ClinicalTrials.gov record NCT07497438
Comparison of Two Etoposide Initiation Strategies for Severe Hemophagocytic Lymphohistiocytosis
Comparison of Two Etoposide Initiation Strategies for Severe Hemophagocytic Lymphohistiocytosis in Intensive Care: a Randomized Trial
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AI-written from the registry record, not the study's own wording. May contain errors or omissions. Check the registry text on this page and the original record ↗ before acting on it.
This Phase 3 randomized trial compares starting etoposide soon after inclusion versus waiting and reassessing in adults with severe Hemophagocytic lymphohistiocytosis (HLH) who are in intensive care. Participants in both arms routinely receive dexamethasone unless contraindicated; etoposide is given as a 100 mg/m² IV infusion either within 12 hours (early) or after reassessment at 48 hours (delayed) if organ failures persist or worsen. The main measurement is onset or worsening of organ failures using a modified SOFA score; clinical outcomes are followed up to 60 days.
What it is studying. The study tests whether initiating etoposide within 12 hours versus delaying and reassessing at 48 hours changes the course of organ failures in adults with severe HLH in intensive care. It also records timing and amount of etoposide given and monitors for side effects while all patients receive routine dexamethasone unless contraindicated.
What the researchers hope to learn. Primary scientific goal: compare the effect of early versus delayed etoposide initiation on new or worsening organ failures measured by a modified SOFA score. Secondary goals: measure survival, ventilator- and vasopressor-free days, need for renal replacement therapy, ICU and hospital lengths of stay, how many and how much etoposide is given, time to treatment, use of other immunosuppressive therapies, laboratory markers of HLH (including HScore), and rates of infections, neutropenia, and bleeding. The study also aims to identify risk factors for mortality and describe comorbidities associated with severe HLH in intensive care.
What this study is about
The study's own summary, as published on ClinicalTrials.gov. Underlined terms have a short explanation.
Hemophagocytic lymphohistiocytosis (HLH) is an immune-mediated disorder characterized by hyperactivation of the immune system, leading to a cytokine storm responsible for organ failures. Consequently, patients with HLH often require intensive care management, where their short-term prognosis is compromised (1-month mortality: 30 to 40%). Therapeutic management is urgent and consists in treating associated pathologies and employing immunomodulatory therapy. Currently, there are no clear and consistent recommendations for guiding immunomodulatory treatment in HLH due to the lack of high-level evidence studies. Experts recommend corticosteroid therapy for mild forms, whereas etoposide is proposed for severe cases, especially those with organ failures. However, in clinical practice, its use in patients with multi-organ failure is not systematic due to concerns about potential severe side effects and uncertainty regarding the contribution of severe sepsis to the clinical and biological presentation. Consequently, initiation of etoposide is sometimes delayed. Our hypothesis is that early treatment of severe HLH associated with organ failure using etoposide could reduce organ failures associated with this syndrome. Therefore, we aim to compare two strategies for initiating etoposide in severe HLH in intensive care: an early strategy where etoposide is prescribed at the onset of HLH-related organ failure, and a delayed strategy where etoposide is prescribed only if there is unfavorable progression (or lack of improvement) after treating associated pathologies, associated with corticosteroid therapy.
Interventions being studied
Being studied in this trial does not mean the treatment or procedure is approved or available for this condition.
- Drug
- Etoposide (Early strategy)
- Etoposide (Delayed strategy)
Eligibility
The criteria exactly as listed on ClinicalTrials.gov. Only the study team can say whether they apply to you.
Inclusion criteria
- Adult patient
- Confirmed diagnosis of HLH:
- Hscore ≥ 169
- Diagnosis of HLH established by the multidisciplinary team caring for the patient(A 24/7 hotline will be available in case of diagnostic uncertainty: this will be the direct line to the on-call intensivist at Avicenne Hospital, who can contact the coordinating investigator as needed)
- First episode of HLH
- Admission to intensive care unit
- Presence of one or more organ failures:
- Circulatory: mBP < 65 mmHg with lactate > 2 mmol/L, or treatment with catecholamines
- Respiratory: oxygen therapy > 6 L/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, defined by a creatinine increase ≥ 2 times baseline, or urine output < 0.5 mL/kg/h for ≥ 12 hours, or initiation of renal replacement therapy
- Neurological: GCS ≤ 13
Exclusion criteria
- Moribund patient with refractory distributive shock: multi-organ failure requiring noradrenaline > 2.5 µg/kg/min and imminent risk of death.
- Inability to administer etoposide within 12 hours.
- Patient treated with etoposide prior to admission to the intensive care unit.
- Hypersensitivity to etoposide or any of its excipients.
- Hypersensitivity or contraindication to dexamethasone or any of its excipients, as described in the package insert for the dexamethasone specialty used in the trial and in the protocol.
- Patient with a history of CAR-T cell therapy.
- Patient developing HLH within 15 days following chemotherapy for cancer or hematologic malignancy.
- Patient not covered by social security.
- Patient under legal guardianship, tutelage, or curatorship.
- Minor patient.
- Pregnant women (positive βhCG), women for whom pregnancy has not been excluded (βhCG not performed in women of childbearing age), or lactating women.
- Recent vaccination with a live attenuated vaccine.
- Participation in another interventional research study.
Study description and what participation involves
The study's detailed description, as published on ClinicalTrials.gov.
Show the detailed description from the registry
- Objectives
Primary Objective: To compare the effect on the evolution of organ failures of two initiation strategies of etoposide in severe HLH in intensive care:
- An early strategy where etoposide is initiated within 12 hours after inclusion.
- A delayed strategy where this treatment is initiated only in case of unfavorable evolution (or lack of improvement) after 48 hours.
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, from 0 to 20 points), calculated every 12 hours from Day 1 to Day 5 (Day 0 = inclusion), and then every 24 hours from Day 6 to Day 14. 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. Secondary objectives:
- Evaluate the effect of these 2 strategies on:
- Survival
- Duration of mechanical ventilation
- Duration of catecholamine therapy
- Need for renal replacement therapy
- Length of stay in the intensive care unit
- Length of hospital stay
- Proportion of patients receiving etoposide treatment
- Cumulative dose of etoposide
- Time to initiation of etoposide treatment
- Number of patients receiving another immunosuppressive treatment
- Normalization of HLH-related biological abnormalities
- Evolution of the HScore (probability score for HLH)
- Potential side effects attributable to etoposide, such as healthcare-associated infections, incidence of neutropenia, and bleeding events.
- Evolution of the SOFA score and modified SOFA score
- Identify risk factors for mortality in severe HLH in intensive care.
- Identify and describe comorbidities associated with severe HLH in intensive care, and their prognostic impact.
- Investigational treatment
Etoposide is used at a dose of 100 mg/m², administered via slow intravenous infusion over 30 to 60 minutes on Day 0 or Day 2 depending on the arm (early strategy or delayed strategy). Patients in the "early strategy" arm will receive etoposide treatment within 12 hours of inclusion. In the "delayed strategy" arm, patients will be reassessed 48 hours after inclusion. If there is persistence or deterioration of organ failures (similar or higher modified SOFA score), patients will receive etoposide treatment within 12 hours of this reassessment in the absence of formal contraindications. In cases of rapidly deteriorating clinical status with short-term life-threatening prognosis (defined as an increase of 6 or more points in modified SOFA score), patients may receive rescue treatment (before 48 hours) with etoposide at the discretion of the medical team managing the patient; in such cases, the Day-2 infusion will not be administered. This practice will be exceptional and documented, following consultation with the hotline if possible. In the unlikely event of subsequent clinical deterioration from Day 2 to Day 14, etoposide infusion may be considered for patients who did not receive etoposide previously in the "delayed strategy" group. This situation will also be documented. Patients in both arms will routinely receive systemic corticosteroid therapy with dexamethasone 10 mg/m² in a daily injection for the duration of the study, unless contraindicated (adjuvant investigational drug).
- Standard treatment
In case of persistence of HLH signs, a first (for patients in the "delayed strategy" arm) or subsequent (for patients in both arms) injections of etoposide may be performed during follow-up at the discretion of the patient's care team. Other treatments will be:
- Additional injections of etoposide if signs of hemophagocytic lymphohistiocytosis persist, at least 7 days after the previous administration, if applicable.
- Treatment of conditions associated with HLH according to current recommendations and after expert consultation where appropriate.
- In case of clinical deterioration and based on associated conditions, after consultation with experts (hematologist, internist, or immunologist depending on the center), administration of other immunosuppressive treatments may be considered, according to current recommendations and at the discretion of the patient's medical team.
- Practical procedure Recruitment will take place in the investigational ICUs. Inclusion and exclusion criteria will be verified for all patients admitted to the intensive care unit with suspected secondary HLH. Patients meeting all inclusion criteria and having no exclusion criteria will be invited to participate in the study. Patient information and consent will be handled by the intensivist.
Inclusion and randomization will be conducted through a computer server accessible to all study investigators. This will be a 1:1 randomization into two groups, with stratification based on the SOFA score (<9 or ≥9), prior administration of corticosteroid therapy, and the centers. The 2 groups will be:
- The "early strategy" group
- The "delayed strategy" group
Data will be collected as part of routine care for HLH management (clinical and biological characteristics, dates of HLH onset and diagnosis, underlying immunosuppression, HLH-associated pathologies, HScore and Henter criteria, immunomodulatory treatments [date, duration], daily assessment of organ support, occurrence of infectious or hemorrhagic events) by the investigator, and recorded in an e-CRF. Data collection will continue up to 14 days post-randomization. SOFA score and modified SOFA score (excluding hematological component) will be calculated and recorded by the investigator every 12 hours from Day 1 to Day 5, then daily from Day 6 to Day 14. Adverse events will be reported from inclusion to Day 14. Vital status will be collected on Day 14 and Day 60, with a maximum follow-up duration of 60 days. A systematic minimal assessment for HLH-associated pathologies will be proposed to each team. The protocol also includes the establishment of a biobank (serotheca and DNAtheca) at the PRB of Avicenne Hospital.
AI summaryWhat participation may involve, in plain languageShow ▾Hide ▴
AI-written from the registry record, not the study's own wording. May contain errors or omissions. Check the registry text on this page and the original record ↗ before acting on it.
Participants are randomly assigned to an early or delayed etoposide strategy. Early-arm patients receive intravenous etoposide 100 mg/m² (slow infusion over 30–60 minutes) within 12 hours of inclusion; delayed-arm patients are reassessed at 48 hours and receive etoposide within 12 hours of that reassessment if organ failures persist or worsen (with limited allowance for earlier ‘rescue’ dosing in rapidly deteriorating cases). All participants routinely receive daily dexamethasone 10 mg/m² unless contraindicated. Clinical care and routine laboratory data (including frequent SOFA scoring for up to 14 days), adverse events through Day 14, vital status at Day 14 and Day 60, and blood/DNA samples for a biobank will be collected as part of the study.
How the study is structured. Phase 3, open-label, randomized (1:1) trial with two parallel arms: an early-etoposide arm and a delayed-etoposide arm. Randomization is stratified by SOFA score, prior corticosteroid use, and center. Etoposide is given as 100 mg/m² by slow IV infusion over 30–60 minutes on Day 0 or Day 2 depending on the arm; dexamethasone injections are given daily unless contraindicated. Modified SOFA scores are recorded every 12 hours through Day 5 and daily to Day 14; adverse events are recorded through Day 14 and vital status to Day 60. A biobank of blood samples is planned.
Questions you could ask
These questions are suggestions for a conversation with the study team or your own clinician, not advice.
- The registry says recruitment has not started. When is it expected to open, and can I register interest now?
- The listed sites are in France. Is any of them reachable for me, and does the study help with travel?
- Which of the eligibility criteria would need to be checked with tests before I could join?
More on hemophagocytic lymphohistiocytosis
Important dates
- Study start
- April 2026 (estimated)
- Primary completion
- December 2029 (estimated)
- Study completion
- February 2030 (estimated)
- Target enrollment
- 176 participants (estimated)
- Last updated on registry
- Apr 23, 2026
- Data verified
- Oct 10, 2026
Sponsor and research team
The lead sponsor funds and oversees the trial. A pharmaceutical or biotech company sponsor typically means the study is testing that company's drug or device; a hospital, university, or government agency usually indicates investigator-initiated or publicly funded research.
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
Central study contact
If you're interested in participating, the central contact can answer general questions about the study — including eligibility requirements and how to find a recruiting site near you. Actual eligibility is determined by the site's medical team.
- Julien SCHMIDT, MD 📞 +33 (0)1.48.95.52.41 ✉ julien.schmidt@aphp.fr
- Stéphane Gaudry, MD, PhD 📞 +33(0)1.48.95.22.81 ✉ stephane.gaudry@aphp.fr
Participating sites (1)
- Intensive Care Unit - Avicenne Hospital, Assistance Publique des Hôpitaux de Paris
Bobigny, 93000 · France
- Julien SCHMIDT, MD · +33 (0)1.48.95.52.41 · julien.schmidt@aphp.fr
- Stéphane Gaudry, MD, PhD · +33 (0)1.48.95.22.81 · stephane.gaudry@aphp.fr
Terms used on this page · explanations by MedicalUpdates.ai
- corticosteroid
- Steroid medicines, such as prednisone, that reduce inflammation. Studies often require a stable dose at entry or measure whether the study treatment allows the dose to be reduced.
- baseline
- Measurements taken at the start of the study, before any study treatment, so that later results can be compared with them.
- refractory
- A condition that has not responded to a treatment. 'Relapsed' means it responded and then came back; 'refractory' means it did not respond in the first place.
- contraindication
- A reason a particular test or treatment should not be used for a person, for example a metal implant that rules out an MRI scan.
- CAR-T
- A treatment in which a person's own immune cells (T cells) are collected, modified in a laboratory to recognise a target, and returned to the body.
- Inclusion Criteria
- The conditions a person must meet to be considered for the study, for example a confirmed diagnosis, an age range or a test result.
- Exclusion Criteria
- The conditions that rule a person out even if they meet the inclusion criteria, for example other illnesses, certain medicines or pregnancy.
- Primary Objective
- The main result the study is designed to measure and report on. Other results, called secondary outcomes, are also collected.
- follow-up
- The period after treatment or enrolment during which participants are observed or contacted, for example to record side effects or outcomes.
- immunosuppressive
- A medicine that reduces the activity of the immune system. Studies of autoimmune conditions often require a stable dose, a prior failure, or a washout of such medicines.
- Investigational
- A treatment that is being tested and has not been approved for this use. It may be approved for a different condition. Being studied does not mean it works or is available outside the study.
- Standard treatment
- Treatment generally considered appropriate for a condition in a particular clinical setting. It can vary by patient, place and over time. In many studies the new treatment is added to, or compared with, standard of care.
- randomization
- Participants are assigned to the study groups by chance, like a coin toss, rather than chosen by the doctor or the participant. This is done so the groups are comparable.
- 1:1
- How many participants go to each group. In a 2:1 ratio, two are assigned to the first group for every one assigned to the second.
- Adverse events
- Any unwanted medical problem that happens during a study, whether or not it was caused by the treatment. A 'serious' adverse event is one that meets specific criteria, such as causing death, being life-threatening, requiring or prolonging hospital admission, causing significant disability, or another medically important outcome.
- biobank
- A collection of biological samples, such as blood or tissue, stored with medical information so that researchers can study them later.
The study record on this page is reproduced from ClinicalTrials.gov, a database of the U.S. National Library of Medicine, where it was submitted by the study sponsor. MedicalUpdates.ai does not own this content, is not affiliated with or endorsed by ClinicalTrials.gov, NIH, or the U.S. Government, and does not verify the record. Plain-language notes, the glossary and the questions above are added by this site; text in the boxes marked "AI summary" was written by an AI model and may contain errors. Registry records change over time. Check the original record for the current version and discuss eligibility or participation with a qualified healthcare professional.
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