E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cov-2 SARS Disease |
Maladie du Covid-19 |
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E.1.1.1 | Medical condition in easily understood language |
Associated respiratory Distress syndrome with Cov-2 SARS |
Syndrome de détresse respiratyoire aigu lié à l'infection au Covid-19 |
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E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10051905 |
E.1.2 | Term | Coronavirus infection |
E.1.2 | System Organ Class | 100000004862 |
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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 determine if the administration of IVIG at a dose of 2 g / kg over 4 consecutive days (i.e. 0.5 g / Kg / D) started during the first 24 to 120 hours of invasive mechanical ventilation (VM) of a patient suffering from d 'A post-SARS-CoV-2 ARDS improves the number of days living without VM on D28.
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déterminer si l’administration d’IgIV à la dose de 2g/kg sur 4 jours consécutifs (soit 0.5g/Kg/J) débutée au cours des 24 à 120 premières heures de ventilation mécanique invasive (VM) d’un patient atteint d’un SDRA post-SARS-CoV-2 permet d’améliorer le nombre de jours vivant sans VM à J28. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to assess the impact of IVIg on mortality, organ failure, complications of resuscitation and the functional and psychological sequelae at D28 as well as their side effects. |
Les objectifs secondaires sont d’évaluer l’impact des IgIV sur la mortalité, les défaillances d’organe, les complications de la réanimation et les séquelles fonctionnelles et psychologiques à J28 ainsi que leurs effets secondaires. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) VM (mechanical ventilation) invasive for less than 36 hours
2) ARDS meeting the Berlin criteria (Ref)
3) SARS-CoV-2 infection proven by PCR
4) Consent of the patient, a relative or relative or deferred (emergency clause). |
1) VM (ventilation mécanique) invasive depuis moins de 36 heures
2) SDRA répondant aux critères de Berlin (Ref)
3) Infection à SARS-CoV-2 prouvée par une PCR
4) Consentement du patient, d’un proche ou parent ou différé (clause d’urgence). |
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E.4 | Principal exclusion criteria |
- Allergy to polyvalent immunoglobulins.
- Pregnant woman or minor patient
- Known IgA deficiency.
- Patient with renal failure on admission defined by a 3-fold increase in baseline creatinine or serum creatinine> 354 micromol / L or a diuresis of less than 0.3 mL / Kg for 24 hours or anuria for 12 hours.
- Participation in another interventional trial |
- Allergie aux immunoglobulines polyvalentes.
- Femme enceinte ou patient mineur
- Déficit en IgA connu.
- Patient présentant une insuffisance rénale à l’admission définie par une augmentation de 3 fois de la créatininémie de base ou une créatininémie >354 micromol/L ou une diurèse de moins de 0,3 mL/Kg pendant 24 heures ou une anurie pendant 12 heures.
- Participation à un autre essai interventionnel |
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E.5 End points |
E.5.1 | Primary end point(s) |
Survival without invasive ventilatory assistance (i.e. ventilator-free days) until D28. The score is calculated by summing the days on which the patient has not had a VM; but in the event of death before D28, the score is zero. The 28-day delay was recommended because the average duration of VM for post-SARS-CoV-2 ARDS patients is 20 days. |
Survie sans assistance ventilatoire invasive (i.e. ventilator-free days) jusqu’à J28. Le score est calculé en faisant la somme des jours où le patient n’a pas bénéficié d’une VM; mais en cas de décès avant J28, le score est de zéro. Le délai de 28 jours a été préconisé du fait que la durée moyenne de VM des patients en SDRA post-SARS-CoV-2 est de 20 jours. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
28 day delay |
Délai de 28 jours |
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E.5.2 | Secondary end point(s) |
● Mortality at D28 and D90
● Organ failures according to the SOFA score performed on D1, D3 and D7, D14, D21 and D28.
● Clinical efficacy criteria: Radiological score, P / F ratio value, pulmonary compliance on D1, D3 and D7, D14, D21 and D28
● Biological efficacy criteria: inflammatory syndrome on D1, D3 and D7, D14, D21 and D28: perhaps specify on what: CRP, fibrinognene, d.dimers, dosages of complement C3, C4, CH50, proteinuria of 24 hours
● Immunological profile: quantity of CD4 HLA-DR + and CD38 +, CD8 lymphocytes strongly expressing perforin for a subgroup of 10 patients. If a bronchiolo-alveolar lavage, the formula will be studied.
● Administration of other treatments (corticosteroids, antiretrovirals, plaquenil)
● Occurrence of deep vein thrombosis of a pulmonary embolism detected clinically and proven by a Doppler ultrasound of the lower limbs. Occurrence of pulmonary embolism evidenced by a pulmonary angiogram.
● Total duration of mechanical ventilation, ventilatory withdrawal, curarization
● KDIGO score and need to resort to extrarenal purification (Annex 2)
● Occurrence of an adverse event linked to immunoglobulins (renal insufficiency, hypersensitivity manifestations with skin or hemodynamic manifestations, aseptic meningitis, hemolytic anemia, leuko-neutropenia, post-transfusion respiratory distress syndrome (TRALI)
● Occurrence of an NMAR will be evaluated by the MRC sum score on waking (Annex 3).
● Onset of pneumonia acquired under mechanical ventilation defined by an evocative radio-clinical context associated with a bacteriological sample by culture of tracheal secretions, bronchiolo-alveolar lavage or a protected distal sample. |
●Mortalité à J28 et J90
●Défaillances d’organe selon le score SOFA réalisé à J1, J3 et J7, J14, J21 et J28.
●Critères cliniques d’efficacité : Score radiologique, valeur du rapport P/F, compliance pulmonaire à J1, J3 et J7, J14, J21 et J28
●Critères biologiques d’efficacité : syndrome inflammatoire à J1, J3 et J7, J14, J21 et J28 : peut-être préciser sur quoi : CRP, fibrinognène, d.dimers, dosages du complément C3, C4, CH50, protéinurie des 24 heures
●Profil immunologique: quantité de lymphocytes CD4 HLA-DR+ et CD38+, CD8 exprimant fortement la perforine pour un sous-groupe de 10 patients. Si un lavage bronchiolo-alvéolaire, la formule en sera étudiée.
●Administrations d’autres traitements (corticoïdes, antirétroviraux, plaquenil)
●Survenue d’une thrombose veineuse profonde d’une embolie pulmonaire détectée cliniquement et prouvée par une echographie-doppler des membres inférieurs. Survenue d’une embolie pulmonaire mise en évidence par un angioscanner pulmonaire.
●Durée totale de ventilation de mécanique, de sevrage ventilatoire, de curarisation
●Score KDIGO et nécessité de recourir à une épuration extrarénale (Annexe 2)
●Survenue d’un événement indésirable lié aux immunoglobulines (Insuffisance rénale, manifestations d’hypersensibilité avec manifestations cutanés ou hémodynamiques, méningite aseptique, anémie hémolytique, leuco-neutropénie, syndrome de détresse respiratoire post-transfusionnel (TRALI)
●Survenue d’une NMAR sera évaluée par le MRC sum score au réveil (Annexe 3).
●Survenue d’une pneumopathie acquise sous ventilation mécanique définie par un contexte radio-clinique évocateur associé à un prélèvement bactériologique par mise en culture des sécrétions trachéales, un lavage bronchiolo-alvéolaire ou un prélèvement distal protégé. |
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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 | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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 | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 17 |
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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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 | 4 |