¿Qué Nos Dicen Los Ensayos Clínicos Sobre Tratamiento? Dr

XI Jornadas Enfermedades Emergentes Mesa Redonda: Aspectos clínicos y terapéuticos de la COVID-19 Barcelona, 17 de junio de 2021 ¿Qué nos dicen los ensayos clínicos sobre tratamiento? Dr. Josep Mª Miró Infectious Diseases Service Hospital Clinic - IDIBAPS University de Barcelona Barcelona, Spain

E-mail address: [email protected] Transparency Declaration

Dr. José M Miró has received honoraria for speaking or participating in Advisory Boards and/or research grants from the following Pharmaceutical Companies:

Abbvie Merck Angelini-Allergan Medtronic Bristol-Myers Squibb Novartis Contrafect Pfizer Genentech Roche Gilead Sciencies Theravance Jansen ViiV Healthcare What do clinical trials tell us about treatment?

. Introduction . Update on antiviral treatment . Anti-inflammatory Treatment . Update on antiviral prophylaxis . Take-home messages

May 11th 2021 Number of Antivirals and Anti-inflammatory Drugs given weekly against COVID-19 in Catalonia in March and May 2020.

# drug containers Use off-label … HCQ Faith, Hope and …

Tocilizumab RCT showed several disappointments! LPV/rtv

Remdesivir Coronavirus Drug and Treatment Tracker (June 16th 2021)

Remdesivir drug (FDA, EMA but not WHO) Convalescent plasma (FDA EUA) Monoclonal antibodies (FDA EUA) Dexamethasone and other corticosteroids (NIH, IDSA) IL-6 inhibitors: Tocilizumab

https://www.nytimes.com/interactive/2020/science/coronavirus-drugs-treatments.html Objectives COVID-19 Treatment: Treat Early & Hard

2.- Antivirals 3.- Anti-inflammatory drugs

Procoagulant phase

1.‐ Prophylactic‐dose low‐molecular‐weight heparin (LMWH)

Siddiqu HK, Mehra MR. J Heart Lung Transplant. 2020 doi: 10.1016/j.healun.2020.03.012; Pericas JM, Hernandez-Meneses M et al. Eur Heart J. June 8th 2020. Ongoing Antithrombotic Therapy Trials in COVID-19 (N=83)

Talasaz AH, et al. J Am Coll Cardiol. 2021 Apr 20;77(15):1903-1921. What do clinical trials tell us about treatment?

. Introduction . Update on antiviral treatment . Anti-inflammatory Treatment . Update on antiviral prophylaxis . Take-home messages SARS-CoV-2 life cycle: Potential targets for antivirals

Plasma/Neutralizing Antibodies Entry inhibitors hrACE2 – APN01 Ribavirin ACE2 Interferon-beta?* Chloroquine Hydroxychloroquine Ivermectin Nitazoxanide

Lopinavir/rtv Potential for combining several Remdesivir antiviral drugs * Interferon induces hundreds of genes which can act on various parts of the lifecycle from Molnupiravir potentially degrading viral RNA (OAS, RNASL) to inhibiting virus egress (BST-2) De Wit Nature Rev Microbiol, 2016; Sanders JM, et al. JAMA. 2020 Apr 13. doi: 10.1001/jama.2020.6019. Hydroxychloroquine (HCQ): No benefit in RCTs

HCQ PBO/SoC P-value

Non-hospitalized (mild-moderate) Hospitalization - Skipper et al (Annals, 2020)* 2% 3% 0.29 - Mitja et al. (CID, 2020)** 6% 7% 0.38

Hospitalized (severe-critical) Mortality, 28 d - Recovery (NEJM, 2020) 26% 23.5% 0.10 - Solidarity (medRxiv, 2020) 10% 9% 0.23

* More side effects with HCQ than placebo; ***The respiratory tract viral RNA loads over time did not differ between the HCQ recipients and those receiving standard care; FDA rescinded the emergency use authorization (EUA) of HCQ to treat COVID-19 patients on June 15; NIH halts clinical trial of HCQ on June 20. Study showed treatment does no harm, but provides no benefit. Lopinavir/Ritonavir (Kaletra): No benefit in RCTs

LPV/rtv SoC P-value Mortality, 28 d Hospitalized (severe-critical) - Cao et al. (NEJM, 2020)* 19% 25% NS - Recovery (Lancet, 2020)** 23% 22% 0.60 - Solidarity (medRxiv, 2020) 10% 10% 0.97

*The respiratory tract viral RNA loads over time did not differ between the lopinavir–ritonavir recipients and those receiving standard care **No evidence of beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay. The number of patients on invasive mechanical ventilation was low because of difficulty administering the drug to patients on ventilators. Adverse events and particularly gastrointestinal adverse events were more common in the lopinavir–ritonavir group in the three RCT. Remdesevir (GS-5734) . RNA-dependent RNA polymerase inhibitor. . Effective in vitro and in animal models against zoonotic and epidemic SARS- CoV, MERS-CoV and SARS-CoV-2 as both prophylactic and therapeutic agent. . PK: Renal excretion. Not recommended eGFR ≤30 ml/min. Few DDI. . Dosage: 200 mg IV, then 100 mg/24 h during 5-10 days. . Safety: few side effects (hypotension during infusion).

Sheahan TP et al. Sci Transl Med, 2017; De Wit ET al. Proc Natl Acad Sci U S A, 2020; Sheahan TP et al. Nat Commun; 2020; Williamson BN et al. bioRxiv preprint doi: https://doi.org/10.1101/2020.04.15.043166. Remdesivir - Adaptive COVID-19 Treatment Trial (ACTT)

• Double-blind, randomized, placebo-controlled trial involving 1,063 hospitalized patients with advanced COVID-19 disease • A total of 68 sites ultimately joined the study— 47 in the United States and 21 in countries in Europe and Asia. • Primary endpoint: time to recovery was defined as being well enough for hospital discharge or returning to normal activity level. • NIH showed preliminary data of interim analysis on April 29th 2020.

Remdesivir Placebo P-value NIAID trial - Median time to recovery, days* 11 15 <0.001 - Mortality 8% 11.6% 0.059

*Patients who received remdesivir had a 31% faster time to recovery than those who received placebo.

Beigel JH et al. N Engl J Med. 2020. Remdesivir - Adaptive COVID-19 Treatment Trial (ACTT)

Remdesivir Placebo P-value NIAID trialFDA Approval, May 1 2020 - Median time to recovery, days* 11 15 <0.001 - MortalityEMA Approval, June8% 2511.6% 20200.059

*Patients who received remdesivir had a 31% faster time to recovery than those who received placebo.

Beigel JH et al. N Engl J Med. 2020 May 22. doi: 10.1056/NEJMoa2007764. Remdesivir – ACTT (NIH) vs. Solidarity (WHO) ACTT (NIH) Solidarity (WHO)

SAEs: 21% REM vs. 27% PBO Beigel JH et al. N Engl J Med. Nov 5 2020; Solidarity, medRxiv Oct 28 2020

Remdesivir – ACTT (NIH): Only good results in Stage 5

(Stage 5)

Positive results in patients: - ≤ 10 days symptoms duration - Stage 5: receiving oxygen

Beigel JH et al. N Engl J Med. Nov 5 2020 Remdesivir in Solidarity RCT: It does not analyze stages 5 and 6 separately

(Stage 5 & 6)

(Stage 5) (Stage 6)

Beigel JH et al. N Engl J Med. Nov 5 2020; Solidarity, medRxiv Oct 28 2020 Remdesivir Reduced the SARS-CoV-2 VL in BAL from Rhesus Macaques SARS-CoV-2 VL and virus titers in BAL fluid and lung lobes collected from six Rhesus Macaques Infectious virus titers in VL in BAL (N=6) VL in tissues at necropsy (N=36) BAL (N=6)

• Virus shedding from the upper respiratory tract was not reduced by remdesivir treatment. • At necropsy, remdesivir-treated animals had lower lung viral loads and reduced lung damage. VL = Viral load; BAL = Bronchoalveolar lavage Williamson BN et al. Nature. Sep 2020; 585: 273-276. doi: 10.1038/s41586-020-2423-5. Epub 2020 Jun 9. Remdesivir – Phase 3 SIMPLE Trial in Moderate COVID-19

• Open-label, phase 3 SIMPLE RCT 1:1:1 evaluating 5-day vs. 10-day dosing durations of the Remdesivir vs. Standard of Care (SoC) in hospitalized patients with moderate COVID-19 disease. • Gilead announced results on June 1st 2020.

5-d vs. SoC p=0.026

No safety concerns

Spinner CD, et al. JAMA. Aug 21 2020. Ivermectin in Adults with Mild COVID-19

• Double-blind RCT conducted at a single site in Cali, Colombia. A total of 476 adults with mild disease and symptoms for 7 days or fewer (at home or hospitalized) were enrolled between July and November 2020, and followed up through December 2020. • Patients were randomized to receive ivermectin, 300 μg/kg of body weight per day for 5 days (n = 200) or placebo (n = 200). • Primary outcome was time to resolution of symptoms within a 21-day follow-up.

Time to Resolution of Symptoms in the Primary Analysis Population.

• Symptoms resolution: 82% in the ivermectin group and 79% in the placebo group by day 21.

• The trial do not support the use of ivermectin for treatment of mild COVID-19. Lopez-Medina E et al. JAMA. doi:10.1001/jama.2021.3071. Published online March 4, 2021. Molnupiravir – An Oral Drug for COVID-19 Treatment

• Molnupiravir has potent in vitro activity against a broad range of coronaviruses, including SARS-COV-2 (including remdesivir-resistant mutants). • Demonstrated activity in ferret and mouse models of SARS-CoV-2 disease, including prophylaxis, treatment, and prevention of transmission • It is rapidly absorbed and distributed after oral administration and subsequently converted intracellularly to active form. • Inhibits SARS-COV-2 replication by inducing viral error catastrophe. It is not mutagenic or genotoxic in mammals.

• CROI 2021: Phase 2a RCT. 182 participants randomized 1:1 (200 mg) or 3:1 (400 mg, 800 mg) sequentially to receive molnupiravir or placebo twice-daily for 5 days. • 78 cases (42.9%) had positive baseline cultures • Overall, there was a significant reduction in positive viral culture at day 5 in molnupiravir-treated participants. Best activity reached with 800 mg BID. No infectious virus was recovered in any molnupiravir-treated participants. • The drug was safe and well tolerated. Four cases experienced a serious AE (0 drug-related) and 7 discontinued study drug (3 due to an AE). Painter W, et al. CROI 2021 Poster #777. Molnupiravir – An Oral Drug for COVID-19 Treatment

Update on Progress of Clinical Development Program for Molnupiravir, an Investigational Oral Therapeutic for the Treatment of Mild-to-Moderate COVID-19 → Phase 2/3 MOVe-IN Study in Hospitalized Patients Stopped. • Phase 2/3, randomized, placebo-controlled, double-blind, multi-site trial evaluating the efficacy, safety, and pharmacokinetics of orally administered molnupiravir in hospitalized participants at least 18 years of age with laboratory confirmed. 304 participants randomized 1:1:1:1 to who received molnupiravir 200 mg, 400 mg, 800 mg or placebo twice daily for 5 days. The primary efficacy endpoint was to evaluate the rate of sustained recovery from randomization through Day 29. → Phase 3 MOVe-OUT Study in Outpatients to Proceed. • Phase 2/3, randomized, placebo-controlled, double-blind, multisite study evaluating the efficacy, safety and pharmacokinetics of orally administered molnupiravir in non-hospitalized participants with COVID-19 confirmed using PCR. The primary efficacy objective is assessed by the percentage of patients who are hospitalized and/or die from the time of randomization through Day 29. Part 1 of MOVe-OUT enrolled a total of 302 participants, with symptom onset within seven days prior to randomization, who were assigned to receive molnupiravir 200 mg (75), 400 mg (77), or 800 mg (76), or placebo (74). • Final data is estimated to be available in September/ October 2021 → Molnupiravir for PEP in the second half of 2021?

Merck and Ridgeback Biotherapeutics press release. April 14th 2021. Interferon-β1a: Parenteral (Solidarity trial) vs. Inhalation (UK trial) Parenteral* (SC or IV, 6 d) Inhalation (6 MIU/d, 14 d)

*44 µg/d SC three doses; 10 µg IV daily. Solidarity, medRxiv Oct 28 2020; Monk PD et al. Lancet Respir Med Nov 12 2020 Convalescent plasma transfusion does not work

Treatment with convalescent plasma compared with placebo or standard of care was not significantly associated with a decrease in all-cause mortality or with any benefit for other clinical outcomes ((length of hospital stay or mechanical ventilation use) Janiaud P et al. JAMA. February 26, 2021. doi:10.1001/jama.2021.2747 Early convalescent plasma transfusion works . Randomized, double-blind, placebo-controlled trial of convalescent plasma with high IgG titers against SARS-CoV-2 in older adult patients (≥75 years or between 65-74 years with ≥1 comorbidity) ≤72 hours after the onset of mild Covid-19 symptoms. . Primary end point was severe respiratory disease, defined as a respiratory rate of 30 breaths per minute or more, an oxygen saturation of less than 93% while the patient was breathing ambient air, or both. Time to the Development of Primary End Point according to Donor SARS-CoV-2 S IgG Titer. Severe Respiratory Disease (ITT)

-73% -31%

The trial was stopped early at 76% of its projected sample size because cases of Covid-19 in the trial region decreased considerably and enrollment of trial patients became impossible. Libster R et al. INFANT–COVID-19 Group. NEJM. Jan 6th 2021 Monoclonal Antibodies against the SARS-CoV-2 Spike Protein: Early Treatment (<10 d.) in Patients at High Risk of Progression

mAb PBO P-value Hospitalization rates at 28 days Bamlanivimab (iv single dose) - Chen P et al (N=552; 3:1)* 1.6% 6.3% 0.017

Casirivimab plus Imdevimab (iv single dose) - Regeneron mAb (N=799; 2:1)** 3% 9% <0.001

* 452 patients were assigned to receive a single IV infusion of neutralizing antibody LY-CoV555 in one of three doses (700 mg, 2800 mg, or 7000 mg) or placebo ** 266 patients received a single IV infusion of 2,400 milligrams casirivimab and imdevimab (1,200 mg of each), 267 received 8,000 mg casirivimab and imdevimab (4,000 mg of each), and 266 received a placebo, within three days of obtaining a positive SARS-CoV-2 viral test. The combination of casirivimab plus imdevimab is particularly effective in reducing VL in patients who are antibody-negative and those with high baseline VL.

Chen P et al on behalf BLAZE-1 Investigators. NEJM Oct 28 2020; REGN-COV-2. REGENERON Press Release Nov 21 2020 Casirivimab & Imdevimab reduced 28-day mortality in hospitalized baseline seronegative patients: RECOVERY RCT • Randomized, controlled, open-label platform trial. Eligible and consenting patients were randomly allocated (1:1) to either usual SoC (usual care group) or usual care plus a single dose of REGEN-COV 8g (casirivimab 4g and imdevimab 4g) by intravenous infusion (REGEN-COV group). • Primary endpoint was 28-day mortality assessed first among patients without detectable antibodies to SARS-CoV-2 at randomisation (seronegative) and then in the overall population. • Between 18 September 2020 and 22 May 2021, 9785 patients were randomly allocated to receive usual care plus REGEN-COV or usual care alone, including 3153 (32%) seronegative patients 5272 (54%) seropositive patients and 1360 (14%) patients with unknown baseline antibody status.

RECOVERY RCT. medRxiv June 16, 2021 (NCT04381936) What do clinical trials tell us about treatment?

. Introduction . Update on antiviral treatment . Anti-inflammatory Treatment . Update on antiviral prophylaxis . Take-home messages SARS-CoV-2 (COVID19): Anti-inflammatory Treatment • Corticosteroids • IL-6 inhibitors - Tocilizumab - Sarilumab no activity. - Siltuximab ACE2 • IL-1 inhibitors - Anakinra • JAK inhibitors - Baricitinib (also entry inhibitor) Cytokine • Bruton tyrosin-kinase inhibitors Storm - Acalabrutinib → ARDS • GM-CSF blockers (Mavrilimumab) • Colchicine (also entry inhibitor) Adapted from Ware LB et al. NEJM, 2000 • Fluvoxamina Corticosteroids . Effective for treating ARDS of non-viral cause (Meta-Analysis and RCT) . Increasing mortality in influenza-related pneumonia and ARDS. . Short pulse-therapy was beneficial in some SARS-CoV and MERS-CoV studies but also have important side effects. . Observational studies in COVID-19 had controversial results. . Increased plasma viremia and delayed clearance in SARS-CoV and MERS-CoV.

Early corticosteroids Early corticosteroids

Placebo Placebo

Ho JC, AJRCCM, 2003; Sung JJY, Thorax, 2004; Lau ACW, Respirology, 2004; Lee N, JCV, 2004; Chen RC, Chest, 2006; Rabaan AA, JMM, 2017; Arabi YM, AJRCCM, 2018, Sun S, ETM 2019; Zhou Y, Sci Rep, 2020; Wu C et al, JAMA Intern Med. 2020. RECOVERY Trial: Low-dose Dexamethasone Reduced Death • RECOVERY was established as a randomized clinical trial to test a range of potential drugs for COVID-19, including dexamethasone. • The trial has proceeded at unprecedented speed, enrolling over 11,000 patients from 175 NHS hospitals in the UK. • The Independent Data Monitoring Committee (IDMC) has reviewed the emerging data about every two weeks to determine if there is evidence that would be strong enough to affect national and global treatment of COVID-19. • Dexamethasone: 6 mg once per day (either by mouth or by intravenous injection) for 10 days vs. Standard of Care (SoC). • On June 8 IDMC concluded that dexamethasone reduced deaths in hospitalized patients with severe COVID-19. Dexamethasone SoC RR (95%CI) Recovery trial Number of patients 2104 4321 28-day mortality 21.6% 24.6% 0.83 (0.74;0.92) - Mechanical ventilation* 29% 41% 0.65 (0.51;0.82) - Oxygen supply* 21% 25% 0.80 (0.70;0.92) - No respiratory intervention* 17% 13% 1.22 (0.86;1.75)

RECOVERY Trial press release, June 16 2020; Horby PW et al. medRxiv. June 22, 2020; The *Rate Ratio (95% confidence interval) RECOVERY Collaborative Group. NEJM July 17 2020. DOI: 10.1056/NEJMoa2021436. Systemic Corticosteroids & 28-day Mortality in COVID-19 WHO Meta-Analysis

0.66 (0.53-0.82) 0.70 (0.48-1.01) Inhaled budesonide may have a role in early COVID-19*

WHO. JAMA. doi:10.1001/jama.2020.17023. September 2, 2020; * Ramakrishnan S et al. Lancet RD; 2021 preprint. Tocilizumab plus dexamethasone – RECOVERY Trial • Randomized, controlled, open-label, platform trial, including 4,116 patients. • Inclusion criteria: patients with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein [CRP] ≥75 mg/L) • RCT: Standard of care alone (dexamethasone) vs. usual standard of care plus tocilizumab at a dose of 400 mg to 800 mg (depending on weight) given intravenously. A second dose could be given 12-24 h. • The primary outcome was 28-day mortality, assessed in the intention-to-treat population. 28-day Mortality 28-day Discharge from hospital days

RECOVERY Collaborative Group (Horby PW). Lancet 2021; 397: 1637–45. Tocilizumab plus dexamethasone – RECOVERY Trial • Randomized, controlled, open-label, platform trial, including 4,116 patients. • Inclusion criteria: patients with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein [CRP] ≥75 mg/L) • RCT: Standard of care alone (dexamethasone) vs. usual standard of care plus tocilizumab at a dose of 400 mg to 800 mg (depending on weight) given intravenously. A second dose could be given 12-24 h. • The primary outcome was 28-day mortality, assessed in the intention-to-treat population.

*Rate Ratio (95% confidence interval) RECOVERY Collaborative Group (Horby PW). Lancet 2021; 397: 1637–45. Meta-analysis of mortality in RCTs of tocilizumab in hospitalized patients with COVID-19

*Rate Ratio (95% confidence interval) RECOVERY Collaborative Group (Horby PW). Lancet 2021; 397: 1637–45. Baricitinib has antiviral and anti-inflammatory properties

• There is a high expression of TYK2 gene in COVID- 19 patients with poor outcome. JAK 1/2 inhibitors (baricitinib) could be useful to prevent inflammation.

• Baricitinib is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients with an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs. The recommended dose is 4 mg QD orally.

• The first pilot retrospective multicenter study showed that baricitinib 4 mg/day used for 2 weeks (together with LPV/rtv) was not associated with SAEs, reduced SARS-CoV-2 viral burden in nasopharyngeal swabs and ICU admissions of patients with COVID-19 pneumonia* AAK1 = AP2-associated protein kinase 1; GAK = cyclin G- Richardson P et al. Lancet, February 3, 2020; Stebbing J et al. Lancet, Feb 27 associated kinase; JAK1/2 = janus kinase 1/2 inhibitors 2020; *Cantini F et al. J infect. Jun 242020 . doi: 10.1016/j.jinf.2020.06.052; Pairo- Castineira E. et al. Nature. 2020 Dec 11. doi: 10.1038/s41586-020-03065-y. Remdesivir plus Baricitinib – ACTT-2 (NIH): Stage 6

Baseline Ordinal Scale 6 (Stage 6)

Positive results in patients: - Severe disease - Stage 6: high-flow oxygen & NIMV

NIMV = Non-invasive mechanical ventilation Kalil AC et al. N Engl J Med. March 4, 2021. DOI: 10.1056/NEJMoa2031994 Baricitinib – Phase 3 RCT COV-BARRIER

• COV-BARRIER is a Phase 3 study evaluating baricitinib 4 mg once daily plus standard of care (SoC) vs. placebo plus SoC for 14 days. • The trial did not meet statistical significance on the primary endpoint, which was defined as a difference in the proportion of participants progressing to the first occurrence of non-invasive ventilation including high flow oxygen or invasive mechanical ventilation (MV) including extracorporeal membrane oxygenation (ECMO) or death by Day 28. • Baricitinib-treated patients were 2.7 percent less likely than those receiving standard of care to progress to ventilation (non-invasive or mechanical) or death, a difference that was not statistically significant (OR: 0.85; 95% CI 0.67, 1.08; p=0.1800). Baricitinib Placebo P-value End-points by day 28 - Number of patients 764 761 - Combined (MV, ECMO, death) NA NA 0.180 - Only 28-day mortality 8.1% 13.1% <0.001

• A reduction in mortality was also seen for the subgroups of patients being treated with or without corticosteroids at baseline. • Serious infections and venous thromboembolism (VTE) occurred in 8.5 percent and 2.7 percent of patients treated with baricitinib, respectively, versus 9.8 percent and 2.5 percent of patients treated with placebo. • NA = Not available Lilly and Incyte press release, April 8, 2021 Colchicine in Non-Hospitalized Patients with COVID-19 (COLCORONA RCT)

• Double-blind RCT performed in Canada involving non-hospitalized patients with COVID-19 diagnosed by PCR testing or clinical criteria. • The patients were randomly assigned to receive colchicine (0.5 mg twice daily for 3 days and once daily thereafter) or placebo for 30 days. • The primary efficacy endpoint was the composite endpoint of death or hospitalization for COVID-19. Colchicine Placebo P-value

ITT analysis - All patients (N=4,488) 4.7% 5.8% 0.08 - Only PCR positive (N=4,159) 4.6% 6.0% 0.04

• There were no differences in total SAE. However, patients who took colchicine had more gastrointestinal side effects (diarrhea): 23.9% vs. 14.9% p = <0.001.

Tardif JC et al. medRxiv preprint January 27, 2021; doi: https://doi.org/10.1101/2021.01.26.21250494. Colchicine in Hospitalized Patients with COVID-19 (RECOVERY RCT)

• The RECOVERY trial was established as a RCT to test a range of potential treatments for COVID-19. Since November 2020, the RECOVERY trial has included a randomized comparison of colchicine vs. usual care alone. • The preliminary analysis is based on 2178 reported deaths among 11,162 randomized patients, 94% of whom were being treated with a corticosteroid such as dexamethasone. There is no significant difference in the primary endpoint of 28-day mortality (20% colchicine vs. 19% usual care alone; risk ratio 1.02 [95% confidence interval 0.94-1.11]; p=0.63). • DSMB closed recruitment on March 4th 2021.

Colchicine SoC P-value Mortality at 28 days - All patients (N=4,488) 20% 19% 0.63

Statement from the RECOVERY trial chief investigators, 5 March 2021 https://www.recoverytrial.net/news/recovery-trial-closes-recruitment-to-colchicine-treatment-for-patients-hospitalised-with-covid-19. Community Hospital - Ward Hospital - ICU Disease Asymptomatic/Mild Moderate/Severe Critical (MV, ECMO) stages Stages 1-2 Stages 3-5 Stages 6-7 Isolation, at least 10-14 days

Treatment Symptomatic treatment - Early antiviral therapy Close monitoring for early - Proper timing detection of progression. anti-inflammatory drugs Potential use of plasma & IV monoclonal antibodies Remdesivir, IV, 5-10 d. therapy in high risk persons Stages 4 (no oxygen) & 5 (low-flow oxygen supply) Stage 6 plus baricitinib, oral, 14 days Dexamethasone, IV/oral, 10 d. Stages 5-7, low/high-flow oxygen supply, MV and ECMO Tocilizumab, single IV dose Low molecular weight heparin, SC Dr. JM Miro, personal opinion. June 2021. During the entire hospitalization period What do clinical trials tell us about treatment?

. Introduction . Update on antiviral treatment . Anti-inflammatory Treatment . Update on antiviral prophylaxis . Take-home messages PEP trials with Monoclonal Antibodies (mABs)

- Randomized, double-blind, placebo-controlled trials for prevention of SARS-COV-2 infection in residents and staff of skilled nursing and assisted living facilities where at least 1 case of SARS-CoV-2 infection had been confirmed in the previous 7 days or in asymptomatic household contacts of people with COVID-19 documented within the previous 4 days and returning home. - mABs can offer immediate protection for exposed or unvaccinated individuals in high risk settings (in contrast to vaccines that take 7- 14 days to offer protection. mAB PBO P-value

BLAZE-2 57% (80%*) reduction <0.001 - Bamlanivimab (4,200 mg IV) symptomatic COVID-19

R10933-10987-COV-2069A** 81% reduction - Casirivimab/imdevimab (1,200 mg SC) symptomatic COVID-19 <0.001

*Nursing home residents; **Reduction of SARS-CoV-2 infection, shortened time of viral shedding and shortened time of high viral load (>104 copies/mL) shedding suggesting a benefit for reduced transmission.

Lilly press release, January 27, 2021; REGENERON press release, April 12, 2021 What do clinical trials tell us about treatment?

. Introduction . Update on antiviral treatment . Anti-inflammatory Treatment . Update on antiviral prophylaxis . Take-home messages Take-home Messages . We are facing a pandemic of colossal challenges with millions of people infected and deaths. . Antiretrovirals and hydroxychloroquine are not useful for treating or preventing SARS-CoV-2 infection. . Remdesivir (alone or plus baricitinib) is effective against moderate and severe COVID-19 (stages 4-6), although it does not reduce mortality. . Dexamethasone alone or plus Tocilizumab reduced mortality in severe and critical COVID-19. . Monoclonal antibodies can prevent COVID-19 as PEP in nursing homes or household members and might be useful in seronegative hospitalized patients. Acknowledgements

B. Clotet R. Paredes O. Coll M. Peck G. Mora J.M. Pericàs A. Moreno C. Pontes A. Pharris A. Vallano

To all front-line health-care workers To our patients and their families