Cyclophosphamide for Acute Exacerbation of Idiopathic Pulmonary Fibrosis

NCT02460588 | Completed Phase 3

• 2 other identifiers: P 1409082015-000492-27
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a major event of IPF with an annual incidence between 5 and 10% and is responsible for the death of one third of IPF patients. When AE-IPF occurs, it is associated with poor survival with an overall mortality at 3 months upper of 50%. To date, no treatment has been proved to be effective in AE-IPF but the efficacy of cyclophosphamide (CYC) on survival has been suggested, mainly by retrospective series and needs to be confirmed. This confirmation is mandatory to improve prognosis of AE-IPF but also to avoid unsuspected deleterious effect as it as been shown with immunosuppressor in stable IPF.

Conditions

Idiopathic Pulmonary Fibrosis

Outcome Measures

Primary Outcomes (1)

• "Early" survival

  All cause of mortality at 3 months

  3 months

Secondary Outcomes (16)

• Overall Survival

  6 months and 12 montns

• Respiratory disease-specific mortality

  6 months

• Respiratory Morbidity

  6 months

• Chest HRCT features (HRCT images will be scored at 5 levels)

  6 months

• Prognosis factors of AE-IPF

  3 months

Study Arms (2)

Corticosteroid with placebo

PLACEBO COMPARATOR

Population is IPF patients with an AE who meet the inclusion and exclusion criteria defined below. All patients will receive non experimental medication with high dose of corticosteroid.

Drug: Placebo; Drug: Corticosteroid (prednisolone)

Corticosteroid associated with Cyclophosphamide

EXPERIMENTAL

Population is IPF patients with an AE who meet the inclusion and exclusion criteria defined below. All patients will receive non experimental medication with high dose of corticosteroid. Intravenous Cyclophosphamide (CYC), 600 mg/m² (adapted to age and renal function, maximal dose of 1.2 g) at Day 0, Day 15, M1, M2

Drug: Cyclophosphamide; Drug: Corticosteroid (prednisolone)

Interventions

Cyclophosphamide DRUG

Population is IPF patients with an AE who meet the inclusion and exclusion criteria defined below. Intravenous Cyclophosphamide (CYC), 600 mg/m² (adapted to age and renal function, maximal dose of 1.2 g) at Day 0, Day 15, M1, M2

Corticosteroid associated with Cyclophosphamide

Placebo DRUG

Population is IPF patients with an AE who meet the inclusion and exclusion criteria defined below.

Also known as: Control group

Corticosteroid with placebo

Corticosteroid (prednisolone) DRUG

All patients will receive non experimental medication with high dose of corticosteroid.

Also known as: Both groups

Corticosteroid associated with Cyclophosphamide; Corticosteroid with placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• ≥18 years of age
• Definite or probable IPF diagnosis defined on 2011 international recommendations
• Efficient contraceptive method within 1 month for women and 3 months for men after the last dose of treatment
• Affiliation to the social security
• Able to understand and sign a written informed consent form

You may not qualify if:

• Identified etiology for acute worsening (i.e. infectious disease)
• Known hypersensitivity or contra-indication to CYC or to any component of the study treatment
• Patient on mechanical ventilation
• Active bacterial, viral, fungal or parasitic infection
• Active cancer
• Patient on a lung transplantation waiting list
• Treatment with CYC in the last 12 months
• Patient participating to another clinical trial
• Pregnancy or lactation

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Hôpital Tenon

Paris, France

Location

Related Publications (27)

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  PMID: 22607134 BACKGROUND

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  PMID: 17585107 BACKGROUND

• Oishi K, Mimura-Kimura Y, Miyasho T, Aoe K, Ogata Y, Katayama H, Murata Y, Ueoka H, Matsumoto T, Mimura Y. Association between cytokine removal by polymyxin B hemoperfusion and improved pulmonary oxygenation in patients with acute exacerbation of idiopathic pulmonary fibrosis. Cytokine. 2013 Jan;61(1):84-9. doi: 10.1016/j.cyto.2012.08.032. Epub 2012 Sep 26.

  PMID: 23021430 BACKGROUND

• Morawiec E, Tillie-Leblond I, Pansini V, Salleron J, Remy-Jardin M, Wallaert B. Exacerbations of idiopathic pulmonary fibrosis treated with corticosteroids and cyclophosphamide pulses. Eur Respir J. 2011 Dec;38(6):1487-9. doi: 10.1183/09031936.00127311. No abstract available.

  PMID: 22130770 BACKGROUND

• Simon-Blancal V, Freynet O, Nunes H, Bouvry D, Naggara N, Brillet PY, Denis D, Cohen Y, Vincent F, Valeyre D, Naccache JM. Acute exacerbation of idiopathic pulmonary fibrosis: outcome and prognostic factors. Respiration. 2012;83(1):28-35. doi: 10.1159/000329891. Epub 2011 Aug 23.

  PMID: 21860222 BACKGROUND

• Agarwal R, Jindal SK. Acute exacerbation of idiopathic pulmonary fibrosis: a systematic review. Eur J Intern Med. 2008 Jun;19(4):227-35. doi: 10.1016/j.ejim.2007.04.024. Epub 2008 Jan 16.

  PMID: 18471669 BACKGROUND

• Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Muller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schunemann HJ; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011 Mar 15;183(6):788-824. doi: 10.1164/rccm.2009-040GL.

  PMID: 21471066 BACKGROUND

• Cottin V, Crestani B, Valeyre D, Wallaert B, Cadranel J, Dalphin JC, Delaval P, Israel-Biet D, Kessler R, Reynaud-Gaubert M, Cordier JF, Aguilaniu B, Bouquillon B, Carre P, Danel C, Faivre JB, Ferreti G, Just N, Kouzan S, Lebargy F, Marchand Adam S, Philippe B, Prevot G, Stach B, Thivolet-Bejui F; French National Reference and Competence Centers for Rare Diseases; Societe de Pneumologies de Langue Francaise. [French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis. From the National Reference and the Competence centers for rare diseases and the Societe de Pneumologie de Langue Francaise]. Rev Mal Respir. 2013 Dec;30(10):879-902. doi: 10.1016/j.rmr.2013.09.007. Epub 2013 Oct 25. No abstract available. French.

  PMID: 24314711 BACKGROUND

• Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev. 2012 Dec 1;21(126):355-61. doi: 10.1183/09059180.00002512.

  PMID: 23204124 BACKGROUND

• Wuyts WA, Agostini C, Antoniou KM, Bouros D, Chambers RC, Cottin V, Egan JJ, Lambrecht BN, Lories R, Parfrey H, Prasse A, Robalo-Cordeiro C, Verbeken E, Verschakelen JA, Wells AU, Verleden GM. The pathogenesis of pulmonary fibrosis: a moving target. Eur Respir J. 2013 May;41(5):1207-18. doi: 10.1183/09031936.00073012. Epub 2012 Oct 25.

  PMID: 23100500 BACKGROUND

• Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King TE Jr, Flaherty KR, Schwartz DA, Noble PW, Raghu G, Brown KK; IPF Study Group. The clinical course of patients with idiopathic pulmonary fibrosis. Ann Intern Med. 2005 Jun 21;142(12 Pt 1):963-7. doi: 10.7326/0003-4819-142-12_part_1-200506210-00005.

  PMID: 15968010 BACKGROUND

• Collard HR, Yow E, Richeldi L, Anstrom KJ, Glazer C; IPFnet investigators. Suspected acute exacerbation of idiopathic pulmonary fibrosis as an outcome measure in clinical trials. Respir Res. 2013 Jul 13;14(1):73. doi: 10.1186/1465-9921-14-73.

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• Churg A, Muller NL, Silva CI, Wright JL. Acute exacerbation (acute lung injury of unknown cause) in UIP and other forms of fibrotic interstitial pneumonias. Am J Surg Pathol. 2007 Feb;31(2):277-84. doi: 10.1097/01.pas.0000213341.70852.9d.

  PMID: 17255773 BACKGROUND

• Papiris SA, Manali ED, Kolilekas L, Kagouridis K, Triantafillidou C, Tsangaris I, Roussos C. Clinical review: idiopathic pulmonary fibrosis acute exacerbations--unravelling Ariadne's thread. Crit Care. 2010;14(6):246. doi: 10.1186/cc9241. Epub 2010 Dec 22.

  PMID: 21235829 BACKGROUND

• Song JW, Hong SB, Lim CM, Koh Y, Kim DS. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors and outcome. Eur Respir J. 2011 Feb;37(2):356-63. doi: 10.1183/09031936.00159709. Epub 2010 Jul 1.

  PMID: 20595144 BACKGROUND

• Akira M, Kozuka T, Yamamoto S, Sakatani M. Computed tomography findings in acute exacerbation of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2008 Aug 15;178(4):372-8. doi: 10.1164/rccm.200709-1365OC. Epub 2008 May 1.

  PMID: 18451320 BACKGROUND

• Ambrosini V, Cancellieri A, Chilosi M, Zompatori M, Trisolini R, Saragoni L, Poletti V. Acute exacerbation of idiopathic pulmonary fibrosis: report of a series. Eur Respir J. 2003 Nov;22(5):821-6. doi: 10.1183/09031936.03.00022703.

  PMID: 14621091 BACKGROUND

• Kim DS, Park JH, Park BK, Lee JS, Nicholson AG, Colby T. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical features. Eur Respir J. 2006 Jan;27(1):143-50. doi: 10.1183/09031936.06.00114004.

  PMID: 16387947 BACKGROUND

• Fujimoto K, Taniguchi H, Johkoh T, Kondoh Y, Ichikado K, Sumikawa H, Ogura T, Kataoka K, Endo T, Kawaguchi A, Muller NL. Acute exacerbation of idiopathic pulmonary fibrosis: high-resolution CT scores predict mortality. Eur Radiol. 2012 Jan;22(1):83-92. doi: 10.1007/s00330-011-2211-6. Epub 2011 Aug 7.

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• Kondoh Y, Taniguchi H, Kitaichi M, Yokoi T, Johkoh T, Oishi T, Kimura T, Nishiyama O, Kato K, du Bois RM. Acute exacerbation of interstitial pneumonia following surgical lung biopsy. Respir Med. 2006 Oct;100(10):1753-9. doi: 10.1016/j.rmed.2006.02.002. Epub 2006 Apr 3.

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• Rice AJ, Wells AU, Bouros D, du Bois RM, Hansell DM, Polychronopoulos V, Vassilakis D, Kerr JR, Evans TW, Nicholson AG. Terminal diffuse alveolar damage in relation to interstitial pneumonias. An autopsy study. Am J Clin Pathol. 2003 May;119(5):709-14. doi: 10.1309/UVAR-MDY8-FE9F-JDKU.

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• Tomioka H, Sakurai T, Hashimoto K, Iwasaki H. Acute exacerbation of idiopathic pulmonary fibrosis: role of Chlamydophila pneumoniae infection. Respirology. 2007 Sep;12(5):700-6. doi: 10.1111/j.1440-1843.2007.01119.x.

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• de Groot K, Harper L, Jayne DR, Flores Suarez LF, Gregorini G, Gross WL, Luqmani R, Pusey CD, Rasmussen N, Sinico RA, Tesar V, Vanhille P, Westman K, Savage CO; EUVAS (European Vasculitis Study Group). Pulse versus daily oral cyclophosphamide for induction of remission in antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2009 May 19;150(10):670-80. doi: 10.7326/0003-4819-150-10-200905190-00004.

  PMID: 19451574 BACKGROUND

• Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, Arriola E, Silver R, Strange C, Bolster M, Seibold JR, Riley DJ, Hsu VM, Varga J, Schraufnagel DE, Theodore A, Simms R, Wise R, Wigley F, White B, Steen V, Read C, Mayes M, Parsley E, Mubarak K, Connolly MK, Golden J, Olman M, Fessler B, Rothfield N, Metersky M; Scleroderma Lung Study Research Group. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006 Jun 22;354(25):2655-66. doi: 10.1056/NEJMoa055120.

  PMID: 16790698 BACKGROUND

• Cottin V, Cadranel J, Crestani B, Dalphin JC, Delaval P, Israel-Biet D, Kessler R, Reynaud-Gaubert M, Valeyre D, Wallaert B, Bouquillon B, Cordier JF. Management of idiopathic pulmonary fibrosis in France: a survey of 1244 pulmonologists. Respir Med. 2014 Jan;108(1):195-202. doi: 10.1016/j.rmed.2013.11.017. Epub 2013 Dec 3.

  PMID: 24361163 BACKGROUND

• Naccache JM, Jouneau S, Didier M, Borie R, Cachanado M, Bourdin A, Reynaud-Gaubert M, Bonniaud P, Israel-Biet D, Prevot G, Hirschi S, Lebargy F, Marchand-Adam S, Bautin N, Traclet J, Gomez E, Leroy S, Gagnadoux F, Riviere F, Bergot E, Gondouin A, Blanchard E, Parrot A, Blanc FX, Chabrol A, Dominique S, Gibelin A, Tazi A, Berard L, Brillet PY, Debray MP, Rousseau A, Kerjouan M, Freynet O, Dombret MC, Gamez AS, Nieves A, Beltramo G, Pastre J, Le Borgne-Krams A, Degot T, Launois C, Plantier L, Wemeau-Stervinou L, Cadranel J, Chenivesse C, Valeyre D, Crestani B, Cottin V, Simon T, Nunes H; EXAFIP investigators and the OrphaLung network. Cyclophosphamide added to glucocorticoids in acute exacerbation of idiopathic pulmonary fibrosis (EXAFIP): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Respir Med. 2022 Jan;10(1):26-34. doi: 10.1016/S2213-2600(21)00354-4. Epub 2021 Sep 7.

  PMID: 34506761 RESULT

• Naccache JM, Montil M, Cadranel J, Cachanado M, Cottin V, Crestani B, Valeyre D, Wallaert B, Simon T, Nunes H. Study protocol: exploring the efficacy of cyclophosphamide added to corticosteroids for treating acute exacerbation of idiopathic pulmonary fibrosis; a randomized double-blind, placebo-controlled, multi-center phase III trial (EXAFIP). BMC Pulm Med. 2019 Apr 11;19(1):75. doi: 10.1186/s12890-019-0830-x.

  PMID: 30971235 DERIVED

MeSH Terms

Conditions

Idiopathic Pulmonary Fibrosis

Interventions

Cyclophosphamide; Control Groups; Adrenal Cortex Hormones; Prednisolone

Condition Hierarchy (Ancestors)

Pulmonary Fibrosis; Lung Diseases, Interstitial; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Research Design; Methods; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Study Officials

• Jean-Marc NACCACHE, PH

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 16, 2015
• First Posted: June 2, 2015
• Study Start: December 1, 2015
• Primary Completion: January 1, 2019
• Study Completion: July 1, 2019
• Last Updated: June 30, 2022

Record last verified: 2022-06

Locations

FR (1)