Systematic Review on the Therapeutic Options for COVID-19: Clinical Evidence of Drug Efficacy and Implications

Figures & data

Figure 1 A Flow Chart Illustrating the Selection Process of Manuscripts.

Table 1 Evidence of Drugs Efficacy or Otherwise, from Clinical Trials

S/N.	Clinical Trial Identifier	Enrolment	Type of Treatment	Interventions	Study Design	Doses	Main Outcome	Reference
	NCT4304053	293	Outpatients with mild to moderate COVID-19	HCQ	Multicenter Open-Label, Randomized Controlled Trial	800 mg on day 1, then 400 mg daily for 6-days	HCQ did not produce a better treatment outcome than standard care.	Mitjà et al, 2020^Citation95
	ChiCTR2000029559	62	Hospitalized patients with moderate COVID-19	HCQ	Randomized, Double-Blind, Single-Center Trial	400 mg on day 1, then 200 mg twice daily for 5-days	80% of patients were relieved of pneumonia, fever, and cough	Chen et al, 2020^Citation115
	NCT4261517	30	Hospitalized patients with moderate COVID-19	HCQ	Randomized, Single-Center Controlled Trial	400 mg daily for 5-days	There was evidence of efficacy in a patient with moderate COVID-19	Chen et al, 2020^Citation92
	ChiCTR2000030054	67	Hospitalized patients with moderate COVID-19	1. HCQ 2- Chloroquine	A Prospective Open-Label Randomized Controlled Study Single-Center	1. CQ 1000 mg on day 1, Then 500 mg daily for 9-days 2.HCQ 200mg twice for 10-days	The CQ And HCQ showed efficacy in patients with moderate COVID-19	Chen et al, 2020^Citation110
	EuCTR:2020–000890-25.	42	Hospitalized patients with moderate COVID-19	1.HCQ 2. AZM	Open-Label, Non-Randomized, Clinical Trial	1. HCQ 200 mg daily for 10- days 2. AZM 500 mg daily for 5- days	HCQ decreased viral load. AZM produced a synergistic effect	Gautret et al, 2020^Citation30
	NCT4308668	1309	Prophylaxis	HCQ	Randomized, Double-Blind, Placebo-Controlled Multicenter Trial	800 mg single dose, then 600 mg daily for 4- days	HCQ did not protect the patient from contracting COVID-19	Boulware et al, 2020^Citation91
	NCT4308668	423	Outpatients mild COVID-19	HCQ	Randomized, Double-Blind, Placebo-Controlled Trial	800 mg once, then 600 mg 8 Hours later, 600 mg once daily for 4- days	HCQ did not significantly reduce the severity of the disease	Skipper et al, 2020^Citation93
	ChiCTR2000029868	150	Hospitalized patients with severe COVID-19	HCQ	Randomized, Open-Label, Multicenter Controlled Trial	1200 mg daily for 3 days, then 800 mg daily for 2-weeks	Did not produce a significant negative conversion of COVID-19 patients	Tang et al, 2020^Citation107
	NCT4384380	33	Hospitalized patients with mild, moderate, and severe COVID-19	HCQ	A Multicenter, Randomized, Open-Label, Controlled Trial	400 mg twice on day 1, and 200 mg twice for 6- days	HCQ did not produce efficacy in subjects with mild to moderate COVID-19.	Chen et al, 2020^Citation108
	R01ey028027 And R01ey029799	807	Hospitalized patients with severe COVID-19	1. HCQ 2. AZM	Prospective Randomized, Open-Label, Multicenter Controlled Trial	1. HCQ 400 mg twice daily for 5-Days 2. AZM 500 mg daily for 5-days	HCQ With AZM did not reduce mortality or need for mechanical ventilation	Magagnoli et al, 2020^Citation96
	NCT4322123	504	Hospitalized patients with mild to moderate COVID-19	1. HCQ 2. AZM	Open-Label, Randomized Controlled Clinical Trial	1.HCQ 400 mg twice for 7- days 2.AZM 500 mg daily for 7- days	HCQ alone or with AZM did not produce better treatment compared to standard care	Cavalcanti et al, 2020^Citation97
	NCT4280705	1062	Hospitalized patients with moderate COVID-19	Remdesivir	Randomized, Double-Blind, Placebo-Controlled Multicenter Trial	200 mg single dose on day 1, then 100 mg daily for 9-days	Remdesivir shortened the time to recovery	Beigel et al 2020^Citation137
	NCT4292730	584	Hospitalized patients with moderate COVID-19	Remdesivir	Randomized, Open-Label Trial	200 mg on day 1, then 100 mg/day for 4-days	Remdesivir was not effective alone compared to standard care	Spinner et al, 2020^Citation38
	NCT4257656	237	Hospitalized patient with severe COVID-19.	Remdesivir	Randomized, Double-Blind, Placebo-Controlled Multicenter Trial	200 mg on day 1, then 100 mg IV once daily for 9-Days	Remdesivir did Not significantly reduce time to recovery	Wang et al, 2020^Citation32
	NCT4276688	86	1. Outpatients with mild COVID-19; 2. Hospitalized patients with moderate COVID-19.	1. LPV/r 2. Interferon Β-1b 3. Ribavirin	Randomized, Double-Blind, Controlled Multicenter Trial	1. 400 mg/100 mg twice daily 2. Three doses of 8 million IU 3. 400 mg twice daily for 14-days	The triple combination effectively suppressed viral load and duration of hospital stay	Hung et al, 2020^Citation120
	ChiCTR2000029308	199	Hospitalized patients with severe COVID-19	LPV/r	Open-Label, Randomized Controlled Trial	400 mg/100 mg twice daily for 14-days	No benefits were observed in patients with severe COVID-19	Cao et al, 2020^Citation123
	NTC04252885	86	Hospitalized patients with moderate COVID-19	1. LPV/r 2.Umifenovir	Exploratory Randomized Controlled Trial	400/100 mg twice daily for 4-weeks	LPV/r or Umifenovir alone shows little benefit in COVID-19 patients	Li et al, 2020^Citation124
	ChiCTR2000029600	80	Hospitalized patients with moderate-severe COVID-19	Favipiravir	An Open-Label Control Single-Centre Trial	FPV 1600 mg twice daily, then 600 mg twice daily for day 2–14	Favipiravir produced faster recovery in COVID-19 patients than the control group	Cai et al, 2020^Citation123
	jRCTs041190120.	69	Hospitalized patients with moderate COVID-19	Favipiravir	A Prospective, Randomized, Open-Label, Multicenter Trial	1800 mg twice 4 h apart day 1, then 800 mg twice for 10 days	Favipiravir did not significantly improve COVID-19 viral clearance within 6 days	Doi et al, 2020^Citation129
	NCT4434248	60	Hospitalized patients with moderate COVID-19	Favipiravir	A Prospective, Open Label, Randomized Multicenter -Clinical Trial	1600mg twice day 1, then 600mg twice day 2–14	Favipiravir significantly improve COVID-19 viral clearance within 5 days	Ivashchenko et al, 2020^Citation130
	ChiCTR2000030254	240	Hospitalized patients with severe COVID-19	1. Favipiravir 2.Umifenovir	Prospective Randomized, Open-Label, Multicenter Controlled Trial	1. Favipiravir 1600 mg twice on day 1, then 600 mg twice daily for 10-days 2. Umefovir 200 mg three times daily for 7-days	FVR compared to Umifenovir did not significantly improve the patient’s recovery	Chen et al, 2020^Citation128
	ChiCTR20000300001	52	Hospitalized patients with moderate COVID-19	Triazavirin	A Pilot Randomized Multicenter Controlled Clinical Trial	Triazavirin 250 mg versus a placebo three or four times a day for 7- days	Triazavirin group required Fewer therapies for respiratory, cardiac, renal, hepatic, or coagulation supports	Wu et al, 2020^Citation132
	NCT4315480	100	Hospitalized patients with severe COVID-19	TCZ	Off-Label, Non-Randomized, Single-Center Study	TCZ 8mg/Kg twice daily IV	TCZ significantly reduced the need for mechanical ventilation, duration of hospital stays	Toniati et al, 2020^Citation150
		63	Hospitalized patients with severe COVID-19	TCZ	A Prospective Open, Single-Arm Multicentre Trial	TCZ 8 mg/Kg IV or 324 mg SC	TCZ improve respiration in a patient with severe COVID-19	Sciascia et al, 2020^Citation151
	NCT4346355	126	Hospitalized patients with severe COVID-19	TCZ	Prospective, Open-Label, Randomized Clinical Trial	TCZ 8 mg/Kg up to a maximum of 800 mg IV	TCZ did not improve disease progression compared with standard care	Salvarani et al, 2020^Citation169
	EudraCT 2020–001934-37	85	Hospitalized patients with severe COVID-19	Methylprednisolone	Partially Randomized, Open-Label, Multicenter Controlled Trial	400 mg twice daily for 3-days, then 20 mg twice daily for 3-days	The drug effectively reduced lung inflammation in a patient with severe COVID-19	Corral et al, 2020^Citation146
	NCT4381936	6425	Hospitalized patients with severe COVID-19	Dexamethasone	Open-Label, Randomized, Double-Blind, Controlled Multicenter Trial	6mg daily for 10-days	Dexamethasone significantly decreased the duration of hospital stay and mortality	Horby et al, 2020^Citation36
	NCT1731795	277	Hospitalized patients with moderate-severe COVID-19	Dexamethasone	Randomized, Multicenter Controlled Trial	20 mg IV once daily for day 1–5, then 10 mg once daily for Day 6–10	Early administration reduces the duration of mechanical ventilation, mortality	Villar et al, 2020^Citation145
	ChiCTR2000030046	10	Hospitalized patients with moderate COVID-19	Convalescent Plasma (CP)	Multicenter Open-Label, Randomized Trial	One-Dose of 200 mL of CP	CP neutralized COVID-19 and improve the clinical outcomes	Duan et al, 2020^Citation171
	CTRI/2020/04/024775	464	Hospitalized patients with moderate COVID-19	Convalescent Plasma (CP)	Open-Label Multicentre Randomised Controlled Trial	Two doses of 200 mL CP, transfused 24 hours apart	CP did not reduce the disease progression and mortality.	Agarwal et al, 2020^Citation175

Table 2 Clinical Evidence of Drugs Efficacy or Otherwise from Retrospective Observational Studies

S/N	Enrolment	Type of Treatment	Interventions	Study Design	Dose	Main Outcome	Reference
	1067	Outpatients with mild COVID-19	HCQ	Retrospective Cohort, Observational Multi-Center Study	600 mg/day	HCQ reduced the duration of hospital stay	Andrew et al, 2020^Citation111
	3737	Hospitalized patients with moderate COVID-19	1-HCQ 2-AZM	Retrospective Cohort Observational Study	1.200 mg three times daily for 10- days 2. 500 mg on day 1, then 250 mg daily for 4-days	HCQ-AZM treatment for at least 3 days decreased mortality and need for ICU	Lagier et al, 2020^Citation113
	2541	Hospitalized Patients with severe COVID-19	1-HCQ 2-AZM	Retrospective Cohort, Observational Multi-Center Study	1. 400 mg twice on day 1, then 200 mg twice daily for 5-days 2. 500 mg on day 1, then 250 mg daily for 4-days	HCQ, in combination with AZM, reduced the death rate in COVID-19 patients	Arshad et al, 2020^Citation114
	1061	Hospitalized patients with moderate COVID-19	1-HCQ 2-AZM	A Retrospective Cohort, Single Centre Analysis	1.200 mg three times daily for 10- days 2. 500 mg Day 1, then 250 mg daily for 4-days	HCQ, combined with AZM, reduced mortality in patients with uncomplicated COVID-19.	Million et al, 2020^Citation116
	80	Hospitalized patients with mild-moderate COVID-19	1-HCQ 2-AZM	Uncontrolled, Non-Comparative, Observational Cohort Study	1. 400 mg twice daily for 5-days 2. 500 mg daily for 5-days	HCQ Combined with AZM Significantly reduced the Spread Of COVID-19 Infection.	Gautret et al, 2020^Citation117
	51	Outpatients with mild/moderate COVID-19	1-HCQ 2-AZM	Retrospective Observational Study	1.HCQ 600 mg daily for 7–10- days 2.AZM 500 mg on Day 1, then 250 mg daily for 4-Days	The combination of HCQ and AZM improved patients’ recovery	Guérin et al, 2020^Citation112
	1820	Hospitalized patients with mild to moderate COVID-19	HCQ	Retrospective Observational Multicenter Center Study	400 mg twice on Day 1, and 200 mg twice for 6-Days	HCQ yield no significant benefit in subjects with COVID-19	Singh et al, 2020^Citation100
	1376	Hospitalized patients with severe COVID-19	HCQ	Retrospective, Observational Single-Center Study	600 mg twice on Day 1, then 400 mg daily for four times a day	HCQ did not reduce the risk of intubation or fatality	Geleris et al, 2020^Citation99
	181	Hospitalized patients with severe COVID-19	HCQ	Retrospective, Observational Multicenter Study	600 mg/Day	HCQ was not effective in patients with severe COVID-19	Mahévas et al, 2020^Citation94
	37	Hospitalized patients with mild to moderate COVID-19	HCQ	Retrospective Observational Study	400 mg twice on day 1, and 200 mg twice for 6-days	HCQ did not produce efficacy in Patients with mild to moderate COVID-19	Chen et al, 2020^Citation108
	2512	Hospitalized patients with moderate-severe COVID-19	1. HCQ 2. AZM 3. TCZ	Retrospective Cohort, Observational, Multicenter Study	1. 400 mg loading dose then 200 mg twice daily for 5-Days 2. 500 mg daily for 5-days 3.8 mg/Kg	HCQ, in combination with AZM, did not increase survival. However, TCZ reduced mortality among ICU patients	Andrew et al, 2020^Citation111
	11	Hospitalized patients with severe COVID-19	1-HCQ 2-AZM	Prospective, Observational Single-Center Study	HCQ 600 mg/D for 10-days and AZM 500 mg day 1, then 250 mg for 5-days	HCQ combined with AZM produced no antiviral activity	Molina et al, 2020^Citation109
	61	Hospitalized patients with severe COVID-19.	Remdesivir	Prospective, Observational Cohort, Multi-Center Study	200 mg loading dose on day 1, then 100 mg once daily for 9- days	There was faster recovery observed in 68% of patients	Grein et al, 2020^Citation136
	47	Hospitalized patients with moderate COVID-19	LPV/r	A Retrospective Cohort Single Center Study	400/100 mg twice daily for 4- weeks	LPV/r was effective against COVID-19 when combined with standard care	Ye et al, 2020^Citation121
	33	Hospitalized patients with moderate COVID-19	1. LPV/r 2.Umifenovir	A Retrospective Cohort Single Center Study	1.400/100 mg twice daily for 4- weeks 2. Umifenovir At 0.2g three times a day	LPV/r was effective when combined with Umifenovir	Deng et al, 2020^Citation125
	178	Hospitalized patients with moderate COVID-19	1. LPV/r 2.Umifenovir	A Retrospective Cohort Single Center Study	1.400/100 mg twice daily for 4- weeks 2. Umifenovir At 0.2g three times a day	LPV/r and Umifenovir neither improved patients’ health condition nor hastened negative conversion of COVID-19	Wen et al, 2020^Citation126
	32	Hospitalized patients with moderate COVID-19.	LPV/r	Retrospective Cohort, Observational Single-Center Study	400 mg/100 mg twice daily for 14- days	The drugs significantly reduced the duration of hospital stays with no mortality	Bowale et al, 2020^Citation122
	52	Hospitalized patients with severe COVID-19	1.Oseltamivir, 2.Ganciclovir 3. LPV/r	A Single-Centered, Retrospective, Observational Study	Oseltamivir was given to 18 patients, Ganciclovir 14, and LPV/r seven patients	No efficacy produced in all groups	Yang et al, 2020^Citation127
	81	Hospitalized patients with moderate COVID-19.	Umifenovir	A Retrospective Observational Cohort Study	Umifenovir at 0.2g three times a day	Umifenovir was not better than the control group in suppressing viral load	Lian et al, 2020^Citation133
	3924	Hospitalized patients with severe COVID-19	TCZ	A Retrospective Observational Cohort Multi-Center Study	4–8 mg/Kg IV	TCZ decreased mortality at first 2 days of ICU admission compared to control group.	Gupta et al, 2020^Citation162
	630	Hospitalized patients with severe COVID-19	TCZ	A Retrospective Observational Cohort Multi-Center Study	4–8 mg/Kg IV	TCZ reduced mortality among COVID-19 patients requiring ICU	Biran et al, 2020^Citation152
	544	Hospitalized patients with severe COVID-19	TCZ	Retrospective Cohort, Observational Multi-Center Study	8 mg/Kg IV 2-times only in IV fluid	Reduce the risk of mechanical ventilation and death rate	Guaraldi et al, 2020^Citation153
	158	Hospitalized patients with severe COVID-19	TCZ	A Retrospective Cohort Observational Study	400 mg first dose, then 400 mg after 24 hours	TCZ improved ventilation	De Rossi et al, 2020^Citation155
	154	Hospitalized patients with moderate COVID-19	TCZ	Retrospective Observational Study	600 mg twice daily day-1, then 200 mg every 8 hours for 4-Days	TCZ significantly decreased mortality	Somers et al, 2020^Citation156
	104	Hospitalized patients with severe COVID-19	TCZ	Prospective, Observational, Single-Center Study	8 mg/Kg	TCZ reduced requirement for ventilator and improved inflammatory biomarkers	Price et al, 2020^Citation157
	88	Hospitalized patients with severe COVID-19	TCZ	Retrospective Cohort, Observational Single-Center Study	400 mg IV as hour infusion, 400 mg after 12 and 24 hours	TCZ was an effective immunomodulator in severe COVID-19	Fernandez-Ruiz et al, 2020^Citation158
	77	Hospitalized patients with severe COVID-19	TCZ	Retrospective Cohort, Observational Single-Center Study	4–8 mg/Kg	TCZ was associated with increased survival but a high risk of severe infections.	Moreno-Perez et al, 2020^Citation154
	45	Hospitalized patients with severe COVID-19	TCZ	Retrospective Case-Control Study	4–8 mg/Kg	TCZ reduced the number of patients requiring ICU and death rate in patients with severe COVID-19	Klopfenstein et al, 2020^Citation161
	21	Hospitalized patients with severe COVID-19	TCZ	Retrospective Observational Multicentre Study	4–8 mg/Kg	TCZ improved clinical outcomes and reduced mortality in patients with severe COVID-19	Xu et al, 2020^Citation28
	15	Hospitalized patients with moderate COVID-19	TCZ	Retrospective, Observational Single-Center Study	600 mg twice at a time	TCZ was effective in the treatment of Covid‐19 patients with a risk of cytokine storms	Luo et al, 2020^Citation159
	12	Hospitalized patients with Severe COVID-19	TCZ	Retrospective Cohort Observational Single-Center Study	162 mg subcutaneously	TCZ improved lung function.	Mastroianni et al, 2020^Citation160
	196	Hospitalized patients with severe COVID-19	1.TCZ 2.Methylprednisolone	Off-Label Observational Single-Center Study	1.8 mg/Kg IV 2. 1 mg/Kg for 5-days	Produced anti-inflammatory action and reduced negative impact of the immune response to COVID-19	Mikulska et al, 2020^Citation27
	112	Hospitalized patients with severe COVID-19	TCZ	Retrospective Cohort, Observational Study	8 mg/Kg	TCZ did not reduce mortality or ICU admission	Colaneri et al, 2020^Citation149
	66	Hospitalized patient with severe COVID-19	TCZ	Retrospective Cohort, Observational Single‐Center Study	8 mg/Kg, maximum of 800 mg per dose for 28-days	There was no efficacy in patients with severe COVID-19	Knorr et al, 2020^Citation164
	65	Hospitalized patients with severe COVID-19	TCZ	A Single- Centre Retrospective Cohort Observational Study	400 mg first dose, then 400 mg after 24 hours as the second dose	No significant increase in recovery	Campochiaro et al, 2020^Citation166
	51	Hospitalized patients with severe COVID-19	TCZ	Open-Label Prospective Observational Study	400 mg first dose, then 400 mg after 24 hours as the second dose	No significant improvement in the patient’s health condition	Morena et al, 2020^Citation167
	51	Hospitalized patients with severe COVID-19	TCZ	Retrospective Cohort, Observational Single-Center Study	TCZ 4–8 mg/Kg, followed by adjunct treatment	TCZ showed no efficacy in patients with severe COVID-19	Kewan et al, 2020^Citation165
	11	Hospitalized patients with severe COVID-19	TCZ	Retrospective Cohort Observational, Study	600 mg twice daily on day 1, then 200 mg every 8 hours for 4- days	No improvement in the health condition of patients with severe COVID-19	Rimland et al, 2020^Citation168
	242	Hospitalized patients with moderate COVID-19	Methylprednisolone	An Observational Comparative Study	Methylprednisolone 250 mg daily for 3- consecutive days	Relieved inflammation and improved lung functions	Ruiz-Irastorza et al, 2020^Citation147
	136	Hospitalized patients with severe COVID-19	1. Methylprednisolone 2.Hydrocortisone 3.Dexamethasone 4. Prednisone	An Observational Cohort Analysis Of Dosing Patterns		Early administration of corticosteroids improved survival in non-mechanically ventilated patients	Rahman et al, 2020^Citation148
	49	Hospitalized patients with severe COVID-19	Convalescent Plasma (CP)	Prospective, Observational Multi-Center Study	One-dose of 200 mL of CP	CP was effective against COVID-19 if donors with the high level of SARS-CoV2 antibodies used early	Rasheed et al, 2020^Citation172
	25	Hospitalized patients with severe COVID-19	Convalescent Plasma (CP)	Retrospective Observational Single Center Study	300 mL of CP for all	treatment with CP is safe and significantly improve the patients’ health condition	Salazar et al, 2020^Citation173
	50	Hospitalized patients with moderate-severe COVID-19	Anakinra	A Retrospective Cohort Single Center Study	Anakinra 5 mg/Kg twice a day IV or 100 mg twice a day SC	High-dose Anakinra was safe and showed efficacy against COVID-19	Cavalli et al, 2020^Citation177

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