Cyclophosphamide for Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis Clinical Trial

— EXAFIP  

Official title:

Cyclophosphamide Added to Corticosteroid in the Treatment of Acute Exacerbation of Idiopathic Pulmonary Fibrosis: a Placebo-controlled Randomized Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02460588
• Other study ID #: P 140908
• Secondary ID: 2015-000492-27
• Status: Completed
• Phase: Phase 3
• Start date: December 2015
• Est. completion date: July 2019

Study information

• Verified date: June 2022
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 120
• Est. completion date: July 2019
• Est. primary completion date: January 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria :

• =18 years of age
• Definite or probable IPF diagnosis defined on 2011 international recommendations
• Definite or suspicion of AE defined by IPFnet criteria after exclusion of alternative diagnosis of acute worsening.
• 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

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Fibrosis
• Idiopathic Pulmonary Fibrosis
• Pulmonary Fibrosis

Intervention

Drug:
• Cyclophosphamide
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
• Placebo
Population is IPF patients with an AE who meet the inclusion and exclusion criteria defined below.
• Corticosteroid (prednisolone)
All patients will receive non experimental medication with high dose of corticosteroid.

Locations

Country	Name	City	State
France	Hôpital Tenon	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

References & Publications (26)

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. Review. — View Citation

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. — View Citation

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. — View Citation

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Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King TE Jr, Lasky JA, Loyd JE, Noth I, Olman MA, Raghu G, Roman J, Ryu JH, Zisman DA, Hunninghake GW, Colby TV, Egan JJ, Hansell DM, Johkoh T, Kaminski N, Kim DS, Kondoh Y, Lynch DA, Müller-Quernheim J, Myers JL, Nicholson AG, Selman M, Toews GB, Wells AU, Martinez FJ; Idiopathic Pulmonary Fibrosis Clinical Research Network Investigators. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2007 Oct 1;176(7):636-43. Epub 2007 Jun 21. Review. — View Citation

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;14:73. doi: 10.1186/1465-9921-14-73. — View Citation

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. — View Citation

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, Carré P, Danel C, Faivre JB, Ferreti G, Just N, Kouzan S, Lebargy F, Marchand Adam S, Philippe B, Prévot G, Stach B, Thivolet-Béjui 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 Société de Pneumologie de Langue Française]. Rev Mal Respir. 2013 Dec;30(10):879-902. doi: 10.1016/j.rmr.2013.09.007. Epub 2013 Oct 25. French. Erratum in: Rev Mal Respir. 2014 Feb;31(2):194-5. — View Citation

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. — View Citation

Fujimoto K, Taniguchi H, Johkoh T, Kondoh Y, Ichikado K, Sumikawa H, Ogura T, Kataoka K, Endo T, Kawaguchi A, Müller 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. — View Citation

Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012 May 24;366(21):1968-77. doi: 10.1056/NEJMoa1113354. Epub 2012 May 20. — View Citation

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. — View Citation

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. Epub 2006 Apr 3. — View Citation

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. — View Citation

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. — View Citation

Naccache JM, Jouneau S, Didier M, Borie R, Cachanado M, Bourdin A, Reynaud-Gaubert M, Bonniaud P, Israël-Biet D, Prévot G, Hirschi S, Lebargy F, Marchand-Adam S, Bautin N, Traclet J, Gomez E, Leroy S, Gagnadoux F, Rivière F, Bergot E, Gondouin A, Blanchar — View Citation

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. Review. — View Citation

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. — View Citation

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. Review. — View Citation

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, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann 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. — View Citation

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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. — View Citation

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. — View Citation

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. — View Citation

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* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	"Early" survival	All cause of mortality at 3 months	3 months
Secondary	Overall Survival	Overall Survival at M6 and M12	6 months and 12 montns
Secondary	Respiratory disease-specific mortality	Respiratory disease-specific mortality at M3 and M6	6 months
Secondary	Respiratory Morbidity	\Worsening dyspnea (0-100-mm visual analogue (VAS) scale anchored with 0 ''no breathlessness'' and 10 or 100 ''worst imaginable breathlessness". Worsening is defined an absolute decrease of 10 mm); Or Increase need of supplemental oxygen of more than 3l/min to obtained a SaO2 > 90% or decrease of PaO2 of more than 10 mmHg with the same rate of flow supplemental oxygen; Or Decrease FVC of more than 10% of predicted value; Or Decrease diffuse capacity for carbon monoxide (DLCO) of more than 15% prednisolone	6 months
Secondary	Chest HRCT features (HRCT images will be scored at 5 levels)	Chest HRCT features at M3 and M6 compared to inclusion	6 months
Secondary	Prognosis factors of AE-IPF	PFTs results before AE-IPF	3 months
Secondary	Time to visit after clinical worsening		3 months
Secondary	Laboratory evaluation (LDH, CRP) at AE diagnosis (composite)		3 months
Secondary	Prognosis factors of AE-IPF	PaO2 at AE diagnosis	3 months
Secondary	Prognosis factors of AE-IPF	Chest HRCT features at AE diagnosis compared to HRCT before AE-IPF (if available)	3 months
Secondary	Prognosis factors of AE-IPF	Chest HRCT classification before AE-IPF (definite UIP, probable UIP, indeterminate), if available	3 months
Secondary	Time to dispense treatment of AE-IPF		3 months
Secondary	Hemorrhagic cystitis (occurence of hematuria on urine dipstick and pelvic pain and/or dysuria should lead to cystoscopy)		6 months
Secondary	Number of Infectious disease		6 months
Secondary	Diabetes mellitus (capillary blood glucose monitoring and fasting plasma glucose > 1.26 g/l)		6 months
Secondary	Hypertension (Blood pressure > 160/100 mmHg)		6 months
Secondary	Clinical laboratory evaluation (blood count, serum creatinin measurement composite) according to Common Terminology Criteria for Adverse Event (CTCAE).		6 months