Therapeutic Plasma Exchange, Rituximab and Intravenous Immunoglobulins for Severe Acute Exacerbation of Idiopathic Pulmonary Fibrosis Admitted in ICU: an Open, Randomized, Controlled Trial
Trial Snapshot
- Phase
- Not Applicable
- Status
- Terminated
- Enrollment
- 5
- Locations
- 1
- Primary Endpoint
- Overall mortality at day 28 after initiation of therapy (Day1)
Study Overview
Brief Summary
Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative, irreversible disease of unknown cause, occurring mainly in patients older than 50. IPF is a rare but fatal lung disease, with an estimated prevalence of 14 to 28/100000 and a median survival time of 3 years. Acute exacerbation of IPF (AE-IPF) is a major event of IPF, as it is responsible for the death of 30-50 % of IPF patients; its annual incidence varies between 5 and 10%. The current literature indicates that IPF is associated with the development of an auto-immunity process targeting epithelial and endothelial lung cells. Autoantibodies have been associated with a poorer prognosis. A study by DONAHOE et al. (Plos One, 2015) indicates that the combination of corticosteroids, plasma exchanges, rituximab and immunoglobulins may improve the prognosis of the most severe forms of AE-IPF. In that study, the observed survival rate in patients receiving this combination of treatment was 70% as compared with 20% in historical controls. This therapeutic combination approach is designed both to eliminate and inhibit the production of circulating antibodies targeting the lungs. Considering the high mortality rate of an AE-IPF episode and the potential benefit of such an original approach, a well-conducted randomized controlled trial is critical.
Detailed Description
Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative, irreversible disease of unknown cause, occurring mainly in patients older than 50. IPF is a rare but fatal lung disease, with an estimated prevalence of 14 to 28/100000 and a median survival time of 3 years. Acute exacerbation of IPF (AE-IPF) is a major event of IPF, as it is responsible for the death of 30-50 % of IPF patients; its annual incidence varies between 5 and 10%. The current literature indicates that IPF is associated with the development of an auto-immunity process targeting epithelial and endothelial lung cells. Autoantibodies have been associated with a poorer prognosis. A study by DONAHOE et al. (Plos One, 2015) indicates that the combination of corticosteroids, plasma exchanges, rituximab and immunoglobulins may improve the prognosis of the most severe forms of AE-IPF. In that study, the observed survival rate in patients receiving this combination of treatment was 70% as compared with 20% in historical controls. This therapeutic combination approach is designed both to eliminate and inhibit the production of circulating antibodies targeting the lungs. Considering the high mortality rate of an AE-IPF episode and the potential benefit of such an original approach, a well-conducted randomized controlled trial is critical.
The main objective is to evaluate the impact on overall mortality at day 28 of plasma exchanges, rituximab, intravenous immunoglobulins (IVIg), and corticosteroid administration versus standard corticosteroid therapy in hypoxemic patients admitted in ICU for severe acute exacerbation of idiopathic pulmonary fibrosis.
The primary assessment criterion will be overall mortality at day 28 after initiation of therapy (Day 1).
Secondary objectives are the following:
- Efficacy:
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patient ≥ 18 years of age
- •Admitted to ICU in the last 72 h
- •Definite or probable IPF diagnosis defined on 2018 ATS/ERS/JRS/ALAT guidelines or a possible usual interstitial pneumonia pattern on HRCT without etiology.
- •Definite AE-IPF according to the 2018 revised criteria :
- •Previous or concurrent diagnosis of idiopathic pulmonary fibrosis (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 (UIP) pattern on the current evaluation);
- •Acute worsening or development of dyspnea typically of less than one-month duration;
- •Computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with a UIP pattern (if no previous computed tomography is available, the qualifier "new" can be dropped);
- •Deterioration not fully explained by cardiac failure or fluid overload.
- •PaO2/FiO2 ratio < 200 measured on FiO2 1
Exclusion Criteria
- •Known hypersensitivity intravenous immunoglobulins or rituximab
- •Severe heart failure
- •Active and uncontrolled bacterial fungal or parasitic infection ruled out by at least one of these two conditions
- •Procalcitonin value at inclusion < 0.25 ng/mL OR
- •Adapted antimicrobial therapy for at least 48 hours at inclusion
- •Positive multiplex PCR for Influenzae A and B, or VRS
- •Deep Veinous Thrombosis or Pulmonary embolism in the last six months
- •Prior exposures to human-murine chimeric antibodies
- •Ongoing treatment with a cellular immunosuppressant (e.g., cyclophosphamide, methotrexate, mycophenolate, azathioprine, calcineurin inhibitors, etc.)
- •Subject treated with more than 2 boluses of methylprednisolone (total dose > 500mg of methylprednisolone) or one dose > 10mg/kg in the last 72 hours
- •Uncorrectable coagulopathies or thrombocytopenia < 30000/mm3
- •Active cancer (other than basal cell carcinoma of the skin)
- •Other source of immunosuppression (i.e. HIV infection, solid organ transplant, lymphoma or leukemia)
- •Patient listed for lung transplantation
- •Patient on ECMO
- •Patient with a do-not-intubate order at inclusion
- •Concurrent participation in other experimental trials
- •Not Affiliation to the French social security
- •Not Written informed consent from the patient or a legal representative if appropriate
- •Hypersensitivity to corticosteroids, cotrimoxazole / atovaquone
- •Patients with severe renal insufficiency (creatine clearance <15ml / min)
Arms & Interventions
Experimental treatment of AE-IPF
The experimental group will receive a combination of: 1- Methylprednisolone bolus of 1g IV day 1, then 20 mg/day (or oral prednisolone equivalent) for 21 days; 2- Nine therapeutic plasma exchanges of 1,5x the estimated plasma volumes using albumin: saline (3:1) or fresh frozen plasma in case of an INR superior to 1,5, on days 1,2,3,5,7,9,11,13,15; followed by administration of low dose of intravenous immunoglobulin (100mg/kg) 3, Rituximab 1g IV on days 7 and 15 (after therapeutic plasma exchange and premedication) 4, Intravenous immunoglobulin 0,5g/kg/d on days 16 to 19,
Intervention: Therapeutic plasma exchanges (Other)
Conventional treatment of AE-IPF
Intravenous methylprednisolone bolus of 10mg/kg on day1, 2 and 3, then 1mg/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 0,125 mg/kg/d until day 90. Shift to oral prednisone as soon as the oral route is available.
Intervention: Conventional treatment of AE-IPF (Other)
Outcomes
Primary Outcomes
Overall mortality at day 28 after initiation of therapy (Day1)
Time Frame: 28 days
Overall mortality at day 28 after initiation of therapy (Day1)
Secondary Outcomes
- Overall mortality at 12 months(12 months)
- Proportion of major bleeding according to the International Society On Thrombosis and Haemostasis(28 days)
- Proportion of patients with at least one episode of any healthcare-associated infection between inclusion and day 28(28 days)
- Proportion of patients with anaphylactic reaction at day 28(28 days)
- Number of days alive without mechanical ventilation between day 1 and day 28(28 days)
- Variation of global extent of HRCT infiltrates between initial HRCT and Day 90 according to AKIRA et al(90 days)
- Changes in lung injury biomarkers in plasma (KL-6, SP-D) between day 1 and day 90(90 days)
- Proportion of patients with occurrence of an acute renal failure at day 28, according to the KDIGO guidelines(28 days)
- Length of ICU- stay and hospital-stay(12 months)
- Changes in circulating autoantibodies levels (anti-periplakin, anti-HSP70 and anti-vimentin antibodies) between day 1 and day 90(90 days)
- Evolution of the SOFA score between day 1 and day 28 or discharge-day from ICU as appropriate (in case of death before Day 28, the last SOFA score collected will be 24 points)(28 days)
- Changes in the proportion of blood fibrocytes between day 1 and day 90(90 days)
- Proportion of catheter-linked complications between inclusion and day 16(16 days)
- Number of blood units transfused between inclusion and day 28(28 days)