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    Summary
    EudraCT Number:2012-003632-23
    Sponsor's Protocol Code Number:NI-0501-04
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-12-17
    Trial results View 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 ConcernedCzechia - SUKL
    A.2EudraCT number2012-003632-23
    A.3Full title of the trial
    A Pilot, Open-label, Single Arm, Multicentre Study to Explore Safety, Tolerability, Pharmacokinetics and Efficacy of Intravenous Multiple Administrations of NI-0501, an Anti-interferon Gamma (Anti-IFNγ) Monoclonal Antibody, in Paediatric Patients with Primary Haemophagocytic Lymphohistiocytosis in whom the disease has reactivated or an unsatisfactory response has been achieved
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the safety and efficacy of a new drug, NI-0501, in children with a disease that is called "reactivated Primary Haemophagocytic Lymphohistiocytosis".
    A.4.1Sponsor's protocol code numberNI-0501-04
    A.5.4Other Identifiers
    Name:US INDNumber:111015
    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 SponsorNovImmune SA
    B.1.3.4CountrySwitzerland
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNovImmune SA
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovImmune SA
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street Address14 Chemin des Aulx
    B.5.3.2Town/ cityPlan-les-Ouates
    B.5.3.3Post code1228
    B.5.3.4CountrySwitzerland
    B.5.5Fax number0041228397142
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/10/749
    D.3 Description of the IMP
    D.3.1Product nameNI-0501
    D.3.2Product code NI-0501
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN/A
    D.3.9.2Current sponsor codeNI-0501
    D.3.9.3Other descriptive nameHuman anti-interferon gamma monoclonal antibody
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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) Yes
    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
    Primary haemophagocytic lymphohistiocytosis which has reactivated or has not achieved a satisfactory response.
    E.1.1.1Medical condition in easily understood language
    A rare, life-threatening condition affecting predominantly children. The disease is characterized by uncontrolled hyper-inflammation on the basis of underlying immune deficiencies.
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level SOC
    E.1.2Classification code 10010331
    E.1.2Term Congenital, familial and genetic disorders
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To determine the preliminary safety and tolerability profile of multiple IV administrations of NI-0501
    • To determine a preliminary efficacy and benefit/risk profile of NI-0501 in HLH patients
    • To describe the pharmacokinetic (PK) profile of NI-0501 in HLH patients
    • To define an appropriate NI-0501 therapeutic dose regimen for HLH
    • To assess the immunogenicity of NI-0501
    E.2.2Secondary objectives of the trial
    Not applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Primary HLH patients of both genders, up to and including 18 years at diagnosis, who have been previously treated by conventional therapy, and who present a reactivation of the disease.
    2. Patients must also:
    - Present reactivation or Worsening, or No Further Improvement of the disease (for at least 4 weeks from initiation of treatment) after having achieved at least Partial or Incomplete Response (see definitions in Table 1)
    OR
    b. Show No Response for at least 2 weeks from initiation of treatment or Worsening of the disease (see definitions in Table 1)
    OR
    c. Show Intolerance to conventional treatment of HLH, as judged by the treating physician

    3. Diagnosis of primary HLH according to the following criteria (as per the HLH-2004 protocol):
    a. A molecular diagnosis or familial history consistent with primary HLH,
    or
    b. Five out of the eight criteria below are fulfilled:
    - Fever
    - Splenomegaly
    - Cytopenias affecting 2 of 3 lineages in the peripheral blood (haemoglobin < 90 g/L; platelet < 100 x 109/L; neutrophils < 1 x 109/L)
    - Hypertriglyceridemia (fasting triglycerides ≥ 3 mmol/L or ≥ 265 mg/dL) and/or hypofibrinogenemia (≤ 1.5 g/L)
    - Haemophagocytosis in bone marrow, spleen or lymph nodes with no evidence of malignancy
    - Low or absent natural killer (NK)-cell activity
    - Ferritin ≥ 500 mg/L
    - Soluble CD25 (sCD25; i.e. soluble IL-2 receptor) ≥ 2400 U/mL.
    In case the diagnosis of HLH is based on the 5 of the 8 above criteria (and not on a molecular finding or a familial history consistent with primary HLH), the patient is eligible to enter the study if there is
    a. Reactivation, or Worsening, or No Further Improvement (for at least 4 weeks from initiation of treatment) of the disease after having achieved at least Partial or Incomplete Response (see definitions in Table 1). In this specific situation, Worsening and No Further Improvement must include abnormal sCD25 or ferritin > 2000 ng/ml
    OR
    a.b. No Response (for at least 2 weeks from initiation of treatment) or Worsening of the disease (without previous Partial or Incomplete Response). Soluble CD25 must be abnormal or ferritin > 2000 ng/ml and the evaluation and approval by the Scientific Steering Committee is mandatory (see definitions in Table 1)
    OR
    b.c. Intolerance to conventional treatment of HLH, as judged by the treating physician and approval by the Scientific Steering Committee is mandatory

    4. Patients must have received treatment for HLH according to the conventional therapy at the site (e.g. corticosteroids alone or in combination with etoposide, cyclosporin, methotrexate etc.). At the time of enrollment, eligible patients might still be receiving treatment (induction or maintenance) or might have already discontinued it.

    5. Informed consent signed by the patient (if ≥ 18 years old), or by the patient’s legal representative(s) with the assent of patients who are legally capable of providing it.

    6. Having received guidance on contraception for both male and female patients sexually active and having reached puberty:

    Female of child-bearing potential, having a negative urine pregnancy test at screening, unless true abstinence is in line with the preferred and usual lifestyle of the patient, must agree to use adequate method(s) of birth control from screening until 6 months after receiving last dose of the study drug. Men with partners(s) of child-bearing potential must agree to take appropriate precautions to avoid fathering a child from screening until 6 months after receiving last dose of the study drug.
    E.4Principal exclusion criteria
    1. Diagnosis of secondary HLH consequent to a proven rheumatic or neoplastic disease.
    2. Body weight < 3 kg.
    3. Patients treated with:
    - any T-cell depleting agents (such as anti-thymocyte globulin [ATG], anti-CD52) during the previous 2 weeks prior to screening
    - anti-CD20, as part of EBV infection treatment, within the previous week prior to screening
    - any other biologic drug within 5 times their defined half-life period (a list of some of the most commonly used biologic half-lives will be included in the Study Specific Risk Management Plan).
    4. Isolated or multiple acute organ failure(s) (heart, lung or kidney) requiring aggressive therapy such as high doses of inotropic drugs, circulatory assistance, hemofiltration or haemodialysis, artificial ventilation.
    5. Active mycobacteria, Shigella, Campylobacter, Leishmania or Salmonella infections.
    6. Evidence of past or active tuberculosis.
    7. Positive serology for HIV antibodies, hepatitis B surface antigen or hepatitis C antibodies.
    8. History of malignancy.
    9. Patient who have another concomitant disease or malformation severely affecting the cardiovascular, pulmonary, liver or renal function.
    10. History of hypersensitivity or allergy to any components of the study regimen.
    11. Receipt of a live or attenuated live (including BCG) vaccine within the last 12 weeks before screening.
    12. Pregnant or lactating female patients.
    E.5 End points
    E.5.1Primary end point(s)
    • Safety parameters to be collected and assessed:
    - Incidence, severity, causality and outcomes of Adverse Events (serious and non-serious), with particular attention being paid to infections
    - Evolution of laboratory parameters such as complete blood cell count (CBC), with a focus on red cells (haemoglobin), neutrophils and platelets, liver tests, renal function tests and coagulation
    - Number of patients withdrawn for safety issues
    • Evolution of clinical signs (fever, splenomegaly, CNS symptoms) and laboratory parameters (CBC, fibrinogen, serum triglycerides, ferritin, soluble CD-25 levels), which characterize the disease, will be used to assess response and time to response. As this is a pilot study, all endpoints will be considered exploratory.
    - Number of patients showing partial or complete response by week 2, 4 or 8
    - Number of patients achieving non-active disease by week 8
    - Time to achievement of non-active disease state
    - Time to achievement of complete response
    - Time to achievement of partial response
    - Time to reactivation
    - Survival at week 8 and at the end of the follow-up period (week 12)
    - Number of patients achieving no response at any time
    - Number of patients showing reactivation at any time.
    E.5.1.1Timepoint(s) of evaluation of this end point
    See E.5.1.
    E.5.2Secondary end point(s)
    • Other parameters:
    - Blood concentration of NI-0501 to determine NI-0501 pharmacokinetics in patients
    - Determination of pharmacodynamic effects (levels of circulating IFNγ and of any other potential markers of disease activity or predictors of response)
    - Level (if any) of circulating antibodies against NI-0501 to determine immunogenicity (ADA).
    E.5.2.1Timepoint(s) of evaluation of this end point
    See E.5.2.
    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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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.8.2.4Number of treatment arms in the trial1
    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 No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Austria
    Czech Republic
    Germany
    Italy
    Spain
    Turkey
    United States
    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
    LVLS.
    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 months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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: 10
    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: 1
    F.1.1.4Infants and toddlers (28 days-23 months) Yes
    F.1.1.4.1Number of subjects for this age range: 1
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 3
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 4
    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 Yes
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Newborns, infants and toddlers
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state1
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 5
    F.4.2.2In the whole clinical trial 10
    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)
    After study end, a separate long term follow-up study will be initiated to allow long term safety surveillance, investigation of the impact of NI-0501 treatment on survival for all patients who will have received at least one dose of NI-0501 in the pilot study, and completion of the evaluation of NI-0501 PK profile.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Associazione Italiana di Ematologia e Oncologia Pediatrica
    G.4.3.4Network Country Italy
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2013-05-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-14
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-01-04
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