Table 1 Summary of clinical studies on investigational therapies in COVID-19 patients

 Gautret [4]

Marseille, Nice, Avignon, Briançon, France

Prospective cohort study (n = 42)

1. HCQ (200 mg tid for 10 days) + azithromycin (500 mg on day 1, followed by 250 mg od for 4 days) (n = 6)

2. HCQ (200 mg tid for 10 days) (n = 14)

2. Controls (n = 16)

1. Virological clearance at day 6 post-inclusion.

2. Virological clearance over time.

3. Clinical follow-up.

4. Side effects.

Not reported

HCQ improved rate of viral clearance. Its effect appeared enhanced by azithromycin.

2b

^aChen [5]

Wuhan, China

RCT

(n = 62)

1. HCQ (200 mg bid for 5 days)

(n = 31)

2. No HCQ

1. Time to clinical recovery

2. Clinical characteristics and radiologic results 5 days after treatment

3. Severe adverse reactions

Mild: rash, headache

HCQ shortened time to clinical recovery and hastened improvement in pneumonia

2b

 Chen [6]

Shanghai, China

RCT (n = 30)

1. HCQ (400 mg/d for 5 days) (n = 15)

2. Controls (n = 15)

Negative conversion rate of viral nuclei acid in pharyngeal swab on day 7 of treatment

Diarrhoea, elevated aspartate aminotransferase, disease progression

No clear benefit in common COVID-19

2b

^aMagagnoli [7]

South Carolina, Virginia, USA

Retrospective cohort study (n = 368)

1. HCQ (n = 97)

2. HCQ + azithromycin

(n = 113)

3. No HCQ

(n = 158)

(doses and duration unknown)

1. Result of hospitalisation (discharge or death)

2. Need for ventilation

3. Result of hospitalisation among patients requiring ventilation

Not reported

Risk of death from any cause higher in the HCQ group. HCQ with or without azithromycin did not reduce risk of ventilation

2b

^aBorba [8]

Manaus, Brazil

Double-blinded, randomized phase IIb clinical trial (n = 81)

1. High dose chloroquine (600 mg bid for 10 days) + ceftriaxone (1 g bid for 7 days) + azithromycin (500 mg od for 5 days) (n = 41)

2. Low dose chloroquine (450 mg bid on day 1, then od on days 2–5) + ceftriaxone (above dose) + azithromycin (above dose)

(n = 40)

Safety and efficacy of chloroquine at high and low doses

Severe rhabdomyolysis (1 patient), prolonged QTc especially in high dose group at days 2 & 3, ventricular tachycardia followed by death (2 patients)

High dose chloroquine should not be recommended due to safety concerns. Recruitment of patients to high dose arm prematurely halted.

2c

 Molina [9]

Paris, France

Prospective case series (n = 11)

HCQ (600 mg/day for 10 days) + azithromycin (500 mg on day 1, followed by 250 mg od for 4 days)

Nil

Prolonged QT interval resulting in discontinuation of HCQ (1 patient)

No clear evidence of antiviral or clinical benefit of HCQ + azithromycin in severe COVID-19

4

^aMahévas [10]

Paris, France

Cohort study (n = 181)

1. HCQ (600 mg/d) (n = 84)

2. No HCQ (n = 97)

1. Transfer to ICU within 7 days from study inclusion

2. Death from any cause

3. Occurrence of ARDS

9.5% in the HCQ group had ECG changes requiring discontinuation of HCQ

No benefit of HCQ in severe COVID-19

2b

 Cao [11]

Hubei, China

RCT (open-label)

(n = 199)

1. Lopinavir-ritonavir (400 mg/100 mg) PO bid for 14 days

(n = 99)

2. Standard care alone (n = 100)

Time to clinical improvement or discharge from hospital

Gastrointestinal events (anorexia, nausea, abdominal discomfort diarrhoea, acute gastritis, haemorrhage from lower digestive tract), self-limited skin eruptions

No benefit of lopinavir-ritonavir over standard care in clinical improvement or mortality in seriously ill COVID-19

1b

 Zhou [12]

Wuhan, China

Retrospective cohort study (n = 191)

Lopinavir-ritonavir (dose unknown) (n = 41)

Nil

None reported

No improvement in duration of viral shedding

2b

 Young [13]

Singapore

Case series (n = 18)

Lopinavir-ritonavir (400 mg/100 mg bid for up to 14 days)

Nil

Nausea, vomiting, diarrhoea, abnormal liver function test

Equivocal clinical benefit and duration of viral clearance

4

 Kim [14]

Incheon, Seoul, Korea

Case report (n = 1)

Lopinavir-ritonavir (400 mg/100 mg, dose per day and duration unknown.

Nil

None reported

No conclusions can be drawn about efficacy or safety

5

 Lim [15]

Goyang, Korea

Case report (n = 1)

Lopinavir-ritonavir (400 mg/100 mg bid; duration unknown

Nil

None reported

No conclusions can be drawn about efficacy or safety

5

 Deng [16]

Guangdong, China

Retrospective cohort (n = 33)

1. Arbidol (0.2 g tid) and lopinavir-ritonavir (400 mg/100 mg bid) until RT-PCR negative for virus 3 times (n = 16)

2. Lopinavir-ritonavir only (n = 17)

RT-PCR negative for SARS-CoV-2 at days 7 and 14 from date of diagnosis, chest CT findings

Elevated bilirubin, mild gastrointestinal side effects

Arbidol with lopinavir-ritonavir might decrease the viral load of COVID-19 and delay progression of lung lesions

4

 Wang [17]

Hubei, China

Retrospective cohort (n = 67)

Arbidol (0.4 g tid), median duration 9 days (n = 36)

Nil

None reported

Arbidol might improve rate of discharge from hospital and mortality rate

4

 Grein [18]

USA, Japan, Italy, Austria, France, Germany, Netherlands, Spain, Canada

Prospective cohort study (n = 61)

Remdesivir (200 mg on day 1, then 100 mg od for 9 days)

Incidence of key clinical events, hospital discharge, adverse event, proportion of patients with clinical improvement.

Common: Elevated hepatic enzymes, diarrhoea, rash, renal impairment, hypotension. Serious adverse events: multiple organ dysfunction syndrome, septic shock, cute kidney injury, hypotension.

Clinical improvement observed in 68% of patients with severe COVID-19

2b

^aCOVID-19 Investigation Team [19]

Various states, USA

Case series (n = 12)

1. Remdesivir (200 mg once on day 1, then 100 mg od for 4–10 days until clinical improvement (n = 3)

2. No remdesivir (n = 9)

Nil

Transient gastrointestinal symptoms (nausea, vomiting, gastroparesis), elevated aminotransferase

No conclusions can be drawn about efficacy or safety

4

 Lescure [20]

Paris, Bordeaux, France

Case series (n = 5)

Remdesivir (200 mg loading dose, then 100 mg od for 10 days) (n = 3)

Nil

Remdesivir discontinued in 1 patient due to combined elevated alanine aminotransferase and rash (uncertain drug adverse reaction)

No conclusions can be drawn about efficacy or safety

4

 Holshue [21]

Washington, USA

Case report (n = 1)

Remdesivir (dose and duration unknown)

Nil

None reported

No conclusions can be drawn about efficacy or safety

5

^aLu [22]

Hubei, Hangzhou, China

Meta-analysis

Systemic corticosteroids

1. Risk of mortality

2. Duration of pneumonia

3. Duration of hospitalisation

4. Duration of fever

None reported

Reduced duration of fever, but not mortality risk, duration of pneumonia. Associated with longer hospital stay.

2a

 Zhou [23]

Hubei, China

Case series (n = 15)

Median hydrocortisone-equivalent dose of 400 mg per day after ICU admission, for average 9.5 days (n = 15)

Nil

None reported

No survival advantage in ICU patients with severe COVID-19, especially when complicated by ARDS and shock or multi-organ injury

4

 Liu [24]

Hubei, China

Retrospective cohort study (n = 137)

IV methylprednisolone (30–80 mg/d for 3–5 days) (n = 40)

Nil

None reported

No observable benefit of corticosteroids

4

 Tang [25]

Wuhan, China

Case-control study (n = 449)

1. LMWH (enoxaparin 40–60 mg/d, at least 7 days) (n = 94)

2. Unfractionated heparin (10,000–15,000 U/d, at least 7 days) (n = 5)

3. No heparin (n = 350)

Nil

None reported

Heparin may improve 28-day mortality in severe COVID-19 patients meeting sepsis-induced coagulopathy criteria or markedly elevated D-dimer

4

^aShi [26]

Wuhan, China

Retrospective cohort study (n = 42)

1. LMWH (n = 21)

2. Controls (n = 21)

Nil

None reported

Heparin can increase the proportion of lymphocytes and decrease IL-6 levels in severe COVID-19

4

^aXu [27]

Anhui, China

Case series (n = 21)

Tocilizumab (400 mg, once dose) + LPV + methylprednisolone

Nil

None reported

Improved clinical status in severe to critically ill COVID-19

4

^aRoumier [28]

Paris, France

Retrospective cohort (n = 30)

1. Tocilizumab (8 mg/kg, once, renewable once) (n = 30)

2. No tocilizumab

Nil

Hepatic cytolysis

Reduced ICU admission and requirement of mechanical ventilation in severe to critically ill COVID-19

4

 Duan [29]

Wuhan, China

Prospective cohort (n = 10)

1 transfusion of 200 ml of convalescent plasma from donors with neutralising antibody titres > 1:640 (n = 10)

1. Safety of convalescent plasma transfusion

2. Improvement in clinical symptoms & laboratory parameters within 3 days of transfusion

None reported

Convalescent plasma was well-tolerated and could potentially improve clinical outcomes in severe COVID-19

4

 Shen [30]

Shenzhen, China

Case series (n = 5)

2 consecutive transfusions of 200–250 ml of convalescent plasma with neutralizing antibody titre > 40

Nil

None reported

Improved clinical status in critically ill patients with ARDS

4

 Ahn [31]

Seoul, Korea

Case series (n = 2)

2 transfusions of 250 ml of convalescent plasma at 12-h interval (optical density ratio for IgG: 0.532 & 0.586) (n = 2)

Nil

None reported

Favourable clinical outcome in critically ill patients with ARDS (combined with systemic corticosteroids)

5

 Leng [32]

Beijing, China

Pilot trial (n = 10)

1. MSC transplant (n = 7).

2. Placebo (n = 3)

1. Adverse events.

2. Cytokine variation, C-reactive protein, oxygen saturation.

3. Total lymphocyte count and subpopulations, chest CT, respiratory rate, patient symptoms

None reported

Symptoms, pulmonary function biochemistry apparently improved after MSC transplantation

4

^aLiang [33]

Baoshan, China

Case report (n = 1).

MSC transplant 3 times, 3 days apart

Nil

None reported

No conclusion can be drawn

5