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

From: Role of adjunctive treatment strategies in COVID-19 and a review of international and national clinical guidelines

StudyStudy locationStudy designStudy groupsClinical endpointAdverse effectsConclusionsLOE
Chloroquine/ Hydroxychloroquine (HCQ)
 Gautret [4]Marseille, Nice, Avignon, Briançon, FranceProspective 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 reportedHCQ improved rate of viral clearance. Its effect appeared enhanced by azithromycin.2b
aChen [5]Wuhan, ChinaRCT
(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, headacheHCQ shortened time to clinical recovery and hastened improvement in pneumonia2b
 Chen [6]Shanghai, ChinaRCT (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 treatmentDiarrhoea, elevated aspartate aminotransferase, disease progressionNo clear benefit in common COVID-192b
aMagagnoli [7]South Carolina, Virginia, USARetrospective 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 reportedRisk of death from any cause higher in the HCQ group. HCQ with or without azithromycin did not reduce risk of ventilation2b
aBorba [8]Manaus, BrazilDouble-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 dosesSevere 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, FranceProspective 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)NilProlonged QT interval resulting in discontinuation of HCQ (1 patient)No clear evidence of antiviral or clinical benefit of HCQ + azithromycin in severe COVID-194
aMahévas [10]Paris, FranceCohort 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 HCQNo benefit of HCQ in severe COVID-192b
Lopinavir-ritonavir
 Cao [11]Hubei, ChinaRCT (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 hospitalGastrointestinal events (anorexia, nausea, abdominal discomfort diarrhoea, acute gastritis, haemorrhage from lower digestive tract), self-limited skin eruptionsNo benefit of lopinavir-ritonavir over standard care in clinical improvement or mortality in seriously ill COVID-191b
 Zhou [12]Wuhan, ChinaRetrospective cohort study (n = 191)Lopinavir-ritonavir (dose unknown) (n = 41)NilNone reportedNo improvement in duration of viral shedding2b
 Young [13]SingaporeCase series (n = 18)Lopinavir-ritonavir (400 mg/100 mg bid for up to 14 days)NilNausea, vomiting, diarrhoea, abnormal liver function testEquivocal clinical benefit and duration of viral clearance4
 Kim [14]Incheon, Seoul, KoreaCase report (n = 1)Lopinavir-ritonavir (400 mg/100 mg, dose per day and duration unknown.NilNone reportedNo conclusions can be drawn about efficacy or safety5
 Lim [15]Goyang, KoreaCase report (n = 1)Lopinavir-ritonavir (400 mg/100 mg bid; duration unknownNilNone reportedNo conclusions can be drawn about efficacy or safety5
Umifenovir (Arbidol®)
 Deng [16]Guangdong, ChinaRetrospective 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 findingsElevated bilirubin, mild gastrointestinal side effectsArbidol with lopinavir-ritonavir might decrease the viral load of COVID-19 and delay progression of lung lesions4
 Wang [17]Hubei, ChinaRetrospective cohort (n = 67)Arbidol (0.4 g tid), median duration 9 days (n = 36)NilNone reportedArbidol might improve rate of discharge from hospital and mortality rate4
Remdesivir
 Grein [18]USA, Japan, Italy, Austria, France, Germany, Netherlands, Spain, CanadaProspective 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-192b
aCOVID-19 Investigation Team [19]Various states, USACase 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)
NilTransient gastrointestinal symptoms (nausea, vomiting, gastroparesis), elevated aminotransferaseNo conclusions can be drawn about efficacy or safety4
 Lescure [20]Paris, Bordeaux, FranceCase series (n = 5)Remdesivir (200 mg loading dose, then 100 mg od for 10 days) (n = 3)NilRemdesivir discontinued in 1 patient due to combined elevated alanine aminotransferase and rash (uncertain drug adverse reaction)No conclusions can be drawn about efficacy or safety4
 Holshue [21]Washington, USACase report (n = 1)Remdesivir (dose and duration unknown)NilNone reportedNo conclusions can be drawn about efficacy or safety5
Corticosteroids
aLu [22]Hubei, Hangzhou, ChinaMeta-analysisSystemic corticosteroids1. Risk of mortality
2. Duration of pneumonia
3. Duration of hospitalisation
4. Duration of fever
None reportedReduced duration of fever, but not mortality risk, duration of pneumonia. Associated with longer hospital stay.2a
 Zhou [23]Hubei, ChinaCase series (n = 15)Median hydrocortisone-equivalent dose of 400 mg per day after ICU admission, for average 9.5 days (n = 15)NilNone reportedNo survival advantage in ICU patients with severe COVID-19, especially when complicated by ARDS and shock or multi-organ injury4
 Liu [24]Hubei, ChinaRetrospective cohort study (n = 137)IV methylprednisolone (30–80 mg/d for 3–5 days) (n = 40)NilNone reportedNo observable benefit of corticosteroids4
Heparin
 Tang [25]Wuhan, ChinaCase-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)
NilNone reportedHeparin may improve 28-day mortality in severe COVID-19 patients meeting sepsis-induced coagulopathy criteria or markedly elevated D-dimer4
aShi [26]Wuhan, ChinaRetrospective cohort study (n = 42)1. LMWH (n = 21)
2. Controls (n = 21)
NilNone reportedHeparin can increase the proportion of lymphocytes and decrease IL-6 levels in severe COVID-194
Tocilizumab
aXu [27]Anhui, ChinaCase series (n = 21)Tocilizumab (400 mg, once dose) + LPV + methylprednisoloneNilNone reportedImproved clinical status in severe to critically ill COVID-194
aRoumier [28]Paris, FranceRetrospective cohort (n = 30)1. Tocilizumab (8 mg/kg, once, renewable once) (n = 30)
2. No tocilizumab
NilHepatic cytolysisReduced ICU admission and requirement of mechanical ventilation in severe to critically ill COVID-194
Convalescent plasma
 Duan [29]Wuhan, ChinaProspective 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 reportedConvalescent plasma was well-tolerated and could potentially improve clinical outcomes in severe COVID-194
 Shen [30]Shenzhen, ChinaCase series (n = 5)2 consecutive transfusions of 200–250 ml of convalescent plasma with neutralizing antibody titre > 40NilNone reportedImproved clinical status in critically ill patients with ARDS4
 Ahn [31]Seoul, KoreaCase 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)NilNone reportedFavourable clinical outcome in critically ill patients with ARDS (combined with systemic corticosteroids)5
Mesenchymal stem cell (MSC) treatment
 Leng [32]Beijing, ChinaPilot 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 reportedSymptoms, pulmonary function biochemistry apparently improved after MSC transplantation4
aLiang [33]Baoshan, ChinaCase report (n = 1).MSC transplant 3 times, 3 days apartNilNone reportedNo conclusion can be drawn5
  1. LOE Level of evidence, tid Three times a day, od Once a day, RCT Randomized controlled trial, bid twice a day, ECG Electrocardiogram, SpO2 Oxygen saturation, ICU Intensive care unit, ARDS Acute respiratory distress syndrome, LMWH Low molecular weight heparin, RT-PCR Reverse transcription polymerase chain reaction, CT Computed tomography; aPublished on pre-print medical server without peer review