Covid-19 living Data

Anakinra vs Standard care/Placebo (RCT)

Hospitalized patients

On Jan 26th, 2022, we published results of the Interleukin‐1 blocking agents for treating COVID‐19 which included all preprints and published trials published online up to November 5, 2021.

FOREST PLOTS -2022-10-07

Studies description

Trial NCT04324021
Publication Andersson H, Unpublished (2022) (results posted on registry)

Funding: Private (Swedish Orphan Biovitrum)
Conflict of interest: *

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / USA, Italy Follow-up duration (days): 70
Inclusion criteria	Signed informed consent provided by the patient, or by the patient's legally authorized representative(s), as applicable Documented presence of SARS-CoV-2 infection as per hospital routine Age > 18 to < 85 years at the time of screening Presence of respiratory distress, defined as: PaO2/FiO2 < 300 mm Hg and >200 mm Hg or Respiratory Rate (RR) ≥30 breaths/min or SpO2 < 93 percent in air at rest. Note: Patients given continous positive airway pressure (CPAP) ventilator support are eligible for inclusion Presence of hyperinflammation defined as: 1. Lymphocyte counts: < 1000 cells/µL, in patients who have not received systemic glucocorticoids for at least 2 days prior to the assessment of the lymphocyte count < 1200 cells/µL, in patients who have received systemic glucocorticoids for at least 2 days prior to the assessment of the lymphocyte count and 2. One of the following three criteria: i. Ferritin > 500ng/mL ii. LDH > 300 U/L iii. D-Dimers > 1000 ng/mL
Exclusion criteria	Patients in mechanical ventilation or with modified early warning score (MEWS) >4 with evidence of moderate or above ARDS (Berlin definition, namely with PaO2/FiO2 >100, but <200 mm Hg) or severe respiratory insufficiency or evidence of rapid worsening (respiratory distress requiring mechanical ventilation or presence of shock or presence of concomitant organ failure requiring ICU admission). Note: For the evaluation of patient eligibility, temperature will not be considered in the calculation of the total MEWS score since presence of fever is a hallmark of SARS-CoV-2 infection Impairment of cardiac function defined as poorly controlled heart diseases, such as New York heart association (NYHA) class II (mild) and above, cardiac insufficiency, unstable angina pectoris, myocardial infarction within 1 year before enrollment, supraventricular or ventricular arrhythmia need treatment or intervention Severe renal dysfunction (estimated glomerular filtration rate ≤ 30 mL/min/1.73 m2) or receive continuous renal replacement therapy, hemodialysis, or peritoneal dialysis Uncontrolled hypertension (seated systolic blood pressure >180 mmHg, or diastolic blood pressure >110mmHg) Administration of plasma from convalescent patients who recovered from SARS-CoV-2 infection Clinical suspicion of latent tuberculosis History of hypersensitivity or allergy to any component of the study drug Pregnant women 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 Enrollment in another concurrent clinical interventional study, or intake of an investigational drug within three months or 5 half-lives prior to inclusion in this study, if considered interfering with this study objectives as assessed by the Investigator Foreseeable inability to cooperate with given instructions or study procedures Clinical suspicion of active mycobacteria, histoplasma capsulatum, herpes zoster, salmonella, and shigella Infections Patients with liver dysfunction defined as AST or ALT > 5 × ULN
Interventions
	Treatment Emapalumab Initial dose: 6 mg/kg IV infusion on day 1. Maintenance dose: 3 mg/kg IV infusion every 3rd day on days 4, 7, 10, 13. Anakinra 100 mg IV infusion 4 times daily for 15 days
	Control Standard care
Participants
	Randomized participants : Emapalumab=5 Anakinra=5 Standard care=6
	Characteristics of participants N= 16 Mean age : NR 14 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=16 Critical: n=0
Primary outcome
	In the register Number of Participants With Treatment Success [ Time Frame: Up to Day 15 ] Defined as the number of patients not requiring invasive mechanical ventilation or Extracorporeal membrane oxygenation (ECMO)
	In the report NR
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Not reported
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	This is an unpublished trial whose results have been reported in ClinicalTrials.gov. The trial registry, protocol and statistical analysis plan were used in data extraction and assessment of risk of bias. The trial was registered prospectively and no important changes were made to primary or secondary outcomes after recruitment start. The trial (n = 16) did not achieve its target sample size (n = 52) and is underpowered to assess statistical significance between the treatment and placebo group. The trial was terminated Quote: "Standard of care evolved during the timeframe of the study and had critical impact on recruitment. Early termination was not based on safety reasons but due to the reasons mentioned above. The ongoing patients were completed."

Trial NCT04364009
Publication ANACONDA - Audemard-Verger A, Plos One (2022) (published paper)
Dates: 2020-04-27 to 2020-10-06
Funding: Public/non profit (Tours university hospital)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / France Follow-up duration (days): 28
Inclusion criteria	Confirmed SARS-CoV-2 infection: positive rRT-PCR and/or typical chest or computed tomographic scan of COVID 19 pneumonia and required oxygen therapy defined by either (i) O2 ≥ 4L/min to maintain Sp02> 92% and respiratory rate≥ 24/min or (ii) O2≥ 1L/min and oxygen requirement deterioration defined by an increase in oxygen therapy ≥ 2L/min to maintain Sp02> 92% inflammatory component (reactive C-protein ≥ 50mg/L) and were treated with antibiotics (according to local practice)
Exclusion criteria	Need for mechanical ventilation or O2 > = 11 L/min in order to maintain Sp02> 92% contra indication to anakinra and concurrent bacterial infection
Interventions
	Treatment Anakinra Initial dose: 400mg/day (100mg IV every 6 hours) by IV for 3 days - Maintenance dose: 200mg/day (100mg every 12 hours) by IV for 7 days. In case of renal failure (eGFR<30ml/min), anakinra was administrated 1 day out 2.
	Control Standard care
Participants
	Randomized participants : Anakinra=37 Standard care=34
	Characteristics of participants N= 71 Mean age : NR 52 males Severity : Mild: n=0 / Moderate: n=* / Severe: n=* Critical: n=0
Primary outcome
	In the register Treatment success [ Time Frame: After 14 days of treatment ] 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)
	In the report Treatment success at day 14, defined as a patient being alive and not requiring either of the following: invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO)
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: N
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the registry, protocol, and statistical analysis plan were available for data extraction and risk of bias assessment. The trial was terminated because of safety concerns therefore the study (n=71) did not achieve the target sample size (n=240).There is no change from the trial registration in the intervention and control treatments. The primary outcome indicated in registry reflects the primary outcome reported in the paper.

Trial NCT04330638; EudraCT2020-001500-41
Publication COV-AID - Declercq J, Lancet Respir Med (2021) (published paper)
Dates: 2020-04-04 to 2020-12-06
Funding: Public/non profit (Belgian Health Care Knowledge Center; VIB Grand Challenges (Flemish Institute for Biotechnology))
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Belgium Follow-up duration (days): 90
Inclusion criteria	older than 18 years had a laboratory proven diagnosis of COVID-19 with symptoms between 6 and 16 days a ratio of the partial pressure of oxygen (PaO2) to the fraction of inspired oxygen (FiO2 P:F ratio) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen and bilateral pulmonary infiltrates either a single ferritin concentration measurement of more than 2000 μg/L at inclusion when they immediately required high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 μg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 μg/L, an increasing lactate dehydrogenase concentration of more than 300 international units (IU)/L, an increasing CRP concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL. If the patient had three of the previous criteria at hospital admission with lymphopenia of less than 800/μL, there was no need to document an increase over 24 h.
Exclusion criteria	mechanical ventilation for more than 24 h at randomisation a clinical frailty score greater than 3 before SARS-CoV-2 infection unlikelihood to survive beyond 48 h based on clinical assessment an active co-infection defined on clinical grounds (positive blood or sputum cultures) thrombocytopenia of less than 50 000/μL neutropenia of less than 1500/μL a history of bowel perforation or diverticulitis high dose systemic steroid or immunosuppressive drug use for a COVID-19-unrelated disorder.
Interventions
	Treatment Anakinra 100 mg once daily subcutaneously for 28 days or until hospital discharge Anakinra+Tocilizumab Anakinra 100 mg once daily subcutaneously for 28 days or until hospital discharge + Tocilizumab 8 mg/kg IV single dose (not exceeding 800 mg) Anakinra+Siltuximab Anakinra 100 mg once daily subcutaneously for 28 days or until hospital discharge + Siltuximab 11 mg/kg IV single dose Tocilizumab 8 mg/kg IV single dose (not exceeding 800 mg) Siltuximab 11 mg/kg IV single dose
	Control Standard care
Participants
	Randomized participants : Anakinra =43 Anakinra+Tocilizumab=32 Anakinra+Siltuximab=37 Tocilizumab=82 Siltuximab=76 Standard care=72
	Characteristics of participants N= 342 Mean age : NR 90 males Severity : Mild: n=1 / Moderate: n=58 / Severe: n=39 Critical: n=17
Primary outcome
	In the register Time to Clinical Improvement [Time Frame: at day 15]: defined as the time from randomization to either an improvement of two points on a six-category ordinal scale or discharge from the hospital: a) Death; b) Hospitalized, on invasive mechanical ventilation or ECMO; c) Hospitalized, on non-invasive ventilation or high flow oxygen devices; d) Hospitalized, requiring supplemental oxygen; e) Hospitalized, not requiring supplemental oxygen; f) Not hospitalized.
	In the report time to clinical improvement, defined as the time in days from randomisation until either an increase of at least two points on a 6-category ordinal scale (compared with the worst status at day of randomisation) or to discharge from the hospital alive, whichever occurred first. The 6-category ordinal scale was defined as 1=death; 2=hospitalised, on invasive mechanical ventilation or extracorporeal membrane oxygenation; 3=hospitalised, on non-invasive ventilation or high-flow oxygen devices; 4=hospitalised, requiring supplemental oxygen; 5=hospitalised, not requiring supplemental oxygen; 6=not hospitalised.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the study registry, supplementary material, protocol and statistical analysis plan were used in data extraction and risk of bias assessment. The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group "Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis." JAMA. 2021;326(6):499-518 was also available. The study achieved the target sample size specified in the trial registry. There are no important changes from the trial registration in the primary outcome, procedures, intervention and control treatments. Total adverse events were not reported (but this had been pre-specified). 11% were critical at study start. Overall median age was 65 years (IQR 54–73) and 77% were male. Data presented for the outcomes mortality (D28), time to death, score 7 and above (D28), serious adverse events and clinical improvement (D28) (this last only for Tocilizumab and Siltuximab) were extracted from The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group "Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis." JAMA. 2021;326(6):499 518. The authors have been contacted in order to obtain the results.

Trial NCT02735707
Publication REMAP-CAP - Derde L, medRxiv (2021) (preprint)
Dates: 2020-03-25 to 2021-04-10
Funding: Mixed (PREPARE consortium by the European Union; FP7-HEALTH-2013-INNOVATION-1; RECOVER consortium by the European Union Horizon 2020 research and innovation program; Australian National Health and Medical Research Council; Health Research Council of New Zealand; Canadian Institute of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program Grant; UK NIHR; NIHR Imperial Biomedical Research Centre; Health Research Board of Ireland; UPMC Learning While Doing Program; Translational Breast Cancer Research Consortium; Global Coalition for Adaptive Research; French Ministry of Health; Minderoo Foundation; Wellcome Trust Innovations Project; Netherlands Organization for Health Research and Development ZonMw; NIHR Research Professorship; NIHR Clinician Scientist Fellowship; Australian National Health and Medical Research Council Career Development Fellowship; Roche Products Ltd; Sanofi (Aventis Pharma Ltd); Swedish Orphan Biovitrum AB (Sobi); Faron Pharmaceuticals (drug provision in some countries) )
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / UK, Netherlands, Ireland, Australia, New Zealand, Canada, Finland, Italy, Saudi-Arabia Follow-up duration (days): 90
Inclusion criteria	Participants aged > 18 years suspected or microbiologically confirmed COVID-19 receiving or not respiratory or cardiovascular organ support within 24 hours in an ICU.
Exclusion criteria	Death deemed to be imminent and inevitable during the next 24 hours one or more of the participant, substitute decision maker or attending physician are not committed to full active treatment more than 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to suspected or proven pandemic infection or more than 24 hours elapsed since ICU admission previous participation in this REMAP within the last 90 days patient has already received any dose of one or more of any form of interferon, anakinra, tocilizumab, or sarilumab during this hospitalization long-term therapy with any of these agents prior to this hospital admission patient has been randomized in a trial evaluating an immune modulation agent for proven or suspected COVID-19 infection where the protocol of that trial requires ongoing administration of study drug known condition or treatment resulting in ongoing immune suppression including neutropenia prior to this hospitalization intention to prescribe systemic corticosteroids for any reason, other than participation in the Corticosteroid domain of this platform, is an exclusion criterion to receive IFN-β1a known hypersensitivity to proteins produced by E. coli will result in exclusion criterion to receive anakinra known or suspected pregnancy is an exclusion criterion to receive the anakinra, IFN-β1a, tocilizumab, and sarilumab interventions a baseline alanine aminotransferase or an aspartate aminotransferase that is more than five times the upper limit of normal is an exclusion criterion to receive tocilizumab or sarilumab a baseline platelet count < 50 x 109 / L is an exclusion criterion to receive tocilizumab or sarilumab.
Interventions
	Treatment Anakinra Initial dose: 300 mg intravenously for the first 24 hours - Maintenance dose: 100 mg intravenously 4 times a day for 14 days or until either free from invasive mechanical ventilation for more than 24 hours, or discharge from ICU. Sarilumab 400 mg IV single dose Tocilizumab 8 mg/kg IV infusio single dose, maximum 800 mg, a second infusion could be administered 12 to 24 hours after the first.
	Control Standard care
Participants
	Randomized participants : Standard care=418 Anakinra=378 Sarilumab=485 Tocilizumab=972
	Characteristics of participants N= 2253 Mean age : NR 1536 males Severity : Mild: n=0 / Moderate: n=4 / Severe: n=1482 Critical: n=730
Primary outcome
	In the register All-cause mortality [Time Frame: Day 90]; Days alive and not receiving organ support in ICU [Time Frame: Day 21]
	In the report An ordinal scale that is a composite of in-hospital mortality and duration of respiratory and cardiovascular organ support, censored at 21 days, where all deaths within hospital and up to day 90 were assigned the worst outcome
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the pre-print version of the article, the study registry and protocol were used in data extraction and risk of bias assessment. The report contains definite results of tocilizumab, sarilumab and anakinra from the Immune Modulation Therapy domain of the REMAP-CAP clinical trial (an international, adaptive platform trial). There is no change from the trial registration in the intervention and control treatments. The platform initially included only participants admitted to an intensive care unit and receiving respiratory or cardiovascular organ support, a moderate state enrolling hospitalized participants not receiving respiratory or cardiovascular organ support was added subsequently. A blinded International Trial Steering Committee (ITSC) closed all arms of the domain on April 10, 2021. The primary outcome indicated in the registry reflects the primary outcome reported in the paper. Adverse events are not reported.

Trial NCT04643678
Publication Elmekaty E, medRxiv (2022) (preprint)
Dates: 2020-10-30 to 2021-04-30
Funding: Public/non profit (Hamad Medical Corporation, Qatar)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / Qatar Follow-up duration (days): 28
Inclusion criteria	Hospitalized adults (age ≥ 18yrs) confirmed COVID-19 diagnosis by positive SARS-CoV2 Polymerase Chain Reaction (PCR) test associated presence of respiratory distress [defined as: PaO2/FiO2 ≤ 300 mm Hg or respiratory Rate (RR) 152 ≥24 breaths/min or SpO2 ≤ 94% at room air] signs of cytokine release syndrome [defined as any of the following at baseline: Ferritin >600 mcg/L at presentation or >300 mcg/l with doubling within 24 hours, LDH >250 IU/L, D-dimers > 1 mg/L, CRP > 70mg/L and rising since last 24h with the absence of bacterial infection, Interleukin-6 level > 10 x UNL (reference range ≤7 pg/ml)] radiological evidence of pneumonia based on chest X-ray and/or computed tomography (CT) scan findings signed informed consent provided by the patient, or by the patient's legal representative.
Exclusion criteria	Known serious allergic reactions including anaphylaxis to the study medication or any component of the product active infectious diseases such as active bacterial infections (defined as the isolation of bacteria from a sterile body site or other body sites and is causing clinical symptoms and signs and therefore are treated with antibiotics) invasive fungal infections Human Immunodeficiency Virus (HIV) Hepatitis B Virus (HBV) infection Hepatitis C Virus (HCV) infection active tuberculosis patients on immunosuppressants or immunomodulatory drugs or had received any in the past 30 days neutrophil count below 500 cells/microliter platelets below 50,000/microliter pregnant or breastfeeding females.
Interventions
	Treatment Anakinra Initial dose: 100 mg subcutaneous (SC) injection every 12 hours for 3 days - Maintenance dose: 100 mg SC once daily from day 4 to day 7
	Control Standard care
Participants
	Randomized participants : Anakinra=40 Standard care=40
	Characteristics of participants N= 80 Mean age : NR 66 males Severity : Mild: n=0 / Moderate: n=0 / Severe: n=77 Critical: n=3
Primary outcome
	In the register Treatment Success at day 14 [ Time Frame: Day 14 ] Defined as WHO Clinical Progression score of ≤3 [Ambulatory mild disease: symptomatic; assistance needed].
	In the report Treatment success on day 14, defined as a WHO Clinical Progression score of ≤3 [Ambulatory mild disease: symptomatic, assistance needed]
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	“In addition to the preprint article, the retrospective study registry was used in data extraction and risk of bias assessment. The protocol and statistical analysis plan were not available. As the registry was retrospective, we are unable to determine if the sample size, interventions and outcomes were determined a priori."

Trial IRCT20120703010178N20
Publication Kharazmi AB, Immun Inflamm Dis (2021) (published paper)
Dates: 2020-05-01 to 2020-07-30
Funding: Private (Persisgen Par Pharmaceutical Company)
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Single center / Iran Follow-up duration (days): 14
Inclusion criteria	Confirmed diagnosis of COVID‐19 based on the reverse transcriptase‐polymerase chain reaction Admitted to the intensive care unit (ICU) age of 18 years old or more Elevated C‐reactive protein (CRP) levels Oxygen saturation less than or equal to 93% measured using a peripheral capillary pulse oximeter Fever (core temperature of 37.8°C or more), or cough or shortness of breath PaO2/FiO2 less than 300
Exclusion criteria	Positive results for tuberculosis (i.e., positive Mendel–Mantoux or QuantiFERON test) Viral hepatitis B or C Hemoglobin less than 7.5 g/dl Platelet count of fewer than 100,000 cells/µl Serum glutamic–oxaloacetic transaminase, or serum glutamic–pyruvic transaminase more than five upper limits of normal Untreated active infection Previous administration of canakinumab or anakinra
Interventions
	Treatment Anakinra 100 mg/day intravenously for up to 14 days
	Control Standard care
Participants
	Randomized participants : Anakinra=15 Standard care=15
	Characteristics of participants N= 30 Mean age : NR 19 males Severity : Mild: n=0 / Moderate: n=9 / Severe: n=16 Critical: n=5
Primary outcome
	In the register 1) No need for hospitalization; 2) Hospitalization without need for oxygenation therapy; 3) Hospitalization with oxygen therapy; 4) Hospitalization with receiving non-invasive ventilation or high flow oxygen cannula; 5) Hospitalization with receiving mechanical ventilation or extra-corporeal membrane oxygenation ; 6) Death (During first 14 days or hospitalization period)
	In the report Need for endotracheal intubation due to hypoxemia
Documents avalaible	Protocol NR Statistical plan NR Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the retrospective trial registry was used in data extraction and assessment of risk of bias. Neither protocol nor statistical analysis plan was available. The primary outcome in the article (mechanical ventilation) differed from that in the registry (score on a 7-point ordinal scale). As the registry is retrospective, there is no information on whether the sample size, outcomes or data analysis were determined a-priori. Patients in the control group were considerably older than the treatment group (mean 59.00 ± 1.79 years versus 49.25 ± 19.12) and more had hypertension (53.3% versus 13.3%), diabetes (53.3% versus 20.0%) and coronary artery disease (33.3% versus 20.0%). The study (n = 30) achieved its target sample size (n = 30).

Trial NCT04680949; EudraCT 2020-005828-11
Publication SAVE-MORE - Kyriazopoulou E, Nat Med (2021) (published paper)
Dates: 2020-12-23 to 2021-03-31
Funding: Mixed (Hellenic Institute for the Study of Sepsis and Swedish Orphan Biovitrum AB (Sobi))
Conflict of interest: Yes

Methods
	RCT Blinding: double blinding
	Location : Multicenter / Greece, Italy Follow-up duration (days): 28
Inclusion criteria	adult patients of either gender for women, unwillingness to remain pregnant during the study period confirmed infection by SARS-CoV-2 virus by molecular test findings in chest-X-ray or in chest computed tomography compatible with lower respiratory tract infection need for hospitalization plasma suPAR 675 ≥6ng/ml
Exclusion criteria	any stage IV malignancy any do not resuscitate decision ratio or partial oxygen pressure to fraction of inspired oxygen less than 150 need of non-invasive ventilation (CPAP or BPAP) or mechanical ventilation any primary immunodeficiency less than 1,500 neutrophils/mm3 oral or intravenous intake of corticosteroids at a daily dose equal or greater than 0.4 mg/kg prednisone for a period greater than the last 15 days any anti-cytokine biological treatment including JAK inhibitors the last one month severe hepatic failure end-stage renal failure necessitating hemofiltration or peritoneal hemodialysis pregnancy or lactation.
Interventions
	Treatment Anakinra 100 mg subcutaneously once daily for 7-10 days
	Control Placebo
Participants
	Randomized participants : Placebo=194 Anakinra=412
	Characteristics of participants N= 606 Mean age : NR 344 males Severity : Mild: n=33 / Moderate: n=118 / Severe: n=440 Critical: n=0
Primary outcome
	In the register Comparison of the distribution of frequencies of each score of a 5-scale patient state evaluated from the 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment [ Time Frame: 28 days ]
	In the report Overall comparison of the distribution of frequencies of the scores from the 11-point WHO Clinical Progression ordinal Scale (CPS) between the two arms of treatment at Day 28
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication: Yes
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published/pre-print articles, the protocol, statistical analysis plan, prospective study registries, supplementary appendices and contact with authors were used in data extraction and risk of bias assessment. Protocol and statistical analysis plan were not available at the time of data extraction. The study achieved the target sample size specified in the trial registries. There is no change from the trial registration in the population or intervention and control treatments. Some timepoints for outcomes listed in the registry were not reported in the paper (e.g. negative viral conversion on day 7 (reported on day 28, day 7 results gained from contact with authors), serious adverse events on day 60 and 90 (reported on day 28). This trial was updated on July 28th, 2021 with data gained from contact with authors. This trial was updated on August 25th, 2021 with day 90 data gained from further contact with authors. This trial was updated on October 25th, 2021 with data from the peer-reviewed published report.

Trial NCT04341584
Publication CORIMUNO-ANA-1 - Mariette X, Lancet Respir Med (2021) (published paper)
Dates: 2020-04-08 to 2020-04-26
Funding: Public/non profit (The Ministry of Health, Programme Hospitalier de Recherche Clinique, Foundation for Medical Research, and AP-HP Foundation )
Conflict of interest: No

Methods
	RCT Blinding: Unblinded
	Location : Multicenter / France Follow-up duration (days): 90
Inclusion criteria	CORIMUNO-19 cohort: SARS-CoV-2 infection (positive on real-time RT-PCR or chest CT scan typical of COVID-19 pneumonia, or both) Mild-to-moderate, severe, or critical pneumonia (ie, receiving oxygen at a flow of >3 L/min via mask or nasal cannula and a score of ≥5 points on the WHO Clinical Progression Scale [WHO-CPS] 10-point ordinal scale CORIMUNO-ANA-1: C-reactive protein serum concentration of more than 25 mg/L Not requiring ICU at admission Mild-to-moderate COVID-19 pneumonia with a WHO-CPS score of 5 points, receiving at least 3 L/min of oxygen but without ventilation assistance (eg, high-flow oxygen, non-invasive ventilation, or mechanical ventilation)
Exclusion criteria	Known hypersensitivity to anakinra or any of its excipients Pregnancy Current documented bacterial infection An absolute neutrophil count of 1·0 × 109 per L or less A platelet concentration of less than 50 G/L Serum aspartate aminotransferase or serum alanine aminotransferase of more than five- times the upper limit of normal Severe renal insufficiency defined by an estimated glomerular filtration rate of less than 30 mL/min
Interventions
	Treatment Anakinra 200 mg IV twice daily on days 1-3, 100 mg twice daily on day 4, 100 mg once daily on day 5. If no improvement on morning day 4 (>50% reduction in oxygen requirement), 200 mg twice daily days 4–6, 100mg twice daily day 7, 100 mg once daily day 8
	Control Standard care
Participants
	Randomized participants : Standard care=57 Anakinra=59
	Characteristics of participants N= 116 Mean age : NR 80 males Severity : Mild: n=0 / Moderate: n=114 / Severe: n=0 Critical: n=0
Primary outcome
	In the register Survival without needs of ventilator utilization at day 14 [ Time Frame: 14 days ]; WHO progression scale ≤ 5 [ Time Frame: 4 days ]; Cumulative incidence of successful tracheal extubation (defined as duration extubation > 48h) or withdrawal of NIV or high flow (for > 48h), at day 14 [ Time Frame: 14 days ]; Decrease of at least one point in WHO progression scale score [ Time Frame: 4 days ]
	In the report The proportion of patients who had died or needed non-invasive or mechanical ventilation by day 4 (ie, a score of >5 points on the WHO-CPS); and Survival with no need for mechanical or non-invasive ventilation (including high- flow oxygen) at day 14.
Documents avalaible	Protocol Yes. In English Statistical plan Yes Data-sharing willing stated in the publication:
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published paper, the trial registry, statistical analysis plan and supplementary methods and results were used in data extraction and assessment of risk of bias. The SAP was dated September 21st, 2020 and was version 2.1. This was likely after unblinded data was available for analysis hence it was not used in the risk of bias assessment of domain 5, selection of the reported result. One co-primary outcome in the registry was not reported (decrease of at least one point in WHO progression scale score), but raw data for WHO progression scale scores were reported. This was one of a series of randomized controlled trials testing different therapeutic regimens. Quote: "On April 23, 2020, the DSMB met and recommended suspension of recruitment for futility on the basis of the interim analysis of the 102 first patients recruited, although the futility boundaries were not formally crossed. The sponsor decided to discontinue the study on April 26, 2020." As a result, the target sample size specified in the registry was not achieved. Quote: "Another trial within the CORIMUNO platform (CORIMUNO-ANA-2) that aims to assess the effect of anakinra in patients with more severe COVID-19 who are in intensive care units (WHO-CPS score ≥6 points) has now been completed and is being analysed."