EVIDENCE BASED

MEDICINE
INTRODUCTION
Dr. Jarir At Thobari, DPharm, PhD
1
Clinical Epidemiology and Biostatistic Unit (CEBU)
2
Indonesia Cochrane Center (ICC)
Dept. Pharmacology & Therapy Div. Pharmacoepidemiology, Pharmacovigilance & Pharmacoeconomic
3

Faculty of Medicine, Public Health & Nursing Universitas Gadjah Mada

What is
Evidence-
Based
Medicine?
https://www.ncbi.nlm.
nih.gov/research/coro
navirus/faq
Hierarchy of
Evidence-
Based
Medicine
 EBM in Pandemic

Theory Theory
Animal Model Relevant
Small human trials Scientific Animal Model
Larger RCT Evidence
Repetition Small human study
Meta analysis
 The Dilemma in Pandemic

Do Nothing Do Something

Underestimate benefit Overestimate benefit

Overestimate harm Underestimate harm

Drug Discoveries & Therapeutics.
2020; 14(1):58-60.
Covid virus Clinical Trials update (October 2020)

Covid-19 Clinical
Trials Worldwide
Drug Interventions # of Trials
Anti-Infective Agents 308
Antibodies 223
Immunoglobulins 223

Antirheumatic Agents 221

Antiparasitic Agents 202

Hydroxychloroquine 169
Antimalarials 163
Antiprotozoal Agents 161
Immunologic Factors 159
Antiviral Agents 151
 Hydroxychloroquine for COVID-19
• What is the evidence informing this recommendation?
Evidence comes from 13 randomized trials that compared hydroxychloroquine with standard care in nearly 8300
patients. The majority of evidence is from the RECOVERY trial, which randomized 4716 patients hospitalized with
COVID-19.
STANDARD CARE HYDROXYCHLOROQUINE

All-cause mortality (end FU) 186/1000 No importance difference 201/1000

Invasive Mechanical Ventilation/ECMO (end FU) 76/1000 No importance difference 84/1000
Requiring ventilation (mechanic & no mechanic) 80/1000 No importance difference 87/1000
Virological clearance (7d) 489/1000 Highly uncertainties 455/1000
Hospital discharge (28d) 687/1000 No importance difference 666/1000
Adverse events (severe-critical) 206/1000 468/1000

Pan H, Peto R, Karim AQ, on behalf of the WHO Solidarity trial consortium : Repurposed antiviral drugs for COVID-19 - interim WHO SOLIDARITY trial results. MedRxiv 2020;
Chen J, Liu D, Lui L : A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19. Zhejiang Da Xue Xue Bao Yi Xue Ban 2020;49(2):215-9
Chen Z, Hu J, et al, Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv 2020; 2020.03.22.20040758
Tang W, Cao Z, et al, Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ 2020;
Chen L, Zhang Z-Y, et al, Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study. MedRxiv 2020;
Mitjà O, et al, Hydroxychloroquine for early treatment of adults with mild Covid-19: a randomized-controlled trial. Clinical Infectious Diseases 2020;
Skipper CP, et al, Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial. Annals of Internal Medicine 2020;
Lopinavir-ritonavir for COVID-19

• What is the evidence informing this recommendation?

Evidence comes from five randomized trials that compared lopinavir-ritonavir with standard care in 8121
patients with COVID-19

• The majority of data come from the RECOVERY and WHO SOLIDARITY trials, which included 5040
patients and 2771 patients with moderate to critical illness. The SOLIDARITY trial of L/R was stopped early
for reasons of futility.

• The remaining three trials included 199 patients with severe illness, 60 patients with moderate or severe
illness and 51 patients with mild or moderate illness.

Pan H, Peto R, Karim AQ, on behalf of the WHO Solidarity trial consortium : Repurposed antiviral drugs for COVID-19 - interim WHO SOLIDARITY trial results. MedRxiv
2020
Li Y, Xie Z, et al., Efficacy and safety of lopinavir/ritonavir or arbidol in adult patients with mild/moderate COVID-19: an exploratory randomized controlled trial. Med (N Y)
2020
Cao B, Wang Y, et al, A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19. NEJM 2020
Zheng F, Zhou Y, et al, SARS-CoV-2 clearance in COVID-19 patients with novaferon treatment: a RCT. International Journal of Infectious Diseases 2020
Lopinavir-ritonavir for COVID-19

STANDARD CARE LOPINAVIR / RITONAVIR

Mortality (end of treatment) 191/1000 No importance difference 195/1000

Invasive Mechanical Ventilation/ECMO 84/1000 No importance difference 97/1000
Noninvasive or invasive ventilation (28d) 95/1000 No importance difference 97/1000
Hospital discharge (28d) 747/1000 Highly uncertainties 747/1000
Respiratory failure/ARDS (28d) 233/1000 137/1000
Remdesivir for COVID-19
Remdesivir for COVID-19
• What is the evidence informing this recommendation?
Evidence comes from four randomized trials that compared remdesivir with standard care in
7333 adults hospitalized with COVID-19. The majority of evidence is from the WHO SOLIDARITY
and ACTT-1 trials, which randomized 5451 and 1062 patients with moderate to critical COVID-19

STANDARD CARE REMDESIVIR

All-cause mortality (day 28) 112/1000 No importance difference 104/1000

All-cause mortality (day 28; no oxygen) 22/1000 No importance difference 18/1000
All-cause mortality (day 28; oxygen, no ventilation) 121/1000 77/1000
All-cause mortality (day 28; ventilation) 248/1000 298/1000
HR 1.24, (1.08-1.42)
Time to recovery (Days)
Time to clinical improvement (Days) HR 1.17, (1.00-1.38)

1
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS : Remdesivir for the treatment of Covid-19 - final report. NEJM 2020;
2
Wang Y, Zhang D, et al., Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;
3
Spinner CD, Gottlieb RL, et al., Effect of Remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA 2020;
4
Pan H, Peto R, Karim AQ, on behalf of the WHO Solidarity trial consortium : Repurposed antiviral drugs for COVID-19 - interim WHO SOLIDARITY trial results. MedRxiv
Remdesivir for COVID-19
What is the evidence informing this recommendation? Evidence comes from two randomized trials that compared 5-day
to 10-day treatment with remdesivir in 781 hospitalized patients with severe COVID-19
Outcome Study results Absolute Effect Conclusion
Up to 10 days Up to 5 days
All-cause mortality (14d) RR 0.73 (0.40-1.33)  59/1000 43 /1000 5-day treatment probably has little or no
Based on data from 781 patients Difference: 16 fewer per 1000  difference on all-cause mortality 14 days
in 2 studies (CI 95% 35 fewer - 19 more)
All-cause mortality (28d) RR 0.67 (0.11-3.99) 16/1000 11/1000 5-day treatment has little or no difference on
Based on data from 384 patients Difference: 5 fewer per 1000  all-cause mortality at 28 days
in 1 study (CI 95% 14 fewer - 48 more)

Clinical recovery (14d) RR 1.20 (1.02-1.41)  538/1000 646/1000 5-day treatment improve clinical recovery
Based on data Difference: 108 more per 1000  slightly
from 397 patients in 1 study (CI 95% 11 more - 221 more)

Hospital Discharged (14d) RR 1.06 (0.93-1.20)  638/1000 676/1000 5-day treatment probably has little or no
Based on data from 781 patients Difference: 38 more per 1000 difference on number of patients discharged
in 2 studies  (CI 95% 45 fewer - 128 more) from hospital at day 14
Hospital Discharged (28d) RR 0.99 (0.92-1.06)  902/1000 893/1000 5-day treatment may have little or no
Based on data from 384 patients Difference: 9 fewer per 1000  difference on number of patients discharged
in 1 study (CI 95% 72 fewer - 54 more) from hospital at day 28

1
Goldman JD, Lye DC, et al., Remdesivir for 5 or 10 days in patients with severe Covid-19. NEJM 2020
2
Spinner CD, Gottlieb Rl et al., Effect of Remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA 2020;
Corticosteroid for COVID-19

• What is the evidence informing this recommendation?

•
Evidence comes from a recent meta-analysis and associated living guidance of seven randomized trials of
patients with critical COVID-19, one study of patients with moderate, severe and critical COVID-19, and one
study of patients with severe COVID-19.

• Over 5700 patients are included in the meta-analysis. All trials compared corticosteroids plus standard care
with standard care alone.

World Health Organization : Corticosteroids for COVID-19, Living Guidance. 2 September 2020;
Dequin P-F, Heming N, et al, Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA 2020;
Du B, Weng LI : Glucocorticoid therapy for COVID-19 critically ill patients with severe acute respiratory failure. ClinicalTrials.gov 2020;
Angus DC, et al, Effect of hydrocortisone on mortality and organ support in patients with severe COVID-19: the REMAP-CAP COVID-19 corticosteroid domain RCT. JAMA 2020;
Tomazini, et al, Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe ARDS and COVID-19: the CoDEX randomized clinical trial. JAMA 2020;
Petersen MW, et al., Low-dose HCQ in patients with COVID-19 and severe hypoxia (COVID STEROID) trial: protocol and statistical analysis plan. Acta Anaesthesiologica Scandinavica
2020;
Villar J, et al, Efficacy of dexamethasone treatment for patients with the ARDS caused by COVID-19: study protocol for a randomized controlled superiority trial. Trials 2020;21(1):717
Jeronimo CMP, et al., Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (Metcovid): a RCT, Clinical Infectious Diseases 2020;
RECOVERY Collaborative Group, Dexamethasone in hospitalized patients with Covid-19 - preliminary report. New England Journal of Medicine 2020;
Edalatifard M, et al, Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. Eur Resp. J 2020;
 Corticosteroid for COVID-19
Outcome
All-cause mortality
(requiring O2 - 28d)
Mechanical ventilation/death
(requiringO2 - 28d)
Hospital discharge
(requiringO2 - 28d)
All-cause mortality
(no requiring O2 - 28d)
Hospital discharge
(no requiringO2 - 28d)
Superinfection
Hyperglycemia
Study results Absolute Effect Conclusion
Standard care Corticosteroid
RR 0.84 (0.73-0.98)  316/1000 265 /1000 Corticosteroids decrease death at
Based on data from 5789 patients Difference: 51 fewer per 1000  day 28 in adults who require oxygen.
in 9 studies (CI 95% 85 fewer - 6 fewer)
RR 0.88 (0.79-0.97)  320/1000 282/1000 Corticosteroids decrease invasive
Based on data from 3883 patients Difference: 38 fewer per 1000  mechanical ventilation or death in
in 1 study (CI 95% 67 fewer - 10 fewer) adults who require oxygen.
RR 1.10 (1.06-1.15)  582/1000 640/1000 Corticosteroids increases discharge
Based on data from 4952 patients Difference: 58 more per 1000  from hospital in adults who require
in 2 studies (CI 95% 35 more - 87 more) oxygen
RR 1.27 (1.00-1.61)  140/1000 178 /1000 Corticosteroids probably increase
Based on data from 1535 patients Difference: 38 more per 1000  death in adults who do not require
in 1 study (CI 95% 0 - 85 more) oxygen.
RR 0.96 (0.90-1.01)  804/1000 772/1000 Corticosteroids may have little
Based on data from 1535 patients Difference: 58 more per 1000  impact on discharge from hospital in
in 1 study (CI 95% 35 more - 87 more) adults who do not require oxygen.
RR 1.01 (0.90-1.13)  186/1000 188/1000 Corticosteroids may have little
Based on data from 6027 patients Difference: 2 more per 1000  impact on number of patients with
in 32 studies (CI 95% 19 fewer - 24 more) super infections.
RR 1.16 (1.08-1.25)  286/1000 332/1000 Corticosteroids probably increase the
Based on data from 8938 patients Difference: 46 more per 1000  risk of hyperglycemia
in 24 studies (CI 95% 23 more - 72 more)
Cochrane Library, 12 November 2019
Favipiravir
• Evidence comes from two randomized trials that compared favipiravir with standard care in 79 adults
hospitalized with COVID-19

For the critical outcomes (death, respiratory failure and mechanical

ventilation) there were too few events to determine whether
favipiravir makes a difference. 
There are uncertain whether favipiravir increases/decreases
likelihood of clinical improvement RR=1.11 (0.47-2.60), negative PCR
in 10d RR=1.16 (0.91-1.46), & hospital discharge RR=0.88 (0.68 -
1.14)
Favipiravir selectively inhibit RNA
Polymerase involved in influenza viral replication
Two patients experienced serious adverse events.

Lou Y, Liu L, et al., Clinical outcomes and plasma concentrations of baloxavir marboxil and favipiravir in COVID-19 patients: an exploratory randomized, controlled trial.
European Journal of Pharmaceutical Sciences 2020; Ivashchenko AA, Dmitriev KA, et al., AVIFAVIR for treatment of patients with moderate COVID-19: interim results of a
phase II/III multicenter randomized clinical trial. Clinical Infectious Disease 2020;
Tocilizumab

Medication Class:
• Interleukin-6 (IL-6) receptor blocker

Regulatory Approved for:

• Cytokine release syndrome
• Rheumatoid arthritis and other rheumatologic conditions

Rational Use in COVID-19:

• Elevated levels of inflammatory cytokines, including IL-6 have been associated with increased mortality
from ARDS
• Patients with COVID-19 have elevated levels of IL-6 and other inflammatory markers consistent with
cytokine storm
• Tocilizumab has been effective in treating the cytokine storm associated with CAR-T cell therapy

Kellum JA, et al, Crit Care Med. 2017 Mar; 45:438–45.; Chen N, et al. Lancet 2020; 395(10223):507-13., Huang C, et al. Lancet 2020;395:497-506.; Le RQ, et al.
Oncologist. 2018;23:943-7.
Tocilizumab

Tocilizumab probably has little impact on death, adverse events or serious adverse

events. 

Tocilizumab decreases slightly the number of patients who require invasive mechanical

ventilation (60 fewer per 1000 patients; RR 0.75 (0.54-1.04); 515 patients in 2 studies)

May decrease the number of patients who require admission to ICU (137 fewer per 1000
patients; RR 0.65 (0.48-0.87); 397 patients in 2 studies).

The effect of tocilizumab on other outcomes is uncertain.

Kellum JA, et al, Crit Care Med. 2017 Mar; 45:438–45.; Chen N, et al. Lancet 2020; 395(10223):507-13., Huang C, et al. Lancet 2020;395:497-506.; Le RQ, et al.
Oncologist. 2018;23:943-7. Rosas I, Brau N, Waters M : Tocilizumab in hospitalized patients with COVID-19 pneumonia. medRxiv 2020; Stone JH, Frigault MJ, et al,
Efficacy of tocilizumab in patients hospitalized with Covid-19. New England Journal of Medicine 2020; Wang D, Fu B : Tocilizumab ameliorates the hypoxia in
COVID-19 moderate patients with bilateral pulmonary lesions: a randomized, controlled, open-label, multicenter trial. Lancet Preprint 2020; Hermine O, Mariette X, et
al, Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Internal Medicine
Convalescent Plasma
 Pengembangan Vaksin Traditional vs. Vaksin di Era Pandemic

Nature, Sept 2020; 586, 516–527(2020)

 Steps in Evidence-Based Medicine

See a patient Ask a question Seek the best evidence

Monitor the change Apply the evidence Appraise that evidence