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Clinical Trial Results:
An Open-label, Single Arm, Multicenter Study to Broaden Access to Emapalumab, an Anti-Interferon Gamma (Anti-IFNγ) Monoclonal Antibody, and to Assess its Efficacy, Safety, Impact on Quality of Life, and Long-term Outcome in Pediatric Patients with Primary Hemophagocytic Lymphohistiocytosis

Summary
EudraCT number	2017-003114-10
Trial protocol	DE ES GB IT SE
Global end of trial date	14 Sep 2022

Results information
Results version number	v1(current)
This version publication date	17 Sep 2023
First version publication date	17 Sep 2023
Other versions
Summary report(s)	Global substantial amendments to the protocol

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

NI-0501-09

ISRCTN number

US NCT number

NCT01818492

WHO universal trial number (UTN)

Other trial identifiers

US IND number: 111015

Sponsor organisation name

Swedish Orphan Biovitrum AG

Sponsor organisation address

10 Messeplatz, Basel, Switzerland, 4058

Public contact

Radmila Kanceva, MD, Swedish Orphan Biovitrum AG, +41 793048899, Radmila.Kanceva@sobi.com

Scientific contact

Radmila Kanceva, MD , Swedish Orphan Biovitrum AG, +41 793048899, Radmila.Kanceva@sobi.com

Is trial part of an agreed paediatric investigation plan (PIP)

Yes

EMA paediatric investigation plan number(s)

EMEA-002031-PIP01-16

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

29 Nov 2022

Is this the analysis of the primary completion data?

Yes

Primary completion date

18 Aug 2021

Global end of trial reached?

Yes

Global end of trial date

14 Sep 2022

Was the trial ended prematurely?

Main objective of the trial

The purpose of this study is to expand the knowledge on the efficacy and safety of emapalumab (previously known as NI-0501) in children, as a treatment for primary haemophagocytic lymphohistiocytosis (HLH) patients, including long-term outcomes and quality of life assessments. Emapalumab can be administered as the first-line therapy to patients not previously treated with the current standard of care, or can be given to patients who have either failed or were unable to tolerate the available standard of care. Emapalumab is to be administered until the start of conditioning for hematopoietic stem cell transplantation (HSCT), with an anticipated duration ranging from a minimum of 4 weeks to approximately 12 weeks and not exceeding 6 months. After treatment completion, patients will continue in the study for long-term follow-up (in the follow-up period [FUP]) until 1 year after either HSCT or last emapalumab infusion (if HSCT is not performed).

Protection of trial subjects

Written informed consent/assent was obtained from all patients or their parents/legal guardian prior to enrolment into the study, as dictated by the Declaration of Helsinki. The method of obtaining and documenting informed consent and the contents of the consent complied with ICH-GCP and all applicable regulatory requirement(s). If an amended protocol impacted the content of the informed consent document, the consent/assent document had to be revised. Patients already participating in the study when the amended protocol was implemented had to be reconsented/re-assented with the revised version of the informed consent/assent document. From Protocol V2.0 for North America (dated 18 July 2018), an Independent Data Monitoring Committee (iDMC) was appointed in place of the safety management team to regularly assess the benefit/risk profile of emapalumab treatment.

Background therapy

Dexamethasone from Study Day -1.

Evidence for comparator

Actual start date of recruitment

06 Feb 2019

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

12 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Spain: 3

Country: Number of subjects enrolled

United Kingdom: 9

Country: Number of subjects enrolled

Germany: 4

Country: Number of subjects enrolled

Italy: 10

Country: Number of subjects enrolled

United States: 6

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

Switzerland: 1

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was open to enrollment of pediatric patients with pHLH who were treatment-naïve, failed conventional HLH therapy, or showed signs of intolerance to it.

Screening details

Screening was carried out within 2 weeks prior to first administration of emapalumab (SD0) to enable confirmation of patient eligibility, and following the completion of the Informed Consent Form (and Informed Assent Form, when applicable). A total of 41 patients were screened for this study, with 6 patients failing screening (due to not meeting th

Period 1 title

Overall Trial (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

All patients (emapalumab)

Arm description

Emapalumab was administered by intravenous infusion, twice weekly to all patients during the treatment period. The duration of treatment was foreseen until the start of conditioning for HSCT but was not to exceed 6 months. The minimum treatment duration was 4 weeks if the patient’s condition and donor availability allowed HSCT to be performed. After treatment completion or treatment discontinuation (for any reason), patients could continue in the study for long-term follow-up until 1 year after either HSCT or the last emapalumab infusion (if HSCT was not performed).

Arm type

Experimental

Investigational medicinal product name

emapalumab

Investigational medicinal product code

NI-0501

Other name

Pharmaceutical forms

Concentrate for solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Emapalumab was administered by IV infusion over 1 to 2 hours, at a dose of 3 mg/kg, twice weekly (not >4 days apart), except the second infusion was to be administered on SD3. The 3 mg/kg-dose was maintained unless the Investigator deemed a dose increase appropriate. At any time during the study the dose could be increased to 6 mg/kg. A further dose increase to 10 mg/kg could be considered based on the patient’s clinical and laboratory response. If a patient experienced HLH reactivation during the follow up, they could be retreated upon discussion with the Sponsor. Retreated patients followed the same schedule of assessments as applicable during initial treatment (i.e., starting from Visit 1) and re-entered the follow up after completion of retreatment. Upon achievement of a complete response the dose of emapalumab was to be lowered to achieve 1 mg/kg twice a week and maintained until conditioning for transplant. Decrease of the emapalumab dose was to occur in a stepwise fashion.

Number of subjects in period 1	All patients (emapalumab)
Started	35
Completed	18
Not completed	17
Death	16
Other	1

Baseline characteristics

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Reporting group title

All patients (emapalumab)

Reporting group description

Reporting group values	All patients (emapalumab)	Total
Number of subjects	35	35
Age categorical
Units: Subjects
Newborns (0-27 days)	5	5
Infants and toddlers (28 days-23 months)	22	22
Children (2-11 years)	6	6
Adolescents (12-17 years)	2	2
Gender categorical
Units: Subjects
Female	14	14
Male	21	21

Subject analysis set title

All-treated analysis set

Subject analysis set type

Full analysis

Subject analysis set description

The All-treated analysis set included all patients who received any part of an infusion of study drug. The All-treated analysis set was the primary analysis set for efficacy endpoints and was used for safety and PK/PD endpoints.

Subject analysis set title

All-treated analysis set - treatment naïve

Subject analysis set type

Sub-group analysis

Subject analysis set description

Patients in the All-treated analysis set who were naïve to HLH treatment.

Subject analysis set title

All-treated analysis set - treatment experienced

Subject analysis set type

Sub-group analysis

Subject analysis set description

Patients in the All-treated analysis set who have received conventional HLH therapy (as per site standard of care), without having obtained a satisfactory response according to the Investigator or having shown signs of intolerance to previous HLH therapy.

Subject analysis set title

Baseline

Subject analysis set type

Full analysis

Subject analysis set description

This analysis set was entered only to allow the addition of the statistical analyses for the primary endpoint which uses a comparison within each group to the null hypothesis.

Subject analysis sets values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced	Baseline
Number of subjects	35	16	19	35
Age categorical
Units: Subjects
Newborns (0-27 days)	5	4	1	5
Infants and toddlers (28 days-23 months)	22	10	12	22
Children (2-11 years)	6	2	4	6
Adolescents (12-17 years)	2	0	2	2
Age continuous
Units:
	±	±	±	±
Gender categorical
Units: Subjects
Female	14	3	11	14
Male	21	13	8	21

End points

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Reporting group title

All patients (emapalumab)

Reporting group description

Subject analysis set title

All-treated analysis set

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

All-treated analysis set - treatment naïve

Subject analysis set type

Sub-group analysis

Subject analysis set description

Patients in the All-treated analysis set who were naïve to HLH treatment.

Subject analysis set title

All-treated analysis set - treatment experienced

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Baseline

Subject analysis set type

Full analysis

Subject analysis set description

This analysis set was entered only to allow the addition of the statistical analyses for the primary endpoint which uses a comparison within each group to the null hypothesis.

Primary: Overall Response at Week 8 or End of Treatment (if earlier)

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End point title

Overall Response at Week 8 or End of Treatment (if earlier)

End point description

The overall response rate (ORR) of patients achieving either Complete or Partial Response or HLH Improvement, at Week 8 or EOT (whichever occurs earlier). ORR comprised complete response, partial response, or HLH improvement. The 1-sided p-value was based on a 1-sided exact binomial test comparing proportion of patients with overall response to hypothesized null hypothesis of at most 40%. The ORR for the all-treated analysis set was 62.9% (95% CI [exact]: 44.9% to 78.5%), with a statistically significant difference from the pre-set null hypothesis of 40% (p-value = 0.0053). The number of patients with a compete response was 5; there were 16 patients with a partial response, 1 patient with HLH improvement, and 13 patients with no response.

End point type

Primary

End point timeframe

Up to Week 8.

End point values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced	Baseline
Number of subjects analysed	35	16	19	35
Units: Overall response rate
number (confidence interval 95%)
Overall response rate	62.9 (44.9 to 78.5)	50.0 (24.7 to 75.3)	73.7 (48.8 to 90.9)	0 (0 to 0)

Exact binomial test - all-treated analysis set

Statistical analysis description

The analysis of the primary endpoint utilized an exact binomial test to evaluate the null hypotheses that the overall response rate (ORR) was, at most, 40%. The test was undertaken at the 1-sided 0.025 level. Due to the inability of presenting the statistical analysis for single arm studies within EudraCT, it is presented here as a comparison to baseline. The number of subjects analyzed was 35, as the comparison was within a single group.

Comparison groups

Baseline v All-treated analysis set

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.0053 ^[2]

Method

Exact binomial

Confidence interval

Notes
[1] - The pre-specified null hypothesis was that the ORR was, at most, 40%.
[2] - This test was undertaken at the one-sided 0.025 significance level.

Exact binomial test - treatment-naïve

Statistical analysis description

Comparison groups

Baseline v All-treated analysis set - treatment naïve

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.2839 ^[4]

Method

Exact binomial

Confidence interval

Notes
[3] - The pre-specified null hypothesis was that the ORR was, at most, 40%.
[4] - This test was undertaken at the one-sided 0.025 significance level.

Exact binomial test - treatment-experienced

Statistical analysis description

Comparison groups

Baseline v All-treated analysis set - treatment experienced

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.0031 ^[6]

Method

Exact binomial

Confidence interval

Notes
[5] - The pre-specified null hypothesis was that the ORR was, at most, 40%.
[6] - This test was undertaken at the one-sided 0.025 significance level.

Secondary: Overall Survival

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End point title

Overall Survival

End point description

Number of patients surviving, including survival to HSCT and survival after either HSCT or last emapalumab infusion (if HSCT was not performed). 25 patients (71.4 %) overall in the All-treated analysis set received HSCT or were alive at end of study if HSCT was not deemed as indicated by the Investigators (treatment naïve: 12 patients [75.0 %] and treatment-experienced: 13 patients [68.4 %]). Among the 23 patients who underwent HSCT, 17 patients (73.9 %) overall were alive at the end of the study (8 treatment-naïve patients [72.7 %] and 9 treatment-experienced patients [75.0 %]). Six patients died after HSCT (3 treatment-naïve and 3 treatment-experienced).

End point type

Secondary

End point timeframe

Up to 18 months

End point values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced
Number of subjects analysed	25 ^[7]	12 ^[8]	13 ^[9]
Units: Patients
Alive without having received HSCT	2	1	1
Alive at end of the study having undergone HSCT	17	8	9
Died after receiving HSCT	6	3	3

Notes
[7] - 25 patients received HSCT or were alive at end of study
[8] - 12 patients received HSCT or were alive at end of study
[9] - 13 patients received HSCT or were alive at end of study

No statistical analyses for this end point

Secondary: Event-free Survival

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End point title

Event-free Survival

End point description

The duration of event-free survival was defined as time from HSCT to date of (whichever occurs first): death from any cause, graft failure, or HLH reactivation. 23 patients (65.7%) underwent HSCT, with a similar number of treatment-naïve patients (11 patients [68.8%]) and treatment-experienced patients (12 patients [63.2%]). One treatment-experienced patient experienced graft failure, and 6 patients overall died (3 treatment-naïve and 3 treatment-experienced patients) post-HSCT. There were no patients with HLH reactivation post-HSCT.

End point type

Secondary

End point timeframe

Up to 18 months.

End point values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced
Number of subjects analysed	35	16	19
Units: Patients
Event-free at the end of the study	16	8	8

No statistical analyses for this end point

Secondary: Overall Response at Start of Conditioning

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End point title

Overall Response at Start of Conditioning

End point description

Number of patients achieving either a Complete or Partial Response or HLH Improvement, at start of conditioning (or at last emapalumab infusion if HSCT is not performed). Overall response in the All-treated analysis set at the start of conditioning for HSCT (or at last emapalumab infusion, if HSCT was not performed) showed an ORR of 45.7% (95% CI: 28.8% to 63.4%); the responses comprised 4 complete responses, 11 partial responses, and 1 HLH improvement.

End point type

Secondary

End point timeframe

Up to 6 months.

End point values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced
Number of subjects analysed	35	16	19
Units: Patients
Complete response	4	3	1
Partial response	11	5	6
HLH improvement	1	0	1
No response	19	8	11

No statistical analyses for this end point

Secondary: Duration of Response

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End point title

Duration of Response

End point description

Duration of response, i.e., maintenance of the response achieved at any time during the study (with censoring time at start of conditioning for patients with no event) calculated only for patients showing confirmed overall response. 28 patients in the All-treated analysis set (80.0%) experienced at least 1 response that was maintained for at least 4 days, at some point during the study (in contrast with the primary efficacy analysis, responses included here were not necessarily observed at EOT or Week 8). Patients who never had a response were not included in the analysis. Median time to loss of response was 40 days (95% CI: 19.0 to not calculable [NC]) in the treatment-naïve group and 61 days (95% CI: 21.0 to NC). In the All-treated analysis set, median time to loss of response was 61 days (95% CI: 21.0 to NC).

End point type

Secondary

End point timeframe

Up to 18 months.

End point values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced
Number of subjects analysed	28 ^[10]	12 ^[11]	16 ^[12]
Units: Patients
In response at EOT	11	4	7
Treatment discontinued due to AE	1	0	1
Treatment discontinued due to physician’s decision	2	1	1

Notes
[10] - Only patients with a response were included
[11] - Only patients with a response were included
[12] - Only patients with a response were included

No statistical analyses for this end point

Secondary: Time to Response

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End point title

Time to Response

End point description

Time to first response at any time during the study. 7 patients (20.0%) did not experience a response at any time during the study and were censored in the analysis at the date of last contact (time of their death in all of them). In the All-treated analysis set, 28 patients (80%) achieved a response (maintained for at least 4 days) at some point during the study.

End point type

Secondary

End point timeframe

Up to 18 months.

End point values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced
Number of subjects analysed	28 ^[13]	12 ^[14]	16 ^[15]
Units: Days
median (confidence interval 95%)	4 (4.0 to 13.0)	5 (4.0 to 21.0)	4 (4.0 to 30.0)

Notes
[13] - Only patients with a response were included
[14] - Only patients with a response were included
[15] - Only patients with a response were included

No statistical analyses for this end point

Secondary: Number of Patients Able to Reduce Glucocorticoids by 50% or More of the Baseline Dose During Emapalumab Treatment

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End point title

Number of Patients Able to Reduce Glucocorticoids by 50% or More of the Baseline Dose During Emapalumab Treatment

End point description

Number of patients able to reduce glucocorticoids by 50% or more of the baseline dose during emapalumab treatment. In the All-treated analysis set, 15 patients (42.9%) were able to reduce their glucocorticoid dose by 50% of the baseline dose or more until EOT; these included 8 treatment-naïve patients (50.0%) and 7 treatment-experienced patients (36.8%).

End point type

Secondary

End point timeframe

Up to 6 months.

End point values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced
Number of subjects analysed	35	16	19
Units: Patients
Able to reduce glucocorticoids by 50 % or more	15	8	7

No statistical analyses for this end point

Secondary: Number of Patients Proceeding to HSCT

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End point title

Number of Patients Proceeding to HSCT

End point description

Number of patients able to proceed to HSCT when deemed indicated. A total of 23 patients (65.7%) in the All-treated analysis set were able to proceed to HSCT, including 11 treatment-naïve patients (68.8%) and 12 treatment-experienced patients (63.2%).

End point type

Secondary

End point timeframe

Up to 18 months.

End point values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced
Number of subjects analysed	35	16	19
Units: Patients
Patients proceeding to HSCT	23	11	12

No statistical analyses for this end point

Secondary: Quality of Life Assessed Through PedsQL™, Pediatric Quality of Life Inventory™

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End point title

Quality of Life Assessed Through PedsQL™, Pediatric Quality of Life Inventory™

End point description

Assessment of the quality of life using the PedsQL “Pediatric Quality of Life Inventory”. The PedsQL uses a 100-point scale ranging from 0 to 100 with higher values indicating better quality of life. Mean change from baseline for each age group is provided. There were no treatment-naïve patients available in the 13-24 months, 2-4 years, and 13-18 years age groups; no treatment experienced patients were available in the 8-12 years age group. No patients were available in the 5-7 years age group. Mean (SD) values for these categories are presented as "0" where no patients are available.

End point type

Secondary

End point timeframe

Up to Week 8.

End point values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced
Number of subjects analysed	35	16	19
Units: scale score
arithmetic mean (standard deviation)
Change from Baseline at EOT/Week 8 - 1-12 months	0.208 ± 18.0737	-6.514 ± 14.8977	5.810 ± 19.8220
Change from Baseline at EOT/Week 8 - 13-24 months	0.794 ± 4.8152	0 ± 0	0.794 ± 4.8152
Change from Baseline at EOT/Week 8 - 2-4 years	8.469 ± 9.6897	0 ± 0	8.469 ± 9.6897
Change from Baseline at EOT/Week 8 - 8-12 years	15.978 ± 0	15.978 ± 0	0 ± 0
Change from Baseline at EOT/Week 8 - 13-18 years	-7.862 ± 13.4760	0 ± 0	-7.862 ± 13.4760

No statistical analyses for this end point

Secondary: Quality of Life Assessed Through Behavioral, Affective and Somatic Experiences Scales (BASES)

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End point title

Quality of Life Assessed Through Behavioral, Affective and Somatic Experiences Scales (BASES)

End point description

Assessment of the quality of life using the BASES questionnaires, a validated 38-item questionnaire; a reduced non-validated 22-item version of the questionnaire was used in an exploratory nature for the secondary endpoint. BASES subscale scores were calculated using a 5-point Likert scale from 1 to 5 for all items and they were weighted equally to calculate subscale scores for the following domains: • Physical Discomfort (5 items – 1 is considered best response) • Cooperation/Compliance (5 items – 1 is considered best response) • Mood/Behavior (7 items – 5 is considered best response) • Quality of Interactions (3 items – 1 is considered best response) • Activity/Sleep (2 items – 5 is considered best response for patient’s activity level and 1 is considered best response for patient’s sleeping) Only patients with HSCT performed were analyzed. The BASES scores showed comparable mean values between treatment-naïve and treatment-experienced patients at the end of treatment.

End point type

Secondary

End point timeframe

Up to 6 months.

End point values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced
Number of subjects analysed	15 ^[16]	7 ^[17]	8 ^[18]
Units: Scale score
arithmetic mean (standard deviation)
Physical discomfort	10.0 ± 3.57	9.4 ± 2.99	10.5 ± 4.14
Cooperation/compliance	9.3 ± 3.02	9.6 ± 2.76	9.1 ± 3.4
Mood/behavior	20.4 ± 8.82	15.1 ± 8.88	25.0 ± 6.02
Quality of interactions	5.8 ± 2.34	6.1 ± 2.48	5.5 ± 2.33
Activity	3.1 ± 1.22	2.7 ± 0.95	3.4 ± 1.41
Sleep	2.1 ± 1.04	1.8 ± 1.10	2.3 ± 1.03

Notes
[16] - For all categories but sleep, n = 15 For sleep, n = 11
[17] - For all categories but sleep, n = 7 For sleep, n = 5
[18] - For all categories but sleep, n = 8 For sleep, n = 6

No statistical analyses for this end point

Secondary: Incidence, Severity, Causality and Outcomes of AEs (serious and non-serious)

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End point title

Incidence, Severity, Causality and Outcomes of AEs (serious and non-serious)

End point description

All 35 patients (100%) experienced at least 1 TEAE, with 9 patients (25.7%) experiencing 30 TEAEs assessed as related to the study drug. Related TEAEs were reported in 3 of 16 treatment-naïve patients and in 6 of 19 treatment-experienced patients. 129 serious TEAEs were reported in 32 patients (91.4%), in all of the treatment-naïve patients (100%) and in 84.2% of the treatment-experienced patients. Six of these events were assessed as related to the study drug in 4 patients (11.4%). No patient withdrew from the study due to an AE. There were 21 SAEs with an outcome of death in 16 patients (45.7%). None were assessed as related to the study drug. The incidence of related serious TEAEs and serious TEAEs with an outcome of death was similar in treatment-naïve and treatment-experienced patients.

End point type

Secondary

End point timeframe

Up to 18 months.

End point values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced
Number of subjects analysed	35	16	19
Units: Patients
Non-TEAEs	15	5	10
TEAEs	35	16	19
TEAEs related to study drug	9	3	6
Mild TEAEs	30	12	18
Moderate TEAEs	27	12	15
Severe TEAEs	31	15	16
TEAEs leading to discontinuation of study drug	7	3	4
TEAEs with an outcome of death	16	7	9
Serious TEAEs	32	16	16
Treatment-emergent SAEs related to study drug	4	2	2
TEAEs with infections	29	14	15
Mild infections	21	10	11
Moderate infections	15	8	7
Severe infections	16	7	9
TEAEs with infusion-related reactions	7	3	4

No statistical analyses for this end point

Secondary: Evolution of Laboratory Parameters

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End point title

Evolution of Laboratory Parameters

End point description

Number of patients experiencing shifts from baseline in the following relevant laboratory parameters are reported: • Biochemistry: glucose ferritin, C-reactive protein (CRP), liver function (alkaline phosphatase [ALP], alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma glutamyl transferase [γGT], lactate dehydrogenase [LDH], bilirubin, renal function (albumin, creatinine, urea, urea nitrogen), triglycerides • Complete blood count: basophils, basophils/leukocytes, eosinophils, eosinophils/leukocytes, hematocrit, hemoglobin, large unstained cells, lymphocytes, lymphocytes/leukocytes, monocytes, monocytes/leukocytes, neutrophils band form, neutrophils band form/leukocytes, platelets, erythrocytes, leukocytes • Coagulation tests (activated partial thromboplastin time [aPTT], aPTT ratio, prothrombin time, prothrombin international normalized ratio [INR]), D-dimer, fibrinogen

End point type

Secondary

End point timeframe

Up to 6 months.

End point values	All-treated analysis set
Number of subjects analysed	35
Units: Patients
Albumin: low to within	6
Albumin: within to low	2
Alkaline phosphatase: low to within	5
Alkaline phosphatase: within to low	8
Alkaline phosphatase: high to within	2
Alanine aminotransferase: within to high	3
Alanine aminotransferase: high to within	8
Aspartate aminotransferase: within to high	3
Aspartate aminotransferase: high to low	1
Aspartate aminotransferase: high to within	8
Bilirubin: within to low	1
Bilirubin: within to high	1
Bilirubin: high to within	4
Creatinine: low to within	1
Creatinine: within to low	5
Creatinine: within to high	1
Creatinine: high to within	2
C-reactive protein: within to high	6
C-reactive protein: high to within	4
Ferritin: high to low	1
Ferritin: high to within	5
γGT: within to high	3
γGT: high to within	4
Glucose: within to high	2
Glucose: high to within	8
Lactate dehydrogenase: low to within	1
Lactate dehydrogenase: within to high	4
Lactate dehydrogenase: high to within	8
Triglycerides: within to high	1
Triglycerides: high to within	5
Urea: within to low	5
Urea: within to high	4
Urea: high to within	4
Urea nitrogen: low to within	1
Urea nitrogen: within to low	1
Urea nitrogen: within to high	1
Basophils: low to within	1
Basophils: within to high	1
Basophils: high to within	1
Basophils/leukocytes: high to within	1
Eosinophils: low to within	3
Eosinophils: within to low	1
Eosinophils/leukocytes: within to high	2
Hematocrit: low to within	9
Hematocrit: within to low	5
Hemoglobin: low to within	9
Hemoglobin: low to high	1
Hemoglobin: within to low	5
Large unstained cells: high to within	1
Lymphocytes: low to within	4
Lymphocytes: within to low	6
Lymphocytes: within to high	1
Lymphocytes: high to within	1
Lymphocytes/leukocytes: within to low	4
Lymphocytes/leukocytes: within to high	1
Lymphocytes/leukocytes: high to within	2
Monocytes: low to within	6
Monocytes: low to high	3
Monocytes: within to low	2
Monocytes: within to high	2
Monocytes: high to within	2
Monocytes/leukocytes: within to high	3
Monocytes/leukocytes: high to within	1
Neutrophils band form: low to within	9
Neutrophils band form: within to low	2
Neutrophils band form: within to high	2
Neutrophils band form: high to within	1
Neutrophils band form/leukocytes: low to within	2
Neutrophils band form/leukocytes: within to low	1
Neutrophils band form/leukocytes: within to high	1
Platelets: low to within	5
Platelets: low to high	2
Platelets: within to low	3
Platelets: within to high	1
Platelets: high to within	1
Erythrocytes: low to within	8
Erythrocytes: within to low	4
Erythrocytes: within to high	1
Leukocytes: low to within	9
Leukocytes: low to high	1
Leukocytes: within to low	4
Leukocytes: high to within	1
aPTT: low to within	2
aPTT: within to low	4
aPTT: within to high	3
aPTT: high to within	4
aPTT ratio: low to within	2
aPTT ratio: within to low	1
aPTT ratio: within to high	2
aPTT ratio: high to within	2
D-dimer: within to high	4
D-dimer: high to within	6
Fibrinogen: low to within	13
Fibrinogen: low to high	1
Fibrinogen: within to low	2
Fibrinogen: within to high	2
Fibrinogen: high to within	3
Prothrombin time: within to high	3
Prothrombin time: high to within	6
Prothrombin INR: within to high	1
Prothrombin INR: high to low	1
Prothrombin INR: high to within	4

No statistical analyses for this end point

Secondary: Number of Patients who Discontinued Emapalumab Treatment

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End point title

Number of Patients who Discontinued Emapalumab Treatment

End point description

Number of patients who discontinued emapalumab treatment for safety reasons. The study drug was discontinued due to 10 TEAEs in 7 patients overall (20.0%); 3 of 16 treatment-naïve patients and 4 of 19 treatment-experienced patients. In 5 patients (14.2%), emapalumab was discontinued in connection to worsening of the disease under study. In 1 patient (2.9%) emapalumab was discontinued due to pulmonary hypertension. In 1 patient (2.9%), the TEAE of acute respiratory failure leading to discontinuation of study drug was the only TEAE assessed as related to the study drug; the outcome was reported as resolved.

End point type

Secondary

End point timeframe

Up to 6 months.

End point values	All-treated analysis set	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced
Number of subjects analysed	35	16	19
Units: Patients
Treatment discontinuation due to AE	7	3	4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Signing of ICF until end of follow-up period.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

25.1

Reporting group title

All-treated analysis set - treatment naïve

Reporting group description

Patients naïve to HLH treatment.

Reporting group title

All-treated analysis set - treatment experienced

Reporting group description

Patients could have received conventional HLH therapy without having obtained a satisfactory response according to the Investigator or having shown signs of intolerance to previous HLH therapy.

Reporting group title

All-treated analysis set

Reporting group description

Serious adverse events	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced	All-treated analysis set
Total subjects affected by serious adverse events
subjects affected / exposed	16 / 16 (100.00%)	16 / 19 (84.21%)	32 / 35 (91.43%)
number of deaths (all causes)	7	9	16
number of deaths resulting from adverse events	7	9	16
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Epstein-Barr virus associated lymphoma
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Capillary leak syndrome
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Shock
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Venoocclusive disease
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Condition aggravated
subjects affected / exposed	4 / 16 (25.00%)	8 / 19 (42.11%)	12 / 35 (34.29%)
occurrences causally related to treatment / all	0 / 4	0 / 8	0 / 12
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Multiple organ dysfunction syndrome
subjects affected / exposed	1 / 16 (6.25%)	4 / 19 (21.05%)	5 / 35 (14.29%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 1	0 / 3	0 / 4
Pyrexia
subjects affected / exposed	2 / 16 (12.50%)	3 / 19 (15.79%)	5 / 35 (14.29%)
occurrences causally related to treatment / all	1 / 2	0 / 3	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Catheter site haemorrhage
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Engraftment syndrome
subjects affected / exposed	2 / 16 (12.50%)	1 / 19 (5.26%)	3 / 35 (8.57%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Acute graft versus host disease
subjects affected / exposed	2 / 16 (12.50%)	0 / 19 (0.00%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Respiratory distress
subjects affected / exposed	2 / 16 (12.50%)	2 / 19 (10.53%)	4 / 35 (11.43%)
occurrences causally related to treatment / all	1 / 2	0 / 2	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	2 / 16 (12.50%)	2 / 19 (10.53%)	4 / 35 (11.43%)
occurrences causally related to treatment / all	0 / 3	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 2
Acute respiratory failure
subjects affected / exposed	3 / 16 (18.75%)	0 / 19 (0.00%)	3 / 35 (8.57%)
occurrences causally related to treatment / all	1 / 4	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute respiratory distress syndrome
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	2 / 16 (12.50%)	0 / 19 (0.00%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Pulmonary haemorrhage
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Asthma
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laryngeal oedema
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laryngeal stenosis
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung consolidation
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Respiratory disorder
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Klebsiella test positive
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Graft loss
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound secretion
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Fanconi syndrome
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Cardio-respiratory arrest
subjects affected / exposed	1 / 16 (6.25%)	2 / 19 (10.53%)	3 / 35 (8.57%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Cardiac arrest
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Cardiac failure
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Nervous system disorders
Seizure
subjects affected / exposed	0 / 16 (0.00%)	3 / 19 (15.79%)	3 / 35 (8.57%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Nervous system disorder
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Neurological decompensation
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 16 (6.25%)	3 / 19 (15.79%)	4 / 35 (11.43%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coagulopathy
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphadenitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Visual field defect
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Pneumatosis intestinalis
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Liver disorder
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Venoocclusive liver disease
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Renal failure
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary bladder haemorrhage
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia viral
subjects affected / exposed	1 / 16 (6.25%)	2 / 19 (10.53%)	3 / 35 (8.57%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 16 (6.25%)	2 / 19 (10.53%)	3 / 35 (8.57%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	2 / 16 (12.50%)	1 / 19 (5.26%)	3 / 35 (8.57%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Septic shock
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 2
Bacterial sepsis
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Catheter site cellulitis
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cytomegalovirus infection reactivation
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cytomegalovirus viraemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterobacter sepsis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Enterococcal infection
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epstein-Barr virus infection reactivation
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis adenovirus
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes simplex viraemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia cytomegaloviral
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia staphylococcal
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hypervolaemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	All-treated analysis set - treatment naïve	All-treated analysis set - treatment experienced	All-treated analysis set
Total subjects affected by non serious adverse events
subjects affected / exposed	16 / 16 (100.00%)	19 / 19 (100.00%)	35 / 35 (100.00%)
Vascular disorders
Hypertension
subjects affected / exposed	6 / 16 (37.50%)	5 / 19 (26.32%)	11 / 35 (31.43%)
occurrences all number	6	5	11
Hypotension
subjects affected / exposed	2 / 16 (12.50%)	1 / 19 (5.26%)	3 / 35 (8.57%)
occurrences all number	2	2	4
Haematoma
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Superficial vein thrombosis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Venoocclusive disease
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Surgical and medical procedures
Pain management
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Vitamin supplementation
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Pregnancy, puerperium and perinatal conditions
Umbilical granuloma
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	6 / 16 (37.50%)	8 / 19 (42.11%)	14 / 35 (40.00%)
occurrences all number	11	17	28
Pain
subjects affected / exposed	3 / 16 (18.75%)	6 / 19 (31.58%)	9 / 35 (25.71%)
occurrences all number	7	9	16
Mucosal inflammation
subjects affected / exposed	1 / 16 (6.25%)	4 / 19 (21.05%)	5 / 35 (14.29%)
occurrences all number	1	4	5
Oedema peripheral
subjects affected / exposed	2 / 16 (12.50%)	2 / 19 (10.53%)	4 / 35 (11.43%)
occurrences all number	2	5	7
Condition aggravated
subjects affected / exposed	2 / 16 (12.50%)	1 / 19 (5.26%)	3 / 35 (8.57%)
occurrences all number	2	1	3
Hypothermia
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Catheter site rash
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Crying
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	2	0	2
Generalised oedema
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Malaise
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Oedema
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Vascular device occlusion
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Immune system disorders
Graft versus host disease in gastrointestinal tract
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Acute graft versus host disease in intestine
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Acute graft versus host disease in skin
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Cell-mediated immune deficiency
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Chronic graft versus host disease in skin
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Cytokine release syndrome
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Drug hypersensitivity
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	2	2
Graft versus host disease in liver
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Graft versus host disease in skin
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Haemophagocytic lymphohistiocytosis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Immune system disorder
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 16 (12.50%)	3 / 19 (15.79%)	5 / 35 (14.29%)
occurrences all number	3	3	6
Pleural effusion
subjects affected / exposed	2 / 16 (12.50%)	1 / 19 (5.26%)	3 / 35 (8.57%)
occurrences all number	2	1	3
Stridor
subjects affected / exposed	2 / 16 (12.50%)	1 / 19 (5.26%)	3 / 35 (8.57%)
occurrences all number	2	1	3
Tachypnoea
subjects affected / exposed	2 / 16 (12.50%)	1 / 19 (5.26%)	3 / 35 (8.57%)
occurrences all number	2	1	3
Dyspnoea
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	2	3
Epistaxis
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	2	2	4
Nasal congestion
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	3	3
Rhinorrhoea
subjects affected / exposed	2 / 16 (12.50%)	0 / 19 (0.00%)	2 / 35 (5.71%)
occurrences all number	2	0	2
Dysphonia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Interstitial lung abnormality
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Lung consolidation
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Lung disorder
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Nasal dryness
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Pneumothorax
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Pulmonary haemorrhage
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Pulmonary hypertension
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Respiratory distress
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Confusional state
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Delirium
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Irritability
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	2	2
Restlessness
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Investigations
Adenovirus test positive
subjects affected / exposed	1 / 16 (6.25%)	2 / 19 (10.53%)	3 / 35 (8.57%)
occurrences all number	1	3	4
Alanine aminotransferase increased
subjects affected / exposed	0 / 16 (0.00%)	3 / 19 (15.79%)	3 / 35 (8.57%)
occurrences all number	0	3	3
C-reactive protein increased
subjects affected / exposed	1 / 16 (6.25%)	2 / 19 (10.53%)	3 / 35 (8.57%)
occurrences all number	1	2	3
Platelet count decreased
subjects affected / exposed	0 / 16 (0.00%)	3 / 19 (15.79%)	3 / 35 (8.57%)
occurrences all number	0	3	3
Weight increased
subjects affected / exposed	1 / 16 (6.25%)	2 / 19 (10.53%)	3 / 35 (8.57%)
occurrences all number	1	2	3
Blood creatinine increased
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Fibrin D dimer increased
subjects affected / exposed	2 / 16 (12.50%)	0 / 19 (0.00%)	2 / 35 (5.71%)
occurrences all number	2	0	2
Gram stain positive
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Haemoglobin decreased
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	8	8
Human rhinovirus test positive
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Respirovirus test positive
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Aspartate aminotransferase increased
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Bacterial test positive
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Blood creatinine decreased
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Blood glucose decreased
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Blood magnesium decreased
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Candida test positive
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Culture
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Cytomegalovirus test positive
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Enterobacter test positive
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Epstein-Barr virus test positive
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
General physical condition abnormal
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Glycocholic acid increased
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Klebsiella test positive
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Oxygen saturation decreased
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Pseudomonas test positive
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
SARS-CoV-2 test positive
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Sapovirus test positive
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Staphylococcus test positive
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Ultrasound abdomen abnormal
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Ultrasound kidney abnormal
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Ultrasound liver abnormal
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Urine output decreased
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Vitamin D increased
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Injury, poisoning and procedural complications
Anal injury
subjects affected / exposed	2 / 16 (12.50%)	1 / 19 (5.26%)	3 / 35 (8.57%)
occurrences all number	2	2	4
Perineal injury
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Genital injury
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Scratch
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Subcutaneous haematoma
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Cardiac disorders
Tachycardia
subjects affected / exposed	3 / 16 (18.75%)	4 / 19 (21.05%)	7 / 35 (20.00%)
occurrences all number	3	4	7
Sinus tachycardia
subjects affected / exposed	1 / 16 (6.25%)	3 / 19 (15.79%)	4 / 35 (11.43%)
occurrences all number	1	5	6
Bradycardia
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Left ventricular hypertrophy
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Sinus bradycardia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Nervous system disorders
Cerebral atrophy
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Hypotonia
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Cerebral ventricle dilatation
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Cerebrospinal fluid leakage
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Depressed level of consciousness
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Dyskinesia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Headache
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Hyperaesthesia
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Leukoencephalopathy
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Myoclonus
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Nervous system disorder
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Seizure
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 16 (12.50%)	1 / 19 (5.26%)	3 / 35 (8.57%)
occurrences all number	3	1	4
Thrombotic microangiopathy
subjects affected / exposed	2 / 16 (12.50%)	1 / 19 (5.26%)	3 / 35 (8.57%)
occurrences all number	2	1	3
Febrile neutropenia
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Iron deficiency anaemia
subjects affected / exposed	2 / 16 (12.50%)	0 / 19 (0.00%)	2 / 35 (5.71%)
occurrences all number	2	0	2
Lymphadenopathy
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Coagulopathy
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Hypofibrinogenaemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Pancytopenia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Thrombocytopenia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Middle ear effusion
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Eye disorders
Eyelid oedema
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Blepharitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Conjunctival haemorrhage
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Eye swelling
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	2	0	2
Glaucoma
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Lagophthalmos
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Ocular hyperaemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Periorbital oedema
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Swelling of eyelid
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Gastrointestinal disorders
Vomiting
subjects affected / exposed	7 / 16 (43.75%)	10 / 19 (52.63%)	17 / 35 (48.57%)
occurrences all number	10	15	25
Diarrhoea
alternative dictionary used: MedDRA 25.1
subjects affected / exposed	5 / 16 (31.25%)	10 / 19 (52.63%)	15 / 35 (42.86%)
occurrences all number	7	16	23
Abdominal pain
subjects affected / exposed	2 / 16 (12.50%)	5 / 19 (26.32%)	7 / 35 (20.00%)
occurrences all number	5	6	11
Stomatitis
subjects affected / exposed	2 / 16 (12.50%)	4 / 19 (21.05%)	6 / 35 (17.14%)
occurrences all number	2	7	9
Constipation
subjects affected / exposed	2 / 16 (12.50%)	3 / 19 (15.79%)	5 / 35 (14.29%)
occurrences all number	2	3	5
Nausea
subjects affected / exposed	2 / 16 (12.50%)	2 / 19 (10.53%)	4 / 35 (11.43%)
occurrences all number	2	3	5
Pneumatosis intestinalis
subjects affected / exposed	1 / 16 (6.25%)	2 / 19 (10.53%)	3 / 35 (8.57%)
occurrences all number	1	2	3
Abdominal distension
subjects affected / exposed	2 / 16 (12.50%)	0 / 19 (0.00%)	2 / 35 (5.71%)
occurrences all number	2	0	2
Anal erythema
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Proctalgia
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Anal blister
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Ascites
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Colitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	2	2
Dyschezia
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Flatulence
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Gastrointestinal wall thickening
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Mouth haemorrhage
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Mouth swelling
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Oral pain
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Rectal prolapse
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Small intestinal obstruction
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Hypertransaminasaemia
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Drug-induced liver injury
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Gallbladder disorder
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Gallbladder enlargement
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Gallbladder oedema
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Hepatobiliary disease
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Hepatomegaly
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Hepatosplenomegaly
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Liver disorder
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Liver injury
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	4 / 16 (25.00%)	4 / 19 (21.05%)	8 / 35 (22.86%)
occurrences all number	6	7	13
Dermatitis diaper
subjects affected / exposed	3 / 16 (18.75%)	2 / 19 (10.53%)	5 / 35 (14.29%)
occurrences all number	4	2	6
Pruritus
subjects affected / exposed	1 / 16 (6.25%)	4 / 19 (21.05%)	5 / 35 (14.29%)
occurrences all number	1	5	6
Erythema
subjects affected / exposed	2 / 16 (12.50%)	2 / 19 (10.53%)	4 / 35 (11.43%)
occurrences all number	3	2	5
Rash maculo-papular
subjects affected / exposed	0 / 16 (0.00%)	4 / 19 (21.05%)	4 / 35 (11.43%)
occurrences all number	0	7	7
Blister
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Dry skin
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Erythema multiforme
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	3
Petechiae
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Rash erythematous
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Skin lesion
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Hyperhidrosis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Livedo reticularis
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Macule
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Papule
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Seborrhoeic dermatitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Skin disorder
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Skin irritation
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Skin mass
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Skin ulcer
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Urticaria
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	3 / 16 (18.75%)	1 / 19 (5.26%)	4 / 35 (11.43%)
occurrences all number	3	1	4
Nephrocalcinosis
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Azotaemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Cystitis haemorrhagic
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Glycosuria
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Haematuria
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Kidney enlargement
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Nephrolithiasis
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Proteinuria
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Renal failure
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	2 / 16 (12.50%)	2 / 19 (10.53%)	4 / 35 (11.43%)
occurrences all number	2	2	4
Adrenal suppression
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Cushingoid
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Musculoskeletal and connective tissue disorders
Pain in extremity
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Arthritis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	2	2
Bone pain
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Muscle spasms
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Muscular weakness
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	2	2
Spinal deformity
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	2	2
Infections and infestations
Cytomegalovirus infection reactivation
subjects affected / exposed	3 / 16 (18.75%)	1 / 19 (5.26%)	4 / 35 (11.43%)
occurrences all number	4	2	6
Epstein-Barr virus infection
subjects affected / exposed	1 / 16 (6.25%)	3 / 19 (15.79%)	4 / 35 (11.43%)
occurrences all number	1	4	5
Bacteraemia
subjects affected / exposed	1 / 16 (6.25%)	2 / 19 (10.53%)	3 / 35 (8.57%)
occurrences all number	1	3	4
Candida infection
subjects affected / exposed	2 / 16 (12.50%)	1 / 19 (5.26%)	3 / 35 (8.57%)
occurrences all number	2	1	3
Urinary tract infection
subjects affected / exposed	2 / 16 (12.50%)	1 / 19 (5.26%)	3 / 35 (8.57%)
occurrences all number	2	2	4
Adenovirus reactivation
subjects affected / exposed	2 / 16 (12.50%)	0 / 19 (0.00%)	2 / 35 (5.71%)
occurrences all number	2	0	2
Cytomegalovirus infection
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Epstein-Barr virus infection reactivation
subjects affected / exposed	2 / 16 (12.50%)	0 / 19 (0.00%)	2 / 35 (5.71%)
occurrences all number	2	0	2
Fungal infection
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Oral fungal infection
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Paronychia
subjects affected / exposed	2 / 16 (12.50%)	0 / 19 (0.00%)	2 / 35 (5.71%)
occurrences all number	2	0	2
Rhinitis
subjects affected / exposed	2 / 16 (12.50%)	0 / 19 (0.00%)	2 / 35 (5.71%)
occurrences all number	2	0	2
Skin infection
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Adenovirus infection
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	2	2
Bacterial disease carrier
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	4	4
Bacterial sepsis
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	2	0	2
Bronchitis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
COVID-19
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Clostridium difficile infection
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	2	2
Cytomegalovirus viraemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Enterocolitis viral
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	2	0	2
Gastroenteritis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Gastroenteritis norovirus
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Influenza
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Lymph gland infection
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Norovirus infection
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Oral candidiasis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Pneumonia fungal
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Sepsis
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Sepsis neonatal
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Staphylococcal bacteraemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Systemic candida
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Upper respiratory tract infection
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Viral infection
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Viral upper respiratory tract infection
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	3	0	3
Metabolism and nutrition disorders
Hypokalaemia
subjects affected / exposed	3 / 16 (18.75%)	4 / 19 (21.05%)	7 / 35 (20.00%)
occurrences all number	3	6	9
Hypomagnesaemia
subjects affected / exposed	2 / 16 (12.50%)	2 / 19 (10.53%)	4 / 35 (11.43%)
occurrences all number	2	2	4
Hypervolaemia
subjects affected / exposed	1 / 16 (6.25%)	2 / 19 (10.53%)	3 / 35 (8.57%)
occurrences all number	1	3	4
Acidosis
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Decreased appetite
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Hypoglycaemia
subjects affected / exposed	0 / 16 (0.00%)	2 / 19 (10.53%)	2 / 35 (5.71%)
occurrences all number	0	2	2
Hyponatraemia
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Hypophosphataemia
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Malnutrition
subjects affected / exposed	1 / 16 (6.25%)	1 / 19 (5.26%)	2 / 35 (5.71%)
occurrences all number	1	1	2
Fluid retention
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	2	2
Hyperchloraemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	2	2
Hypercholesterolaemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Hyperglycaemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Hyperkalaemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	2	0	2
Hyperphosphataemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Hypertriglyceridaemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Hyperuricaemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Hypoalbuminaemia
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Hypophagia
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Hypovolaemia
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1
Iron overload
subjects affected / exposed	0 / 16 (0.00%)	1 / 19 (5.26%)	1 / 35 (2.86%)
occurrences all number	0	1	1
Metabolic acidosis
subjects affected / exposed	1 / 16 (6.25%)	0 / 19 (0.00%)	1 / 35 (2.86%)
occurrences all number	1	0	1

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Were there any global substantial amendments to the protocol? Yes

31 Mar 2020

There was 1 global protocol amendment (version 4.0, global, dated 31-Mar-2020). Full details of the changes introduced in that amendment are included in the uploaded PDF.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall Response at Week 8 or End of Treatment (if earlier)

Primary: Overall Response at Week 8 or End of Treatment (if earlier)

Secondary: Overall Survival

Secondary: Overall Survival

Secondary: Event-free Survival

Secondary: Event-free Survival

Secondary: Overall Response at Start of Conditioning

Secondary: Overall Response at Start of Conditioning

Secondary: Duration of Response

Secondary: Duration of Response

Secondary: Time to Response

Secondary: Time to Response

Secondary: Number of Patients Able to Reduce Glucocorticoids by 50% or More of the Baseline Dose During Emapalumab Treatment

Secondary: Number of Patients Able to Reduce Glucocorticoids by 50% or More of the Baseline Dose During Emapalumab Treatment

Secondary: Number of Patients Proceeding to HSCT

Secondary: Number of Patients Proceeding to HSCT

Secondary: Quality of Life Assessed Through PedsQL™, Pediatric Quality of Life Inventory™

Secondary: Quality of Life Assessed Through PedsQL™, Pediatric Quality of Life Inventory™

Secondary: Quality of Life Assessed Through Behavioral, Affective and Somatic Experiences Scales (BASES)

Secondary: Quality of Life Assessed Through Behavioral, Affective and Somatic Experiences Scales (BASES)

Secondary: Incidence, Severity, Causality and Outcomes of AEs (serious and non-serious)

Secondary: Incidence, Severity, Causality and Outcomes of AEs (serious and non-serious)

Secondary: Evolution of Laboratory Parameters

Secondary: Evolution of Laboratory Parameters

Secondary: Number of Patients who Discontinued Emapalumab Treatment

Secondary: Number of Patients who Discontinued Emapalumab Treatment

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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