In considerazione del particolare stato di emergenza dovuta all’epidemia da SARS-CoV-2 e della velocità con cui si stanno registrando ricerche sulle strategie per contrastare la Covid-19, il DEP ritiene importante monitorare e sintetizzare le informazioni relative alle prove di efficacia e sicurezza che si renderanno a mano a mano disponibili.

 

Stiamo per questo lavorando ad una revisione sistematica sull'efficacia dei farmaci per il trattamento della malattia COVID-19 che si aggiornerà costantemente nel tempo con la pubblicazione dei risultati di nuovi studi clinici.

FARMACI E COVID-19: COSA SAPPIAMO



Fonte: International Clinical Trials Registry Platform

IL NOSTRO LAVORO È IN PROGRESS


 

 

Trattamenti a confronto


clicca qui per andare alla versione in inglese delle tabelle di evidenza GRADE

Network degli interventi farmacologici per COVID-19


Sono inclusi solo gli studi con un numero di partecipanti superiore a 100

Aggiornamento al 21/01/2021

I NOSTRI METODI


Per l’identificazione, la valutazione e la sintesi dei risultati seguiremo un processo rigoroso e trasparente.


 

 

 

Identificazione di un nuovo trattamento

 

Criteri di inclusione

  • Popolazione: persone affette da COVID-19, come definito dagli autori dello studio. Nessun limite in base al genere o provenienza geografica
  • Intervento: Verranno considerati studi che valutano interventi farmacologici per il trattamento di persone con COVID-19, (es. antibiotici, anticorpi, antimalarici, antivirali, antiretrovirali, immunosoppressori/modulatori, inibitori della chinasi proteica) e la loro combinazione
  • Confronto: qualsiasi trattamento attivo, placebo o terapia standard
  • Esiti primari: mortalità per tutte le cause
  • Esiti secondari: negatività al test molecolare con metodo Real Time PCR per 2019-nCoV, PaO2/FiO2, durata della ventilazione meccanica, durata della degenza ospedaliera, miglioramento dell’imaging radiologico, eventi avversi, eventi avversi gravi
  • Disegno di studio: studi randomizzati controllati

Ricerca di trial

 

Ricerca bibliografica

Banche dati elettroniche:

  • Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Library
  • MEDLINE (via OVID)
  • Embase (via OVID)
  • MedRxiv Health Sciences e bioRxiv Biology (articoli in pre-print)

La ricerca nelle banche dati predere l’utilizzo di specifiche strategie di ricerca che includono una combinazione di parole chiave, prese da un vocabolario medico controllato, e parole libere.

  • Registri di studi clinici: Clinicaltrials.gov, International Clinical Trials Registry Platform (ICTRP), Cochrane COVID-19 Register

Strategia di ricerca degli studi (adatta per MEDLINE-via OVID)

1

exp coronavirus/

2

((corona* or corono*) adj1 (virus* or viral* or virinae*)).ti,ab,kw.

3

(coronavirus* or coronovirus* or coronavirinae* or Coronavirus* or Coronovirus* or Wuhan* or Hubei* or Huanan or "2019-nCoV" or 2019nCoV or nCoV2019 or "nCoV-2019" or "COVID-19" or COVID19 or "CORVID-19" or CORVID19 or "WN-CoV" or WNCoV or "HCoV-19" or HCoV19 or CoV or "2019 novel*" or Ncov or "n-cov" or "SARS-CoV-2" or "SARSCoV-2" or "SARSCoV2" or "SARS-CoV2" or SARSCov19 or "SARS-Cov19" or "SARSCov-19" or "SARS-Cov-19" or Ncovor or Ncorona* or Ncorono* or NcovWuhan* or NcovHubei* or NcovChina* or NcovChinese*).ti,ab,kw.

4

(((respiratory* adj2 (symptom* or disease* or illness* or condition*)) or "seafood market*" or "food market*") adj10 (Wuhan* or Hubei* or China* or Chinese* or Huanan*)).ti,ab,kw.

5

((outbreak* or wildlife* or pandemic* or epidemic*) adj1 (China* or Chinese* or Huanan*)).ti,ab,kw.

6

"severe acute respiratory syndrome*".ti,ab,kw.

7

or/1-6

Selezione ed estrazione dei dati

 

Verranno selezionati gli studi ed estratti indipendentemente da due autori i seguenti dati:

  • Autore dello studio, anno di pubblicazione, disegno dello studio
  • Diagnosi, dimensione del campione, età media, genere, gravita della malattia, setting
  • Numero di pazienti assegnati a ciascun gruppo di trattamento, nome del farmaco, dosaggio, durata dell’intervento e periodo di follow up
  • Esiti primari e secondari

Valutazione della qualità globale degli studi

 

Per ogni singolo esito viene valutata la qualità (certezza) delle prove, considerando vari fattori quali:

  1. i possibili rischi di distorsione (bias) degli studi che contribuiscono a fornire informazioni su quell’esito;
  2. la variabilità (inconsistency) nelle stime di efficacia degli studi inclusi;
  3. la non diretta trasferibilità (indirectness) dei risultati al contesto di interesse;
  4. l’imprecisione quando gli studi includono pochi pazienti e/o si verificano pochi eventi;
  5. pubblicazione selettiva degli esiti, si tratta di una distorsione che si verifica quando la probabilità che un studio scientifico venga pubblicato dipende dal tipo di risultato.

 

La certezza delle prove viene sintetizzata in 4 livelli: alta, moderata, bassa, molto bassa.

Alto: Alto grado di certezza nei risultati. E’ molto improbabile che ulteriori studi possano cambiare la fiducia nella stima di effetto.

Moderato: Discreto grado di certezza nei risultati. È probabile che ulteriori studi possano confermare o cambiare la fiducia nella stima dell’effetto.

Basso: I risultati sono poco credibili. È necessaria ulteriore ricerca per ottenere stime affidabili sugli effetti positivi e negativi dell’intervento.

Molto basso: I dati esaminati sono inaffidabili. Non è possibile fare affidamento sulle stime di effetto disponibili.

Analisi statistica

 

In una prima fase verranno condotte, se possibile, meta-analisi pairwise per il confronto diretto tra due interventi. Nella meta-analisi:

  • Ogni studio è sintetizzato in una misura di effetto
  • Queste sintesi sono combinate in una stima di effetto globale che tiene in considerazione la quantità di informazioni disponibili per singolo studio
  • La misura di effetto complessivo consiste nell’effetto medio pesato dei risultati dei singoli studi
  • Si verifica se le variazioni dei risultati tra i vari studi sono più grandi di quelle attendibili in base al caso (eterogeneità)
  • I risultati della meta-analisi saranno presentati come dimensioni di effetto relativo usando il Rischio relativo (RR) o la Differenza tra medie standardizzata (SMD - a seconda che il dato sia dicotomico o continuo), con i relativi intervalli di confidenza al 95%, per ogni possibile coppia di trattamenti.

Network meta-analisi

  • La network meta-analisi (NMA), o meta-analisi a rete, è un metodo per sintetizzare le informazioni provenienti da una rete di studi scientifici che affrontano la stessa domanda ma che prevedono interventi diversi. Mentre una meta-analisi pairwise compara solo due confronti diretti, la NMA dispone a rete gli studi randomizzati, ed utilizza tutte le informazioni della rete, sia dirette che indirette, e può aumentare la precisione delle stime di effetto.
  • Nel nostro studio eseguiremo la NMA utilizzando un random effect model all'interno di un approccio «frequentista», assumendo un'uguale eterogeneità in tutti i confronti, e terremo conto delle correlazioni indotte da studi con più bracci. Il modello ci permetterà di stilare una classifica di quale sia il farmaco migliore per il trattamento del Covid-19. Eseguiremo la NMA in Stata 16 utilizzando il comando 'mvmeta' e le routine di Stata disponibili su www.mtm.uoi.gr. I risultati della meta-analisi e della NMA saranno applicati quando ragionevoli e presentati come dimensioni di effetto relativo sommario usando la odds ratio o la standardised mean difference (a seconda che il dato sia dicotomico o continuo), con i relativi intervalli di confidenza al 95%, per ogni possibile coppia di trattamenti.

Sintesi dei risultati

 

I dati verranno presentati in tabelle sinottiche in cui per ciascun esito vengono riassunti i risultati disponibili e viene valutata l’attendibilità/certezza delle prove presentate (alta, moderata, bassa, molto bassa).

Studi randomizzati inclusi


  1. Abbaspour Kasgari H, Moradi S, Shabani AM, Babamahmoodi F, Davoudi Badabi AR, Davoudi L, et al. Evaluation of the efficacy of sofosbuvir plus daclatasvir in combination with ribavirin for hospitalized COVID-19 patients with moderate disease compared with standard care: a single-centre, randomized controlled trial. J Antimicrob Chemother. 2020 Nov 1;75(11):3373-3378. doi: 10.1093/jac/dkaa332
  2. Abd-Elsalam S, Esmail ES, Khalaf M, Abdo EF, Medhat MA, Abd El Ghafar MS, et al. Hydroxychloroquine in the Treatment of COVID-19: A Multicenter Randomized Controlled Study. The American Journal of Tropical Medicine and Hygiene. 2020;103(4):1635-9.
  3. Abd-Elsalam S, Soliman S, Esmail ES, Khalaf M, Mostafa EF, Medhat MA, et al. Do Zinc Supplements Enhance the Clinical Efficacy of Hydroxychloroquine? a Randomized, Multicenter Trial. Biol Trace Elem Res. 2020 Nov 27. doi: 10.1007/s12011-020-02512-1 Epub ahead of print
  4. ACTIV-3/TICO LY-CoV555 Study Group, Lundgren JD, Grund B, Barkauskas CE, Holland TL, Gottlieb RL, Sandkovsky U, et al. A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19. N Engl J Med. 2020 Dec 22:NEJMoa2033130. doi: 10.1056/NEJMoa2033130. Epub ahead of print
  5. Ader F, Peiffer-Smadja N, Poissy J, Bouscambert-Duchamp M, Belhadi D, Diallo A, et al. Antiviral drugs in hospitalized patients with COVID-19 - the DisCoVeRy trial. medRxiv. 2021:2021.01.08.20248149
  6. Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P; PLACID Trial Collaborators. Convalescent plasma in the management of moderate covid-19 in adults in India: open label phase II multicentre randomised controlled trial (PLACID Trial). BMJ. 2020 Oct 22;371:m3939. doi: 10.1136/bmj.m3939 Erratum in: BMJ. 2020 Nov 3;371:m4232.
  7. Ahmed S, Karim MM, Ross AG, Hossain MS, Clemens JD, Sumiya MK, et al. A five-day course of ivermectin for the treatment of COVID-19 may reduce the duration of illness. Int J Infect Dis. 2020 Dec 2:S1201-9712(20)32506-6. doi: 10.1016/j.ijid.2020.11.191 Epub ahead of print
  8. AlQahtani M, Abdulrahman A, AlMadani A, AlAli SY, Al Zamrooni AM, Hejab A, et al. Randomized controlled trial of convalescent plasma therapy against standard therapy in patients with severe COVID-19 disease. medRxiv. 2020:2020.11.02.20224303.
  9. Angus DC, Derde L, Al-Beidh F, Annane D, Arabi Y, Beane A, et al. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA. 2020 Oct 6;324(13):1317-1329. doi: 10.1001/jama.2020.17022
  10. Ansarin K, Tolouian R, Ardalan M, Taghizadieh A, Varshochi M, Teimouri S, et al. Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial. Bioimpacts. 2020;10(4):209-215. doi: 10.34172/bi.2020.27 Epub 2020 Jul 19
  11. Avendano-Sola C, Ramos-Martinez A,Munez-Rubio E,et al.. Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial. medRxiv 2020.08.26.20182444; 2020
  12. Bajpai M, Kumar S, Maheshwari A, Chhabra K, kale P, Gupta A, et al. Efficacy of Convalescent Plasma Therapy compared to Fresh Frozen Plasma in Severely ill COVID-19 Patients: A Pilot Randomized Controlled Trial. medRxiv. 2020:2020.10.25.20219337
  13. Balykova LA, Granovskaya MV, Zaslavskaya KY, Simakina EN, Agaf'ina AS, Ivanova AY, et al. New possibilities for targeted antiviral therapy for COVID-19. Results of a multi center clinical study of the efficacy and safety of using the drug Areplivir. Infectious diseases: News, Opinions, Training. 2020;9:16-29
  14. Beigel JH, Tomashek KM, Dodd LE, Mehta AK, Zingman BS, Kalil AC, et al; ACTT-1 Study Group Members. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020 Nov 5;383(19):1813-1826. doi: 10.1056/NEJMoa2007764 Epub 2020 Oct 8
  15. Brown SM, Peltan ID, Webb B, Kumar N, Starr N, Grissom C, et al. Hydroxychloroquine versus Azithromycin for Hospitalized Patients with Suspected or Confirmed COVID-19 (HAHPS). Protocol for a Pragmatic, Open-Label, Active Comparator Trial. Ann Am Thorac Soc. 2020 Aug;17(8):1008-1015. doi: 10.1513/AnnalsATS.202004-309SD PMID: 32425051; PMCID: PMC7393787
  16. Cao B, Wang Y, Wen D, et al. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020;382(19):1787-1799. doi: 10.1056/NEJMoa2001282
  17. Cao Y, Wei J, Zou L, Jiang T, Wang G, Chen L, et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. J Allergy Clin Immunol. 2020 Jul;146(1):137-146.e3. doi: 10.1016/j.jaci.2020.05.019 Epub 2020 May 26
  18. Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, et al; Coalition Covid-19 Brazil I Investigators. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. N Engl J Med. 2020 Jul 23:NEJMoa2019014. doi: 10.1056/NEJMoa2019014 Epub ahead of print
  19. Chen C, Zhang Y, Huang J, Yin P, Cheng Z, Wu J, et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. medRxiv. 2020:2020.03.17.20037432.
  20. Chen C-P, Lin Y-C, Chen T-C, Tseng T-Y, Wong H-L, Kuo C-Y, 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). medRxiv. 2020:2020.07.08.20148841
  21. Chen J, Liu D, Liu L, Liu P, Xu Q, Xia L, et al. [A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19]. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020 May 25;49(2):215-219. Chinese. doi: 10.3785/j.issn.1008-9292.2020.03.03
  22. Chen J, Xia L, Liu L, Xu Q, Ling Y, Huang D, et al. Antiviral Activity and Safety of Darunavir/Cobicistat for the Treatment of COVID-19. Open Forum Infect Dis. 2020 Jun 21;7(7):ofaa241. doi: 10.1093/ofid/ofaa241
  23. Chen L, Zhang Z-y, Fu J-g, Feng Z-p, Zhang S-Z, Han Q-Y, et al. Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study. medRxiv. 2020:2020.06.19.20136093.
  24. Chen P, Nirula A, Heller B, Gottlieb RL, Boscia J, Morris J, et al; BLAZE-1 Investigators. SARS-CoV-2 Neutralizing Antibody LY-CoV555 in Outpatients with Covid-19. N Engl J Med. 2020 Oct 28:NEJMoa2029849. doi: 10.1056/NEJMoa2029849 Epub ahead of print
  25. Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. medRxiv. 2020:2020.03.22.20040758.
  26. Cheng LL, Guan WJ, Duan CY, Zhang NF, Lei CL, Hu Y, et al. Effect of Recombinant Human Granulocyte Colony-Stimulating Factor for Patients With Coronavirus Disease 2019 (COVID-19) and Lymphopenia: A Randomized Clinical Trial. JAMA Intern Med. 2020 Sep 10:e205503. doi: 10.1001/jamainternmed.2020.5503 Epub ahead of print
  27. Chowdhury AT, Shahbaz M Karim Md R et al. A Randomized Trial of Ivermectin-Doxycycline and Hydroxychloroquine-Azithromycin therapy on COVID19 patients.. PREPRINT (Version 1) available at Research Square doi: rs.3.rs-38896/v1+
  28. Corral L, Bahamonde A, Arnaiz delas Revillas F, Gomez-Barquero J, Abadia-Otero J, Garcia-Ibarbia C, et al. GLUCOCOVID: A controlled trial of methylprednisolone in adults hospitalized with COVID-19 pneumonia. medRxiv. 2020:2020.06.17.20133579
  29. Dabbous HM, El-Sayed MH,El Assal G,et al.. . A Randomized Controlled Study Of Favipiravir Vs Hydroxychloroquine In COVID-19 Management: What Have We Learned So Far?, 29 September 2020, PREPRINT (Version 1) available at Research Square doi: 10.21203/rs.3.rs-83677/v1+
  30. Davoudi-Monfared E, Rahmani H Khalili H al. et. Efficacy and safety of interferon beta-1a in treatment of severe COVID-19: A randomized clinical trial. medRxiv. doi: 10.1101/2020.05.28.20116467
  31. Deftereos SG, Giannopoulos G, Vrachatis DA, Siasos GD, Giotaki SG, Gargalianos P, et al; GRECCO-19 investigators. Effect of Colchicine vs Standard Care on Cardiac and Inflammatory Biomarkers and Clinical Outcomes in Patients Hospitalized with Coronavirus Disease 2019: The GRECCO-19 Randomized Clinical Trial. JAMA Netw Open. 2020 Jun 1;3(6):e2013136. doi: 10.1001/jamanetworkopen.2020.13136
  32. Dequin PF, Heming N, Meziani F, Plantefève G, Voiriot G, Badié Jet al; CAPE COVID Trial Group and the CRICS-TriGGERSep Network. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020 Oct 6;324(13):1298-1306. doi: 10.1001/jama.2020.16761
  33. Duarte M, Pelorosso FG, Nicolosi L, Salgado MV, Vetulli H, Aquieri A, et al. Telmisartan for treatment of Covid-19 patients: an open randomized clinical trial. Preliminary report. medRxiv. 2020:2020.08.04.20167205.
  34. Dubée V, Roy P-M, Vielle B, Parot-Schinkel E, Blanchet O, Darsonval A, et al. A placebo-controlled double blind trial of hydroxychloroquine in mild-to-moderate COVID-19. medRxiv. 2020:2020.10.19.20214940.
  35. Edalatifard M, Akhtari M, Salehi M, Naderi Z, Jamshidi A, Mostafaei S, et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. Eur Respir J. 2020 Sep 17:2002808. doi: 10.1183/13993003.02808-2020 Epub ahead of print
  36. Entrenas Castillo M, Entrenas Costa LM, Vaquero Barrios JM, Alcalá Díaz JF, López Miranda J, Bouillon R, Quesada Gomez JM. "Effect of calcifediol treatment and best available therapy versus best available therapy on intensive care unit admission and mortality among patients hospitalized for COVID-19: A pilot randomized clinical study". J Steroid Biochem Mol Biol. 2020 Oct;203:105751. doi: 10.1016/j.jsbmb.2020.105751 Epub 2020 Aug 29
  37. Esquivel-Moynelo I, Perez-Escribano J, Duncan-Robert Y, Vazquez-Blonquist D, Bequet-Romero M et al. Effect and safety of combination of interferon alpha-2b and gamma or interferon alpha-2b for negativization of SARS-CoV-2 viral RNA. Preliminary results of a randomized controlled clinical trial. medRxiv preprint doi: 10.1101/2020.07.29.20164251
  38. Furtado RHM, Berwanger O, Fonseca HA, Corrêa TD, Ferraz LR, Lapa M, et al; COALITION COVID-19 Brazil II Investigators. Azithromycin in addition to standard of care versus standard of care alone in the treatment of patients admitted to the hospital with severe COVID-19 in Brazil (COALITION II): a randomised clinical trial. Lancet. 2020 Oct 3;396(10256):959-967. doi: 10.1016/S0140-6736(20)31862-6 Epub 2020 Sep 5
  39. Gharbharan A, Jordans C E, Geurtsvan K, den Hollander J, Karim F, Mollema FP, et al. Convalescent Plasma for COVID-19. A randomized clinical trial. medRxiv 2020 doi: 10.1101/2020.07.01.20139857
  40. Gharebaghi N, Nejadrahim R, Mousavi SJ, Sadat-Ebrahimi SR, Hajizadeh R. The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: a randomized placebo-controlled double-blind clinical trial. BMC Infect Dis. 2020 Oct 21;20(1):786. doi: 10.1186/s12879-020-05507-4 Erratum in: BMC Infect Dis. 2020 Nov 26;20(1):895.
  41. Gonzalez-Ochoa AJ, Raffetto JD, Hernández AG, Zavala N, Gutiérrez O, Vargas A, et al. Sulodexide in the treatment of patients with early stages of COVID-19: a randomized controlled trial. medRxiv 2020:2020.12.04.20242073
  42. Gordon AC, Mouncey PR, Al-Beidh F, Rowan KM, Nichol AD, Arabi YM, et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 – Preliminary report. medRxiv. 2021:2021.01.07.21249390
  43. Guvenmez O, Keskin H, Ay B, Birinci S, Kanca MF. The comparison of the effectiveness of lincocin® and azitro® in the treatment of covid-19-associated pneumonia: A prospective study. J Popul Ther Clin Pharmacol. 2020 Jun 3;27(S Pt 1):e5-e10. doi: 10.15586/jptcp.v27iSP1.684
  44. Hashim HA, Maulood MF, Rasheed AM, Fatak DF, Kabah KK, Abdulamir AS. Controlled randomized clinical trial on using Ivermectin with Doxycycline for treating COVID-19 patients in Baghdad, Iraq. medRxiv. 2020:2020.10.26.20219345
  45. Hermine O, Mariette X, Tharaux PL, Resche-Rigon M, Porcher R, Ravaud P; CORIMUNO-19 Collaborative Group. Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2020 Oct 20:e206820. doi: 10.1001/jamainternmed.2020.6820 Epub ahead of print.
  46. Huang M, Tang T, Pang P, Li M, Ma R, Lu J, et al. Treating COVID-19 with Chloroquine. J Mol Cell Biol. 2020 May 18;12(4):322-325. doi: 10.1093/jmcb/mjaa014
  47. Huang YQ, Tang SQ, Xu XL, et al. No Statistically Apparent Difference in Antiviral Effectiveness Observed Among Ribavirin Plus Interferon-Alpha, Lopinavir/Ritonavir Plus Interferon-Alpha, and Ribavirin Plus Lopinavir/Ritonavir Plus Interferon-Alpha in Patients with Mild to Moderate Coronavirus Disease 2019: Results of a Randomized, Open-Labeled Prospective Study. Front Pharmacol. 2020;11:1071. Published 2020 Jul 14. doi: 10.3389/fphar.2020.01071
  48. Hung IF, Lung KC, Tso EY, Liu R, Chung TW, Chu MY, et al. Triple combination of interferon beta-1b, lopinavir-ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. Lancet. 2020 May 30;395(10238):1695-1704. doi: 10.1016/S0140-6736(20)31042-4 Epub 2020 May 10
  49. Ivashchenko AA, Dmitriev KA, Vostokova NV, et al. AVIFAVIR for Treatment of Patients with Moderate COVID-19: Interim Results of a Phase II/III Multicenter Randomized Clinical Trial [published online ahead of print, 2020 Aug 9]. Clin Infect Dis. 2020;ciaa1176. doi: 10.1093/cid/ciaa1176
  50. Jagannathan P, Andrews JR, Bonilla H, Hedlin H, Jacobson KB, Balasubramanian V, et al. Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial. medRxiv. 2020:2020.11.18.20234161.
  51. Jeronimo CMP, Farias MEL, Val FFA, Sampaio VS, Alexandre MAA, Melo GCet al, for the Metcovid Team. Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With COVID-19 (Metcovid): A Randomised, Double-Blind, Phase IIb, Placebo-Controlled Trial. Clin Infect Dis. 2020 Aug 12:ciaa1177. doi: 10.1093/cid/ciaa1177 Epub ahead of print
  52. Kalil AC, Patterson TF, Mehta AK, Tomashek KM, Wolfe CR, Ghazaryan V, et al. Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19. N Engl J Med. 2020 Dec 11:NEJMoa2031994. doi: 10.1056/NEJMoa2031994 Epub ahead of print.
  53. Kamran SM, Mirza Z-e-H, Naseem A, Azam R, Ullah N, Saeed F, et al. Clearing the fog: Is Hydroxychloroquine effective in reducing Corona virus disease-2019 progression: A randomized controlled trial. medRxiv. 2020:2020.07.30.20165365.
  54. Khamis F, Al Naabi H, Al Lawati A, Ambusaidi Z, Al Sharji M, Al Barwani U, et al. Randomized Controlled Open Label Trial on the Use of Favipiravir Combined with Inhaled Interferon beta-1b in Hospitalized Patients with Moderate to Severe COVID-19 Pneumonia. Int J Infect Dis. 2020 Nov 9:S1201-9712(20)32319-5. doi: 10.1016/j.ijid.2020.11.008 Epub ahead of print. PMID: 33181328.
  55. Krolewiecki AJ, Lifschitz A, Moragas M, Travacio M, Valentini R, Alonso DF, et al. Antiviral Effect of High-Dose Ivermectin in Adults with COVID-19: A Pilot Randomised, Controlled, Open Label, Multicentre Trial. 2020. Available at SSRN: https://ssrn.com/abstract=3714649 or http://dx.doi.org/10.2139/ssrn.3714649
  56. Kumar S, de Souza R, Nadkar M, Guleria R, Trikha A, Joshi SR, et al. A two-arm, randomized, controlled, multi-centric, open-label Phase-2 study to evaluate the efficacy and safety of Itolizumab in moderate to severe ARDS patients due to COVID-19. medRxiv. 2020:2020.12.01.20239574.
  57. Lanzoni G, Linetsky E, Correa D, Messinger Cayetano S, Alvarez RA, Kouroupis D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl Med. 2021 Jan 5. doi: 10.1002/sctm.20-0472. Epub ahead of print
  58. Lemos ACB, do Espírito Santo DA, Salvetti MC, Gilio RN, Agra LB, Pazin-Filho A, Miranda CH. Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID). Thromb Res. 2020 Dec;196:359-366. doi: 10.1016/j.thromres.2020.09.026. Epub 2020 Sep 21
  59. Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, et al. Fluvoxamine vs Placebo and Clinical Deterioration in Outpatients with Symptomatic COVID-19: A Randomized Clinical Trial. JAMA. 2020 Nov 12. doi: 10.1001/jama.2020.22760 Epub ahead of print. PMID: 33180097
  60. Li L, Zhang W, Hu Y, Tong X, Zheng S, Yang J, et al. Effect of Convalescent Plasma Therapy on Time to Clinical Improvement in Patients With Severe and Life-threatening COVID-19: A Randomized Clinical Trial. JAMA. 2020 Aug 4;324(5):460-470. doi: 10.1001/jama.2020.10044 Erratum in: JAMA. 2020 Aug 4;324(5):519.
  61. Li T, Sun L, Zhang W, Zheng C, Jiang C, Chen M, et al. Bromhexine Hydrochloride Tablets for the Treatment of Moderate COVID-19: An Open-Label Randomized Controlled Pilot Study. Clin Transl Sci. 2020 Sep 3. doi: 10.1111/cts.12881 Epub ahead of print
  62. Li Y, Xie Z, Lin W, et al. Efficacy and Safety of Lopinavir/Ritonavir or Arbidol in Adult Patients with Mild/Moderate COVID-19: An Exploratory Randomized Controlled Trial [published online ahead of print, 2020 May 19]. Med (N Y). 2020; doi: 10.1016/j.medj.2020.04.001
  63. Libster R, Marc GP, Wappner D, Coviello S, Bianchi A, Braem V, et al. Prevention of severe COVID-19 in the elderly by early high-titer plasma. medRxiv. 2020:2020.11.20.20234013.
  64. Liesenborghs L, Spriet I, Jochmans D, Belmans A, Gyselinck I, Teuwen L-A, et al. Itraconazole for COVID-19: Preclinical Studies and a Proof-of-Concept Pilot Clinical Study. SSRN Electronic Journal. 2020
  65. Lopes MIF, Bonjorno LP, Giannini MC, Amaral NB, Benatti MN, Rezek UC, et al. Beneficial effects of colchicine for moderate to severe COVID-19: an interim analysis of a randomized, double-blinded, placebo controlled clinical trial. medRxiv. 2020:2020.08.06.20169573.
  66. Lou Y, Liu L, Yao H, et al. Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: An Exploratory Randomized, Controlled Trial. medRxiv doi: 10.1101/2020.04.29.20085761
  67. Maldonado V, Hernandez-Ramírez C, Oliva-Pérez EA, Sánchez-Martínez CO, Pimentel-González JF, Molina-Sánchez JR, et al. Pentoxifylline decreases serum LDH levels and increases lymphocyte count in COVID-19 patients: Results from an external pilot study. International Immunopharmacology. 2021;90:107209.
  68. Mansour E, Palma AC, Ulaf RG, Ribeiro LC, Bernardes AF, Nunes TA, et al. Pharmacological inhibition of the kinin-kallikrein system in severe COVID-19 A proof-of-concept study. medRxiv. 2020:2020.08.11.20167353.
  69. Mehboob R, Ahmad F, Qayyum A, Rana MA, Gilani SA, Tariq MA, et al. Aprepitant as a combinant with Dexamethasone reduces the inflammation via Neurokinin 1 Receptor Antagonism in severe to critical Covid-19 patients and potentiates respiratory recovery: A novel therapeutic approach. medRxiv. 2020:2020.08.01.20166678.
  70. Miller J, Bruen C, Schnaus M, Zhang J, Ali S, Lind A, et al. Auxora versus standard of care for the treatment of severe or critical COVID-19 pneumonia: results from a randomized controlled trial. Crit Care. 2020 Aug 14;24(1):502. doi: 10.1186/s13054-020-03220-x
  71. Mitjà O, Corbacho-Monné M, Ubals M, Tebe C, Peñafiel J, Tobias Aet al; BCN PEP-CoV-2 RESEARCH GROUP. Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial. Clin Infect Dis. 2020 Jul 16:ciaa1009. doi: 10.1093/cid/ciaa1009 Epub ahead of print
  72. Monk PD, Marsden RJ, Tear VJ, Brookes J, Batten TN, Mankowski M, et al; Inhaled Interferon Beta COVID-19 Study Group. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med. 2020 Nov 12:S2213-2600(20)30511-7. doi: 10.1016/S2213-2600(20)30511-7 Epub ahead of print
  73. Morteza SN, Nematollah G,Peyman N, Abbas A, Leila Z, Amir Jet al. Ivermectin as an adjunct treatment for hospitalized adult COVID-19 patients: A randomized multi-center clinical trial.. PREPRINT (Version 1) available at Research Square 10.21203/rs.3.rs-109670/v1
  74. Nojomi M, Yasin Z, Keyvani H, Makiani MJ, Roham M, Laali A et al. Effect of Arbidol on COVID-19: A Randomized Controlled Trial. Research Square; 2020. 10.21203/rs.3.rs-78316/v1
  75. Omrani AS, Pathan SA, Thomas SA, Harris TRE, Coyle PV, Thomas CE, et al. Randomized double-blinded placebo-controlled trial of hydroxychloroquine with or without azithromycin for virologic cure of non-severe Covid-19. E Clinical Medicine. 2020 Dec;29:100645. doi: 10.1016/j.eclinm.2020.100645 Epub 2020 Nov 20
  76. Rahmani H, Davoudi-Monfared E, Nourian A, Khalili H, Hajizadeh N, Jalalabadi NZ, et al. Interferon β-1b in treatment of severe COVID-19: A randomized clinical trial. Int Immunopharmacol. 2020 Nov;88:106903. doi: 10.1016/j.intimp.2020.106903 Epub 2020 Aug 24
  77. Ray Y, Paul SR, Bandopadhyay P, D’Rozario R, Sarif J, Lahiri A, et al. Clinical and immunological benefits of convalescent plasma therapy in severe COVID-19: insights from a single center open label randomised control trial. medRxiv. 2020:2020.11.25.20237883.
  78. RECOVERY Trial:
    1. a. Horby P, Mafham M, Linsell L, Bell JL, Staplin N, Emberson JR, et al. Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial. medRxiv. 2020:2020.07.15.20151852.;
    2. b. Horby PW, Mafham M,Bell JL,et al, RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2020 Oct 5:S0140-6736(20)32013-4. doi: 10.1016/S0140-6736(20)32013-4. Epub ahead of print;
    3. c. Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, Linsell L, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report. N Engl J Med. 2020 Jul 17:NEJMoa2021436. doi: 10.1056/NEJMoa2021436. Epub ahead of print. PMID: 32678530; PMCID: PMC7383595;
    4. d. Horby PW, Roddick A, Spata E, Staplin N, Emberson JR, Pessoa-Amorim G, et al. Azithromycin in Hospitalised Patients with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. medRxiv. 2020:2020.12.10.20245944.
  79. Ren Z, Luo H, Yu Z, Song J, Liang L, Wang L, et al. A Randomized, Open-label, Controlled Clinical Trial of Azvudine Tablets in the Treatment of Mild and Common COVID-19, A Pilot Study. Adv Sci (Weinh). 2020 Jul 14;7(19):2001435. doi: 10.1002/advs.202001435 Epub ahead of print
  80. Rocco PRM, Silva PL, Cruz FF, Junior MACM, Tierno PF, Moura MA, et al. Early use of nitazoxanide in mild Covid-19 disease: randomized, placebo-controlled trial. medRxiv. 2020:2020.10.21.20217208.
  81. Rosas I, Bräu N,Waters M,et al.. Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia. medRxiv 2020.08.27.20183442; 2020.
  82. Ruzhentsova T, Chukhliaev P, Khavkina D, Garbuzov A, Oseshnyuk R, Soluyanova T, et al. Phase 3 Trial of Coronavir (Favipiravir) in Patients with Mild to Moderate COVID-19. Available at SSRN: https://ssrn.com/abstract=3696907 or http://dx.doi.org/10.2139/ssrn.3696907
  83. Sadeghi A, Ali Asgari A, Norouzi A, Kheiri Z, Anushirvani A, Montazeri M, et al. Sofosbuvir and daclatasvir compared with standard of care in the treatment of patients admitted to hospital with moderate or severe coronavirus infection (COVID-19): a randomized controlled trial. J Antimicrob Chemother. 2020 Nov 1;75(11):3379-3385. doi: 10.1093/jac/dkaa334
  84. Sakoulas G, Geriak M, Kullar R, Greenwood KL, Habib M, Vyas Aet al. Intravenous Immunoglobulin Plus Methylprednisolone Mitigate Respiratory Morbidity in Coronavirus Disease 2019. Crit Care Explor. 2020 Nov 16;2(11):e0280. doi: 10.1097/CCE.0000000000000280
  85. Salama C, Han J, Yau L, Reiss WG, Kramer B, Neidhart JD, et al. Tocilizumab in nonventilated patients hospitalized with Covid-19 pneumonia. medRxiv. 2020:2020.10.21.20210203
  86. Salvarani C, Dolci G, Massari M, Merlo DF, Cavuto S, Savoldi L, et al; RCT-TCZ-COVID-19 Study Group. Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2020 Oct 20:e206615. doi: 10.1001/jamainternmed.2020.6615
  87. Self WH, Semler MW, Leither LM, Casey JD, Angus DC, Brower RG, et al, and Blood Institute PETAL Clinical Trials Network. Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial. JAMA. 2020 Dec 1;324(21):2165-2176. doi: 10.1001/jama.2020.22240
  88. Sekhavati E, Jafari F, SeyedAlinaghi S, Jamalimoghadamsiahkali S, Sadr S, Tabarestani M, et al. Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial. Int J Antimicrob Agents. 2020 Oct;56(4):106143. doi: 10.1016/j.ijantimicag.2020 Epub 2020 Aug 25
  89. Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R, et al. Treatment with human umbilical cord-derived mesenchymal stem cells for COVID-19 patients with lung damage: a randomised, double-blind, placebo-controlled phase 2 trial. medRxiv. 2020:2020.10.15.20213553.
  90. Shu L, Niu C, Li R, Huang T, Wang Y, Huang M, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. Stem Cell Res Ther. 2020 Aug 18;11(1):361. doi: 10.1186/s13287-020-01875-5.
  91. Simonovich VA, Burgos Pratx LD, Scibona P, Beruto MV, Vallone MG, Vázquez C, et al; PlasmAr Study Group. A Randomized Trial of Convalescent Plasma in Covid-19 Severe Pneumonia. N Engl J Med. 2020 Nov 24. doi: 10.1056/NEJMoa2031304 Epub ahead of print
  92. Spinner CD, Gottlieb RL, Criner GJ, Arribas López JR, Cattelan AM, Soriano Viladomiu A, et al; GS-US-540-5774 Investigators. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial. JAMA. 2020 Sep 15;324(11):1048-1057. doi: 10.1001/jama.2020.16349
  93. Tabarsi P, Barati S, Jamaati H, Haseli S, Marjani M, Moniri A, et al. Evaluating the effects of Intravenous Immunoglobulin (IVIg) on the management of severe COVID-19 cases: A randomized controlled trial. Int Immunopharmacol. 2020 Nov 13:107205. doi: 10.1056/NEJMoa2028836 Epub ahead of print
  94. Tabarsi P, Barati S, Jamaati H, Haseli S, Marjani M, Moniri A, et al. Evaluating the effects of Intravenous Immunoglobulin (IVIg) on the management of severe COVID-19 cases: A randomized controlled trial. Int Immunopharmacol. 2020 Nov 13:107205. doi: 10.1016/j.intimp.2020.107205 Epub ahead of print
  95. Tang W, Cao Z, Han M, Wang Z, Chen J, Sun W, et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020 May 14;369:m1849. doi: 10.1136/bmj.m1849
  96. Tomazini BM, Maia IS, Cavalcanti AB, Berwanger O, Rosa RG, Veiga VC, et al; COALITION COVID-19 Brazil III Investigators. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA. 2020 Oct 6;324(13):1307-1316. doi: 10.1001/jama.2020.17021
  97. Udwadia ZF, Singh P, Barkate H, Patil S, Rangwala S, Pendse A, et al. Efficacy and Safety of Favipiravir, an Oral RNA-Dependent RNA Polymerase Inhibitor, in Mild-to-Moderate COVID-19: A Randomized, Comparative, Open-Label, Multicenter, Phase 3 Clinical Trial. Int J Infect Dis. 2020 Nov 16:S1201-9712(20)32453-X. doi: 10.1016/j.ijid.2020.11.142 Epub ahead of print
  98. Ulrich RJ, Troxel AB, Carmody E, Eapen J, Bäcker M, DeHovitz JA, et al. Treating COVID-19 With Hydroxychloroquine (TEACH): A Multicenter, Double-Blind Randomized Controlled Trial in Hospitalized Patients, Open Forum Infectious Diseases, Volume 7, Issue 10, October 2020, ofaa446 doi: 10.1093/ofid/ofaa446
  99. Vlaar APJ, de Bruin S, Busch M, Timmermans SAMEG, van Zeggeren IE, Koning R, et al. Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial. Lancet Rheumatol. 2020 Dec;2(12):e764-e773. doi: 10.1016/S2665-9913(20)30341-6 Epub 2020 Sep 28
  100. Wang D, Fu B, Peng Z, Yang D, Han M, Li M, et al. Tocilizumab Ameliorates the Hypoxia in COVID-19 Moderate Patients with Bilateral Pulmonary Lesions: A Randomized, Controlled, Open-Label, Multicenter Trial. SSRN Electronic Journal. 2020. Available at SSRN: https://ssrn.com/
  101. Wang M, Zhao Y, Hu W, Zhao D, Zhang Y, Wang T, et al Treatment of COVID-19 Patients with Prolonged Post-Symptomatic Viral Shedding with Leflunomide -- a Single-Center, Randomized, Controlled Clinical Trial. Clin Infect Dis. 2020 Sep 21:ciaa1417. doi: 10.1093/cid/ciaa1417 Epub ahead of print
  102. Wang Y, Zhang D, Du G, Du R, Zhao J, Jin Y, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020 May 16;395(10236):1569-1578. doi: 10.1016/S0140-6736(20)31022-9 Epub 2020 Apr 29. Erratum in: Lancet. 2020 May 30;395(10238):1694
  103. WHO Solidarity Trial Consortium, Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Qet al. Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results. N Engl J Med. 2020 Dec 2. doi: 10.1056/NEJMoa2023184 Epub ahead of print
  104. Wu X, Yu K, Wang Y, Xu W, Ma H, Hou Y, et al. Efficacy and safety of triazavirin therapy for coronavirus disease 2019: A pilot randomized controlled trial. Engineering (Beijing). 2020 Sep 8. doi: 10.1016/j.eng.2020.08.011 Epub ahead of print
  105. Yakoot M, Eysa B,Gouda E, Hill A, Helmy SA, Elsayed MR,et al. Efficacy and Safety of Sofosbuvir/Daclatasvir in the Treatment of COVID-19: A Randomized, Controlled Study. Available at SSRN: https://ssrn.com/abstract=3705289 or http://dx.doi.org/10.2139/ssrn.3705289
  106. Zhao H, Zhu Q, Zhang C, Li J, Wei M, Qin Y, et al. Tocilizumab combined with favipiravir in the treatment of COVID-19: A multicenter trial in a small sample size. Biomedicine & Pharmacotherapy. 2021;133:110825 doi: 10.1016/j.biopha.2020.110825
  107. Zheng F, Zhou Y, Zhou Z, Ye F, Huang B, Huang Y, et al. SARS-CoV-2 clearance in COVID-19 patients with Novaferon treatment: A randomized, open-label, parallel-group trial. Int J Infect Dis. 2020 Oct;99:84-91. doi: 10.1016/j.ijid.2020.07.053 Epub 2020 Aug 3

Studi esclusi e motivo di esclusione


Studio Motivo di esclusione
Abdelalim 2021 Tipo di confronto ed esiti che non rientrano nei criteri di inclusione
Altay 2020 Tipo di esiti che non rientrano nei criteri di inclusione
Amat Santos 2020 Tipo di popolazione che non rientra nei criteri di inclusione: pazienti con stenosi aortica a rischio COVID-19
Balcells 2020 Tipo di confronto che non rientra nei criteri di inclusione: stesso trattamento in tempi diversi
Balykova 2020b Articolo in cirillico
Barnabas 2020 Tipo di popolazione che non rientra nei criteri di inclusione: contatto con una persona con una recente infezione nota di SARS-CoV-2.
Borba 2020 Tipo di confronto che non rientra nei criteri di inclusione: stesso farmaco a dosaggi diversi.
Cadegiani 2020a Tipo di disegno di studio che non rientra nei criteri di inclusione: studio non randomizzato
Cadegiani 2020b Tipo di esiti che non rientrano nei criteri di inclusione
Cohen 2021 Tipo di confronto che non rientra ne criteri di inclusione
Cruz 2020 Tipo di esiti che non rientrano nei criteri di inclusione.
Davoodi 2020 Tipo di popolazione che non rientra nei criteri di inclusione: COVID-19 sospetta e non confermata e tipo di esiti.
Delgado-Enciso 2020 Tipo di intervento che non rientra nei criteri di inclusione
de Alencar 2020 Tipo di popolazione che non rientra nei criteri di inclusione: parte dei partecipanti con COVID-19 sospetta e non confermata
Doi 2020 Tipo di confronto che non rientra nei criteri di inclusione: stesso trattamento in tempi diversi
Duarte Silveira 2021 Tipo di intervento che non rientra nei criteri di inclusione
Farahani 2020 Tipo di esiti che non rientrano nei criteri di inclusione.
Fu 2020 Tipo di esiti che non rientrano nei criteri di inclusione.
Ghaderkhani 2020 Tipo di esiti che non rientrano nei criteri di inclusione.
Goldman 2020 Tipo di confronto che non rientra nei criteri di inclusione: stesso farmaco somministrato per durate diverse
Hemila 2020 Tipo di popolazione che non rientra nei criteri di inclusione
Ibrahim 2020 Tipo di disegno di studio che non rientra nei criteri di inclusione: studio non randomizzato
Lemos 2020 Tipo di popolazione che non rientra nei criteri di inclusione
Lyngbakken 2020 Tipo di esiti che non rientrano nei criteri di inclusione.
MeiLan 2020 Nessun dato utilizzabile
Mitjà 2020b Tipo di popolazione che non rientra nei criteri di inclusione: storia recente di esposizione a contatto ravvicinato a un paziente con Covid-19 con un caso confermato dalla PCR
Padmanabham 2020 Tipo di intervento che non rientra nei criteri di inclusione
Painter 2020 Tipo di popolazione ed esiti che non rientrano nei criteri di inclusione
Podder 2020 Dati non utilizzabili.
Rastogi 2020 Tipo di popolazione: pazienti con deficit di vitamina D e tipo di intervento: non farmacologico vitamina D
Roozbeh 2020 Tipo di esiti che non rientrano nei criteri di inclusione
Sigamani 2020 Tipo di disegno di studio: studio di fattibilità di un RCT
Skipper 2020 Tipo di popolazione che non rientra nei criteri di inclusione: mista con sospetti COVID-19 non confermati e tipo di esiti
Wang 2020 Tipo di disegno di studio che non rientra nei criteri di inclusione: studio non randomizzato
Yadegarinia 2020 Tipo di disegno di studio che non rientra nei criteri di inclusione: studio non randomizzato
Zhong 2020 Tipo di intervento che non rientra nei criteri di inclusione: acido α-lipoico

 

 

Bibliografia studi esclusi

 

  1. Abdelalim AA, Mohamady AA, Elsayed RA, Elawady MA, Ghallab AF. Corticosteroid nasal spray for recovery of smell sensation in COVID-19 patients: A randomized controlled trial. Am J Otolaryngol. 2021 Jan 4;42(2):102884. doi: 10.1016/j.amjoto.2020.102884. Epub ahead of print.
  2. Alltay O, Yang H, Aydin M, Alkurt G, Altunal LN, Kim W, et al. Combined metabolic cofactor supplementation accelerates recovery in mild-to-moderate COVID-19. medRxiv. 2020:2020.10.02.20202614.
  3. Amat-Santos IJ, Santos-Martinez S, López-Otero D, et al. Ramipril in High-Risk Patients With COVID-19. J Am Coll Cardiol. 2020;76(3):268-276. doi:10.1016/j.jacc.2020.05.040
  4. Balcells ME, Rojas L, Le Corre N, Martínez-Valdebenito C, Ceballos ME, Ferrés M, et al. Early Anti-SARS-CoV-2 Convalescent Plasma in Patients Admitted for COVID-19: A Randomized Phase II Clinical Trial. medRxiv. 2020:2020.09.17.20196212.
  5. Balykova LA, Govorov AV, Vasilyev AO, Simakina EN, Agafyina AS, Ivanova AYu, et al. Characteristics of COVID-19 and possibilities of early causal therapy. Results of favipiravir use in clinical practice. Infekc. bolezni (Infectious diseases). 2020; 18(3): 30–40. (In Russian). doi: 10.20953/1729-9225-2020-3-30-40
  6. Barnabas RV, Brown ER, Bershteyn A, Stankiewicz Karita HC, Johnston C, Thorpe LE, et al. Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial. Ann Intern Med. 2020 Dec 8:M20-6519. doi: 10.7326/M20-6519. Epub ahead of print. PMID: 33284679; PMCID: PMC7732017.
  7. Borba MGS, Val FFA, Sampaio VS, et al. Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. JAMA Netw Open. 2020;3(4):e208857. Published 2020 Apr 24. doi: https://doi.org/10.1001/jamanetworkopen.2020.8857
  8. Cadegiani FA, Goren A, Wambier CG, McCoy J. Early COVID-19 Therapy with Azithromycin Plus Nitazoxanide, Ivermectin or Hydroxychloroquine in Outpatient Settings Significantly Reduced Symptoms Compared to Known Outcomes in Untreated Patients. medRxiv 2020.10.31.20223883; doi: https://doi.org/10.1101/2020.10.31.20223883.
  9. Cadegiani FA, McCoy J, Wambier CG, et al. 5-Alpha-Reductase Inhibitors Reduce Remission Time of COVID-19: Results From a Randomized Double Blind Placebo Controlled Interventional Trial in 130 SARS-CoV-2 Positive Men. medRxiv 2020.11.16.20232512; doi: https://doi.org/10.1101/2020.11.16.20232512
  10. Cohen JB, Hanff TC, William P, Sweitzer N, Rosado-Santander NR, Medina C, et al. Continuation versus discontinuation of renin-angiotensin system inhibitors in patients admitted to hospital with COVID-19: a prospective, randomised, open-label trial. Lancet Respir Med. 2021 Jan 7:S2213-2600(20)30558-0. doi: 10.1016/S2213-2600(20)30558-0. Epub ahead of print.
  11. Cruz LR, Baladron I, Rittoles A, Diaz PA, Valenzuela C, Santana R, et al. Treatment with an Anti-CK2 Synthetic Peptide Improves Clinical Response in Covid-19 Patients with Pneumonia. A Randomized and Controlled Clinical Trial. medRxiv. 2020:2020.09.03.20187112.
  12. Davoodi L, Abedi SM, Salehifar E, et al. Febuxostat therapy in outpatients with suspected COVID-19: A clinical trial [published online ahead of print, 2020 Jun 30]. Int J Clin Pract. 2020;e13600. doi:10.1111/ijcp.13600.
  13. Delgado-Enciso I, Paz-Garcia J, Barajas-Saucedo CE, Mokay-Ramírez KA, Meza-Robles C, Lopez-Flores R, et al. Patient-Reported Health Outcomes After Treatment of COVID-19 with Nebulized and/or Intravenous Neutral Electrolyzed Saline Combined with Usual Medical Care Versus Usual Medical care alone: A Randomized, Open-Label, Controlled Trial. Res Sq [Preprint]. 2020 Sep 10:rs.3.rs-68403. doi: 10.21203/rs.3.rs-68403/v1. PMID: 32935090; PMCID: PMC7491578
  14. de Alencar JCG, Moreira CdL, Müller AD, Chaves CE, Fukuhara MA, da Silva EA, et al. Double-blind, randomized, placebo-controlled trial with N-acetylcysteine for treatment of severe acute respiratory syndrome caused by COVID-19. Clinical Infectious Diseases. 2020.
  15. Doi 2020
    • - Doi Y, Hibino M, Hase R, Yamamoto M, Kasamatsu Y, Hirose M, et al. A prospective, randomized, open-label trial of early versus late favipiravir in hospitalized patients with COVID-19. Antimicrobial Agents and Chemotherapy. 2020:AAC.01897-20.
    • - Doi Y, Hibino M, Hase R, Yamamoto M, Kasamatsu Y, Hirose M, et al. A Prospective, Randomized, Open-Label Trial of Early versus Late Favipiravir Therapy in Hospitalized Patients with COVID-19. Antimicrob Agents Chemother. 2020 Nov 17;64(12):e01897-20. doi: 10.1128/AAC.01897-20. PMID: 32958718; PMCID: PMC7674035.
  16. Duarte Silveira MA, De Jong D, Batista dos Santos Galvão E, Caldas Ribeiro J, Cerqueira Silva T, Aparecida Berretta A, et al. for the BeeCovid Team Efficacy of propolis as an adjunct treatment for hospitalized COVID-19 patients: a randomized, controlled clinical trial medRxiv 2021.01.08.20248932; doi: https://doi.org/10.1101/2021.01.08.20248932
  17. Farahani RM, Mosaed R, Nezami-Asl A, et al. Evaluation of the Efficacy of Methylprednisolone Pulse Therapy in Treatment of Covid-19 Adult Patients with Severe Respiratory Failure: Randomized, Clinical Trial, 09 September 2020, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-66909/v1
  18. Fu W, Liu Y, Liu L, Hu H, Cheng X, Liu P, et al. An open-label, randomized trial of the combination of IFN-κ plus TFF2 with standard care in the treatment of patients with moderate COVID-19. EClinicalMedicine.
  19. Ghaderkhani S, Arezoo, Salami A, Emadi H, Hossein, Sayed, et al. Efficacy and Safety of Arbidol in Treatment of Patients with COVID-19 Infection: A Randomized Clinical Trial2020.
  20. Goldman JD, Lye DCB, Hui DS, et al. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19 [published online ahead of print, 2020 May 27]. N Engl J Med. 2020;NEJMoa2015301. doi:10.1056/NEJMoa2015301.
  21. Hemilä H, Chalker E. Carrageenan nasal spray may double the rate of recovery from coronavirus and influenza virus infections: re-analysis of randomized trial data, 16 November 2020, PREPRINT (Version 1) available at Research Square [+https://doi.org/10.21203/rs.3.rs-108775/v1+]
  22. Ibrahim D, Dulipsingh L, Zapatka L, et al. Factors Associated with Good Patient Outcomes Following Convalescent Plasma in COVID-19: A Prospective Phase II Clinical Trial. medRxiv. 2020:2020.08.27.20183293.
  23. Lemos ACB, do Espírito Santo DA, Salvetti MC, Gilio RN, Agra LB, Pazin-Filho A, et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: A randomized phase II clinical trial (HESACOVID). Thrombosis Research. 2020;196:359-66.
  24. Lyngbakken, M.N., Berdal, J., Eskesen, A. et al. A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics. Nat Commun 11, 5284 (2020). https://doi.org/10.1038/s41467-020-19056-6
  25. MeiLan K, Bender Ignacio RA, RUXCOVID: A phase 3, randomized, placebo-controlled study evaluating the efficacy and safety of ruxolitinib in patients with COVID-19–associated cytokine storm. American Association for Cancer Research. 2020;26(18):Supplement, pp. PO-002. doi: https://doi.org/10.1158/1557-3265.COVID-19-PO-002.
  26. Mitjà O, Corbacho-Monné M, Ubals M, Alemany A, Suñer C, Tebé C, et al; BCN-PEP-CoV2 Research Group. A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19. N Engl J Med. 2020 Nov 24:NEJMoa2021801. doi: 10.1056/NEJMoa2021801. Epub ahead of print. PMID: 33289973; PMCID: PMC7722693.
  27. Padmanabhan U, Mukherjee S, Borse R, et al. Phase II Clinical trial for Evaluation of BCG as potential therapy for COVID-19 medRxiv 2020.10.28.20221630; doi: https://doi.org/10.1101/2020.10.28.20221630
  28. Painter WP, Holman W, Bush JA, Almazedi F, Malik H, Eraut NCJE, et al.Human Safety, Tolerability, and Pharmacokinetics of a Novel Broad-Spectrum Oral Antiviral Compound, Molnupiravir, with Activity Against SARS-CoV-2. medRxiv 2020.12.10.20235747; doi: https://doi.org/10.1101/2020.12.10.20235747
  29. Podder C, Chowdhury N, Sina M, Haque W. Outcome of ivermectin treated mild to moderate COVID-19 cases: a single-centre, open-label, randomised controlled study. IMC Journal of Medical Science. 2020;
  30. Rastogi A, Bhansali A, Khare N, et al. Short term, high-dose vitamin D supplementation for COVID-19 disease: a randomised, placebo-controlled, study (SHADE study)Postgraduate Medical Journal Published Online First: 12 November 2020. doi: 10.1136/postgradmedj-2020-139065
  31. Roozbeh F, Saeedi M, Alizadeh-Navaei R, Hedayatizadeh-Omran A, Merat S, Wentzel H, et al. Sofosbuvir and daclatasvir for the treatment of COVID-19 outpatients: a double-blind, randomized controlled trial. J Antimicrob Chemother. 2020 Dec 18:dkaa501. doi: 10.1093/jac/dkaa501. Epub ahead of print. PMID: 33338232.
  32. Sigamani A, Shetty S, Madhavi, Ruthra M, Sudhishma, Chugani A, et al. Galectin antagonist use in mild cases of SARS-CoV-2; pilot feasibility randomised, open label, controlled trial. medRxiv 2020.12.03.20238840; doi: https://doi.org/10.1101/2020.12.03.20238840.
  33. Skipper CP, Pastick KA, Engen NW, et al. Hydroxychloroquine in Nonhospitalized Adults With Early COVID-19: A Randomized Trial [published online ahead of print, 2020 Jul 16]. Ann Intern Med. 2020;M20-4207. doi:10.7326/M20-4207.
  34. Wang Q, Guo H, L Y, et al. Efficacy and Safety of Leflunomide for Refractory COVID-19: An Open-label Controlled Study. 2020. medRxiv 2020.05.29.20114223.
  35. Yadegarinia D, Tehrani S, Abolghasemi S, Zarghi A, Sali S, Zolfaghari F. Evaluation of the Efficacy of Arbidol in Comparison with the Standard Treatment Regimen of Hospitalized Patients with Covid-19: A Randomized Clinical Trial. Arch Clin Infect Dis. 2020;15(5):e106622.
  36. Zhong M, Sun A, Xiao T, et al. A Randomized, Single-blind, Group sequential, Active-controlled Study to evaluate the clinical efficacy and safety of α-Lipoic acid for critically ill patients with coronavirus disease 2019（COVID-19). 2020. medRxiv 2020.04.15.20066266

Dipartimento di Epidemiologia del Servizio Sanitario Regionale, Regione Lazio - Laura Amato l.amato@deplazio.it