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


 

 

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 5/10/2020

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, 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 [published online ahead of print, 2020 Aug 19]. J Antimicrob Chemother. 2020; dkaa332. doi: https://doi.org/10.1093/jac/dkaa332
  2. Abd-Elsalam S, Esmail ES, Khalaf M, et al. Hydroxychloroquine in the Treatment of COVID-19: A Multicenter Randomized Controlled Study [published online ahead of print, 2020 Aug 14]. Am J Trop Med Hyg. 2020;10.4269/ajtmh.20-0873. doi: https://doi.org/10.4269/ajtmh.20-0873
  3. Agarwal A, Mukherjee A, Kumar G, Chatterjee P, Bhatnagar T, Malhotra P, et al. Convalescent plasma in the management of moderate COVID-19 in India: An open-label parallel-arm phase II multicentre randomized controlled trial (PLACID Trial). medRxiv. 2020:2020.09.03.20187252
  4. Ansarin K, Tolouian R, Ardalan M, Taghizadieh A, Varshochi M, Teimouri S, Vaezi T, Valizadeh H, Saleh P, Safiri S, Chapman KR. Effect of bromhexine on clinical outcomes and mortality in COVID-19 patients: A randomized clinical trial. Bioimpacts. 2020;10(4):209-215. doi: https://doi.org/10.34172/bi.2020.27. Epub 2020 Jul 19. PMID: 32983936; PMCID: PMC7502909
  5. Avendano-Sola C, Ramos-Martinez A, Munez-Rubio E, Ruiz-Antoran B, Malo de Molina R, Torres F, et al. Convalescent Plasma for COVID-19: A multicenter, randomized clinical trial. medRxiv. 2020:2020.08.26.20182444.
  6. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, 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
  7. Yang Cao et al. Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial. Journal of Allergy and Clinical Immunology 2020. doi: https://doi.org/10.1016/j.jaci.2020.05.019
  8. Castillo ME, Entrenas Costa LM, Vaquero Barrios JM, et al. "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" [published online ahead of print, 2020 Aug 29]. J Steroid Biochem Mol Biol. 2020;105751. doi: https://doi.org/10.1016/j.jsbmb.2020.105751
  9. Cavalcanti AB, Zampieri FG, Rosa RG, Azevedo LCP, Veiga VC, Avezum A, et al. Hydroxychloroquine with or without Azithromycin in Mild-to-Moderate Covid-19. NEJM 2020. doi: https://doi.org/10.1056/NEJMoa2019014
  10. Chen C, Huang J,Cheng Z,Wu J,Chen S,Zhang Y,et al. Favipiravir versus Arbidol for COVID-19: A Randomized Clinical Trial. 2020 medRxiv 2020. doi: https://doi.org/10.1101/2020.03.17.20037432
  11. Jun Chen et al. A pilot study of hydroxychloroquine in treatment of patients with common coronavirus disease-19 (COVID-19). Zhejiang Da Xue Xue Bao Yi Xue Ban. 2020 May 25;49(2):215-219
  12. Chen, Jun, Xia, Lu, Liu, Li, Xu, Qingnian, Ling, Yun, Huang, Dan, Huang, Wei, Song, Shuli, Xu, Shuibao, Shen, Yingzhong, Lu, Hongzhou. Antiviral Activity and Safety of Darunavir/Cobicistat for the Treatment of COVID-19. Open Forum Infectious Diseases 2020
  13. Chen L et al. Efficacy and safety of chloroquine or hydroxychloroquine in moderate type of COVID-19: a prospective open-label randomized controlled study. medRxiv preprint doi: https://doi.org/10.1101/2020.06.19.20136093
  14. 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
  15. Zhaowei Chen, Hu et al. Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial. MedRxiv 2020. doi: https://doi.org/10.1101/2020.03.22.20040758
  16. Cheng LL, Guan WJ, Duan CY, et al. Effect of Recombinant Human Granulocyte Colony-Stimulating Factor for Patients With Coronavirus Disease 2019 (COVID-19) and Lymphopenia: A Randomized Clinical Trial [published online ahead of print, 2020 Sep 10]. JAMA Intern Med. 2020;10.1001/jamainternmed.2020.5503. doi: https://doi.org/10.1001/jamainternmed.2020.5503
  17. 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: https://doi.org/10.21203/rs.3.rs-38896/v1
  18. 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
  19. 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: https://doi.org/10.21203/rs.3.rs-83677/v1
  20. Davoudi-Monfared E, Rahmani H, Khalili H, Hajiabdolbaghi M, Salehi M et a. Efficacy and safety of interferon β-1a in treatment of severe COVID-19: A randomized clinical trial. Antimicrob Agents Chemother. 2020 Jul 13. pii: AAC.01061-20. doi: https://doi.org/10.1128/AAC.01061-20 [Epub ahead of print]
  21. Deftereos SG, Giannopoulos G, Vrachatis DA, et al. 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;3(6):e2013136. Published 2020 Jun 1. doi: https://doi.org/10.1001/jamanetworkopen.2020.1313
  22. Dequin PF, Heming N, Meziani F, et al. Effect of Hydrocortisone on 21-Day Mortality or Respiratory Support Among Critically Ill Patients With COVID-19: A Randomized Clinical Trial [published online ahead of print, 2020 Sep 2]. JAMA. 2020;10.1001/jama.2020.16761. doi: https://doi.org/10.1001/jama.2020.16761
  23. 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
  24. 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: https://doi.org/10.1183/13993003.02808-2020. Epub ahead of print. PMID: 32943404.
  25. 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: https://doi.org/10.1101/2020.07.29.20164251
  26. Furtado RHM, Berwanger O, Fonseca HA, et al. 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 [published online ahead of print, 2020 Sep 4]. Lancet. 2020;S0140-6736(20)31862-6. doi: https://doi.org/10.1016/S0140-6736(20)31862-6
  27. Gharbharan A et al. Convalescent Plasma for COVID-19. A randomized clinical trial. medRxiv 2020 doi: https://doi.org/10.1101/2020.07.01.20139857
  28. 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: https://doi.org/10.15586/jptcp.v27iSP1.684. PMID: 32543164.
  29. 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: https://doi.org/10.1016/S0140-6736(20)32013-4. Epub ahead of print. PMID: 33031764; PMCID: PMC7535623.
  30. Horby,P, Mafham M, Linsell L, Bell J L, Staplin N, Emberson J R, et al. Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19: Preliminary results from a multi-centre, randomized, controlled trial. medRxiv; 2020.
  31. Huang M, Tang T Pang P,Man Li M,Ma R, Lu J et al. Treating COVID-19 with Chloroquine. J Mol Cell Biol 2020;12(4):322-325. doi: https://doi.org/10.1093/jmcb/mjaa014
  32. Huang Yin-Qiu, Tang Sheng-Quan, Xu Xiao-Lei, Zeng Yan-Ming, He Xiao-Qing 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. Frontiers in Pharmacology 2020
  33. Hung Ivan Fan-Ngai, Lung, Kwok-Cheung, al., Eugene Yuk-Keung Tso et. Triple combination of interferon beta-1b, lopinavir–ritonavir,and ribavirin in the treatment of patients admitted to hospitalwith COVID-19: an open-label, randomised, phase 2 trial. Lancet May 8, 2020. doi: https://doi.org/10.1016/ S0140-6736(20)31042-4
  34. 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: https://doi.org/10.1093/cid/ciaa1176
  35. Jeronimo CMP, Farias MEL, Val FFA, et al. Methylprednisolone as Adjunctive Therapy for Patients Hospitalized With COVID-19 (Metcovid): A Randomised, Double-Blind, Phase IIb, Placebo-Controlled Trial [published online ahead of print, 2020 Aug 12]. Clin Infect Dis. 2020;ciaa1177. doi: https://doi.org/10.1093/cid/ciaa1177
  36. Kamran SM, Mirza ZeH, Naseem A, Saeed F, Azam R, Ullah N, et al. Clearing the fog: Is HCQ effective in reducing COVID-19 progression: A randomized controlled trial. medRxiv. 2020:2020.07.30.20165365.
  37. 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;10.1016/j.medj.2020.04.001. doi: https://doi.org/10.1016/j.medj.2020.04.001
  38. Ling Li, Wei Zhang, Yu Hu, Xunliang Tong, Shangen Zheng, Juntao Yang, Yujie Kong, Lili Ren, QingWei, Heng Mei 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. doi: https://doi.org/10.1001/jama.2020.10044
  39. Li T, Sun L, Zhang W, et al. Bromhexine Hydrochloride Tablets for the Treatment of Moderate COVID-19: An Open-label Randomized Controlled Pilot Study [published online ahead of print, 2020 Sep 3]. Clin Transl Sci. 2020;10.1111/cts.12881. doi: https://doi.org/10.1111/cts.12881
  40. 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.
  41. Lou Y, Liu L, Qiu Y. Clinical Outcomes and Plasma Concentrations of Baloxavir Marboxil and Favipiravir in COVID-19 Patients: an Exploratory Randomized, Controlled Trial. medRxiv. 2020:2020.04.29.20085761. doi: https://doi.org/10.1101/2020.04.29.20085761
  42. Mansour E, Palma A, Ulaf R et al. Pharmacological inhibition of the kinin-kallikrein system in severe COVID-19 A proof-of-concept study. medRxiv 2020.08.11.20167353; 2020
  43. Mehboob R, Ahmad F, Qayyum A 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 2020.08.01.20166678
  44. Miller J, Bruen C, Schnaus M, 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;24(1):502. Published 2020 Aug 14. doi: https://doi.org/10.1186/s13054-020-03220-x
  45. Mitjà O, Corbacho-Monné M, Ubals M,et al. Hydroxychloroquine for Early Treatment of Adults with Mild Covid-19: A Randomized-Controlled Trial.Clinical Infectious Diseases. Clinical Infectious Diseases,2020 ciaa1009, doi: https://doi.org/10.1093/cid/ciaa1009
  46. 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
  47. Rahmani H, Davoudi-Monfared E, Nourian A, et al. Interferon β-1b in treatment of severe COVID-19: A randomized clinical trial [published online ahead of print, 2020 Aug 24]. Int Immunopharmacol. 2020;88:106903. doi: https://doi.org/10.1016/j.intimp.2020.106903
  48. Ren Z, Luo H, Yu Z, et al. A Randomized, Open-label, Controlled Clinical Trial of Azvudine Tablets in the Treatment of Mild and Common COVID-19, A Pilot Study [published online ahead of print, 2020 Jul 14]. Adv Sci (Weinh). 2020;2001435. doi: https://doi.org/10.1002/advs.202001435
  49. Rosas I, Bräu N, Waters M, Go RC, Hunter BD, Bhagani S, et al. Tocilizumab in Hospitalized Patients With COVID-19 Pneumonia. medRxiv. 2020:2020.08.27.20183442.
  50. Sadeghi A, Ali Asgari A, Norouzi A, 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 [published online ahead of print, 2020 Aug 19]. J Antimicrob Chemother. 2020;dkaa334. doi: https://doi.org/10.1093/jac/dkaa334
  51. Salvarani et al. Efficacy of Early Administration of Tocilizumab in COVID-19 Patients. https://www.aifa.gov.it/web/guest/-/covid-19-studio-randomizzato-italiano-nessun-beneficio-dal-tocilizumab
  52. Sakoulas G, Geriak M, Kullar R, Greenwood K, Habib M, Vyas A, et al. Intravenous Immunoglobulin (IVIG) Significantly Reduces Respiratory Morbidity in COVID-19 Pneumonia: A Prospective Randomized Trial. medRxiv. 2020:2020.07.20.20157891
  53. Spinner CD, Gottlieb RL, Criner GJ, et al. Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19: A Randomized Clinical Trial [published online ahead of print, 2020 Aug 21]. JAMA. 2020;e2016349. doi: https://doi.org/10.1001/jama.2020.16349
  54. RECOVERY Trial (NCT04381936). Randomised Evaluation of COVID-19 Therapy. available from https://www.recoverytrial.net/ on 05 June 2020
  55. RECOVERY Collaborative Group, Horby P, Lim WS, et al. Dexamethasone in Hospitalized Patients with Covid-19 - Preliminary Report [published online ahead of print, 2020 Jul 17]. N Engl J Med. 2020;NEJMoa2021436. doi: https://doi.org/10.1056/NEJMoa2021436
  56. Ren Z, Luo H, Yu Z 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 2020
  57. Sekhavati E, Jafari F, SeyedAlinaghi S, et al. Safety and effectiveness of azithromycin in patients with COVID-19: An open-label randomised trial [published online ahead of print, 2020 Aug 25]. Int J Antimicrob Agents. 2020;106143. doi: https://doi.org/10.1016/j.ijantimicag.2020.106143
  58. Shu L, Niu C, Li R, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. Stem Cell Res Ther. 2020;11(1):361. Published 2020 Aug 18. doi: https://doi.org/10.1186/s13287-020-01875-5
  59. SIMPLE trial (NCT04292730) available from https://www.gilead.com/news-and-press/press-room/press-releases/2020/6/gilead-announces-results-from-phase-3-trial-of-remdesivir-in-patients-with-moderate-covid-19 on 1st June 2020; 2020
  60. Tang Wei et al. Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial. BMJ 2020;369:m1849. doi: https://doi.org/10.1136/bmj.m1849
  61. Tomazini BM, Maia IS, Cavalcanti AB, et al. 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 [published online ahead of print, 2020 Sep 2]. JAMA. 2020;10.1001/jama.2020.17021. doi: https://doi.org/10.1001/jama.2020.17021
  62. 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. 2020, ofaa446, doi: https://doi.org/10.1093/ofid/ofaa446
  63. Vlaar APJ, de Bruin S, Busch M, Timmermans S, van Zeggeren IE, Koning R et al Anti-C5a Antibody (IFX-1) Treatment of Severe COVID-19: An Exploratory Phase 2 Randomized Controlled Trial. TLRHEU-D-20-00358, Available at SSRN: https://ssrn.com/abstract=3658226 or http://dx.doi.org/10.2139/ssrn.3658226
  64. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial [published correction appears in Lancet. 2020 May 30;395(10238):1694]. Lancet. 2020;395(10236):1569-1578. doi: https://doi.org/10.1016/S0140-6736(20)31022-9
  65. 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: https://doi.org/10.1093/cid/ciaa1417. Epub ahead of print.
  66. 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.. The Lancet. 2020 . Available at SSRN: https://ssrn.com/abstract=3667681 or http://dx.doi.org/10.2139/ssrn.3667681
  67. Writing Committee for the REMAP-CAP Investigators, Angus DC, Derde L, 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 [published online ahead of print, 2020 Sep 2]. JAMA
  68. Zheng F, Zhou Y, Zhou Z, Ye F, Huang B, Huang Y, et al. A Novel Protein Drug, Novaferon, as the Potential Antiviral Drug for COVID-19. MedRxiv. 2020. doi: https://doi.org/10.1101/2020.04.24.20077735
  69. Zheng F, Zhou Y, Zhou Z, et al. SARS-CoV-2 clearance in COVID-19 patients with Novaferon treatment: A randomized, open-label, parallel-group trial [published online ahead of print, 2020 Aug 3]. Int J Infect Dis. 2020;99:84-91. doi: https://doi.org/10.1016/j.ijid.2020.07.053

Studi esclusi e motivo di esclusione


Studio Motivo di esclusione
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
Borba 2020 Tipo di confronto che non rientra nei criteri di inclusione: stesso farmaco a dosaggi diversi
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
Farahani 2020 Tipo di esiti che non rientrano nei criteri di inclusione
Fu 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
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 obiettivo ed esiti che non rientrano nei criteri di inclusione
Farahani 2020 Tipo di esiti che non rientrano nei criteri di inclusione
Podder 2020 Dati non utilizzabilli
Wang 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. 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
  2. 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
  3. 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:10.1001/jamanetworkopen.2020.8857
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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. 11. 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
  11. 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. 13. 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
  12. Lyngbakken MN, Berdal J-E, Eskesen A, Kvale D, Olsen I, Rueegg C, et al. A pragmatic randomized controlled trial reports the efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics2020. 17 July 2020, PREPRINT (Version 1) available at Research Square https://doi.org/10.21203/rs.3.rs-44055/v
  13. 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
  14. 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
  15. 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
  16. 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