Новые возможности терапии идиопатического легочного фиброза


https://doi.org/10.18093/0869-0189-2017-27-4-502-514

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Аннотация

Идиопатический легочный фиброз (ИЛФ) является прогрессирующим фиброзирующим заболеванием легких со средней выживаемостью пациентов около 2–3 лет от момента постановки диагноза. Нинтеданиб – ингибитор тирозинкиназы, мишенью которого являются рецепторы факторов роста PDGF, FGF и VEGF. Использование нинтеданиба одобрено для терапии ИЛФ во многих странах на основе результатов исследования II фазы TOMORROW и 2 репликативных исследований III фазы INPULSIS. В исследованиях INPULSIS на фоне терапии нинтеданибом продемонстрировано значительное уменьшение ежегодной скорости снижения форсированной жизненной емкости легких (ФЖЕЛ), а время до 1-го обострения ИЛФ и стабилизация показателей качества жизни по шкале SGRQ положительно изменились в исследовании INPULSIS-2. В совокупном анализе исследований TOMORROW и INPULSIS показано, что при терапии нинтеданибом по сравнению с плацебо снижается летальность пациентов с ИЛФ. В исследовании INPULSIS не выявлено различий по способности нинтеданиба замедлять падение показателя ФЖЕЛ между пациентами с классическим ИЛФ и возможным ИЛФ (т. е. у больных с возможным паттерном ОИП с тракционными бронхоэктазами по данным КТВР без хирургической биопсии легких). В субгрупповых анализах исследования INPULSIS эффективность терапии нинтеданибом подтверждена у всех пациентов с ИЛФ, независимо от возраста, пола, расы, исходных значений ФЖЕЛ, диффузионной способности легких по окиси углерода, наличия эмфиземы, использования антирефлюксной терапии или системных глюкокортикостероидов. В исследовании INPULSIS частота тяжелых нежелательных явлений (НЯ) между группами нинтеданиба и плацебо значительно не различалась. Диарея была наиболее частым НЯ при терапии нинтеданибом, частота ее развития составила около 60 %, но в большинстве случаев – легкой или средней тяжести, отмены препарата не требовалось. Необходимо проведение дальнейших исследований по изучению эффективности нинтеданиба у больных ИЛФ с более широкими критериями включения, другими фибротическими интерстициальными заболеваниями легких, а также изучение эффективности и безопасности комбинации нинтеданиба и пирфенидона. Стратегия терапия больных ИЛФ в идеале должна быть основана на индивидуальных характеристиках каждого больного.


Об авторе

С. Н. Авдеев
Федеральное государственное бюджетное учреждение «Научно-исследовательский институт пульмонологии Федерального медико-биологического агентства России»
Россия

д. м. н., член-корр. Российской академии наук, профессор, главный внештатный специалист-пульмонолог Министерства здравоохранения Российской Федерации, руководитель клинического отдела,

105077, Россия, Москва, ул. 11-я Парковая, 32, корп. 4



Список литературы

1. Raghu G., Collard H.R., Egan J.J. et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am. J. Respir. Crit. Care Med. 2011; 183 (3): 788‒824. DOI: 10.1164/rccm.2009-040GL.

2. Raghu G., Chen S.Y., Yeh W.S. et al. Idiopathic pulmonary fibrosis in US Medicare beneficiaries aged 65 years and older: incidence, prevalence, and survival, 2001-11. Lancet Respir. Med. 2014; 2 (7): 566‒572. DOI: 10.1016/S2213-2600(14)70101-8.

3. van Manen M.J., Birring S.S., Vancheri C. et al. Cough in idiopathic pulmonary fibrosis. Eur. Respir. Rev. 2016; 25 (141): 278‒286. DOI: 10.1183/16000617.0090-2015.

4. Yount S.E., Beaumont J.L., Chen S.Y. et al. Health-related quality of life in patients with idiopathic pulmonary fibrosis. Lung. 2016; 194 (2): 227‒234. DOI: 10.1007/s00408-016-9850-y

5. Ley B., Collard H.R., King T.E. Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2011; 183 (4): 431–440. DOI: 10.1164/rccm.201006-0894CI.

6. Collard H.R., Ryerson C.J., Corte T.J. et al. Acute exacerbation of idiopathic pulmonary fibrosis. An international working group report. Am. J. Respir. Crit. Care Med. 2016; 194 (3): 265–275. DOI: 10.1164/rccm.201604-0801CI.

7. Cottin V. The impact of emphysema in pulmonary fibrosis. Eur. Respir. Rev. 2013; 22 (128): 153–157. DOI: 10.1183/09059180.00000813.

8. Behr J., Kreuter M., Hoeper M.M. et al. Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry. Eur. Respir. J. 2015; 46 (1): 186–196. DOI: 10.1183/09031936.00217614.

9. Raghu G., Amatto V.C., Behr J. et al. Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. Eur. Respir. J. 2015; 46 (4): 1113‒1130. DOI: 10.1183/13993003.02316-2014.

10. Bonella F., Kreuter M., Hagmeyer L. et al. Insights from the German compassionate use program of nintedanib for the treatment of idiopathic pulmonary fibrosis. Respiration. 2016; 92 (2): 98‒106. DOI: 10.1159/000448288.

11. Maher R.L., Hanlon J., Hajjar E.R. Clinical consequences of polypharmacy in elderly. Exp. Opin. Drug Saf. 2014; 13 (1): 57–65. DOI: 10.1517/14740338.2013.827660.

12. Vancheri C., Cottin V., Kreuter M. et al. IPF, comorbidities and management implications. Sarcoidos. Vasc. Diffuse Lung Dis. 2015; 32 (Suppl. 1): 17‒23.

13. Demedts M., Behr J., Buhl R. et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2005; 353 (21): 2229–2242. DOI: 10.1056/NEJMoa042976.

14. Raghu G., Anstrom K.J., King T.E. Jr et al. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N. Engl. J. Med. 2012; 366 (21): 1968–1977. DOI: 10.1056/NEJMoa1113354.

15. Raghu G., Brown K.K., Costabel U. et al. Treatment of idiopathic pulmonary fibrosis with etanercept: an exploratory, placebo-controlled trial. Am. J. Respir. Crit. Care Med. 2008; 178 (9): 948–955. DOI: 10.1164/rccm.200709-1446OC.

16. King T.E. Jr, Albera C., Bradford W.Z. et al. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet. 2009; 374 (9685): 222–228. DOI: 10.1016/S0140-6736(09)60551-1.

17. Daniels C.E., Lasky J.A., Limper A.H. et al. Imatinib treatment for idiopathic pulmonary fibrosis: Randomized placebo-controlled trial results. Am. J. Respir. Crit. Care Med. 2010; 181 (6): 604–610. DOI: 10.1164/rccm.200906-0964OC.

18. Noth I., Anstrom K.J., Calvert S.B. et al. A placebo-controlled randomized trial of warfarin in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2012; 186 (1): 88–95. DOI: 10.1164/rccm.201202-0314OC.

19. King T.E. Jr, Behr J., Brown K.K. et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2008; 177 (1): 75–81. DOI: 10.1164/rccm.200705-732OC.

20. King T.E. Jr, Brown K.K., Raghu G. et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2011; 184 (1): 92–99. DOI: 10.1164/rccm.201011-1874OC.

21. Raghu G., Million-Rousseau R., Morganti A. et al. Macitentan for the reatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur. Respir. J. 2013; 42 (6): 1622–1632. DOI: 10.1183/09031936.00104612.

22. Raghu G., Behr J., Brown K.K. et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Ann. Intern. Med. 2013; 158 (9): 641–649. DOI: 10.7326/0003-4819-158-9-201305070-00003.

23. Martinez F.J., de Andrade J.A., Anstrom K.J. et al. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370 (22): 2093–2101. DOI: 10.1056/NEJMoa1401739.

24. Richeldi L., Costabel U., Selman M. et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2011; 365 (12): 1079–1087. DOI: 10.1056/NEJMoa1103690.

25. Richeldi L., du Bois R.M., Raghu G. et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N. Engl. J. Med. 2014; 370 (22): 2071–2082. DOI: 10.1056/NEJMoa1402584.

26. Raghu G., Rochwerg B., Zhang Y. et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: Treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am. J. Respir. Crit. Care Med. 2015; 192 (2): e3–e19. DOI: 10.1164/rccm.201506-1063ST.

27. King T.E., Pardo A., Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011; 378 (9807): 1949–1961. DOI: 10.1016/S0140-6736(11)60052-4.

28. Ahluwalia N., Shea B.S., Tager A.M. New therapeutic targets in idiopathic pulmonary fibrosis. Aiming to rein in runaway wound-healing responses. Am. J. Respir. Crit. Care Med. 2014; 190 (8): 867–878. DOI: 10.1164/rccm.201403-0509PP.

29. Selman M., King T.E., Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann. Intern. Med. 2001; 134 (2): 136–151.

30. Borensztajn K., Crestani B., Kolb M. Idiopathic pulmonary fibrosis: from epithelial injury to biomarkers – insights from the bench side. Respiration. 2013; 86 (6): 441–452. DOI: 10.1159/000357598.

31. Günther A., Korfei M., Mahavadi P. et al. Unravelling the progressive pathophysiology of idiopathic pulmonary fibrosis. Eur. Respir. Rev. 2012; 21 (124): 152–160. DOI: 10.1183/09059180.00001012.

32. Noble P.W., Barkauskas C.E., Jiang D. Pulmonary fibrosis: patterns and perpetrators. J. Clin. Invest. 2012; 122 (8): 2756–2762. DOI: 10.1172/JCI60323.

33. Selman M., Pardo A. Revealing the pathogenic and aging-related mechanisms of the enigmatic idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2014; 189 (10): 1161–1172. DOI: 10.1164/rccm.201312-2221PP.

34. Wuyts W.A., Agostini C., Antoniou K.M. et al. The pathogenesis of pulmonary fibrosis: a moving target. Eur. Respir. J. 2013; 41 (5): 1207–1218. DOI: 10.1183/09031936.00073012.

35. Fukihara J., Kondoh Y. Nintedanib (OFEV) in the treatment of idiopathic pulmonary fibrosis. Exp. Rev. Respir. Med. 2016; 10 (12): 1247–1254. DOI: 10.1080/17476348.2016.1249854.

36. Clark J.G., Madtes D.K., Raghu G. Effects of platelet-derived growth factor isoforms on human lung fibroblast proliferation and procollagen gene expression. Exp. Lung Res. 1993; 19 (3): 327–344.

37. Bonner J.C. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev. 2004; 15 (4): 255–273. DOI: 10.1016/j.cytogfr.2004.03.006.

38. Martinet Y., Rom W.N., Grotendorst G.R. et al. Exaggerated spontaneous release of platelet-derived growth factor by alveolar macrophages from patients with idiopathic pulmonary fibrosis. N. Engl. J. Med. 1987; 317 (4): 202–209. DOI: 10.1056/NEJM198707233170404.

39. Adamali H.I., Maher T.M. Current and novel drug therapies for idiopathic pulmonary fibrosis. Drug Des. Devel. Ther. 2012; 6: 261–272. DOI: 10.2147/DDDT.S29928.

40. Xiao L., Du Y., Shen Y. et al. TGF-β 1 induced fibroblast proliferation is mediated by the FGF-2/ERK pathway. Front. Biosci. (Landmark Ed). 2012; 17: 2667–2674.

41. Yu Z.H., Wang D.D., Zhou Z.Y. et al. Mutant soluble ectodomain of fibroblast growth factor receptor-2 IIIc attenuates bleomycin-induced pulmonary fibrosis in mice. Biol. Pharm. Bull. 2012; 35 (5): 731–736.

42. Chen Y., Zhao M., Fu M. et al. The role of calcineurin in the lung fibroblasts proliferation and collagen synthesis induced by basic fibroblast growth factor. Chin. Med. J. (Engl.) 2003; 116 (6): 857–862.

43. Inoue Y., King T.E. Jr, Tinkle S.S. et al. Human mast cell basic fibroblast growth factor in pulmonary fibrotic disorders. Am. J. Pathol. 1996; 149 (6): 2037–2054.

44. Hetzel M., Bachem M., Anders D. et al. Different effects of growth factors on proliferation and matrix production of normal and fibrotic human lung fibroblasts. Lung. 2005; 183 (4): 225–237. DOI: 10.1007/s00408-004-2534-z.

45. Wygrecka M., Dahal B.K., Kosanovic D. et al. Mast cells and fibroblasts work in concert to aggravate pulmonary fibrosis: role of transmembrane SCF and the PAR-2/PKC-α/Raf-1/p44/42 signaling pathway. Am. J. Pathol. 2013; 182 (6): 2094–2108. DOI: 10.1016/j.ajpath.2013.02.013.

46. McKeown S., Richter A.G., O’Kane C. et al. MMP expression and abnormal lung permeability are important determinants of outcome in IPF. Eur. Respir. J. 2009; 33 (1): 77–84. DOI: 10.1183/09031936.00060708.

47. Simler N.R., Brenchley P.E., Horrocks A.W. et al. Angiogenic cytokines in patients with idiopathic interstitial pneumonia. Thorax. 2004; 59: 581–585. DOI: 10.1136/thx.2003.009860.

48. Ando M., Miyazaki E., Ito T. et al. Significance of serum vascular endothelial growth actor level in patients with idiopathic pulmonary fibrosis. Lung. 2010; 188 (3): 247–252. DOI: 10.1007/s00408-009-9223-x.

49. Hamada N., Kuwano K., Yamada M. et al. Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice. J. Immunol. 2005; 175 (2): 1224–1231.

50. Farkas L., Gauldie J., Voelkel N.F., Kolb M. Pulmonary hypertension and idiopathic pulmonary fibrosis: a tale of angiogenesis, apoptosis, and growth factors. Am. J. Respir. Cell. Mol. Biol. 2011; 45 (1): 1–15. DOI: 10.1165/rcmb.2010-0365TR.

51. Farkas L., Farkas D., Ask K. et al. VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats. J. Clin. Invest. 2009; 119 (5): 1298–1311. DOI: 10.1172/JCI36136.

52. Inomata M., Nishioka Y., Azuma A. Nintedanib: evidence for its therapeutic potential in idiopathic pulmonary fibrosis. Core Evid. 2015; 10: 89–98. DOI: 10.2147/CE.S82905.

53. Hilberg F., Roth G.J., Krssak M. et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res. 2008; 68: 4774–4782.

54. Hostettler K.E., Zhong J., Papakonstantinou E. et al. Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis. Respir. Res. 2014; 15: 157. DOI: 10.1186/s12931-014-0157-3.

55. Wollin L., Maillet I., Quesniaux V. et al. Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis. J. Pharmacol. Exp. Ther. 2014; 349 (2): 209–220. DOI: 10.1124/jpet.113.208223.

56. Wollin L., Wex E., Pautsch A. et al. Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis. Eur. Respir. J. 2015; 45 (5): 1434–1445. DOI: 10.1183/09031936.00174914.

57. Ackermann M., Kim Y.O., Wagner W.L. et al. Effects of nintedanib on the microvascular architecture in a lung fibrosis model. Angiogenesis. 2017; 20 (3): 359–372. DOI: 10.1007/s10456-017-9543-z.

58. Tandon K., Herrmann F.E., Ayaub E. et al. Nintedanib attenuates the polarization of profibrotic macrophages through the inhibition of tyrosine phosphorylation on CSF1 receptor. Abstract accepted for presentation at: American Thoracic Society International Conference; 2017, 19–24 May; Washington, DC, USA. Am. J. Respir. Crit. Care Med. 2017; 195: А2397.

59. Arakawa H., Honma K. Honeycomb lung: history and current concepts. AJR Am. J. Roentgenol. 2011; 196 (4): 773–782. DOI: 10.2214/AJR.10.4873.

60. Tomassetti S., Wells A.U., Costabel U. et al. Bronchoscopic lung cryobiopsy increases diagnostic confidence in the multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2016; 193 (7): 745–752. DOI: 10.1164/rccm.201504-0711OC.

61. Travis W.D., Costabel U., Hansell D.M. et al. An official American Thoracic Society/European Respiratory Society Statement: Update of the international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. Am. J. Respir. Crit. Care Med. 2013; 188 (6): 733–748. DOI: 10.1164/rccm.201308-1483ST.

62. Raghu G., Wells A.U., Nicholson A.G. et al. Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria. Am. J. Respir. Crit. Care Med. 2017; 195 (1): 78–85. DOI: 10.1164/rccm.201602-0402OC.

63. Richeldi L., Cottin V., du Bois R.M. et al. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS® trials. Respir. Med. 2016; 113: 74–79. DOI: 10.1016/j.rmed.2016.02.001.

64. Loveman E., Copley V.R., Scott D.A. et al. Comparing new treatments for idiopathic pulmonary fibrosis – a network meta-analysis. BMC Pulm. Med. 2015; 15: 37. DOI: 10.1186/s12890-015-0034-y.

65. Rogliani P., Calzetta L., Cavalli F. et al. Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: A systematic review and meta-analysis. Pulm. Pharm. Ther. 2016; 40: 95–103. DOI: 10.1016/j.pupt.2016.07.009.

66. Costabel U., Inoue Y., Richeldi L. et al. Efficacy of nintedanib in idiopathic pulmonary fibrosis across prespecified subgroups in INPULSIS. Am. J. Respir. Crit. Care Med. 2016; 193 (2): 178‒185. DOI: 10.1164/rccm.201503-0562OC.

67. Kolb M., Richeldi L., Behr J. et al. Nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax. 2017; 72 (4): 340–346. DOI: 10.1136/thoraxjnl-2016-208710.

68. Maher T.M., Flaherty K.R., Noble P.W. et al. Effect of baseline FVC on lung function decline with nintedanib in patients with IPF. Eur. Respir. J. 2015; 46 (Suppl. 59): OA4499. DOI: 10.1183/13993003.congress-2015.OA4499.

69. Raghu G., Crestani B., Bailes Z. et al. Effect of anti-acid medication on reduction in FVC decline with nintedanib. Eur. Respir. J. 2015; 46 (Suppl. 59): OA4502.

70. Wuyts WA, Kolb M, Stowasser S. et al. First data on efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis and forced vital capacity of ≤ 50% of predicted value. Lung. 2016; 194 (5): 739–743.

71. Hambly N., Cox G., Kolb M. Acute exacerbations of idiopathic pulmonary fibrosis: tough to define; tougher to manage. Eur. Respir. J. 2017; 49: 1700811. DOI: 10.1183/13993003.00811-2017.

72. Tomioka H., Takada H. Treatment with nintedanib for acute exacerbation of idiopathic pulmonary fibrosis. Respir. Case Rep. 2017; 5 (2): e00215. DOI: 10.1002/rcr2.215.

73. Corte T., Bonella F., Crestani B. et al. Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis. Respir. Res. 2015; 16: 116. DOI: 10.1186/s12931-015-0276-5.

74. Ley B., Collard H.R., King T.E. Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 2011; 183 (4): 431–440. DOI: 10.1164/rccm.201006-0894CI.

75. Schmidt S.L., Tayob N., Han M.K. et al. Predicting pulmonary fibrosis disease course from past trends in pulmonary function. Chest. 2014; 145 (3): 579–585. DOI: 10.1378/chest.13-0844.

76. Huang J., Beyer C., Palumbo-Zerr K. et al. Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis. Ann. Rheum. Dis. 2016; 75 (5): 883–890. DOI: 10.1136/annrheumdis-2014-207109.

77. Maurer B., Distler J.H., Distler O. The Fra-2 transgenic mouse model of systemic sclerosis. Vascul. Pharmacol. 2013; 58 (3): 194–201. DOI: 10.1016/j.vph.2012.12.001.

78. National Institutes of Health Clinical Center. A Trial to Compare Nintedanib with Placebo for Patients with Scleroderma Related Lung Fibrosis. NCT02597933. Available at: https://clinicaltrials.gov/ct2/show/NCT02597933 [Accessed 20 July, 2017].

79. National Institutes of Health Clinical Center. Efficacy and Safety of Nintedanib in Patients with Progressive Fibrosing Interstitial Lung Disease (PF-ILD). NCT02999178. Available at: https://clinicaltrials.gov/ct2/show/NCT02999178 [Accessed 20 July, 2017].

80. Milger K., Kneidinger N., Neurohr C. et al. Switching to nintedanib after discontinuation of pirfenidone due to adverse events in IPF. Eur. Respir. J. 2015; 46 (4): 1217–1221. DOI: 10.1183/13993003.00584-2015.

81. Hagmeyer L., Treml M., Priegnitz C., Randerath W.J. Successful concomitant therapy with pirfenidone and nintedanib in idiopathic pulmonary fibrosis: a case report. Respiration. 2016; 91 (4): 327–332. DOI: 10.1159/000444690.

82. Ogura T., Taniguchi H., Azuma A. et al. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. Eur. Respir. J. 2015; 45 (5): 1382–1392. DOI: 10.1183/09031936.00198013.

83. National Institutes of Health Clinical Center. A Study to Compare the Amount of Nintedanib and Pirfenidone in the Blood When Nintedanib and Pirfenidone Are Given Separately or in Combination. NCT02606877. Available at: https://clinicaltrials.gov/ct2/show/NCT02606877 [Accessed 20 July, 2017].


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Для цитирования: Авдеев С.Н. Новые возможности терапии идиопатического легочного фиброза.  Пульмонология. 2017;27(4):502-514. https://doi.org/10.18093/0869-0189-2017-27-4-502-514

For citation: Avdeev S.N. New abilities in therapy of idiopathic pulmonary fibrosis. Russian Pulmonology. 2017;27(4):502-514. (In Russ.) https://doi.org/10.18093/0869-0189-2017-27-4-502-514

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