Jean-Marc Naccache1, Stéphane Jouneau2, Morgane Didier3, Raphaël Borie4, Marine Cachanado5, Arnaud Bourdin6, Martine Reynaud-Gaubert7, Philippe Bonniaud8, Dominique Israël-Biet9, Grégoire Prévot10, Sandrine Hirschi11, François Lebargy12, Sylvain Marchand-Adam13, Nathalie Bautin14, Julie Traclet15, Emmanuel Gomez16, Sylvie Leroy17, Frédéric Gagnadoux18, Frédéric Rivière19, Emmanuel Bergot20, Anne Gondouin21, Elodie Blanchard22, Antoine Parrot23, François-Xavier Blanc24, Alexandre Chabrol25, Stéphane Dominique26, Aude Gibelin27, Abdellatif Tazi28, Laurence Berard5, Pierre Yves Brillet29, Marie-Pierre Debray30, Alexandra Rousseau5, Mallorie Kerjouan31, Olivia Freynet3, Marie-Christine Dombret4, Anne-Sophie Gamez6, Ana Nieves7, Guillaume Beltramo8, Jean Pastré9, Aurélie Le Borgne-Krams10, Tristan Dégot11, Claire Launois12, Laurent Plantier13, Lidwine Wémeau-Stervinou14, Jacques Cadranel23, Cécile Chenivesse32, Dominique Valeyre33, Bruno Crestani4, Vincent Cottin15, Tabassome Simon5, Hilario Nunes3. 1. Assistance Publique-Hôpitaux de Paris (APHP), Service de Pneumologie et Oncologie Thoracique, Centre Constitutif Maladies Pulmonaires Rares de l'adulte et Sorbonne Université, Hôpital Tenon, Paris; Service de Pneumologie, Groupe Hospitalier Paris Saint Joseph, Paris, France; Service de Pneumologie, Hôpital Foch, Suresnes, Paris, France. Electronic address: jmnaccache@ghpsj.fr. 2. Service de Pneumologie, Hôpital de Pontchaillou, Rennes, France; University of Rennes, INSERM, Ecole des hautes études en santé publique, Institut de Recherche en Santé Unité Mixte de Recherche (UMR) S1085, Rennes, France. 3. APHP, Service de Pneumologie et Oncologie Thoracique, Centre Constitutif Maladies Pulmonaires Rares de l'Adulte, Hôpital Avicenne, Bobigny, Paris, France. 4. Université de Paris, INSERM, Laboratoire D'Excellence Inflamex, Paris, France; APHP, Service de Pneumologie A, Centre de Référence Constitutif des Maladies Pulmonaires Rares, Fédération Hospitalo-Universitaire Apollo, Hôpital Bichat, Paris, France. 5. Department of Clinical Pharmacology and Clinical Research Platform of the East of Paris, APHP, Hôpital St Antoine, Paris, France. 6. Department of Respiratory Diseases and PhyMedExp, Centre National de la Recherche Scientifique, INSERM, University of Montpellier, Centre Hospitalo-Universitaire Montpellier, Montpellier, France. 7. CHU de Marseille, Hôpital Nord, Assistance Publique-Hôpitaux de Marseille, Pneumologie, Marseille, France. 8. Centre de Référence Constitutif des Maladies Pulmonaires Rares de l'Adulte, Service de Pneumologie et Soins Intensifs Respiratoires, Centre Hospitalier Universitaire de Dijon Bourgogne, Bourgogne-Franche-Comte, Dijon, France; Unité de Formation et de Recherche des Sciences de Santé, Université de Bourgogne-Franche Comté et INSERM, Dijon, France. 9. APHP, Service de pneumologie, CHU Hôpital Européen Georges Pompidou, Paris, France. 10. Service de Pneumologie, Hôpital Larrey, Toulouse, France. 11. Service de Pneumologie, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, France. 12. Service des Maladies Respiratoires, CHU de la Maison Blanche, Reims, France. 13. Service De Pneumologie et d'explorations Fonctionnelles Respiratoires, Centre Hospitalier Regional Universitaire Tours, Tours, France. 14. CHU Lille, Service de Pneumologie et Immuno-Allergologie, Centre de Référence Constitutif des Maladies Pulmonaires Rares, Hôpital Calmette, Lille, France. 15. Centre Coordonnateur National De Référence Des Maladies Pulmonaires Rares, Hôpital Louis-Pradel, Hospices Civils de Lyon, Université de Lyon, Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (INSERM), Department of Pneumologie, Centre d'Investigation Clinique de Lyon, INSERM, Lyon, France. 16. Département de Pneumologie, Pôles de Spécialités Médicales Centre Hospitalier Regional Universitaire Brabois, Vandoeuvre les Nancy, France. 17. Université Côte d'Azur, Département de Pneumologie, CHU de Nice, Nice, France. 18. Université d'Angers, Département de Pneumologie, CHU d'Angers, Angers, France. 19. Hôpital d'Instruction des Armées Percy, Service de Pneumologie, Clamart, France. 20. Service de Pneumologie et Oncologie Thoracique, CHU Côte de Nacre, Caen, Normandy, France. 21. Service de Pneumologie, CHU Jean Minjoz, Besançon, France. 22. Service des Maladies Respiratoires, CHU Bordeaux, Hôpital Haut-Lévêque, Bordeaux, France. 23. Assistance Publique-Hôpitaux de Paris (APHP), Service de Pneumologie et Oncologie Thoracique, Centre Constitutif Maladies Pulmonaires Rares de l'adulte et Sorbonne Université, Hôpital Tenon, Paris. 24. Department of Respiratory Medicine, L'Institut du Thorax, Nantes University Hospital, and the Medical School, University of Nantes, Nantes, France. 25. Service de Pneumologie, Hôpital Foch, Suresnes, Paris, France. 26. Departement of Pneumology, Rouen University Hospital, Rouen, France. 27. APHP, Service de Réanimation, Hôpital Tenon, Paris. 28. Université de Paris, INSERM U976, Institut de Recherche Saint-Louis, Paris, France; Centre National de Référence des Histiocytoses, Service de Pneumologie, APHP, Hôpital Saint-Louis, Paris, France. 29. APHP, Service de Radiologie, Hôpital Avicenne, Bobigny, Paris, France. 30. Service de Radiologie, Hôpital Bichat Claude Bernard, APHP et INSERM UMR-1152, Paris, France. 31. Service de Pneumologie, Hôpital de Pontchaillou, Rennes, France. 32. CHU Lille, Service de Pneumologie et Immuno-Allergologie, Centre de Référence Constitutif des Maladies Pulmonaires Rares, Hôpital Calmette, Lille, France; CHU Lille, University of Lille, Centre National de la Recherche Scientifique, INSERM, Institut Pasteur de Lille, Centre d'Infection et d'Immunité de Lille, Lille, France. 33. Service de Pneumologie, Groupe Hospitalier Paris Saint Joseph, Paris, France; APHP, Service de Pneumologie et Oncologie Thoracique, Centre Constitutif Maladies Pulmonaires Rares de l'Adulte, Hôpital Avicenne, Bobigny, Paris, France; INSERM UMR 1272, Université Sorbonne Paris Nord, Bobigny, Paris, France.
Abstract
BACKGROUND: The use of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is unknown. Our study was designed to evaluate the efficacy and safety of four cyclophosphamide pulses in addition to high-dose methylprednisolone in this population. METHODS: In this double-blind, placebo-controlled trial done in 35 departments across 31 hospitals in France, adult patients (≥18 years) with acute exacerbation of IPF and those with suspected acute exacerbation of IPF were randomly assigned in a 1:1 ratio using a web-based system to receive either intravenous pulses of cyclophosphamide (600 mg/m2) plus uromitexan as haemorrhagic cystitis prophylaxis (200 mg/m2) at the time of cyclophosphamide administration and then again, 4 h later, or placebo at days 0, 15, 30, and 60. Random assignment was stratified according to the severity of IPF and was block-balanced with variable block sizes of four or six patients. Patients receiving mechanical ventilation, with active infection, with active cancer, or who were registered on the lung transplant waiting list were excluded. All patients received standardised high-dose glucocorticoids. The investigators, patients, and the sponsor were masked to the treatment assignments. The primary endpoint was 3-month all-cause mortality, analysed by a χ2 test adhering to an intention-to-treat principle. The trial is now complete and registered with ClinicalTrials.gov, NCT02460588. FINDINGS: Between Jan 22, 2016, and July 19, 2018, 183 patients were assessed for eligibility, of whom 120 patients were randomly assigned and 119 patients (62 [52%] with severe IPF) received at least one dose of cyclophosphamide (n=60) or placebo (n=59), all of whom were included in the intention-to-treat analysis. The 3-month all-cause mortality was 45% (27/60) in patients given cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14·5% [95% CI -3·1 to 31·6]; p=0·10). Similar results were found after adjustment by IPF severity (odds ratio [OR] 1·89 [95% CI 0·89-4·04]). The risk of death at 3 months, independent of the treatment received, was higher with severe than non-severe IPF (OR 2·62 [1·12-6·12]) and was lower with the use of antifibrotic therapy (OR 0·33 [0·13-0·82]). Adverse events were similar between groups by 6 months (25 [42%] in the cyclophosphamide group vs 30 [51%] in the placebo group) and their proportion, including infections, did not differ. Overall infection was the main adverse event and occurred in 20 (33%) of 60 patients in the cyclophosphamide group versus 21 (36%) of 59 patients in the placebo group. INTERPRETATION: In patients with acute exacerbation of IPF, adding intravenous cyclophosphamide pulses to glucocorticoids increased 3-month mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC 2014-502), Roche Pharmaceuticals.
BACKGROUND: The use of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is unknown. Our study was designed to evaluate the efficacy and safety of four cyclophosphamide pulses in addition to high-dose methylprednisolone in this population. METHODS: In this double-blind, placebo-controlled trial done in 35 departments across 31 hospitals in France, adult patients (≥18 years) with acute exacerbation of IPF and those with suspected acute exacerbation of IPF were randomly assigned in a 1:1 ratio using a web-based system to receive either intravenous pulses of cyclophosphamide (600 mg/m2) plus uromitexan as haemorrhagic cystitis prophylaxis (200 mg/m2) at the time of cyclophosphamide administration and then again, 4 h later, or placebo at days 0, 15, 30, and 60. Random assignment was stratified according to the severity of IPF and was block-balanced with variable block sizes of four or six patients. Patients receiving mechanical ventilation, with active infection, with active cancer, or who were registered on the lung transplant waiting list were excluded. All patients received standardised high-dose glucocorticoids. The investigators, patients, and the sponsor were masked to the treatment assignments. The primary endpoint was 3-month all-cause mortality, analysed by a χ2 test adhering to an intention-to-treat principle. The trial is now complete and registered with ClinicalTrials.gov, NCT02460588. FINDINGS: Between Jan 22, 2016, and July 19, 2018, 183 patients were assessed for eligibility, of whom 120 patients were randomly assigned and 119 patients (62 [52%] with severe IPF) received at least one dose of cyclophosphamide (n=60) or placebo (n=59), all of whom were included in the intention-to-treat analysis. The 3-month all-cause mortality was 45% (27/60) in patients given cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14·5% [95% CI -3·1 to 31·6]; p=0·10). Similar results were found after adjustment by IPF severity (odds ratio [OR] 1·89 [95% CI 0·89-4·04]). The risk of death at 3 months, independent of the treatment received, was higher with severe than non-severe IPF (OR 2·62 [1·12-6·12]) and was lower with the use of antifibrotic therapy (OR 0·33 [0·13-0·82]). Adverse events were similar between groups by 6 months (25 [42%] in the cyclophosphamide group vs 30 [51%] in the placebo group) and their proportion, including infections, did not differ. Overall infection was the main adverse event and occurred in 20 (33%) of 60 patients in the cyclophosphamide group versus 21 (36%) of 59 patients in the placebo group. INTERPRETATION: In patients with acute exacerbation of IPF, adding intravenous cyclophosphamide pulses to glucocorticoids increased 3-month mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients. FUNDING: Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC 2014-502), Roche Pharmaceuticals.
Authors: Sabina A Guler; Sara Cuevas-Ocaña; Mouhamad Nasser; Wim A Wuyts; Marlies S Wijsenbeek; Antoine Froidure; Elena Bargagli; Elisabetta A Renzoni; Marcel Veltkamp; Paolo Spagnolo; Hilario Nunes; Cormac McCarthy; Maria Molina-Molina; Francesco Bonella; Venerino Poletti; Michael Kreuter; Katerina M Antoniou; Catharina C Moor Journal: ERJ Open Res Date: 2022-05-23