Background

• Hydroxychloroquine - antiviral effects in vitro

• In association with azithromycin - decrease viral load in a small,
nonrandomized study

• National regulations in Brazil – use of HCQ in hospitalised patients

• Observational studies showed no benefit.

Gautret P, Lagier JC, Parola P, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020 March 20
Liu J, Cao R, Xu M, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARSCoV-2 infection in vitro. Cell Discov 2020; 6:16
Objective
• To assess HCQ , either alone or with Azithromycin would be effective
in improving clinical status at 15 days after hospital admission due to
mild to moderate COVID 19
• Population: >18 years; admitted with suspected / confirmed COVID 19; O2
<4L/min
• Intervention: HCQ 400 mg BD for 7 days + standard care
HCQ 400 mg BD x 7 days + Azithromycin 500 mg OD x 7 days + standard care
• Control: Standard care
• Outcome: clinical status at 15 days – seven level ordinal score
• Time: March 29 2020 till June 2 2020; 15 days follow up
Was the study population clearly defined?
• Yes
Inclusion criteria
• Admitted with suspected/confirmed COVID 19
• Time between symptom onset and study enrolment ≤ 14 days.
Exclusion criteria
• Need for oxygen supplementation > 4L
• Use of high flow nasal catheter
• Use of non-invasive ventilation
• Use of mechanical ventilation
• Use hydroxochloroquine, chloroquine, azithromycin or another macrolide for
more than 24 hours
• History of severe ventricular cardiac arrhythmias or QTc≥480ms
• Known history of liver disease (liver cirrhosis), defined as the patient's report
or medical record of cirrhosis, esophageal varices, or clinical ascites;
• Renal dysfunction (estimated glomerular filtration rate [eGFR]
Were the outcome measures clearly defined?
• Yes
Primary Outcome
• Effect of HCQ/HCQ + Azithromycin/standard care in adult patients
with mild to moderate COVID 19 at the ordinal outcome at 15 days.

1 - Patient at home without limitations in daily activities.

2. Patient at home with limitations in daily activities.
3. Patient in hospital, without oxygen.
4. Patient in hospital, with oxygen.
5. Patient in hospital on noninvasive ventilation or high flow cannula.
6. Patient on mechanical ventilation.
7. Death
Secondary outcomes
1. Ordinal outcome in 7 days.
2. Need for intubation and mechanical ventilation in 15 days.
3. Need for noninvasive mechanical ventilation or high-flow nasal
cannula in 15 days.
4. Length of stay in the hospital.
5. Hospital mortality.
6. Occurrence of thromboembolic complications.
Were the patients randomized?
• Yes
• Electronic case report form system – R software
• 1:1:1
Was the randomisation concealed?
• Yes
• RedCap software
Was the follow up complete?
• Yes
Were the patients analysed in the groups to
which they were randomized?
• Yes
• Modified intention to treat analysis
Were adequate number of people included in
the study?
• Originally
630
- hoped to include 510 confirmed cases
- 6 level ordinal scale – 35 %, 15%, 20%, 10%, 10%, 10%
- 210 cases per arm
80 % power to detect a mean odds ratio of 1.76 between the arms with
a significance level of 5 % with Bonferroni correction for multiple
comparisons ( alpha = 5%/3 for each comparison )
• Changed to 7 level ordinal scale
• mITT of positive cases

510
- after first 120 patients (60%, 19%, 7%, 1 %, 1%, 5%, 7%)
Power – 80 %
Odds ratio of 2 between two arms with a level of significance of 5%
Did the intervention and control groups start
with the same prognosis?
• Yes
 Validity of the study
•
Study population: well defined

•
Outcomes: well defined

•
Randomization: done

•
Allocation concealment: done

•
Blinding: open labeled

•
Sample size calculation: adequate

•
Intention to treat analysis: no

•
Baseline characteristics: Similar
Results
Were all clinically relevant outcomes
considered?
• Yes
Were the study patients similar to the patients
in my practice?
• Yes
Conclusion
• No significant difference