Table 1 Summary of clinical studies: chloroquine and hydroxychloroquine with or without azithromycin

Borba et al. [33]

Randomized phase IIb, double-blinded, clinical trial (n = 81)

1. High-dose chloroquine diphosphate 600 mg twice daily for 10 days (n = 40)

2. Low-dose chloroquine diphosphate 450 mg twice daily on day 1 and once daily for 4 days (n = 41)

Primary:

Lethality by day 28

Secondary:

Lethality on day 13; participant clinical status; laboratory examinations;

ECG on days 13 and 28; daily clinical status during hospitalization; duration of mechanical ventilation and supplementary oxygen (if applicable); time in days from treatment initiation to death

Higher lethality in high-dose group (39%) compared to low-dose group (15%)

More QTc interval prolongation in high-dose group than in low-dose group (18.9% vs 11.1%)

Huang et al. [34]

Randomized controlled trial (n = 22)

1. Chloroquine 500 mg orally twice daily for 10 days (n = 10)

2. Lopinavir/Ritonavir

400/100 mg orally twice daily for 10 days (n = 12)

Viral clearance; time of hospital discharge; clinical recovery; lung clearance on CT

Superiority of chloroquine in viral clearance by day 14 (100% vs 91.7%), lung improvement on CT by day 14 (100% vs 75%), and earlier hospital discharge at day 14 (100% vs 50%)

Tang et al. [36]

Randomised, open-label, controlled trial (n = 150)

1. Standard of care (n = 75)

2. Standard of care plus hydroxychloroquine 1200 mg daily for 3 days, then 800 mg daily for 2 to 3 weeks (n = 75)

Primary:

Negative conversion of SARS-CoV-2 by day 28

Secondary:

Probability of negative conversion at day 4, 7, 10, 14, or 21; probabilities of alleviation of clinical symptoms; improvement of C reactive protein, erythrocyte sedimentation rate, tumour necrosis factor α, interleukin 6, and absolute blood lymphocyte count; improvement of lung lesions on chest radiology; all cause death

Similar results between the study arms

28-day negative conversion rate was 85.4% (73.8–93.8%) in hydroxychloroquine vs 81.3% (71.2–89.6%) in the standard of care group

Negative conversion rates at specific days were similar between the groups

Alleviation of symptoms at 28 days was 59.9% (45–75.3%) with hydroxychloroquine vs 66.6% (39.5–90.9%) with standard of care

More adverse events in the hydroxychloroquine than in the standard of care arm (30% vs 9%)

Geleris et al. [37]

Observational cohort study (n = 1376)

1. Hydroxychloroquine

600 mg twice on day one, then 400 mg daily for 4 days (n = 811)

2. No hydroxychloroquine (n = 565)

Time from study baseline to intubation or death

No significant differences between the groups for the risk of intubation or death. In total, 346 patients (25.1%) developed respiratory failure

Gautret et al. [38]

Non-randomised, open-label, clinical trial (n = 36)

1. Hydroxychloroquine sulphate 200 mg 3 times a day for 10 days (n = 20); six participants additionally received azithromycin 500 mg on the first day, then 250 mg per day for 4 days

2. Control group (n = 16)

Primary:

Virological clearance at day six post-inclusion

Secondary:

Virological clearance over

time; clinical follow-up; occurrence of side effects

70% of hydroxychloroquine group had virological clearance at day 6 (100% in the group with azithromycin and 57.1% in the hydroxychloroquine-only group) compared to 12.5% in the control group

Molina et al. [41]

Prospective observational study (n = 11)

Hydroxychloroquine 600 mg per day for 10 days and azithromycin 500 mg on day one and 250 mg on days 2 to five

Virologic and clinical outcomes

No patient had virological clearance after 6 days

Cavalcanti et al. [42]

Randomised, open-label, controlled trial (n = 665)

1. Standard of care (control group) (n = 227)

2. Standard of care plus hydroxychloroquine 400 mg twice daily for 7 days (n = 221)

3. Standard of care plus hydroxychloroquine (dosage as second group) plus azithromycin 500 mg once a day for 7 days (n = 217)

Primary:

Clinical status at day 15

Secondary:

Clinical status at day 7; intubation within

15 days; use of supplemental oxygen or non-invasive ventilation within 15 days; use of mechanical ventilation within 15 days; duration of hospital stay; in-hospital death; thromboembolic complications; acute kidney injury; number of days alive and free from respiratory support up to 15 days

No significant difference between the groups regarding clinical improvement at day 15, nor in any of the secondary outcomes

Increased frequency of QTc prolongation and increased liver enzymes in the second and third group

Boulware et al. [43]

Randomized, double-blind, placebo-controlled trial (n = 821)

1. Hydroxychloroquine loading dose of 800 mg with subsequent 600 mg after 6 to 8 h, then 600 mg once a day for 4 days (n = 414)

2. Placebo (n = 407)

Primary:

Symptomatic illness confirmed by PCR or COVID-19-related symptoms

Secondary:

Incidence of hospitalization for COVID-19 or death; incidence of PCR-confirmed SARS-CoV-2 infection; incidence of COVID-19 symptoms; the incidence of discontinuation of the trial intervention due to any cause; severity of symptoms, if applicable, at days 5 and 14

No significant difference in incidence of new illness compatible with COVID-19 between hydroxychloroquine and placebo (11.8% vs 14.3%) as post-exposure prophylaxis

Chorin et al. [44]

Retrospective cohort study (n = 251)

Hydroxychloroquine 400 mg twice a day on day 1, followed by 200 mg twice daily for 4 days, plus azithromycin 500 mg once a day for 5 days

Extreme QTc interval prolongation on ECG

Significant correlation between drug treatment and prolongations of QTc. Extreme QTc prolongation in 23% of patients