (0.6) 7.2 8.3 (0.1) 7.2 (0.5) 4.4 (3.8) 6.8 (2.1)

Median (Min, Max) 7.2 (6.8, 8.0) 7.2 (7.2, 7.2) 8.3 (8.2, 8.3) 7.1 (6.8, 7.9) 6.4 (0.0, 6.8) 7.2 (0.0, 8.3)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 7.0 (0.9) 6.8 7.3 (0.3) 6.7 (0.7) 6.0 (0.2) 6.8 (0.7)

Median (Min, Max) 6.5 (6.4, 8.0) 6.8 (6.8, 6.8) 7.4 (7.0, 7.5) 6.5 (6.0, 7.5) 6.0 (5.8, 6.1) 6.7 (5.8, 8.0)


N 3 1 2 4 2 12

Mean (SD) -0.4 (0.4) -0.4 -0.8 (0.1) -0.7 (0.4) 2.6 (4.6) -0.1 (1.9)

Median (Min, Max) -0.4 (-0.7, 0.0) -0.4 (-0.4, -0.4) -0.8 (-0.9, -0.7) -0.6 (-1.1, -0.3) 2.6 (-0.7, 5.8) -0.6 (-1.1, 5.8)

95% CI for Median 1 (-0.8, -0.3)

Percentage Change

N 3 1 2 4 1 11

Mean (SD) -5.2 (4.9) -5.6 -9.7 (1.6) -9.0 (5.1) -10.3 -7.9 (4.2)

Median (Min, Max) -5.9 (-9.7, 0.0) -5.6 (-5.6, -5.6) -9.7 (-10.8, -8.5) -8.4 (-14.9, -4.4) -10.3 (-10.3, -10.3) -8.5 (-14.9, 0.0)


0 0 0 0 1 (33.3%) 1 (6.7%)






17


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Sodium (mEq/L)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 138.7 (1.5) 139.0 139.0 (2.6) 138.4 (2.9) 141.0 (1.0) 139.1 (2.2)

Median (Min, Max) 139.0 (137.0, 140.0) 139.0 (139.0, 139.0) 140.0 (136.0, 141.0) 138.0 (134.0, 141.0) 141.0 (140.0, 142.0) 140.0 (134.0, 142.0)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 138.3 (1.5) 139.0 137.7 (0.6) 137.8 (3.2) 138.7 (5.1) 138.1 (2.7)

Median (Min, Max) 138.0 (137.0, 140.0) 139.0 (139.0, 139.0) 138.0 (137.0, 138.0) 137.0 (134.0, 142.0) 140.0 (133.0, 143.0) 138.0 (133.0, 143.0)


N 3 1 3 5 3 15

Mean (SD) -0.3 (1.5) 0.0 -1.3 (3.1) -0.6 (2.4) -2.3 (5.9) -1.0 (3.0)

Median (Min, Max) 0.0 (-2.0, 1.0) 0.0 (0.0, 0.0) -2.0 (-4.0, 2.0) 0.0 (-4.0, 2.0) 0.0 (-9.0, 2.0) 0.0 (-9.0, 2.0)

95% CI for Median 1 (-2.0, 1.0)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) -0.2 (1.1) 0.0 -0.9 (2.2) -0.4 (1.7) -1.6 (4.1) -0.7 (2.1)

Median (Min, Max) 0.0 (-1.4, 0.7) 0.0 (0.0, 0.0) -1.4 (-2.8, 1.5) 0.0 (-2.8, 1.4) 0.0 (-6.3, 1.4) 0.0 (-6.3, 1.5)


0 0 0 0 1 (33.3%) 1 (6.7%)






18


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Calculated eGFR (mL/min per 1.73m²)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 37.5 (12.1) 52.6 90.3 (13.7) 78.1 (12.7) 92.7 (32.0) 73.6 (26.4)

Median (Min, Max) 31.3 (29.6, 51.5) 52.6 (52.6, 52.6) 87.7 (78.1, 105.1) 74.8 (63.6, 98.2) 99.7 (57.9, 120.6) 74.8 (29.6, 120.6)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 40.4 (8.1) 57.0 86.4 (12.2) 78.2 (17.4) 92.9 (42.0) 73.8 (27.3)

Median (Min, Max) 37.5 (34.3, 49.6) 57.0 (57.0, 57.0) 83.5 (75.9, 99.8) 76.5 (59.0, 103.3) 78.4 (60.1, 140.2) 75.9 (34.3, 140.2)


N 3 1 3 5 3 15

Mean (SD) 3.0 (4.8) 4.4 -3.9 (1.6) 0.1 (6.5) 0.2 (20.5) 0.2 (9.1)

Median (Min, Max) 2.9 (-1.9, 7.8) 4.4 (4.4, 4.4) -4.3 (-5.3, -2.2) 2.3 (-8.7, 6.2) 2.3 (-21.3, 19.6) 2.3 (-21.3, 19.6)

95% CI for Median 1 (-4.6, 5.2)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) 10.7 (15.1) 8.3 -4.2 (1.2) -0.6 (8.4) -0.4 (19.1) 1.6 (11.7)

Median (Min, Max) 9.3 (-3.6, 26.4) 8.3 (8.3, 8.3) -4.9 (-5.0, -2.8) 3.0 (-11.7, 7.8) 3.9 (-21.3, 16.2) 3.0 (-21.3, 26.4)


0 0 0 0 2 (66.7%) 2 (13.3%)






1


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Albumin (g/dL)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 4.5 (0.2) 4.2 (0.0) 4.5 (0.3) 4.4 (0.3) 4.4 (0.3)

Median (Min, Max) 4.5 (4.3, 4.6) 4.2 (4.2, 4.2) 4.5 (4.0, 4.9) 4.4 (4.2, 4.6) 4.5 (4.0, 4.9)

Post-dose value

N 2 2 4 1 9

Mean (SD) 4.4 (0.1) 3.8 (0.3) 4.5 (0.1) 4.4 4.3 (0.3)

Median (Min, Max) 4.4 (4.3, 4.4) 3.8 (3.6, 4.0) 4.6 (4.3, 4.6) 4.4 (4.4, 4.4) 4.4 (3.6, 4.6)


N 2 2 4 1 9

Mean (SD) -0.1 (0.1) -0.4 (0.3) 0.0 (0.4) -0.2 -0.1 (0.3)

Median (Min, Max) -0.1 (-0.2, 0.0) -0.4 (-0.6, -0.2) -0.2 (-0.3, 0.6) -0.2 (-0.2, -0.2) -0.2 (-0.6, 0.6)

95% CI for Median 1 (-0.3, 0.0)

Percentage Change

N 2 2 4 1 9

Mean (SD) -2.2 (3.1) -9.5 (6.7) 0.6 (9.8) -4.4 -2.8 (7.7)

Median (Min, Max) -2.2 (-4.3, 0.0) -9.5 (-14.3, -4.8) -3.3 (-6.1, 15.0) -4.4 (-4.3, -4.3) -4.4 (-14.3, 15.0)


0 0 0 0 0






2


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Alkaline phosphatase (U/L)

Pre-dose value

N 2 1 5 2 10

Mean (SD) 181.0 (89.1) 142.0 136.8 (38.4) 221.0 (8.5) 163.0 (52.9)

Median (Min, Max) 181.0 (118.0, 244.0) 142.0 (142.0, 142.0) 123.0 (96.0, 193.0) 221.0 (215.0, 227.0) 149.5 (96.0, 244.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 172.0 (93.3) 240.5 (164.8) 135.3 (32.2) 198.0 173.8 (82.5)

Median (Min, Max) 172.0 (106.0, 238.0) 240.5 (124.0, 357.0) 130.5 (107.0, 173.0) 198.0 (198.0, 198.0) 151.0 (106.0, 357.0)


N 2 1 4 1 8

Mean (SD) -9.0 (4.2) -18.0 -7.0 (13.3) -29.0 -11.6 (11.9)

Median (Min, Max) -9.0 (-12.0, -6.0) -18.0 (-18.0, -18.0) -9.5 (-20.0, 11.0) -29.0 (-29.0, -29.0) -12.5 (-29.0, 11.0)

95% CI for Median 1 (-20.0, 11.0)

Percentage Change

N 2 1 4 1 8

Mean (SD) -6.3 (5.5) -12.7 -3.3 (10.3) -12.8 -6.4 (8.2)

Median (Min, Max) -6.3 (-10.2, -2.5) -12.7 (-12.7, -12.7) -7.1 (-10.6, 11.5) -12.8 (-12.8, -12.8) -10.3 (-12.8, 11.5)


0 0 0 0 0






3


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

ALT (U/L)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 23.5 (13.4) 25.0 (26.9) 20.8 (8.9) 21.5 (12.0) 22.2 (11.8)

Median (Min, Max) 23.5 (14.0, 33.0) 25.0 (6.0, 44.0) 20.0 (10.0, 32.0) 21.5 (13.0, 30.0) 20.0 (6.0, 44.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 25.0 (17.0) 21.5 (20.5) 13.5 (3.8) 9.0 17.3 (11.4)

Median (Min, Max) 25.0 (13.0, 37.0) 21.5 (7.0, 36.0) 15.0 (8.0, 16.0) 9.0 (9.0, 9.0) 14.0 (7.0, 37.0)


N 2 2 4 1 9

Mean (SD) 1.5 (3.5) -3.5 (6.4) -4.5 (6.0) -4.0 -2.9 (5.2)

Median (Min, Max) 1.5 (-1.0, 4.0) -3.5 (-8.0, 1.0) -3.0 (-13.0, 1.0) -4.0 (-4.0, -4.0) -2.0 (-13.0, 4.0)

95% CI for Median 1 (-8.0, 1.0)

Percentage Change

N 2 2 4 1 9

Mean (SD) 2.5 (13.6) -0.8 (24.6) -20.4 (22.4) -30.8 -12.1 (21.2)

Median (Min, Max) 2.5 (-7.1, 12.1) -0.8 (-18.2, 16.7) -20.0 (-48.1, 6.7) -30.8 (-30.8, -30.8) -18.2 (-48.1, 16.7)


0 0 0 0 0






4


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

AST (U/L)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 20.0 (7.1) 34.5 (23.3) 21.2 (7.9) 30.0 (4.2) 25.0 (11.0)

Median (Min, Max) 20.0 (15.0, 25.0) 34.5 (18.0, 51.0) 23.0 (13.0, 32.0) 30.0 (27.0, 33.0) 24.0 (13.0, 51.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 23.0 (7.1) 38.5 (6.4) 16.8 (4.5) 25.0 23.9 (9.9)

Median (Min, Max) 23.0 (18.0, 28.0) 38.5 (34.0, 43.0) 15.5 (13.0, 23.0) 25.0 (25.0, 25.0) 23.0 (13.0, 43.0)


N 2 2 4 1 9

Mean (SD) 3.0 (0.0) 4.0 (17.0) -1.8 (5.1) -2.0 0.6 (7.3)

Median (Min, Max) 3.0 (3.0, 3.0) 4.0 (-8.0, 16.0) -0.5 (-9.0, 3.0) -2.0 (-2.0, -2.0) 0.0 (-9.0, 16.0)

95% CI for Median 1 (-8.0, 3.0)

Percentage Change

N 2 2 4 1 9

Mean (SD) 16.0 (5.7) 36.6 (73.9) -5.5 (25.1) -7.4 8.4 (35.6)

Median (Min, Max) 16.0 (12.0, 20.0) 36.6 (-15.7, 88.9) -2.1 (-39.1, 21.4) -7.4 (-7.4, -7.4) 0.0 (-39.1, 88.9)


0 1 (50.0%) 0 0 1 (9.1%)






5


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Bicarbonate (mEq/L)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 19.0 (0.0) 19.5 (3.5) 23.6 (1.1) 24.5 (3.5) 22.2 (2.9)

Median (Min, Max) 19.0 (19.0, 19.0) 19.5 (17.0, 22.0) 24.0 (22.0, 25.0) 24.5 (22.0, 27.0) 22.0 (17.0, 27.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 18.0 (5.7) 19.0 (1.4) 21.0 (3.2) 20.0 19.8 (3.1)

Median (Min, Max) 18.0 (14.0, 22.0) 19.0 (18.0, 20.0) 20.5 (18.0, 25.0) 20.0 (20.0, 20.0) 20.0 (14.0, 25.0)


N 2 2 4 1 9

Mean (SD) -1.0 (5.7) -0.5 (2.1) -2.5 (3.4) -2.0 -1.7 (3.1)

Median (Min, Max) -1.0 (-5.0, 3.0) -0.5 (-2.0, 1.0) -3.0 (-6.0, 2.0) -2.0 (-2.0, -2.0) -2.0 (-6.0, 3.0)

95% CI for Median 1 (-5.0, 2.0)

Percentage Change

N 2 2 4 1 9

Mean (SD) -5.3 (29.8) -1.6 (10.6) -10.5 (14.3) -9.1 -7.2 (14.7)

Median (Min, Max) -5.3 (-26.3, 15.8) -1.6 (-9.1, 5.9) -13.3 (-24.0, 8.7) -9.1 (-9.1, -9.1) -9.1 (-26.3, 15.8)


1 (50.0%) 0 2 (40.0%) 0 3 (27.3%)






6


0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2)

0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Bilirubin, direct (mg/dL)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 0.2 (0.0) 0.1 (0.1) 0.1 (0.1) 0.2 (0.0) 0.2 (0.1)

Median (Min, Max) 0.2 (0.2, 0.2) 0.1 (0.0, 0.2) 0.2 (0.0, 0.2) 0.2 (0.2, 0.2) 0.2 (0.0, 0.2)

Post-dose value

N 2 2 4 1 9

Mean (SD) 0.2 (0.0) 0.2 (0.0) 0.2 (0.0) 0.2 0.2 (0.0)

Median (Min, Max) 0.2 (0.2, 0.2) 0.2 (0.2, 0.2) 0.2 (0.2, 0.2) 0.2 (0.2, 0.2) 0.2 (0.2, 0.2)


N 2 2 4 1 9

Mean (SD) 0.0 (0.0) 0.1 (0.1) 0.1 (0.1) 0.0 0.0 (0.1)

Median (Min, Max) 0.0 (0.0, 0.0) 0.1 (0.0, 0.2) 0.0 (0.0, 0.2) 0.0 (0.0, 0.0) 0.0 (0.0, 0.2)

95% CI for Median 1 (0.0, 0.2)

Percentage Change

N 2 1 3 1 7

Mean (SD) 0.0 (0.0) 0.0 0.0 (0.0) 0.0 0.0 (0.0)

Median (Min, Max) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0) 0.0 (0.0, 0.0)


0 0 0 0 0






7


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Bilirubin, total (mg/dL)

Pre-dose value

N 2 1 5 2 10

Mean (SD) 0.2 (0.0) 0.1 0.2 (0.1) 0.1 (0.0) 0.2 (0.1)

Median (Min, Max) 0.2 (0.2, 0.2) 0.1 (0.1, 0.1) 0.2 (0.1, 0.3) 0.1 (0.1, 0.1) 0.2 (0.1, 0.3)

Post-dose value

N 2 2 4 1 9

Mean (SD) 0.3 (0.2) 0.2 (0.1) 0.2 (0.1) 0.1 0.2 (0.1)

Median (Min, Max) 0.3 (0.1, 0.4) 0.2 (0.1, 0.2) 0.2 (0.1, 0.2) 0.1 (0.1, 0.1) 0.1 (0.1, 0.4)


N 2 1 4 1 8

Mean (SD) 0.1 (0.2) 0.1 -0.1 (0.1) 0.0 -0.0 (0.1)

Median (Min, Max) 0.1 (-0.1, 0.2) 0.1 (0.1, 0.1) -0.1 (-0.2, 0.0) 0.0 (0.0, 0.0) 0.0 (-0.2, 0.2)

95% CI for Median 1 (-0.1, 0.2)

Percentage Change

N 2 1 4 1 8

Mean (SD) 25.0 (106.1) 100.0 -25.0 (31.9) 0.0 6.3 (63.0)

Median (Min, Max) 25.0 (-50.0, 100.0) 100.0 (100.0, 100.0) -16.7 (-66.7, 0.0) 0.0 (0.0, 0.0) 0.0 (-66.7, 100.0)


0 0 0 0 0






8


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Blood urea nitrogen (BUN) (mg/dL)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 26.5 (6.4) 26.0 (7.1) 15.4 (3.0) 29.5 (4.9) 21.9 (7.4)

Median (Min, Max) 26.5 (22.0, 31.0) 26.0 (21.0, 31.0) 15.0 (12.0, 19.0) 29.5 (26.0, 33.0) 21.0 (12.0, 33.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 30.0 (11.3) 25.0 (12.7) 16.3 (3.4) 26.0 22.3 (8.8)

Median (Min, Max) 30.0 (22.0, 38.0) 25.0 (16.0, 34.0) 15.5 (13.0, 21.0) 26.0 (26.0, 26.0) 21.0 (13.0, 38.0)


N 2 2 4 1 9

Mean (SD) 3.5 (4.9) -1.0 (5.7) 0.8 (4.6) -7.0 0.1 (5.0)

Median (Min, Max) 3.5 (0.0, 7.0) -1.0 (-5.0, 3.0) 2.5 (-6.0, 4.0) -7.0 (-7.0, -7.0) 2.0 (-7.0, 7.0)

95% CI for Median 1 (-6.0, 4.0)

Percentage Change

N 2 2 4 1 9

Mean (SD) 11.3 (16.0) -7.1 (23.7) 8.5 (27.9) -21.2 2.3 (22.9)

Median (Min, Max) 11.3 (0.0, 22.6) -7.1 (-23.8, 9.7) 16.0 (-31.6, 33.3) -21.2 (-21.2, -21.2) 9.7 (-31.6, 33.3)


2 (100.0%) 1 (50.0%) 1 (20.0%) 0 4 (36.4%)






9


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Calcium (mg/dL)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 9.7 (0.0) 9.6 (0.1) 9.9 (0.8) 10.0 (0.6) 9.8 (0.5)

Median (Min, Max) 9.7 (9.7, 9.7) 9.6 (9.5, 9.7) 9.8 (9.1, 11.0) 10.0 (9.5, 10.4) 9.7 (9.1, 11.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 9.5 (0.0) 9.5 (0.1) 9.8 (0.1) 9.9 9.7 (0.2)

Median (Min, Max) 9.5 (9.5, 9.5) 9.5 (9.4, 9.5) 9.8 (9.6, 9.9) 9.9 (9.9, 9.9) 9.6 (9.4, 9.9)


N 2 2 4 1 9

Mean (SD) -0.2 (0.0) -0.2 (0.1) -0.3 (0.7) -0.5 -0.3 (0.4)

Median (Min, Max) -0.2 (-0.2, -0.2) -0.2 (-0.2, -0.1) -0.4 (-1.1, 0.5) -0.5 (-0.5, -0.5) -0.2 (-1.1, 0.5)

95% CI for Median 1 (-0.5, -0.1)

Percentage Change

N 2 2 4 1 9

Mean (SD) -2.1 (0.0) -1.6 (0.7) -2.9 (6.4) -4.8 -2.6 (4.1)

Median (Min, Max) -2.1 (-2.1, -2.1) -1.6 (-2.1, -1.1) -3.5 (-10.0, 5.4) -4.8 (-4.8, -4.8) -2.1 (-10.0, 5.4)


0 0 1 (20.0%) 0 1 (9.1%)






10


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Chloride (mEq/L)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 106.0 (1.4) 108.0 (2.8) 102.8 (2.4) 104.5 (4.9) 104.6 (3.2)

Median (Min, Max) 106.0 (105.0, 107.0) 108.0 (106.0, 110.0) 103.0 (100.0, 106.0) 104.5 (101.0, 108.0) 105.0 (100.0, 110.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 106.5 (0.7) 104.5 (0.7) 102.0 (2.9) 105.0 103.9 (2.7)

Median (Min, Max) 106.5 (106.0, 107.0) 104.5 (104.0, 105.0) 102.0 (99.0, 105.0) 105.0 (105.0, 105.0) 105.0 (99.0, 107.0)


N 2 2 4 1 9

Mean (SD) 0.5 (2.1) -3.5 (2.1) 0.0 (3.4) -3.0 -1.0 (2.9)

Median (Min, Max) 0.5 (-1.0, 2.0) -3.5 (-5.0, -2.0) 0.0 (-4.0, 4.0) -3.0 (-3.0, -3.0) -1.0 (-5.0, 4.0)

95% CI for Median 1 (-4.0, 2.0)

Percentage Change

N 2 2 4 1 9

Mean (SD) 0.5 (2.0) -3.2 (1.9) 0.0 (3.3) -2.8 -0.9 (2.8)

Median (Min, Max) 0.5 (-0.9, 1.9) -3.2 (-4.5, -1.9) -0.0 (-3.9, 4.0) -2.8 (-2.8, -2.8) -1.0 (-4.5, 4.0)


0 0 0 0 0






11


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Cholesterol (mg/dL)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 153.5 (14.8) 166.0 (19.8) 190.4 (22.6) 140.0 (55.2) 170.1 (31.9)

Median (Min, Max) 153.5 (143.0, 164.0) 166.0 (152.0, 180.0) 190.0 (165.0, 213.0) 140.0 (101.0, 179.0) 171.0 (101.0, 213.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 151.0 (14.1) 146.0 (9.9) 169.0 (22.7) 137.0 156.3 (19.8)

Median (Min, Max) 151.0 (141.0, 161.0) 146.0 (139.0, 153.0) 168.0 (146.0, 194.0) 137.0 (137.0, 137.0) 153.0 (137.0, 194.0)


N 2 2 4 1 9

Mean (SD) -2.5 (0.7) -20.0 (29.7) -21.5 (28.7) -42.0 -19.2 (23.6)

Median (Min, Max) -2.5 (-3.0, -2.0) -20.0 (-41.0, 1.0) -19.0 (-59.0, 11.0) -42.0 (-42.0, -42.0) -19.0 (-59.0, 11.0)

95% CI for Median 1 (-42.0, 1.0)

Percentage Change

N 2 2 4 1 9

Mean (SD) -1.6 (0.3) -11.1 (16.6) -10.4 (14.0) -23.5 -10.1 (12.2)

Median (Min, Max) -1.6 (-1.8, -1.4) -11.1 (-22.8, 0.7) -10.2 (-27.7, 6.4) -23.5 (-23.5, -23.5) -8.9 (-27.7, 6.4)


0 0 1 (20.0%) 0 1 (9.1%)






12


0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Creatinine (mg/dL)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 1.5 (0.5) 1.5 (1.0) 0.8 (0.3) 0.9 (0.2) 1.1 (0.5)

Median (Min, Max) 1.5 (1.1, 1.8) 1.5 (0.8, 2.2) 0.7 (0.4, 1.2) 0.9 (0.8, 1.1) 1.0 (0.4, 2.2)

Post-dose value

N 2 2 4 1 9

Mean (SD) 1.5 (0.5) 1.5 (0.9) 0.9 (0.3) 0.6 1.2 (0.6)

Median (Min, Max) 1.5 (1.2, 1.9) 1.5 (0.8, 2.1) 0.9 (0.6, 1.4) 0.6 (0.6, 0.6) 1.0 (0.6, 2.1)


N 2 2 4 1 9

Mean (SD) 0.1 (0.1) -0.0 (0.1) 0.0 (0.1) -0.1 0.0 (0.1)

Median (Min, Max) 0.1 (0.0, 0.1) -0.0 (-0.1, 0.0) 0.0 (-0.1, 0.2) -0.1 (-0.1, -0.1) 0.0 (-0.1, 0.2)

95% CI for Median 1 (-0.1, 0.1)

Percentage Change

N 2 2 4 1 9

Mean (SD) 3.6 (2.6) 0.8 (6.2) 3.7 (14.0) -14.7 1.0 (10.7)

Median (Min, Max) 3.6 (1.8, 5.5) 0.8 (-3.6, 5.2) 5.1 (-12.1, 16.7) -14.7 (-14.7, -14.7) 1.8 (-14.7, 16.7)


1 (50.0%) 1 (50.0%) 2 (40.0%) 0 4 (36.4%)






13


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Glucose (mg/dL)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 101.0 (22.6) 99.0 (11.3) 111.8 (30.1) 90.5 (6.4) 103.6 (22.5)

Median (Min, Max) 101.0 (85.0, 117.0) 99.0 (91.0, 107.0) 94.0 (88.0, 155.0) 90.5 (86.0, 95.0) 94.0 (85.0, 155.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 95.5 (6.4) 86.5 (4.9) 151.5 (117.8) 82.0 116.9 (79.4)

Median (Min, Max) 95.5 (91.0, 100.0) 86.5 (83.0, 90.0) 94.5 (89.0, 328.0) 82.0 (82.0, 82.0) 90.0 (82.0, 328.0)


N 2 2 4 1 9

Mean (SD) -5.5 (16.3) -12.5 (16.3) 34.3 (95.1) -13.0 9.8 (63.3)

Median (Min, Max) -5.5 (-17.0, 6.0) -12.5 (-24.0, -1.0) 3.5 (-43.0, 173.0) -13.0 (-13.0, -13.0) -1.0 (-43.0, 173.0)

95% CI for Median 1 (-24.0, 6.0)

Percentage Change

N 2 2 4 1 9

Mean (SD) -3.7 (15.3) -11.8 (15.1) 21.7 (62.4) -13.7 4.7 (42.3)

Median (Min, Max) -3.7 (-14.5, 7.1) -11.8 (-22.4, -1.1) 3.8 (-32.6, 111.6) -13.7 (-13.7, -13.7) -1.1 (-32.6, 111.6)


1 (50.0%) 0 0 0 1 (9.1%)






14


0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2)

0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Phosphorus (mg/dL)

Pre-dose value

N 1 1 3 1 6

Mean (SD) 3.5 5.9 3.8 (0.3) 4.7 4.3 (0.9)

Median (Min, Max) 3.5 (3.5, 3.5) 5.9 (5.9, 5.9) 4.0 (3.4, 4.0) 4.7 (4.7, 4.7) 4.0 (3.4, 5.9)


0 0 0 0 0






15


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Potassium (mEq/L)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 4.8 (0.6) 5.1 (1.1) 4.1 (0.6) 5.2 (0.9) 4.6 (0.8)

Median (Min, Max) 4.8 (4.4, 5.2) 5.1 (4.3, 5.9) 3.8 (3.6, 5.0) 5.2 (4.5, 5.8) 4.4 (3.6, 5.9)

Post-dose value

N 2 2 4 1 9

Mean (SD) 4.4 (0.4) 5.0 (0.4) 4.0 (0.5) 4.5 4.4 (0.5)

Median (Min, Max) 4.4 (4.1, 4.7) 5.0 (4.7, 5.2) 4.2 (3.3, 4.4) 4.5 (4.5, 4.5) 4.4 (3.3, 5.2)


N 2 2 4 1 9

Mean (SD) -0.4 (0.1) -0.2 (1.5) -0.2 (0.8) -1.3 -0.3 (0.8)

Median (Min, Max) -0.4 (-0.5, -0.3) -0.2 (-1.2, 0.9) -0.2 (-0.9, 0.6) -1.3 (-1.3, -1.3) -0.5 (-1.3, 0.9)

95% CI for Median 1 (-1.2, 0.6)

Percentage Change

N 2 2 4 1 9

Mean (SD) -8.2 (2.0) 0.3 (29.2) -2.5 (19.9) -22.4 -5.4 (17.5)

Median (Min, Max) -8.2 (-9.6, -6.8) 0.3 (-20.3, 20.9) -2.2 (-21.4, 15.8) -22.4 (-22.4, -22.4) -9.6 (-22.4, 20.9)


0 0 1 (20.0%) 0 1 (9.1%)






16


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2)

0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Protein, total (g/d)

Pre-dose value

N 2 1 5 2 10

Mean (SD) 7.3 (0.1) 7.0 7.2 (0.7) 7.9 (1.7) 7.3 (0.8)

Median (Min, Max) 7.3 (7.2, 7.4) 7.0 (7.0, 7.0) 7.1 (6.4, 8.3) 7.9 (6.7, 9.1) 7.2 (6.4, 9.1)

Post-dose value

N 2 2 4 1 9

Mean (SD) 7.0 (0.1) 6.4 (0.4) 6.8 (0.5) 8.4 6.9 (0.7)

Median (Min, Max) 7.0 (6.9, 7.1) 6.4 (6.1, 6.7) 6.7 (6.4, 7.5) 8.4 (8.4, 8.4) 6.8 (6.1, 8.4)


N 2 1 4 1 8

Mean (SD) -0.3 (0.0) -0.3 -0.4 (0.3) -0.7 -0.4 (0.3)

Median (Min, Max) -0.3 (-0.3, -0.3) -0.3 (-0.3, -0.3) -0.3 (-0.8, 0.0) -0.7 (-0.7, -0.7) -0.3 (-0.8, 0.0)

95% CI for Median 1 (-0.7, 0.0)

Percentage Change

N 2 1 4 1 8

Mean (SD) -4.1 (0.1) -4.3 -4.6 (3.9) -7.7 -4.8 (2.8)

Median (Min, Max) -4.1 (-4.2, -4.1) -4.3 (-4.3, -4.3) -4.3 (-9.6, 0.0) -7.7 (-7.7, -7.7) -4.3 (-9.6, 0.0)


0 0 0 0 0






17


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Sodium (mEq/L)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 138.5 (0.7) 140.5 (2.1) 140.0 (2.7) 137.5 (2.1) 139.4 (2.3)

Median (Min, Max) 138.5 (138.0, 139.0) 140.5 (139.0, 142.0) 140.0 (137.0, 144.0) 137.5 (136.0, 139.0) 139.0 (136.0, 144.0)

Post-dose value

N 2 2 4 1 9

Mean (SD) 138.0 (2.8) 138.0 (2.8) 136.5 (3.3) 136.0 137.1 (2.6)

Median (Min, Max) 138.0 (136.0, 140.0) 138.0 (136.0, 140.0) 137.0 (132.0, 140.0) 136.0 (136.0, 136.0) 137.0 (132.0, 140.0)


N 2 2 4 1 9

Mean (SD) -0.5 (3.5) -2.5 (4.9) -2.5 (2.4) 0.0 -1.8 (2.8)

Median (Min, Max) -0.5 (-3.0, 2.0) -2.5 (-6.0, 1.0) -2.5 (-5.0, 0.0) 0.0 (0.0, 0.0) -1.0 (-6.0, 2.0)

95% CI for Median 1 (-5.0, 1.0)

Percentage Change

N 2 2 4 1 9

Mean (SD) -0.4 (2.6) -1.8 (3.5) -1.8 (1.7) 0.0 -1.3 (2.0)

Median (Min, Max) -0.4 (-2.2, 1.4) -1.8 (-4.2, 0.7) -1.8 (-3.6, 0.0) 0.0 (0.0, 0.0) -0.7 (-4.2, 1.4)


0 0 0 0 0






18


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)


Pre-dose value

N 2 2 5 2 11

Mean (SD) 45.2 (9.1) 40.6 (16.1) 84.2 (20.5) 65.0 (6.3) 65.7 (24.2)

Median (Min, Max) 45.2 (38.8, 51.6) 40.6 (29.2, 52.0) 87.4 (62.5, 111.2) 65.0 (60.5, 69.4) 62.5 (29.2, 111.2)

Post-dose value

N 2 2 4 1 9

Mean (SD) 43.7 (9.9) 39.9 (13.5) 76.3 (22.5) 81.3 61.5 (24.0)

Median (Min, Max) 43.7 (36.7, 50.7) 39.9 (30.3, 49.5) 71.4 (54.7, 107.5) 81.3 (81.3, 81.3) 54.7 (30.3, 107.5)


N 2 2 4 1 9

Mean (SD) -1.5 (0.8) -0.7 (2.6) -1.1 (11.4) 11.9 0.3 (8.3)

Median (Min, Max) -1.5 (-2.0, -0.9) -0.7 (-2.6, 1.1) -2.5 (-12.5, 13.0) 11.9 (11.9, 11.9) -0.9 (-12.5, 13.0)

95% CI for Median 1 (-7.8, 11.9)

Percentage Change

N 2 2 4 1 9

Mean (SD) -3.5 (2.5) -0.6 (6.2) -2.2 (13.5) 17.2 0.0 (10.8)

Median (Min, Max) -3.5 (-5.2, -1.7) -0.6 (-4.9, 3.8) -4.2 (-14.3, 13.8) 17.2 (17.2, 17.2) -1.7 (-14.3, 17.2)


1 (50.0%) 1 (50.0%) 2 (40.0%) 0 4 (36.4%)


Table 14.3.2.4.1 Summary of Clinical Laboratory Measurements by Enrollment Group: Urine Results




1


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Urine creatinine

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 50.8 (4.3) 205.9 128.0 (36.4) 130.8 (46.8) 58.4 (16.8) 104.8 (55.0)

Median (Min, Max) 49.2 (47.6, 55.7) 205.9 (205.9, 205.9) 120.4 (96.1, 167.6) 107.4 (89.5, 205.2) 56.0 (43.0, 76.3) 96.1 (43.0, 205.9)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 54.5 (9.4) 254.6 151.4 (49.1) 127.5 (44.6) 60.1 (12.7) 116.4 (64.6)

Median (Min, Max) 53.8 (45.5, 64.2) 254.6 (254.6, 254.6) 127.1 (119.3, 207.9) 102.5 (88.1, 180.2) 60.1 (51.1, 69.1) 98.8 (45.5, 254.6)


N 3 1 3 5 2 14

Mean (SD) 3.7 (9.8) 48.7 23.4 (16.8) -3.3 (68.9) -6.1 (27.1) 7.2 (42.9)

Median (Min, Max) -1.9 (-2.1, 15.0) 48.7 (48.7, 48.7) 23.2 (6.7, 40.3) 13.0 (-110.2, 75.9) -6.1 (-25.2, 13.1) 13.1 (-110.2, 75.9)

95% CI for Median 1 (-2.1, 40.3)

Percentage Change

N 3 1 3 5 2 14

Mean (SD) 7.6 (19.9) 23.7 17.9 (10.7) 6.4 (46.8) -4.8 (39.9) 8.7 (30.7)

Median (Min, Max) -3.4 (-4.4, 30.5) 23.7 (23.7, 23.7) 24.1 (5.6, 24.1) 14.5 (-53.7, 72.8) -4.8 (-33.0, 23.4) 15.4 (-53.7, 72.8)


0 1 (100.0%) 0 0 0 1 (6.7%)






2


0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Microalbuminuria

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 651.9 (640.7) 4.0 73.7 (109.3) 86.4 (80.5) 496.0 (830.8) 273.4 (477.8)

Median (Min, Max) 631.0 (21.9, 1302.8) 4.0 (4.0, 4.0) 14.9 (6.4, 199.9) 96.1 (5.5, 189.9) 18.8 (14.0, 1455.3) 21.9 (4.0, 1455.3)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 408.8 (399.7) 4.0 16.4 (16.1) 34.9 (23.1) 154.4 (184.1) 125.9 (230.4)

Median (Min, Max) 373.5 (27.9, 824.9) 4.0 (4.0, 4.0) 8.1 (6.2, 35.0) 22.2 (13.6, 61.2) 154.4 (24.2, 284.6) 26.1 (4.0, 824.9)


N 3 1 3 5 2 14

Mean (SD) -243.1 (242.3) 0.0 -57.3 (93.3) -51.6 (68.3) -580.3 (835.0) -165.7 (321.1)

Median (Min, Max) -257.5 (-477.9, 6.0) 0.0 (0.0, 0.0) -8.7 (-164.9, 1.7) -34.9 (-131.1, 16.7) -580.3 (-1171, 10.2) -21.8 (-1171, 16.7)

95% CI for Median 1 (-165, 6.6)

Percentage Change

N 3 1 3 5 2 14

Mean (SD) -16.7 (38.2) 0.0 -38.1 (57.3) 41.3 (162.8) -3.8 (108.4) 2.5 (104.1)

Median (Min, Max) -36.7 (-40.8, 27.4) 0.0 (0.0, 0.0) -58.4 (-82.5, 26.6) -36.3 (-86.1, 303.6) -3.8 (-80.4, 72.9) -36.5 (-86.1, 303.6)


0 0 0 1 (20.0%) 1 (33.3%) 2 (13.3%)






3


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Protein

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 101.6 (79.8) 22.3 34.0 (24.7) 34.1 (19.5) 82.4 (125.1) 56.4 (65.5)

Median (Min, Max) 107.6 (18.9, 178.2) 22.3 (22.3, 22.3) 28.1 (12.8, 61.2) 29.6 (10.7, 59.7) 12.0 (8.3, 226.8) 28.1 (8.3, 226.8)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 66.9 (46.5) 21.4 26.3 (14.9) 21.7 (10.3) 40.0 (34.3) 35.0 (28.8)

Median (Min, Max) 66.7 (20.5, 113.5) 21.4 (21.4, 21.4) 21.3 (14.5, 43.0) 21.5 (9.6, 32.9) 40.0 (15.7, 64.2) 21.5 (9.6, 113.5)


N 3 1 3 5 2 14

Mean (SD) -34.7 (33.6) -0.9 -7.8 (28.6) -12.3 (16.5) -79.5 (117.6) -24.9 (45.8)

Median (Min, Max) -40.9 (-64.7, 1.6) -0.9 (-0.9, -0.9) 1.7 (-39.9, 14.9) -16.1 (-28.6, 10.0) -79.5 (-162.6, 3.7) -8.6 (-162.6, 14.9)

95% CI for Median 1 (-39.9, 3.7)

Percentage Change

N 3 1 3 5 2 14

Mean (SD) -22.0 (26.4) -4.0 0.4 (60.2) -24.7 (42.4) -20.4 (72.5) -16.7 (41.6)

Median (Min, Max) -36.3 (-38.0, 8.5) -4.0 (-4.0, -4.0) 13.3 (-65.2, 53.0) -47.9 (-54.6, 43.7) -20.4 (-71.7, 30.8) -23.3 (-71.7, 53.0)


0 0 1 (33.3%) 1 (20.0%) 1 (33.3%) 3 (20.0%)






4


0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Albumin/creatinine ratio

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 1353.0 (1350.4) 2.0 60.7 (91.2) 79.6 (89.3) 658.6 (1081.2) 441.1 (843.1)

Median (Min, Max) 1283.0 (39.0, 2737.0) 2.0 (2.0, 2.0) 9.0 (7.0, 166.0) 47.0 (4.0, 212.0) 44.0 (24.9, 1907.0) 44.0 (2.0, 2737.0)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 815.7 (903.5) 2.0 12.7 (13.4) 31.8 (26.4) 296.0 (369.1) 231.3 (496.1)

Median (Min, Max) 582.0 (52.0, 1813.0) 2.0 (2.0, 2.0) 7.0 (3.0, 28.0) 15.0 (10.0, 64.0) 296.0 (35.0, 557.0) 31.5 (2.0, 1813.0)


N 3 1 3 5 2 14

Mean (SD) -537.3 (489.5) 0.0 -48.0 (78.0) -47.8 (82.1) -670.0 (961.7) -238.2 (432.4)

Median (Min, Max) -701.0 (-924.0, 13.0) 0.0 (0.0, 0.0) -6.0 (-138.0, 0.0) 8.0 (-155.0, 17.0) -670.0 (-1350, 10.1) -3.0 (-1350, 17.0)

95% CI for Median 1 (-155, 10.1)

Percentage Change

N 3 1 3 5 2 14

Mean (SD) -18.4 (46.0) 0.0 -49.9 (44.0) 42.0 (132.3) -15.1 (78.7) -1.8 (88.6)

Median (Min, Max) -33.8 (-54.6, 33.3) 0.0 (0.0, 0.0) -66.7 (-83.1, 0.0) 36.2 (-92.2, 225.0) -15.1 (-70.8, 40.6) -16.9 (-92.2, 225.0)


0 0 0 1 (20.0%) 1 (33.3%) 2 (13.3%)






5


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Protein/creatinine ratio

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 2.1 (1.7) 0.1 0.3 (0.2) 0.3 (0.2) 1.1 (1.7) 0.8 (1.2)

Median (Min, Max) 2.2 (0.3, 3.7) 0.1 (0.1, 0.1) 0.2 (0.1, 0.5) 0.3 (0.1, 0.5) 0.2 (0.0, 3.0) 0.3 (0.0, 3.7)

Post-dose value

N 3 1 3 5 2 14

Mean (SD) 1.3 (1.1) 0.1 0.2 (0.0) 0.2 (0.1) 0.8 (0.7) 0.5 (0.7)

Median (Min, Max) 1.0 (0.4, 2.5) 0.1 (0.1, 0.1) 0.2 (0.1, 0.2) 0.2 (0.1, 0.3) 0.8 (0.2, 1.3) 0.2 (0.1, 2.5)


N 3 1 3 5 2 14

Mean (SD) -0.8 (0.7) -0.0 -0.1 (0.2) -0.1 (0.2) -0.7 (1.4) -0.3 (0.6)

Median (Min, Max) -1.2 (-1.3, 0.0) -0.0 (-0.0, -0.0) -0.0 (-0.3, 0.0) 0.0 (-0.3, 0.0) -0.7 (-1.7, 0.2) -0.0 (-1.7, 0.2)

95% CI for Median 1 (-0.3, 0.0)

Percentage Change

N 3 1 3 5 1 13

Mean (SD) -24.7 (33.0) -27.3 -16.9 (45.8) -18.6 (45.2) -57.6 -23.3 (36.5)

Median (Min, Max) -33.4 (-52.5, 11.8) -27.3 (-27.3, -27.3) -7.7 (-66.7, 23.5) 10.0 (-75.0, 18.8) -57.6 (-57.6, -57.6) -27.3 (-75.0, 23.5)


0 0 1 (33.3%) 1 (20.0%) 1 (33.3%) 3 (20.0%)






1


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Urine creatinine

Post-dose value

N 2 2 5 1 10

Mean (SD) 89.7 (56.5) 128.1 (64.8) 78.5 (48.6) 83.5 91.1 (47.6)

Median (Min, Max) 89.7 (49.7, 129.6) 128.1 (82.3, 173.9) 73.5 (8.3, 128.1) 83.5 (83.5, 83.5) 82.9 (8.3, 173.9)


0 0 0 0 0






2


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Microalbuminuria

Post-dose value

N 2 2 5 1 10

Mean (SD) 66.9 (54.0) 129.8 (179.0) 118.6 (219.2) 5.0 99.1 (163.9)

Median (Min, Max) 66.9 (28.7, 105.0) 129.8 (3.2, 256.3) 13.5 (7.2, 509.4) 5.0 (5.0, 5.0) 21.1 (3.2, 509.4)


0 0 0 0 0






3


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Protein

Pre-dose value

N 0 1 2 0 3

Mean (SD) 100.0 10.0 (0.0) 40.0 (52.0)

Median (Min, Max) 100.0 (100.0, 100.0) 10.0 (10.0, 10.0) 10.0 (10.0, 100.0)

Post-dose value

N 2 2 5 1 10

Mean (SD) 20.0 (0.2) 52.3 (42.0) 30.5 (41.6) 13.2 31.0 (33.6)

Median (Min, Max) 20.0 (19.8, 20.1) 52.3 (22.6, 82.0) 10.0 (6.2, 104.1) 13.2 (13.2, 13.2) 20.0 (6.2, 104.1)


N 0 1 2 0 3

Mean (SD) -18.0 6.0 (8.9) -2.0 (15.2)

Median (Min, Max) -18.0 (-18.0, -18.0) 6.0 (-0.3, 12.3) -0.3 (-18.0, 12.3)

95% CI for Median 1 (-18.0, 12.3)

Percentage Change

N 0 1 2 0 3

Mean (SD) -18.0 60.0 (89.1) 34.0 (77.4)

Median (Min, Max) -18.0 (-18.0, -18.0) 60.0 (-3.0, 123.0) -3.0 (-18.0, 123.0)


0 1 (50.0%) 0 0 1 (9.1%)






4


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Albumin/creatinine ratio

Post-dose value

N 2 2 5 1 10

Mean (SD) 116.5 (133.6) 75.5 (101.1) 116.8 (160.5) 6.0 97.4 (126.1)

Median (Min, Max) 116.5 (22.0, 211.0) 75.5 (4.0, 147.0) 69.0 (11.0, 398.0) 6.0 (6.0, 6.0) 45.5 (4.0, 398.0)


0 0 0 0 0






5


0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Protein/creatinine ratio

Pre-dose value

N 0 0 1 0 1

Mean (SD) 0.2 0.2

Median (Min, Max) 0.2 (0.2, 0.2) 0.2 (0.2, 0.2)

Post-dose value

N 2 2 5 1 10

Mean (SD) 0.3 (0.2) 0.4 (0.1) 0.4 (0.3) 0.2 0.4 (0.3)

Median (Min, Max) 0.3 (0.2, 0.4) 0.4 (0.3, 0.5) 0.3 (0.1, 0.8) 0.2 (0.2, 0.2) 0.3 (0.1, 0.8)


N 0 0 1 0 1

Mean (SD) 0.1 0.1

Median (Min, Max) 0.1 (0.1, 0.1) 0.1 (0.1, 0.1)


Percentage Change

N 0 0 1 0 1

Mean (SD) 50.0 50.0

Median (Min, Max) 50.0 (50.0, 50.0) 50.0 (50.0, 50.0)


0 0 0 0 0


Table 14.3.2.5.1 Summary of Clinical Laboratory Measurements by Enrollment Group: Iohexol GFR


1


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Iohexol Glomerular Filtration

Post-dose value

N 2 1 3 4 2 12

Mean (SD) 37.3 (5.6) 89.7 91.7 (6.4) 91.8 (21.9) 117.4 (37.2) 86.8 (30.0)

Median (Min, Max) 37.3 (33.3, 41.3) 89.7 (89.7, 89.7) 93.0 (84.8, 97.4) 85.5 (73.1, 123.0) 117.4 (91.0, 143.7) 89.6 (33.3, 143.7)


Table 14.3.2.5.2 Summary of Clinical Laboratory Measurements by Enrollment Group: Iohexol GFR


1


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Iohexol Glomerular Filtration

Post-dose value

N 2 1 5 1 9

Mean (SD) 45.79 (3.49) 72.87 98.16 (10.35) 75.62 81.21 (23.68)

Median (Min, Max) 45.79 (43.32, 48.25) 72.87 (72.87, 72.87) 97.12 (86.47, 110.30) 75.62 (75.62, 75.62) 86.47 (43.32, 110.30)


Table 14.3.2.6 Summary of Clinical Laboratory Measurements by Enrollment Group using Valid Pre-Lisinopril Records

Safety Population - IC2 with Valid Pre-Lisinopril Records


Pre-lisinopril values are the average of the chart review records collected <=6 weeks prior to first lisinopril dose recorded on prior and concomitant medications form. Post-dose value calculated as last value while the participant was on drug.

1


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Creatinine (mg/dL)

Pre-Lisinopril value

N 1 2 2 0 5

Mean (SD) 1.8 1.3 (0.6) 0.7 (0.1) 1.2 (0.5)

Median (Min, Max) 1.8 (1.8, 1.8) 1.3 (0.9, 1.7) 0.7 (0.6, 0.8) 0.9 (0.6, 1.8)

Post-dose value

N 1 2 2 0 5

Mean (SD) 1.9 1.5 (0.9) 0.9 (0.1) 1.3 (0.6)

Median (Min, Max) 1.9 (1.9, 1.9) 1.5 (0.8, 2.1) 0.9 (0.8, 1.0) 1.0 (0.8, 2.1)


N 1 2 2 0 5

Mean (SD) 0.2 0.2 (0.4) 0.2 (0.0) 0.2 (0.2)

Median (Min, Max) 0.2 (0.2, 0.2) 0.2 (-0.1, 0.4) 0.2 (0.2, 0.2) 0.2 (-0.1, 0.4)

95% CI for Median 1 (-0.1, 0.4)

Percentage Change

N 1 2 2 0 5

Mean (SD) 9.7 7.7 (25.1) 25.4 (4.1) 15.2 (15.8)

Median (Min, Max) 9.7 (9.7, 9.7) 7.7 (-10.0, 25.4) 25.4 (22.5, 28.3) 22.5 (-10.0, 28.3)






2


0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Potassium (mEq/L)


N 2 2 2 0 6

Mean (SD) 4.7 (0.4) 4.7 (0.2) 3.9 (0.1) 4.4 (0.5)

Median (Min, Max) 4.7 (4.4, 5.0) 4.7 (4.5, 4.8) 3.9 (3.8, 3.9) 4.5 (3.8, 5.0)

Post-dose value

N 2 2 2 0 6

Mean (SD) 4.4 (0.4) 5.0 (0.4) 3.9 (0.8) 4.4 (0.7)

Median (Min, Max) 4.4 (4.1, 4.7) 5.0 (4.7, 5.2) 3.9 (3.3, 4.4) 4.6 (3.3, 5.2)


N 2 2 2 0 6

Mean (SD) -0.3 (0.0) 0.3 (0.1) -0.0 (0.7) 0.0 (0.4)

Median (Min, Max) -0.3 (-0.3, -0.3) 0.3 (0.2, 0.4) -0.0 (-0.5, 0.5) -0.0 (-0.5, 0.5)

95% CI for Median 1 (-0.5, 0.5)

Percentage Change

N 2 2 2 0 6

Mean (SD) -5.9 (1.2) 6.4 (2.7) -0.7 (17.7) -0.1 (9.7)

Median (Min, Max) -5.9 (-6.8, -5.1) 6.4 (4.4, 8.3) -0.7 (-13.2, 11.9) -0.3 (-13.2, 11.9)






3


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)



N 1 2 2 0 5

Mean (SD) 40.3 41.3 (4.6) 89.7 (9.1) 60.4 (27.2)

Median (Min, Max) 40.3 (40.3, 40.3) 41.3 (38.0, 44.5) 89.7 (83.2, 96.1) 44.5 (38.0, 96.1)

Post-dose value

N 1 2 2 0 5

Mean (SD) 36.7 39.9 (13.5) 71.4 (4.9) 51.9 (19.3)

Median (Min, Max) 36.7 (36.7, 36.7) 39.9 (30.3, 49.5) 71.4 (67.9, 74.9) 49.5 (30.3, 74.9)


N 1 2 2 0 5

Mean (SD) -3.6 -1.4 (9.0) -18.3 (4.2) -8.6 (10.2)

Median (Min, Max) -3.6 (-3.6, -3.6) -1.4 (-7.7, 4.9) -18.3 (-21.2, -15.3) -7.7 (-21.2, 4.9)

95% CI for Median 1 (-21.2, 4.9)

Percentage Change

N 1 2 2 0 5

Mean (SD) -8.9 -4.6 (22.2) -20.2 (2.6) -11.7 (13.7)

Median (Min, Max) -8.9 (-8.9, -8.9) -4.6 (-20.3, 11.1) -20.2 (-22.1, -18.4) -18.4 (-22.1, 11.1)


Table 14.3.3.1 Summary of Vital Signs by Enrollment Group


Note: Baseline measurement defined as closest measurement before first dose administration.

Post-dose value calculated as last value while the participant was on study drug (PK visit if completed and interim otherwise). Trough PK visit blood pressure evaluation before the PK visit dose is used as post-dose value.

1


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Weight (kg)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 58.0 (5.4) 110.8 46.2 (5.7) 52.4 (10.7) 26.3 (6.2) 51.0 (21.2)

Median (Min, Max) 57.2 (53.0, 63.7) 110.8 (110.8, 110.8) 44.4 (41.7, 52.6) 55.1 (34.0, 60.9) 25.1 (20.8, 33.0) 53.0 (20.8, 110.8)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 57.5 (4.7) 110.3 47.2 (5.0) 51.4 (11.2) 26.4 (6.0) 50.7 (21.0)

Median (Min, Max) 55.9 (53.8, 62.7) 110.3 (110.3, 110.3) 45.4 (43.3, 52.8) 54.4 (32.6, 61.9) 25.2 (21.0, 32.9) 52.8 (21.0, 110.3)


N 3 1 3 5 3 15

Mean (SD) -0.5 (1.1) -0.5 0.9 (0.7) -1.0 (1.2) 0.1 (0.2) -0.3 (1.1)

Median (Min, Max) -1.0 (-1.3, 0.8) -0.5 (-0.5, -0.5) 1.0 (0.2, 1.6) -1.4 (-2.0, 1.0) 0.1 (-0.1, 0.2) -0.1 (-2.0, 1.6)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) -0.8 (2.0) -0.5 2.2 (1.7) -2.1 (2.4) 0.4 (0.6) -0.4 (2.3)

Median (Min, Max) -1.6 (-2.3, 1.5) -0.5 (-0.5, -0.5) 2.3 (0.4, 3.8) -3.4 (-4.1, 1.6) 0.4 (-0.3, 1.0) -0.3 (-4.1, 3.8)






2


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Height (cm)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 148.2 (14.9) 165.5 147.0 (17.7) 149.4 (17.4) 126.7 (15.2) 145.2 (17.5)

Median (Min, Max) 151.0 (132.1, 161.5) 165.5 (165.5, 165.5) 145.0 (130.4, 165.7) 157.1 (122.0, 164.7) 125.6 (112.1, 142.4) 145.0 (112.1, 165.7)






3


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Temperature (0c)

Pre-dose value

N 3 1 3 4 3 14

Mean (SD) 37.0 (0.5) 37.3 36.6 (0.4) 36.5 (0.5) 37.0 (0.4) 36.8 (0.5)

Median (Min, Max) 36.9 (36.6, 37.5) 37.3 (37.3, 37.3) 36.8 (36.1, 36.8) 36.3 (36.1, 37.2) 37.0 (36.7, 37.4) 36.8 (36.1, 37.5)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 37.1 (0.1) 36.6 36.7 (0.2) 36.4 (0.4) 36.6 (0.1) 36.7 (0.4)

Median (Min, Max) 37.2 (37.0, 37.2) 36.6 (36.6, 36.6) 36.8 (36.5, 36.9) 36.6 (35.7, 36.7) 36.6 (36.5, 36.7) 36.7 (35.7, 37.2)


N 3 1 3 4 3 14

Mean (SD) 0.1 (0.6) -0.7 0.2 (0.2) 0.1 (0.6) -0.4 (0.5) -0.1 (0.5)

Median (Min, Max) 0.3 (-0.5, 0.6) -0.7 (-0.7, -0.7) 0.1 (0.0, 0.4) 0.1 (-0.5, 0.6) -0.4 (-0.9, 0.0) 0.0 (-0.9, 0.6)

Percentage Change

N 3 1 3 4 3 14

Mean (SD) 0.4 (1.5) -1.9 0.5 (0.6) 0.2 (1.5) -1.2 (1.2) -0.1 (1.4)

Median (Min, Max) 0.8 (-1.3, 1.6) -1.9 (-1.9, -1.9) 0.3 (0.0, 1.1) 0.3 (-1.3, 1.7) -1.1 (-2.4, 0.0) 0.0 (-2.4, 1.7)






4


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Systolic Blood Pressure (mm Hg)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 119.7 (5.5) 133.0 122.7 (0.6) 125.8 (9.2) 127.0 (7.8) 124.7 (7.1)

Median (Min, Max) 117.0 (116.0, 126.0) 133.0 (133.0, 133.0) 123.0 (122.0, 123.0) 126.0 (114.0, 137.0) 131.0 (118.0, 132.0) 123.0 (114.0, 137.0)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 114.7 (11.1) 127.0 116.0 (4.6) 117.0 (5.5) 115.7 (5.9) 116.7 (6.6)

Median (Min, Max) 116.0 (103.0, 125.0) 127.0 (127.0, 127.0) 117.0 (111.0, 120.0) 119.0 (110.0, 124.0) 118.0 (109.0, 120.0) 118.0 (103.0, 127.0)


N 3 1 3 5 3 15

Mean (SD) -5.0 (11.4) -6.0 -6.7 (4.0) -8.8 (11.7) -11.3 (2.1) -7.9 (8.1)

Median (Min, Max) -10.0 (-13.0, 8.0) -6.0 (-6.0, -6.0) -6.0 (-11.0, -3.0) -10.0 (-19.0, 10.0) -12.0 (-13.0, -9.0) -10.0 (-19.0, 10.0)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) -4.1 (9.6) -4.5 -5.4 (3.3) -6.5 (9.3) -8.9 (1.2) -6.2 (6.5)

Median (Min, Max) -7.9 (-11.2, 6.8) -4.5 (-4.5, -4.5) -4.9 (-9.0, -2.4) -8.3 (-14.4, 8.8) -9.1 (-9.9, -7.6) -7.9 (-14.4, 8.8)






5


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Diastolic Blood Pressure (mm Hg)

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 76.0 (18.7) 73.0 75.3 (7.8) 75.4 (8.1) 78.3 (11.9) 75.9 (10.0)

Median (Min, Max) 82.0 (55.0, 91.0) 73.0 (73.0, 73.0) 73.0 (69.0, 84.0) 78.0 (63.0, 83.0) 82.0 (65.0, 88.0) 78.0 (55.0, 91.0)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 72.0 (3.5) 80.0 66.3 (8.6) 69.4 (13.5) 74.3 (13.4) 71.0 (10.2)

Median (Min, Max) 74.0 (68.0, 74.0) 80.0 (80.0, 80.0) 68.0 (57.0, 74.0) 69.0 (50.0, 86.0) 80.0 (59.0, 84.0) 74.0 (50.0, 86.0)


N 3 1 3 5 3 15

Mean (SD) -4.0 (20.0) 7.0 -9.0 (7.5) -6.0 (6.7) -4.0 (5.3) -4.9 (9.8)

Median (Min, Max) -14.0 (-17.0, 19.0) 7.0 (7.0, 7.0) -10.0 (-16.0, -1.0) -7.0 (-13.0, 5.0) -6.0 (-8.0, 2.0) -7.0 (-17.0, 19.0)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) -0.4 (30.3) 9.6 -11.8 (10.2) -8.6 (9.7) -5.3 (6.7) -5.7 (14.6)

Median (Min, Max) -17.1 (-18.7, 34.5) 9.6 (9.6, 9.6) -11.9 (-21.9, -1.4) -9.7 (-20.6, 6.2) -9.1 (-9.2, 2.4) -9.2 (-21.9, 34.5)






6


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Pulse

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 87.3 (16.2) 102.0 81.7 (8.0) 88.2 (8.2) 96.7 (4.7) 89.3 (10.3)

Median (Min, Max) 90.0 (70.0, 102.0) 102.0 (102.0, 102.0) 81.0 (74.0, 90.0) 86.0 (79.0, 99.0) 95.0 (93.0, 102.0) 90.0 (70.0, 102.0)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 91.0 (6.6) 104.0 71.7 (11.9) 89.0 (9.0) 89.7 (7.5) 87.1 (11.6)

Median (Min, Max) 92.0 (84.0, 97.0) 104.0 (104.0, 104.0) 77.0 (58.0, 80.0) 92.0 (78.0, 98.0) 90.0 (82.0, 97.0) 90.0 (58.0, 104.0)


N 3 1 3 5 3 15

Mean (SD) 3.7 (9.6) 2.0 -10.0 (6.0) 0.8 (5.7) -7.0 (7.8) -2.3 (8.1)

Median (Min, Max) 2.0 (-5.0, 14.0) 2.0 (2.0, 2.0) -10.0 (-16.0, -4.0) -1.0 (-5.0, 10.0) -11.0 (-12.0, 2.0) -2.0 (-16.0, 14.0)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) 5.8 (12.8) 2.0 -12.6 (8.4) 1.0 (6.7) -7.2 (8.0) -2.3 (10.1)

Median (Min, Max) 2.2 (-4.9, 20.0) 2.0 (2.0, 2.0) -11.1 (-21.6, -4.9) -1.0 (-6.0, 11.6) -11.8 (-11.8, 2.1) -2.1 (-21.6, 20.0)






7


0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

Respiration

Pre-dose value

N 3 1 3 5 3 15

Mean (SD) 17.3 (2.3) 14.0 14.7 (1.2) 17.2 (4.1) 22.0 (2.0) 17.5 (3.7)

Median (Min, Max) 16.0 (16.0, 20.0) 14.0 (14.0, 14.0) 14.0 (14.0, 16.0) 18.0 (12.0, 22.0) 22.0 (20.0, 24.0) 16.0 (12.0, 24.0)

Post-dose value

N 3 1 3 5 3 15

Mean (SD) 19.3 (4.2) 18.0 20.7 (4.2) 17.2 (1.8) 20.0 (2.0) 18.9 (2.9)

Median (Min, Max) 18.0 (16.0, 24.0) 18.0 (18.0, 18.0) 22.0 (16.0, 24.0) 16.0 (16.0, 20.0) 20.0 (18.0, 22.0) 18.0 (16.0, 24.0)


N 3 1 3 5 3 15

Mean (SD) 2.0 (2.0) 4.0 6.0 (5.3) 0.0 (4.9) -2.0 (2.0) 1.5 (4.5)

Median (Min, Max) 2.0 (0.0, 4.0) 4.0 (4.0, 4.0) 8.0 (0.0, 10.0) 2.0 (-6.0, 6.0) -2.0 (-4.0, 0.0) 2.0 (-6.0, 10.0)

Percentage Change

N 3 1 3 5 3 15

Mean (SD) 10.8 (10.1) 28.6 42.9 (37.8) 5.6 (30.9) -8.9 (8.4) 12.7 (28.9)

Median (Min, Max) 12.5 (0.0, 20.0) 28.6 (28.6, 28.6) 57.1 (0.0, 71.4) 11.1 (-27.3, 50.0) -10.0 (-16.7, 0.0) 11.1 (-27.3, 71.4)






1


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Weight (kg)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 77.4 (29.0) 31.2 (22.6) 53.7 (21.9) 45.7 (23.1) 52.5 (24.6)

Median (Min, Max) 77.4 (56.9, 97.9) 31.2 (15.2, 47.2) 54.0 (19.7, 75.7) 45.7 (29.4, 62.0) 54.0 (15.2, 97.9)

Post-dose value

N 2 2 5 1 10

Mean (SD) 77.1 (30.1) 30.8 (22.8) 53.4 (22.4) 29.5 51.2 (26.0)

Median (Min, Max) 77.1 (55.8, 98.3) 30.8 (14.6, 46.9) 53.3 (19.1, 76.5) 29.5 (29.5, 29.5) 50.8 (14.6, 98.3)


N 2 2 5 1 10

Mean (SD) -0.4 (1.1) -0.5 (0.2) -0.2 (0.7) 0.1 -0.3 (0.6)

Median (Min, Max) -0.4 (-1.1, 0.4) -0.5 (-0.6, -0.3) -0.6 (-0.9, 0.8) 0.1 (0.1, 0.1) -0.5 (-1.1, 0.8)

Percentage Change

N 2 2 5 1 10

Mean (SD) -0.8 (1.7) -2.3 (2.3) -0.9 (1.7) 0.3 -1.1 (1.7)

Median (Min, Max) -0.8 (-1.9, 0.4) -2.3 (-3.9, -0.6) -1.3 (-3.0, 1.1) 0.3 (0.3, 0.3) -1.0 (-3.9, 1.1)






2


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Height (cm)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 156.0 (21.0) 126.3 (41.4) 148.2 (27.4) 143.6 (24.9) 144.8 (26.0)

Median (Min, Max) 156.0 (141.1, 170.8) 126.3 (97.0, 155.6) 151.0 (107.7, 181.5) 143.6 (126.0, 161.2) 151.0 (97.0, 181.5)






3


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Temperature (0c)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 36.9 (0.4) 36.9 (0.6) 36.6 (0.3) 36.6 (0.2) 36.7 (0.4)

Median (Min, Max) 36.9 (36.6, 37.2) 36.9 (36.4, 37.3) 36.7 (36.2, 37.0) 36.6 (36.4, 36.7) 36.7 (36.2, 37.3)

Post-dose value

N 2 2 5 1 10

Mean (SD) 36.8 (0.4) 36.6 (0.3) 36.7 (0.2) 36.7 36.7 (0.2)

Median (Min, Max) 36.8 (36.5, 37.1) 36.6 (36.4, 36.8) 36.8 (36.4, 36.9) 36.7 (36.7, 36.7) 36.8 (36.4, 37.1)


N 2 2 5 1 10

Mean (SD) -0.1 (0.0) -0.3 (0.9) 0.1 (0.4) 0.3 0.0 (0.5)

Median (Min, Max) -0.1 (-0.1, -0.1) -0.3 (-0.9, 0.4) 0.1 (-0.4, 0.6) 0.3 (0.3, 0.3) 0.0 (-0.9, 0.6)

Percentage Change

N 2 2 5 1 10

Mean (SD) -0.3 (0.0) -0.7 (2.5) 0.4 (1.1) 0.8 0.1 (1.2)

Median (Min, Max) -0.3 (-0.3, -0.3) -0.7 (-2.4, 1.1) 0.3 (-1.1, 1.7) 0.8 (0.8, 0.8) 0.0 (-2.4, 1.7)






4


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Systolic Blood Pressure (mm Hg)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 118.0 (12.7) 107.5 (0.7) 118.6 (13.8) 116.0 (4.2) 116.0 (10.6)

Median (Min, Max) 118.0 (109.0, 127.0) 107.5 (107.0, 108.0) 114.0 (106.0, 140.0) 116.0 (113.0, 119.0) 113.0 (106.0, 140.0)

Post-dose value

N 2 2 5 1 10

Mean (SD) 112.0 (29.7) 106.5 (3.5) 125.0 (14.0) 112.0 117.4 (16.0)

Median (Min, Max) 112.0 (91.0, 133.0) 106.5 (104.0, 109.0) 124.0 (112.0, 145.0) 112.0 (112.0, 112.0) 112.0 (91.0, 145.0)


N 2 2 5 1 10

Mean (SD) -6.0 (17.0) -1.0 (4.2) 6.4 (6.9) -1.0 1.7 (9.1)

Median (Min, Max) -6.0 (-18.0, 6.0) -1.0 (-4.0, 2.0) 5.0 (0.0, 18.0) -1.0 (-1.0, -1.0) 2.5 (-18.0, 18.0)

Percentage Change

N 2 2 5 1 10

Mean (SD) -5.9 (15.0) -0.9 (3.9) 5.6 (6.1) -0.9 1.3 (8.1)

Median (Min, Max) -5.9 (-16.5, 4.7) -0.9 (-3.7, 1.9) 3.6 (0.0, 15.8) -0.9 (-0.9, -0.9) 2.3 (-16.5, 15.8)






5


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Diastolic Blood Pressure (mm Hg)

Pre-dose value

N 2 2 5 2 11

Mean (SD) 71.0 (7.1) 67.5 (2.1) 71.0 (16.0) 63.0 (1.4) 68.9 (10.9)

Median (Min, Max) 71.0 (66.0, 76.0) 67.5 (66.0, 69.0) 64.0 (57.0, 92.0) 63.0 (62.0, 64.0) 66.0 (57.0, 92.0)

Post-dose value

N 2 2 5 1 10

Mean (SD) 65.0 (1.4) 61.0 (11.3) 74.4 (17.9) 61.0 68.5 (14.1)

Median (Min, Max) 65.0 (64.0, 66.0) 61.0 (53.0, 69.0) 73.0 (55.0, 101.0) 61.0 (61.0, 61.0) 65.0 (53.0, 101.0)


N 2 2 5 1 10

Mean (SD) -6.0 (5.7) -6.5 (9.2) 3.4 (14.0) -3.0 -1.1 (11.1)

Median (Min, Max) -6.0 (-10.0, -2.0) -6.5 (-13.0, 0.0) 5.0 (-11.0, 23.0) -3.0 (-3.0, -3.0) -2.5 (-13.0, 23.0)

Percentage Change

N 2 2 5 1 10

Mean (SD) -8.1 (7.2) -9.9 (13.9) 6.2 (21.9) -4.7 -1.0 (17.3)

Median (Min, Max) -8.1 (-13.2, -3.0) -9.9 (-19.7, 0.0) 8.8 (-14.1, 39.7) -4.7 (-4.7, -4.7) -3.9 (-19.7, 39.7)






6


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Pulse

Pre-dose value

N 2 2 5 2 11

Mean (SD) 85.0 (24.0) 92.5 (10.6) 88.6 (11.9) 81.5 (3.5) 87.4 (11.9)

Median (Min, Max) 85.0 (68.0, 102.0) 92.5 (85.0, 100.0) 81.0 (79.0, 104.0) 81.5 (79.0, 84.0) 84.0 (68.0, 104.0)

Post-dose value

N 2 2 5 1 10

Mean (SD) 82.5 (9.2) 93.0 (2.8) 76.4 (6.1) 72.0 80.5 (8.9)

Median (Min, Max) 82.5 (76.0, 89.0) 93.0 (91.0, 95.0) 74.0 (70.0, 86.0) 72.0 (72.0, 72.0) 77.0 (70.0, 95.0)


N 2 2 5 1 10

Mean (SD) -2.5 (14.8) 0.5 (13.4) -12.2 (14.1) -12.0 -7.7 (12.9)

Median (Min, Max) -2.5 (-13.0, 8.0) 0.5 (-9.0, 10.0) -10.0 (-30.0, 7.0) -12.0 (-12.0, -12.0) -9.5 (-30.0, 10.0)

Percentage Change

N 2 2 5 1 10

Mean (SD) -0.5 (17.3) 1.4 (14.7) -12.5 (14.3) -14.3 -7.5 (14.0)

Median (Min, Max) -0.5 (-12.7, 11.8) 1.4 (-9.0, 11.8) -12.5 (-28.8, 8.9) -14.3 (-14.3, -14.3) -10.8 (-28.8, 11.8)






7


0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

Respiration

Pre-dose value

N 0 2 4 1 7

Mean (SD) 22.0 (0.0) 19.0 (4.8) 18.0 19.7 (3.7)

Median (Min, Max) 22.0 (22.0, 22.0) 21.0 (12.0, 22.0) 18.0 (18.0, 18.0) 22.0 (12.0, 22.0)

Post-dose value

N 2 2 5 1 10

Mean (SD) 18.0 (0.0) 21.0 (1.4) 18.0 (2.0) 22.0 19.0 (2.2)

Median (Min, Max) 18.0 (18.0, 18.0) 21.0 (20.0, 22.0) 18.0 (16.0, 20.0) 22.0 (22.0, 22.0) 19.0 (16.0, 22.0)


N 0 2 4 1 7

Mean (SD) -1.0 (1.4) -0.5 (5.0) 4.0 0.0 (4.0)

Median (Min, Max) -1.0 (-2.0, 0.0) -1.0 (-6.0, 6.0) 4.0 (4.0, 4.0) 0.0 (-6.0, 6.0)

Percentage Change

N 0 2 4 1 7

Mean (SD) -4.6 (6.4) 3.4 (33.1) 22.2 3.8 (25.2)

Median (Min, Max) -4.6 (-9.1, 0.0) -4.6 (-27.3, 50.0) 22.2 (22.2, 22.2) 0.0 (-27.3, 50.0)


Table 14.3.4.1 Summary of Concomitant Medications by Drug Classification, Drug Name and Enrollment Group


Note: The percentages are based on the total number of enrolled participants in each treatment group or total.

Participants are counted once for each medication after the start of study dose.

1

30 – 59 ml/min per 1.73m² > 60 ml/min per 1.73m²

0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=1) 0.1 mg/kg/day

(N=3) 0.2 mg/kg/day

(N=5) 0.4 mg/kg/day

(N=3) Total

(N=15)

WHO Class Medication Name

Pts With Medn N (%)

Total Medns

N

Pts With Medn N (%)

Total Medns

N

Pts With Medn N (%)

Total Medns

N

Pts With Medn N (%)

Total Medns

N

Pts With Medn N (%)

Total Medns

N

Pts With Medn N (%)

Total Medns

N

ALIMENTARY TRACT AND METABOLISM 0 0 0 0 0 0 1 (20%) 1 1 (33.3%) 1 2 (13.3%) 2

ONDANSETRON 0 0 0 0 0 0 1 (20%) 1 0 0 1 (6.7%) 1

VITAMIN D NOS 0 0 0 0 0 0 0 0 1 (33.3%) 1 1 (6.7%) 1

CARDIOVASCULAR SYSTEM

2 (66.7%)

2

1 (100%)

1

1 (33.3%)

1

3 (60%)

3

2 (66.7%)

2

9 (60%)

9

LISINOPRIL 2 (66.7%) 2 1 (100%) 1 1 (33.3%) 1 3 (60%) 3 2 (66.7%) 2 9 (60%) 9

DERMATOLOGICALS

1 (33.3%)

1

0

0

0

0

0

0

0

0

1 (6.7%)

1

BENZOYL PEROXIDE 1 (33.3%) 1 0 0 0 0 0 0 0 0 1 (6.7%) 1

SENSORY ORGANS

0

0

0

0

0

0

1 (20%)

1

0

0

1 (6.7%)

1

CIPRO HC 0 0 0 0 0 0 1 (20%) 1 0 0 1 (6.7%) 1


Table 14.3.4.2 Summary of Concomitant Medications by Drug Classification, Drug Name and Enrollment Group


Note: The percentages are based on the total number of enrolled participants in each treatment group or total.

Participants are counted once for each medication after the start of study dose.

1

30 – 59 ml/min per 1.73m² > 60 ml/min per 1.73m²

0.1 mg/kg/day

(N=2) 0.2 mg/kg/day

(N=2) 0.1 mg/kg/day

(N=5) 0.2 mg/kg/day

(N=2) Total

(N=11)

WHO Class Medication Name

Pts With Medn N (%)

Total Medns

N

Pts With Medn N (%)

Total Medns

N

Pts With Medn N (%)

Total Medns

N

Pts With Medn N (%)

Total Medns

N

Pts With Medn N (%)

Total Medns

N

ALIMENTARY TRACT AND METABOLISM 0 0 1 (50%) 1 0 0 0 0 1 (9.1%) 1

ESOMEPRAZOLE 0 0 1 (50%) 1 0 0 0 0 1 (9.1%) 1

ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

1 (50%)

1

0

0

0

0

0

0

1 (9.1%)

1

MYCOPHENOLATE MOFETIL 1 (50%) 1 0 0 0 0 0 0 1 (9.1%) 1

RESPIRATORY SYSTEM

0

0

1 (50%)

1

0

0

0

0

1 (9.1%)

1

MONTELUKAST SODIUM 0 0 1 (50%) 1 0 0 0 0 1 (9.1%) 1


Table 14.3.5.1 Summary of Physical Examination Abnormal Findings by Body System and Enrollment Group



Post-dose value calculated as last value while the participant was on study drug (PK visit if completed and interim otherwise). 1


1.73m² >60 ml/min per 1.73m²

Timepoint

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5)

0.4 mg/kg/day

(N=3) Total

(N=15)

Abnormal Findings at Baseline

Participant with at least one abnormal finding at baseline

2 (66.7%) 1 (100.0%) 0 2 (40.0%) 1 (33.3%) 6 (40.0%)

General appearance 0 0 0 0 0 0

General behavior 0 0 0 0 0 0

Skin 1 (33.3%) 1 (100.0%) 0 0 0 2 (13.3%)

Head 0 0 0 0 0 0

Eyes and vision 0 0 0 0 0 0

Ears, nose and throat 1 (33.3%) 0 0 1 (20.0%) 1 (33.3%) 3 (20.0%)

Neck/thyroid 0 0 0 0 0 0

Blood/lymphatic 0 0 0 0 0 0

Cardiovascular 0 0 0 1 (20.0%) 0 1 (6.7%)

Respiratory 0 0 0 0 0 0

Abdomen 0 0 0 1 (20.0%) 1 (33.3%) 2 (13.3%)

Nervous system 0 0 0 0 0 0

Musculoskeletal 1 (33.3%) 0 0 0 0 1 (6.7%)

Extremities 1 (33.3%) 1 (100.0%) 0 0 0 2 (13.3%)

Anorectal/genital 0 0 0 0 0 0

Edema 2 (66.7%) 1 (100.0%) 0 0 0 3 (20.0%)







1.73m² >60 ml/min per 1.73m²

Timepoint

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=1)

0.1 mg/kg/day

(N=3)

0.2 mg/kg/day

(N=5)

0.4 mg/kg/day

(N=3) Total

(N=15)

Newly Emergent Abnormal Findings After Study Drug Administration


1 (33.3%) 1 (100.0%) 0 0 0 2 (13.3%)

General appearance 0 1 (100.0%) 0 0 0 1 (6.7%)

General behavior 0 0 0 0 0 0

Skin 0 0 0 0 0 0

Head 0 0 0 0 0 0

Eyes and vision 0 0 0 0 0 0

Ears, nose and throat 0 0 0 0 0 0

Neck/thyroid 0 0 0 0 0 0

Blood/lymphatic 0 0 0 0 0 0

Cardiovascular 0 0 0 0 0 0

Respiratory 0 0 0 0 0 0

Abdomen 0 0 0 0 0 0

Nervous system 0 0 0 0 0 0

Musculoskeletal 0 0 0 0 0 0

Extremities 0 0 0 0 0 0

Anorectal/genital 0 0 0 0 0 0

Edema 1 (33.3%) 0 0 0 0 1 (6.7%)







1.73m² >60 ml/min per 1.73m²

Timepoint

0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2)

0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Abnormal Findings at Baseline

Participant with at least one abnormal finding at baseline

0 2 (100.0%) 2 (40.0%) 1 (50.0%) 5 (45.5%)

General appearance 0 1 (50.0%) 2 (40.0%) 0 3 (27.3%)

General behavior 0 0 1 (20.0%) 0 1 (9.1%)

Skin 0 0 0 0 0

Head 0 0 1 (20.0%) 0 1 (9.1%)

Eyes and vision 0 1 (50.0%) 0 0 1 (9.1%)

Ears, nose and throat 0 0 0 0 0

Neck/thyroid 0 0 0 0 0

Blood/lymphatic 0 0 0 0 0

Cardiovascular 0 0 0 0 0

Respiratory 0 0 0 0 0

Abdomen 0 1 (50.0%) 1 (20.0%) 1 (50.0%) 3 (27.3%)

Nervous system 0 0 0 0 0

Musculoskeletal 0 0 0 0 0

Extremities 0 0 0 0 0

Anorectal/genital 0 0 0 0 0

Edema 0 0 0 0 0







1.73m² >60 ml/min per 1.73m²

Timepoint

0.1 mg/kg/day

(N=2)

0.2 mg/kg/day

(N=2)

0.1 mg/kg/day

(N=5)

0.2 mg/kg/day

(N=2) Total

(N=11)

Newly Emergent Abnormal Findings After Study Drug Administration


2 (100.0%) 1 (50.0%) 0 0 3 (27.3%)

General appearance 1 (50.0%) 0 0 0 1 (9.1%)

General behavior 0 0 0 0 0

Skin 2 (100.0%) 1 (50.0%) 0 0 3 (27.3%)

Head 0 0 0 0 0

Eyes and vision 0 0 0 0 0

Ears, nose and throat 1 (50.0%) 0 0 0 1 (9.1%)

Neck/thyroid 0 0 0 0 0

Blood/lymphatic 0 0 0 0 0

Cardiovascular 0 0 0 0 0

Respiratory 0 0 0 0 0

Abdomen 2 (100.0%) 0 0 0 2 (18.2%)

Nervous system 0 0 0 0 0

Musculoskeletal 0 0 0 0 0

Extremities 0 0 0 0 0

Anorectal/genital 0 0 0 0 0

Edema 0 0 0 0 0

Table 14.3.1.1.1 Summary of Adverse Events by Enrollment ......Table 14.3.1.3 Adverse Events by...

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