Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis.

Bayes Theorem Cyclic Nucleotide Phosphodiesterases, Type 4 Double-Blind Method Humans Idiopathic Pulmonary Fibrosis / drug therapy Phosphodiesterase 4 Inhibitors / therapeutic use Phosphodiesterase Inhibitors / therapeutic use Treatment Outcome Vital Capacity / physiology

Journal

The New England journal of medicine
ISSN: 1533-4406
Titre abrégé: N Engl J Med
Pays: United States
ID NLM: 0255562

Informations de publication

Date de publication:
09 06 2022
Historique:
pubmed: 16 5 2022
medline: 11 6 2022
entrez: 15 5 2022
Statut: ppublish

Résumé

Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis. In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent. A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550 group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups. In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis. (Funded by Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.).

Sections du résumé

BACKGROUND
Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis.
METHODS
In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent.
RESULTS
A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550 group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups.
CONCLUSIONS
In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis. (Funded by Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.).

Identifiants

DOI: 10.1056/NEJMoa2201737 PMID: 35569036
pubmed: 35569036
doi: 10.1056/NEJMoa2201737
doi:

Substances chimiques

Phosphodiesterase 4 Inhibitors 0
Phosphodiesterase Inhibitors 0
Cyclic Nucleotide Phosphodiesterases, Type 4 EC 3.1.4.17

Banques de données

ClinicalTrials.gov
['NCT04419506']

Types de publication

Clinical Trial, Phase II Journal Article Randomized Controlled Trial

Langues

eng

Sous-ensembles de citation

IM

Pagination

2178-2187

Subventions

Organisme : Boehringer Ingelheim
ID : N/A

Investigateurs

María Otaola (M)
Pedro Elias (P)
German Arce (G)
Ian Glaspole (I)
Tamera Corte (T)
Horst Olschewski (H)
Marco Idzko (M)
Bernd Lamprecht (B)
Syed Anees (S)
Onofre Moran Mendoza (O)
Marcel Mallet (M)
Chris Ryerson (C)
Helene Manganas (H)
Absalon Silva Orellana (A)
Mauricio Salinas Fénero (M)
Jie Zhang (J)
Jinfu Xu (J)
Zuojun Xu (Z)
Qunying Hong (Q)
Fuqiang Wen (F)
Martina Sterclova (M)
Norbert Pauk (N)
Elisabeth Bendstrup (E)
Saher Shaker (S)
Ingrid Titlestad (I)
Marjukka Myllärniemi (M)
Maritta Kilpeläinen (M)
Ismo Strander (I)
Minna Purokivi (M)
Riitta Kaarteenaho (R)
Dirk Koschel (D)
Rainer Wiewrodt (R)
Jürgen Behr (J)
Michael Kreuter (M)
Peter Hammerl (P)
Francesco Bonella (F)
Stefan Blaas (S)
Aikaterini Antoniou (A)
Demosthenes Bouros (D)
Argyrios Tzouvelekis (A)
Veronika Muller (V)
Luca Richeldi (L)
Carlo Albera (C)
Elisabetta Balestro (E)
Elena Bargagli (E)
Donato Lacedonia (D)
Claudia Ravaglia (C)
Paola Rogliani (P)
Yasuhiro Kondo (Y)
Shinyu Izumi (S)
Yutaro Nakamura (Y)
Hideya Kitamura (H)
Yoshikazu Inoue (Y)
Masaki Okamoto (M)
Rémy L M Mostard (RLM)
Marlies Wijsenbeek-Lourens (M)
Marcel Veltkamp (M)
Esther J Nossent (EJ)
Wojciech Piotrowski (W)
Alicja Sieminska (A)
Yong-Hyun Kim (YH)
Jin Woo Song (JW)
Sun Mi Choi (SM)
Evgeny Bazdyrev (E)
Sergey Moiseev (S)
Vladimir Yakusevich (V)
Evgeniy Shmelev (E)
Olga Rumyantseva (O)
María Molina-Molina (M)
Juan Roldán Sánchez (J)
Claudia Valenzuela (C)
Jacobo Sellares (J)
Jaume Sauleda (J)
Miguel Arias (M)
Oleksandr Dziublyk (O)
Kseniia Bielosludtseva (K)
Philip Molyneaux (P)
Huzaifa Adamali (H)
Divya Patel (D)
Barry Sigal (B)
Stephen Weigt (S)
Charles Andrews (C)
Francis Averill (F)
Mary Scholand (M)
Mark Hamblin (M)
Nitin Bhatt (N)
Neil Ettinger (N)
Gerard Criner (G)
Lee Morrow (L)
Teng Moua (T)
Arata Azuma (A)
Vincent Cottin (V)
Marlies S Wijsenbeek (MS)
Toby M Maher (TM)
Ulrich Costabel (U)
Johannes Cornelis Grutters (J)
Maureen R Horton (MR)
Milton D Rossman (MD)
Kevin Anstrom (K)

Commentaires et corrections

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Informations de copyright

Copyright © 2022 Massachusetts Medical Society.

Auteurs

Luca Richeldi (L)

From Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome (L.R.); Nippon Medical School, Tokyo (A.A.); Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon, Unité Mixte de Recherche 754 Institut National de la Recherche Agronomique and Université Claude Bernard Lyon 1, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), RespiFil, OrphaLung, Lyon, France (V.C.); Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim International, Biberach (C.H.), and TA Inflammation Medicine (S.S.), Boehringer Ingelheim Pharma (F.V.), Ingelheim am Rhein - both in Germany; the Interstitial Lung Disease Unit, Department of Pulmonology, Hospital Universitario de la Princesa, University Autonoma de Madrid, Madrid (C.V.); the Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (M.S.W.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.F.Z.); Keck School of Medicine, University of Southern California, Los Angeles (T.M.M.); and the National Heart and Lung Institute, Imperial College London, London (T.M.M.).

Arata Azuma (A)

From Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome (L.R.); Nippon Medical School, Tokyo (A.A.); Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon, Unité Mixte de Recherche 754 Institut National de la Recherche Agronomique and Université Claude Bernard Lyon 1, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), RespiFil, OrphaLung, Lyon, France (V.C.); Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim International, Biberach (C.H.), and TA Inflammation Medicine (S.S.), Boehringer Ingelheim Pharma (F.V.), Ingelheim am Rhein - both in Germany; the Interstitial Lung Disease Unit, Department of Pulmonology, Hospital Universitario de la Princesa, University Autonoma de Madrid, Madrid (C.V.); the Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (M.S.W.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.F.Z.); Keck School of Medicine, University of Southern California, Los Angeles (T.M.M.); and the National Heart and Lung Institute, Imperial College London, London (T.M.M.).

Vincent Cottin (V)

From Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome (L.R.); Nippon Medical School, Tokyo (A.A.); Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon, Unité Mixte de Recherche 754 Institut National de la Recherche Agronomique and Université Claude Bernard Lyon 1, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), RespiFil, OrphaLung, Lyon, France (V.C.); Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim International, Biberach (C.H.), and TA Inflammation Medicine (S.S.), Boehringer Ingelheim Pharma (F.V.), Ingelheim am Rhein - both in Germany; the Interstitial Lung Disease Unit, Department of Pulmonology, Hospital Universitario de la Princesa, University Autonoma de Madrid, Madrid (C.V.); the Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (M.S.W.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.F.Z.); Keck School of Medicine, University of Southern California, Los Angeles (T.M.M.); and the National Heart and Lung Institute, Imperial College London, London (T.M.M.).
ORCID: 0000-0002-5591-0955

Christian Hesslinger (C)

From Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome (L.R.); Nippon Medical School, Tokyo (A.A.); Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon, Unité Mixte de Recherche 754 Institut National de la Recherche Agronomique and Université Claude Bernard Lyon 1, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), RespiFil, OrphaLung, Lyon, France (V.C.); Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim International, Biberach (C.H.), and TA Inflammation Medicine (S.S.), Boehringer Ingelheim Pharma (F.V.), Ingelheim am Rhein - both in Germany; the Interstitial Lung Disease Unit, Department of Pulmonology, Hospital Universitario de la Princesa, University Autonoma de Madrid, Madrid (C.V.); the Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (M.S.W.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.F.Z.); Keck School of Medicine, University of Southern California, Los Angeles (T.M.M.); and the National Heart and Lung Institute, Imperial College London, London (T.M.M.).

Susanne Stowasser (S)

From Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome (L.R.); Nippon Medical School, Tokyo (A.A.); Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon, Unité Mixte de Recherche 754 Institut National de la Recherche Agronomique and Université Claude Bernard Lyon 1, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), RespiFil, OrphaLung, Lyon, France (V.C.); Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim International, Biberach (C.H.), and TA Inflammation Medicine (S.S.), Boehringer Ingelheim Pharma (F.V.), Ingelheim am Rhein - both in Germany; the Interstitial Lung Disease Unit, Department of Pulmonology, Hospital Universitario de la Princesa, University Autonoma de Madrid, Madrid (C.V.); the Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (M.S.W.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.F.Z.); Keck School of Medicine, University of Southern California, Los Angeles (T.M.M.); and the National Heart and Lung Institute, Imperial College London, London (T.M.M.).

Claudia Valenzuela (C)

From Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome (L.R.); Nippon Medical School, Tokyo (A.A.); Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon, Unité Mixte de Recherche 754 Institut National de la Recherche Agronomique and Université Claude Bernard Lyon 1, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), RespiFil, OrphaLung, Lyon, France (V.C.); Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim International, Biberach (C.H.), and TA Inflammation Medicine (S.S.), Boehringer Ingelheim Pharma (F.V.), Ingelheim am Rhein - both in Germany; the Interstitial Lung Disease Unit, Department of Pulmonology, Hospital Universitario de la Princesa, University Autonoma de Madrid, Madrid (C.V.); the Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (M.S.W.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.F.Z.); Keck School of Medicine, University of Southern California, Los Angeles (T.M.M.); and the National Heart and Lung Institute, Imperial College London, London (T.M.M.).

Marlies S Wijsenbeek (MS)

From Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome (L.R.); Nippon Medical School, Tokyo (A.A.); Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon, Unité Mixte de Recherche 754 Institut National de la Recherche Agronomique and Université Claude Bernard Lyon 1, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), RespiFil, OrphaLung, Lyon, France (V.C.); Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim International, Biberach (C.H.), and TA Inflammation Medicine (S.S.), Boehringer Ingelheim Pharma (F.V.), Ingelheim am Rhein - both in Germany; the Interstitial Lung Disease Unit, Department of Pulmonology, Hospital Universitario de la Princesa, University Autonoma de Madrid, Madrid (C.V.); the Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (M.S.W.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.F.Z.); Keck School of Medicine, University of Southern California, Los Angeles (T.M.M.); and the National Heart and Lung Institute, Imperial College London, London (T.M.M.).
ORCID: 0000-0002-4527-6962

Donald F Zoz (DF)

From Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome (L.R.); Nippon Medical School, Tokyo (A.A.); Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon, Unité Mixte de Recherche 754 Institut National de la Recherche Agronomique and Université Claude Bernard Lyon 1, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), RespiFil, OrphaLung, Lyon, France (V.C.); Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim International, Biberach (C.H.), and TA Inflammation Medicine (S.S.), Boehringer Ingelheim Pharma (F.V.), Ingelheim am Rhein - both in Germany; the Interstitial Lung Disease Unit, Department of Pulmonology, Hospital Universitario de la Princesa, University Autonoma de Madrid, Madrid (C.V.); the Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (M.S.W.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.F.Z.); Keck School of Medicine, University of Southern California, Los Angeles (T.M.M.); and the National Heart and Lung Institute, Imperial College London, London (T.M.M.).

Florian Voss (F)

From Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome (L.R.); Nippon Medical School, Tokyo (A.A.); Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon, Unité Mixte de Recherche 754 Institut National de la Recherche Agronomique and Université Claude Bernard Lyon 1, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), RespiFil, OrphaLung, Lyon, France (V.C.); Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim International, Biberach (C.H.), and TA Inflammation Medicine (S.S.), Boehringer Ingelheim Pharma (F.V.), Ingelheim am Rhein - both in Germany; the Interstitial Lung Disease Unit, Department of Pulmonology, Hospital Universitario de la Princesa, University Autonoma de Madrid, Madrid (C.V.); the Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (M.S.W.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.F.Z.); Keck School of Medicine, University of Southern California, Los Angeles (T.M.M.); and the National Heart and Lung Institute, Imperial College London, London (T.M.M.).

Toby M Maher (TM)

From Unità Operativa Complessa di Pneumologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome (L.R.); Nippon Medical School, Tokyo (A.A.); Hôpital Louis Pradel, Centre National de Référence des Maladies Pulmonaires Rares, Hospices Civils de Lyon, Unité Mixte de Recherche 754 Institut National de la Recherche Agronomique and Université Claude Bernard Lyon 1, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), RespiFil, OrphaLung, Lyon, France (V.C.); Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim International, Biberach (C.H.), and TA Inflammation Medicine (S.S.), Boehringer Ingelheim Pharma (F.V.), Ingelheim am Rhein - both in Germany; the Interstitial Lung Disease Unit, Department of Pulmonology, Hospital Universitario de la Princesa, University Autonoma de Madrid, Madrid (C.V.); the Department of Respiratory Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (M.S.W.); Boehringer Ingelheim Pharmaceuticals, Ridgefield, CT (D.F.Z.); Keck School of Medicine, University of Southern California, Los Angeles (T.M.M.); and the National Heart and Lung Institute, Imperial College London, London (T.M.M.).

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Classifications MeSH

questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Théorème de Bayes › Trial of a Preferential Phosphodiesterase 4B...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › 3',5'-Cyclic-AMP Phosphodiesterases › Cyclic Nucleotide Phosphodiesterases, Type 4 › Trial of a Preferential Phosphodiesterase 4B...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Méthodologie en recherche épidémiologique › Méthode en double aveugle › Trial of a Preferential Phosphodiesterase 4B...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Trial of a Preferential Phosphodiesterase 4B...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Maladies pulmonaires › Pneumopathies interstitielles › Fibrose pulmonaire idiopathique › Trial of a Preferential Phosphodiesterase 4B...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de la phosphodiestérase › Inhibiteurs de la phosphodiestérase-4 › Trial of a Preferential Phosphodiesterase 4B...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de la phosphodiestérase › Trial of a Preferential Phosphodiesterase 4B...
questionsmedicales.fr › Qualité, accès, évaluation des soins de santé › Qualité des soins de santé › Mécanismes d'évaluation des soins de santé › Évaluation des résultats et des processus en soins de santé › Évaluation de résultat (soins) › Résultat thérapeutique › Trial of a Preferential Phosphodiesterase 4B...
questionsmedicales.fr › Phénomènes physiologiques respiratoires et circulatoires › Phénomènes physiologiques respiratoires › Capacité pulmonaire totale › Capacité vitale › Trial of a Preferential Phosphodiesterase 4B...