E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
• Patient with Haemophagocytic lymphohistiocytosis (HLH) or lymphohistiocytic syndrome |
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E.1.1.1 | Medical condition in easily understood language |
• Patient with HLH syndrome |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main 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. |
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E.2.2 | Secondary 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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
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E.4 | Principal 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
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E.5 End points |
E.5.1 | Primary 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.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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- 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |