Trial of Imatinib for Hospitalized Adults With COVID-19

Summary

This study is a randomized Double-Blind Placebo-Controlled Trial on the Safety and Efficacy of Imatinib for Hospitalized Adults with COVID-19

Timeline

Start

2020-06-02

Primary completion

2024-06-30

Completion

2025-07-17

Outcome

Outcome not reported

Stopped: “The Principal Investigator left the institution. The study was halted prematurely.”

Publications

• Background Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, Qiu Y, Wang J, Liu Y, Wei Y, Xia J, Yu T, Zhang X, Zhang L. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020 Feb 15;395(10223):507-513. doi: 10.1016/S0140-6736(20)30211-7. Epub 2020 Jan 30.
• Background Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24.
• Background Liu K, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, Xiao W, Wang YN, Zhong MH, Li CH, Li GC, Liu HG. Clinical characteristics of novel coronavirus cases in tertiary hospitals in Hubei Province. Chin Med J (Engl). 2020 May 5;133(9):1025-1031. doi: 10.1097/CM9.0000000000000744.
• Background Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA. 2020 Mar 17;323(11):1061-1069. doi: 10.1001/jama.2020.1585.
• Background Al-Bari MA. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J Antimicrob Chemother. 2015;70(6):1608-21. doi: 10.1093/jac/dkv018. Epub 2015 Feb 17.
• Background Daniel WA, Bickel MH, Honegger UE. The contribution of lysosomal trapping in the uptake of desipramine and chloroquine by different tissues. Pharmacol Toxicol. 1995 Dec;77(6):402-6. doi: 10.1111/j.1600-0773.1995.tb01050.x.
• Background Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: an old drug against today's diseases? Lancet Infect Dis. 2003 Nov;3(11):722-7. doi: 10.1016/s1473-3099(03)00806-5.
• Background Yan Y, Zou Z, Sun Y, Li X, Xu KF, Wei Y, Jin N, Jiang C. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res. 2013 Feb;23(2):300-2. doi: 10.1038/cr.2012.165. Epub 2012 Dec 4. No abstract available.
• Background Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M. In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun. 2004 Oct 8;323(1):264-8. doi: 10.1016/j.bbrc.2004.08.085.
• Background Devaux CA, Rolain JM, Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020 May;55(5):105938. doi: 10.1016/j.ijantimicag.2020.105938. Epub 2020 Mar 12.
• Background Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, Shi Z, Hu Z, Zhong W, Xiao G. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res. 2020 Mar;30(3):269-271. doi: 10.1038/s41422-020-0282-0. Epub 2020 Feb 4. No abstract available.
• Background Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 Mar 16;14(1):72-73. doi: 10.5582/bst.2020.01047. Epub 2020 Feb 19.
• Background Biot C, Daher W, Chavain N, Fandeur T, Khalife J, Dive D, De Clercq E. Design and synthesis of hydroxyferroquine derivatives with antimalarial and antiviral activities. J Med Chem. 2006 May 4;49(9):2845-9. doi: 10.1021/jm0601856.
• Background Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, Liu X, Zhao L, Dong E, Song C, Zhan S, Lu R, Li H, Tan W, Liu D. In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Clin Infect Dis. 2020 Jul 28;71(15):732-739. doi: 10.1093/cid/ciaa237.
• Background Chapuy B, Panse M, Radunski U, Koch R, Wenzel D, Inagaki N, Haase D, Truemper L, Wulf GG. ABC transporter A3 facilitates lysosomal sequestration of imatinib and modulates susceptibility of chronic myeloid leukemia cell lines to this drug. Haematologica. 2009 Nov;94(11):1528-36. doi: 10.3324/haematol.2009.008631.
• Background Gotink KJ, Broxterman HJ, Labots M, de Haas RR, Dekker H, Honeywell RJ, Rudek MA, Beerepoot LV, Musters RJ, Jansen G, Griffioen AW, Assaraf YG, Pili R, Peters GJ, Verheul HM. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res. 2011 Dec 1;17(23):7337-46. doi: 10.1158/1078-0432.CCR-11-1667. Epub 2011 Oct 6.
• Background Gotink KJ, Rovithi M, de Haas RR, Honeywell RJ, Dekker H, Poel D, Azijli K, Peters GJ, Broxterman HJ, Verheul HM. Cross-resistance to clinically used tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib. Cell Oncol (Dordr). 2015 Apr;38(2):119-29. doi: 10.1007/s13402-015-0218-8. Epub 2015 Feb 11.
• Background Colombo F, Trombetta E, Cetrangolo P, Maggioni M, Razini P, De Santis F, Torrente Y, Prati D, Torresani E, Porretti L. Giant Lysosomes as a Chemotherapy Resistance Mechanism in Hepatocellular Carcinoma Cells. PLoS One. 2014 Dec 10;9(12):e114787. doi: 10.1371/journal.pone.0114787. eCollection 2014.
• Background Ruzickova E, Skoupa N, Dolezel P, Smith DA, Mlejnek P. The Lysosomal Sequestration of Tyrosine Kinase Inhibitors and Drug Resistance. Biomolecules. 2019 Oct 31;9(11):675. doi: 10.3390/biom9110675.
• Background Burger H, den Dekker AT, Segeletz S, Boersma AW, de Bruijn P, Debiec-Rychter M, Taguchi T, Sleijfer S, Sparreboom A, Mathijssen RH, Wiemer EA. Lysosomal Sequestration Determines Intracellular Imatinib Levels. Mol Pharmacol. 2015 Sep;88(3):477-87. doi: 10.1124/mol.114.097451. Epub 2015 Jun 24.
• Background Fu D, Zhou J, Zhu WS, Manley PW, Wang YK, Hood T, Wylie A, Xie XS. Imaging the intracellular distribution of tyrosine kinase inhibitors in living cells with quantitative hyperspectral stimulated Raman scattering. Nat Chem. 2014 Jul;6(7):614-22. doi: 10.1038/nchem.1961. Epub 2014 May 25.
• Background Chilakapati SR, Serasanambati M, Vissavajjhala P, Kanala JR, Chilakapati DR. Amelioration of bleomycin-induced pulmonary fibrosis in a mouse model by a combination therapy of bosentan and imatinib. Exp Lung Res. 2015 May;41(4):173-88. doi: 10.3109/01902148.2014.939312. Epub 2015 Apr 6.
• Background Li M, Abdollahi A, Grone HJ, Lipson KE, Belka C, Huber PE. Late treatment with imatinib mesylate ameliorates radiation-induced lung fibrosis in a mouse model. Radiat Oncol. 2009 Dec 21;4:66. doi: 10.1186/1748-717X-4-66.
• Background Wolf AM, Wolf D, Rumpold H, Ludwiczek S, Enrich B, Gastl G, Weiss G, Tilg H. The kinase inhibitor imatinib mesylate inhibits TNF-alpha production in vitro and prevents TNF-dependent acute hepatic inflammation. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13622-7. doi: 10.1073/pnas.0501758102. Epub 2005 Sep 8.
• Background Rizzo AN, Sammani S, Esquinca AE, Jacobson JR, Garcia JG, Letsiou E, Dudek SM. Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2015 Dec 1;309(11):L1294-304. doi: 10.1152/ajplung.00031.2015. Epub 2015 Oct 2.
• Background Schrezenmeier E, Dorner T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat Rev Rheumatol. 2020 Mar;16(3):155-166. doi: 10.1038/s41584-020-0372-x. Epub 2020 Feb 7.
• Background Horne GA, Stobo J, Kelly C, Mukhopadhyay A, Latif AL, Dixon-Hughes J, McMahon L, Cony-Makhoul P, Byrne J, Smith G, Koschmieder S, BrUmmendorf TH, Schafhausen P, Gallipoli P, Thomson F, Cong W, Clark RE, Milojkovic D, Helgason GV, Foroni L, Nicolini FE, Holyoake TL, Copland M. A randomised phase II trial of hydroxychloroquine and imatinib versus imatinib alone for patients with chronic myeloid leukaemia in major cytogenetic response with residual disease. Leukemia. 2020 Jul;34(7):1775-1786. doi: 10.1038/s41375-019-0700-9. Epub 2020 Jan 10.
• Background Wang Y, Fan G, Salam A, Horby P, Hayden FG, Chen C, Pan J, Zheng J, Lu B, Guo L, Wang C, Cao B. Comparative Effectiveness of Combined Favipiravir and Oseltamivir Therapy Versus Oseltamivir Monotherapy in Critically Ill Patients With Influenza Virus Infection. J Infect Dis. 2020 Apr 27;221(10):1688-1698. doi: 10.1093/infdis/jiz656.
• Background Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7;382(19):1787-1799. doi: 10.1056/NEJMoa2001282. Epub 2020 Mar 18.
• Background Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, Doudier B, Courjon J, Giordanengo V, Vieira VE, Tissot Dupont H, Honore S, Colson P, Chabriere E, La Scola B, Rolain JM, Brouqui P, Raoult D. RETRACTED: Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. Int J Antimicrob Agents. 2020 Jul;56(1):105949. doi: 10.1016/j.ijantimicag.2020.105949. Epub 2020 Mar 20.
• Background Rainsford KD, Parke AL, Clifford-Rashotte M, Kean WF. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology. 2015 Oct;23(5):231-69. doi: 10.1007/s10787-015-0239-y. Epub 2015 Aug 6.
• Background Cutler DJ, MacIntyre AC, Tett SE. Pharmacokinetics and cellular uptake of 4-aminoquinoline antimalarials. Agents Actions Suppl. 1988;24:142-57. doi: 10.1007/978-3-0348-9160-8_13. No abstract available.
• Background Tett SE. Clinical pharmacokinetics of slow-acting antirheumatic drugs. Clin Pharmacokinet. 1993 Nov;25(5):392-407. doi: 10.2165/00003088-199325050-00005.
• Background Carmichael SJ, Charles B, Tett SE. Population pharmacokinetics of hydroxychloroquine in patients with rheumatoid arthritis. Ther Drug Monit. 2003 Dec;25(6):671-81. doi: 10.1097/00007691-200312000-00005.
• Background Yusuf IH, Foot B, Galloway J, Ardern-Jones MR, Watson SL, Yelf C, Burdon MA, Bishop PN, Lotery AJ. The Royal College of Ophthalmologists recommendations on screening for hydroxychloroquine and chloroquine users in the United Kingdom: executive summary. Eye (Lond). 2018 Jul;32(7):1168-1173. doi: 10.1038/s41433-018-0136-x. Epub 2018 Jun 11. No abstract available.
• Background Chatre C, Roubille F, Vernhet H, Jorgensen C, Pers YM. Cardiac Complications Attributed to Chloroquine and Hydroxychloroquine: A Systematic Review of the Literature. Drug Saf. 2018 Oct;41(10):919-931. doi: 10.1007/s40264-018-0689-4.
• Background McHenry AR, Wempe MF, Rice PJ. Stability of Extemporaneously Prepared Hydroxychloroquine Sulfate 25-mg/mL Suspensions in Plastic Bottles and Syringes. Int J Pharm Compd. 2017 May-Jun;21(3):251-254.
• Emadi A, Chua JV, Talwani R, Bentzen SM, Baddley J. Safety and Efficacy of Imatinib for Hospitalized Adults with COVID-19: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020 Oct 28;21(1):897. doi: 10.1186/s13063-020-04819-9.
• Zhao H, Mendenhall M, Deininger MW. Imatinib is not a potent anti-SARS-CoV-2 drug. Leukemia. 2020 Nov;34(11):3085-3087. doi: 10.1038/s41375-020-01045-9. Epub 2020 Sep 30. No abstract available.

Drugs

Indications