Pneumonies à SARS-CoV-2

22es JNI, Montpellier du 30/08 au 1er/09/2021

Pneumonies à SARS-CoV-2Actualités et perspectives

thérapeutiquesDr Paul Loubet


Déclaration de liens d’intérêt avec les industries de santé en rapport avec le thèmede la présentation (loi du 04/03/2002) :

Consultant ou membre d’un conseil scientifique : Astrazeneca, GSK, Pfizer

Conférencier ou auteur/rédacteur rémunéré d’articles oudocumentsPrise en charge de frais de voyage, d’hébergement oud’inscription à des congrès ou autres manifestations Gilead, Pfizer

Investigateur principal d’une recherche ou d’une étude clinique

OUI NON

OUI NON

OUI NON

OUI NON

L’orateur ne souhaite pas répondre

Intervenant : Paul Loubet

Titre : Pneumonies à SARS-CoV-2 Actualités et perspectives thérapeutiques


Plan

• Thérapies antivirales§ Remdesivir§ Plasma convalescents§ Ac Monoclonaux

• Thérapies Immunomodulatrices§ Corticoïdes§ Anti-IL6§ Anti-IL1§ Inhibiteur JAK

3

1269Pharmaco-Immunomodulatory Therapy in COVID-19

vs. 73%, hazard ratio (HR) 0.22, 95% confidence interval (CI) 0.11–0.41, p < 0.0001] [21]. The efficacy of high-dose anakinra was evaluated in intensive care unit COVID-19 patients with a positive hemophagocytosis score (HScore) and diagnosed sHLH [22]. The mortality was lower than previous series of patients with sHLH in sepsis, although three patients died. The use of anakinra was associated

with less need for vasopressors, significantly improved pulmonary function, and lower HScore.

A phase III, randomized, open-label, multicenter trial (NCT04324021) evaluating the efficacy and safety of anakinra and emapalumab, an anti-interferon (IFN)-γ antibody, in the treatment of hyperinflammatory syn-drome caused by the cytokine storm commenced on 2

Fig. 1 Schematic representation of the immunomodulators’ site of action. Hydroxychloroquine, azithromycin, statins, RAASi and their combinations have not been reliably shown to be of benefit in hospi-talized patients with COVID-19, and therefore are represented here to define a potential pathophysiological target for therapy. This should not be seen as endorsement for use of such agents. The use of hydrox-ychloroquine and azithromycin in COVID-19 patients may be asso-ciated with harm. Whether such agents are beneficial in other stages of infection remains a matter of study. Created with biorender.com. Ang II angiotensin II, GM-CSF granulocyte–macrophage colony-

stimulating factor, IFN interferon, IL interleukin, IL-6R interleukin-6 receptor, IVIG intravenous immunoglobulin, JAK Janus kinase, JAK-STAT Janus kinase-signal transducer and activator of transcription, MIP-1α macrophage inflammatory protein 1-α, MyD88 myeloid dif-ferentiation primary response 88, NF-κB nuclear factor-κB, RAAS renin–angiotensin–aldosterone system, rhuGM-CSF recombinant human granulocyte–macrophage colony-stimulating factor, sIL-6R soluble IL-6 receptor, TLR toll-like receptor, TNF tumor necrosis fac-tor reserve

Rizk Drugs 2020


Remdesivir, Plasma de convalescents, mAbsThérapies antivirales

4


Remdesivir (analogue nucleosidique)

5n engl j med 383;19 nejm.org November 5, 2020 1823

Remdesivir for Covid-19

13.0 to 28.0) in the remdesivir group and 23.0 days (95% CI, 15.0 to 28.0) in the placebo group (hazard ratio for clinical improvement, 1.23; 95% CI, 0.87 to 1.75).14 That trial did not com-plete full enrollment owing to local control of the outbreak, had lower power than ACTT-1 ow-ing to the smaller sample size and a 2:1 random-ization, and was unable to demonstrate any statistically significant clinical benefits of rem-desivir. In the recently published, open-label, randomized study of remdesivir in hospitalized patients with moderate-severity Covid-19 (83% were not receiving oxygen at baseline), patients who received remdesivir for 5 days had higher odds of clinical improvement than those receiv-ing standard care (odds ratio, 1.65; 95% CI, 1.09

to 2.48; P = 0.02). This benefit was not seen with the 10-day course (P = 0.18).15 We believe that these other studies support our findings regard-ing the efficacy of remdesivir; however, our study was larger, blinded, and fully enrolled.

The primary outcome of the current trial was changed early in the trial, from a comparison of the eight-category ordinal scale scores on day 15 to a comparison of time to recovery up to day 29. Little was known about the natural clinical course of Covid-19 when the trial was designed in February 2020. Emerging data suggested that Covid-19 had a more protracted course than was previously known, which aroused concern that a difference in outcome after day 15 would have been missed by a single assessment at day 15.

Figure 3. Time to Recovery According to Subgroup.

The widths of the confidence intervals have not been adjusted for multiplicity and therefore cannot be used to infer treatment effects. Race and ethnic group were reported by the patients.

1.00 3.002.00

Remdesivir BetterPlacebo Better

All patientsGeographic region

North AmericaEuropeAsia

RaceWhiteBlackAsianOther

Ethnic groupHispanic or LatinoNot Hispanic or Latino

Age18 to <40 yr40 to <65 yr≥65 yr

SexMaleFemale

Symptoms duration≤10 days>10 days

Baseline ordinal score4 (not receiving oxygen)5 (receiving oxygen)6 (receiving high-flow oxygen or

noninvasive mechanical ventilation)7 (receiving mechanical ventilation or ECMO)

No. ofPatients Recovery Rate Ratio (95% CI)Subgroup

0.98 (0.70–1.36)

1.09 (0.76–1.57)

1.37 (1.14–1.64)1.20 (0.94–1.52)

1.45 (1.18–1.79)1.29 (0.91–1.83)

1.31 (1.03–1.66)1.30 (1.09–1.56)

1.19 (0.98–1.44)1.29 (1.00–1.67)

1.95 (1.28–2.97)

1.28 (0.94–1.73)1.31 (1.10–1.55)

1.68 (1.10–2.58)

1.25 (0.91–1.72)1.07 (0.73–1.58)

1.30 (0.91–1.87)1.36 (0.74–2.47)

1.29 (1.06–1.57)

1.30 (1.10–1.53)

1.29 (1.12–1.49)

0.500.33

1062

84716352

566226135135

250755

119559384

684278

676383

138435193

285

The New England Journal of Medicine Downloaded from nejm.org on August 18, 2021. For personal use only. No other uses without permission.

Copyright © 2020 Massachusetts Medical Society. All rights reserved.

Beigel NEJM 2020ACTT-1

CJS: Mortalité Patient sous 02 HR 0.30 (0.14-0.64)

NEJM 2021SOLIDARITY

n engl j med 384;6 nejm.org February 11, 2021 507

Repurposed Antivir al Drugs for Covid-19

or in any particular subgroup. The findings for mortality and for initiation of ventilation cannot have been appreciably biased by the open-label design without placebos, or by variation in local care or patient characteristics, and were little affected when homogeneity was increased by stratification according to geographic region, age, or use of ventilation at entry. No trial drug reduced the initiation of mechanical ventilation. The simi-larity of this null effect for all four drugs is further evidence that none has any material ef-

fect on major disease progression, a conclusion supported by analyses of the combined outcome of death or ventilation initiation.

Although assignment to any of the active trial treatments in this open-label trial somewhat delayed discharge from the hospital, this could have been because some recovered patients oth-erwise fit for discharge were kept in the hospital merely to continue their trial treatment. In all patients and in those not receiving ventilation, assignment to each active trial drug increased

Figure 4. Meta-Analysis of Mortality in Trials of Random Assignment of Remdesivir or Its Control to Hospitalized Patients with Covid-19.

Percentages show Kaplan–Meier 28-day mortality. Values for observed minus expected number of deaths (O − E) are log-rank O − E for the Solidarity trial, O − E from 2-by-2 tables for the Wuhan7 and international8 trials, and w.loge hazard ratio for each stratum in the Adap-tive Covid-19 Treatment Trial (ACTT-1)6 (with the weight w being the inverse of the variance of the loge hazard ratio, which was calculated from the confidence interval of the hazard ratio). Rate ratios were calculated by taking the loge rate ratio to be (O − E)/V with a Normal distribution and variance 1/V. Subtotals or totals of (O − E) and of V yield inverse-variance–weighted averages of the loge rate ratios. For balance, controls in the 2:1 trials were counted twice in the control totals and subtotals. Diamonds show 95% confidence intervals for treatment effects. Squares and horizontal lines show treatment effects in particular subgroups and their 99% confidence intervals, with an arrow if the upper 99% confidence limit is outside the range shown. The area of each square is proportional to the variance of O − E in the subgroup it describes.

0.5 1.0 2.0 2.51.5 3.0

Control BetterRemdesivir Better

Solidarity (stratified according tooxygen use and ventilation)

No supplemental oxygenLow-flow or high-flow oxygenVentilationStratified total: Solidarity

ACTT-1 (stratified according to 4 ordinal score levels)

No supplemental oxygenLow-flow oxygenHigh-flow oxygen or noninvasive

ventilationInvasive ventilationStratified total: ACTT-1

Trials with few deaths (and randomization ratio of 2:1)

Wuhan: low-flow oxygenWuhan: high-flow oxygen or ventilationInternational: no supplemental oxygenStratified total: 2:1 trials

Risk groups (calculated by summationof relevant strata)

Lower risk: strata with noventilation

Higher riskStratified totalHeterogeneity between trials (Solidarity vs. ACTT-1 vs. 2:1 trials): χ2

2=0.5

RemdesivirRate Ratio for Death

(99% CI; 95% CI for totals)

Observed–ExpectedNo. of Deaths in Remdesivir GroupControlSubgroup

no. of deaths reported/no. of patients (%)

Value Variance

11/661 (2.0) 13/664 (2.1)

0.0

0.90 (0.31–2.58) 192/1828 (12.2) 219/1811 (13.8) 0.85 (0.66–1.09) 98/254 (43.0) 71/233 (37.8) 1.20 (0.80–1.80)

301/2743 (12.5) 303/2708 (12.7) 0.94 (0.80–1.10)

3/75 (4.1) 3/63 (4.8) 0.82 (0.10–6.61) 9/232 (4.0) 25/203 (12.7) 0.30 (0.11–0.81)19/95 (21.2) 20/98 (20.4) 1.02 (0.44–2.34)

28/131 (21.9) 29/154 (19.3) 1.13 (0.57–2.23) 59/533 (11.1) 77/518 (14.9) 0.82 (0.58–1.16)

11/129 (8.5) (7/68)×2 (10.3) 0.81 (0.21–3.07)11/29 (37.9) (3/10)×2 (30.0) 1.40 (0.20–9.52)5/384 (1.3) (4/200)×2 (2.0) 0.64 (0.10–3.94)27/542 (5.0) (14/278)×2 (5.0) 0.86 (0.42–1.77)

231/3309 (7.0) 282/3277 (8.6) 0.80 (0.63–1.01)

156/509 (30.6) 126/505 (25.0) 1.16 (0.85–1.60) 387/3818 (10.1) 408/3782 (10.8)

−0.6−16.9

7.6−10.0

−0.3−8.00.2

1.8−6.4

−0.80.6

−0.9−1.1

−27.6

10.1

6.0101.840.8

148.6

1.56.79.6

14.332.1

3.71.82.07.5

121.6

66.5−17.5 188.1 0.91 (0.79–1.05)

P=0.20



Meta-AnalyseKaka Ann Inter Med 2021

Remdesivir 10-Day Course Compared With Control(Placebo or Standard Care [4 trials])

Of the 4 RCTs comparing remdesivir with control(placebo or standard care), 2 used a placebo (5, 13) and2 used standard care as the control (4, 12) (Table andAppendix Table). One RCT included only patients withmoderate disease (12), but the other 3 RCTs includedpatients with more severe COVID-19, including criticaldisease (4, 5, 13). We used 28-day (instead of 11-day)data from SIMPLE-2 (Study to Evaluate the Safety andAntiviral Activity of Remdesivir [GS-5734] in ParticipantsWith Moderate Coronavirus Disease [COVID-19] Compared

to Standard of Care Treatment) (12) to allow pooling withstudies that had longer follow-up.

All-CauseMortalityOur updated analyses, including new results from

Solidarity, show that remdesivir, compared with control,probably results in little to no difference in mortality (riskratio [RR], 0.93 [95% CI, 0.82 to 1.06]; absolute risk differ-ence [ARD], �0.8% [CI, �2.2% to 0.7%]; 4 RCTs) (moder-ate COE) (Figure 1, top). Mortality results varied littlewhen we did sensitivity analyses that included results of a5-day course of remdesivir.

Figure 1.Mortality for remdesivir 10-d course vs. control (placebo or standard care).

Favors Control Favors Remdesivir0.1 1 2 5 100.2 0.5

Favors ControlFavors Remdesivir0.1 1 2 100.5

Study, Year (Reference)

Beigel et al [ACTT-1], 2020 (5)

Wang et al, 2020 (13)

Spinner et al [SIMPLE-2], 2020 (12)

Pan et al [Solidarity], 2020 (4)

Fixed-effects model

Heterogeneity: I2 = 6%

Control ControlRemdesivir

Events, n Total, n Events, n Total, n RR RR (95% CI)

Study, Year (Reference)

Control ControlRemdesivir

Events, n Total, n Events, n Total, n RR RR (95% CI)

Placebo

Placebo

Usual care

Usual care

Placebo

Usual care

Usual care

Placebo

Placebo

Usual care

Placebo

Placebo

Placebo

Usual care

3

2

11

16

9

11

192

212

19

28

11

98

156

95

131

29

254

509

20

29

3

71

123

98

154

10

233

495

232

129

1828

2189

25

7

219

251

203

68

1811

2082

3

4

13

20

63

200

664

927

75

193

661

929

59

22

2

301

384

541

158

193

2743

3635

77

10

4

303

394

521

78

200

2708

3507

0.74 (0.54–1.01)

1.09 (0.54–2.18)

0.52 (0.10–2.80)

0.98 (0.84–1.14)

0.93 (0.82–1.06)

0.84 (0.18–4.02)

0.52 (0.10–2.80)

0.85 (0.38–1.88)

0.78 (0.41–1.50)

0.32 (0.15–0.66)

0.83 (0.34–2.04)

0.87 (0.72–1.04)

0.81 (0.68–0.96)

0.98 (0.56–1.72)

1.14 (0.71–1.81)

1.26 (0.44–3.63)

1.27 (0.99–1.62)

1.19 (0.98–1.46)

No supplemental oxygen at baseline


Spinner et al [SIMPLE-2], 2020 (12)


Fixed-effects model


Supplemental oxygen and not ventilated at baseline


Wang et al, 2020 (13)


Fixed-effects model


Ventilated or ECMO at baseline

Beigel et al [ACTT-1], 2020 (5): high-flow

oxygen or noninvasive ventilation

Beigel et al [ACTT-1], 2020 (5): ventilation

Wang et al, 2020 (13)


Fixed-effects model


The black diamonds reflect pooled results from randomized controlled trials (listed above) that enrolled patients in the corresponding respiratory sup-port subgroups. ACTT-1 = Adaptive COVID-19 Treatment Trial; ECMO = extracorporeal membrane oxygenation; RR = risk ratio; SIMPLE-2 = Study toEvaluate the Safety and Antiviral Activity of Remdesivir [GS-5734] in Participants With Moderate Coronavirus Disease [COVID-19] Compared toStandard of Care Treatment. Top.Overall. Bottom. Results by initial respiratory status.

Major Update: Remdesivir for Adults With COVID-19 REVIEW

Annals.org Annals�of�Internal�Medicine� � � � � � � � � � � � � � � � � � � � 3

CJS: Evolution vers VM/ECMO HR 0.7 (0.6-0.9)


Plasma de convalescents• Meta-analyse, 10 RCTs, mortalité J15-30

6

included because it did not present quantitative results. How-ever, according to their reported preliminary analysis includ-ing 912 participants requiring intensive care unit support, treat-

ment with convalescent plasma did not show a beneficial effecton the number of days requiring intensive support or on mor-tality. The REMAP-CAP preliminary findings are consistent with

Figure 2. Association of Convalescent Plasma With All-Cause Mortality, Length of Hospital Stay, and MechanicalVentilation Use in Peer-Reviewed Trials and Non–Peer-Reviewed Trials (Preprints and the RECOVERY Trial)

Weight, %Favors

plasmaFavorscontrol

510.1RR (95% CI)

Events, No./total

Plasma ControlTrialStudies published in peer-reviewed journals

RR (95% CI)

Heterogeneity: I2 = 0%, τ2 = 0, P = .656.9Summary for peer-reviewed studies 0.93 (0.63-1.38)

All-cause mortalityA

3.734/235 31/229PLACID17 1.07 (0.68-1.68)1.825/228 12/105PlasmAr18 0.96 (0.50-1.83)1.28/52 12/51ChiCTR200002975719 0.65 (0.29-1.47)0.32/80 4/80NCT0447916316 0.50 (0.09-2.65)

Studies published as preprints0.23/14 1/15ILBS-COVID-0221 3.21 (0.38-27.40)

Study published as press release90.2NA/NA NA/NARECOVERY8 1.04 (0.95-1.14)100.0Summary for all studies

Heterogeneity: I2 = 0%, τ2 = 0, P = .48Test for overall effect: P = .68

1.02 (0.92-1.12)

1.610/40 14/40PICP1924 0.71 (0.36-1.41)0.96/43 11/43ConCOVID22 0.55 (0.22-1.34)0.11/20 2/20NCT0435653420 0.50 (0.05-5.08)0.10/38 4/43ConPlas-1923 0.13 (0.01-2.26)

Weight, %Favors

plasmaFavorscontrol

0.3 10 3010.1HR (95% CI)

Events, No./total


HR (95% CI)

Heterogeneity: I2 = 49%, τ2 = 0.0559, P = .1668.1Summary for peer-reviewed studies 1.17 (0.07-20.34)

Length of hospital stayB

11.7NA/52 NA/51ChiCTR200002975719 1.61 (0.88-2.95)56.4NA/228 NA/105PlasmAr18 1.00 (0.76-1.32)

Studies published as preprints19.6NA/38 NA/43ConPlas-1923 1.13 (0.71-1.80)

100.0Summary for all studiesa

Heterogeneity: I2 = 0%, τ2 = 0, P = .48Test for overall effect: P = .55

1.07 (0.79-1.45)12.3NA/43 NA/43ConCOVID22 0.88 (0.49-1.59)

Weight, %Favors

plasmaFavorscontrol

0.1 51RR (95% CI)

Events, No./total


RR (95% CI)

Heterogeneity: I2 = 29%, τ2 = 0.1194, P = .2579.9Summary for peer-reviewed studies 0.76 (0.20-2.87)

Mechanical ventilation useC

37.819/235 19/229PLACID17 0.97 (0.53-1.79)29.619/228 10/105PlasmAr18 0.87 (0.42-1.82)12.43/80 10/80NCT0447916316 0.30 (0.09-1.05)

Studies published as preprints4.63/14 1/15ILBS-COVID-0221 3.21 (0.38-27.40)

100.0Summary for all studiesa

Heterogeneity: I2 = 11%, τ2 = 0.0559, P = .34Test for overall effect: P = .44

0.81 (0.42-1.58)15.54/20 6/20NCT0435653420 0.67 (0.22-2.01)

Three of the trials did not have studyacronyms (only trial registrationnumbers) and ILBS-COVID-02 andPLACID did not have expansions inthe original publications.Hartung-Knapp adjustment was usedfor the random-effects model and thePaule-Mandel estimator was used forτ2. The weight percentagescorrespond to the secondary analysisfor all studies. ConCOVID indicatesConvalescent Plasma as Therapy forCovid-19 Severe SARS-CoV-2 Disease;ConPlas-19, Convalescent PlasmaTherapy vs SOC for the Treatment ofCOVID-19 in Hospitalized Patients;HR, hazard ratio; NA, not available;PICP19, Passive Immunization WithConvalescent Plasma in SevereCOVID-19 Disease; PlasmAr,Convalescent Plasma and Placebo forthe Treatment of COVID-19 SeverePneumonia; RECOVERY, RandomizedEvaluation of COVID-19 Therapy; RR,risk ratio.a Includes only the studies shown

that were published inpeer-reviewed journals or aspreprints.

Association of Convalescent Plasma Treatment With Clinical Outcomes in Patients With COVID-19 Original Investigation Research

jama.com (Reprinted) JAMA March 23/30, 2021 Volume 325, Number 12 1193

© 2021 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 08/03/2021

Janiaud, JAMA 2021


Plasma de convalescents• RECOVERY Trial (UK)

§ 11 558 patients, Plasma + SOC vs SOC (1:1), mortalité à J28• 5% VM, 87% O2, 8% pas O2

• Médiane début symptômes 9j (6-12)

7

Mortalité J28 24%

0.6 0.8 1 1.2 1.4 1.6

Figure 3: Effect of allocation to convalescent plasma on 28−day mortalityby prespecified characteristics at randomisation

Convalescent plasma Usual care RR (95% CI)

Convalescent plasma better

Usual carebetter

Age, years (χ12=

<70 533/3705 (14%) 545/3748 (15%) 1.00 (0.88−1.12) 70 to 79 495/1310 (38%) 494/1280 (39%) 0.99 (0.87−1.13) ≥80 370/780 (47%) 369/735 (50%) 0.94 (0.81−1.09)

0.3; p=0.57)

Sex (χ12=

Men 952/3643 (26%) 972/3787 (26%) 1.03 (0.94−1.13) Women 446/2152 (21%) 436/1976 (22%) 0.94 (0.82−1.07)

1.3; p=0.25)

Ethnicity (χ12=

White 1089/4362 (25%) 1096/4293 (26%) 0.98 (0.90−1.07) Black, Asian or minority ethnic 200/853 (23%) 203/889 (23%) 1.04 (0.85−1.26)

0.2; p=0.62)

Days since symptom onset (χ12=

≤7 606/2226 (27%) 659/2240 (29%) 0.92 (0.83−1.03) >7 789/3564 (22%) 749/3522 (21%) 1.06 (0.96−1.17)

3.2; p=0.07)

Respiratory support received (χ12=

No oxygen received 56/442 (13%) 69/455 (15%) 0.83 (0.58−1.18) Oxygen only 1184/5051 (23%) 1194/4993 (24%) 0.99 (0.91−1.07) Invasive mechanical ventilation 158/302 (52%) 145/315 (46%) 1.19 (0.95−1.50)

3.5; p=0.06)

Use of corticosteroids (χ12=

Yes 1313/5370 (24%) 1299/5311 (24%) 1.01 (0.93−1.09) No 74/391 (19%) 100/413 (24%) 0.78 (0.58−1.05)

2.7; p=0.10)

Patient SARS−CoV−2 antibody test result (χ12=

Negative 626/1982 (32%) 549/1629 (34%) 0.94 (0.84−1.06) Positive 566/3022 (19%) 495/2752 (18%) 1.05 (0.93−1.19)

Not done 206/791 (26%) 364/1382 (26%) 1.01 (0.85−1.19)

1.6; p=0.21)

All participants 1398/5795 (24%) 1408/5763 (24%)p=0.93

1.00 (0.93−1.07)

. CC-BY 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted March 10, 2021. ; https://doi.org/10.1101/2021.03.09.21252736doi: medRxiv preprint

Recovery Collaborative Group, Lancet 2021

Articles

2054 www.thelancet.com Vol 397 May 29, 2021

Role of the funding sourceThe funders of the trial had no role in trial design, data collection, data analysis, data interpretation, or writing of the report.

ResultsBetween May 28, 2020, and Jan 15, 2021, 13127 (81%) of 16 287 patients enrolled into the RECOVERY trial were eligible to receive convalescent plasma (figure 1). 1569 (12%) were randomly assigned to the REGN-COV-2 group and are not included in the analyses reported here. Of the remaining 11558 patients, 5795 (50%) were randomly assigned to the convalescent plasma group and 5763 (50%) to the usual care group. The mean age of the patients was 63·5 (SD 14·7) years, and the median time from symptom onset to ran-domisation was 9 days (IQR 6–12; table 1; appendix p 51). At randomisation, 617 (5%) of 11 558 patients were receiving invasive mechanical ventilation, 10 044 (87%) were receiving oxygen only (with or without non-invasive respiratory support), and 897 (8%) were receiving no oxygen therapy (appendix p 51). 10 681 (92%) of 11 558 patients were receiving cortico-steroids at time of randomisation. By chance, a slightly lower proportion of men were randomly assigned to the convalescent plasma group than the usual care group, so Cox regression analyses adjusted for sex are provided Figure 2: Effect of allocation to convalescent plasma on 28-day mortality

Number at riskConvalescent plasma

Usual care

0

57955763

7

51525215

14

47254740

21

44844472

28

43734339

Days since randomisation

0

5

10

15

20

25

30

Mor

talit

y (%

)

Rate ratio 1·00 (0·93−1·07); log-rank p=0·95

Convalescent plasmaUsual care

100

Figure 3: Effect of allocation to convalescent plasma on 28-day mortality by prespecified characteristics at randomisationThe ethnicity, days since onset, and use of corticosteroids subgroups exclude those with missing data, but these patients are included in the overall summary. Information on use of corticosteroids was collected from June 18, 2020, onwards following announcement of the results of the dexamethasone comparison from the RECOVERY trial. RR=rate ratio.

Convalescent plasma group

Usual caregroup

RR (95% CI)

Favours convalescent plasma Favours usual care

Age, years (χ21=0·4; p=0·53)

<7070–79≥80Sex (χ2

1=1·3; p=0·25)MenWomenEthnicity (χ2

1=0·8; p=0·37) WhiteBlack, Asian or minority ethnicDays since symptom onset (χ2

1=3·4; p=0·06)≤7>7Respiratory support received (χ2

1=3·5; p=0·06) No oxygen receivedOxygen onlyInvasive mechanical ventilationUse of corticosteroids (χ2

1=2·7; p=0·10)YesNoPatient SARS-CoV-2 antibody test result (χ2

1=1·4; p=0·23)PositiveNegativeNot doneAll participants

534/3705 (14%)495/1310 (38%)370/780 (47%)

953/3643 (26%)446/2152 (21%)

1111/4493 (25%)198/833 (24%)

606/2226 (27%)790/3564 (22%)

56/442 (13%)1185/5051 (23%)

158/302 (52%)

1314/5370 (24%)74/391 (19%)

575/3078 (19%)642/2016 (32%)182/701(26%)

1399/5795 (24%)

545/3748 (15%)494/1281 (39%)369/734 (50%)

972/3787 (26%)436/1976 (22%)

1129/4421 (26%)199/887 (22%)

660/2240 (29%)748/3522 (21%)

69/455 (15%)1194/4993 (24%)

145/315 (46%)

1299/5311 (24%)100/413 (24%)

501/2810 (18%)558/1660 (34%)349/1293 (27%)

1408/5763 (24%)

1·00 (0·89−1·13) 0·99 (0·87−1·13) 0·94 (0·81−1·09)

1·03 (0·95−1·13) 0·94 (0·82−1·07)

0·97 (0·90−1·06) 1·07 (0·88−1·31)

0·92 (0·82−1·03) 1·06 (0·96−1·17)

0·83 (0·58−1·18) 0·99 (0·91−1·07) 1·19 (0·95−1·50)

1·01 (0·94−1·09) 0·78 (0·58−1·05)

1·06 (0·94−1·19) 0·96 (0·85−1·07) 0·98 (0·82−1·17) 1·00 (0·93−1·07)p=0·95

0·6 0·8 1 1·2 1·4 1·6


Plasma de convalescents

• 966 patients, 70 centres• 143 PC vs 843 contrôles• 1/3 sous VM• Score Propension• HR 0.52 (IC95% 0.29-0.92)

8

Brief Report

CLINICAL TRIALS AND OBSERVATIONS

Convalescent plasma therapy for B-cell–depleted patientswith protracted COVID-19Thomas Hueso,1,2 Cecile Pouderoux,3 Helene Pere,4,5 Anne-Lise Beaumont,6 Laure-Anne Raillon,3 Florence Ader,3,7 Lucienne Chatenoud,8,9

Deborah Eshagh,10 Tali-Anne Szwebel,10 Martin Martinot,11 Fabrice Camou,12 Etienne Crickx,13 Marc Michel,13 Matthieu Mahevas,13

David Boutboul,14,15 Elie Azoulay,16 Adrien Joseph,16 Olivier Hermine,17,18 Claire Rouzaud,19 Stanislas Faguer,20 Philippe Petua,21

Fanny Pommeret,22 Sebastien Clerc,23 Benjamin Planquette,23 Fatiha Merabet,24 Jonathan London,25 Valerie Zeller,25 David Ghez,1

David Veyer,6,26 Amani Ouedrani,8,9 Pierre Gallian,27,28 Jerome Pacanowski,6 Arsene Mekinian,29 Marc Garnier,30 France Pirenne,28,31

Pierre Tiberghien,28,32 and Karine Lacombe6,33

1Hematology Department, Gustave Roussy, Villejuif, France; 2Paris-Sud University, Paris-Saclay University, Le Kremlin-Bicetre, France; 3Infectious DiseasesDepartment, Croix Rousse Hospital, Hospices Civils de Lyon, Lyon, France; 4Laboratoire de Virologie, Hopital Europeen Georges Pompidou, AssistancePublique–Hopitaux de Paris (AP-HP), Paris, France; 5Universite de Paris, INSERM U970, Paris Cardiovascular Research Center, Paris, France; 6Infectious DiseasesDepartment, Saint-Antoine Hospital, AP-HP, Paris, France; 7Universite Claude Bernard Lyon 1, INSERM 1111, Centre International de Recherche en InfectiologieUCBL1, Lyon, France; 8Paris University, Institut Necker-Enfants Malades, CNRS UMR 8253 and INSERM UMR1151, Hopital Necker-Enfants Malades, Paris, France;9Laboratoire d’immunologie Biologique, Hopital Necker-Enfants Malades, Paris, France; 10Internal Medicine Department, Cochin Hospital, AP-HP, Paris, France;11Infectious Diseases Department, Hopitaux Civils de Colmar, Colmar, France; 12Intensive Care and Infectious Diseases Department, Saint-Andre Hospital,Bordeaux, France; 13Internal Medicine Department, Centre National de Reference des Cytopenies Auto-Immunes de l’Adulte, Centre Hospitalier UniversitaireHenri-Mondor, AP-HP, Universite Paris Est Creteil, Creteil, France; 14Department of Clinical Immunology, Hopital Saint-Louis Hospital, AP-HP, Paris, France;15Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Imagine Institute, INSERM, Paris, France; 16Intensive Care Unit, Hopital Saint-Louis,AP-HP, Paris Diderot Sorbonne University, Paris, France; 17Laboratory of Molecular Mechanisms of Hematologic Disorders and Therapeutic Implications, ImagineInstitute, Paris, France; 18Department of Clinical Hematology, Hopital Necker-Enfants-Malades, Paris, France; 19Infectious Diseases Department, Necker-EnfantsMalades Hospital, AP-HP, Paris, France; 20Departement de Nephrologie et Transplantation d’Organes, Centre de Reference des Maladies Renales Rares, CentreHospitalier Universitaire de Toulouse, Toulouse, France; 21Intensive Care Unit, Tarbes Hospital, Tarbes, France; 22Oncology Department, Gustave Roussy, Villejuif,France; 23Respiratory Diseases Intensive Care Unit, Hopital Europeen Georges Pompidou, AP-HP, Paris, France; 24Hematology Department, Versailles Hospital,Versailles, France; 25Department of Internal Medicine and Infectious Diseases, Hopital Diaconesses Croix Saint-Simon, Paris, France; 26Universite de Paris andSorbonne Universite, INSERM, Centre de Recherche des Cordeliers, Functional Genomics of Solid Tumors (FunGeST), Paris, France; 27Unite des Virus Emergents(UVE) (Aix-Marseille Universite-Institut de recherche pour le developpement 190-INSERM 1207-IHU Mediterranee Infection), Marseille, France; 28EtablissementFrançais du Sang, La Plaine St-Denis, France; 29Sorbonne Universite, Internal Medicine Department, Inflammation-Immunopathology-Biotherapy Department(DMU i3D), Saint-Antoine Hospital, AP-HP, Paris, France; 30Sorbonne University, GRC 29, AP-HP, DMU DREAM, Anesthesiology and Intensive Care Department,Saint-Antoine Hospital, AP-HP, Paris, France; 31Institut Mondor de Recherche Biomedicale, Unite 955, Equipe 2: Transfusion et Maladies du Globule Rouge,INSERM, Etablissement Français du Sang, Universite Paris-Est Creteil, Creteil, France; 32UMR 1098 RIGHT INSERM Universite de Franche-Comte EtablissementFrançais du Sang, Besançon, France; and 33Sorbonne University, INSERM IPLESP, AP-HP, Paris, France

KEY PO INT S

l As a proof of concept,COVID-19convalescent plasmarepresents aninteresting approachin B-cell–depletedpatients withprotracted COVID-19.

l COVID-19convalescent plasmainduces a decrease intemperature andinflammatoryparameters within1 week associatedwith oxygen weaning.

Anti-CD20 monoclonal antibodies are widely used for the treatment of hematologicalmalignancies or autoimmune disease but may be responsible for a secondary humoraldeficiency. In the context of COVID-19 infection, this may prevent the elicitation of aspecific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients withprofound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immuno-globulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digitalpolymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma.Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinicalsymptoms. The inflammatory syndrome abated within a week. Only 1 patient who neededmechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immuno-spot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event wasreported. Convalescent plasma with anti–SARS-CoV-2 antibodies appears to be a verypromising approach in the context of protracted COVID-19 symptoms in patients unable tomount a specific humoral response to SARS-CoV-2. (Blood. 2020;136(20):2290-2295)

2290 blood® 12 NOVEMBER 2020 | VOLUME 136, NUMBER 20 © 2020 by The American Society of Hematology

Dow

nloaded from http://ashpublications.org/blood/article-pdf/136/20/2290/1789235/bloodbld2020008423.pdf by guest on 29 August 2021

Hueso, Blood 2020

Correspondence

www.thelancet.com/microbe Vol 2 April 2021 e138

Medical Clinical III (RNR, AB, MAc, MAr, SRB), Anaesthesiology (PS), and Medical Clinical I (KH, MK), University Hospital Carl Gustav Carus of TU Dresden, Dresden, Germany; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy (GM); Department of Diabetes, School of Life Course Sciences, King’s College London, London, UK (GM, SRB); Charité-Universitätsmedizin Berlin Institute of Virology, Berlin, Germany (VMC, CD); Transfusion Medicine, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Institute for Transfusion Medicine, German Red Cross Blood Donation Service North-East, 01307 Dresden, Germany (TT)

1 Simonovich VA, Burgos Pratx LD, Scibona P, et al. A randomized trial of convalescent plasma in COVID-19 severe pneumonia. N Engl J Med 2020; published online Nov 24. https://doi.org/10.1056/NEJMoa2031304.

2 Libster R, Pérez Marc G, Wappner D, et al. Early high-titer plasma therapy to prevent severe COVID-19 in older adults. N Engl J Med 2021; published online Jan 6. https://doi.org/10.1056/NEJMoa2033700.

3 Hueso T, Pouderoux C, Péré H, et al. Convalescent plasma therapy for B-cell-depleted patients with protracted COVID-19. Blood 2020; 136: 2290–95.

4 Tonn T, Corman VM, Johnsen M, et al. Stability and neutralising capacity of SARS-CoV-2-specific antibodies in convalescent plasma. Lancet Microbe 2020; 1: e63.

5 Aydillo T, Gonzalez-Reiche AS, Aslam S, et al. Shedding of viable SARS-CoV-2 after immunosuppressive therapy for cancer. N Engl J Med 2020; 383: 2586–88.

Potential benefit of convalescent plasma transfusions in immunocompromised patients with COVID-19

Randomised controlled trials on convalescent plasma in patients with COVID-19 have given conflicting results with regards to therapeutic benefit.1,2 Possible factors include previous seroconversion in reci pients1 and late treatment when proinflammatory factors dominate tissue damage.2 Patients with impaired immune function due to B-cell depletion might develop chronic SARS-CoV-2 infections, which can be controlled by convalescent plasma transfusions.3

Here, we report our experience with convalescent plasma administered to 14 patients with COVID-19 (seven [50%] were female, and median age was 65 years [IQR 58–70]) with acquired immunodeficiencies due to: solid organ transplantation (eight patients), allogeneic stem cell transplantation (four patients), or active haematological malignancy (two patients). All patients had no detectable IgG against SARS-CoV-2 at the time of transfusion (LIAISON SARS-CoV-2 S1/S2 IgG, DiaSorin, Stillwater, MN, USA). Mean time from positive SARS-CoV-2 PCR to transfusion was 5·14 days (SD 5·14). Median initial disease severity on the 10-point WHO Clinical Progression Scale was 5 (range 4–6). Convalescent plasma preparations were subjected to pathogen inactivation (Intercept Blood System, Cerus, Concord, CA USA), as reported previously.4 All plasma preparations had plaque reduction neutralisation test 50 (PRNT50) values of 40 or higher. 11 patients received three transfusions, two received two transfusions, and one patient received one transfusion, each of 200 mL.

Transfusion of convalescent plasma was well tolerated. 13 patients

developed detectable anti-SARS-CoV-2 IgG 24–48 h after the last transfusion. Eight (57%) of 14 patients showed clinical improvement on day 5 after the last transfusion, defined as an improvement of 1 point or more on the WHO Clinical Progression Scale. 12 (86%) patients were discharged from hospital. Two (14%) patients died due to a secondary infection. Interestingly, we found a significant correlation between the serum level of anti-SARS-CoV-2 IgG after the last transfusion and the degree of clinical improvement on day 5 (figure). Because an early intrinsic antibody response to SARS-CoV-2 infection in severely immunocompromised patients seems unlikely,5 we assume that the IgG titres reflected transfused anti-SARS-CoV-2 IgG from the convalescent plasma. More importantly, our data suggest that anti-SARS-CoV-2 IgG serum titres of more than 20 IU/mL are able to confer a more than 2-point improvement in the WHO Clinical progression Scale (figure) and could act to guide the use of convalescent plasma transfusions.

In summary, our pilot study, which is limited by the small number of participants, suggests patients who are immunosuppressed with early stage SARS-CoV-2 infection and no detectable anti-SARS-CoV-2 IgG are potential candidates for treatment with convalescent plasma, and the IgG titre after transfusion could be used as a potential predictive parameter for treatment success.We declare no competing interests. RNR and AB contributed equally.

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.

Roman N Rodionov, Anne Biener, Peter Spieth, Martin Achleitner, Kristina Hölig, Martin Aringer, Geltrude Mingrone, Victor M Corman, Christian Drosten, Stefan R Bornstein, *Torsten Tonn, Martin [email protected]

Figure: Correlation between anti-SARS-CoV-2 IgG titres 24–48 h after the last transfusion and improvement in clinical status in patients with COVID-19 (n=14)Datapoints represent each patient. Clinical improvement was defined as an improvement of 1 point or more on the 10-point WHO Clinical Progression Scale for COVID-19 5 days after the last transfusion and the clinical status before transfusion.

0 20 40 60 80–10

–5

0

5

Chan

ge o

n th

e W

HO C

linica

l Pro

gres

sion

Scal

e

Anti-SARS-CoV-2 IgG after transfusion (IU/mL)

R2 = 0·54p = 0·003

Rodionov, Lancet 2021Association of Convalescent Plasma Therapy With Survival in PatientsWith Hematologic Cancers and COVID-19Michael A. Thompson, MD, PhD; Jeffrey P. Henderson, MD, PhD; Pankil K. Shah, MD, MSPH; Samuel M. Rubinstein, MD; Michael J. Joyner, MD;Toni K. Choueiri, MD; Daniel B. Flora, MD, PharmD; Elizabeth A. Griffiths, MD; Anthony P. Gulati, MD; Clara Hwang, MD; Vadim S. Koshkin, MD;Esperanza B. Papadopoulos, MD; Elizabeth V. Robilotti, MD, MPH; Christopher T. Su, MD, MPH; Elizabeth M. Wulff-Burchfield, MD; Zhuoer Xie, MD, MS;Peter Paul Yu, MD; Sanjay Mishra, MS, PhD; Jonathon W. Senefeld, PhD; Dimpy P. Shah, MD, PhD; Jeremy L. Warner, MD, MS;for the COVID-19 and Cancer Consortium

IMPORTANCE COVID-19 is a life-threatening illness for many patients. Prior studies haveestablished hematologic cancers as a risk factor associated with particularly poor outcomesfrom COVID-19. To our knowledge, no studies have established a beneficial role foranti–COVID-19 interventions in this at-risk population. Convalescent plasma therapy maybenefit immunocompromised individuals with COVID-19, including those with hematologiccancers.

OBJECTIVE To evaluate the association of convalescent plasma treatment with 30-daymortality in hospitalized adults with hematologic cancers and COVID-19 from amulti-institutional cohort.

DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study using data from theCOVID-19 and Cancer Consortium registry with propensity score matching evaluated patientswith hematologic cancers who were hospitalized for COVID-19. Data were collected betweenMarch 17, 2020, and January 21, 2021.

EXPOSURES Convalescent plasma treatment at any time during hospitalization.

MAIN OUTCOMES AND MEASURES The main outcome was 30-day all-cause mortality. Coxproportional hazards regression analysis with adjustment for potential confounders wasperformed. Hazard ratios (HRs) are reported with 95% CIs. Secondary subgroup analyseswere conducted on patients with severe COVID-19 who required mechanical ventilatorysupport and/or intensive care unit admission.

RESULTS A total of 966 individuals (mean [SD] age, 65 [15] years; 539 [55.8%] male) wereevaluated in this study; 143 convalescent plasma recipients were compared with 823untreated control patients. After adjustment for potential confounding factors, convalescentplasma treatment was associated with improved 30-day mortality (HR, 0.60; 95% CI,0.37-0.97). This association remained significant after propensity score matching (HR, 0.52;95% CI, 0.29-0.92). Among the 338 patients admitted to the intensive care unit, mortalitywas significantly lower in convalescent plasma recipients compared with nonrecipients (HRfor propensity score–matched comparison, 0.40; 95% CI, 0.20-0.80). Among the 227patients who required mechanical ventilatory support, mortality was significantly lower inconvalescent plasma recipients compared with nonrecipients (HR for propensityscore–matched comparison, 0.32; 95% CI, 0.14-0.72).

CONCLUSIONS AND RELEVANCE The findings of this cohort study suggest a potential survivalbenefit in the administration of convalescent plasma to patients with hematologic cancersand COVID-19.

JAMA Oncol. 2021;7(8):1167-1175. doi:10.1001/jamaoncol.2021.1799Published online June 17, 2021.

Invited Commentarypage 1175

Supplemental content

Author Affiliations: Authoraffiliations are listed at the end of thisarticle.

Group Information: A complete listof members of the COVID-19 andCancer Consortium at sitescontributing to this analysis appearsin Supplement 2.

Corresponding Author: Jeremy L.Warner, MD, MS, Division ofHematology/Oncology, VanderbiltUniversity, 2220 Pierce Ave, 777 PRB,Nashville, TN 37232 ([email protected]).

Research

JAMA Oncology | Original Investigation

(Reprinted) 1167


Thompson, JAMA Oncol 2021

higher than in the matched control patients, and this findingbears additional scrutiny in larger cohorts.

LimitationsThis study has limitations, including its retrospective natureand unmeasured variables, such as the exact timing of conva-lescent plasma administration with respect to the date ofCOVID-19 diagnosis, the antibody titers and levels in the plasmathat was administered, and whether repeat dosing was used.Although timing information is valuable, the feasibility of cre-ating and maintaining a large, primarily voluntary, registry ef-fort has necessitated study design decisions that would mini-mize the data entry burden for respondents; temporality isparticularly burdensome and is only collected for very lim-ited events (eg, death). As with many pharmacoepidemiologi-cal studies, immortal time bias is possible for both the time toconvalescent plasma exposure in the treatment group and timefrom COVID-19 diagnosis to hospitalization in both recipientsand nonrecipients.33 The registry data also lack details on tim-ing and sequence of other treatment exposures in relation toconvalescent plasma administration. Despite propensitymatching, it is possible that residual confounding remains, andresults should be interpreted with caution. For example, evenafter propensity matching, the convalescent plasma recipi-ents received more corticosteroids and remdesivir. Althoughthese agents have not been found to have a clear survival ben-efit in cancer populations,34 it is possible that at least part ofthe observed protective effect of convalescent plasma couldbe attributable to concomitant medications, including feweradministrations of hydroxychloroquine. There are some no-table differences in blood cancer type and stage between therecipients and matched control patients, all of which wouldbe expected to lead to worse outcomes in the recipients, wherein fact the opposite was observed. These differences includemore patients with multiple myeloma in the matched controlpatients, who have an intermediate prognosis.35-37 Con-versely, more convalescent plasma recipients had CLL, whichhas been associated with poor outcomes.38 Convalescent

Figure. Overall Survival Rates Among Recipients vs Nonrecipients of Convalescent Plasma

0

No. at risk

0 10 20 30

1.0

0.8

Over

all s

urvi

val p

roba

bilit

y

Time, d

0.6

0.4

0.2

Nonrecipients ofconvalescent plasmaRecipients ofconvalescent plasma

Overall comparisonA

823 702 613 507

143 137 129 108

Log-rank test P <.0010

No. at risk

0 10 20 30

1.0

0.8

Over

all s

urvi

val p

roba

bilit

y

Time, d

0.6

0.4

0.2

Nonrecipients ofconvalescent plasmaRecipients ofconvalescent plasma

Propensity score-matched comparisonB

143 128 109 79

143 137 129 108

Stratified log-rank test P =.004

Nonrecipients of convalescent plasma

Recipients of convalescent plasma

Nonrecipients of convalescent plasma

Recipients of convalescent plasma

Table 3. Association Between Convalescent Plasma Useand Death Within the Crude Analysis, Multivariable Analysis,and Propensity Score Analyses

VariableHR (95% CI) for deathwithin 30 days

Overall population

No. of events/No. of patientsat risk (%)

223/966 (23.1)

Convalescent plasma 19/143 (13.3)

No convalescent plasma 204/823 (24.8)

Crude analysisa 0.47 (0.30-0.76)

Multivariable analysisb 0.60 (0.37-0.97)

Propensity score matchingc 0.52 (0.29-0.92)

Subgroup requiring ICU admission


135/338 (39.9)






Subgroup requiring mechanical ventilatory support


105/227 (46.3)






Abbreviations: ICU, intensive care unit; HR, hazard ratio.a The HRs from the bivariable model in all patients from the unmatched study

cohort.b The HRs form the multivariable stratified Cox proportional hazards regression

model, with stratification by trimester of diagnosis with additional covariateadjustment.

c Marginal HRs from propensity score–matched sample, constructed using 1:1nearest neighbor matching with calipers of width equal to 0.2 of the SD of thedistance measure.

Research Original Investigation Survival in Patients With Hematologic Cancers and COVID-19

1172 JAMA Oncology August 2021 Volume 7, Number 8 (Reprinted) jamaoncology.com



Anticorps monoclonaux

9studies (REGN-COV2 dosed at 1.2, 2.4, and 8 g; bamlanivi-mab dosed at 0.7, 2.8, and 7 g; and regdanvimab dosed at40 and 80 mg/kg). The broad range of doses tested forcedthe initial use of intravenous administration due to the highvolume that would be required for the highest doses thatwould not be compatible with intramuscular or subcutaneousroutes. Dose sparing is also key to increase the overall num-ber of available doses for each lot of produced drug product.So far, intravenous administration has limited the use of theseapproved mAbs, since this route requires a hospital setting oraccess to infusion centers. The shift to different routes, suchas intramuscular or subcutaneous (Table 1), is underway andwill possibly contribute to a facilitated and larger access tothese mAbs.Another important finding relates to primary endpoints used to

measure the success of these clinical trials. Virological endpointsdid not always reflect clinical endpoints, and the latter were ulti-mately the key drivers for approval. For instance, combination ofbamlanivimab with etesevimab or bamlanivimab monotherapyshowed similar efficacy on clinical endpoints, while combinationtherapy appeared to be more efficacious on virological end-points. It is unclear whether measuring viral replication in the up-per airways with molecular-based methods (i.e., RT-PCR) is anaccurate measure of viral neutralization, since viral RNA maypersist even in the absence of replication-competent virus. Inaddition, viral load in the lower respiratory tract would betterreflect the injury response than the viral load in nasopharyngeal

secretions, but this type of sampling is highly invasive and overallunpractical. Two factors were shown to influence the level ofbenefit of themAb in the early therapy setting, the immune statusat baseline (i.e., seropositive versus seronegative) and the viraltiter at baseline (i.e., high versus low). The greatest benefitfrom mAbs (particularly for REGN-COV2 mAbs) was observedfor seronegative patients with a high viral load at baseline, sug-gesting that the early development of endogenous antibodiesmay contribute to reduced disease severity and that high viralreplication is associated with higher probability of severe dis-ease outcome.It is remarkable that approval was obtained in only 9–

10 months from the initial discovery of these mAbs. This rapidprocess was made possible thanks to several factors, includinga rapid isolation of the mAbs, an accelerated manufacturing pro-cess to generate clinical grade mAbs in only 3–4 months (Kelley,2020), all-in-one clinical studies assessing both safety and effi-cacy, and a rapid analysis and approval by regulatory agencies.An inherent limitation of this rapid development process was thatthese mAbs could not be characterized for their resistance pro-file against variants that did not exist at that time. Indeed, allthese four mAbs (etesevimab, bamlanivimab, casirivimab, andregdanvimab) are sensitive to one ormore of themutations foundin RBD residues at positions 417, 452, or 484 that are carried bymultiple circulating VOCs, including the recently emergingB.1.617 (Hoffmann et al., 2021; McCallum et al., 2021a; Starret al., 2021b; Wang et al., 2021b) (Figure 5C).

Figure 6. Prophylactic and therapeutic approaches to COVID-19Vaccines are listed in purple, and mAb-based prophylactic or therapeutic modalities completed successfully or in progress are shown in blue. Other therapeuticmodalities are not shown.

ll

Cell 184, June 10, 2021 3097

Review

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ATU 03/08/21

ATU 15/03/21

???

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med nejm.org 1

The members of the writing committee (J.D. Lundgren, B. Grund, C.E. Barkaus-kas, T.L. Holland, R.L. Gottlieb, U. Sand-kovsky, S.M. Brown, K.U. Knowlton, W.H. Self, D.C. Files, M.K. Jain, T. Benfield, M.E. Bowdish, B.G. Leshnower, J.V. Bak-er, J.-U. Jensen, E.M. Gardner, A.A. Ginde, E.S. Harris, I.S. Johansen, N. Markowitz, M.A. Matthay, L. Østergaard, C.C. Chang, V.J. Davey, A. Goodman, E.S. Higgs, D.D. Murray, T.A. Murray, R. Paredes, M.K.B. Parmar, A.N. Phillips, C. Reilly, S. Sharma, R.L. Dewar, M. Teitelbaum, D. Wentworth, H. Cao, P. Klekotka, A.G. Babiker, A.C. Gelijns, V.L. Kan, M.N. Polizzotto, B.T. Thompson, H.C. Lane, and J.D. Neaton) assume responsibility for the overall con-tent and integrity of this article. The full names, academic degrees, and affilia-tions of the members of the writing com-mittee are listed in the Appendix. Ad-dress reprint requests to Dr. Lundgren at CHIP, Department of Infectious Diseas-es, Rigshospitalet, University of Copen-hagen, Copenhagen, Denmark, or at jens . lundgren@ regionh . dk.

*A complete list of members in the ACTIV-3/TICO LY-CoV555 Study Group is provided in the Supplementary Ap-pendix, available at NEJM.org.

This article was published on December 22, 2020, at NEJM.org.

DOI: 10.1056/NEJMoa2033130Copyright © 2020 Massachusetts Medical Society.

BACKGROUNDLY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19.

METHODSIn this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5.

RESULTSOn October 26, 2020, the data and safety monitoring board recommended stop-ping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median in-terval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence in-terval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47).

CONCLUSIONSMonoclonal antibody LY-CoV555, when coadministered with remdesivir, did not dem-onstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov num-ber, NCT04501978.)

A BS TR AC T

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19

ACTIV-3/TICO LY-CoV555 Study Group*

Original Article

The New England Journal of Medicine Downloaded from nejm.org at INSERM DISC DOC on February 23, 2021. For personal use only. No other uses without permission.


Bamlavinimab

Arrêt prématuré

ACTIV-3 Study Group, NEJM 2021


Anticorps monoclonaux : Casirivimab + Indevimab• RECOVERY Trial (UK)

§ 9 785 patients, RONAPREVE (8g) + SOC vs SOC (1:1), mortalité à J28 chez les séro –puis globale

• 54% Séro +, 32% séro -, 14% inconnu• 6% VM, 24% VNI, 62% O2 , 8% pas O2

• Médiane début symptômes 9j (6-12)

10

Mortalité J28 Séro –

30% vs 24%

Recovery Collaborative Group, MedRxiv 2021

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35SeronegativeRate ratio, 0.80 (0.70−0.91) P=0.0010 by log−rank test

1633 1429 1325 1260 12241520 1308 1173 1088 1059

No. at risk, SeronegativeREGEN−COVUsual Care


Mor

talit

y, %

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REGEN−COV

SeropositiveRate ratio, 1.09 (0.95−1.26)

a) Seronegative vs seropositive

2636 2452 2322 2252 22012636 2503 2375 2292 2243

No. at risk, SeropositiveREGEN−COVUsual Care

Usual care

REGEN−COV

Figure 2: Effect of allocation to REGEN−COV on 28−day mortality in: a) seronegative vsseropositive participants; and b) all participants

0 7 14 21 280

5

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35

Rate ratio, 0.94 (0.86−1.03) P=0.17 by log−rank test

b) All participants

4839 4388 4112 3952 38484946 4504 4182 3980 3888

No. at riskREGEN−COVUsual Care


Mor

talit

y, % Usual care

REGEN−COV


The copyright holder for this preprint this version posted June 16, 2021. ; https://doi.org/10.1101/2021.06.15.21258542doi: medRxiv preprint

0.6 0.8 1 1.2 1.4 1.6

Figure 3: Primary and secondary outcomes, overall and by baseline antibodystatus

Outcome, subgroup REGEN−COV Usual care RR (95% CI)

Outcomeless likely withREGEN−COV

Outcomemore likely withREGEN−COV

Death within 28 days (χ12=

Seronegative 396/1633 (24%) 451/1520 (30%) 0.80 (0.70−0.91) Seropositive 411/2636 (16%) 383/2636 (15%) 1.09 (0.95−1.26) Unknown 137/570 (24%) 192/790 (24%) 0.98 (0.78−1.22)

10.1; p=0.001)

All participants 944/4839 (20%) 1026/4946 (21%) 0.94 (0.86−1.03)

Discharge alive from hospital (χ12=


16.6; p<0.001)

All participants 3375/4839 (70%) 3413/4946 (69%) 1.01 (0.97−1.07)

Invasive mechanical ventilation or death (χ12=


12.0; p<0.001)

All not on invasive 1089/4556 (24%) 1151/4642 (25%) 0.96 (0.90−1.04) mechanical ventilationat randomisation


The copyright holder for this preprint this version posted June 16, 2021. ; https://doi.org/10.1101/2021.06.15.21258542doi: medRxiv preprint


Synthèse• Remdesivir

§ Si 02

• Plasma convalescent § Pas effet§ Déficit Immunité B

• mABs§ Uniquement chez les séro nég§ Attente plus de données

11


Perspectives• Autres Ac monoclonaux

§ AZD 7442 (Discovery 2.0, EU Response, ACTIV3, NIH)

• Anticorps polyclonaux (XAV-19, Résultats phase 2 POLYCOR) (Gaborit, Trials 2021)

• Antiviraux direct § Molnupiravir (MK 4482, analogue nucléotidique)

• résultats phase 2a, patients ambulatoires clairance virale plus rapide, négativation PCR tous les patients traités à J5 (Fischer, MedRxiv 2021).

• Essai phase 2/3 à venir patients hospitalisés avec O2 simple, USA (NCT04575584)

§ AT-527/RO7496998 (analogue nucléotidique). Phase 2 : Réduction charge virale patients hospitalisés

§ Inhibiteurs protéases (PF 07304814 et PF 07321332)12


Corticoides, Anti-IL1, Anti-IL6, Inhib JAKImmunomodulateurs

13


Corticoïdes systémiques

• Meta-Analyse§ 7 essais, 1700 patients, CTC vs Placebo, mortalité à J28

14

In the RECOVERY trial (NCT04381936), approximately 16%of patients in the control group received dexamethasone. Thiswas regarded as reflecting usual practice,22 and was notconsidered to introduce a risk of bias in the effect of assignmentto the intervention. Furthermore, any such bias would betoward the null.

There were 222 deaths among 678 patients randomized tocorticosteroids and 425 deaths among 1025 patients random-ized to usual care or placebo. Based on a fixed-effect meta-analysis, the summary OR was 0.66 (95% CI, 0.53-0.82;P < .001) for all-cause mortality comparing corticosteroids withusual care or placebo (Figure 2). This corresponds to an abso-lute mortality risk of 32% with corticosteroids compared withan assumed mortality risk of 40% with usual care or placebo.There was little inconsistency between the trial results(I2 = 15.6%; P = .31 for heterogeneity), and the summary OR was0.70 (95% CI, 0.48-1.01; P = .053) based on a random-effectsmeta-analysis.

In the analysis that excluded patients recruited to theRECOVERY trial, the OR was 0.77 (95% CI, 0.56-1.07) for all-cause mortality comparing corticosteroids with usual care orplacebo, which was consistent with the corresponding resultbased on patients in the RECOVERY trial who were receivinginvasive mechanical ventilation at randomization (OR, 0.59[95% CI, 0.44-0.78]). This latter OR was not adjusted for ageand therefore differs from the age-adjusted rate ratio in the re-port of the RECOVERY trial.7

The overall inverse variance–weighted fixed-effect risk ra-tio was 0.80 (95% CI, 0.70-0.91) for all-cause mortality com-paring corticosteroids with usual care or placebo. The GRADEassessment of the certainty of the evidence that corticoste-roids reduce all-cause mortality in critically ill patients withCOVID-19 was moderate due to minor concerns across (1) im-precision, (2) a small amount of heterogeneity, and (3) a smallrisk of reporting bias due to some trials not responding to therequests for data.

For all-cause mortality comparing corticosteroids vs usualcare or placebo, the fixed-effect summary OR was 0.64 (95% CI,0.50-0.82; P < .001) for trials of dexamethasone (3 trials, 1282patients, and 527 deaths; corresponding absolute risk of 30%for dexamethasone vs an assumed risk of 40% for usual careor placebo) and the OR was 0.69 (95% CI, 0.43-1.12; P = .13) fortrials of hydrocortisone (3 trials, 374 patients, and 94 deaths;corresponding absolute risk of 32% for hydrocortisone vs an as-sumed risk of 40% for usual care or placebo). Using meta-regression to compare the associations for hydrocortisone anddexamethasone, the ratio of ORs was 1.06 (95% CI, 0.37-2.99).From the random-effects meta-analyses, the OR was 0.65 (95%CI, 0.36-1.17) for dexamethasone and the OR was 0.87 (95% CI,0.072-10.5) for hydrocortisone; the wide 95% CIs reflect the im-precisely estimated between-trial variance because each analy-sis included only 3 trials. Only 1 trial (NCT04244591), whichenrolled 47 patients of whom 26 died, evaluatedmethylprednisolone and the OR was 0.91 (95% CI, 0.29, 2.87;

Figure 2. Association Between Corticosteroids and 28-Day All-Cause Mortality in Each Trial, Overall, and According to Corticosteroid Drug

Weight,%

Favorssteroids

Favors nosteroids

0.2 41Odds ratio (95% CI)

No. of deaths/totalNo. of patientsInitial dose and

administrationDrug and trialDexamethasone

Odds ratio(95% CI)Steroids No steroids

100.0Overall (fixed effect)P = .31 for heterogeneity; I2 = 15.6%

0.66 (0.53-0.82)222/678 425/1025

Overall (random effectsa) 0.70 (0.48-1.01)222/678 425/1025

76.60Subgroup fixed effect 0.64 (0.50-0.82)166/459 361/823

0.92High: 20 mg/d intravenously 2/7 2/12DEXA-COVID 19 NCT04325061 2.00 (0.21-18.69)18.69High: 20 mg/d intravenously 69/128 76/128CoDEX NCT04327401 0.80 (0.49-1.31)57.00Low: 6 mg/d orally or intravenously 95/324 283/683RECOVERY NCT04381936 0.59 (0.44-0.78)

Hydrocortisone

19.94Subgroup fixed effect 0.69 (0.43-1.12)43/195 51/179

6.80Low: 200 mg/d intravenously 11/75 20/73CAPE COVID NCT02517489 0.46 (0.20-1.04)

Methylprednisolone3.46High: 40 mg every 12 h intravenously 13/24 13/23Steroids-SARI NCT04244591 0.91 (0.29-2.87)

1.39Low: 200 mg/d intravenously 6/15 2/14COVID STEROID NCT04348305 4.00 (0.65-24.66)11.75Low: 50 mg every 6 h intravenously 26/105 29/92REMAP-CAP NCT02735707 0.71 (0.38-1.33)

ClinicalTrials.govidentifier

The area of the data marker for each trial is proportional to its weight in thefixed-effect meta-analysis. The Randomized Evaluation of COVID-19 Therapy(RECOVERY) trial result is for patients who were receiving invasive mechanicalventilation at randomization. CAPE COVID indicates Community-AcquiredPneumonia: Evaluation of Corticosteroids in Coronavirus Disease; CoDEX,COVID-19 Dexamethasone; COVID STEROID, Hydrocortisone for COVID-19 andSevere Hypoxia; DEXA-COVID 19, Efficacy of Dexamethasone Treatment forPatients With ARDS Caused by COVID-19; REMAP-CAP, Randomized,Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired

Pneumonia; Steroids-SARI, Glucocorticoid Therapy for COVID-19 Critically IllPatients With Severe Acute Respiratory Failure.a The random-effects analysis estimates both the average and variability of

effects across studies. The 95% CI for the average effect (shown here) is widebecause there is a small number of studies, some of which have very smallsample size. The prespecified primary analysis was the fixed-effect analysis,which should be used to guide clinical interpretation of the results.

Research Original Investigation Association Between Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19

1336 JAMA October 6, 2020 Volume 324, Number 13 (Reprinted) jama.com



WHO REACT Working Group, JAMA 2020

n engl j med 384;8 nejm.org February 25, 2021 699

Dexamethasone in Hospitalized Patients with Covid-19

(Fig. 2A). In a prespecified analysis according to the level of respiratory support that the patients were receiving at randomization, there was a trend showing the greatest absolute and pro-portional benefit among patients who were re-ceiving invasive mechanical ventilation (11.6 by

chi-square test for trend) (Fig. 3). In the dexa-methasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventila-tion (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and in those receiving oxygen with-

Figure 2. Mortality at 28 Days in All Patients and According to Respiratory Support at Randomization.

Shown are Kaplan–Meier survival curves for 28-day mortality among all the patients in the trial (primary outcome) (Panel A) and in three respiratory-support subgroups according to whether the patients were undergoing invasive mechanical ventilation (Panel B), receiving oxygen (with or without noninvasive ventilation) and without invasive mechanical ventilation (Panel C), or receiving no supplemental oxygen (Panel D) at the time of randomization. The Kaplan–Meier curves have not been adjusted for age. The rate ratios have been adjusted for the age of the patients in three categories (<70 years, 70 to 79 years, and ≥80 years). Estimates of the rate ratios and 95% confidence inter-vals in Panels B, C, and D were derived from a single age-adjusted regression model involving an interaction term between treatment assignment and level of respiratory support at randomization.

Mor

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100

80

60

20

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00 7 14 21 28

Days since Randomization

C Oxygen Only (N=3883) D

Invasive Mechanical Ventilation (N=1007)A All Participants (N=6425)

Rate ratio, 0.83 (95% CI, 0.75–0.93)P<0.001

No. at RiskUsual careDexamethasone

43212104

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26041279

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Recovery Collaborative Group, NEJM 2021

RECOVERY


Corticoïdes systémiques

15

. CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted July 24, 2021. ; https://doi.org/10.1101/2021.07.22.21260755doi: medRxiv preprint

COVID STEROID 2 Group, MedRxiv 2021

• RCT, double aveugle, Europe/Inde, 982 patients

• 10 l/min ou VM• 10j DXM 6mg vs 12 mg• Survie sans support à

J28


Anti-IL6• Meta-Analyse

§ 27 essais, 10 930 patients (4299 Tocilizumab, 2073 Sarilumab vs placebo ou SOC), mortalité à J28

16WHO REACT Working Group, JAMA 2021Figure

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Association Between IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19 Original Investigation Research

jama.com (Reprinted) JAMA Published online July 6, 2021 E11



Mortalité J28 23%

Anti-IL6 OR 0.86 (IC95% 0.79-0.95)Tocilizumab OR 0.83 (IC95% 0.74-0.92)Sarilumab OR 1.08 (IC 95% 0.86-1.36)

Table 2. Subgroup Analysis of 3 Outcomes by Treatment Group and Respiratory Support, Organ Support, Age, Sex, and C-Reactive Protein Level

Subgroup

All anti–IL-6 agents Tocilizumab Sarilumab

No. of events/total patients

I2, % OR (95% CI)


I2, % OR (95% CI)


I2, % OR (95% CI)Anti–IL-6 Control Anti–IL-6 Control Anti–IL-6 Control

28-d mortality

Respiratory supportat randomization

Oxygen flow rate≤15 L/min

277/2246 283/1708 0 0.81 (0.67-0.98) 232/1622 256/1407 0 0.82 (0.67-1.00) 41/583 27/301 0 0.74 (0.42-1.30)

Noninvasive ventilation 588/2209 544/1655 8 0.83 (0.72-0.96) 463/1684 505/1479 0 0.80 (0.68-0.93) 119/496 40/191 0 1.20 (0.78-1.84)

IMV or ECMO 496/1289 305/728 0 0.95 (0.78-1.16) 250/634 244/559 6 0.92 (0.72-1.17) 246/650 64/174 20 1.05 (0.74-1.50)

Acute organ supportat randomization

No cardiovascular systemsupport

123/616 135/501 14 0.68 (0.51-0.91) 106/536 120/457 10 0.70 (0.51-0.94) 11/48 18/64 0 0.66 (0.26-1.64)

Cardiovascular systemsupport

70/196 59/153 17 0.89 (0.56-1.42) 69/190 59/153 14 0.93 (0.58-1.47) 1/4 1/1 0 0.14 (0.00-5.95)

Age group, y

<70 674/4209 522/2931 0 0.89 (0.78-1.02) 446/2864 456/2457 0 0.86 (0.74-0.99) 225/1291 67/490 9 1.10 (0.80-1.52)

≥70 703/1727 629/1310 17 0.82 (0.70-0.95) 514/1254 567/1136 8 0.76 (0.64-0.89) 182/450 65/179 0 1.17 (0.80-1.71)

Sex

Female 413/1933 311/1335 0 0.96(0.80-1.15) 294/1365 270/1134 0 0.96 (0.79-1.17) 117/553 43/209 0 0.95 (0.62-1.46)

Male 964/4003 840/2906 1 0.83 (0.74-0.93) 666/2753 753/2459 0 0.78 (0.69-0.88) 290/1188 89/460 0 1.17 (0.88-1.55)

C-reactive protein level,μg/mLa

<75 83/710 57/429 0 0.84 (0.56-1.26) 36/344 36/260 0 0.80 (0.46-1.39) 46/354 21/171 0 0.89 (0.49-1.62)

75-<150 451/1957 467/1635 3 0.79 (0.67-0.92) 357/1484 435/1456 9 0.76 (0.65-0.90) 90/438 33/184 0 1.01 (0.62-1.64)

≥150 678/2366 490/1625 0 0.96 (0.83-1.11) 427/1507 429/1365 0 0.91 (0.77-1.07) 246/831 64/271 4 1.16 (0.83-1.62)

Progression to IMV, EMCO, or death by 28 d

Respiratory supportat randomization

Oxygen flow rate≤15 L/min

362/2266 396/1778 0 0.75 (0.64-0.89) 299/1724 359/1505 0 0.72 (0.60-0.86) 55/501 37/273 0 0.96 (0.60-1.53)

Noninvasive ventilation 856/2129 805/1636 14 0.77 (0.68-0.89) 694/1690 750/1483 0 0.74 (0.64-0.85) 145/410 60/168 0 1.06 (0.71-1.57)

Acute organ supportat randomization

No cardiovascular systemsupport

207/524 202/424 26 0.72 (0.55-0.95) 173/451 183/382 2 0.70 (0.53-0.93) NAb NAb NAb NAb

Cardiovascular systemsupport

12/16 8/15 0 1.58 (0.30-8.30) 12/16 8/15 0 1.58 (0.30-8.30) NAb NAb NAb NAb

(continued)

AssociationBetw

eenIL-6

AntagonistsandM

ortalityAmongPatientsHospitalized

forCOVID-19OriginalInvestigation

Research

jama.com

(Reprinted)JAM

APublished

onlineJuly6,2021

E9

©2021

Am

ericanM

edicalAssociation.A

llrightsreserved.

Dow

nloaded From: https://jam

anetwork.com

/ on 08/04/2021


Anti-IL1• Anakinra : Pas de nouveauté• Meta-Analyses

§ 1 185 patients, 9 études § (8 études observationnelles, 1 essai), mortalité

17Kyriazopoulou, Lancet Rheum 2021

En attente de plus de données

Articles

www.thelancet.com/respiratory Vol 9 March 2021 295

Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial The CORIMUNO-19 Collaborative group*†

SummaryBackground Patients with COVID-19 pneumonia have an excess of inflammation and increased concentrations of cytokines including interleukin-1 (IL-1). We aimed to determine whether anakinra, a recombinant human IL-1 receptor antagonist, could improve outcomes in patients in hospital with mild-to-moderate COVID-19 pneumonia.

Methods In this multicentre, open-label, Bayesian randomised clinical trial (CORIMUNO-ANA-1), nested within the CORIMUNO-19 cohort, we recruited patients from 16 University hospitals in France with mild-to-moderate COVID-19 pneumonia, severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time RT-PCR, requiring at least 3 L/min of oxygen by mask or nasal cannula but without ventilation assistance, a score of 5 on the WHO Clinical Progression Scale (WHO-CPS), and a C-reactive protein serum concentration of more than 25 mg/L not requiring admission to the intensive care unit at admission to hospital. Eligible patients were randomly assigned (1:1) using a web-based secure centralised system, stratified by centre and blocked with varying block sizes (randomly of size two or four), to either usual care plus anakinra (200 mg twice a day on days 1–3, 100 mg twice on day 4, 100 mg once on day 5) or usual care alone. Usual care was provided at the discretion of the site clinicians. The two coprimary outcomes were the proportion of patients who had died or needed non-invasive or mechanical ventilation by day 4 (ie, a score of >5 on the WHO-CPS) and survival without need for mechanical or non-invasive ventilation (including high-flow oxygen) at day 14. All analyses were done on an intention-to-treat basis. The trial is registered with ClinicalTrials.gov, NCT04341584, and is now closed to accrual.

Findings Between April 8 and April 26, 2020, we screened 153 patients. The study was stopped early following the recommendation of the data and safety monitoring board, after the recruitment of 116 patients: 59 were assigned to the anakinra group, and 57 were assigned to the usual care group. Two patients in the usual care group withdrew consent and were not analysed. In the analysable population, the median age was 66 years (IQR 59 to 76) and 80 (70%) participants were men. In the anakinra group, 21 (36%) of 59 patients had a WHO-CPS score of more than 5 at day 4 versus 21 (38%) of 55 in the usual care group (median posterior absolute risk difference [ARD] –2·5%, 90% credible interval [CrI] –17·1 to 12·0), with a posterior probability of ARD of less than 0 (ie, anakinra better than usual care) of 61·2%. At day 14, 28 (47%; 95% CI 33 to 59) patients in the anakinra group and 28 (51%; 95% CI 36 to 62) in the usual care group needed ventilation or died, with a posterior probability of any efficacy of anakinra (hazard ratio [HR] being less than 1) of 54·5% (median posterior HR 0·97; 90% CrI 0·62 to 1·52). At day 90, 16 (27%) patients in the anakinra group and 15 (27%) in the usual care group had died. Serious adverse events occurred in 27 (46%) patients in the anakinra group and 21 (38%) in the usual care group (p=0·45).

Interpretation Anakinra did not improve outcomes in patients with mild-to-moderate COVID-19 pneumonia. Further studies are needed to assess the efficacy of anakinra in other selected groups of patients with more severe COVID-19.

Funding The Ministry of Health, Programme Hospitalier de Recherche Clinique, Foundation for Medical Research, and AP-HP Foundation.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Introduction COVID-19 is a respiratory disease, induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), that has already caused more than 1 million deaths over the word.1–4 Most people with COVID-19 have only mild or uncomplicated symptoms, but approximately 10–15% of patients have moderate or severe disease that requires admission to hospital and oxygen support, and 3–5% require admission to an intensive care unit (ICU)

mainly for ventilation assistance.4,5 In severe cases, COVID-19 can be complicated by acute respiratory distress syndrome. Older age, male sex, and comorbid diseases are risk factors for death.1,6–7

At the beginning of the epidemic in France, when no standard of care was defined, we decided to set up the publicly supported CORIMUNO-19 (Cohort Multiple randomized controlled trials open-label of immune modulatory drugs and other treatments in COVID-19

Lancet Respir Med 2021; 9: 295–304

Published Online January 22, 2021 https://doi.org/10.1016/S2213-2600(20)30556-7

See Comment page 223

For the French translation of the abstract see Online for appendix 1

*Writing committee and trial steering committee are listed at the end of the Article

†Members are listed in full in the appendix 2 (pp 2–11)

Correspondence to: Dr Xavier Mariette, Service D’Immuno-Rhumatologie Hôpital Bicêtre, Assistance Publique - Hôpitaux de Paris, 94270 Le Kremlin Bicêtre, France [email protected]

See Online for appendix 2

Lancet Respir Med 2021Articles

www.thelancet.com/rheumatology Published online August 9, 2021 https://doi.org/10.1016/S2665-9913(21)00216-2 5

patients died versus 137 (25%) of 553 patients receiving standard of care with or without placebo (OR 0·38 [95% CI 0·26–0·56]; p<0·0001; table 2). No interaction effect was observed among the six studies and anakinra treatment for the primary outcome (p=0·15; table 2). After adjusting for age, comorbidities, baseline PaO₂/FiO₂, lymphopenia and CRP concen trations, anakinra was shown to independently protect against mortality (adjusted OR 0·32 [95% CI 0·20–0·51]; p<0·0001; table 2). Similar ORs were estimated for anakinra treatment after adjustment for ferritin (data available for 486 patients; adjusted OR 0·35 [95% CI 0·23–0·52]; p<0·0001) and IL-6 concentrations (data available for 530 patients; 0·54 [0·33–0·87]; p=0·01). The predefined sensitivity analyses for randomised controlled trials were not possible, since only one randomised controlled trial was included in this meta-analysis.

The mortality reduction associated with anakinra treatment was significant in the absence of dexamethasone co-administration (559 patients; OR 0·23 [95% CI 0·12–0·43]), but not with co-administration of dexa-methasone (239 patients; 0·72 [0·37–1·41]; pBreslow=0·012). Similarly, this beneficial effect of anakinra was significant in patients breathing spontaneously at baseline (792 patients; OR 0·30 [95% CI 0·19–0·48]) but not in the smaller subgroup of those who were mechanically ventilated at baseline (103 patients; 0·52 [0·20–1·36]; pBreslow=0·45). Subgroup analyses adjusting for CRP and ferritin concentrations and baseline PaO₂/FiO₂ showed that anakinra was more effective in lowering mortality in patients presenting with CRP concentrations higher than 100 mg/L (OR 0·28 [95% CI 0·17–0·47]), but the therapeutic efficacy of anakinra did not appear to be related to baseline ferritin concentrations or baseline PaO₂/FiO₂ (figure 3). In a subgroup analysis of 116 patients with diabetes and 299 patients without diabetes, the effect of anakinra on mortality was similar in both groups (OR 0·40 [95% CI 0·17–0·91] vs 0·37 [0·19–0·74]; pBreslow=0·90).

The safety of anakinra was investigated as a secondary endpoint. Anakinra treatment was associated with elevation of liver function tests (pooled OR 3·00 [95% CI 0·26–34·66]; I² 85%), as well as onset of leukopaenia (3·71 [0·49–27·84]; I² 51%) and secondary infection (1·35 [0·59–3·10]; I² 79%; appendix p 7). Thrombo embolic events were reported in only two studies;23,28 thus, no meta-analysis was done for this endpoint. Nevertheless, in both studies, anakinra did not increase the thromboembolic risk compared to standard-of-care treatment or placebo, or both.

DiscussionThe results of this systematic review and meta-analysis indicate that, in patients admitted to hospital with pneumonia due to COVID-19, treatment with anakinra reduces mortality when compared with standard of care, with or without placebo. This survival benefit was most profound in patients with hyperinflammation and

Figure 2: Forest plot showing mortality from aggregate data meta-analysisOdds ratios calculated with a fixed-effects Mantel-Haenszel test.

Balkhair et al (2021)30

Bozzi et al (2021)25

Cauchois et al (2020)22

Cavalli et al (2021)26

Huet et al (2020)23

Kooistra et al (2020)28

Kyriazopoulou et al (2021)29

The CORIMUNO-19 Collaborative group (2021)24

Pontali et al (2021)27

Total (95% CI)Heterogeneity: τ2= 0·2966; χ2=11·52, df=8 (p=0·17); I2=31%

Events

13 9 0 3 7 4

1513 9

Total

45 65 12 62 52 21

130 59 63

509

Anakinra

Events

1119 1

6219 7

291319

Total

24 55 10

275 44 39

130 55 44

676

Control Weight

8·0%13·9%

0·9%17·0%13·9%

3·1%20·1%

8·2%15·0%

100·0%

0·48 (0·17–1·34)0·30 (0·12–0·75)0·07 (0·00–46·88)0·17 (0·05–0·58)0·20 (0·08–0·55)1·08 (0·28–4·20)0·45 (0·23–0·90)0·91 (0·38–2·19)0·22 (0·09–0·55)0·37 (0·27– 0·51)

0·05 0·1 0·5 1 2 10 20

Odds ratio (95% CI)

Favours anakinra Favours standard of care

Univariate analysis Multivariate analysis

Odds ratio (95% CI)

p value Odds ratio (95% CI)

p value

Anakinra treatment 0·38 (0·26–0·56) <0·0001 0·32 (0·20–0·51) <0·0001

Age >72 years* 4·97 (3·5–7·06) <0·0001 1·89 (1·12–3·20) 0·018

Charlson comorbidity index >2* 6·35 (4·01–10·06) <0·0001 3·75 (1·99–7·07) <0·0001

PaO₂/FiO₂ <100 2·18 (1·50–3·17) <0·0001 2·89 (1·80–4·64) <0·0001

CRP >100 mg/L 1·76 (1·21–2·55) 0·003 1·21 (0·76–1·92) 0·42

Lymphopenia (<580 lymphocytes per mm³)*

3·08 (2·12–4·49) <0·0001 3·05 (1·90–4·89) <0·0001

Study ·· 0·15 ·· ··

CRP=C-reactive protein. PaO₂/FiO₂=ratio of the arterial partial oxygen pressure divided by the fraction of inspired oxygen. *For continuous variables, the best cutoff was estimated from the receiver operating characteristic using the Youden Index.

Table 2: Univariate and multivariate logistic regression analysis of variables associated with mortality in the individual patient-level data analysis of 895 patients

Effet sur la mortalité Uniquement si

CRP > 100 mg/LPas association à DXM

aOR 0.23 (0.12-0.4) vs 0.72 (0.37-1.41)


Anti-IL1

18Carrichio, JAMA 2021

• Canakimumab• RCT, double aveugle, Canada, 454 patients • Canakimumab dose unique IV + SOC vs SOC + Placebo• 70% O2 simple• Survie sans VM à J29

follow-up before day 29 was considered as a responder ifthey did not require IMV any time after day 2 and either wasdischarged from hospital with clinical status lower than 2 orthe patient’s last clinical status was obtained after day 14 andwas better than at baseline. Otherwise, the patient was con-sidered as a nonresponder. A supplementary analysis wasperformed in which all patients who were lost to follow-up ordiscontinued the study before day 29 with a clinical statushigher than 1 were considered as nonresponders. As a sensi-tivity analysis, the difference in the rates of IMV-free survivalbetween treatment groups was estimated using a marginalstandardization method in which the rate difference wasderived from the predicted rates for every patient using alogistic regression model, with treatment as main effect ofinterest adjusted by region and baseline clinical status.16

The same logistic regression model for the primary analy-sis was used for the key secondary end point of death relatedto COVID-19 during the 29-day period after study treatmentand for the exploratory end point of IMV-free survival with-out use of anakinra or tocilizumab.

The hypothesis tests for primary and key secondary analy-ses were conducted in hierarchical order with the 2-sidedfamily-wise type I error rate controlled at 0.05, which was alsothe threshold for statistical significance. No other secondary,exploratory, or supplementary analyses presented were in-cluded as part of the testing hierarchy that controlled for mul-tiplicity. Because of the potential for type I error due to mul-tiple comparisons, findings for analyses of secondary endpoints should be interpreted as exploratory.

Time to death or use of IMV, time to death, and use of IMVor of anakinra or tocilizumab were evaluated using survivalanalysis. Survival curves were elaborated based on Kaplan-Meier estimates of survival functions, and the hazard ratioswere obtained using a Cox proportional hazard model. Sur-vival curves were visually examined to confirm that there wereno apparent violations of the proportional hazard assump-tion. The exploratory end points of time to discharge from hos-pital, time to recovery, and time to improvement of at least 2levels in clinical status up to day 29 were analyzed based onCox-proportional hazards model adjusted by region and base-line clinical status. Baseline demographic and clinical charac-teristics of the patients, the evolution of serum levels of mark-ers of inflammation, and other exploratory outcomes weresummarized and presented using descriptive statistics. SASsoftware version 9.4 (SAS Institute Inc) was used for the analy-sis of this study.

ResultsTrial PopulationFrom 477 patients screened from April to August 2020, 454adult patients hospitalized with severe COVID-19 were en-rolled and randomized (Figure 1). Six randomized patients dis-continued the study before receiving study drug: 3 withdrewtheir consent to participate immediately after randomizationand 3 did not meet eligibility criteria. In total, 448 patients re-ceived canakinumab (n = 225) or placebo (n = 223).

Figure 2. Use of IMV or Death and Discharge From Hospital

40

30

20

10

0

Patie

nts w

ho d

ied

or re

ceiv

ed IM

V, %

Time, d

Use of IMV or deathA

0

227227

8

201205

15

195202

22

192197

29

191197

No. at riskCanakinumabPlacebo

Canakinumab

Placebo

40

30

20

10

0

Patie

nts w

ho d

ied

or re

ceiv

ed IM

V,an

akin

ra, o

r toc

ilizu

mab

, %

Time, d

Use of IMV, tocilizumab, or anakinra or deathB

0

227227

8

186201

15

179198

22

178194


29

177194

Canakinumab

Placebo

100

80

60

40

20

0

Patie

nts d

ischa

rged

from

hos

pita

l, %

Time, d

Discharge from hospitalC

0

227227

8

137129

15

6662

22

3931

29

3524


Canakinumab

Placebo

Kaplan-Meier estimates are for patients with COVID-19 and hyperinflammation(N = 454, 227 in each group) treated with the standard care plus 1 single dose ofcanakinumab or placebo on day 1. Data markers represent censoring times.A and B, Patients were censored after day 29 or at the last follow-up if theydiscontinued the study; C, patients who died were not censored up to day 29.By day 29, 12 patients died in the canakinumab group and 16 in the placebogroup. Most patients completed the observation period of 29 days, andtherefore the median observation time was 29 days. Of note, 14 patientswere readmitted to the hospital after discharge: 8 in the canakinumab groupand 6 in the placebo group. The median time to hospital discharge was 10 days(95% CI, 9-12) for the canakinumab group and 11 days (95% CI, 10-12) for theplacebo group.

Research Original Investigation Effect of Canakinumab vs Placebo on Survival Without IMV in Patients Hospitalized With Severe COVID-19

234 JAMA July 20, 2021 Volume 326, Number 3 (Reprinted) jama.com


89% Canakimumab86% Placebo OR 1.4 (0.8-2.5)


Inhibiteurs de JAK• Baricitinib (JAK 1&2)• COV-BARRIER, RCT, double aveugle, 1 525 patients (1:1)• Baricitinib 4mg/j + SOC vs SOC + Placebo, 14j, Aggravation à J28

§ OS4 12%, OS5 63%, OS6 24%

19

The new england journal of medicine

n engl j med 384;9 nejm.org March 4, 2021 795

established in 1812 March 4, 2021 vol. 384 no. 9

The authors’ full names, academic de-grees, and affiliations are listed in the Ap-pendix. Address reprint requests to Dr. Kalil at the University of Nebraska Medi-cal Center, 985400 Nebraska Medicine, Omaha, NE 68198-5400, or at akalil@ unmc . edu.

* A complete list of members of the ACTT-2 Study Group is provided in the Supplementary Appendix, available at NEJM.org.

This article was published on December 11, 2020, and updated on January 5, 2021, at NEJM.org.

N Engl J Med 2021;384:795-807.DOI: 10.1056/NEJMoa2031994Copyright © 2020 Massachusetts Medical Society.

BACKGROUNDSevere coronavirus disease 2019 (Covid-19) is associated with dysregulated inflam-mation. The effects of combination treatment with baricitinib, a Janus kinase inhibitor, plus remdesivir are not known.

METHODSWe conducted a double-blind, randomized, placebo-controlled trial evaluating baricitinib plus remdesivir in hospitalized adults with Covid-19. All the patients received remdesivir (≤10 days) and either baricitinib (≤14 days) or placebo (control). The primary outcome was the time to recovery. The key secondary outcome was clinical status at day 15.

RESULTSA total of 1033 patients underwent randomization (with 515 assigned to combina-tion treatment and 518 to control). Patients receiving baricitinib had a median time to recovery of 7 days (95% confidence interval [CI], 6 to 8), as compared with 8 days (95% CI, 7 to 9) with control (rate ratio for recovery, 1.16; 95% CI, 1.01 to 1.32; P = 0.03), and a 30% higher odds of improvement in clinical status at day 15 (odds ratio, 1.3; 95% CI, 1.0 to 1.6). Patients receiving high-flow oxygen or noninvasive ventilation at enrollment had a time to recovery of 10 days with combination treat-ment and 18 days with control (rate ratio for recovery, 1.51; 95% CI, 1.10 to 2.08). The 28-day mortality was 5.1% in the combination group and 7.8% in the control group (hazard ratio for death, 0.65; 95% CI, 0.39 to 1.09). Serious adverse events were less frequent in the combination group than in the control group (16.0% vs. 21.0%; difference, −5.0 percentage points; 95% CI, −9.8 to −0.3; P = 0.03), as were new infections (5.9% vs. 11.2%; difference, −5.3 percentage points; 95% CI, −8.7 to −1.9; P = 0.003).

CONCLUSIONSBaricitinib plus remdesivir was superior to remdesivir alone in reducing recovery time and accelerating improvement in clinical status among patients with Covid-19, notably among those receiving high-flow oxygen or noninvasive ventilation. The combination was associated with fewer serious adverse events. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04401579.)

a bs tr ac t

Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19A.C. Kalil, T.F. Patterson, A.K. Mehta, K.M. Tomashek, C.R. Wolfe, V. Ghazaryan, V.C. Marconi,

G.M. Ruiz-Palacios, L. Hsieh, S. Kline, V. Tapson, N.M. Iovine, M.K. Jain, D.A. Sweeney, H.M. El Sahly, A.R. Branche, J. Regalado Pineda, D.C. Lye, U. Sandkovsky, A.F. Luetkemeyer, S.H. Cohen, R.W. Finberg,

P.E.H. Jackson, B. Taiwo, C.I. Paules, H. Arguinchona, N. Erdmann, N. Ahuja, M. Frank, M. Oh, E.-S. Kim, S.Y. Tan, R.A. Mularski, H. Nielsen, P.O. Ponce, B.S. Taylor, L.A. Larson, N.G. Rouphael, Y. Saklawi, V.D. Cantos,

E.R. Ko, J.J. Engemann, A.N. Amin, M. Watanabe, J. Billings, M.-C. Elie, R.T. Davey, T.H. Burgess, J. Ferreira, M. Green, M. Makowski, A. Cardoso, S. de Bono, T. Bonnett, M. Proschan, G.A. Deye, W. Dempsey, S.U. Nayak,

L.E. Dodd, and J.H. Beigel, for the ACTT-2 Study Group Members*



Kalil, NEJM 2021

Marconi, MedrXiv mai 2021

38

. CC-BY-NC-ND 4.0 International licenseIt is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 30, 2021. ; https://doi.org/10.1101/2021.04.30.21255934doi: medRxiv preprint

Progression à J2828% Baricitinib vs 31% Placebo

OR 0.85 (IC95% 0.67-1.08)

Mortalité J28 (CJS)


Inhibiteurs de JAK• Tofacitinib (JAK 1&3)

§ RCT double aveugle (Brésil, 15 sites), 289 patients (1:1) § Tofacitinib (10mgx2/j) + SOC vs SOC + Placebo, 14 j, Décès ou défaillance respiratoire à J28

• 25% pas 02, 63% O2 simple, 13% OHD

20Guimaraes NEJM 2021

n engl j med 385;5 nejm.org July 29, 2021414


antiviral agent used was oseltamivir, which has not been shown to be effective in patients with Covid-19. Therefore, our trial does not offer evi-dence of a benefit of tofacitinib treatment in addition to established antiviral therapy.

On the basis of current evidence, antiviral therapy is most likely to be effective in early Covid-19. The hyperinflammatory responses are thought to drive the clinical symptoms in later stages of the disease.20 Therefore, antiinflamma-tory interventions are needed in hospitalized pa-tients with mild, moderate, or severe Covid-19.21 Glucocorticoids are likely to be most effective in severely ill patients. Taken together, the results of ACTT-2 and STOP-COVID provide evidence that JAK inhibition represents an additional therapeu-tic option for treating Covid-19 pneumonia in patients who are not yet receiving invasive me-chanical ventilation. These agents are orally ad-ministered and have few drug–drug interactions.

Ongoing trials with tofacitinib (ClinicalTrials.gov numbers, NCT04415151 and NCT04750317) and baricitinib (NCT04390464, NCT04640168, NCT04421027, and NCT04381936) may provide further insights regarding the effects of JAK in-hibitors in patients with Covid-19.

Several other specific immune modulators are being tested in patients with Covid-19 pneu-monia, and the results have been mixed.22 These include anticytokines such as interleukin-1 and interleukin-6 receptor antagonists (e.g., anakinra, tocilizumab, sarilumab, and siltuximab), tumor necrosis factor inhibitors (e.g., adalimumab and infliximab), and granulocyte–macrophage colony-stimulating factors (e.g., gimsilumab, lenzilumab, and namilumab).23-29 In STOP-COVID, the use of these agents was prohibited. Whether the use of JAK inhibitors is superior or additive to other spe-cific immunomodulatory therapies in patients hos-pitalized with Covid-19 remains to be determined.

Figure 3. Subgroup Analyses of Death or Respiratory Failure through Day 28.

In the subgroup analyses, the risk ratios for death or respiratory failure through day 28 (primary outcome) were cal-culated by means of binary regression with Firth correction, with trial group and antiviral therapy for Covid-19 as co-variates. For the analysis according to use of antiviral therapy at baseline, in all cases, the antiviral agent used was oseltamivir. Time from symptom onset was analyzed in two ways: according to thirds (the prespecified analysis) and above versus below or equal to the median (10 days; post hoc analysis). Two patients (one in the tofacitinib group and one in the placebo group) did not have data on the date of symptom onset. The size of the boxes is proportion-al to the number of patients and events, and arrows indicate that the boundary of the 95% confidence interval is outside the graphed area.

4.00

Placebo BetterTofacitinib Better

OverallSex

MaleFemale

Age≤60 yr>60 yr

Antiviral therapyNoYes

GlucocorticoidsNoYes

Days since symptom onset<88 to 11>110 to 10>10

1.0

No. of Patients Risk Ratio (95% CI)Subgroup

0.67 (0.35–1.27)0.28 (0.08–0.96)

0.50 (0.27–0.93)

0.46 (0.25–0.85)

0.71 (0.20–2.55)

0.41 (0.18–0.93)

1.08 (0.28–4.13)

0.81 (0.37–1.78)

0.66 (0.34–1.30)

0.63 (0.41–0.97)

0.13 0.25 0.50 2.001.0

0.36 (0.13–0.96)

289

188101

171118

25138

62227

81100106183104

0.55 (0.21–1.44)0.86 (0.35–2.07)0.27 (0.08–0.92)




n engl j med 385;5 nejm.org July 29, 2021406

The authors’ affiliations are listed in the Appendix. Address reprint requests to Dr. Berwanger at the Hospital Israelita Albert Einstein, Av. Albert Einstein 627, São Paulo 05620-900, Brazil, or at otavioberwanger@ gmail . com.

*A list of the STOP-COVID Trial Investi-gators is provided in the Supplemen-tary Appendix, available at NEJM.org.

This article was published on June 16, 2021, and updated on July 29, 2021, at NEJM.org.

N Engl J Med 2021;385:406-15.DOI: 10.1056/NEJMoa2101643Copyright © 2021 Massachusetts Medical Society.

BACKGROUNDThe efficacy and safety of tofacitinib, a Janus kinase inhibitor, in patients who are hospitalized with coronavirus disease 2019 (Covid-19) pneumonia are unclear.

METHODSWe randomly assigned, in a 1:1 ratio, hospitalized adults with Covid-19 pneumo-nia to receive either tofacitinib at a dose of 10 mg or placebo twice daily for up to 14 days or until hospital discharge. The primary outcome was the occurrence of death or respiratory failure through day 28 as assessed with the use of an eight-level ordinal scale (with scores ranging from 1 to 8 and higher scores indicating a worse condition). All-cause mortality and safety were also assessed.

RESULTSA total of 289 patients underwent randomization at 15 sites in Brazil. Overall, 89.3% of the patients received glucocorticoids during hospitalization. The cumula-tive incidence of death or respiratory failure through day 28 was 18.1% in the to-facitinib group and 29.0% in the placebo group (risk ratio, 0.63; 95% confidence interval [CI], 0.41 to 0.97; P = 0.04). Death from any cause through day 28 occurred in 2.8% of the patients in the tofacitinib group and in 5.5% of those in the pla-cebo group (hazard ratio, 0.49; 95% CI, 0.15 to 1.63). The proportional odds of having a worse score on the eight-level ordinal scale with tofacitinib, as compared with placebo, was 0.60 (95% CI, 0.36 to 1.00) at day 14 and 0.54 (95% CI, 0.27 to 1.06) at day 28. Serious adverse events occurred in 20 patients (14.1%) in the to-facitinib group and in 17 (12.0%) in the placebo group.

CONCLUSIONSAmong patients hospitalized with Covid-19 pneumonia, tofacitinib led to a lower risk of death or respiratory failure through day 28 than placebo. (Funded by Pfizer; STOP-COVID ClinicalTrials.gov number, NCT04469114.)

A BS TR AC T

Tofacitinib in Patients Hospitalized with Covid-19 Pneumonia

Patrícia O. Guimarães, M.D., Ph.D., Daniel Quirk, M.D., M.P.H., Remo H. Furtado, M.D., Ph.D., Lilia N. Maia, M.D., Ph.D., José F. Saraiva, M.D., Ph.D.,

Murillo O. Antunes, M.D., Ph.D., Roberto Kalil Filho, M.D., Ph.D., Vagner M. Junior, M.D., Alexandre M. Soeiro, M.D., Alexandre P. Tognon, M.D., Ph.D., Viviane C. Veiga, M.D., Ph.D., Priscilla A. Martins, M.D., Diogo D.F. Moia, Pharm.D.,

Bruna S. Sampaio, B.Sc., Silvia R.L. Assis, M.S., Ronaldo V.P. Soares, Pharm.D., Luciana P.A. Piano, Ph.D., Kleber Castilho, M.B.A., Roberta G.R.A.P. Momesso, Ph.D.,

Frederico Monfardini, M.Sc., Helio P. Guimarães, M.D., Ph.D., Dario Ponce de Leon, M.D., Majori Dulcine, M.D., Marcia R.T. Pinheiro, M.D., Levent M. Gunay, M.D., J. Jasper Deuring, Ph.D., Luiz V. Rizzo, M.D., Ph.D.,

Tamas Koncz, M.D., Ph.D., and Otavio Berwanger, M.D., Ph.D., for the STOP-COVID Trial Investigators*

Original Article




Synthèse• Corticoïdes

§ SOC§ Posologie, durée, molécules

• Anti-IL6, Anti-JAK§ En association aux CTC

• Anti-IL1§ Manque données de qualité

21


Perspectives• Cadre utilisation Anti-IL6, JAK. Comparaison IL-6 vs JAK (+ CTC)

• Molécules inhalées § INF-β1-a,

• Essai petite taille 48 patients vs 50 placebo, 2/3 sous 02, 14j, Amélioration clinique + fréquente (Monk, Lancet RespMed 2020)

• Phase 3

• Autres immunomodulateurs§ Anti GM-CSF (Mavrilimumab) (De Luca, Lancet Rheumatol 2020 ; Cremer Lancet Rheumatol 2021)

§ Inhibiteur du complément• Anti-C5a (Vilobelimab) (Vlaar, Lancet Rheumatol 2021)• Anti-C5aR1 (Avdoralimab) : résultats négatifs phase 2, Essai Force (Communiqué Presse, Juillet 2021)

§ Antagoniste récepteur bradykinine 2 (van de Veerdonk, JAMA Open Net 2021)

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Conclusions• Attente d’autres molécules antivirales

Utilisation mAbs chez les séronégatifs ?

• A associer au traitement immunomodulateur actuel (SOC) qui risque évoluer

CTC à CTC + Anti-IL6/Inhib JAK

Notions de timing administration et sous groupe patients essentielles23


REMERCIEMENTSMerci de votre attention

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Documents

Pneumonies à SARS-CoV-2