Clinical trial NCT05674994: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Acute Exacerbation of Idiopathic Pulmonary Fibrosis
Lead sponsor: Fondation Hôpital Saint-Joseph
Sponsor class: OTHER
First posted: 2023-01-09
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Eligibility criteria: Inclusion Criteria:

1. Patient is ≥ 18 years of age
2. IPF or IPF (likely) diagnosis defined on 2018 international recommendations
3. 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".

     1. 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.
     2. If no previous computed tomography is available, the qualifier "new" can be dropped from the third criterion.
4. 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)
5. Affiliation to the social security
6. 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:

1. Identified etiology for acute worsening (i.e.: infectious disease)
2. Known hypersensitivity to glucocorticoids or to any component of the study treatment
3. Patient requiring mechanical ventilation or already on mechanical ventilation
4. 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.
5. Active cancer
6. Patient on a lung transplantation waiting list
7. Treatment with glucocorticoids \> 1 mg/kg/d from more than 7 days in the last 15 days
8. Patient participating to another interventional clinical trial
9. Documented pregnancy or lactation
10. Patient under tutorship or curatorship
11. Patient deprived of liberty
12. Patient under court protection

Primary outcomes:
measure: Efficacy of glucocorticoids compared to placebo on mortality
timeFrame: Day 30
Secondary outcomes:
measure: Time to death at Day 30
timeFrame: Day 30
measure: Time to death at Day 90
timeFrame: Day 90
measure: Death or transplantation at Day 90
timeFrame: Day90
measure: Respiratory disease-specific mortality rate at Day 30
timeFrame: Day 30
measure: Respiratory disease-specific mortality rate at Day 90
timeFrame: Day 90
measure: Time to worsening
timeFrame: Day30
measure: Percentage of patients admitted to ICU
timeFrame: Day90
measure: Percentage of patients requiring invasive ventilation
timeFrame: Day90
measure: Length of hospital stay
timeFrame: Day 90
measure: Radiological evolution
timeFrame: Day90
measure: Pulmonary function tests evolution: Forced Vital Capacity
timeFrame: Day90
measure: Pulmonary function tests evolution: DLCO
timeFrame: Day90
measure: Occurence of Infectious disease
timeFrame: Day 90
measure: Occurence of Diabetes mellitus
timeFrame: Day90
measure: Occurence of Cardiovascular disorder
timeFrame: Day90
measure: Occurence of Neuropsychological disturbances
timeFrame: Day90
measure: Occurence of Clinical laboratory evaluation
timeFrame: Day 90
measure: Compare both arms in terms of Dyspnea
timeFrame: Day1, Day30, Day90
measure: Compare both arms in terms of Anxiety
timeFrame: Day 90
measure: Compare both arms in terms of Depression
timeFrame: Day90
measure: Compare both arms in terms of Clinical status at day 15
timeFrame: Day15
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU ANgers
city: Besançon
country: France
facility: CHU de Besancon
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Bordeaux
country: France
facility: CHU BOrdeaux
city: Caen
country: France
facility: CHU Caen
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
city: Créteil
country: France
facility: CHIC
city: Dijon
country: France
facility: CHU de Dijon
city: Grenoble
country: France
facility: CHU Grenoble
city: Lille
country: France
facility: CHRU Lille
city: Lyon
country: France
facility: Hospices Civils de Lyon
city: Marseille
country: France
facility: Hôpital Nord
city: Montpellier
country: France
facility: CHU de Montpellier
city: Nancy
country: France
facility: CHU Nancy
city: Nantes
country: France
facility: CHU de Nantes
city: Nice
country: France
facility: CHU Nice
city: Paris
country: France
facility: Hôpital Paris Saint-Joseph
city: Paris
country: France
facility: Hôpital Bichat
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: Hôpital FOCH
city: Paris
country: France
facility: Hôpital Kremiln Bicetre
city: Paris
country: France
facility: Hôpital Saint-Louis
city: Paris
country: France
facility: Hôpital Tenon
city: Reims
country: France
facility: CHU Reims
city: Rennes
country: France
facility: CHU Rennes
city: Rouen
country: France
facility: CHU Rouen
city: Strasbourg
country: France
facility: CHU Strasbourg
city: Toulouse
country: France
facility: CHU Toulouse
city: Tours
country: France
facility: CHU Tours
Study officials:
affiliation: Fondation Hôpital Saint-Joseph
name: Jean-Marc NACCACHE
role: STUDY_DIRECTOR
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