Cohort Multiple Randomized Controlled Trials Open-label of Immune Modulatory Drugs and Other Treatments in COVID-19 Patients - Sarilumab Trial - CORIMUNO-19 - SARI (CORIMUNO-SARI)

• ClinicalTrials.gov Identifier: NCT04324073
• Recruitment Status: Unknown
• First Posted: March 27, 2020
• Last Update Posted: April 15, 2020
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Tracking Information

• First Submitted Date: March 25, 2020
• First Posted Date: March 27, 2020
• Last Update Posted Date: April 15, 2020
• Actual Study Start Date: March 27, 2020
• Estimated Primary Completion Date: March 27, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 14, 2020)

• Survival without needs of ventilator utilization at day 14. [ Time Frame: 14 days ]
  Survival without needs of ventilator utilization (including non invasive ventilation and high flow) at day 14. Thus, events considered are needing ventilator utilization (including Non Invasive Ventilation, NIV or high flow), or death. New DNR order (if given after the inclusion of the patient) will be considered as an event at the date of the DNR.
• WHO progression scale <=5 at day 4 [ Time Frame: 4 days ]
  Proportion of patients alive without non-invasive ventilation of high low at day 4 (WHO progression scale ≤ 5). A patient with new DNR order at day 4 will be considered as with a score > 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
• Cumulative incidence of successful tracheal extubation (defined as duration extubation > 48h) at day 14 [ Time Frame: 14 days ]
  Cumulative incidence of successful tracheal extubation (defined as duration extubation > 48h) at day 14 if patients have been intubated before day 14 ; or removal of NIV or high flow (for > 48h) if they were included under oxygen by NIV or High flow (score 6) and remained without intubation. Death or new DNR order (if given after the inclusion of the patient) will be considered as a competing event.
• WHO progression scale at day 4 [ Time Frame: 4 days ]
  Cumulative incidence of successful tracheal extubation (defined as duration extubation > 48h) at day 14 if patients have been intubated before day 14 ; or removal of NIV or high flow (for > 48h) if they were included under oxygen by NIV or High flow (score 6) and remained without intubation. Death or new DNR order (if given after the inclusion of the patient) will be considered as a competing event. 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

Original Primary Outcome Measures (submitted: March 25, 2020)

• Survival without needs of ventilator utilization at day 14. [ Time Frame: 14 days ]
  Survival without needs of ventilator utilization (including Non invasive ventilation) at day 14. Thus, events considered are needing ventilator utilization (including Non Invasive Ventilation, NVI), or death. New Do Not Resuscitate (DNR) order will be considered as an event at the date of the DNR.
• WHO progression scale <=5 at day 4 [ Time Frame: 4 days ]
  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
• Cumulative incidence of successful tracheal extubation (defined as duration extubation > 48h) at day 14 [ Time Frame: 14 days ]
  Cumulative incidence of successful tracheal extubation (defined as duration extubation > 48h) at day 14. Death or DNR order will be considered as a competing event.
• WHO progression scale <=7 at day 4 [ Time Frame: 4 days ]
  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

Current Secondary Outcome Measures (submitted: March 25, 2020)

• WHO progression scale [ Time Frame: 7 and 14 days ]
  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
• Survival [ Time Frame: 14, 28 and 90 days ]
  Overall survival
• 28-day ventilator free-days [ Time Frame: 28 days ]
• respiratory acidosis at day 4 [ Time Frame: 4 days ]
  arterial blood pH of <7.25 with a partial pressure of arterial carbon dioxide [Paco2] of ≥60 mm Hg for >6 hours
• PaO2/FiO2 ratio [ Time Frame: day 1 to day 14 ]
  evolution of PaO2/FiO2 ratio
• time to oxygen supply independency [ Time Frame: 14 days ]
  time to oxygen supply independency
• duration of hospitalization [ Time Frame: 90 days ]
  duration of hospitalization
• time to negative viral excretion [ Time Frame: 90 days ]
  time to negative viral excretion
• time to ICU discharge [ Time Frame: 90 days ]
  time to ICU discharge
• time to hospital discharge [ Time Frame: 90 days ]
  time to hospital discharge

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cohort Multiple Randomized Controlled Trials Open-label of Immune Modulatory Drugs and Other Treatments in COVID-19 Patients - Sarilumab Trial - CORIMUNO-19 - SARI
• Official Title: Cohort Multiple Randomized Controlled Trials Open-label of Immune Modulatory Drugs and Other Treatments in COVID-19 Patients - Sarilumab Trial - CORIMUNO-19 - SARI
• Brief Summary: The overall objective of the study is to determine the therapeutic effect and tolerance of Sarilumab in patients with moderate, severe pneumonia or critical 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 Sarilumab administration to patients enrolled in the CORIMUNO-19 cohort. Sarilumab will be administered to consenting adult patients hospitalized with COVID-19 either diagnosed with moderate or severe pneumonia requiring no mechanical ventilation or critical pneumonia requiring mechanical ventilation. Patients who will chose not to receive Sarilumab will receive standard of care. Outcomes of Sarilumab-treated patients will be compared with outcomes of standard of care-treated patients as well as with outcomes of patients treated with other immune modulators.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Bayesian open labelled randomized clinical trial

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: Corona Virus Infection

Intervention

Drug: Sarilumab

(an IV dose of 400 mg of sarilumab in a 1 hour-infusion at D1

Study Arms

• Experimental: SARILUMAB
  Sarilumab (an IV dose of 400 mg of sarilumab in a 1 hour-infusion at D1).
  Intervention: Drug: Sarilumab
• No Intervention: Standard of care
  best standard of care

Publications *

• Hermine O, Mariette X, Porcher R, Resche-Rigon M, Tharaux PL, Ravaud P; on the behalf of the CORIMUNO-19 collaborative group. Effect of Interleukin-6 Receptor Antagonists in Critically Ill Adult Patients with COVID-19 Pneumonia: two Randomised Controlled Trials of the CORIMUNO-19 Collaborative Group. Eur Respir J. 2022 Feb 3. pii: 2102523. doi: 10.1183/13993003.02523-2021. [Epub ahead of print]
• CORIMUNO-19 Collaborative group. Sarilumab in adults hospitalised with moderate-to-severe COVID-19 pneumonia (CORIMUNO-SARI-1): An open-label randomised controlled trial. Lancet Rheumatol. 2022 Jan;4(1):e24-e32. doi: 10.1016/S2665-9913(21)00315-5. Epub 2021 Nov 17.

Recruitment Information

• Recruitment Status: Unknown status
• Actual Enrollment (submitted: April 14, 2020): 239
• Original Estimated Enrollment (submitted: March 25, 2020): 180
• Estimated Study Completion Date: December 31, 2021
• Estimated Primary Completion Date: March 27, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Patients included in the CORIMUNO-19 cohort

2. Patients belonging to one of the 2 following groups:

   • Group 1: patients not requiring ICU at admission with moderate and severe pneumopathy according to the OMS Criteria of severity of COVID pneumopathy.

Moderate cases :

Cases meeting all of the following criteria:

• Showing fever and respiratory symptoms with radiological findings of pneumonia.
• Requiring between 3L/min and 5L/min of oxygen to maintain SpO2 >97% Severe cases

Cases meeting any of the following criteria:

• Respiratory distress (≧30 breaths/ min);
• Oxygen saturation≤93% at rest in ambient air; or Oxygen saturation ≤97 % with O2 > 5L/min.
• PaO2/FiO2≦300mmHg
• Group 2: patients requiring ICU based on Criteria of severity of COVID pneumopathy.
• Respiratory failure and requiring mechanical ventilation
• No do-not-resuscitate order (DNR order)

Exclusion Criteria:

• Patients with exclusion criteria to the CORIMUNO-19 cohort.
• Known hypersensitivity to Sarilumab or to any of their excipients.
• Pregnancy
• 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:
• Absolute neutrophil count (ANC) ≤ 1.0 x 109/L
• Haemoglobin level: no limitation
• Platelets (PLT) < 50 G /L
• SGOT or SGPT > 5N

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France

Administrative Information

• NCT Number: NCT04324073
• Other Study ID Numbers: APHP200375-2
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• Study Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Assistance Publique - Hôpitaux de Paris
• Verification Date: March 2020