Clinical trial • Phase III • Haematology|Immunology
ETOPOSIDE for Hemophagocytic lymphohistiocytosis
Phase III trial of ETOPOSIDE for Hemophagocytic lymphohistiocytosis.
Overview
- Trial Therapeutic Area
- Haematology|Immunology
- Trial Disease
- Hemophagocytic lymphohistiocytosis
- Trial Stage
- Phase III
- Drug Modality
- Small molecule
Key dates
- Initial CTIS Submission Date
- 25-10-2024
- First CTIS Authorization Date
- 10-03-2025
Trial design
Randomised, two randomized strategies: an early strategy where etoposide is initiated within 12 hours after inclusion; a delayed (expectant) strategy where etoposide is initiated only in case of unfavorable evolution after 48 hours (use of rescue etoposide in the delayed arm is considered an event). no dose or schedule for the comparator beyond timing is specified in the ctis record.-controlled Phase III trial in France.
- Randomised
- Yes
- Comparator
- Two randomized strategies: an early strategy where etoposide is initiated within 12 hours after inclusion; a delayed (expectant) strategy where etoposide is initiated only in case of unfavorable evolution after 48 hours (use of rescue etoposide in the delayed arm is considered an event). No dose or schedule for the comparator beyond timing is specified in the CTIS record.
- Target Sample Size
- 130
- Trial Duration For Participant
- 60
Eligibility
Recruits 130 Only adult patients are eligible; minors are explicitly excluded. Patients under legal guardianship, tutelage, or curatorship are excluded. Informed consent is obtained from the adult patient. Subject information and informed consent forms exist for adult patients and for legal representatives (documents: L1_SIS and ICF_adult patient; L1_SIS and ICF_legal representative). The trial does not select a vulnerable population in the CTIS metadata (isVulnerablePopulationSelected: false)..
- Pregnancy Exclusion
- Pregnant or lactating woman
- Vulnerable Population
- Only adult patients are eligible; minors are explicitly excluded. Patients under legal guardianship, tutelage, or curatorship are excluded. Informed consent is obtained from the adult patient. Subject information and informed consent forms exist for adult patients and for legal representatives (documents: L1_SIS and ICF_adult patient; L1_SIS and ICF_legal representative). The trial does not select a vulnerable population in the CTIS metadata (isVulnerablePopulationSelected: false).
Inclusion criteria
- {"criterion_text":"- Adult patient\n- Confirmed diagnosis of HLH: • Presence of 5 or more Henter criteria (HLH-04) out of the 6 achievable in routine care (fever, splenomegaly, cytopenias affecting 2 or 3 blood lineages, hypertriglyceridemia or hypofibrinogenemia, hemophagocytosis in bone marrow, spleen or lymph nodes, hyperferritinemia) • Diagnosis of HLH established by the multidisciplinary team caring for the patient\n- First episode of HLH\n- Admission to intensive care unit\n- Presence of one or more organ failures • Circulatory: mBP < 65 mmHg with lactate > 2 mmol/L, or treatment with catecholamines • Respiratory: oxygen therapy > 6L/min or need for non-invasive ventilation, high-flow nasal cannula oxygen therapy, or invasive mechanical ventilation • Renal: stage 2 or higher according to KDIGO criteria, either creatinine 2-2.9 times baseline, or urine output < 0.5 mL/kg/h for 12 hours • Neurological: GCS ≤ 13"}
Exclusion criteria
- {"criterion_text":"- Moribund patient with refractory distributive shock: multi-organ failure requiring noradrenaline >2.5 μg/kg/min and imminent risk of death\n- Participation in another interventional research study\n- Inability to administer etoposide within 12 hours\n- Patient treated with etoposide prior to admission to the intensive care unit\n- Hypersensitivity to etoposide or any of its excipients\n- Patient not covered by social security\n- Patient under legal guardianship, tutelage, or curatorship\n- Minor patient\n- Pregnant or lactating woman\n- Recent vaccination with a live attenuated vaccine"}
Endpoints
Primary endpoints
- {"endpoint_text":"- The occurrence of an event defined as the onset or worsening of organ failures, evaluated using the modified Sequential Organ Failure Assessment (SOFA) score (excluding the hematologic component). An event will be defined as an increase of at least 1 point for at least two organ systems compared to Day 0. In the delayed arm, the use of rescue etoposide treatment or in case of secondary aggravation during follow-up will also be considered an event.","definition_or_measurement_approach":"Evaluated using the modified SOFA score excluding hematologic component; event = increase ≥1 point in at least two organ systems vs Day 0. In delayed arm, initiation of rescue etoposide or secondary aggravation during follow-up is also counted as an event."}
Secondary endpoints
- {"endpoint_text":"- Time to death after inclusion (with a maximum follow-up duration of 60 days)\n- Number of ventilator-free days between inclusion and Day 14\n- Number of catecholamine-free days between inclusion and Day 14\n- Proportion of patients receiving at least one session of renal replacement therapy between inclusion and Day 14\n- Length of stay in the intensive care unit\n- Length of hospital stay\n- Proportion of patients receiving a dose of etoposide\n- Cumulative dose of etoposide over the first 14 days, within the total study population and among those receiving at least one dose of treatment\n- Number of days between inclusion and initiation of etoposide treatment\n- Number of patients receiving another immunosuppressive treatment during the intensive care unit stay up to Day 14\n- Time from inclusion to normalization of fibrinogen (> 2 g/L), decrease in ferritin (< 2000 μg/L), and decrease in triglycerides (< 1.5 mg/dL) during the intensive care unit stay up to Day 14\n- HScore at Days 2, 7, and 14\n- Proportion of patients experiencing healthcare-associated infections, acquired neutropenia after inclusion (defined by ANC < 500/mm³) and its duration if applicable, and post-inclusion bleeding event requiring transfusion and/or surgical intervention\n- Delta SOFA at Days 2 and 5, maximum SOFA score, including both SOFA and modified SOFA","definition_or_measurement_approach":"Time to death: measured from inclusion up to maximum follow-up of 60 days. Ventilator-/catecholamine-free days: counted between inclusion and Day 14. Renal replacement therapy: proportion receiving ≥1 session between inclusion and Day 14. Cumulative etoposide dose: total over first 14 days (overall and among those treated). Time to initiation: days from inclusion to first etoposide. Other laboratory endpoints: fibrinogen >2 g/L, ferritin <2000 μg/L, triglycerides <1.5 mg/dL measured during ICU stay up to Day14. HScore assessed at Days 2,7,14. Neutropenia defined as ANC <500/mm3. SOFA endpoints: delta SOFA at Days 2 and 5 and maximum SOFA including modified SOFA."}
Recruitment
- Planned Sample Size
- 130
- Recruitment Window Months
- 36
- Consent Approach
- Informed consent is obtained from the adult patient. Subject information and informed consent forms exist for adult patients and for legal representatives (documents listed: L1_SIS and ICF_adult patient; L1_SIS and ICF_legal representative; and pursuit versions). Minors are excluded; patients under legal guardianship/tutelage/curatorship are excluded. Languages of the consent documents are not specified in the CTIS metadata.
Geography
- Total Number Of Sites
- 27
- Total Number Of Participants
- 130
France
- Earliest CTIS Part Ii Submission Date
- 05-12-2024
- Latest Decision Or Authorization Date
- 10-03-2025
- Processing Time Days
- 95
- Number Of Sites
- 27
- Number Of Participants
- 130
Sites
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Bruno Mégarbane
- Principal Investigator Email
- guillaume.chevrel@chsf.fr
- Contact Person Name
- Bruno Mégarbane
- Contact Person Email
- guillaume.chevrel@chsf.fr
- Site Name
- Centre Hospitalier De Versailles
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Stéphane Legriel
- Principal Investigator Email
- slegriel@ght78sud.fr
- Contact Person Name
- Stéphane Legriel
- Contact Person Email
- slegriel@ght78sud.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Etienne De Montmollin
- Principal Investigator Email
- Etienne.demontmollin@aphp.fr
- Contact Person Name
- Etienne De Montmollin
- Contact Person Email
- Etienne.demontmollin@aphp.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Nicholas Heming
- Principal Investigator Email
- nicholas.heming@aphp.fr
- Contact Person Name
- Nicholas Heming
- Contact Person Email
- nicholas.heming@aphp.fr
- Site Name
- CHRU De Nancy
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Pierre Perez
- Principal Investigator Email
- p.perez@chru-nancy.fr
- Contact Person Name
- Pierre Perez
- Contact Person Email
- p.perez@chru-nancy.fr
- Site Name
- Centre Hospitalier Sud Francilien
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Guillaume Chevrel
- Principal Investigator Email
- guillaume.chevrel@chsf.fr
- Contact Person Name
- Guillaume Chevrel
- Contact Person Email
- guillaume.chevrel@chsf.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Fabrice Uhel
- Principal Investigator Email
- fabrice.uhel@aphp.fr
- Contact Person Name
- Fabrice Uhel
- Contact Person Email
- fabrice.uhel@aphp.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Jean-Luc Diehl
- Principal Investigator Email
- jean-luc.diehl@aphp.fr
- Contact Person Name
- Jean-Luc Diehl
- Contact Person Email
- jean-luc.diehl@aphp.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Frédéric Pène
- Principal Investigator Email
- Frederic.pene@aphp.fr
- Contact Person Name
- Frédéric Pène
- Contact Person Email
- Frederic.pene@aphp.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Nicolas De Prost
- Principal Investigator Email
- Nicolas.de-prost@aphp.fr
- Contact Person Name
- Nicolas De Prost
- Contact Person Email
- Nicolas.de-prost@aphp.fr
- Site Name
- Centre Hospitalier Universitaire De Montpellier
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Kada Klouche
- Principal Investigator Email
- k-klouche@chu-montpellier.fr
- Contact Person Name
- Kada Klouche
- Contact Person Email
- k-klouche@chu-montpellier.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Olivier Roux
- Principal Investigator Email
- olivier.roux@aphp.fr
- Contact Person Name
- Olivier Roux
- Contact Person Email
- olivier.roux@aphp.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Eric Maury
- Principal Investigator Email
- eric.maury@aphp.fr
- Contact Person Name
- Eric Maury
- Contact Person Email
- eric.maury@aphp.fr
- Site Name
- Centre Hospitalier Victor Dupouy
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Damien Contou
- Principal Investigator Email
- damien.contou@ch-argenteuil.fr
- Contact Person Name
- Damien Contou
- Contact Person Email
- damien.contou@ch-argenteuil.fr
- Site Name
- Centre Hospitalier Universitaire De Dijon
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Jean-Pierre Quenot
- Principal Investigator Email
- jean-pierre.quenot@chu-dijon.fr
- Contact Person Name
- Jean-Pierre Quenot
- Contact Person Email
- jean-pierre.quenot@chu-dijon.fr
- Site Name
- Centre Hospitalier Universitaire D Orleans
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- François Barbier
- Principal Investigator Email
- francois.barbier@chr-orleans.fr
- Contact Person Name
- François Barbier
- Contact Person Email
- francois.barbier@chr-orleans.fr
- Site Name
- Centre Hospitalier Regional De Marseille
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Sami Hraiech
- Principal Investigator Email
- Sami.hraiech@ap-hm.fr
- Contact Person Name
- Sami Hraiech
- Contact Person Email
- Sami.hraiech@ap-hm.fr
- Site Name
- Centre Hospitalier Universitaire de la Guadeloupe
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Frédéric Martino
- Principal Investigator Email
- frederic.martino@chu-guadeloupe.fr
- Contact Person Name
- Frédéric Martino
- Contact Person Email
- frederic.martino@chu-guadeloupe.fr
- Site Name
- Centre Hospitalier Universitaire Rouen
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Maximilien Grall
- Principal Investigator Email
- maximilien.Grall@chu-rouen.fr
- Contact Person Name
- Maximilien Grall
- Contact Person Email
- maximilien.Grall@chu-rouen.fr
- Site Name
- Centre Hospitalier Universitaire Amiens Picardie
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Yoann Zerbib
- Principal Investigator Email
- Zerbib.yoann@chu-amiens.fr
- Contact Person Name
- Yoann Zerbib
- Contact Person Email
- Zerbib.yoann@chu-amiens.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Adrien Joseph
- Principal Investigator Email
- adrien.joseph@aphp.fr
- Contact Person Name
- Adrien Joseph
- Contact Person Email
- adrien.joseph@aphp.fr
- Site Name
- Centre Hospitalier Universitaire De Lille
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Anne-Sophie Moreau
- Principal Investigator Email
- Annesophie.MOREAU@chu-lille.fr
- Contact Person Name
- Anne-Sophie Moreau
- Contact Person Email
- Annesophie.MOREAU@chu-lille.fr
- Site Name
- Centre Hospitalier Universitaire De Nice
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Mathieu Joswiak
- Principal Investigator Email
- jozwiak.m@chu-nice.fr
- Contact Person Name
- Mathieu Joswiak
- Contact Person Email
- jozwiak.m@chu-nice.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Julien Schmidt
- Principal Investigator Email
- julien.schmidt@aphp.fr
- Contact Person Name
- Julien Schmidt
- Contact Person Email
- julien.schmidt@aphp.fr
- Site Name
- Centre Hospital Region Metz Thionville
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Guillaume Louis
- Principal Investigator Email
- guillaume.louis@chr-metz-thionville.fr
- Contact Person Name
- Guillaume Louis
- Contact Person Email
- guillaume.louis@chr-metz-thionville.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Guillaume Voiriot
- Principal Investigator Email
- Guillaume.voiriot@aphp.fr
- Contact Person Name
- Guillaume Voiriot
- Contact Person Email
- Guillaume.voiriot@aphp.fr
- Site Name
- Assistance Publique Hopitaux De Paris
- Department Name
- Intensive Care Unit
- Principal Investigator Name
- Tai Pham
- Principal Investigator Email
- Tai.pham@aphp.fr
- Contact Person Name
- Tai Pham
- Contact Person Email
- Tai.pham@aphp.fr
Sponsor
Primary sponsor
- Full Name
- Assistance Publique Hopitaux De Paris
- Organisation Type
- Hospital/Clinic/Other health care facility
- Country Of Registered Address
- France
Investigational products
- Investigational Product Name
- ETOPOSIDE
- Active Substance
- ETOPOSIDE
- Modality
- Small molecule
- Routes Of Administration
- IV INJECTION, IV INFUSION
- Route
- IV INJECTION, IV INFUSION
- Maximum Dose
- 100 mg/m2 daily; max total 450 mg
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