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    Clinical Trial Results:
    A pilot, open-label, single arm, multicenter study to evaluate safety, tolerability, pharmacokinetics and efficacy of intravenous administrations of emapalumab, an anti-interferon gamma (anti-IFNγ) monoclonal antibody, in patients with systemic Juvenile Idiopathic Arthritis (sJIA) or Adult-onset Still’s Disease (AOSD) developing Macrophage Activation Syndrome/secondary HLH (MAS/sHLH)

    Summary
    EudraCT number
    		 2016-004223-23
    Trial protocol
    		 IT   FR   GB   ES   NL  
    Global end of trial date
    19 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Dec 2021
    First version publication date
    23 Dec 2021
    Other versions
    Summary report(s)
    		 Long-term follow-up additional information

    Trial information

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    Trial identification
    Sponsor protocol code
    NI-0501-06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03311854
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Swedish Orphan Biovitrum AG
    Sponsor organisation address
    Messeplatz 10, Basel, Switzerland, 4058
    Public contact
    Veronica Asnaghi, MD, Swedish Orphan Biovitrum AG, 41 61 508 72 13, veronica.asnaghi@sobi.com
    Scientific contact
    Veronica Asnaghi, MD, Swedish Orphan Biovitrum AG, 41 61 508 72 13, veronica.asnaghi@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 Jul 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    19 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To describe the pharmacokinetic profile of emapalumab • To confirm the proposed dosing regimen of emapalumab • To evaluate the safety and tolerability profile of intravenous administrations of emapalumab • To assess the efficacy of emapalumab • To assess the levels of relevant pharmacodynamic markers • To assess other potential disease markers • To assess the immunogenicity of emapalumab
    Protection of trial subjects
    Written informed consent/assent was obtained from all subjects or their parents/legal guardian prior to enrolment into the study, as dictated by the Declaration of Helsinki. Of note, one subject (aged 14 years at study entry) was unable to provide assent because their clinical condition required admission to the intensive care unit; in this case, the parents provided informed consent before enrolment in the study, and assent from the subject was acquired retrospectively.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Feb 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research, Safety
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    14
    EEA total number of subjects
    9
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    8
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 16 subjects were screened for this study. Fourteen subjects were enrolled and all completed the study; no subject was withdrawn from the study after the start of treatment with emapalumab.

    Pre-assignment
    Screening details
    		 The study population could comprise subjects of both genders with MAS in confirmed sJIA/adult-onset Still’s disease (AOSD) or high presumption of sJIA and having shown an inadequate response to high dose intravenous (i.v.) glucocorticoid treatment.

    Period 1
    Period 1 title
    Treatment period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study; no blinding occurred. Note regarding baseline period: Data for the baseline demographic characteristics were obtained prior to the start of the treatment period.

    Arms
    Arm title
    		 All treated population
    Arm description
    		 The all treated population included all subjects who received any part of an infusion of emapalumab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Emapalumab
    Investigational medicinal product code
    Other name
    NI-0501
    Pharmaceutical forms
    Concentrate for dispersion for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Emapalumab was administered at an initial dose of 6 mg/kg by intravenous infusion. Emapalumab treatment continued at a dose of 3 mg/kg, every 3 days until study day 15, and then twice-a-week for an additional 2 weeks, i.e., until study day 28. The emapalumab regimen could be adapted (the frequency between infusions shortened, the dose increased, or the treatment prolonged beyond 4 weeks) upon assessment of a favourable benefit-risk profile. The treatment period was followed by a 4-week off-drug follow-up period (up to at least Week 8).

    Number of subjects in period 1
    		All treated population
    Started
    14
    Completed
    14
    Period 2
    Period 2 title
    Follow-up period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study; no blinding occurred.

    Arms
    Arm title
    		 All treated population
    Arm description
    		 The all treated population included all subjects who received any part of an infusion of emapalumab.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		All treated population
    Started
    14
    Completed
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    		 All subjects who received any part of an infusion of emapalumab. Note that data for the baseline demographic characteristics were obtained prior to the start of the treatment period.

    Reporting group values
    		 Treatment period Total
    Number of subjects
    		 14 14
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 8 8
        Adolescents (12-17 years)
    		 5 5
        Adults (18-64 years)
    		 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 9.9 ( 6.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 4 4
    Race
    Units: Subjects
        Black or African American
    		 2 2
        White
    		 11 11
        Unknown or not reported
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    All treated population
    Reporting group description
    		 The all treated population included all subjects who received any part of an infusion of emapalumab.
    Reporting group title
    All treated population
    Reporting group description
    		 The all treated population included all subjects who received any part of an infusion of emapalumab.

    Subject analysis set title
    All treated population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The all treated population included all subjects who received any part of an infusion of emapalumab.

    Subject analysis set title
    All treated population: Study Day 0 (pre-dose)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Levels measured pre-dose on Study Day 0 in subjects. Study Day 0 corresponds to the first treatment date.

    Subject analysis set title
    All treated population: 4-week Follow-up Visit/EoS
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Levels measured at the 4-week follow-up visit/EoS in subjects.

    Primary: 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) [1]
    End point description
    End point type
    Primary
    End point timeframe
    Up to end of study
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All endpoint variables in the study are analyzed descriptively considering the nature of this pilot study.
    End point values
    		 All treated population
    Number of subjects analysed
    14
    Units: Subjects
        Subjects with a TEAE
    13
        Subjects with a serious TEAE
    6
        Subjects with a severe TEAE
    2
        Subjects with a moderate TEAE
    10
        Subjects with a mild TEAE
    13
        Subjects with a TEAE related to emapalumab
    4
        Subjects with a TEAE unrelated to emapalumab
    13
        Subjects with a recovered/resolved TEAE
    13
        Subjects with a not recovered or resolved TEAE
    3
        Subjects with a recovering/resolving TEAE
    1
        Subjects with a TEAE with an unknown outcome
    1
    No statistical analyses for this end point

    Primary: Evolution of Laboratory Parameters

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    End point title
    		 Evolution of Laboratory Parameters [2]
    End point description
    Shifts from baseline in the following MAS-relevant laboratory parameters are reported: • Leukocytes • Platelets • Lactate dehydrogenase (LDH) • Alanine aminotransferase (ALT) • Aspartate aminotransferase (AST) • Ferritin • C-reactive protein (CRP) • Activated partial thromboplastin time (aPTT) • Prothrombin time (PT) • D-dimer • Fibrinogen Laboratory parameters are described as: • Low, within the reference range, or high at baseline • Low, within the reference range, or high at 4th Week Follow-Up/EOS In the categories below, the first description given is the level at baseline; the second is the level at 4th Week Follow-Up/EOS (i.e., shift from baseline to 4th Week Follow-Up/EOS).
    End point type
    Primary
    End point timeframe
    Up to 4th Week Follow-Up/EOS
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All endpoint variables in the study are analyzed descriptively considering the nature of this pilot study.
    End point values
    		 All treated population
    Number of subjects analysed
    14
    Units: Subjects
        Leukocytes: high to within
    2
        Leukocytes: low to within
    4
        Leukocytes: low to high
    2
        Platelets: high to within
    1
        Platelets: low to within
    6
        Platelets: low to high
    3
        LDH: high to within
    6
        ALT: high to within
    10
        ALT: high to low
    1
        AST: high to within
    11
        Ferritin: high to within
    11
        Ferritin: high to low
    2
        CRP: high to within
    9
        aPTT: high to within
    1
        aPTT: high to low
    1
        aPTT: within to low
    3
        aPTT: low to within
    1
        aPTT: low to high
    1
        PT: high to within
    5
        PT: high to low
    1
        PT: within to low
    3
        PT: low to within
    1
        D-dimer: high to within
    8
        Fibrinogen: high to within
    1
        Fibrinogen: within to high
    1
        Fibrinogen: low to within
    5
        Fibrinogen: low to high
    1
    No statistical analyses for this end point

    Primary: Number of Subjects Withdrawn Due to Safety Reasons

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    End point title
    		 Number of Subjects Withdrawn Due to Safety Reasons [3]
    End point description
    End point type
    Primary
    End point timeframe
    Up to end of study
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All endpoint variables in the study are analyzed descriptively considering the nature of this pilot study.
    End point values
    		 All treated population
    Number of subjects analysed
    14
    Units: Subjects
    0
    No statistical analyses for this end point

    Primary: Number of Subjects Achieving MAS Remission at Week 8 After Initiation of Emapalumab Treatment

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    End point title
    		 Number of Subjects Achieving MAS Remission at Week 8 After Initiation of Emapalumab Treatment [4]
    End point description
    Remission from MAS was evaluated according to the following criteria: Resolution of clinical signs and symptoms according to the investigator (MAS clinical signs and symptoms activity score ≤ 1) and Normalization of laboratory parameters relevant to MAS, as follows: • WBC count and platelet count above the LLN. • LDH below 1.5 × the ULN. • ALT and AST both below 1.5 × the ULN. • Fibrinogen higher than 100 mg/dL. • Ferritin levels decreased by at least 80 % from values at screening or baseline (whichever was higher) or below 2000 ng/mL, whichever was lower. Out of the 14 patients in the all treated population, 11 patients (78.6%) met the MAS remission criteria at Week 8 (95% CI: 49.2 to 95.3%).
    End point type
    Primary
    End point timeframe
    Up to Week 8
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All endpoint variables in the study are analyzed descriptively considering the nature of this pilot study.
    End point values
    		 All treated population
    Number of subjects analysed
    14
    Units: Subjects
    11
    No statistical analyses for this end point

    Primary: Time to First MAS Remission

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    End point title
    		 Time to First MAS Remission [5]
    End point description
    Time to the first MAS remission is calculated from the date of first emapalumab infusion until the date of first MAS remission.
    End point type
    Primary
    End point timeframe
    Up to end of study
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All endpoint variables in the study are analyzed descriptively considering the nature of this pilot study.
    End point values
    		 All treated population
    Number of subjects analysed
    14
    Units: Days
        median (confidence interval 95%)
    25 (19 to 56)
    No statistical analyses for this end point

    Primary: Number of Subjects for Whom Glucocorticoids Could be Permanently Tapered at Any Time During the Study

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    End point title
    		 Number of Subjects for Whom Glucocorticoids Could be Permanently Tapered at Any Time During the Study [6]
    End point description
    Permanently tapering by at least 50% of the equivalent dose of prednisone. This was defined as achieving reduction of 50% of the baseline dose [SD0] and maintaining the reduction until the end of study. A total of 12 patients (85.7%) permanently tapered glucocorticoids at any time during the study (95% CI: 57.2 to 98.2%).
    End point type
    Primary
    End point timeframe
    Up to end of study
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All endpoint variables in the study are analyzed descriptively considering the nature of this pilot study.
    End point values
    		 All treated population
    Number of subjects analysed
    14
    Units: Subjects
    12
    No statistical analyses for this end point

    Primary: Time to Achievement of Permanent Glucocorticoids Tapering

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    End point title
    		 Time to Achievement of Permanent Glucocorticoids Tapering [7]
    End point description
    Time to first achievement of permanent glucocorticoid tapering by at least 50% of the equivalent dose of prednisone administered at emapalumab treatment start (SD0).
    End point type
    Primary
    End point timeframe
    Up to end of study
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All endpoint variables in the study are analyzed descriptively considering the nature of this pilot study.
    End point values
    		 All treated population
    Number of subjects analysed
    14
    Units: Days
        median (confidence interval 95%)
    14.5 (4 to 28)
    No statistical analyses for this end point

    Primary: Survival at End of Study

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    End point title
    		 Survival at End of Study [8]
    End point description
    Number of subjects alive at the end of the study
    End point type
    Primary
    End point timeframe
    Up to end of study
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All endpoint variables in the study are analyzed descriptively considering the nature of this pilot study.
    End point values
    		 All treated population
    Number of subjects analysed
    14
    Units: Subjects
    14
    No statistical analyses for this end point

    Primary: Number of Subjects Withdrawn From the Study Due to Lack of Efficacy

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    End point title
    		 Number of Subjects Withdrawn From the Study Due to Lack of Efficacy [9]
    End point description
    End point type
    Primary
    End point timeframe
    Up to end of study
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All endpoint variables in the study are analyzed descriptively considering the nature of this pilot study.
    End point values
    		 All treated population
    Number of subjects analysed
    14
    Units: Subjects
    0
    No statistical analyses for this end point

    Primary: Levels of Emapalumab Concentration

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    End point title
    		 Levels of Emapalumab Concentration [10]
    End point description
    Levels of emapalumab concentration are provided for the following time points: • Study Day 0 (pre-dose) • Study Day 0 (post-dose) • Week 4 Visit 2 (pre-dose) • Week 4 visit 2 (post-dose) • 4-week follow-up visit/EoS Note: Emapalumab concentrations were below the detection limit for all subjects at SD0, except for one subject in whom the emapalumab concentration (pre-dose) was 62108.4 μg/L. It should be noted that on SD1, the measurement results of emapalumab were below the detection limit for that subject; it could not be ruled out that the samples from SD0 and SD1 for this subject were interchanged.
    End point type
    Primary
    End point timeframe
    Up to Week 8
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All endpoint variables in the study are analyzed descriptively considering the nature of this pilot study.
    End point values
    		 All treated population
    Number of subjects analysed
    14 [11]
    Units: ug/L
    arithmetic mean (standard deviation)
        Study Day 0 (pre-dose)
    5455.444 ( 19985.0660 )
        Study Day 0 (post-dose)
    104740.254 ( 20994.1054 )
        Week 4 Visit 2 (pre-dose)
    115472.076 ( 58676.7953 )
        Week 4 Visit 2 (post-dose)
    212900.657 ( 87466.3031 )
        4-week follow-up Visit/EoS
    46447.462 ( 33657.0174 )
    Notes
    [11] - Note: the Week 4 Visit 2 (post-dose) emapalumab concentration levels were based on 7 subjects.
    No statistical analyses for this end point

    Primary: Pharmacodynamic Parameters

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    End point title
    		 Pharmacodynamic Parameters [12]
    End point description
    Levels of total interferon-gamma (free interferon-gamma and interferon-gamma bound to emapalumab), CXCL9 and CXCL10
    End point type
    Primary
    End point timeframe
    Up to Week 8
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All endpoint variables in the study are analyzed descriptively considering the nature of this pilot study.
    End point values
    		 All treated population: Study Day 0 (pre-dose) All treated population: 4-week Follow-up Visit/EoS
    Number of subjects analysed
    14
    14
    Units: ng/L
    arithmetic mean (standard deviation)
        Total interferon-gamma
    425.528 ( 1191.8391 )
    2132.656 ( 2967.4920 )
        CXCL9
    21986.010 ( 29405.8787 )
    255.654 ( 596.4149 )
        CXCL10
    7935.418 ( 9115.2857 )
    639.102 ( 1058.9589 )
    No statistical analyses for this end point

    Primary: Number of Subjects Who Demonstrated a Presence of Circulating Antibodies Against Emapalumab to Determine Immunogenicity

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    End point title
    		 Number of Subjects Who Demonstrated a Presence of Circulating Antibodies Against Emapalumab to Determine Immunogenicity [13]
    End point description
    The presence of circulating antibodies against emapalumab was inferred by positive results for anti-drug antibodies (ADAs).
    End point type
    Primary
    End point timeframe
    Up to end of study
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: All endpoint variables in the study are analyzed descriptively considering the nature of this pilot study.
    End point values
    		 All treated population
    Number of subjects analysed
    14
    Units: Subjects
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All TEAEs reported by the subjects or their relatives or observed by the Investigator or their staff during the clinical study from the first emapalumab administration up to and including the end-of-study visit were recorded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    All treated population
    Reporting group description
    		 The all treated population included all subjects who received any part of an infusion of emapalumab.

    Serious adverse events
    		 All treated population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 14 (42.86%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intracardiac thrombus
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Juvenile myoclonic epilepsy
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Pneumatosis intestinalis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Still's disease
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All treated population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 14 (92.86%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    General disorders and administration site conditions
    Catheter site thrombosis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Chest pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Condition aggravated
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Injection site reaction
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Pyrexia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    4
    Secretion discharge
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Dyspnoea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    3
    Pharyngeal erythema
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Pleural effusion
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Tachypnoea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Confusional state
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Investigations
    Adenovirus test positive
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    BK polyomavirus test positive
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Body temperature increased
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Respirovirus test positive
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Infusion related reaction
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Tachycardia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Nervous system disorders
    Axonal neuropathy
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    4
    Lethargy
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Seizure
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Tympanic membrane hyperaemia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Eye disorders
    Eye oedema
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Eye pruritus
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Hepatic steatosis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acanthosis nigricans
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Dermatitis diaper
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Rash erythematous
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Rash pruritic
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Skin ulcer
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Tenosynovitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Viral infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Hyperkalaemia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jan 2020
    Protocol V2.0: • The sponsor changed from Novimmune to Swedish Orphan Biovitrum AG (Sobi AG). • The protocol was updated to reflect NI-0501 being assigned the international nonproprietary name “emapalumab”. • The amendment allowed the inclusion of MAS patients with AOSD and description of Yamaguchi disease criteria added in Appendix E. • The study, running according to twin protocols in North America and Europe, was updated to enroll approximately 12 patients across these areas, with a minimum of 10 patients diagnosed with sJIA. • The maximum patient age was removed. • An objective list of clinical symptoms for response evaluation was implemented, in addition to laboratory parameters. • It was added that emapalumab treatment could be initiated upon discontinuation of tocilizumab, canakinumab, and TNF inhibitors. • Continuation of anakinra was allowed if started at least 3 days before initiation of emapalumab, and methotrexate was permitted to be continued if ongoing as treatment for the underlying disease. Introduction of concomitant medication during the study was updated and specified. • Additional modifications were implemented to ensure clearer instructions were provided to the investigators (e.g., for AE reporting) and to correct obvious mistakes.

    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
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