TIC-TAC-SAM « Comparison of two strategies of etoposide initiation in severe sporadic hemophagocytic lymphohistiocytosis in intensive care: a randomized trial »

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Pathological Conditions, Signs and Symptoms [C23]

Decision date (initial)

2025-03-10

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

French Ministry of Health (PHRC-IR 2022)

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

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 after 48 hours

Secondary objectives 14

1. Survival
2. Duration of mechanical ventilation
3. Duration of catecholamine therapy
4. Need for renal replacement therapy
5. Length of stay in the intensive care unit
6. Length of hospital stay
7. Proportion of patients receiving etoposide treatment
8. Cumulative dose of etoposide
9. Time to initiation of etoposide treatment
10. Number of patients receiving another immunosuppressive treatment
11. Normalization of HLH-related biological abnormalities
12. Evolution of the HScore (probability score for HLH)
13. Potential side effects attributable to etoposide, such as healthcare-associated infections, incidence of neutropenia, and bleeding events
14. Evolution of the SOFA score and modified SOFA score

Conditions and MedDRA coding

Hemophagocytic lymphohistiocytosis (HLH)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Adult patient
2. 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
3. First episode of HLH
4. Admission to intensive care unit
5. 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 10

1. Moribund patient with refractory distributive shock: multi-organ failure requiring noradrenaline >2.5 μg/kg/min and imminent risk of death
2. Inability to administer etoposide within 12 hours
3. Patient treated with etoposide prior to admission to the intensive care unit
4. Hypersensitivity to etoposide or any of its excipients
5. Patient not covered by social security
6. Patient under legal guardianship, tutelage, or curatorship
7. Minor patient
8. Pregnant or lactating woman
9. Recent vaccination with a live attenuated vaccine
10. Participation in another interventional research study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 14

1. Time to death after inclusion (with a maximum follow-up duration of 60 days)
2. Number of ventilator-free days between inclusion and Day 14
3. Number of catecholamine-free days between inclusion and Day 14
4. Proportion of patients receiving at least one session of renal replacement therapy between inclusion and Day 14
5. Length of stay in the intensive care unit
6. Length of hospital stay
7. Proportion of patients receiving a dose of etoposide
8. Cumulative dose of etoposide over the first 14 days, within the total study population and among those receiving at least one dose of treatment
9. Number of days between inclusion and initiation of etoposide treatment
10. Number of patients receiving another immunosuppressive treatment during the intensive care unit stay up to Day 14
11. 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
12. HScore at Days 2, 7, and 14
13. 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
14. Delta SOFA at Days 2 and 5, maximum SOFA score, including both SOFA and modified SOFA

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Coordinating Investigator

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Coordinating Investigator

Locations

2 EU/EEA countries · 27 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 13 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications