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    Summary
    EudraCT Number:2021-000407-20
    Sponsor's Protocol Code Number:APHP201454
    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:2021-07-23
    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 number2021-000407-20
    A.3Full title of the trial
    Treatment of nonsevere sporadic Hemophagocytosis Lymphohistiocytosis (HLHs) with ITACITINIB: a phase II prospective trial.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Treatment of nonsevere sporadic Hemophagocytosis Lymphohistiocytosis (HLHs) with ITACITINIB: a phase II prospective trial.
    A.3.2Name or abbreviated title of the trial where available
    HLH-JAK
    A.4.1Sponsor's protocol code numberAPHP201454
    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 DE PARIS
    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 supportINCYTE BIOSCIENCES INTERNATIONAL SARL Company,
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationASSISTANCE PUBLIQUE HOPITAUX DE PARIS
    B.5.2Functional name of contact pointProject Manager
    B.5.3 Address:
    B.5.3.1Street AddressDRCI hôpital St louis, 1 avenue claude vellefaux
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number+330140275724
    B.5.6E-mailisabelle.vivaldo@aphp.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    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.2.5The 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.3.1Product nameItacitinib
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNITACITINIB
    D.3.9.2Current sponsor codeITACITINIB
    D.3.9.4EV Substance CodeSUB183665
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    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
    Adults patients having non severe sporadic Hemophagocytosis Lymphohistiocytosis
    E.1.1.1Medical condition in easily understood language
    Adults patients having non severe sporadic Hemophagocytosis Lymphohistiocytosis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Overall response rate (RR) achievement of either a Complete (CR) or a Partial response (PR) at day 15 of ITACITINIB treatment on clinical and biological symptoms of primitive/refractory/relapses in non-severe adults HLHs:
    • Primitive: HLH with no previous treatment or nor flare
    • Refractory: persistent HLH despite corticoid treatment
    • Relapse: new HLH flare despite or not continuous treatment
    E.2.2Secondary objectives of the trial
    1- Response rate of ITACITINIB treatment at D8 and D30 on clinical and biological symptoms of primitive/refractory/relapse adults HLHs without severity criteria
    2- Efficacy at the day of etiologic treatment if they received at least 7 days of treatment (ITACITINIB taken until J15)
    3- Toxicity of ITACITINIB
    4- Rescue therapy
    5- Reduction of plasma cytokines level between D0 and D15 and correlation to the therapeutic response to D15
    6- Clinical, biological, associated diseases characteristics of patients having CR, PR, No Response.
    7- Overall survival at 3 months
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    IFN gamma, Il-6, Il-1, IP-10, IP-9, TNF-alpha levels in patient’s plasma at day 0, 8, 15, 30 days of treatment by ITACITINIB.
    E.3Principal inclusion criteria
    1. Patients age >= 18 years, with front line or recurrent sporadic HLH, without or awaiting diagnosis of associated pathologies that may benefit from specific treatment, without severity criteria, without organ failure
    2. Inclusion criteria were adapted from the revised Diagnostic Guidelines for Hemophagocytic lymphohistiocytosis. Are request to be included:
    1 major and 2 minors criteria including hyperferritinemia or/and hypertriglyceridemia
    or
    3 minors criteria including hyper ferritinemia or/and hypertriglyceridemia
    Major criteria:
    a. Cytological features of hemophagocytosis
    b. Fever
    c. Splenomegaly
    Minor criteria:
    d. Adenopathies
    e. Cytopenia> 2 lineages:
    Haemoglobin < 9 g/dl,
    Platelets < 100 000/mm3
    Neutrophils < 1000/mm3
    f. Hypertriglyceridemia > 3 mmol/l and/or hypofibrigenemia < 1.5 g/l
    g. Ferritin>500 ng/l

    3. Patient is willing to provide written informed consent prior to enrolment and agrees to follow the protocol
    4. Patient known to have systemic juvenile idiopathic arthritis are classified as having HLH if they met the following criteria
    Ferritin >684 ng/mL
    And any 2 of the following:
    Platelet count < 181 000/mm3
    ASAT > 48 UI/ml
    Triglyceride > 4 mmol/L
    Fibrinogen 3.6 g/L

    5. Be willing to avoid pregnancy or fathering children based on 1 of the following criteria:
    a. Women of non-childbearing potential (ie, surgically sterile with a hysterectomy and/or
    bilateral oophorectomy OR ≥ 12 months of amenorrhea).
    b. Women of childbearing potential who has a negative serum pregnancy test at
    screening and who agrees to take appropriate precautions to avoid pregnancy (with at
    least 99% certainty) from screening through safety follow-up. Permitted methods that
    are at least 99% effective in preventing pregnancy (see Appendix 4) should be
    communicated to the subject and their understanding confirmed.
    c. Man who agrees to take appropriate precautions to avoid fathering children (with at
    least 99% certainty) from screening through safety follow-up. Permitted methods that
    are at least 99% effective in preventing pregnancy (see Appendix 4) should be
    communicated to the subject and their understanding confirmed.
    6. Be either affiliated to, or a beneficiary of, a social security category


    E.4Principal exclusion criteria
    1. Organ failure: Confusion, organic kidney failure KADIGO 2liver failure (Factor V < 50%), heart failure, respiratory failure.

    2. Fibrinogenemia < 0.5 g/dl or platelets < 20G/L

    3. Indication to intensive care unit transfer on an organ failure requiring assistance (dialysis, Ventilation (assisted or VNI), shock regardless of the origin

    4. Participation in another interventional study involving human

    5. Breastfeeding women
    6. Women with a positive pregnancy test or not willing to take contraceptive measures
    7. Known allergies, hypersensitivity, or intolerance to any of the ITACITINIB or excipients, or similar compounds
    8. Current or history of recurrent infections, including HBV, HCV

    9. Participants with active HBV or HCV infection that requires treatment or who are at risk for HBV reactivation (ie Positive HBs Ag serology)

    10. Candidates positive for HCV antibody and positive PCR RNA HCV
    11. HIV infection with positive viral charge
    12. Protected adults (including individual under guardianship by court order)
    E.5 End points
    E.5.1Primary end point(s)
    Overall Response Rate: achievement of either a Complete (CR) or a Partial Response (PR) to ITACITINIB treatment for HLHs in adults without any sign of severity at D15 of treatment evaluated at D15 of treatment on the major and minor diagnostic criteria of HLH.

    Major diagnostic criteria:
    - Fever
    - Organomegaly (not related to etiology)

    Minor diagnostic criteria:
    - Cytopenias: hemoglobin, platelets, neutrophils
    - Hypertriglyceridemia
    - Hypofibrinogenemia
    - Ferritin

    • COMPLETE RESPONSE is defined at D15 of treatment, by:
    No HLH progression: none of those criteria, 1 to 7
    1- No decrease of Hb level>2 gr/dL if <10 gr/dL
    2- No decrease of Pq<25000 if <100 000/mm3.
    3- No decrease of PNN > 50% if PNN <1000/mm3.
    4- No decrease of more than 1 gr/l if fibrinogen<2.5 gr/l
    5- No increase of ferritinemia more than 25% of basal value
    6- No worsening of fever more than 1 degree Celsius
    7- No severity criteria

    • PARTIAL RESPONSE is defined at D15 of treatment by: no Complete Response and no Progression and no gravity criteria

    • PROGRESSION is defined at day 15 of treatment by presence of at least one severity criteria:

    1- Presence of 6/6 of the following criteria:

    1- Decrease of Hb level>2 gr/dL if <10 gr/dL
    2- Decrease of Pq<25000 if <100 000/mm3
    3- Decrease of PNN > 50% if PNN <1000/mm3
    4- Decrease of more than 1 gr/l if fibrinogen<2.5 gr/l
    5- Increase of ferritinemia more than 25% of basal value
    6- Worsening of fever more than 1 degree Celsius


    2- Organ failure (at least one of those criteria): confusion, organic kidney failure (< 60 ml/min), liver failure (Factor V < 50%), heart failure, respiratory failure, fibrinogen < 0.5 g/l, platelets < 20G/L

    3- Indication to intensive care unit transfer or an organ failure requiring assistance (dialysis, Ventilation (assisted or NIV), shock regardless of the origin)

    4- HLH specific treatment: VP 16, cyclosporine, biotherapies(s)

    In this case, ITACITINIB will be stopped and patient will be considered in failure.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 15
    E.5.2Secondary end point(s)
    1. Response rate at D8, and D30 of treatment.
    2. Response rate to ITACITINIB treatment for HLHs in adults without any sign of severity at the day of etiologic treatment if patients have been treated by ITACITINIB at least during seven days. Response to ITACITINIB is evaluated at the day of etiologic treatment on the major and minor diagnostic criteria of HLHs
    3. Toxicity of ITACITINIB not related to evolution of HLHs (cytopenia, worsening of hepatic balance, secondary infections)
    4. Rescue therapy
    5. Range of decrease in plasma rate of IFN gamma IP-10, Il-1, Il-6, IL-10, TNF alfa between D0 and D15 of ITACITINIB treatment in each patient group: response and progression
    6. Clinical, biological, associated diseases and evolutions characteristics of patients in each response group
    7. Overall survival at 3 months
    E.5.2.1Timepoint(s) of evaluation of this end point
    Day 0, Day 8, Day 15, Day 30 and Day 90
    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 No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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 No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned13
    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 Yes
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months9
    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 No
    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) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 13
    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 state63
    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 Decision2021-09-22
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-09-17
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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