This Phase IIb trial will compare effectiveness and safety of a multi-component autoantibody reduction therapy (AART), consisting of therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIg) for treatment of patients with progressive idiopathic pulmonary fibrosis (IPF).

Patients with progressive pulmonary fibrosis, identified at any of nine participating leading U.S. medical centers, will be randomized (by computer) in a 1:1 ratio to either AART or treatment as usual (TAU). Stratification factors for randomization are sex (self-identified) and whether or not patients are taking any IPF-approved medication. Patients will be observed for six (6) months, with observations and assessments made at baseline, 30 days after randomization, and 90 and 180 days after randomization.

Data will be electronically submitted via electronic case report forms (eCRF) to a Data Coordinating Center.

The University of Alabama Medical Center Institutional Review Board (IRB) will be the central IRB for all sites.

Specimens collected will also be used in experimental B-cell studies conducted in the laboratory of the Principal Investigator.

Inclusion Criteria:

1. Age between 40-85 years old.
2. A diagnosis of IPF that fulfills latest ATS/ERS Consensus Criteria.
3. A diagnosis of Progressive IPF (P-IPF), defined as a relative decrease of FVC%p >10% during the preceding twelve months, and substantiated by replicate values at least three weeks apart.
4. Ability and willingness to give informed consent (no surrogates) and adhere to requirements.
5. Have eligibility confirmed by a consensus of trial investigators.
6. Is not now or has been in experimental regimen for at least 2 weeks (or 5 half-lives of agent) and agrees to not become participants in other experimental regimens (other than solely observational registries) for the duration of their participation in this trial (180 days).
7. Has been immunized with 2025-2026 COVID-19 vaccine (and later versions as they become available) between 1 and 26 weeks prior to randomization.
8. IPF duration <10 years, based on the date of definitive diagnosis.
9. Ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) >0.70

Exclusion Criteria:

1. Diagnoses of current infection by clinical or microbial assessments.

2. Diagnoses of an additional or alternative etiology for lung dysfunction based upon clinical assessment, including sepsis, congestive heart failure, thromboembolism, worsened pulmonary artery hypertension, etc. using routine clinical evaluations under direction of the attending physician.

3. History or serologic evidence of hepatitis B or C infection. Positive serology for Hepatitis C will not exclude patients if their circulating HC virus RNA test is negative.

4. Coagulopathy, defined as an INR >1.6, PTT >2x control, fibrinogen <100 mg/dL, or platelet count <50,000 unless these abnormalities can be reversed.

5. Uncontrolled diabetes or hypertension (systolic BP >160 mm Hg and diastolic BP >100 mm Hg) that would contraindicate use of corticosteroids.

6. Hemodynamic instability, defined as an inotrope or vasopressor requirement.

7. History of reactions to blood products, murine-derived products, or prior rituximab use within the last six months.

8. History of malignancy, excluding basal or squamous cell skin cancer and low-risk prostate cancer, the latter defined as stage T1 or T2a, with prostate specific antigen <10 ng/dl. AART is not known to promote cancer, and these criteria are within current guidelines.

9. Unwillingness to accept blood product transfusion.

10. Diagnosis of major comorbidities expected to interfere with study participation.

11. Treatment for >14 days within the preceding month with >20 mg. prednisone (or equivalent) or any treatment during the last month with a cellular immuno-suppressant (e.g., cyclophosphamide, methotrexate, calcineurin inhibitors, etc.), or with rituximab (or other anti-B-cell biological agents) within the last 6 months.

12. Current treatment with an angiotensin converting enzyme inhibitor that cannot be discontinued and/or substituted (to obviate hemodynamic lability during TPE).

13. Fertile women who do not agree to contraception or abstinence. IPF is a disease of older adults, and male predominant, so this will not be a frequent consideration.

14. An alternative, concordant or historical diagnosis of interstitial lung diseases other than IPF, including idiopathic fibrosis with autoimmune features (IPAF) per clinical domain.1

15. IgA deficiency, to preclude IVIg reactions.

16. Listed with the United Network for Organ Sharing (UNOS) for lung transplant at the time of enrollment, to minimize the number of censoring due to very early transplants.

17. Ongoing suspected or known acute exacerbations of IPF (AE-IPF), defined as new onset (within the last 30 days) of dyspnea with increased hypoxemia or oxygen requirement, and new radiographic infiltrates especially with ground glass opacities (GGO).

18. Patients taking antifibrotic agents at randomization who have not been on a stable dose for at least 6 weeks: these therapies could be initiated, at the discretion of their attending physicians, at or after the midpoint of their participation in STRIVE II (i.e., three months after randomization).

19. Patients whose oxygen requirements at rest (per an arterial oxygen saturation [SaO2] >0.92) cannot be met with simple nasal cannula at <10L/min.

20. Patients who are not expected to survive 180 days or, in the opinion of the local attending physician, have a high likelihood of not tolerating the trial interventions due to underlying comorbidities or frailties.

21. >10% of whole lung images are emphysematous on High Resolution CT scan

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Any shared data would need to be de-identified, shared only with qualified researchers and otherwise be sanctioned by university regulations.