Evaluation of Global Post-Outbreak COVID-19 Treatment Interventions: A Systematic Review and Bibliometric Analysis of Randomized Controlled Trials

Figures & data

Figure 1 PRISMA diagram of the study selection process of the randomized controlled trials (RCTs) included in the analysis for the treatment of COVID-19.

Notes: PRISMA figure adapted from Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Creative Commons.²¹

Table 1 The Demographic and Clinical Characteristics of the Randomized Controlled Trials (RCTs) Included in the Analysis for the Treatment of COVID-19

Intervention	Dose	Author/s	Duration of Treatment	Registration No.	Ethics Approval	Sample Size (ITT Population)	Blinding	Date of Release
Remdesivir	200 mg on day 0 and 100 mg on days 1 through 9	Karim Ali et al^Citation51	10 days	NCT04330690	Y	1282	Open label	19/01/2022
Favipiravir	1800 mg BID on Day 1, followed by 800 mg BID on Days 2–10	Yoav Golan et al^Citation50	10 days	NCT04600895	Y	1231	Double-blinded	6/9/2022
Umifenovir	Hydroxychloroquine 400 mg BID on the first day followed by Umifenovir 200mg TID 7 to 14 days based on the severity of the disease	Marzieh Nojomi et al^Citation47	7 to 14 days based on the severity of the disease	IRCT20180725040596N2	Y	100	Open label	14/12/2020
Hydroxychloroquine	400 mg BID for 1 d or HCQ 200 mg BID for seven days	Cheng-Pin Chen et al^Citation46	7 days	NCT04384380	Y	33	Open label	2/12/2020
	Hydroxychloroquine 400 mg BID on the first day, 400 mg once daily for a total of seven days	Álvaro Avezum et al^Citation52	7 days	NCT04466540	Y	1372	Double-blinded	31/03/2022
	400 mg BID for day 1 followed by 200 mg 12 hourly for the next five days.	Sultan M. Kamran et al^Citation48	6 days	NCT04491994	Y	540	Open label	30/03/2021
Hydroxychloroquine + Azithromycin	Two 200 mg Hydroxychloroquine capsules BID for a total course of 7 days and one 500 mg Azithromycin capsule taken on day 1, followed by one 250 mg Azithromycin capsule daily for the next 4 days	Cristhieni Rodrigues et al^Citation42	7 days	30,413,020.8.0000.0008	Y	84	Double-blinded	25/08/2021
Ivermectin + Doxycycline	Ivermectin 200 μgm/kg single dose + Doxycycline 100mg BID for ten days	Abu Taiub Mohammed Mohiuddin Chowdhury et al^Citation40	10 days	NP	Y	116	a	25/02/2021
Ivermectin + Metronidazole	Ivermectin 0.2 mg/kg of body weight (max. 12 mg) as a single dose, Metronidazole 8 mg/kg q6hr for five days	Mohammad Reza Heydari et al^Citation44	5 days	IRCT20180612040068N1	Y	135	Triple-blinded	19/11/2022
Methylprednisolone	Methylprednisolone (2 mg/kg/day) over 60 min, and tapered to half dosage every five days	Keivan Ranjbar et al^Citation43	10 days	IRCT20200204046369N1	Y	93	Triple-blinded	11/5/2021
	Intravenous methylprednisolone 10 mg/kg per dose once daily for 3 days, maximum dose 1000 mg per day	Tatjana Welzel et al^Citation41	3 Days	NCT04826588	Y	76	Open label	3/2/2023
Tocilizumab	Intravenous infusion of tocilizumab (8 mg/ Kg, with a starting dosage of 400 mg and a maximum dose of 800 mg, followed by a second dose 12–24 h later	Al Shaimaa Ibrahim Rabie et al^Citation30	7 days	NCT0487185	Y	110	Open label	17/02/2023
	Tocilizumab intravenously within 8 hours from randomization at a dose of 8mg/kg up to a maximum of 800 mg, followed by a second dose after 12 hours.	Carlo Salvarani et al^Citation38	One day	NCT04346355	Y	126	Open label	20/10/2020
Convalescent plasma	5 mL/kg body weight of convalescent	Manuel E. Baldeón et al^Citation31	One day	NP	Y	158	Double-blinded	9/1/2022
Vitamin D	A single oral dose of either 400,000 IU or 50,000 IU cholecalciferol	Ce´dric Annweiler et al^Citation49	One day	NCT04344041	Y	260	Open label	31/05/2022
Vitamin C	50 mg/kg/day	Poona Kumari et al^Citation39	NP	NP	Y	150	Open label	30/11/2020
L-Arginine	100 mL solution containing 5 g powdered formulation, 3 g of L-Arginine, followed by a 100 mL water rinse, 10 days or until the patients were off O2 support	Jananee Muralidharan et al^Citation32	10 days or until the patients were off O2 support	CTRI/2022/01/039549	Y	74	Triple-blinded	26/09/2021
Sentinox	Sentinox TID for Arm I and Sentinox 5 times/day for Arm II, for 5 days	Donatella Panatto et al^Citation35	5 days	NCT04909996	Y	57	Open label	12/5/2022
Nigella sativa oil	Oral Nigella sativa oil 500 mg BID postprandial for 10 days	Abdulrahman E. Koshak et al^Citation37	10 days	NCT04401202	Y	183	Open label	15/08/2021
Nilavembu Kudineer + Kaba Sura Kudineer	60 mL of Nilavembu Kudineer for Arm I and 60 mL of Kaba Sura Kudineer for Arm II, BID post morning and evening meals for a maximum of 10 days	Anurag Srivastava et al^Citation34	10 days	2020/08/027286	Y	125	Double-blinded	28/08/2021
Lianhua Qingwen	Lianhua Qingwen capsule (0.35 g per capsule), 4 capsules TID for 14 days	Ling Zhang et al^Citation36	14 days	ChiCTR2100042066	Y	120	a	14/11/2022
Qigong exercise and acupressure rehabilitation program	BID at 10 am and 4 pm from the first day for the therapists until the participants were deemed competent.	Shu-ting Liu et al^Citation33	From the first day for the therapists until the participants were deemed competent.	ChiCTR2000029994	Y	128	a	29/10/2021

Note: ^aBlinding not implemented.

Abbreviations: NP, not provided; Y, yes; N, no; ITT, intention-to-treat; q, every; BID, twice daily; TID, three times daily.

Table 2 Frequently Used Finding Measures in the Randomized Controlled Trials (RCTs) Included in the Analysis for the Treatment of COVID-19

Category	Finding Measure/s	Specifics	Number (%)
Finding*	Laboratory tests	PCR	1/22 (4.5)
	Clinical events	Recovery and disappearance of symptoms	1/22 (4.5)
		Hospitalization time	1/22 (4.5)
		Need for ventilation	1/22 (4.5)
		Mortality	1/22 (4.5)
Primary finding	Laboratory tests	RT-PCR, lymphocyte levels, inflammatory markers (IL6), nucleic acid negative time and rate	4/22 (18.1)
	Clinical events	Recovery, the disappearance of symptoms (eg shortness of breath and complete cessation in O2 support), and viral clearance	8/22 (36.4)
		Hospitalization time	4/22 (18.1)
		Clinical deterioration, progression of the disease, survival and mortality	7/22 (31.8)
	Vital signs	Respiration rate, pulse rate, blood pressure, blood oxygen levels, and temperature	1/22 (4.5)
	Severity of dyspnea	Modified Medical Research Council dyspnea scale	1/22 (4.5)
Secondary outcome	Laboratory tests	RT-PCR, PCR, routine blood tests, and biochemical indicators.	5/22 (22.7)
	Non-laboratory tests	CT scan	1/22 (4.5)
	Clinical events	Recovery, the disappearance of symptoms (eg shortness of breath and complete cessation in O2 support) and viral clearance	9/22 (40.9)
		Hospitalization time and admission to ICU	13/22 (59.1)
		Clinical deterioration, progression of the disease, mechanical ventilation use, and all-cause mortality	13/22 (59.1)
		Safety, tolerability, adverse events and adverse reactions to treatment	8/22 (36.4)
	Vital signs	Respiration rate, pulse rate, blood pressure, blood oxygen levels, and temperature	1/22 (4.5)
	Exercise intensity rating	Modified Borg dyspnea scale	1/22 (4.5)
	Fatigue assessment	Fatigue Scale-14	1/22 (4.5)
	Mental assessment	Patient health questionnaire-9 scale	1/22 (4.5)
	Tolerability	Visual analog scale	1/22 (4.5)
	Patient satisfaction	5-point anchored Likert scale	1/22 (4.5)

Note: *Finding encompasses findings without specifying whether they are primary or secondary findings,

Abbreviations: RT-PCR, reverse transcription polymerase chain reaction; O2, oxygen; CPR, cardiopulmonary resuscitation; IL6, interleukin-6; ICU, intensive care unit.

Figure 2 Risk of bias assessment of the randomized controlled trials (RCTs) included in the analysis for the treatment of COVID-19.

Table 3 Comparison of Reports with Registration Information of the Randomized Controlled Trials (RCTs) Included in the Analysis for the Treatment of COVID-19

Category	Content	Number and Percentage of Studies in Content [n (%)]	Number and Percentage of Studies in Category [n (%)]
Inclusion criteria	Items reduced	2/18 (11.1)	18/18 (100)
	Item content revised	1/18 (5.6)
	Consistent with registration information	15/18 (83.3)
Exclusion criteria	Items increased	1/18 (5.5)	18/18 (100)
	Items reduced	4/18 (22.2)
	Item content revised	1/18 (5.6)
	Consistent with registration information	12/18 (66.7)
Sample size	Sample size increased	2/18 (11.1)	18/18 (100)
	Sample size reduced	4/18 (22.2)
	Consistent with registration information	12/18 (66.7)
Primary finding	Items reduced	1/18 (5.6)	18/18 (100)
	Consistent with registration information	17/18 (94.4)
Secondary finding	Items increased	1/18 (5.6)	17/18 (94)
	Items reduced	2/18 (11.1)
	Item content missing	2/18 (11.1)
	Item content revised	5/18 (27.8)
	Consistent with registration information	8/18 (44.4)
Sites	Locations increased	1/18 (5.6)	18/18 (100)
	Locations reduced	2/18 (11.1)
	Consistent with registration information	16/18 (88.9)
Intervention	Intervention revised	3/18 (16.7)	18/18 (100)
	Consistent with registration information	15/18 (83.3)
Blinding	Blinding not implemented	2/18 (11.1)	18/18 (100)
	Consistent with registration information	16/18 (88.9)

Figure 3 Keyword co-occurrence network of the randomized controlled trials (RCTs) included in the analysis for the treatment of COVID-19.

Figure 4 The global distribution of the randomized controlled trials (RCTs) included in the analysis for the treatment of COVID-19.

Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi:10.1136/BMJ.N71

 PubMed Web of Science ®Google Scholar

Ali K, Azher T, Baqi M, et al. Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial. CMAJ. 2022;194(7):E242–E251. doi:10.1503/CMAJ.211698

 PubMed Web of Science ®Google Scholar

Golan Y, Campos JAS, Woolson R, et al. Favipiravir in patients with early mild-to-moderate coronavirus disease 2019 (COVID-19): a randomized controlled trial. Clin Infect Dis. 2023;76(3):E10–E17. doi:10.1093/cid/ciac712

 PubMed Web of Science ®Google Scholar

Nojomi M, Yassin Z, Keyvani H, et al. Effect of Arbidol (Umifenovir) on COVID-19: a randomized controlled trial. BMC Infect Dis. 2020;20(1). doi:10.1186/s12879-020-05698-w

 PubMed Web of Science ®Google Scholar

Chen CP, Lin YC, Chen TC, et al. A multicenter, randomized, open-label, controlled trial to evaluate the efficacy and tolerability of hydroxychloroquine and a retrospective study in adult patients with mild to moderate coronavirus disease 2019 (COVID-19). PLoS One. 2020;15(12 December). doi:10.1371/journal.pone.0242763

 Web of Science ®Google Scholar

Avezum Á, Oliveira GBF, Oliveira H, et al. Hydroxychloroquine versus placebo in the treatment of non-hospitalised patients with COVID-19 (COPE – coalition V): a double-blind, multicentre, randomised, controlled trial. Lancet Regional Health. 2022;11:100243. doi:10.1016/j.lana.2022.100243

 Google Scholar

Kamran SM, Moeed HA, Mirza Z, et al. Clearing the fog: is hydroxychloroquine effective in reducing coronavirus disease-2019 progression? A randomized controlled trial. Cureus. 2021;30. doi:10.7759/cureus.14186

 Google Scholar

Rodrigues C, Freitas-Santos RS, Levi JE, et al. Hydroxychloroquine plus azithromycin early treatment of mild COVID-19 in an outpatient setting: a randomized, double-blinded, placebo-controlled clinical trial evaluating viral clearance. Int J Antimicrob Agents. 2021;58(5):106428. doi:10.1016/j.ijantimicag.2021.106428

 PubMed Web of Science ®Google Scholar

Chowdhury AT, Shahbaz M, Karim MR, Islam J, Dan G, He S. A comparative study on ivermectin-doxycycline and hydroxychloroquine-azithromycin therapy on COVID-19 patients. Eurasian J Med Oncol. 2021;5(1):63–70. doi:10.14744/ejmo.2021.16263

 Google Scholar

Heydari M, Rahimi J, Foroozanfar Z, et al. The efficacy of ivermectin and metronidazole vs. standard treatment protocols on outcomes of COVID-19 in hospitalized patients: a triple-blinded randomized controlled trial. Arch Clin Infect Dis. 2022;17(5). doi:10.5812/archcid-122525

 Web of Science ®Google Scholar

Ranjbar K, Moghadami M, Mirahmadizadeh A, et al. Methylprednisolone or dexamethasone, which one is superior corticosteroid in the treatment of hospitalized COVID-19 patients: a triple-blinded randomized controlled trial. BMC Infect Dis. 2021;21(1). doi:10.1186/s12879-021-06045-3

 Web of Science ®Google Scholar

Welzel T, Atkinson A, Schöbi N, et al. Methylprednisolone versus intravenous immunoglobulins in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS): an open-label, multicentre, randomised trial. Lancet Child Adolesc Health. 2023;7(4):238–248. doi:10.1016/S2352-4642(23)00020-2

 PubMedGoogle Scholar

Rabie ASI, Salah H, Said ASA, et al. Clinical consequences for individuals treated with tocilizumab for serious COVID-19 Infection. Healthcare. 2023;11(4). doi:10.3390/healthcare11040607

 Web of Science ®Google Scholar

Salvarani C, Dolci G, Massari M, et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):24–31. doi:10.1001/jamainternmed.2020.6615

 PubMed Web of Science ®Google Scholar

Baldeón ME, Maldonado A, Ochoa-Andrade M, et al. Effect of convalescent plasma as complementary treatment in patients with moderate COVID-19 infection. Transfus Med. 2022;32(2):153–161. doi:10.1111/tme.12851

 PubMed Web of Science ®Google Scholar

Annweiler C, Beaudenon M, Gautier J, et al. High-dose versus standard-dose vitamin D supplementation in older adults with COVID-19 (COVIT-TRIAL): a multicenter, open-label, randomized controlled superiority trial. PLoS Med. 2022;19(5):e1003999. doi:10.1371/journal.pmed.1003999

 PubMed Web of Science ®Google Scholar

Kumari P, Dembra S, Dembra P, et al. The role of vitamin c as adjuvant therapy in COVID-19. Cureus. 2020. doi:10.7759/cureus.11779

 Web of Science ®Google Scholar

Muralidharan J, Kashyap S, P S, et al. The effect of L-arginine supplementation on amelioration of oxygen support in severe COVID-19 pneumonia. Clin Nutr ESPEN. 2022;52:431–435. doi:10.1016/j.clnesp.2022.09.024

 PubMedGoogle Scholar

Panatto D, Orsi A, Bruzzone B, et al. Efficacy of the sentinox spray in reducing viral load in mild COVID-19 and its virucidal activity against other respiratory viruses: results of a randomized controlled trial and an in vitro study. Viruses. 2022;14(5):1033. doi:10.3390/v14051033

 PubMed Web of Science ®Google Scholar

Koshak AE, Koshak EA, Mobeireek AF, et al. Nigella sativa for the treatment of COVID-19: an open-label randomized controlled clinical trial. Complement Ther Med. 2021:61. doi:10.1016/j.ctim.2021.102769

 Google Scholar

Srivastava A, Rengaraju M, Srivastava S, et al. Efficacy of two siddha polyherbal decoctions, Nilavembu Kudineer and Kaba Sura Kudineer, along with standard allopathy treatment in the management of mild to moderate symptomatic COVID-19 patients—a double-blind, placebo-controlled, clinical trial. Trials. 2021;22(1). doi:10.1186/s13063-021-05478-0

 Web of Science ®Google Scholar

Zhang L, Wu L, Xu X, et al. Effectiveness of lianhua qingwen capsule in treatment of asymptomatic COVID-19 patients: a randomized, controlled multicenter trial. J Complement Integr Med. 2022;28(11):887–894. doi:10.1089/jicm.2021.0352

 Google Scholar

Liu ST, Zhan C, Ma YJ, et al. Effect of qigong exercise and acupressure rehabilitation program on pulmonary function and respiratory symptoms in patients hospitalized with severe COVID-19: a randomized controlled trial. Integr Med Res. 2021:10. doi:10.1016/j.imr.2021.100796

 Web of Science ®Google Scholar