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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

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    Trial identification
    Sponsor protocol code
    NI-0501-09
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01818492
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    US IND number: 111015
    Sponsors
    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
    Paediatric regulatory details
    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?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    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?
    No
    General information about the trial
    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
    Population of trial subjects
    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
    35
    EEA total number of subjects
    17
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    5
    Infants and toddlers (28 days-23 months)
    22
    Children (2-11 years)
    6
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    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.

    Pre-assignment
    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
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    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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    Baseline characteristics reporting groups
    Reporting group title
    All patients (emapalumab)
    Reporting group 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).

    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 sets

    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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    End points reporting groups
    Reporting group title
    All patients (emapalumab)
    Reporting group 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).

    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.

    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)
    Statistical analysis title
    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
    70
    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.
    Statistical analysis title
    Exact binomial test - treatment-naïve
    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 16, as the comparison was within a single group.
    Comparison groups
    Baseline v All-treated analysis set - treatment naïve
    Number of subjects included in analysis
    51
    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.
    Statistical analysis title
    Exact binomial test - treatment-experienced
    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 19, as the comparison was within a single group.
    Comparison groups
    Baseline v All-treated analysis set - treatment experienced
    Number of subjects included in analysis
    54
    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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    Adverse events information
    Timeframe for reporting adverse events
    Signing of ICF until end of follow-up period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.1
    Reporting groups
    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

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    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.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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