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An Investigational Immuno-therapy Study of Nivolumab Monotherapy and Nivolumab in Combination With Ipilimumab in Pediatric Patients With High Grade Primary CNS Malignancies (CheckMate 908)

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ClinicalTrials.gov Identifier: NCT03130959
Recruitment Status : Active, not recruiting
First Posted : April 27, 2017
Results First Posted : April 1, 2021
Last Update Posted : April 1, 2021
Sponsor:
Information provided by (Responsible Party):
Bristol-Myers Squibb

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Various Advanced Cancer
Interventions Biological: Nivolumab
Biological: Ipilimumab
Enrollment 166
Recruitment Details  
Pre-assignment Details 166 treated participants
Arm/Group Title Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
Hide Arm/Group Description

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Period Title: Treatment Period
Started [1] 23 22 16 15 15 15 12 10 19 19
Completed [2] 2 1 1 0 0 0 0 0 0 1
Not Completed 21 21 15 15 15 15 12 10 19 18
Reason Not Completed
Disease progression             18             15             12             8             12             11             6             9             15             9
Study drug toxicity             2             3             1             2             1             2             3             0             3             4
Other reasons             1             0             0             0             0             0             1             0             0             0
Participant request to stop therapy             0             1             1             1             0             0             1             1             0             0
Not reported             0             2             0             1             0             2             0             0             0             2
Adverse Event unrelated to drug             0             0             1             1             1             0             1             0             1             1
Participant withdrew consent             0             0             0             2             1             0             0             0             0             2
[1]
Started = initiated treatment
[2]
Completed = ongoing treatment (did not discontinue)
Period Title: Follow-up Period
Started [1] 23 22 16 15 15 15 12 10 19 19
Completed [2] 3 2 4 1 1 5 3 2 1 3
Not Completed 20 20 12 14 14 10 9 8 18 16
Reason Not Completed
Death             16             17             12             10             11             8             9             7             17             10
Participant withdrew consent             3             1             0             3             3             0             0             1             1             3
Lost to Follow-up             1             1             0             0             0             2             0             0             0             1
Other reasons             0             1             0             1             0             0             0             0             0             2
[1]
Started = initiated treatment
[2]
Completed = ongoing study (did not discontinue)
Arm/Group Title Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5 Total
Hide Arm/Group Description

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Total of all reporting groups
Overall Number of Baseline Participants 23 22 16 15 15 15 12 10 19 19 166
Hide Baseline Analysis Population Description
[Not Specified]
Age, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants 22 participants 16 participants 15 participants 15 participants 15 participants 12 participants 10 participants 19 participants 19 participants 166 participants
< 2 years old
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  10.0%
1
   5.3%
1
   5.3%
3
   1.8%
>= 2 and < 12 years old
15
  65.2%
16
  72.7%
6
  37.5%
5
  33.3%
4
  26.7%
4
  26.7%
8
  66.7%
4
  40.0%
13
  68.4%
12
  63.2%
87
  52.4%
>= 12 and < 18 years old
6
  26.1%
5
  22.7%
6
  37.5%
8
  53.3%
11
  73.3%
9
  60.0%
3
  25.0%
3
  30.0%
4
  21.1%
6
  31.6%
61
  36.7%
>= 18 years old
2
   8.7%
1
   4.5%
4
  25.0%
2
  13.3%
0
   0.0%
2
  13.3%
1
   8.3%
2
  20.0%
1
   5.3%
0
   0.0%
15
   9.0%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants 22 participants 16 participants 15 participants 15 participants 15 participants 12 participants 10 participants 19 participants 19 participants 166 participants
Female
12
  52.2%
16
  72.7%
6
  37.5%
3
  20.0%
5
  33.3%
5
  33.3%
6
  50.0%
3
  30.0%
4
  21.1%
10
  52.6%
70
  42.2%
Male
11
  47.8%
6
  27.3%
10
  62.5%
12
  80.0%
10
  66.7%
10
  66.7%
6
  50.0%
7
  70.0%
15
  78.9%
9
  47.4%
96
  57.8%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants 22 participants 16 participants 15 participants 15 participants 15 participants 12 participants 10 participants 19 participants 19 participants 166 participants
Hispanic or Latino
2
   8.7%
3
  13.6%
2
  12.5%
2
  13.3%
0
   0.0%
1
   6.7%
1
   8.3%
1
  10.0%
2
  10.5%
0
   0.0%
14
   8.4%
Not Hispanic or Latino
7
  30.4%
10
  45.5%
4
  25.0%
5
  33.3%
6
  40.0%
4
  26.7%
5
  41.7%
5
  50.0%
8
  42.1%
6
  31.6%
60
  36.1%
Unknown or Not Reported
14
  60.9%
9
  40.9%
10
  62.5%
8
  53.3%
9
  60.0%
10
  66.7%
6
  50.0%
4
  40.0%
9
  47.4%
13
  68.4%
92
  55.4%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 23 participants 22 participants 16 participants 15 participants 15 participants 15 participants 12 participants 10 participants 19 participants 19 participants 166 participants
White
19
  82.6%
11
  50.0%
13
  81.3%
14
  93.3%
14
  93.3%
14
  93.3%
7
  58.3%
9
  90.0%
18
  94.7%
13
  68.4%
132
  79.5%
Black or African American
2
   8.7%
4
  18.2%
0
   0.0%
0
   0.0%
0
   0.0%
1
   6.7%
1
   8.3%
0
   0.0%
1
   5.3%
0
   0.0%
9
   5.4%
Asian
0
   0.0%
2
   9.1%
1
   6.3%
1
   6.7%
0
   0.0%
0
   0.0%
3
  25.0%
1
  10.0%
0
   0.0%
2
  10.5%
10
   6.0%
American Indian or Alaska Native
0
   0.0%
1
   4.5%
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
   0.6%
Native Hawaiian or Other Pacific Islander
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%
Other
2
   8.7%
4
  18.2%
2
  12.5%
0
   0.0%
1
   6.7%
0
   0.0%
1
   8.3%
0
   0.0%
0
   0.0%
4
  21.1%
14
   8.4%
1.Primary Outcome
Title Number of Safety Lead-In Participants With Dose Limiting Toxicities (DLTs)
Hide Description A dose-limiting toxicity (DLT) is defined as a drug-related AE occurring in the first 6 weeks of study treatment. A participant was considered evaluable for a DLT if study treatment was delayed > 2 weeks or was discontinued due to a related Adverse Event (AE), or if planned study treatment (3 doses of nivolumab in Module A, 2 doses of nivolumab plus ipilimumab in Module B) was administered and safety evaluation after 6 weeks on study is available to the study steering committee (SSC).
Time Frame up to 6 weeks post-dosing
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Lead-in participants: In Module A, the first 6 DLT-evaluable participants in Cohort 1 and the first 10 DLT-evaluable participants in Cohorts 2-5; in Module B, the first 10 DLT-evaluable participants.
Arm/Group Title Arm A1, Safety Lead-in Arms A2-A5, Safety Lead-in Arms B2-B5, Safety Lead-in
Hide Arm/Group Description:
Module A, Cohort 1
Module A, Cohorts 2 through 5
Module B, Cohorts 2 through 5
Overall Number of Participants Analyzed 15 10 16
Measure Type: Number
Unit of Measure: Number of participants
0 0 0
2.Primary Outcome
Title Number of Safety Lead-In Participants With Serious Adverse Events (SAEs)
Hide Description The number of Safety Lead-In Participants who experienced a Serious Adverse Event (SAE) during the course of the study.
Time Frame up to 6 weeks post-dosing
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Lead-in participants: In Module A, the first 6 DLT-evaluable participants in Cohort 1 and the first 10 DLT-evaluable participants in Cohorts 2-5; in Module B, the first 10 DLT-evaluable participants.
Arm/Group Title Arm A1, Safety Lead-in Arms A2-A5, Safety Lead-in Arms B2-B5, Safety Lead-in
Hide Arm/Group Description:
Module A, Cohort 1
Module A, Cohorts 2 through 5
Module B, Cohorts 2 through 5
Overall Number of Participants Analyzed 15 10 16
Measure Type: Number
Unit of Measure: Number of participants
7 6 8
3.Primary Outcome
Title Number of Safety Lead-In Participants With Adverse Events (AEs) Leading to Discontinuation
Hide Description The number of Safety Lead-In Participants who experienced an Adverse Event (AE) during the course of the study that lead to discontinuation of study therapy.
Time Frame up to 6 weeks post-dosing
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Lead-in participants: In Module A, the first 6 DLT-evaluable participants in Cohort 1 and the first 10 DLT-evaluable participants in Cohorts 2-5; in Module B, the first 10 DLT-evaluable participants.
Arm/Group Title Arm A1, Safety Lead-in Arms A2-A5, Safety Lead-in Arms B2-B5, Safety Lead-in
Hide Arm/Group Description:
Module A, Cohort 1
Module A, Cohorts 2 through 5
Module B, Cohorts 2 through 5
Overall Number of Participants Analyzed 15 10 16
Measure Type: Number
Unit of Measure: Number of participants
3 4 3
4.Primary Outcome
Title Overall Survival (OS), Cohort 1 Only
Hide Description Overall survival (OS) is defined as the time between the date of diagnosis and the date of death in Cohort 1.
Time Frame up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A1 Arm B1
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Overall Number of Participants Analyzed 23 22
Median (80% Confidence Interval)
Unit of Measure: months
11.66
(10.32 to 16.46)
10.78
(9.13 to 15.77)
5.Primary Outcome
Title Progression-Free Survival (PFS), Cohorts 2-4
Hide Description Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.
Time Frame up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Overall Number of Participants Analyzed 16 15 15 15 12 10
Median (80% Confidence Interval)
Unit of Measure: months
1.74
(1.35 to 2.73)
1.31
(1.18 to 1.45)
1.38
(1.22 to 1.38)
2.76
(1.48 to 4.53)
1.41
(1.41 to 2.60)
4.60
(1.41 to 5.39)
6.Primary Outcome
Title Progression-Free Survival (PFS), Cohort 5 Only
Hide Description Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.
Time Frame up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A5 Arm B5
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Overall Number of Participants Analyzed 19 19
Median (95% Confidence Interval)
Unit of Measure: months
1.22
(1.08 to 1.31)
1.61
(1.31 to 3.45)
7.Secondary Outcome
Title Progression-Free Survival (PFS), Cohort 1 Only
Hide Description Progression-free survival (PFS) is defined as the time from first dose to the date of the first documented tumor progression or death due to any cause.
Time Frame up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A1 Arm B1
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Overall Number of Participants Analyzed 23 22
Median (95% Confidence Interval)
Unit of Measure: months
6.21
(3.75 to 6.54)
4.53
(2.76 to 6.44)
8.Secondary Outcome
Title Overall Survival at 12 Months (OS12), Cohorts 1-4
Hide Description Overall survival at 12 months (OS12) is defined as the percentage of participants who are alive at 12 months, measured as the survival rate at 12 months from Kaplan-Meier product limit cumulative probability.
Time Frame up to 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Overall Number of Participants Analyzed 23 22 16 15 15 15 12 10
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
48.0
(25.6 to 67.3)
42.9
(21.9 to 62.3)
37.5
(15.4 to 59.8)
35.4
(11.3 to 60.9)
38.9
(14.3 to 63.2)
86.7
(56.4 to 96.5)
41.7
(15.2 to 66.5)
44.4
(13.6 to 71.9)
9.Secondary Outcome
Title Progression-Free Survival at 6 Months (PFS6), Cohorts 2-5
Hide Description Progression-free survival at 6 months (PFS6) is defined as the percentage of participants who are progression free and alive at 6 months following first dose date, measured as the survival rate at 6 months from Kaplan-Meier product limit cumulative probability of progression free.
Time Frame up to 6 months
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Overall Number of Participants Analyzed 16 15 15 15 12 10 19 19
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentage of participants
9.4
(0.7 to 31.8)
15.4
(2.5 to 38.8)
0 [1] 
(NA to NA)
20.0
(4.9 to 42.4)
27.3
(6.5 to 53.9)
11.4
(0.6 to 39.5)
5.3
(0.4 to 21.4)
14.0
(2.8 to 34.1)
[1]
No participants at risk by 6-month timepoint
10.Secondary Outcome
Title Overall Survival (OS), Cohorts 2-5
Hide Description Overall survival (OS) is defined as the time between date of first dose and the date of death for Cohorts 2-5.
Time Frame up to approximately 42 months
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Overall Number of Participants Analyzed 16 15 15 15 12 10 19 19
Median (95% Confidence Interval)
Unit of Measure: months
6.67
(2.99 to 14.62)
8.54
(2.14 to 13.63)
7.36
(2.46 to 30.23)
22.21 [1] 
(13.77 to NA)
5.70 [1] 
(1.81 to NA)
9.82 [1] 
(2.50 to NA)
5.91
(1.97 to 7.98)
8.48
(3.45 to 24.34)
[1]
Upper limit not calculable as upper CI bound does not cross 50% threshold
11.Secondary Outcome
Title Number of Treated Participants With Adverse Events (AEs)
Hide Description The number of treated participants who experienced an Adverse Event (AE) during the course of the study.
Time Frame from first dose to 30 days post-last dose, assessed up to 13Jan2021 (up to approximately 42 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Overall Number of Participants Analyzed 23 22 16 15 15 15 12 10 19 19
Measure Type: Number
Unit of Measure: Number of participants
23 21 15 14 14 15 12 10 18 18
12.Secondary Outcome
Title Number of Treated Participants With Serious Adverse Events (SAEs)
Hide Description

The number of treated participants who experienced a Serious Adverse Event (SAE) during the course of the study.

Note: The reporting timeframe of the SAEs for this Outcome Measure (first dose to 30 days post last dose) differs than that of the reporting timeframe of the SAEs reported under the AE section of the results form (first dose to 100 days post last dose) and thus, the data in each table of SAEs reflects the specific timeframe applied.

Time Frame from first dose to 30 days post-last dose, assessed up to 13Jan2021 (up to approximately 42 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Overall Number of Participants Analyzed 23 22 16 15 15 15 12 10 19 19
Measure Type: Number
Unit of Measure: Number of participants
10 14 10 9 6 7 7 5 13 14
13.Secondary Outcome
Title Number of Treated Participants With Drug-Related Adverse Events
Hide Description The number of treated participants who experienced a Drug-Related Adverse Event during the course of the study.
Time Frame from first dose to 30 days post-last dose, assessed up to 13Jan2021 (up to approximately 42 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Overall Number of Participants Analyzed 23 22 16 15 15 15 12 10 19 19
Measure Type: Number
Unit of Measure: Number of participants
14 16 12 8 6 11 6 6 11 11
14.Secondary Outcome
Title Number of Treated Participants With Adverse Events Leading to Discontinuation
Hide Description The number of treated participants who experienced an Adverse Event leading to discontinuation during the course of the study.
Time Frame from first dose to 30 days post-last dose, assessed up to 13Jan2021 (up to approximately 42 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Overall Number of Participants Analyzed 23 22 16 15 15 15 12 10 19 19
Measure Type: Number
Unit of Measure: Number of participants
5 7 3 5 2 3 6 2 6 8
15.Secondary Outcome
Title Number of Treated Participant Deaths
Hide Description The number of treated participants who died during the course of the study.
Time Frame from first dose assessed up to 13Jan2021 (up to approximately 42 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Overall Number of Participants Analyzed 23 22 16 15 15 15 12 10 19 19
Measure Type: Number
Unit of Measure: Number of participants
16 18 12 11 11 9 9 7 18 14
16.Secondary Outcome
Title Number of Treated Participant With Laboratory Abnormalities - Liver
Hide Description

The number of treated participants who experienced a laboratory abnormality of the liver during the course of the study.

Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Upper Limit of Normal (ULN)

Time Frame from first dose assessed up to 13Jan2021 (up to approximately 42 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants
Arm/Group Title Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Overall Number of Participants Analyzed 23 21 16 12 13 14 11 10 19 18
Measure Type: Number
Unit of Measure: Number of participants
ALT OR AST > 3XULN Number Analyzed 23 participants 21 participants 16 participants 12 participants 13 participants 14 participants 11 participants 10 participants 19 participants 18 participants
3 7 2 0 0 3 1 1 3 2
ALT OR AST > 5XULN Number Analyzed 23 participants 21 participants 16 participants 12 participants 13 participants 14 participants 11 participants 10 participants 19 participants 18 participants
2 4 1 0 0 1 0 1 2 2
ALT OR AST > 10XULN Number Analyzed 23 participants 21 participants 16 participants 12 participants 13 participants 14 participants 11 participants 10 participants 19 participants 18 participants
2 1 1 0 0 1 0 1 2 2
ALT OR AST > 20XULN Number Analyzed 23 participants 21 participants 16 participants 12 participants 13 participants 14 participants 11 participants 10 participants 19 participants 18 participants
0 1 1 0 0 0 0 0 0 2
TOTAL BILIRUBIN > 2XULN Number Analyzed 23 participants 21 participants 15 participants 12 participants 13 participants 14 participants 11 participants 10 participants 19 participants 18 participants
0 2 0 0 0 0 0 0 1 1
ALP > 1.5XULN Number Analyzed 1 participants 1 participants 2 participants 12 participants 13 participants 14 participants 11 participants 10 participants 1 participants 2 participants
0 0 0 0 0 0 0 0 0 1
ALT or AST > 3xULN w/ Tbili > 1.5*ULN within 1 day Number Analyzed 23 participants 21 participants 15 participants 12 participants 13 participants 14 participants 11 participants 10 participants 19 participants 18 participants
0 1 1 0 0 0 0 0 0 1
ALT or AST > 3xULN w/ Tbili > 1.5*ULN within 30 days Number Analyzed 23 participants 21 participants 15 participants 12 participants 13 participants 14 participants 11 participants 10 participants 19 participants 18 participants
0 2 1 0 0 0 0 0 0 1
ALT or AST > 3xULN w/ Tbili > 2*ULN within 1 day Number Analyzed 23 participants 21 participants 15 participants 12 participants 13 participants 14 participants 11 participants 10 participants 19 participants 18 participants
0 1 0 0 0 0 0 0 0 1
ALT or AST > 3xULN w/ Tbili > 2*ULN within 30 days Number Analyzed 23 participants 21 participants 15 participants 12 participants 13 participants 14 participants 11 participants 10 participants 19 participants 18 participants
0 2 0 0 0 0 0 0 0 1
17.Secondary Outcome
Title Number of Treated Participant With Laboratory Abnormalities - Thyroid
Hide Description

The number of treated participants who experienced a laboratory abnormality of the thyroid during the course of the study.

Free T3 (FT3) Free T4 (FT4) Lower Limit of Normal (LLN)

Time Frame from first dose assessed up to 13Jan2021 (up to approximately 42 months)
Hide Outcome Measure Data
Hide Analysis Population Description
All treated participants with at least one on-treatment TSH measurement
Arm/Group Title Arm A1 Arm B1 Arm A2 Arm B2 Arm A3 Arm B3 Arm A4 Arm B4 Arm A5 Arm B5
Hide Arm/Group Description:

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Overall Number of Participants Analyzed 20 20 10 8 8 13 9 8 11 14
Measure Type: Number
Unit of Measure: Number of participants
TSH > ULN 2 1 3 1 3 7 2 3 1 5
TSH > ULN, WITH TSH <= ULN AT BASELINE 2 1 2 1 0 7 1 3 1 2
TSH > ULN, WITH AT LEAST ONE FT3/FT4 TEST < LLN 1 1 1 1 1 6 2 2 0 2
TSH > ULN, WITH ALL OTHER FT3/FT4 TEST >= LLN 0 0 1 0 0 0 0 0 1 3
TSH > ULN, WITH FT3/FT4 TEST MISSING 1 0 1 0 2 1 0 1 0 0
TSH < LLN 2 7 2 2 0 3 0 0 0 1
TSH < LLN, WITH TSH >= LLN AT BASELINE 2 6 1 2 0 1 0 0 0 1
TSH<LLN, LLN WITH AT LEAST ONE FT3/FT4 TEST>ULN 0 1 0 0 0 2 0 0 0 0
TSH < LLN, WITH ALL OTHER FT3/FT4 TEST <= ULN 0 2 1 2 0 1 0 0 0 1
TSH < LLN, WITH FT3/FT4 TEST MISSING 2 4 1 0 0 0 0 0 0 0
Time Frame From first dose to 100 days post last dose, assessed up to 13Jan2021 (approximately 42 months)
Adverse Event Reporting Description Note: The reporting timeframe of the below SAEs (first dose to 100 days post last dose) differs than that of the reporting timeframe of the SAEs reported under the Outcome Measures section of the results form (first dose to 30 days post last dose) and thus, the data in each table of SAEs reflects the specific timeframe applied.
 
Arm/Group Title Cohort 1, Module A Cohort 1, Module B Cohort 2, Module A Cohort 2, Module B Cohort 3, Module A Cohort 3, Module B Cohort 4, Module A Cohort 4, Module B Cohort 5, Module A Cohort 5, Module B
Hide Arm/Group Description

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 1: participants with newly-diagnosed DIPG, including midline glioma with H3K27M mutation.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 2: participants with recurrent or progressive non-brainstem HGG, regardless of mutation status, including glioblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 3: participants with relapsed or resistant medulloblastoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 4: participants with relapsed or resistant ependymoma.

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 4: participants with relapsed or resistant ependymoma.

Module A: nivolumab 3 mg/kg every 2 weeks.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

Module B: nivolumab 3 mg/kg + ipilimumab 1 mg/kg every 3 weeks, for 4 doses, then nivolumab 3 mg/kg every 2 weeks thereafter.

Cohort 5: participants with other recurrent subtypes of high-grade CNS malignancy (eg, pineoblastoma, AT/RT, germ cell tumor, and others).

All-Cause Mortality
Cohort 1, Module A Cohort 1, Module B Cohort 2, Module A Cohort 2, Module B Cohort 3, Module A Cohort 3, Module B Cohort 4, Module A Cohort 4, Module B Cohort 5, Module A Cohort 5, Module B
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   16/23 (69.57%)   18/22 (81.82%)   12/16 (75.00%)   11/15 (73.33%)   11/15 (73.33%)   9/15 (60.00%)   9/12 (75.00%)   7/10 (70.00%)   18/19 (94.74%)   14/19 (73.68%) 
Hide Serious Adverse Events
Cohort 1, Module A Cohort 1, Module B Cohort 2, Module A Cohort 2, Module B Cohort 3, Module A Cohort 3, Module B Cohort 4, Module A Cohort 4, Module B Cohort 5, Module A Cohort 5, Module B
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   17/23 (73.91%)   16/22 (72.73%)   13/16 (81.25%)   12/15 (80.00%)   7/15 (46.67%)   10/15 (66.67%)   11/12 (91.67%)   6/10 (60.00%)   14/19 (73.68%)   15/19 (78.95%) 
Blood and lymphatic system disorders                     
Anaemia  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Cardiac disorders                     
Cardio-respiratory arrest  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Eye disorders                     
Vision blurred  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Gastrointestinal disorders                     
Abdominal pain  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Ascites  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Colitis  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  2/15 (13.33%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Constipation  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Diarrhoea  1  0/23 (0.00%)  2/22 (9.09%)  1/16 (6.25%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Enterocolitis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Gastric ulcer  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Gastritis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Immune-mediated enterocolitis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Nausea  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  2/12 (16.67%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Pancreatitis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Vomiting  1  0/23 (0.00%)  3/22 (13.64%)  1/16 (6.25%)  2/15 (13.33%)  0/15 (0.00%)  1/15 (6.67%)  2/12 (16.67%)  1/10 (10.00%)  1/19 (5.26%)  1/19 (5.26%) 
General disorders                     
Fatigue  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
General physical health deterioration  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Pyrexia  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  2/10 (20.00%)  1/19 (5.26%)  2/19 (10.53%) 
Hepatobiliary disorders                     
Autoimmune hepatitis  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Hepatitis  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  1/19 (5.26%) 
Hepatitis acute  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Immune system disorders                     
Haemophagocytic lymphohistiocytosis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Hypersensitivity  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Immune-mediated adverse reaction  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Infections and infestations                     
Bacterial infection  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Coronavirus infection  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Device related infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  2/19 (10.53%) 
Diarrhoea infectious  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Escherichia urinary tract infection  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Gastroenteritis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Measles  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Pneumonia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Respiratory tract infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Sepsis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Staphylococcal bacteraemia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Staphylococcal infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Tonsillitis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Upper respiratory tract infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Urinary tract infection  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Vascular device infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Wound infection staphylococcal  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Injury, poisoning and procedural complications                     
Brain herniation  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Facial bones fracture  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Infusion related reaction  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Lower limb fracture  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Shunt malfunction  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Wound dehiscence  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Investigations                     
Alanine aminotransferase increased  1  1/23 (4.35%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Aspartate aminotransferase increased  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Chest X-ray abnormal  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Gamma-glutamyltransferase increased  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Hepatic enzyme increased  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Metabolism and nutrition disorders                     
Dehydration  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Hypercalcaemia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Hypocalcaemia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Hypokalaemia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Hyponatraemia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Hypophagia  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Steroid diabetes  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Musculoskeletal and connective tissue disorders                     
Back pain  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Mobility decreased  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Muscular weakness  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Spinal deformity  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                     
Malignant neoplasm progression  1  8/23 (34.78%)  6/22 (27.27%)  5/16 (31.25%)  5/15 (33.33%)  6/15 (40.00%)  2/15 (13.33%)  4/12 (33.33%)  5/10 (50.00%)  7/19 (36.84%)  5/19 (26.32%) 
Neoplasm  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Neoplasm progression  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Schwannoma  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Tumour flare  1  1/23 (4.35%)  3/22 (13.64%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Tumour haemorrhage  1  0/23 (0.00%)  0/22 (0.00%)  2/16 (12.50%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Nervous system disorders                     
Dizziness  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Dysarthria  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Dyskinesia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Facial nerve disorder  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Haemorrhage intracranial  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  1/19 (5.26%) 
Headache  1  1/23 (4.35%)  2/22 (9.09%)  0/16 (0.00%)  2/15 (13.33%)  1/15 (6.67%)  1/15 (6.67%)  1/12 (8.33%)  2/10 (20.00%)  1/19 (5.26%)  2/19 (10.53%) 
Hemiparesis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Hydrocephalus  1  0/23 (0.00%)  4/22 (18.18%)  1/16 (6.25%)  0/15 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  3/12 (25.00%)  2/10 (20.00%)  1/19 (5.26%)  2/19 (10.53%) 
Intracranial pressure increased  1  1/23 (4.35%)  0/22 (0.00%)  1/16 (6.25%)  1/15 (6.67%)  1/15 (6.67%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  2/19 (10.53%)  1/19 (5.26%) 
Lethargy  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Motor dysfunction  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Myoclonus  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Nervous system disorder  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Neurological decompensation  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Paraesthesia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Partial seizures  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Peripheral motor neuropathy  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Seizure  1  1/23 (4.35%)  1/22 (4.55%)  1/16 (6.25%)  1/15 (6.67%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  1/19 (5.26%) 
Somnolence  1  1/23 (4.35%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Status epilepticus  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Transient ischaemic attack  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Psychiatric disorders                     
Delirium  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Psychotic disorder  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Renal and urinary disorders                     
Bladder dysfunction  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Urinary incontinence  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Respiratory, thoracic and mediastinal disorders                     
Aspiration  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Bronchospasm  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Dyspnoea  1  2/23 (8.70%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Hypoxia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Pneumonitis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Respiratory failure  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Skin and subcutaneous tissue disorders                     
Rash  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Toxic skin eruption  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Vascular disorders                     
Hypertension  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Hypotension  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Kawasaki's disease  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
1
Term from vocabulary, 23.1
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Cohort 1, Module A Cohort 1, Module B Cohort 2, Module A Cohort 2, Module B Cohort 3, Module A Cohort 3, Module B Cohort 4, Module A Cohort 4, Module B Cohort 5, Module A Cohort 5, Module B
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   22/23 (95.65%)   21/22 (95.45%)   15/16 (93.75%)   14/15 (93.33%)   14/15 (93.33%)   14/15 (93.33%)   11/12 (91.67%)   10/10 (100.00%)   18/19 (94.74%)   18/19 (94.74%) 
Blood and lymphatic system disorders                     
Anaemia  1  1/23 (4.35%)  1/22 (4.55%)  1/16 (6.25%)  3/15 (20.00%)  3/15 (20.00%)  3/15 (20.00%)  2/12 (16.67%)  0/10 (0.00%)  5/19 (26.32%)  1/19 (5.26%) 
Neutropenia  1  1/23 (4.35%)  0/22 (0.00%)  1/16 (6.25%)  1/15 (6.67%)  1/15 (6.67%)  3/15 (20.00%)  1/12 (8.33%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Coagulopathy  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Leukopenia  1  0/23 (0.00%)  0/22 (0.00%)  2/16 (12.50%)  0/15 (0.00%)  1/15 (6.67%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Lymphadenopathy  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Lymphopenia  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  2/15 (13.33%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Pancytopenia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Thrombocytopenia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  1/15 (6.67%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  3/19 (15.79%)  0/19 (0.00%) 
Cardiac disorders                     
Sinus bradycardia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Sinus tachycardia  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Tachycardia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Congenital, familial and genetic disorders                     
Von Willebrand's disease  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Ear and labyrinth disorders                     
Ear pain  1  2/23 (8.70%)  3/22 (13.64%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  2/15 (13.33%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  2/19 (10.53%) 
Deafness  1  0/23 (0.00%)  2/22 (9.09%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Ear pruritus  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Middle ear effusion  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Motion sickness  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Tinnitus  1  0/23 (0.00%)  2/22 (9.09%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  2/15 (13.33%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Tympanic membrane perforation  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Vertigo  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  1/10 (10.00%)  0/19 (0.00%)  1/19 (5.26%) 
Endocrine disorders                     
Hypothyroidism  1  1/23 (4.35%)  1/22 (4.55%)  1/16 (6.25%)  2/15 (13.33%)  0/15 (0.00%)  2/15 (13.33%)  2/12 (16.67%)  1/10 (10.00%)  1/19 (5.26%)  0/19 (0.00%) 
Cushingoid  1  0/23 (0.00%)  2/22 (9.09%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Diabetes insipidus  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Hyperthyroidism  1  0/23 (0.00%)  2/22 (9.09%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  1/19 (5.26%) 
Eye disorders                     
Diplopia  1  2/23 (8.70%)  3/22 (13.64%)  1/16 (6.25%)  0/15 (0.00%)  1/15 (6.67%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  2/19 (10.53%)  2/19 (10.53%) 
Blepharospasm  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Blindness  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Conjunctival hyperaemia  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Corneal epithelium defect  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Dry eye  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  2/19 (10.53%)  0/19 (0.00%) 
Eye discharge  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Eye haemorrhage  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Eye inflammation  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Eye irritation  1  2/23 (8.70%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Eye movement disorder  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Eye pain  1  1/23 (4.35%)  1/22 (4.55%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  2/15 (13.33%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Eye swelling  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Eyelid function disorder  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Eyelid oedema  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Eyelid ptosis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Lacrimation increased  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Mydriasis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Ocular hyperaemia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Photophobia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Pupillary reflex impaired  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Vision blurred  1  0/23 (0.00%)  2/22 (9.09%)  2/16 (12.50%)  1/15 (6.67%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Gastrointestinal disorders                     
Abdominal pain  1  4/23 (17.39%)  7/22 (31.82%)  2/16 (12.50%)  1/15 (6.67%)  2/15 (13.33%)  3/15 (20.00%)  1/12 (8.33%)  0/10 (0.00%)  5/19 (26.32%)  4/19 (21.05%) 
Constipation  1  5/23 (21.74%)  5/22 (22.73%)  5/16 (31.25%)  5/15 (33.33%)  0/15 (0.00%)  3/15 (20.00%)  1/12 (8.33%)  2/10 (20.00%)  5/19 (26.32%)  4/19 (21.05%) 
Diarrhoea  1  6/23 (26.09%)  3/22 (13.64%)  4/16 (25.00%)  4/15 (26.67%)  4/15 (26.67%)  3/15 (20.00%)  3/12 (25.00%)  2/10 (20.00%)  3/19 (15.79%)  5/19 (26.32%) 
Dysphagia  1  3/23 (13.04%)  4/22 (18.18%)  1/16 (6.25%)  2/15 (13.33%)  1/15 (6.67%)  0/15 (0.00%)  0/12 (0.00%)  1/10 (10.00%)  1/19 (5.26%)  0/19 (0.00%) 
Gastrooesophageal reflux disease  1  1/23 (4.35%)  3/22 (13.64%)  2/16 (12.50%)  0/15 (0.00%)  1/15 (6.67%)  2/15 (13.33%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Nausea  1  8/23 (34.78%)  4/22 (18.18%)  4/16 (25.00%)  4/15 (26.67%)  1/15 (6.67%)  3/15 (20.00%)  4/12 (33.33%)  1/10 (10.00%)  3/19 (15.79%)  5/19 (26.32%) 
Vomiting  1  8/23 (34.78%)  11/22 (50.00%)  7/16 (43.75%)  4/15 (26.67%)  4/15 (26.67%)  3/15 (20.00%)  5/12 (41.67%)  4/10 (40.00%)  8/19 (42.11%)  10/19 (52.63%) 
Abdominal distension  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Abdominal pain upper  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Anal erythema  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Anal fissure  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Anal haemorrhage  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Anal incontinence  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Chronic gastritis  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Colitis  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Dry mouth  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Duodenal ulcer  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Duodenitis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Dyspepsia  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Flatulence  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Gastric ulcer  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Gastritis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Immune-mediated enterocolitis  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Lip swelling  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Loose tooth  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Mouth ulceration  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Oral dysaesthesia  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Paraesthesia oral  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Periodontal disease  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Post-tussive vomiting  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Proctalgia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Salivary hypersecretion  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Stomatitis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Tongue oedema  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Toothache  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
General disorders                     
Asthenia  1  3/23 (13.04%)  0/22 (0.00%)  2/16 (12.50%)  3/15 (20.00%)  0/15 (0.00%)  3/15 (20.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Fatigue  1  8/23 (34.78%)  6/22 (27.27%)  4/16 (25.00%)  3/15 (20.00%)  2/15 (13.33%)  4/15 (26.67%)  2/12 (16.67%)  1/10 (10.00%)  5/19 (26.32%)  4/19 (21.05%) 
Gait disturbance  1  4/23 (17.39%)  1/22 (4.55%)  0/16 (0.00%)  1/15 (6.67%)  1/15 (6.67%)  1/15 (6.67%)  1/12 (8.33%)  0/10 (0.00%)  2/19 (10.53%)  1/19 (5.26%) 
Pain  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  4/19 (21.05%)  2/19 (10.53%) 
Pyrexia  1  5/23 (21.74%)  6/22 (27.27%)  2/16 (12.50%)  4/15 (26.67%)  1/15 (6.67%)  2/15 (13.33%)  3/12 (25.00%)  2/10 (20.00%)  2/19 (10.53%)  5/19 (26.32%) 
Application site pruritus  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Chills  1  0/23 (0.00%)  2/22 (9.09%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Device related thrombosis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Facial pain  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
General physical health deterioration  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  1/19 (5.26%) 
Generalised oedema  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Hypothermia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Influenza like illness  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  1/19 (5.26%)  1/19 (5.26%) 
Mucosal inflammation  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Non-cardiac chest pain  1  1/23 (4.35%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  1/15 (6.67%)  0/12 (0.00%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Oedema peripheral  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  2/15 (13.33%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Sensation of foreign body  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Xerosis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Hepatobiliary disorders                     
Hepatitis acute  1  0/23 (0.00%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Immune system disorders                     
Drug hypersensitivity  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Hypersensitivity  1  1/23 (4.35%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  2/10 (20.00%)  0/19 (0.00%)  1/19 (5.26%) 
Infusion related hypersensitivity reaction  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Seasonal allergy  1  0/23 (0.00%)  2/22 (9.09%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Infections and infestations                     
Nasopharyngitis  1  1/23 (4.35%)  1/22 (4.55%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  1/10 (10.00%)  3/19 (15.79%)  0/19 (0.00%) 
Upper respiratory tract infection  1  5/23 (21.74%)  2/22 (9.09%)  2/16 (12.50%)  1/15 (6.67%)  0/15 (0.00%)  1/15 (6.67%)  2/12 (16.67%)  3/10 (30.00%)  3/19 (15.79%)  1/19 (5.26%) 
Urinary tract infection  1  1/23 (4.35%)  3/22 (13.64%)  2/16 (12.50%)  1/15 (6.67%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  2/19 (10.53%)  0/19 (0.00%) 
Bronchitis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Catheter site infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Clostridium difficile infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Ear infection  1  0/23 (0.00%)  1/22 (4.55%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Enterobiasis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Eye infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Febrile infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Fungal skin infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Gastroenteritis  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Gastroenteritis Escherichia coli  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Herpes zoster  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Infection parasitic  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Influenza  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Lip infection  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Localised infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Oral candidiasis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Oral herpes  1  1/23 (4.35%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Otitis externa  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Otitis media  1  0/23 (0.00%)  1/22 (4.55%)  1/16 (6.25%)  0/15 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Paronychia  1  2/23 (8.70%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Pneumococcal infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Pneumonia  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  1/12 (8.33%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Postoperative wound infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Respiratory syncytial virus infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Respiratory tract infection  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Respiratory tract infection viral  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  1/15 (6.67%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Rhinitis  1  2/23 (8.70%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  2/15 (13.33%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Sepsis  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  1/15 (6.67%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Sinusitis  1  0/23 (0.00%)  1/22 (4.55%)  2/16 (12.50%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Sinusitis bacterial  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  1/19 (5.26%) 
Injury, poisoning and procedural complications                     
Arthropod bite  1  0/23 (0.00%)  1/22 (4.55%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  1/19 (5.26%)  0/19 (0.00%) 
Contusion  1  2/23 (8.70%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  0/10 (0.00%)  0/19 (0.00%)  0/19 (0.00%) 
Facial bones fracture  1  0/23 (0.00%)  0/22 (0.00%)  0/16 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)  0/12 (0.00%)  1/10 (10.00%)  0/19 (0.00%)  0/19 (0.00%) 
Fall  1  1/23 (4.35%)  0/22 (0.00%)  1/16 (6.25%)  0/15 (0.00%)  0/15 (0.00%)  0/15 (0.00%)