Robert Sinto

Formal education
2008: dr. , Universitas Indonesia
2014: Sp.PD, Universitas Indonesia
2018: K-PTI, Universitas Indonesia

Informal education
2015:
Clinical training on Transplant-Oncology-
Immunocompromised Host Infectious Diseases,
Singapore General Hospital, Singapore
2018-now:
Clinical Epidemiology, Julius Centre UMC Utrecht,
University College of London and
Autonomous University of Barcelona

Workplace & Position

2016-now:
Department of Internal Medicine,
RS Cipto Mangunkusumo - FM Universitas Indonesia
2015-now:
Indonesian College of Internal Medicine (Officer)
2014-now:
The Indonesian Society of
Tropical Medicine and Infectious Diseases (Officer)
 The Truth about Magic “6”:
Collecting Evidences from RCTs on COVID-19

Robert Sinto
Division of Tropical and Infectious Diseases, Department of Internal Medicine
Cipto Mangunkusumo National Hospital - FM Universitas Indonesia
March, 14th 2021
Disclaimer
 The information is current as of the date
of the presentation, which means at
some point it may (and likely will be)
outdated.
 No potential conflict of interest.
Disease Stage, WHO 2020

Mild Severe Sepsis &

Pneumonia ARDS
illness pneumonia Septic shock

WHO.Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. 2020.
WHO-China Joint Mission. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). 2020.
Definition, WHO 2020
Severe Critical

Mild Severe Sepsis &

Pneumonia ARDS
illness pneumonia Septic shock

 Severe pneumonia:
◦ RR > 30 breaths/min; severe respiratory distress; or SpO2 ≤ 93%
on room air
◦ PaO2/FiO2 < 300 mmHg
◦ Increase in lung infiltrate >50% within 24-48 hours

WHO.Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. 2020.
WHO-China Joint Mission. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19). 2020.
COVID-19:
A Clinical – Therapeutic Staging

Siddiqi HK, et al. The Journal of Heart and Lung Transplantation, 2020;39:405-7.
mg dexamethasone
JAMA Intern Med. doi:10.1001/jamainternmed.2020.0994
Corticosteroids in COVID-19
 CS in ICU viral pneumonia: increase in viral
shedding, potentially indicating viral replication, but
uncertain clinical implication.
 SSC panel ~ IDSA:
◦ Against routine use for respiratory failure in COVID-19.
◦ Suggestion to use in the sicker population of COVID- 19
with ARDS; context of clinical trial.
 ATS: no recommendation.
 WHO:
◦ Do not recommend unless another concomitant indication
exists such as COPD exacerbation or pressor-refractory
shock.
WHO.Clinical management of severe acute respiratory infection (SARI) when COVID-19 disease is suspected. 2020.
Intensive Care Med. doi.org/10.1007/s00134-020-06022-5.
www.idsociety.org/COVID19guidelines.
Wilson KC, et al American Thoracic Society‐led International Task Force. 2020.
 The right bullet for the right target…

Mild Severe Sepsis &

Pneumonia ARDS
illness pneumonia Septic shock

Dexamethasone

R. Sinto- March, 2021

 mg dexamethasone
Anti IL-
JAMA. doi:10.1001/jama.2020.6019. Published online April 13, 2020.
https://www.roche.com/investors/updates/inv-update-2020-07-29.htm
doi: https://doi.org/10.1101/2020.08.27.20183442.
 N Engl J Med 2021;384:20-30.
DOI: 10.1056/NEJMoa2030340.
 N Engl J Med 2021;384:20-30.
DOI: 10.1056/NEJMoa2030340.
 N Engl J Med 2021;384:20-30.
DOI: 10.1056/NEJMoa2030340.
 REMAP-CAP: Enrollment at 113 Sites in 6 Countries

▪ Primary outcome: respiratory and cardiovascular organ support-free days, up to Day 21

Tocilizumab 8 mg/kg (max 800 mg) IV x 1 or 2 doses

(n = 350; 366 randomized, 13 withdrew consent, 3 - outcome not available)
Critically ill adults
with suspected or
confirmed severe Sarilumab† 400 mg IV x 1 dose
COVID-19 admitted (n = 45; 48 randomized, 3 - outcome not available)
to ICU and receiving
organ support, Control (current standard of care)
Apr 19 - Nov 19, (n = 397; 412 randomized, 10 withdrew consent, 5 - outcome not available)
2020
Anakinra or interferon beta 1a
(N = 895) (n = 61; 69 randomized, 7 withdrew consent, 1 - outcome not available)
*Tocilizumab met statistical trigger for efficacy by interim analysis on Oct 28, 2020; subsequent
interim analysis revealed that sarilumab had also met statistical trigger for efficacy. †Fewer
enrollees in sarilumab arm because it opened later than tocilizumab arm.

Gordon. medRXiv [preprint]. https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v1.full.pdf. Slide credit: clinicaloptions.com

 REMAP-CAP: Baseline Characteristics

Tocilizumab Sarilumab Control* Tocilizumab Sarilumab Control*

Characteristic Characteristic
(n = 353) (n = 48) (n = 402) (n = 353) (n = 48) (n = 402)
Mean age (SD), yrs 61.5 (12.5) 63.4 (13.4) 61.1 (12.8) Preexisting condition,
Male sex, n (%) 261 (73.9) 39 (81.3) 283 (70.4) n/N (%)
▪ Diabetes mellitus 123/349 150/401
Race, % (n = 228) 13/48 (27)
▪ Kidney disease (35) (37) 43/372
▪ Asian 18.0 20.5 16.9 4/45(8.9)
▪ Respiratory disease 30/312 (10) (12) 98/401
▪ Black 5.3 2.6 3.2 15/48 (31)
▪ Immunosuppressiv 82/349 (24) (24)
▪ White 70.2 74.4 73.8 0/48 (0.0)
e disease 8/348 (2.3) 14/401 (3.5)
▪ Mixed 0.9 0.0 1.8 ▪ Immunosuppressiv
▪ Other 5.7 2.6 4.3 1/48 (2.1)
e therapy, chronic 3/349 (0.9) 6/401 (1.5)
Median BMI (IQR), 30 (27-35) 29 (26-34) 31 (27-35) ▪ Severe CV disease
1/48 (2.1)
kg/m2 (n = 342) (n = 39) (n = 377) ▪ Liver 34/339 (10) 47/395 (12)
0/48 (0.0)
cirrhosis/failure 2/339 (0.6) 1/395 (0.3)
Median APACHE II score 13 (8-19) 10 (7-16) 12 (8-18)
(IQR) (n = 337) (n = 42) (n = 381) Median time to
enrollment (IQR)
101/353 110/402 ▪ From hospital 1.2 1.4 1.2
High flow NC, n/N (%) 17/48 (35)
(29) (27) admission, dys (0.8-2.8) (0.9-2.8) (0.8-2.8)
Non-invasive ventilation 147/353 23/48 169/402 ▪ From ICU 13.1 16.0 14.0
only, n/N (%) (41.6) (47.9) (42.0) admission, hrs (6.6-19.0) (11.4-20.8) (6.8-19.5)
Invasive mechanical 104/353 8/48 121/402 Confirmed SARS-CoV-2 284/345 44/47 334/394
ventilation, n/N (%) (29.5) (16.7) (30.1) infection n/N (%) (82.3) (93.6) (84.8)

*Control patients include all patient randomized to control who were also eligible to be randomized to tocilizumab and/or sarilumab.
Gordon. medRXiv [preprint-not yet peer-reviewed]. https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v1.full.pdf. Slide credit: clinicaloptions.com
 REMAP-CAP: Tocilizumab, Sarilumab Interim Results
▪ IL-6 receptor antagonists compared with current standard of care alone: overall, > 80% patients
received corticosteroids, 32.8% received remdesivir
Tocilizumab Sarilumab Control
Outcome/Analysis
(n = 350) (n = 45) (n = 397)
Primary outcome: organ support-free days (OSFDs)*
▪ Median (IQR) 10 (-1 to 6) 11 (0 to 16) 0 (-1 to 15)
▪ Adjusted OR, mean (SD) 1.65 (0.23) 1.83 (0.44) 1
▪ Median (95% CI) 1.64 (1.25-2.14) 1.76 (1.17-2.91) 1
▪ Probability of superiority to control, % > 99.9 > 99.5 -
Subcomponent of OSFDs
▪ In-hospital deaths, n/N (%) 98/350 (28.0) 10/45 (22.2) 142/397 (35.8)
▪ OSFDs in survivors, median (IQR) 14 (7-17) 15 (6.5-17) 13 (4-17)
Primary hospital survival
▪ Adjusted OR, mean (SD) 1.66 (0.31) 2.25 (0.96) 1
▪ Median (95% CI) 1.64 (1.14-2.35) 2.01 (1.18-4.71) 1
▪ Probability of superiority to control, % 99.6 99.5 -
Serious adverse events during analysis, n 9† 0 11‡

*Within-hospital deaths assigned OSFD value of -1. †1 secondary infection, 5 bleeds, 2 cardiac events, 1 deterioration of vision.
‡4 bleeds, 7 thromboses.

Gordon. medRXiv [preprint]. https://www.medrxiv.org/content/10.1101/2021.01.07.21249390v1.full.pdf. Slide credit: clinicaloptions.com

 The right bullet for the right target…

Mild Severe Sepsis &

Pneumonia ARDS
illness pneumonia Septic shock

Dexamethasone

Tocilizumab

R. Sinto- March, 2021

 The right bullet for the right target…

Mild Severe Sepsis &

Pneumonia ARDS
illness pneumonia Septic shock

Dexamethasone

AND / OR ?
Tocilizumab

R. Sinto- March, 2021

Ann Rheum Dis. 2020;79:1143–1151.
DOI: 10.1056/NEJMp2009405
Thank you…