Journal Club Adaptive Covid-19 Treatment Trial 1 - A critical appraisal Review of the ACTT - 1 trial from a critical and statistical analysis perspective

1. ACTT - 1 Trial
A Critical Appraisal
Dr. P
a
rth
a
S
a
r
a
thi Ghosh
MBBS, MD An
a
esthesiology
Dep
a
rtment of Critic
a
l C
a
re Medicine
M
a
nip
a
l Hospit
a
l White
f
ield

2. Background
▪ The Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) was identi
fi
ed in December 2019 in
Wuhan, China. It is a single-stranded RNA virus and has been responsible for a global pandemic, with an
estimated 300,000 deaths worldwide as of May 2020
▪ There are currently no e
ff
ective interventions, other than supportive management, to improve outcomes
following hospitalisation with Covid-19 infection
▪ Remdesivir is an anti-viral medication. The active metabolite of remdesivir interferes with the action of
viral RNA-dependent RNA polymerase causing a decrease in viral RNA production
▪ Remdesivir has been shown to have activity against other serious coronavirus infections (SARS-CoV and
the Middle East Respiratory Syndrome (MERS-CoV)) in animal models
▪ Remdesivir is therefore a potential treatment option for patients hospitalised with Covid-19 infection
▪ A recent RCT published in the Lancet found no di
ff
erence in the time to clinical improvement, however
this was stopped early Wang April 2020
Ad
a
ptive COVID-19 Tre
a
tment Tri
a
l
2

3. StudyDesign
▪ Double-blind, randomised, placebo-controlled trial in hospitalised patients with
Covid-19 using an adaptive platform
▪ Patients randomised in a 1:1 ratio to receive either remdesivir or a matched
placebo for up to 10 days
▪ Study designed to achieve 85% power for detecting a recovery rate ratio of 1.35
with a two-sided type-I error rate of 5% (recovery rate ratio is similar to hazard
ratio in survival analysis)
▪ Randomisation strati
fi
ed by study site and disease severit
3

4. StudyDesign
▪ The primary outcome measure was the time to recovery, de
fi
ned as the
fi
rst day, during the 28 days after enrolment,
on which a patient satis
fi
ed categories 1, 2, or 3 on the eight-category ordinal scale:
▪ 1: not hospitalised, no limitations of activities
▪ 2: not hospitalised, limitation of activities, home oxygen requirement, or both
▪ 3: hospitalised not requiring supplementary oxygen and no longer requiring ongoing medical care (used if
hospitalisation was extended for infection-control reasons)
▪ 4: hospitalised, not requiring supplemental oxygen but requiring ongoing medical care (Covid-19 related or other
medical conditions)
▪ 5: hospitalised, requiring any supplemental oxygen
▪ 6: hospitalised, requiring non-invasive ventilation or use of high-
fl
ow oxygen devices
▪ 7: hospitalised, receiving invasive mechanical ventilation or ECMO
▪ 8: death
4

5. StudyDesign
▪ Primary outcome was a log-rank test of time to recovery between remdesivir and placebo,
strati
fi
ed by disease severity
▪ Primary outcome changed (on March 22nd after enrolment of 72 patients) from di
ff
erence in
clinical status to time to recovery
▪ As part of the adaptive study design, with the aim of enrolling su
ffi
cient patients to reach 400
recoveries, the data and safety monitoring board (DSMB) planned to actively monitor the
interim data in order to make recommendations about early study closure or changes to the
study arms
▪ On April 27th, the National Institute of Allergy and Infectious Diseases (NIAID) decided to make
the study results public after recommendation by the DSMB, even though the trial was ongoing
▪ Registered on clinicaltrials.gov
5

6. Setting
▪ 60 trial sites and 13 sub-sites in the USA (45 sites), Denmark (8), UK (5), Greece (4),
Germany (3), Korea (2), Mexico (2), Spain (2), Japan (1) and Singapore (1)
▪ Data collected from February 21 2020 until April 19 2020
6

7. Intervention
Remdesivir
▪ 200mg IV loading dose on day 1, followed by a 100mg maintenance dose
administered daily on days 2-10 or until hospital discharge or death
7

8. Control
Placebo
▪ Matched placebo administered according to the same schedule and in the same
volume as the active drug
▪ A normal saline placebo was used at the European sites and at some non-
European sites due to a shortage of matched placebo
8

9. ManagementCommontobothgroups
• Supportive care according to the standard of care for the trial site hospital
9

10. 10

11. 11

12. Inclusioncriteria
Inclusion:
▪ Adults 18 years of age or older who were hospitalised with symptoms suggestive of
COVID-19 assessed for eligibility
▪ Participants had to have a laboratory-con
fi
rmed SARS-CoV-2 infection and had to
meet one of the following criteria:
▪ Radiographic in
fi
ltrates on imaging
▪ Oxygen saturation (SpO2) ≤94% on room air
▪ Requiring supplemental oxygen, mechanical ventilation, or extracorporeal
membrane oxygenation (ECMO)
12

13. Exclusioncriteria
▪ Alanine aminotransferase (ALT) or an aspartate aminotransferase (AST) > 5
times the upper limit of the normal range
▪ Impaired renal function as determined by calculating an estimated glomerular
fi
ltration rate (eGFR), or need for haemodialysis or haemo
fi
ltration
▪ Allergy to study product
▪ Pregnancy or breast-feeding
▪ Anticipated discharge from the hospital or transfer to another hospital within 72
hours of enrolment
13

14. 14

15. 15

16. Primaryoutcome
• Patients in the remdesivir group had a signi
fi
cantly shorter time to recovery than
patients in the placebo group
• median 11 days vs. 15 days; rate ratio for recovery 1.32; 95% CI 1.12-1.55; p<0.001
• In total, 482 patients (45.5%) recovered and 81 patients (7.6%) died
• Recovery was most pronounced in the 422 patients with a baseline ordinal score of
5: these were patients who were hospitalised and required supplemental
oxygen (rate ratio for recovery 1.47; 95% CI 1.17-1.84)
• No di
ff
erence in recovery times in patients receiving mechanical ventilation or
ECMO (rate ratio for recovery 0.95; 95% CI 0.64-1.42)
16

17. 17

18. Secondaryoutcomes
▪ The odds of improvement in the ordinal scale score measured at day 15 were signi
fi
cantly
higher in the remdesivir group, when compared with the placebo group
▪ odds ratio for improvement, 1.50; 95% CI, 1.18 to 1.91; P=0.001
▪ No signi
fi
cant di
ff
erence in mortality
▪ 32 deaths in remdesivir arm vs. 54 deaths in placebo arm
▪ Kaplan-Meier estimate 7.1% (95% CI 5.0-9.9) for remdesivir vs 11.9% (95% CI 9.2-15.4) for
placebo (p = 0.059)
▪ Hazard ratio for death 0.70 (95% CI, 0.47 to 1.04)
▪ No di
ff
erence in patients discontinuing medication due to an adverse event between the
treatment and control arms
18

19. 19

20. Critical Appraisal
20

21. DoesitmeetPICOcriteria
• Population - In adults with COVID19 disease
• Intervention - Remdesivir 200mg stat followed by 100mg OD for 5 days
• Control - Placebo
• Outcome - primary and secondary outcomes
• Does the trial ask a valid question?
• Was it an RCT? Yes
• Was allocation to intervention and control groups properly followed? Yes
• Was it blinded? Yes double blinded
21

22. • Were all participants accounted for? Yes - intention to treat analysis
• Was there any loss to follow up?
• Was sample size adequate?
• power calculation done for 85% alpha
•
22

23. Qualityoftrial
• Randomised control trial
• Double blinded
• Multicenter
• Di
ff
erent countries and population groups
• Internal validity
• external validity
23

24. Strengths
▪ Matched placebo used in the majority of patients
▪ Intention to treat analysis
▪ Patients reviewed on a daily basis and visited at home if discharged from hospital
▪ Randomisation strati
fi
ed by study site and disease severity
▪ Participants from multiple countries improved the generalisability of the study
results
▪ Safety evaluation performed
24

25. Weaknesses
25

26. Weaknesses
• Initial primary outcome was changed to a secondary outcome - power calculation
was done on the initial primary outcome
• Treating physician could request to be made aware of treatment assignment of
patients who had not completed day 29 - if clinically indicated
• Patients originally in placebo group could be given remdesivir
26

27. Weaknesses
• The main driver of the treatment e
ff
ect was patients who required oxygen therapy
(ordinal score 5) recovering to be discharged from hospital by day 15 (ordinal score 1
or 2). There was, however, no protocolised oxygen therapy, so the threshold for
administering oxygen may have di
ff
ered between the remdesivir and placebo arms
• At time of randomisation 28.2% of patients in the control arm received mechanical
ventilation or ECMO, vs. 23.1% in the intervention arm
27

28. Weaknesses
• The primary outcome was initially planned as the di
ff
erence in clinical status at day
15, but was changed after commencement of the study due to a longer than
expected time course of Covid-19 infection. This was after 72 patients had been
enrolled in the study
• Data and safety monitoring board review occurred after completion of enrolment
while follow-up was still ongoing on 22nd April, so outcome data on 301 patients
who had not recovered or completed 29 study days was not available
28

29. Weaknesses
• No matched placebo used in the European sites. Blinding could have been
compromised as a result. In a study in which the primary endpoint was based on
clinician decision (whether or not to administer oxygen and/or discharge from
hospital) this may be relevant
• The time to recovery di
ff
ered from the April 2020 Lancet paper by Wang et al (21
and 23 days for remdesivir and placebo respectively) but this may be partially due to
patient inclusion in the Wang study being limited to symptoms of ≤12 days
29

30. Weaknesses
• Patients with renal failure were excluded but there was no de
fi
nition of what GFR
constituted renal failure
• No laboratory data was made available in the study results
• Participants only followed up for 29 days in this preliminary report so longer-term
outcomes are unknown
• Baseline ordinal scores were missing in 42 patients
30

31. Willthistrialchangemypractice?
▪Remdesivir may be effective in shortening the time to recovery in
hospitalised patients with Covid-19 infection, particularly those
patients who require oxygen therapy onl
y
▪It is unclear how clinically relevant this result is, particularly in view
of the methodological limitations of the study and the lack of long-
term outcome data

32. Thank you