Combined PEX, Rituximab and Steroids in Acute Idiopathic Pulmonary Fibrosis Exacerbations

Study Overview
=================
Brief Summary
-----------------
This is an open-label Phase I/II trial to assess the feasibility and safety of combined plasma exchange (PEX), rituximab, and conventional corticosteroid administration on the outcome of hospitalized patients with acute IPF exacerbations. The specific aims of this study are: To assess the feasibility and safety of combined PEX, rituximab, and conventional corticosteroid administrations for the treatment of hospitalized patients with acute IPF exacerbations by monitoring indices of respiratory (PaO2) and cardiovascular function during the treatment interval. To assess the efficacy of combined PEX, rituximab, and conventional corticosteroid administrations for the treatment of hospitalized patients with acute IPF exacerbations on patient survival in comparison to historical controls. Patient survival for this investigation will be defined using the composite outcome of 60 day survival and/or survival to lung transplantation. Subjects between 18 and 80 years of age who have a confirmed diagnosis of IPF, and meet all the study requirements will be enrolled in this study. A total of 10 subjects of both genders and all ethnic backgrounds with acute IPF exacerbations hospitalized at University of Pittsburgh Medical Center will be enrolled in this study.

Detailed Description
-----------------
This is a prospective, open-label Phase II, non-randomized clinical trial to assess the feasibility and safety of combined plasma exchange (PEX), rituximab, and conventional corticosteroid administration in patients with acute IPF exacerbations. INCLUSION CRITERIA: A diagnosis of idiopathic pulmonary fibrosis that fulfills American Thoracic Society Consensus Criteria. Unexplained worsening or development of dyspnea or hypoxemia within 30 days leading to the current hospitalization. Radiographic imaging showing ground-glass abnormality and/or consolidation superimposed on a background of reticular or honeycomb pattern consistent with UIP. Intent on the part of the treating physician to use high dose steroid therapy as a therapeutic effort to treat a diagnosis of acute IPF exacerbation. EXCLUSION CRITERIA Diagnosis of documented infection based upon clinical evaluation and microbial testing. Diagnosis of thromboembolic disease by clinical assessment. Diagnosis of an additional etiology for ALI/ARDS based upon clinical assessment to include sepsis, aspiration, trauma, inhalational injury, acute pancreatitis, drug toxicity, blood product transfusion reaction, or stem cell transplantation. Diagnosis of congestive heart failure that accounts for the hypoxemia. Presence of active hepatitis B infection. Coagulopathy defined as an INR > 1.8, PTT > 2 x control, and platelet count < 50K. Hyperosmolar state or diabetic ketoacidosis to suggest uncontrolled diabetes mellitus or uncontrolled hypertension (systolic BP > 160 mm Hg and diastolic BP > 100 mm Hg) which would contraindicated the use of corticosteroids. Hemodynamic instability defined as a vasopressor requirement which would contraindicate the use of plasmapheresis. History of reaction to blood products, murine-derived products, or prior exposures to human-murine chimeric antibodies, History of malignancy. Inability or unwillingness to accept a blood transfusion. Inability or unwillingness to complete post- treatment surveillance for 60 days. Diagnosis of major comorbidities expected to interfere with subjects study participation for 60 days.

Official Title
-----------------
Open-Label, Feasibility Study of Combined Plasma Exchange (PEX), Rituximab, and Corticosteroids in Patients With Acute Idiopathic Pulmonary Fibrosis Exacerbations

Conditions
-----------------
IPF

Intervention / Treatment
-----------------
* Drug: Combined Plasma Exchange (PEX), Rituximab, and Corticosteroids


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A diagnosis of idiopathic pulmonary fibrosis that fulfills American Thoracic Society Consensus Criteria. Unexplained worsening or development of dyspnea or hypoxemia within 30 days leading to the current hospitalization. Radiographic imaging showing ground-glass abnormality and/or consolidation superimposed on a background of reticular or honeycomb pattern consistent with usual interstitial pneumonia. Intent on the part of the treating physician to use high dose steroid therapy as a therapeutic effort to treat a diagnosis of acute IPF exacerbation. Exclusion Criteria: Diagnosis of documented infection based upon clinical evaluation and microbial testing. Diagnosis of thromboembolic disease by clinical assessment. Diagnosis of an additional etiology for Acute Lung Injury/Acute Respiratory Distress Syndrome based upon clinical assessment to include sepsis, aspiration, trauma, inhalational injury, acute pancreatitis, drug toxicity, blood product transfusion reaction, or stem cell transplantation. Diagnosis of congestive heart failure that accounts for the hypoxemia. Presence of active hepatitis B infection. Coagulopathy defined as an International Normalized Ratio > 1.8, Partial Thromboplastin Time > 2 x control, and platelet count < 50,000. Hyperosmolar state or diabetic ketoacidosis to suggest uncontrolled diabetes mellitus or uncontrolled hypertension (systolic BP > 160 mm Hg and diastolic BP > 100 mm Hg) which would contraindicated the use of corticosteroids. Hemodynamic instability defined as a vasopressor requirement which would contraindicate the use of plasmapheresis. History of reaction to blood products, murine-derived products, or prior exposures to human-murine chimeric antibodies, History of malignancy. Inability or unwillingness to accept a blood transfusion. Inability or unwillingness to complete post- treatment surveillance for 60 days. Diagnosis of major comorbidities expected to interfere with subjects study participation for 60 days.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combined PEX, Rituximab and Steroids<br>Standard Steroid Treatment: One gm of methylprednisolone I.V., on day 0, followed by 40 mg/day I.V. on days 1-4, and days 6-12 (or the P.O. prednisone equivalent). Methylprednisolone 100 mg I.V. will be administered on days 5 and 13. Steroid doses will then be 20 mg methylprednisolone I.V. (or P.O. prednisone equivalent) from days 14-28, and then reduced thereafter at the discretion of the principle investigator. Plasma exchange (PEX) will consist of 1.5x estimated plasma volume exchanges for 3 successive days (0, 1,2) and then, after a one day interval to enable equilibration of autoantibodies sequestered in tissues, two more daily treatments on days 4 and 5. Rituximab: One gm I.V. will be administered on day 5 (after completion of the last PEX) and day 13. | Drug: Combined Plasma Exchange (PEX), Rituximab, and Corticosteroids<br>* Standard Steroid Treatment, Plasma exchange will consist of 1.5x estimated plasma volume exchanges, Rituximab<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Respiratory and/or Hemodynamic Deteriorations | To assess the feasibility and safety of combined PEX, rituximab, and conventional corticosteroid administrations for the treatment of hospitalized patients with acute IPF exacerbations by monitoring indices of respiratory (PaO2) and cardiovascular function during the treatment interval. Respiratory deterioration was defined by a compilations of respiratory deteriorations (deteriorating gas exchange) and hemodynamic deteriorations (defined as a need for medical intervention). | 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Survived to 60 Days or to Transplantation | The secondary outcome measures a composite outcome defined as survival to 60 days or survival to transplantation at any time post therapy. | 60 days |