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    Summary
    EudraCT Number:2021-006878-23
    Sponsor's Protocol Code Number:APHP200023
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2022-01-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2021-006878-23
    A.3Full title of the trial
    Efficacy of Ruxolitinib as first line treatment in primary haemophagocytic lymphohistiocytosis (HLH) in children: a Phase 2, multicentre, non-comparative study
    R-HLH
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy of Ruxolitinib as first line treatment in primary haemophagocytic lymphohistiocytosis (HLH) in children:
    A.3.2Name or abbreviated title of the trial where available
    R-HLH
    A.4.1Sponsor's protocol code numberAPHP200023
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAssistance Publique Hopitaux Paris - APHP
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAPHP
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAPHP
    B.5.2Functional name of contact pointPROJECT MANAGER
    B.5.3 Address:
    B.5.3.1Street Address1 avenue Claude Vellefaux
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number33140245266
    B.5.5Fax number33144841701
    B.5.6E-mailcoralie.villeret@aphp.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP Role
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMP
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    • Patient with Haemophagocytic lymphohistiocytosis (HLH) or lymphohistiocytic syndrome
    E.1.1.1Medical condition in easily understood language
    • Patient with HLH syndrome
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To study the survival of patients until Haematopoietic Stem Cell Transplantation following the use of Ruxolitinib as first-line treatment associated to corticosteroids in primary HLH.
    E.2.2Secondary objectives of the trial
    1. Evaluation of the efficacy of Ruxolitinib through the rate of patients achieving a complete or partial response at Day 14, Day 28, Week 8 and at Day-1 of the conditioning for HSCT, and through the delay that is necessary to obtain a response.
    2. Estimation of the incidence and timing of HLH reactivation
    3. Evaluation of treatment tolerance and adverse effects
    4. Study of pharmacokinetics of Ruxolitinib and the link between the pharmacokinetic and treatment efficacy.
    5. Study of the cytokine profile and gene expression at different time points during treatment and the link to treatment efficacy.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Patient aged 0 to 22 years
    • Patient with HLH syndrome confirmed by at least one of the two criteria:
    1) Confirmed genetic diagnosis of a condition predisposing to primary HLH (see table 1 and table 2) or abnormal expression of perforin, MUNC13-4, SAP or XIAP in FACS and/or positive family history
    OR
    2) Presence of at least 5 of the 8 following HLH diagnostic criteria:
    o Fever
    o Splenomegaly
    o Cytopenia (affecting at least two cell lineages)
     Haemoglobin < 9 g/dl (<10 g/dL in neonates)
     Platelets < 100.000/µL
     Absolute neutrophil count (ANC) < 1.000/µL
    o Hypertriglyceridemia and/or hypofibrinogenemia
     Fasting triglycerides ≥ 3 mmol/l
     Fibrinogen <1.5 g/L
    o Haemophagocytosis found in a histological sample (without evidence of a malignant process or an underlying rhematic disorder)
    o Decreased or absent NK function
    o Ferritin ≥ 500 µg/l
    o Presence of activated T cells in the immune phenotyping as evidenced by expression of the activation marker DR (superior to the normal value of the laboratory) OR CD25 soluble (sIL-2 receptor) ≥ 2.400 U/mL.
    • For patients of childbearing age : using an effective method of contraception during the trial, and through to 90 days after EOS for male participants
    • and 30 days after EOS for female participants
    • Freely given, informed and written consent of legal representative of the participant or consent of the adult participant
    • Affiliation to Social Security
    E.4Principal exclusion criteria
    • Previous treatment with ATG, Alemtuzumab, Etoposide, JAK-inhibitors, rifampicin and/or anti-Interferon gamma antibodies. St. John’s Wort, or any other strong CYP3A4 inducers.
    • Previous treatment with corticosteroids and/or cyclosporine A for more than 14 days
    • Isolated CNS disease.
    • Contraindication to receive Ruxolitinib:
    o History of hypersensitivity to the active substance or to any of the excipients
    • Pregnant or lactating female patient
    • Contraindication to receive methylprednisolone or prednisolone
    o History of hypersensitivity to the active substance or to any of the excipients
    o Any infectious condition with the exception of infections, which are the trigger for lymphohistiocytic activation.
    • Patient with acute very severe renal impairment (Creatinine Clearance <15 mL/min/1.73m²) who are NOT receiving dialysis.
    • Patient with Grade 4 hepatic failure according to the CTCAE v5.0 of 27 November 2017 (Life-threatening consequences; moderate to severe encephalopathy; coma)
    • Past or know active tuberculosis
    • Known rheumatologic disorder.
    • Known active malignancy.
    • Patient who is taking another investigational agent or is enrolled in another treatment protocol.
    • Patient who cannot tolerate administration of drugs PO or through NG
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the survival until HSCT. All causes of death will be taken into account, whether or not related to the course of the disease.
    E.5.1.1Timepoint(s) of evaluation of this end point
    28 days
    E.5.2Secondary end point(s)
    1) Evaluation of the efficacy through the rate of patients achieving a complete or partial response at Day 14, Day 28, Week 8 and Day-1 of the conditioning for HSCT and through the delay that is necessary to obtain a response:
    The response will be evaluated in accordance with the following definitions.
    Importantly, the treating physician must determine that continued or new symptoms are related to active HLH and not due to infection or other causes.

    • Complete response (CR) is defined by the normalization of clinical and laboratory parameters, as measured by:
    o Resolution of fever
    o Resolution of splenomegaly or reduced and isolated splenomegaly
    o Improvement of cytopenias: absolute neutrophil count ≥ 500/µl AND platelets count ≥ 100.000/µl (unsupported by transfusions), in the absence of myelotoxic treatments or other non-HLH related reasons as judged by the treating physician
    o Normalization of serum fibrinogen level (fibrinogen ≥ 1.5 g/l)
    o Resolution of hyperferritinemia (ferritin level < 2000 μg/l)
    o Absence of activated T cells OR normalization of CD25 soluble (sIL-2 receptor) < 2400 U/ml
    o Normalization of CSF pleocytosis (WBC < 5/µl and absence of haemophagocytosis) AND decrease of CSF protein by ≥ 50%

    • Partial response (PR) is defined by an improvement without complete normalization of the clinical and biological parameters in comparison to the initial status of the patient at inclusion. Patient must meet at least 3 of the below mentioned criteria with no worsening of clinical aspects of disease (i.e. worsening CNS disease, new requirement for intensive care support such as mechanical ventilation, vasopressor support, renal replacement therapy), as determined by the treating physician:
    o Resolution of fever
    o Improvement of cytopenias: absolute neutrophil count ≥ 500/µl OR platelets count ≥ 50.000/µl (unsupported by transfusions), in the absence of myelotoxic treatments or other non-HLH related reasons as judged by the treating physician
    o Improvement of hyperferritinemia with a decrease of ferritin level from peak level by ≥ 30%
    o Normalization of serum fibrinogen level (fibrinogen ≥ 1.5 g/l)
    o Improvement of activated T cells level with a decrease of the percentage of activated T cells from peak level by ≥ 30% OR decrease of CD25 soluble (sIL-2 receptor) level with a decrease from peak level by ≥ 30%
    o Normalization of CSF pleocytosis (WBC < 5/µl and absence of haemophagocytosis) AND decrease of CSF protein from peak level by ≥ 50%

    • Non response (NR) is defined by a patient who meets ≤ 2 of the above criteria with no worsening of clinical aspects of disease (i.e. worsening CNS disease, new requirement for intensive care support such as mechanical ventilation, vasopressor support, renal replacement therapy), as determined by the treating physician.

    • Progressive Disease (PD) is defined by a patient who shows evidence of worsening as determined by the treating physician through the below criteria:
    o Worsening of patient’s clinical status, i.e. NEW need for intensive care including need for intubation (non-elective), renal replacement therapy, vasopressor support.
    o Increase of ferritin level from peak level by ≥ 30% AND ferritin ≥ 2000 μg/L
    o Increase of the percentage of activated T cells from peak level by ≥ 30% (and superior to the age-adjusted normal laboratory value) OR increase of CD25 soluble (sIL-2 receptor) from peak level by ≥ 30% AND sIL-2 receptor ≥ 2.400 U/ml
    o Worsening clinical CNS symptoms OR radiologic evidence of progressive CNS disease judged by the treating physician to be due to HLH OR worsening CSF pleocytosis with increasing CSF protein from peak level by ≥ 30% OR evidence of haemophagocytosis in the absence of an ongoing infection in the CSF.
    Note: Aberrant laboratory findings should be controlled on a second assessment at least one day apart EXCEPT CNS radiologic/laboratory findings in which a single abnormal value is sufficient to define progressive disease.
    E.5.2.1Timepoint(s) of evaluation of this end point
    28 days
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned9
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    - Inclusion period: 30 months
    - Participation period (treatment + follow-up):
    o For patient eligible for HSCT
    • Duration of treatment = D0 (start date of treatment) to D-1 of the conditioning regimen (median duration approximately 35 days)
    • Duration of post-transplantation follow-up = 6 months
    o For patient not eligible for HSCT:
    • Duration of treatment = 8 weeks
    • Duration of follow-up 6 months after the first Ruxolitinib administration
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 20
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) Yes
    F.1.1.3.1Number of subjects for this age range: 2
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 2
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 6
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 9
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 1
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    none
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-08-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-02-22
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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