STRIVE-IPF: Autoantibody Reduction for Acute Exacerbations of Idiopathic Pulmonary Fibrosis

Sponsor

University of Alabama at Birmingham (Other)

Overall Status

Recruiting

CT.gov ID

NCT03286556

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH), Brigham and Women's Hospital (Other), Temple University (Other), University of Pittsburgh (Other)

Enrollment

Locations

Arms

48.9

Anticipated Duration (Months)

7.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Idiopathic Pulmonary Fibrosis, Acute Fatal Form	Drug: Autoantibody Reductive Therapy Drug: Treatment as Usual (TAU)	Phase 2

Detailed 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

51 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Open label randomized controlled trial.Open label randomized controlled trial.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Sep 4, 2018

Anticipated Primary Completion Date :

Aug 1, 2022

Anticipated Study Completion Date :

Sep 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Autoantibody Reductive Therapy Therapeutic Plasma Exchange (TPE) consisting 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 All subjects in this trial, including patients in this arm, will receive identical empiric antibiotics and steroids. The steroid dose is: 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). Methylprednisolone 100 mg i.v. will be administered on days 6 and 15, as a premedication prior to the rituximab.	Drug: Autoantibody Reductive Therapy TPE x 9, rituximab x 2, IVIG x 4. See arm/group descriptions for additional details.
Active Comparator: Treatment as Usual (TAU) The same steroid regimen as described for the experimental arm, 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, as well as empiric antibiotics.	Drug: Treatment as Usual (TAU) Antibiotics and steroids Other Names: Antibiotics and steroids

Arm

Intervention/Treatment

Experimental: Autoantibody Reductive Therapy

Therapeutic Plasma Exchange (TPE) consisting 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 All subjects in this trial, including patients in this arm, will receive identical empiric antibiotics and steroids. The steroid dose is: 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). Methylprednisolone 100 mg i.v. will be administered on days 6 and 15, as a premedication prior to the rituximab.

Drug: Autoantibody Reductive Therapy

TPE x 9, rituximab x 2, IVIG x 4. See arm/group descriptions for additional details.

Active Comparator: Treatment as Usual (TAU)

The same steroid regimen as described for the experimental arm, 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, as well as empiric antibiotics.

Drug: Treatment as Usual (TAU)

Antibiotics and steroids

Other Names:

Antibiotics and steroids

Outcome Measures

Primary Outcome Measures

Survival [6 months]
Actuarial survival

Secondary Outcome Measures

Oxygen requirements [6 months]
Measures of oxygen required to maintain arterial oxygen concentration (SaO2) >/=93%
Walk distance [6 months]
6 minute walk distance using standardized American Thoracic Society/European Respiratory Society (ATS/ERS) protocols.
Adverse Events [Through study completion, an average of 1 year]
The presence of adverse events attributable to the trial intervention

Eligibility Criteria

Criteria

Ages Eligible for Study:

40 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age between 40-85 years old.
A diagnosis of IPF that fulfills ATS/ERS Consensus Criteria.1
Worsening or new development of dyspnea or hypoxemia within the last 30 days.
Ground-glass abnormality and/or consolidation superimposed on a reticular or honeycomb usual interstitial pneumonitis (UIP) pattern on locally read chest CT scan.
Ability and willingness to give informed consent (no surrogates) and adhere to study requirements.

Exclusion Criteria:

Diagnoses of current infection per clinical or microbial assessments.
Diagnoses of an additional or alternative etiology for respiratory dysfunction based upon clinical assessment, including congestive heart failure, sepsis, thromboembolism, etc.
History or serologic evidence of hepatitis B or C infection.
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.
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.
Hemodynamic instability, defined as an inotrope or vasopressor requirement.
History of reaction to blood products or murine-derived products or prior rituximab use.
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.
Unwillingness to accept blood product transfusion.
Diagnosis of major comorbidities expected to interfere with study participation.
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.
Current treatment with an angiotensin converting enzyme inhibitor that cannot be discontinued and/or substituted (to obviate hemodynamic complications during TPE).
Concurrent participation in other experimental trials.
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.
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.
IgA deficiency (IgA level <7 mg/dL)- to preclude IVIG reactions.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	Dan Dilling	Chicago	Illinois	United States	60611
3	Thomas Jefferson University Medical Center	Philadelphia	Pennsylvania	United States	19107
4	Temple University Hospital	Philadelphia	Pennsylvania	United States	19140
5	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15213
6	Baylor University Medical Center	Houston	Texas	United States	77030
7	University of Utah Medical Center	Salt Lake City	Utah	United States	84112