Glucocorticoids Versus Placebo for the Treatment of Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Official title

Glucocorticoids Versus Placebo for the Treatment of Acute Exacerbation of Idiopathic Pulmonary Fibrosis: a Randomized Controlled Trial

Overview

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is associated with a poor prognosis, with a 3-month mortality rate of over 50%. To date, no treatment has been proven to be effective in AI-FPI. The interest of glucocorticoids is controversial and needs to be confirmed. This confirmation is mandatory to validate the improvement of the prognosis of EA-IPF under this treatment but also to search for unsuspected deleterious effects as it has been shown with immunosuppressants in stable idiopathic pulmonary fibrosis.

Detailed description

Idiopathic pulmonary fibrosis (IPF) is the most frequent idiopathic interstitial lung disease (ILD) in adults. Its prognosis is poor with a median survival time ranging from 2 to 3 years. Acute exacerbation of IPF (IPF-AE) is defined as acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormalities. Recently, diagnosis criteria were defined now allowing standardized diagnosis of IPF-AE and thus its study. IPF-AE is a major event of the disease having a 5 to 10% annual incidence. In-hospital mortality after IPF-AE exceeds 50% and current evidence suggests that up to 46% of deaths in IPF patients are associated with IPF-AE.

For the time being, no treatment has been proved to be effective in IPF-AE. While the clinical practice guideline suggests treatment with steroids, this recommendation is based only on expert opinion (low level evidence). Retrospective studies suggested the efficacy of thrombomodulin, cyclophosphamide or of therapeutic strategy including plasma exchange, rituximab and intravenous immunoglobulins. A recent Japanese randomized trial failed to show the efficacy of thrombomodulin alfa. Investigators performed a randomized trial assessing the role of cyclophosphamide on top of pulse steroid (EXAFIP-NCT02460588) and showed that cyclophosphamide did not reduce the 3-month mortality. A study assessing the effect of therapeutic plasma exchange, rituximab and intravenous immunoglobulins for severe form of IPF-AE patients admitted to Intensive Care Unit (ICU) is still ongoing (NCT03286556). Presently, the clinical benefit of corticosteroids is questioned. Indeed, 2 retrospective series reported an absence of outcome improvement by corticosteroids among IPF-AE patients and even suggested a potential detrimental outcome.

It is therefore necessary to set-up a placebo-controlled randomized trial: investigator's goal is to test the hypothesis that a corticosteroid treatment is highly efficient in IPF-AE, compared to placebo.

This underlines that, as no good evidence is available to support the use of glucocorticoids in IPF-AE, randomized controlled trials are also needed to address their efficacy and safety in this indication.

The choices of glucocorticoids' dosage, primary objective (mortality) and primary assessment criteria (all cause mortality rate at Day 30) are driven by investigator's previous study, EXAFIP. In this study, glucocorticoids dosage was as follow: intravenous methylprednisolone, 10 mg/kg/d (without exceeding 1000 mg/d), 3 days in a row shift to prednisone at 1 mg/kg/d for 1 week, and 0.75 mg/kg/d for 1 week, then 0.5 mg/kg/d for 1 week, and 0.25 mg/kg/d for 1 week, and 10 mg/d if weight \> 65 kg; 7.5 mg if weight ≤ 65 kg until M6. The 1-month mortality of patient under this high dose of glucocorticoids was 20%.

In view of the poor prognosis of IPF-AE, it seems also important to evaluate the effect of treatment on overall mortality at Day 90.

Interventions

• Drug Methylprednisone/Prednisone
  Patients will be enrolled during their hospitalization in pneumology department, as part of current practice, within 7 days of the screening visit. The investigator will perform randomization by connecting to the eCRF, randomization be stratified for the severity of IPF and the treatment with antifibrotic therapy (Nintedanib or Pirfenidone) (yes/no). If patient is randomized in Glucocorticoids Group: * Day 1, 2 and 3: Intravenous Methylprednisolone 10 mg/kg/d (without exceeding 1000 mg/d). Via
• Other Placebo
  Patients will be enrolled during their hospitalization in pneumology department, as part of current practice, within 7 days of the screening visit. The investigator will perform randomization by connecting to the eCRF, randomization be stratified for the severity of IPF and the treatment with antifibrotic therapy (Nintedanib or Pirfenidone) (yes/no). If patient is randomized in Placebo Group: Day 1, 2 and 3: Intravenous Methylprednisolone-Placebo From Day 4 to Day 30: Oral Prednisone-Placebo T

Primary outcome measures

• Efficacy of glucocorticoids compared to placebo on mortality [Time frame: Day 30]

Secondary outcome measures (12)

• Time to death at Day 30 [Time frame: Day 30]
• Time to death at Day 90 [Time frame: Day 90]
• Death or transplantation at Day 90 [Time frame: Day90]
• Respiratory disease-specific mortality rate at Day 30 [Time frame: Day 30]
• Respiratory disease-specific mortality rate at Day 90 [Time frame: Day 90]
• Time to worsening [Time frame: Day30]
• Percentage of patients admitted to ICU [Time frame: Day90]
• Percentage of patients requiring invasive ventilation [Time frame: Day90]
• Length of hospital stay [Time frame: Day 90]
• Radiological evolution [Time frame: Day90]
• Pulmonary function tests evolution: Forced Vital Capacity [Time frame: Day90]
• Pulmonary function tests evolution: DLCO [Time frame: Day90]

Eligibility criteria

Inclusion criteria

• Patient is ≥ 18 years of age
• IPF or IPF (likely) diagnosis defined on 2018 international recommendations
• Definite or suspected Acute Exacerbation defined by the international working group criteria after exclusion of alternative diagnoses of acute worsening

\*The criteria of IPF-AE are as follows:

• Previous or concurrent diagnosis of IPF (a)
• Acute worsening or development of dyspnea typically < 1-month duration
• Computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with usual interstitial pneumonia pattern (b)
• Deterioration not fully explained by cardiac failure or fluid overload Patients who fail to meet all 4 criteria due to missing computed tomography should be considered as having "suspected Acute Exacerbation".

• If the diagnosis of IPF is not previously established, this criterion can be met by the presence of radiologic and/or histopathologic changes consistent with usual interstitial pneumonia pattern on the current evaluation.
• If no previous computed tomography is available, the qualifier "new" can be dropped from the third criterion.
• For women of childbearing age: efficient contraception for the duration of the study\*

\*Effective contraception is defined as any contraceptive method that is used consistently and appropriately and has a low failure rate (i.e., less than 1% per year)

• Affiliation to the social security
• Patient able to understand and sign a written informed consent form or in case of incapacity of the patient to a relative whom understand and sign a written informed consent form

Exclusion criteria

• Identified etiology for acute worsening (i.e.: infectious disease)
• Known hypersensitivity to glucocorticoids or to any component of the study treatment
• Patient requiring mechanical ventilation or already on mechanical ventilation
• Active bacterial, viral, fungal or parasitic infection. On swab collected, only positive for SARS-CoV-2, Influenzae A, Influenzae B and Respiratory Syncytial Virus (RSV) result, are considered active viral infection. The others viruses (i.e. Rhinovirus, Adenovirus…) are not considered to be responsible of pneumonia.
• Active cancer
• Patient on a lung transplantation waiting list
• Treatment with glucocorticoids > 1 mg/kg/d from more than 7 days in the last 15 days
• Patient participating to another interventional clinical trial
• Documented pregnancy or lactation
• Patient under tutorship or curatorship
• Patient deprived of liberty
• Patient under court protection

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Treatment

Study locations

France · 29 centers

• CHU ANgers — Angers
• CHU de Besancon — Besançon
• Hôpital Avicenne — Bobigny
• CHU BOrdeaux — Bordeaux
• CHU Caen — Caen
• CHU Clermont-Ferrand — Clermont-Ferrand
• CHIC — Créteil
• CHU de Dijon — Dijon
• … and 21 more centers

Publications

• 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/s128 PMID 30971235
• 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 M PMID 34506761
• Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, Behr J, Cottin V, Danoff SK, Morell F, Flaherty KR, Wells A, Martinez FJ, Azuma A, Bice TJ, Bouros D, Brown KK, Collard HR, Duggal A, Galvin L, Inoue Y, Jenkins RG, Johkoh T, Kazerooni EA, Kitaichi M, Knight SL, Mansour G, Nicholson AG, Pipavath SNJ, Buendia-Roldan I, Selman M, Travis WD, Walsh S, Wilson KC; American Thoracic So PMID 30168753
• Collard HR, Ryerson CJ, Corte TJ, Jenkins G, Kondoh Y, Lederer DJ, Lee JS, Maher TM, Wells AU, Antoniou KM, Behr J, Brown KK, Cottin V, Flaherty KR, Fukuoka J, Hansell DM, Johkoh T, Kaminski N, Kim DS, Kolb M, Lynch DA, Myers JL, Raghu G, Richeldi L, Taniguchi H, Martinez FJ. Acute Exacerbation of Idiopathic Pulmonary Fibrosis. An International Working Group Report. Am J Respir Crit Care Med. 2016 PMID 27299520
• Kondoh Y, Azuma A, Inoue Y, Ogura T, Sakamoto S, Tsushima K, Johkoh T, Fujimoto K, Ichikado K, Matsuzawa Y, Saito T, Kishi K, Tomii K, Sakamoto N, Aoshima M, Araya J, Izumi S, Arita M, Abe M, Yamauchi H, Shindoh J, Suda T, Okamoto M, Ebina M, Yamada Y, Tohda Y, Kawamura T, Taguchi Y, Ishii H, Hashimoto N, Abe S, Taniguchi H, Tagawa J, Bessho K, Yamamori N, Homma S. Thrombomodulin Alfa for Acute Ex PMID 31917621
• Papiris SA, Kagouridis K, Kolilekas L, Papaioannou AI, Roussou A, Triantafillidou C, Baou K, Malagari K, Argentos S, Kotanidou A, Karakatsani A, Manali ED. Survival in Idiopathic pulmonary fibrosis acute exacerbations: the non-steroid approach. BMC Pulm Med. 2015 Dec 14;15:162. doi: 10.1186/s12890-015-0146-4. PMID 26666385
• Farrand E, Vittinghoff E, Ley B, Butte AJ, Collard HR. Corticosteroid use is not associated with improved outcomes in acute exacerbation of IPF. Respirology. 2020 Jun;25(6):629-635. doi: 10.1111/resp.13753. Epub 2019 Dec 17. PMID 31846126
• 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

Identifiers

NCT: NCT05674994 · EXAFIP2

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗