Autoantibody Reduction for Acute Exacerbations of Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis, Acute Fatal Form Clinical Trial

— STRIVE-IPF  

Official title:

Study of Therapeutic Plasma Exchange, Rituximab and Intravenous Immunoglobulin for Acute Exacerbations of Idiopathic Pulmonary Fibrosis (STRIVE-IPF)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03286556
• Other study ID #: F170530011
• Secondary ID: 1U01HL133232-01A
• Status: Recruiting
• Phase: Phase 2
• Start date: September 4, 2018
• Est. completion date: September 30, 2024

Study information

• Verified date: August 2023
• Source: University of Alabama at Birmingham
• Contact: Steven R Duncan, MD
• Phone: 205-934-5018
• Email: srduncan[@]uabmc.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Acute exacerbations (AE) are a dreaded manifestation of idiopathic pulmonary fibrosis (IPF) that presents with rapidly worsening respiratory function over days to weeks. AE account for about 1/2 the deaths in IPF patients, and are refractory to all medical therapies attempted to date. Considerable preliminary data shows pathological B-cell abnormalities and autoantibodies are present in AE-IPF and associated with disease severity. The experimental therapy here (therapeutic plasma exchange plus rituximab plus intravenous immunoglobulin) is mechanistically targeted to ameliorate autoantibody-mediated pulmonary injury. Anecdotal pilot studies indicate these treatments have significant benefit for a disease syndrome that has, until now, been almost invariably inexorable. This clinical trial has the potential to profoundly affect current paradigms and treatment approaches to patients with AE-IPF.

Description:

The primary goal of clinical trial is to determine effects of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG) in comparison to effects of treatment as usual (TAU), among AE-IPF patients. Our central hypothesis is "AUTOANTIBODY REDUCTION IS BENEFICIAL FOR AE-IPF PATIENTS." A corollary of this hypothesis is that antibody-mediated autoimmunity can play an important role in IPF exacerbations. Following baseline screening assessments, hospitalized AE-IPF patients at the collaborating sites that meet all inclusion/exclusion criteria will be randomly assigned to receive one of the following treatments in a ratio of 2:1: • Arm A (n=34) - Experimental Treatment: Steroids: Prednisone 60 mg (p.o.) on day 1, followed by 20 mg/day on days 2-5, 7-14, and 16-19 (or the i.v. methylprednisolone equivalent). Methyl-prednisolone 100 mg i.v. will be administered on days 6 and 15, as a premedication prior to the rituximab. Insertion of a dialysis/apheresis catheter into a central vein, and initiation of therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG) regimens: Therapeutic Plasma Exchange (TPE) will consist of 1x estimated plasma volume exchanges for 3 successive days (1-3) and then, after a one day interval to enable equilibration of autoantibodies between intra- and extra-vascular spaces, again on days 5, 6, 9, 11, 13, and 15. Rituximab: One gm i.v. will be administered on day 6 and day 15 after completion of the TPE on those days. Intravenous immunoglobulin (IVIG): 0.5 gm/kg/day i.v. on days 16-19 • Arm B (n=17) - Treatment as Usual (TAU): The same steroid regimen as described for Arm A, i.e., prednisone 60 mg (p.o.) on day 1, followed by 20 mg/day on days 2-5, 7-14, and 16-19 (or the i.v. methylprednisolone equivalent), and methylprednisolone 100 mg i.v. administered on days 6 and 15. All patients enrolled in both cohorts at all sites will also receive empiric broad-spectrum antibiotics for 8 days. The empiric antibiotic regimen will be reassessed and tailored based on any subsequent cultures and sensitivity results. Patients will be monitored carefully for occurrences of adverse events, laboratory test abnormalities, and changes in vital signs. The respective treatment courses can be finished on an outpatient basis among enrolled patients who are able to be discharged from the hospital, if medically indicated, and if those treatment compliance can be assured. Patients will be followed for the duration of their hospital admission after enrollment, and then observed as either inpatients or outpatients on days 19, 60, 90, 180, 270, and 365. A telephone contact will occur at monthly intervals, aside from those visits above. The total observation/subject is 365 days.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 51
• Est. completion date: September 30, 2024
• Est. primary completion date: August 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 85 Years

Eligibility

Inclusion Criteria:

1. Age between 40-85 years old.

2. A diagnosis of IPF that fulfills ATS/ERS Consensus Criteria.1

3. Worsening or new development of dyspnea or hypoxemia within the last 30 days.

4. Ground-glass abnormality and/or consolidation superimposed on a reticular or honeycomb usual interstitial pneumonitis (UIP) pattern on locally read chest CT scan.

5. Ability and willingness to give informed consent (no surrogates) and adhere to study requirements.

Exclusion Criteria:

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

2. Diagnoses of an additional or alternative etiology for respiratory dysfunction based upon clinical assessment, including congestive heart failure, sepsis, thromboembolism, etc.

3. History or serologic evidence of hepatitis B or C infection.

4. Coagulopathy, defined as a International Normalized Ratio (INR) >1.6, partial thromboplastin time (PTT) > 2x control, fibrinogen <100 mg/dL, or platelet count <50 thousand (K) unless these abnormalities can be reversed safely.

5. Hyperosmolar state or diabetic ketoacidosis to suggest uncontrolled diabetes, or uncontrolled 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 reaction to blood products or murine-derived products or prior rituximab use.

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 (PSA) less than 10 ng/dl. The experimental treatments are not known to promote cancer progression, 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, mycophenolate, azathioprine, etc.). An exception will be made if the patient has a bronchoalveolar lavage (BAL) negative for pathogens.

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

13. Concurrent participation in other experimental trials.

14. Fertile females who do not agree to contraception or abstinence, or have a positive pregnancy test (urine or blood). IPF is a disease of older adults, and male predominant, so this will not be a frequent consideration.

15. Presence of positive (abnormal) classical autoimmune tests: anti-nuclear antibody (ANA), rheumatoid factor (RF), Anti- Sjögren's-syndrome-related antigen (SSA) , and Anti-Cyclic Citrullinated Peptide (CCP). This criterion will eliminate patients with confounding classical autoimmune syndromes. Many IPF patients will have already had these tests, which are standard of practice (SOP) at many IPF centers, and these prior results will suffice if the tests were performed within the last year. Otherwise, these tests need to be performed prior to enrollment and they can usually be procured in 1-2 days. Based on experience, we anticipate ~10% of patients who fulfill all other IPF criteria will nonetheless be positive for one of these classical autoantibody tests.

16. IgA deficiency (IgA level <7 mg/dL)- to preclude IVIG reactions.

Related Conditions & MeSH terms

• Fibrosis
• Idiopathic Pulmonary Fibrosis
• Idiopathic Pulmonary Fibrosis, Acute Fatal Form
• Pulmonary Fibrosis

Intervention

Drug:
• Autoantibody Reductive Therapy
TPE x 9, rituximab x 2, IVIG x 4. See arm/group descriptions for additional details.
• Treatment as Usual (TAU)
Antibiotics and steroids

Locations

Country	Name	City	State
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Dan Dilling	Chicago	Illinois
United States	Baylor University Medical Center	Houston	Texas
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Thomas Jefferson University Medical Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	University of Utah Medical Center	Salt Lake City	Utah

Sponsors (5)

Lead Sponsor	Collaborator
University of Alabama at Birmingham	Brigham and Women's Hospital, National Heart, Lung, and Blood Institute (NHLBI), Temple University, University of Pittsburgh

Country where clinical trial is conducted

United States, 

References & Publications (8)

Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King TE Jr, Lasky JA, Loyd JE, Noth I, Olman MA, Raghu G, Roman J, Ryu JH, Zisman DA, Hunninghake GW, Colby TV, Egan JJ, Hansell DM, Johkoh T, Kaminski N, Kim DS, Kondoh Y, Lynch DA, Muller-Quernheim — View Citation

Donahoe M, Valentine VG, Chien N, Gibson KF, Raval JS, Saul M, Xue J, Zhang Y, Duncan SR. Autoantibody-Targeted Treatments for Acute Exacerbations of Idiopathic Pulmonary Fibrosis. PLoS One. 2015 Jun 17;10(6):e0127771. doi: 10.1371/journal.pone.0127771. e — View Citation

Feghali-Bostwick CA, Tsai CG, Valentine VG, Kantrow S, Stoner MW, Pilewski JM, Gadgil A, George MP, Gibson KF, Choi AM, Kaminski N, Zhang Y, Duncan SR. Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis. J Immunol. 2007 Aug 15;179(4):259 — View Citation

Gilani SR, Vuga LJ, Lindell KO, Gibson KF, Xue J, Kaminski N, Valentine VG, Lindsay EK, George MP, Steele C, Duncan SR. CD28 down-regulation on circulating CD4 T-cells is associated with poor prognoses of patients with idiopathic pulmonary fibrosis. PLoS — View Citation

Kahloon RA, Xue J, Bhargava A, Csizmadia E, Otterbein L, Kass DJ, Bon J, Soejima M, Levesque MC, Lindell KO, Gibson KF, Kaminski N, Banga G, Oddis CV, Pilewski JM, Sciurba FC, Donahoe M, Zhang Y, Duncan SR. Patients with idiopathic pulmonary fibrosis with — View Citation

Vuga LJ, Tedrow JR, Pandit KV, Tan J, Kass DJ, Xue J, Chandra D, Leader JK, Gibson KF, Kaminski N, Sciurba FC, Duncan SR. C-X-C motif chemokine 13 (CXCL13) is a prognostic biomarker of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2014 Apr 15; — View Citation

Xue J, Gochuico BR, Alawad AS, Feghali-Bostwick CA, Noth I, Nathan SD, Rosen GD, Rosas IO, Dacic S, Ocak I, Fuhrman CR, Cuenco KT, Smith MA, Jacobs SS, Zeevi A, Morel PA, Pilewski JM, Valentine VG, Gibson KF, Kaminski N, Sciurba FC, Zhang Y, Duncan SR. Th — View Citation

Xue J, Kass DJ, Bon J, Vuga L, Tan J, Csizmadia E, Otterbein L, Soejima M, Levesque MC, Gibson KF, Kaminski N, Pilewski JM, Donahoe M, Sciurba FC, Duncan SR. Plasma B lymphocyte stimulator and B cell differentiation in idiopathic pulmonary fibrosis patien — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival	Actuarial survival	6 months
Secondary	Oxygen requirements	Measures of oxygen required to maintain arterial oxygen concentration (SaO2) >/=93%	6 months
Secondary	Walk distance	6 minute walk distance using standardized American Thoracic Society/European Respiratory Society (ATS/ERS) protocols.	6 months
Secondary	Adverse Events	The presence of adverse events attributable to the trial intervention	Through study completion, an average of 1 year