Therapeutic Plasma Exchange, Rituximab and IV Ig for Severe Acute Exacerbation of IPF Admitted in ICU (EXCHANGE-IPF)

• ClinicalTrials.gov Identifier: NCT03584802
• Recruitment Status: Recruiting
• First Posted: July 12, 2018
• Last Update Posted: July 29, 2019
• Sponsor: Assistance Publique - Hôpitaux de Paris
• Information provided by (Responsible Party): Assistance Publique - Hôpitaux de Paris

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Exacerbation of Idiopathic Pulmonary Fibrosis	Other: Therapeutic plasma exchanges; Other: Conventional treatment of AE-IPF	Not Applicable

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:

1. Efficacy:

   1.1. To compare the overall mortality at day 90, at 6 months and at 12 months after the initiation of therapy 1.2. To compare the exposition to mechanical ventilation 1.3. To compare the length of ICU and hospital-stay 1.4. To compare the evolution of Sequential Organ Failure Assessment (SOFA) score 1.5. To compare the radiological evolution 1.6. To compare the evolution of lung injury biomarkers in plasma 1.7. To compare the changes in circulating autoantibodies levels before and after therapy 1.8. To compare the evolution of blood fibrocytes proportion 1.9. To evaluate respiratory functional at 3 months and compare data previously available.

   1.10. To assess quality of life (SF36), autonomy (ADL) and muscle strength scores (MRC) at 3 months of inclusion (Cf annexe)

2. Safety:

   2.1. To compare the occurrence of healthcare-associated infection 2.2. To describe the specific complications associated to the experimental treatment

   Secondary assessment criteria are the following:

3. Efficacy:

   3.1. Overall mortality at day 90, at 6 months and at 12 months 3.2. Number of days alive without mechanical ventilation between inclusion and day 28 3.3. Length of ICU-stay and hospital-stay 3.4. Changes in SOFA score from D1 to D3, D7, D16, D21, D28 or discharge-day from ICU as appropriate 3.5. Variation of global extent of High Resolution Computed Tomography (HRCT) infiltrates between initial HRCT and D90 3.6. Changes in lung injury plasmatic biomarkers (KL-6, SP-D) from D1 to D16, D21, D28 and D90 3.7. Changes in circulating antibodies levels (anti-periplakin, anti-HSP70 and anti-vimentin antibodies) from D1 to D28 and D90 3.8. Changes in the proportion of blood fibrocytes from D1 to D16, D28 and D90

4. Safety:

4.1. Proportion of patients with at least one episode of any healthcare-associated infection between inclusion and D28 4.2. The following complications in the experimental group will be described: 4.2.1. Proportion of catheter-linked complications between inclusion and D16 4.2.2. Number of blood units transfused between inclusion and day 28. 4.2.3. Proportion of major bleeding according to the International Society On Thrombosis And Haemostasis 4.2.4. Proportion of patients with occurrence of an acute renal failure at D28, according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines 4.2.5. Proportion of patients with anaphylactic reaction at day 28

The experimental design is multicenter, randomized, controlled, open-label superiority trial in parallel groups. The population involved is ICU patients with a Partial pressure of oxygen/ Fraction inspired by oxygen (PaO2/FIO2) ratio < 200 and a diagnosis of acute exacerbation of idiopathic pulmonary fibrosis.

The experimental group will receive a combination of:

1. Methylprednisolone bolus of 1g i.v. day 1, then 20 mg/day (or oral prednisone 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 International Normalised Ratio (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 (100 mg/kg)
3. Rituximab 1 g i.v. on days 7 and 15 (after therapeutic plasma exchange and premedication);
4. Intravenous immunoglobulin 0.5 g/kg/d on days 16 to 19.

The reference group will receive:

Intravenous methylprednisolone bolus of 10 mg/kg (max. 1g) on day 1, 2 and 3, then 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 0.125 mg/kg/d until day 90. Shift to oral prednisone as soon as the oral route is available.

Other procedures added by the research:

Blood sampling for serial serum lung injury biomarkers, fibrocytes determination and circulating antibodies measurements

Risks added by the research: C Number of subjects chosen: 40 Number of centres : 17

Research period:

Inclusion period: 36months Length of participation: one year

• Maximum period between selection and inclusion: 3 days
• Treatment period: 90 days
• Follow up period: 1 year +/- 2 weeks
• Total research period: 48 months

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Therapeutic Plasma Exchange, Rituximab and Intravenous Immunoglobulins for Severe Acute Exacerbation of Idiopathic Pulmonary Fibrosis Admitted in ICU: an Open, Randomized, Controlled Trial
• Actual Study Start Date: May 16, 2019
• Estimated Primary Completion Date: October 1, 2020
• Estimated Study Completion Date: March 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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,	Other: Therapeutic plasma exchanges; The patient will initially receive Methylprednisolone bolus of 1g i.v. day 1, then 20 mg/day (or oral prednisone equivalent) for 21 days; and then he will have 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 (100 mg/kg). On days 7 and 15, the patient will receive rituximab 1 g i.v. on days 7 and 15 (after therapeutic plasma exchange and premedication); and intravenous immunoglobulin 0.5 g/kg/d on days 16 to 19.
Active Comparator: 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.	Other: Conventional treatment of AE-IPF; Conventional treatment of AE-IPF

Outcome Measures

Primary Outcome Measures :

1. 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 Outcome Measures :

1. Overall mortality at 12 months [ Time Frame: 12 months ]
   Overall mortality at 12 months
2. Number of days alive without mechanical ventilation between day 1 and day 28 [ Time Frame: 28 days ]
   Number of days alive without mechanical ventilation
3. Length of ICU- stay and hospital-stay [ Time Frame: 12 months ]
   Length of ICU- stay and hospital-stay
4. 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) [ Time Frame: 28 days ]

   The Sequential Organ Failure Assessment (SOFA) score is calculated with the combination of 6 scores:

   • respiratory score with the parameter PaO2/ FiO2
   • neurological score with Mean arterial pressure parameter
   • hepatic score with bilirubin parameter
   • coagulation score with measure of platelets
   • renal score with creatinine parameter

   The total score will range to 0 at 24; 0 being the better outcome and 24 the worse.

5. Variation of global extent of HRCT infiltrates between initial HRCT and Day 90 according to AKIRA et al [ Time Frame: 90 days ]
   Variation of global extent of HRCT infiltrates
6. Changes in lung injury biomarkers in plasma (KL-6, SP-D) between day 1 and day 90 [ Time Frame: 90 days ]
   Changes in lung injury biomarkers in plasma
7. Changes in circulating autoantibodies levels (anti-periplakin, anti-HSP70 and anti-vimentin antibodies) between day 1 and day 90 [ Time Frame: 90 days ]
   Changes in circulating autoantibodies levels
8. Changes in the proportion of blood fibrocytes between day 1 and day 90 [ Time Frame: 90 days ]
   Changes in the proportion of blood fibrocytes between day 1 and day 90
9. Proportion of patients with at least one episode of any healthcare-associated infection between inclusion and day 28 [ Time Frame: 28 days ]
   Proportion of patients with at least one episode of any healthcare-associated infection
10. Proportion of catheter-linked complications between inclusion and day 16 [ Time Frame: 16 days ]
    Proportion of catheter-linked complications between inclusion and day 16
11. Number of blood units transfused between inclusion and day 28 [ Time Frame: 28 days ]
    Number of blood units transfused between inclusion and day 28
12. Proportion of major bleeding according to the International Society On Thrombosis and Haemostasis [ Time Frame: 28 days ]
    Proportion of major bleeding
13. Proportion of patients with occurrence of an acute renal failure at day 28, according to the KDIGO guidelines [ Time Frame: 28 days ]
    Proportion of patients with occurrence of an acute renal failure
14. Proportion of patients with anaphylactic reaction at day 28 [ Time Frame: 28 days ]
    Proportion of patients with anaphylactic reaction

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 75 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• ≥ 18 years of age and < 75 years
• Admitted to ICU in the last 72 h
• Definite or probable IPF diagnosis defined on 2011 ATS/ERS/JRS/ALAT guidelines or a possible usual interstitial pneumonia pattern on HRCT without etiology.

• Definite AE-IPF according to the 2016 revised criteria:

  1. 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);
  2. Acute worsening or development of dyspnea typically of less than one-month duration;
  3. 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);
  4. Deterioration not fully explained by cardiac failure or fluid overload.
• PaO2/FiO2 ratio < 200
• Affiliation to the French social security
• Written informed consent from the patient or a legal representative if appropriate

Exclusion Criteria:

• Known hypersensitivity intravenous immunoglobulin or rituximab
• Severe heart failure
• Active and uncontrolled bacterial and, fungal or parasitic infection
• Positive multiplex Polymerase Chain Reaction (PCR) for Influenzae A and B, and for Respiratory Syncytial Virus (VRS)
• Deep Veinous Thrombosis or embolism pulmonary 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 in the last 72 hours
• Subject treated with a cumulative dose higher than 500 mg of methylprednisolone in the last 48 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)
• Pregnancy
• Patient listed for lung transplantation
• Patient on ExtraCorporeal Membrane Oxygenation (ECMO)
• Patient with a do-not-intubate order at admission to ICU
• Concurrent participation in other experimental trials

Contacts and Locations

Contacts

Contact: Bruno CRESTANI, Professor; 00 33 (1) 40 25 86 86 or 00 33; bruno.crestani@aphp.fr

Contact: Mathilde NEUVILLE, Doctor; 00 33 (1) 40 25 77 98; mathilde.neuville@aphp.fr

Locations

France

Hôpital Bichat Claude Bernard; Recruiting

Paris, France, 75018

Contact: Bruno BC CRESTANI, Professor bruno.crestani@aphp.fr

Contact: Mathilde MN NEUVILLE, Doctor m.neuville@hopital-foch.com

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators

• Principal Investigator: Bruno CRESTANI, Professor; Assistance Publique - Hôpitaux de Paris

More Information

• Responsible Party: Assistance Publique - Hôpitaux de Paris
• ClinicalTrials.gov Identifier: NCT03584802
• Other Study ID Numbers: P160915J
• First Posted: July 12, 2018
• Last Update Posted: July 29, 2019
• Last Verified: July 2019

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Assistance Publique - Hôpitaux de Paris:

severe acute exacerbation of idiopathic pulmonary fibrosis

Additional relevant MeSH terms:

Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis; Pathologic Processes; Lung Diseases; Respiratory Tract Diseases; Idiopathic Interstitial Pneumonias; Lung Diseases, Interstitial; Methylprednisolone; Rituximab; Immunoglobulins; Antibodies; Immunoglobulins, Intravenous; gamma-Globulins; Rho(D) Immune Globulin; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents; Protective Agents