Anakinra for COVID-19 Respiratory Symptoms

Study Overview
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Brief Summary
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The main objective of the ANACONDA-COVID-19 trial is to assess the efficacy of Anakinra + optimized Standard of Care (oSOC) as compared to oSOC alone on the condition of patients with COVID-19 infection and worsening respiratory symptoms. Success defined as patient alive and free of invasive mechanical ventilation (IMV) and free of Extracorporeal Membrane Oxygenation (ECMO) at Day 14.

Official Title
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Efficacy and Safety of ANAkinra During Adult  COVID-19  With Aggravating Respiratory Symptoms: a Multicenter Open-label Controlled Randomized Trial

Conditions
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COVID-19 Infection, ANAKINRA Treatment, Optimized Standard of Care (oSOC)

Intervention / Treatment
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* Drug: Anakinra plus oSOC
* Drug: oSOC


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female≥ 18 years of age Written informed consent of the patient or a proxy Ability for participant to comply with the requirements of the study Hospitalized patient with COVID-19 defined as Positive SARS-CoV2 RT-PCR Or typical COVID-19 Radiographic infiltrates on the CT scan (peripheral ground glass without lung cavitation, lymphadenopathy, or pulmonary nodules) other non COVID-19 diagnosis ruled out. Patient with respiratory symptoms and requirement of oxygen therapy as defined: Oxygen therapy >= 4L/min to maintain Sp02>92% and respiratory rate >=24/min. Or patients under oxygen >= 1L/min and presenting worsening of oxygen requirement defined by an increase of oxygen therapy >= 2L/min to maintain Sp02>92%. Inflammatory component C-Reactive Protein ≥ 50mg/L. Patients within the first 20 days from the onset of the first COVID-19 symptoms Probabilistic antibiotics therapy according to local practice Non-inclusion criteria: Respiratory failure related to other cause than COVID-19 Patients requiring mechanical ventilation at inclusion or requiring oxygen therapy equal or more than 11 liters per min to maintain Sp02>92% Infectious diseases such as severe bacterial infections, aspergillosis, HIV, active HCV, active HBV, active tuberculosis Contra indication to anti-IL1 receptor Known hypersensitivity to Anakinra Absolute neutrophil count (ANC)< 1500/mm3 Liver cirrhosis Child-Pugh Score C Live or attenuated vaccine in the past 8 weeks Pregnant or breast-feeding women Patients with either legally protected status or who have been deprived of their freedom Patient included in other interventional therapeutic research (e.g. = concurrent participation in French CoVID-19 is accepted) Patients who have received previous treatment by anti-IL6R, anti-IL-6, anti-IL1R, anti-IL1 or anti-TNFα within 21 days preceding inclusion Absence of Health Insurance Existence of any life-threatening co-morbidity or any other medical condition which,in the opinion of the investigator, makes the patient unsuitable for inclusion.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: ANACONDA study is a French multicentre, open-label, randomized, controlled superiority trial comparing the administration of optimized standard of care and Anakinra versus optimized standard of care alone in patients hospitalized in a medical unit with COVID-19.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Optimized Standard of Care (oSOC)<br>The control group will receive optimized standard of care alone, including all treatments authorized for COVID-19 by the French Health Ministry and/or the center COVID-19 therapeutic committees at inclusion and during the follow-up. | Drug: oSOC<br>* Optimized Standard of Care (oSOC) on the condition of patients with COVID-19 infection and worsening respiratory symptoms.<br>|
| Experimental: Anakinra plus Optimized Standard of Care (oSOC)<br>The experimental group will receive Anakinra plus optimized Standard of Care. The patients will receive Intravenous injection (IV) of Anakinra 400mg/day (100mg IV every 6 hours) at Day 1, 2 and 3. From Day 4 to Day 10, the patient will receive IV injection of Anakinra 200mg/day (100mg every 12 hours). The total duration of Anakinra is 10 Days | Drug: Anakinra plus oSOC<br>* Anakinra plus Optimized Standard of Care (oSOC) on the condition of patients with COVID-19 infection and worsening respiratory symptoms. The patients will receive intraveinous injection of Anakinra 400mg from Day 1 to Day 3 (two injections of 100 mg each 12 hours) and 200mg the remaining 7 days. The total duration of Anakinra is 10 Days. Efficient dosage of Anakinra as previously described will be continued until Day 10<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment success | The primary endpoint is treatment success at Day 14, defined as a patient alive and not requiring any of the following: Invasive mechanical ventilation (IMV) or Extracorporeal membrane oxygenation (ECMO). | After 14 days of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment success | Defined as a patient alive and not requiring any of the following: Invasive mechanical ventilation (IMV) or Extracorporeal membrane oxygenation (ECMO). | After 3 days, 10 days and 28 days of treatment | 
| OMS progression scale (on a 7 point ordinal scale) | 1. Not hospitalized, no limitations on activities 2. Not hospitalized, limitation on activities; 3. Hospitalized, not requiring supplemental oxygen; 4. Hospitalized, requiring supplemental oxygen; 5. Hospitalized, on non-invasive ventilation or high flow oxygen devices;6. Hospitalized, on invasive mechanical ventilation or ECMO;7. Death. | After 3 days, 10 days, 14 days and 28 days of treatment | 
| Overall survival | Overall survival | After 3 days, 10 days, 14 days and 28 days of treatment | 
| Time to ICU admission | Time to ICU admission | Up to 28 days | 
| Time to ventilatory support | Time to ventilatory support : extracorporeal membrane oxygenation (ECMO), invasive mechanical ventilation, non-invasive ventilation, high flow oxygen therapy) | Up to 28 days | 
| Change in National Early Warning Score (NEW)from baseline to Day 3, Day 10, Day 14 and Day 28 | The National Early Warning Score (NEWS) determines the degree of illness of a patient using six physiological findings and one observation. Score from 0 to 20, 0 mean a worse outcome, 20 mean a better outcome | After 3 days, 10 days, 14 days and 28 days of treatment | 
| Change in inflammatory parameter | C-reactive proteine (mg/L) | From baseline to Day 3, Day 10, Day 14 and Day 28 | 
| Change in inflammatory parameter | ferritin (ng/mL) | From baseline to Day 3, Day 10, Day 14 and Day 28 | 
| Change in inflammatory parameter | lymphocyte count (G/L) | From baseline to Day 3, Day 10, Day 14 and Day 28 | 
| Change in inflammatory parameter | fibrinogen (g/l) | From baseline to Day 3, Day 10, Day 14 and Day 28 | 
| Hospital length of stay | Hospital length of stay | Up to 28 days | 
| ICU parameter | Need for Vasopressors (yes or no) | Up to 28 days | 
| ICU parameter | Evolution of SpO2/FIO2 ratio (no unit) | Up to 28 days | 
| ICU parameter | Evolution of PaO2/FiO2 ratio (no unit) | Up to 28 days | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Occurrence of serious adverse events during the study, including infection (bacterial, parasitic, mycotic and viral infection), septic shock, Ankanira hypersensitivity, hepatic damages (SGOT/SGPT, alkaline phosphatase, gammaGT) and neutropenia (Blood count). | Up to 28 days | 
| Predictors of efficacy of Anakinra | The correlation between several of clinical parameters at inclusion (including level of oxygen requirement (saturation), respiratory rate (per min), temperature (°C)…), biological parameters :including, CRP (mg/L), ferritin (µg/L), LDH (UI/L), lymphocyte count (G/L), eosinophil count (G/L), Ddimers (ng/mM), platelet count (G/L), polymorphonuclear count (G/L)...with the primary end point will be explored. | After 14 days of treatment |