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DSMB recommendation (futility)
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The overall objective of the study is to determine the therapeutic effect and tolerance of Sarilumab in combination with Azithromycin and Hydroxychloroquine, compared to Sarilumab only, patients with moderate, severe pneumonia associated with Coronavirus disease 2019 (COVID-19). Sarilumab is a human IgG1 monoclonal antibody that binds specifically to both soluble and membrane-bound IL-6Rs (sIL-6Rα and mIL-6Rα) and has been shown to inhibit IL-6-mediated signaling through these receptors. The study has a cohort multiple Randomized Controlled Trials (cmRCT) design. Randomization will occur prior to offering investigational treatments administration to patients enrolled in the CORIMUNO-19 cohort (NCT04324047). Sarilumab+Azithromycin+Hydroxychloroquine, or Sarilumab only will be administered to consenting adult patients hospitalized with COVID-19 either diagnosed with moderate or severe pneumonia requiring no mechanical ventilation. All patients will receive standard of care along with randomized investigational treatments. Outcomes of included patients will be compared between groups as well as with outcomes of patients in the CORIMUNO-19 cohort treated with other immune modulators or standard of care.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Sarilumab + Azithromycin + Hydroxychloroquine | Experimental | Sarilumab combined with Azithromycin and Hydroxychloroquine |
|
| Sarilumab | Active Comparator | Sarilumab only |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Sarilumab | Drug | Sarilumab: 400 mg in a 1 hour - I.V. infusion on D1 |
|
| Measure | Description | Time Frame |
|---|---|---|
| Need for ventilation (including invasive and non invasive ventilation), intensive care or death | Events considered are: need for ventilation (including invasive and non invasive ventilation), transfer to the Intensive Care Unit, death or new do-not-resuscitate (DNR) decision in the absence ventilation and outside ICU. | 14 days |
| Measure | Description | Time Frame |
|---|---|---|
| Early improvement: OMS progression scale <= 5 | WHO progression scale: Uninfected; non viral RNA detected: 0 Asymptomatic; viral RNA detected: 1 Symptomatic; Independent: 2 Symptomatic; Assistance needed: 3 Hospitalized; No oxygen therapy: 4 Hospitalized; oxygen by mask or nasal prongs: 5 Hospitalized; oxygen by NIV or High flow: 6 Intubation and Mechanical ventilation, pO2/FIO2>=150 OR SpO2/FIO2>=200: 7 Mechanical ventilation, (pO2/FIO2<150 OR SpO2/FIO2<200) OR vasopressors (norepinephrine >0.3 microg/kg/min): 8 Mechanical ventilation, pO2/FIO2<150 AND vasopressors (norepinephrine >0.3 microg/kg/min), OR Dialysis OR ECMO: 9 Dead: 10 |
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Inclusion Criteria:
Patients included in the CORIMUNO-19 cohort (NCT04324047)
COVID-19 cases not requiring ICU at admission with moderate or severe pneumopathy according to the WHO Criteria of severity of COVID pneumopathy:
Exclusion Criteria:
Patients with exclusion criteria to the CORIMUNO-19 cohort.
Respiratory failure requiring non invasive or mechanical ventilation
Patients requiring intensive care
Do-not-resuscitate order (DNR order)
Known hypersensitivity to sarilumab or to any of their excipients.
Known contra-indication to hydroxychloroquine or chloroquine: including hypersensitivity/allergy, retinopathy, G6PD deficiency and QT prolongation
Known contra-indication to azithromycin: including hypersensitivity/allergy and QT prolongation
Pregnancy or breastfeeding
Current documented bacterial infection.
Patient with any of following laboratory results out of the ranges detailed below at screening should be discussed depending of the medication:
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| AP-HP Hôpital Avicenne | Bobigny | France | ||||
| AP-HP Hôpital Ambroise Paré |
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Bayesian open labelled randomized clinical trial
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| Azithromycin | Drug | Azithromycin: oral administration, 500mg on D1 then 250mg QD on D2 to D5 (total duration 5 days) |
|
| Hydroxychloroquine | Drug | Hydroxychloroquine: oral administration, 600mg QD (200mg TID) from D1 to D10 (total duration 10 days) |
|
| 4 days |
| OMS progression scale | WHO progression scale: Uninfected; non viral RNA detected: 0 Asymptomatic; viral RNA detected: 1 Symptomatic; Independent: 2 Symptomatic; Assistance needed: 3 Hospitalized; No oxygen therapy: 4 Hospitalized; oxygen by mask or nasal prongs: 5 Hospitalized; oxygen by NIV or High flow: 6 Intubation and Mechanical ventilation, pO2/FIO2>=150 OR SpO2/FIO2>=200: 7 Mechanical ventilation, (pO2/FIO2<150 OR SpO2/FIO2<200) OR vasopressors (norepinephrine >0.3 microg/kg/min): 8 Mechanical ventilation, pO2/FIO2<150 AND vasopressors (norepinephrine >0.3 microg/kg/min), OR Dialysis OR ECMO: 9 Dead: 10 | 4, 7 and 14 days |
| Survival | Overall survival | 14, 28 and 90 days |
| ICU-free days alive | Number of ICU-free days alive | 14, 28 and 90 days |
| Ventilation-free days alive | Number of ventilation(invasive or non invasive)-free days alive | 14 and 28 days |
| Hospital-free days alive | Number of hospital-free days alive | 14, 28 and 90 days |
| Oxygen therapy-free days alive | Number of oxygen therapy-free days alive | 14 and 28 days |
| Time to negative viral excretion | SARS-CoV-2 viral load measurement by rtPCR | 90 days |
| Immunophenotyping and multiplex cytokines | Immunophenotyping and multiplex cytokines (blood sample) | 8 days |
| Boulogne-Billancourt |
| France |
| AP-HP Hôpital Beaujon | Clichy | France |
| AP-HP Hôpital Pitié Salpétrière | Paris | France |
| AP-HP Hôpital Saint Antoine | Paris | France |
| ID | Term |
|---|---|
| D000086382 | COVID-19 |
| ID | Term |
|---|---|
| D011024 | Pneumonia, Viral |
| D011014 | Pneumonia |
| D012141 | Respiratory Tract Infections |
| D007239 | Infections |
| D014777 | Virus Diseases |
| D018352 | Coronavirus Infections |
| D003333 | Coronaviridae Infections |
| D030341 | Nidovirales Infections |
| D012327 | RNA Virus Infections |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
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| ID | Term |
|---|---|
| C000592401 | sarilumab |
| D017963 | Azithromycin |
| D006886 | Hydroxychloroquine |
| ID | Term |
|---|---|
| D004917 | Erythromycin |
| D018942 | Macrolides |
| D061065 | Polyketides |
| D007783 | Lactones |
| D009930 | Organic Chemicals |
| D002738 | Chloroquine |
| D000634 | Aminoquinolines |
| D011804 | Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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