Hemophagocytic LymphohistiocytosisPhase 3TIC-TAC-SAMNCT07497438
Comparison of Two Etoposide Initiation Strategies for Severe Hemophagocytic Lymphohistiocytosis
A Phase 3 study testing Etoposide (Early strategy) and Etoposide (Delayed strategy) in people with Hemophagocytic Lymphohistiocytosis, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial summary
Hemophagocytic lymphohistiocytosis (HLH) is an immune-mediated disorder characterized by hyperactivation of the immune system, leading to a cytokine storm responsible for organ failures. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Hemophagocytic Lymphohistiocytosis
- What is being tested?
- Etoposide (Early strategy) and Etoposide (Delayed strategy)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 176 participants
- Where
- 1 siteFrance
- Study dates
- Apr 2026to Feb 2030
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 11Show fewer
- 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
Who cannot join
- 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.
Show all 13Show fewer
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
France1 site
Intensive Care Unit - Avicenne Hospital, Assistance Publique des Hôpitaux de Paris
Bobigny, 93000
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
About this study
Official title: Comparison of Two Etoposide Initiation Strategies for Severe Hemophagocytic Lymphohistiocytosis in Intensive Care: a Randomized Trial
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.
Read the detailed description
- 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.
- Conditions
- Hemophagocytic Lymphohistiocytosis
- Being tested
- Etoposide (Early strategy), Etoposide (Delayed strategy)
- Keywords
- Hemophagocytic lymphohistiocytosis, Etoposide, Intensive care unit, cytokine storm, organe failures
- Medical subject headings
- Lymphohistiocytosis, Hemophagocytic, Cytokine Release Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Etoposide (Early strategy)Drug
Also called 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 arm: patients will receive etoposide treatment within 12 hours of inclusion.
Etoposide (Delayed strategy)Drug
Also called 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.
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.
| Study group | Role | What they receive |
|---|---|---|
| Early strategy | Experimental | Etoposide treatment will be administered within 12 hours of inclusion. Receives: Drug: Etoposide (Early strategy) |
| Delayed strategy | Active comparator | The need for etoposide treatment will be reassessed after 48 hours of management. If organ failure worsens or fails to improve (modified SOFA increase ≥1 point or stable), etoposide will be administered within 12 hours of reassessment. 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. Receives: Drug: Etoposide (Delayed strategy) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Increase of at least 1 point in the modified SOFA score (excluding the hematologic component) 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
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.
Measured: every 12 hours from Day 1 to Day 5 (Day 0 = inclusion), and then every 24 hours from Day 6 to Day 14
Secondary outcomes (14)
Survival
Time to death after inclusion (with a maximum follow-up duration of 60 days)
Measured: 60 days
Duration of mechanical ventilation
Number of ventilator-free days between inclusion and Day 14. A live discharge from the intensive care unit will be considered equivalent to no mechanical ventilation (event) from the date of discharge. Patients who died before day 14 will be assigned a value of 0 days, corresponding to no days alive without ventilation.
Measured: 14 days after inclusion
Duration of catecholamine therapy
Number of catecholamine-free days between inclusion and Day 14. A live discharge from the intensive care unit will be considered equivalent to an absence of catecholamines (event) from the date of discharge. Patients who died before D14 will be assigned a value of 0 days, corresponding to an absence of live days without catecholamines.
Measured: 14 days after inclusion
Need for renal replacement therapy.
Proportion of patients receiving at least one session of renal replacement therapy between inclusion and Day 14. Discharge from intensive care without prior extrarenal purification will be considered a non-event. Death without prior extrarenal purification will be considered a non-event.
Measured: 14 days after inclusion
Length of stay in the intensive care unit
Length of stay in the intensive care unit
Measured: 60 days
Length of hospital stay
Length of hospital stay
Measured: 60 days
Proportion of patients receiving etoposide treatment
Proportion of patients receiving a dose of etoposide
Measured: 60 days
Cumulative dose of etoposide
Cumulative dose of etoposide over the first 14 days, within the total study population and among those receiving at least one dose of treatment
Measured: 14 days after inclusion
Time to initiation of etoposide treatment
Number of days between inclusion and initiation of etoposide treatment in patients who received etoposide.
Measured: 60 days
Number of patients receiving another immunosuppressive treatment
Number of patients receiving another immunosuppressive treatment during the intensive care unit stay up to Day 14. Treatment received outside the intensive care unit will not be taken into account.
Measured: 60 days
Normalization of HLH-related biological abnormalities
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. These blood tests will be performed daily as part of routine care during the period of intensive care.
Measured: 14 days after inclusion
Evolution of the HScore (probability score for HLH)
HScore at Days 2, 7, and 14. In the event of missing data (particularly for hemophagocytosis), the latest available data will be used
Measured: 2, 7, and 14 days after inclusion
Potential side effects attributable to etoposide, such as healthcare-associated infections, incidence of neutropenia, and bleeding events
Proportion of patients with at least one healthcare-associated infection, neutropenia acquired after inclusion and its duration, if applicable (defined by PNN <500/mm³), a bleeding event after inclusion requiring transfusion and/or surgery. Patients with neutropenia on admission will be excluded from the neutropenia analysis. Complete blood counts, bleeding events, and transfusions will be monitored daily.
Measured: 60 days
Evolution of the SOFA score and modified SOFA score.
Delta SOFA at Days 2 and 5, maximum SOFA score, including both SOFA and modified SOFA. The SOFA score will be calculated daily, in accordance with the protocol for the primary endpoint. The maximum SOFA score during the first 14 days will be used.
Measured: 14 days after inclusion
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Mar 2026
- Study startApr 2026 (estimated)
- Primary completionDec 2029 (estimated)
- Study completionFeb 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Hemophagocytic LymphohistiocytosisStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 176 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Julien SCHMIDT, MD, Principal investigator, Assistance Publique - Hôpitaux de Paris
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07497438
- Sponsor's protocol ID
- APHP230874
- Other IDs
- 2024-511807-41-01
- Acronym
- TIC-TAC-SAM
- Status last verified
- Mar 2026
- First submitted
- 23 Mar 2026
- Last updated
- 23 Apr 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 23 Apr 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Comparison of Two Etoposide Initiation Strategies for Severe Hemophagocytic Lymphohistiocytosis in Intensive Care: a Randomized Trial
- ClinicalTrials.gov ID
- NCT07497438
- Acronym / sponsor ID
- TIC-TAC-SAM / APHP230874
- Conditions
- Hemophagocytic Lymphohistiocytosis
- Keywords
- Hemophagocytic lymphohistiocytosis, Etoposide, Intensive care unit, cytokine storm, organe failures
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 176 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- Apr 2026 (estimated)
- Primary completion
- Dec 2029 (estimated)
- Study completion
- Feb 2030 (estimated)
- First posted
- 27 Mar 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Early strategy | Experimental | Drug: Etoposide (Early strategy)Etoposide treatment will be administered within 12 hours of inclusion. |
| Delayed strategy | Active comparator | Drug: Etoposide (Delayed strategy)The need for etoposide treatment will be reassessed after 48 hours of management. If organ failure worsens or fails to improve (modified SOFA increase ≥1 point or stable), etoposide will be administered within 12 hours of reassessment. 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- Adult patient
- Confirmed diagnosis of HLH:
- First episode of HLH
- Admission to intensive care unit
- Presence of one or more organ failures:
Key exclusion criteria (13 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Etoposide (Early strategy)Also: 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 arm: patients will receive etoposide treatment within 12 hours of inclusion. | Drug | Early strategy |
| Etoposide (Delayed strategy)Also: 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.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. | Drug | Delayed strategy |
Primary outcome
Increase of at least 1 point in the modified SOFA score (excluding the hematologic component) 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
Time frame: every 12 hours from Day 1 to Day 5 (Day 0 = inclusion), and then every 24 hours from Day 6 to Day 14
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.
14 secondary outcomes
Survival
Time frame: 60 days
Duration of mechanical ventilation
Time frame: 14 days after inclusion
Duration of catecholamine therapy
Time frame: 14 days after inclusion
Need for renal replacement therapy.
Time frame: 14 days after inclusion
Length of stay in the intensive care unit
Time frame: 60 days
Length of hospital stay
Time frame: 60 days
Proportion of patients receiving etoposide treatment
Time frame: 60 days
Cumulative dose of etoposide
Time frame: 14 days after inclusion
Time to initiation of etoposide treatment
Time frame: 60 days
Number of patients receiving another immunosuppressive treatment
Time frame: 60 days
Normalization of HLH-related biological abnormalities
Time frame: 14 days after inclusion
Evolution of the HScore (probability score for HLH)
Time frame: 2, 7, and 14 days after inclusion
Potential side effects attributable to etoposide, such as healthcare-associated infections, incidence of neutropenia, and bleeding events
Time frame: 60 days
Evolution of the SOFA score and modified SOFA score.
Time frame: 14 days after inclusion
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 Apr 2026.
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Hemophagocytic Lymphohistiocytosis (HLH), Macrophage Activation Syndrome (MAS)
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Hemophagocytic Lymphohistiocytosis (HLH)
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Julien SCHMIDT, MD principal investigator
Assistance Publique - Hôpitaux de Paris
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Etoposide (Early strategy) and Etoposide (Delayed strategy) in people with Hemophagocytic Lymphohistiocytosis, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 23 Apr 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Julien SCHMIDT, MD (+33 (0)1.48.95.52.41, julien.schmidt@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Increase of at least 1 point in the modified SOFA score (excluding the hematologic component) 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 (time frame: every 12 hours from Day 1 to Day 5 (Day 0 = inclusion), and then every 24 hours from Day 6 to Day 14). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Apr 2026.