Study of Therapeutic Plasma Exchange, Rituximab and Intravenous Immunoglobulin for Acute Exacerbations of Idiopathic Pulmonary Fibrosis (STRIVE-IPF)
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis, Acute Fatal Form
Sponsor: University of Alabama at Birmingham

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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STUDY OF THERAPEUTIC PLASMA EXCHANGE, RITUXIMAB, AND 
INTRAVENOUS IMMUNOGLOBULIN FOR ACUTE EXACERBATIONS OF 
IDIOPATHIC PULMONARY FIBROSIS 
 
(STRIVE-IPF) 
 
 
Steven R. Duncan, M.D. 
Principal Investigator (Contact) 
Department of Medicine 
University of Alabama at Birmingham 
Birmingham, AL 
 
Gerard Criner, M.D.  
Principle Investigator 
Department of Thoracic Medicine and Surgery 
Temple University 
Philadelphia, PA 
 
Daniel J. Kass, M.D.  
Principle Investigator 
Department of Medicine 
University of Pittsburgh School of Medicine 
Pittsburgh, PA 
 
Ivan O. Rosas, M.D.  
Principle Investigator 
Department of Medicine 
Baylor  University 
Houston, TX 
 
Mary Beth Scholand, M.D. 
Co-Investigator 
Department of Medicine 
University of Utah 
Salt Lake City, UT 
 
Ross S. Summer M.D. 
Co-Investigator 
Thomas Jefferson University 
Philadelphia, PA 
 
 
 
Version 6.0 
May 7, 2020 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS………………………………………………………………………………...4 
 
 
1. 
STUDY OBJECTIVE, SPECIFIC AIMS, BACKGROUND AND SIGNIFICANCE ................. 9 
 
1.1 
OBJECTIVE .................................................................................................................. 9 
1.2 
SPECIFIC AIMS ............................................................................................................ 9 
1.3 
BACKGROUND ............................................................................................................ 9 
1.4 
SIGNIFICANCE .......................................................................................................... 14 
 
2. 
RESEARCH DESIGN AND METHODS ............................................................................. 14 
 
2.1 
CLASSIFICATION AND METHODOLOGICAL DESIGN .................................. 14 
2.2 
STUDY DESIGN  ........................................................................................................ 14 
2.3 
STUDY TREATMENTS ............................................................................................... 15 
2.4 
RANDOMIZATION ...................................................................................................... 16 
2.5 
STUDY TREATMENT SCHEMATIC................................................................. 17 
2.6      RELAPSES…………………………………………………………………………..17 
2.7     STUDY PROCEDURES .................................................................................. 19 
2.8 
STUDY ENDPOINTS .................................................................................................. 24 
2.9 
DATA AND POWER ANALYSES ................................................................................ 27 
2.10 DATA COODINATING CENTER…...…………………………………………….  29 
2.11     ANTICIPATED RESULTS .................................................................................. 30 
2.12 TIMELINES AND MILESTONES .......................................................................... 31 
 
3. 
HUMAN SUBJECTS ......................................................................................................... 32 
 
3.1 
SUBJECT POPULATION ............................................................................................ 32 
3.2 
INCLUSION AND EXCLUSION CRITERIA ........................................................... 32 
3.3 
INFECTIOUS CONSIDERATIONS .................................................................. 34 
 
4. 
RECRUITMENT AND INFORMED CONSENT PROCEDURES ........................................ 35 
4.1 
RECRUITMENT METHODS ....................................................................................... 35 
4.2 
INFORMED CONSENT PROCEDURES .......................................................... 35 
 
5. 
POTENTIAL RISKS AND BENEFITS ................................................................................ 36 
5.1 
POTENTIAL RISKS .................................................................................................... 36 
5.2 
ALTERNATIVE TREATMENTS ................................................................................... 37 
5.3 
POTENTIAL BENEFITS .............................................................................................. 37 
5.4 
DATA SAFETY MONITORING PLAN ............................................................... 38 
                 5.4.7 Adverse Event Reporting Timeline……………………………………….42 
5.5 
RISK MANAGEMENT PROCEDURES ............................................................ 42 
 
6. 
STUDY ADMINSTRATION ................................................................................................ 44 
6.1 
REGULATORY AND ETHICAL CONSIDERATIONS ....................................... 44 
6.2 
PROTOCOL DEVELOPMENT .................................................................................... 44 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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6.3 
PROTOCOL MANAGEMENT...................................................................................... 45 
               6.3.4  Protocol Deviations and Violations…………………………………......46     
6.4 
INFORMED CONSENT REQUIREMENTS ...................................................... 46 
    6.5      IRB DOCUMENTATION…………………………………………………………….….……47 
6.6     QUALITY CONTROL AND QUALITY ASSURANCE………………………………….….47 
6.7     DATA HANDLING AND RECORD KEEPING……………………………………………..47 
 
7. 
COSTS AND PAYMENTS ................................................................................................. 49 
7.1 
COSTS ....................................................................................................................... 49 
7.2 
PAYMENT .................................................................................................................. 50 
 
8. 
QUALIFICATIONS AND SOURCE OF SUPPORT ............................................................ 50 
8.1 
QUALIFICATIONS OF INVESTIGATORS ........................................................ 50 
8.2 
SOURCE OF SUPPORT ............................................................................................. 51 
 
9. 
REFERENCES .................................................................................................................. 52 
 
10. AMENDMENTS AND MODIFICATIONS TO THIS PROTOCOL and ICF……………….......57 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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PROTOCOL SYNOPSIS 
 
Protocol Title: 
Study of Therapeutic Plasma Exchange, Rituximab, and Intravenous 
Immunoglobulin for Acute Exacerbations of Idiopathic Pulmonary 
Fibrosis  (STRIVE-IPF) 
 
Protocol Number: 
UAB OSP#: 000513913 
 
NCT Number: 
NCT03286556 
Version # and Date: 
Version 6.0 / May 7, 2020 
 
Clinical Phase: 
 
Phase IIb clinical investigation 
 
Trial Site: 
Multi-Center Trial 
 
Contact Principal 
Investigator: 
 
Steven R. Duncan, M.D. 
Professor of Medicine 
Division of Pulmonary, Allergy, and Critical Care Medicine 
University of Alabama at Birmingham 
513C THT, 1900 University Blvd 
Birmingham, AL 35294 
205-934-5018 
srduncan@uabmc.edu 
 
Other Principal 
Investigators: 
 
 
Gerard Criner, M.D.                        
Professor 
Temple University 
Philadelphia, PA 
 
Daniel J. Kass, MD 
Assoc. Professor 
University of Pittsburgh 
Pittsburgh, PA 
 
Ivan O. Rosas, M.D. 
Professor 
Baylor  University 
Houston, TX 
 
 
 
Co-Investigators 
 
Rahman Fazlur, Ph.D. 
University of Alabama at Birmingham 
Birmingham, AL 
 
Mary Beth Scholand, M.D. 
University of Utah 
Salt Lake City, UT 
 
Ross S. Summer, M.D. 
Thomas Jefferson University 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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Philadelphia, PA 
 
Participating Medical 
Centers: 
1. University of Alabama at Birmingham (UAB) 
2. Brigham and Women's Hospital (BWH) (No Longer Active) 
3. Temple University Hospital (TUH) 
4. University of Pittsburgh Medical Center (UPMC) 
5. Baylor University Medical Center 
6. University of Utah Medical Center 
7. Thomas Jefferson Medical Center 
UAB Data Coordinating 
Center: 
Rahman Fazlur  Ph.D., Director 
 
Sponsor: 
National Heart, Lung, and Blood Institute (UO1HL133232) 
Study Rationale: 
 
 
 
The experimental therapy here, mechanistically targeted to ameliorate autoantibody-
mediated pulmonary injury, seems to result during pilot studies in 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 acute exacerbations of IPF (AE-IPF). 
Study Objectives: 
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.  
 
Study Hypothesis: 
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.  
Study Aims: 
 
1. To conduct a mechanistically-driven trial to examine effects of autoantibody 
reductive treatments on the 6 month survival of patients with acute exacerbations 
of IPF.   
 
2. To determine the effects of the experimental treatment (TPE+rituximab+IVIG), 
compared to TAU, on secondary endpoints of 1.) supplemental oxygen 
requirments; 2.) six-minute walk distances (6MWD); 3.) adverse events, and; 4.) 
     the number of AE-IPF relapses after initial responses to therapy.   
 
Study Design: 
 
 
Following baseline screening assessments, all patients at all sites that meet all 
inclusion/exclusion criteria (including confirmation of their eligibility by another 
study investigator) 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 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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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. 
 
Planned Sample Size: 
A total of 51 subjects will be enrolled in this multi-center trial from the 6 participating 
medical centers (34 experimental and 17 TAU).  It is anticipated that each site will 
enroll approximately equal numbers of subjects (e.g., ~9 each) over the duration of 
this project. 
 
Duration of Treatment: 
19 days 
Inclusion Criteria: 
1.)  Age between 40-85 years old.   
 
2.)  A diagnosis of IPF that fulfills ATS/ERS Consensus Criteria.1   
 
3.)  Hospitalized patient with a diagnosis of AE-IPF, as ascertained by the 
responsible Primary Investigator (PI), with findings that include worsening or new 
development of dyspnea or hypoxemia within the last 30 days.  

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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4.)  Ground-glass abnormality and/or consolidation superimposed on a reticular or 
honeycomb UIP pattern on locally read chest CT scan.  
 
5.) Ability and willingness to give informed consent and adhere to study 
requirements.  
 
Major 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 serological evidence of hepatitis B, or current hepatitis C infection.   
 
4.) Coagulopathy, defined as an INR >1.6, PTT > 2x control, fibrinogen <100 mg/dL, 
or platelet count <50K 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.  
 
8.) Active malignancy or undergoing treatment 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, or other considerations, that the responsible 
physician-investigators believe should disqualify subjects, or are 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.) Presence of a condition or ongoing treatment with a medication that precludes 
TPE.   
 
13.) Concurrent participation in other experimental trials.  
 
14.) Fertile females who do not agree to contraception or abstinence, or have a 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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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: ANA, RF, Anti-
SSA, and Anti-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.  ANCA will continue to be tested during screening but negative results are no 
longer a requirement for randomization.  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.  
 
17.) Listed with the United Network for Organ Sharing for lung transplant at the time 
of enrollment.  
 
18.) Patients who are intubated at time of STRIVE enrollment. 
 
19.) Prior use of rituximab within the year preceding enrollment. 
 
20.) Clinical or Morphologic Domain criteria of IPAF.2 
 
Study Endpoints: 
 
• Primary endpoints: 
The primary end-point is 6-month survival.  Deaths from any cause are 
uncensored.  Lung transplantations, if any, will be censored events. 
 
• Secondary endpoints:  
Secondary end-points are: a.) treatment-related effects on supplemental O2 
requirements; b.) 6MWD; c.) adverse event (AE) rates; and d.) number of AE-IPF 
relapses   
 
 
 
1. OBJECTIVE, SPECIFIC AIMS, BACKGROUND, AND SIGNIFICANCE 
 
1.1 OBJECTIVE 
The primary goal of this randomized, multi-center, open-label Phase IIb clinical trial is to 
determine effects of combined therapeutic plasma exchange (TPE), rituximab, and intravenous 
immunoglobulin (IVIG), in comparison to standard, conventional treatment as usual (TAU), on 
the survival of patients with acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF).  
 
1.2 SPECIFIC AIMS 
Hypothesis: 
Our central hypothesis is that AUTOANTIBODY REDUCTION IS BENEFICIAL FOR AE-IPF 
PATIENTS.  We propose to test our central hypothesis by examining selected effects of TPE 
plus rituximab plus IVIG on AE-IPF patients. 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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Specific Aims: 
Specific Aim 1: To conduct a Phase IIB clinical trial in 51 hospitalized AE-IPF subjects at four 
major medical centers.  Subjects will be randomized 2:1 into the experimental arm or control arm 
(treatment as usual [TAU]), respectively.  The primary endpoint of this trial will be a comparison of 
six-month survival.   
We hypothesize the experimental therapy will improve six-month survival of AE-IPF patients. 
 
Specific Aim 2: To determine effects of the experimental regimen in AE-IPF patients, compared to 
TAU, on four secondary endpoints: A.) Changes in supplemental oxygen requirements 
pretreatment and after completion of therapy on day 19, as well as on days 60, 90, 180, 270, and 
365; B.) Six-minute walk distances (6MWD), which are facile, inexpensive, integrative measures of 
cardiopulmonary function, measured at the same times. These longitudinal O2 and 6MWD 
measures will enable us examine the duration of treatment effects; C.) Adverse event rates (e.g., 
comparative frequencies of infections, catheter-related problems, hemodynamic or metabolic 
perturbations, and other complications); and D.) The number of AE-IPF relapses following initial 
responses to therapy.  
We hypothesize the experimental therapy will improve pulmonary gas exchange and functional 
capabilities of AE-IPF patients, and have an acceptable adverse event profile. 
 
1.3 BACKGROUND: 
Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative lung disease of older individuals that 
causes unremitting dyspnea and hypoxemia.1 The disease usually progresses relatively slowly, if 
episodically, and median survival is ~3 years.  However, a sizeable proportion of idiopathic 
pulmonary fibrosis (IPF) patients, variously estimated as 10%-50%, develop acute exacerbations 
of their lung disease (AE-IPF) that are not attributable to other causes.3 Because the etiology of 
AE-IPF is enigmatic, it has been impossible to rationally select agents that specifically target the 
underlying pathological mechanism(s).  No medical intervention yet tried has efficacy for AE-IPF, 
and these patients have very poor prognoses.1,3-7 Recent studies have revealed several parallels 
between conventional autoimmune syndromes and progressive IPF.  On the basis of considerable 
data (to follow), we believe that antibody-mediated autoimmunity plays an important role in AE-IPF.  
 
The role of immune processes in IPF has generally been discounted, primarily because this lung 
disorder does not respond to glucocorticoids.  However, many other antibody-mediated lung 
diseases are similarly resistant to steroids and nonspecific agents.  Among these examples, 
granulomatosis with polyangitis (“Wegener's syndrome”), Goodpasture’s syndrome, acute 
interstitial lung diseases (ILD) associated with polymyositis, rheumatoid arthritis (RA), or other 
classical autoimmune diseases, and lung transplant rejection due to alloantibodies, also have very 
high rates of progression and mortality when treated primarily (or solely) with steroids.8-19  In 
contrast, targeted treatments that reduce autoantibodies are frequently beneficial for these 
syndromes. The experimental AE-IPF therapy proposed in this clinical trial was adapted from 
regimens used in other antibody-mediated lung diseases.8-15    
 
While considerable effort has been directed at understanding and treating IPF per se, and two 
therapeutic agents for the disease were recently approved, AE-IPF is comparatively understudied, 
despite the lethality of this syndrome.  The results of this clinical trial could provide compelling 
evidence that autoantibody reduction therapy benefits AE-IPF patients. This trial has the potential 
to be paradigm-shifting, alter current approaches to AE-IPF treatment, and could ultimately save 
the lives of untold future patients. 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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PRELIMINARY DATA:   
Autoantibody Reduction Therapy in AE-IPF Patients: We conducted a pilot trial of autoantibody 
reduction in AE-IPF patients at the University of Pittsburgh Medical Center (UPMC) (n = 10) and 
University of Texas Medical Branch (n = 1).27 All were admitted to ICUs or specialized high-level 
respiratory care units for severe, rapidly worsening AE-IPF.3-7 None had other causes of lung 
dysfunction or conventional autoimmune diseases.  None were eligible for transplantation due to 
age, irreparable coronary artery disease, or being too ill to have necessary evaluation procedures 
(e.g., heart catheterizations, colonoscopies, etc.).   
 
We empirically developed and optimized a protocol now consisting of 9 TPE treatments over 15 
days plus 2 doses of rituximab plus 4 days of intravenous immune globulin (IVIG).27 TPE rapidly 
removes circulating autoantibodies and can result in dramatic clinical improvement,17,18,29 as it did 
in all but two AE-IPF patients.  Rituximab depletes autoantibody-producing B-cells, but it's onset of 
action may take weeks or months.9,11-13  IVIG has many effects on autoantibody production, and is 
often added to TPE and/or rituximab to treat autoimmune diseases.17,19,29  Subject outcomes were 
compared to a cohort of 20 AE-IPF patients admitted to UPMC prior to the pilot trial.  The historical 
controls fulfilled the same criteria as trial subjects.27 
 
We found the experimental therapy improved gas exchange, walk distances, and survival of 
AE-IPF patients in pilot trials (Figures 1 and 2).  
 
Figure 1. (right) A.) Requirements for supplemental O2 
decreased in 11/13 treated subjects, and by more than 50% in 10 
(compared to one reduction among 20 historical controls) (OR = 
Odds Ratio).  B.) Maximal walk distance (not a formal 6MWD) was 
measured in the last 7 treated patients.  All but one increased by 
>100%.  Horizontal bar denotes median.  Walk distances were not 
systematically recorded in historical controls, but only one patient 
clinically improved during their hospitalization.   
 
 
 
 
Figure 2.  (left) A.) AE-IPF patients treated with autoantibody reduction 
therapy (n = 13) had better 6-month survival (51%) than the 20 
historical controls (13%).  Cross-hatches and numbers in parenthesis 
denote censored events (end of observations), including lung 
transplants, which are indicated by T.  
 
 
 
 
 
 
Underlying Biology:  Numerous, interrelated pathological B-cell abnormalities that are diagnostic 
for autoantibody syndromes are also present in IPF patients, especially among those with 
progressive disease:   
 
B-cells in IPF Lungs:  We have found highly abnormal focal B-cell infiltrates, particularly near 
fibroblast foci, in every IPF lung we have examined (Figure 3),25,28 and others report similar 
results.30-34 In diseases other than IPF, B-cell infiltrates in diseased tissues are recognized as an 
abnormal feature of an immunological disorder.35,36 Moreover, the B-cells within these infiltrates 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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typically produce vasoactive, profibrotic, and proinflammatory mediators, as well as antibodies (or 
autoantibodies).36 A very recent study confirmed B-cells are especially prevalent in AE-IPF 
lungs.34 
 
 
Figure 3.  Intrapulmonary B-cells.  Normal lung (left panel) 
and IPF lungs (right panel) immunostained for CD20 (specific 
for B-cells).  These B-cells have immigrated from 
extrapulmonary origins, being only infrequently positive for 
Ki-67 (x100).25,28   
 
 
Autoantibodies in IPF:  Many different autoantibodies have been detected in IPF patients by use 
of various methods.20,23,24,27,37-46 The concurrent presence of diverse autoantibodies is a 
characteristic feature of autoimmune syndromes.47-50 We found IgG autoantibodies in >80% of 
a cross-sectional cohort of mostly stable IPF in an early assay,20 and in >90% using new, more 
sensitive methods (manuscript in preparation).  
 
All AE-IPF tested so far (n=16) had circulating IgG autoantibodies detected by HEp-2 
indirect immunofluorescence assays (IFA) (Figure 3), 27 whereas ~10% of healthy controls 
have weak positive IFA.47    
 
 
Figure 3. (right) HEp-2 IFA, which are universally positive 
in AE-IPF patients, simultaneously detect any/all anti-HEp-
2 autoantibodies. Left panel is AE-IPF plasma (1:40 
dilution) right panel is normal plasma. 24,27  
 
 
Do These IPF Autoantibodies Do Anything?  IPF 
autoantibodies can have deleterious effects, and are 
not merely epiphenomenal:  
 
A.) Cytotoxicity:  IgG autoantibodies can aggregate antigens and form immune complexes (IC) in 
tissues.  IC activate NK cells and complement, which are highly cytotoxic.51,52 IC and complement 
also trigger cascades that have multiple downstream effects, including neutrophil recruitment.51 
These processes are very abnormal and are universally recognized as being highly pathogenic in 
other diseases.51,53,54   
IC are also present in the circulation,37,55 bronchoalveolar lavage (BAL),56 and lung 
parenchyma of IPF patients,24,25 especially among those with AE-IPF (Figure 4).  Complement 
deposits are also prevalent in IPF lungs,24,25 again, particularly in AE-IPF (Fig. 4). It is very 
unlikely these abnormalities are benign.36,51-54   
 
 
 
 
 
 
 
 
 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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Figure 4. (left) Replicate studies show immune complex (IgG) 
and complement (C3 or C4d) deposits are common in IPF 
lungs.24,25 These abnormalities are even more striking in AE-
IPF lungs explanted during emergent transplantations (“AE” –
top row).  Normal lungs are shown in the bottom row, and 
isotype controls (Cnt) are shown in far right columns.   
 
 
 
 
 
 
 
 
 
 
 
B.) Physiological Actions:  Autoantibodies can also alter cell functions by various mechanisms 
which include binding to surface receptors that transduce signals.20,52,54,57,58,60   
 
We discovered IgG autoantibodies against heat shock protein 70 (HSP70) in 25% of a cross-
sectional IPF cohort, 50% of those who died, and 70% of the AE-IPF patients (p<0.001).23,24 Anti-
HSP70 IgG portends a poor prognses in IPF (Figure 5).  
 
 
 
Figure 5. (right) IPF patients with HSP70 autoreactivity have worse survival.23 
 
 
In addition to function as an intracellular protein chaperone, HSP70 is 
exported extracellularly by stressed cells.57-60  Extracellular HSP70 
acts like a cytokine, binding to and stimulating various cell surface 
receptors, including scavenging receptors and CD33-related 
lectins.57,58  
 
We isolated anti-HSP70 IgG from several AE-IPF plasmas by protein 
G and affinity columns.  These cross-link and stimulate HSP70-receptor complexes on target cells 
and, among other effects, increase apoptosis resistence and production of IL-8 (Figure 6).  
   
 
 
 
 
 
 
 
 
 
 
 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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Figure 6. (A and B) Sub-physiological concentrations (1 g/ml) of anti-HSP70 IgG autoantibodies, isolated 
from AE-IPF patients, bind to HSP70 on surfaces of primary human lung fibroblast surfaces (not shown), and 
increase fibroblast Bcl-2 protein and mRNA productions.  The treated fibroblasts become resistent to 
apoptosis induced by staurosporine (STP), as ascertained by caspace 3 (C) and vital dye exclusion (D).  
Apoptosis resistence  of fibroblasts has been implicated in IPF pathogenesis.61  Data represent replicate 
experiments in 3 primary normal fibroblast lines each treated with 3 different AE-IPF patient anti-HSP70 IgG.  
E.) We previously showed IPF anti-HSP70 increased monocyte production of IL-8, 23 another mediator of 
IPF.  These autoantibody effects on fibroblasts and monocyte lineage cells are mediated by AKT and JNK 
pathways (not shown), and are consistent with known biological actions of receptor-bound HSP7058-60 
(manuscript in preparation). Nl IgG = normal IgG.  
 
Numerous other IPF autoantibodies also have deleterious effects on various target cells, 
such as direct cytopathy, and/or increasing productions of inflammatory or fibrotic 
mediators.38,40-42,44-46    
 
More Features of Autoimmunity in IPF:  Space constraints preclude detailed presentations of all 
the parallels between conventional autoantibody syndromes and progressive IPF.  In brief these 
include:    
 
B-cell Mediators in IPF:  B-lymphocyte Stimulating Factor (BLyS, aka BAFF) is a trophic factor 
for B-cell survival, maturation, and autoantibody production.61 Plasma BLyS levels are increased in 
autoantibody disorders (e.g., SLE, RA, etc.),62-64 and this mediator is also pro-fibrotic.65 We found 
BLyS levels are abnormally increased in IPF patients and inversely correlated with lung function 
and outcomes.25  C-X-C motif chemokine 13 (CXCL13) mediates B-cell homing to inflammatory 
foci and is important in the genesis of autoimmunity.66-70  We found CXCL13 is over-expressed in 
AE-IPF and inversely correlated with survival,28 and these findings have been corroborated.33 
 
T-cells and HLA:  Production of IgG autoantibodies with specificities for peptides requires help 
from T-cells that share avidity for those autoantigens.71  T-cell autoimmunity is near ubiquitous in 
autoimmune diseases, and we find it is also present in IPF.20,23 Other studies show T-cell 
differentiations in IPF patients that typify immune disorders, and are predictive of poor 
outcomes.21,26,72  HLA allele biases are another hallmark of autoimmunity.73 We found HLA-biases 
in IPF patients22 and these associate with specific autoantibodies.23 
 
How Does Autoimmunity Arise?  Autoimmunity often develops subsequent to other injurious 
processes such as infections, cancer, etc., [and, perhaps, the primary injury of IPF?] by epitope 
spread or mimicry.74-79 “Secondary” autoimmunities may be benign, but in many cases these “new” 
immune responses cause striking additional morbidity, e.g., carditis or nephritis following otherwise 
self-limited Streptococcal infections, neurologic syndromes associated with cancer, etc.74-77 
 
1.4 SIGNIFICANCE  
If our central hypothesis is correct, the experimental therapy here, mechanistically targeted to 
reduce autoantibodies, could result in significant benefit for a lung 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 AE-IPF, and could ultimately be broadly 
relevant to IPF patients with more slowly progressive disease 
 
 
 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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14 
 
 
2   RESEARCH DESIGN AND METHODS 
 
2.1  CLASSIFICATION AND METHODOLOGICAL DESIGN 
This is a randomized, multi-center, open-label Phase IIb clinical trial to determine the efficacy of 
combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin 
(IVIG), in comparison to treatment as usual (TAU), among patients with acute IPF 
exacerbations.  
 
 
 
2.2  STUDY DESIGN  
Subjects will be recruited from the inpatient populations of the collaborating institutions.  The 
primary care physician/clinical care team, who may be study investigators or colleagues of the 
study investigators, will first identify potential research subjects and obtain their approval for 
discussion of the research project with the study investigators.  
 
Following procurement of informed consent and completion of baseline/screening assessments, 
study subjects (total n=51) will be randomized 2:1 into one of two treatment arms: the combined 
TPE, rituximab, and IVIG (experimental therapy) vs. TAU. It is anticipated that each site will 
enroll approximately equal numbers of subjects (e.g., ~13 each) over the duration of this project. 
 
Subject eligibility will be confirmed prior to randomization by an adjudication process.  After 
screening, but immediately prior to randomization, the PI who is evaluating the potential subject 
will notify PIs at the other centers by cellphone and email messaging, to inform them a patient 
seems eligible.  The initiating PI will then send out a checklist of the randomization criteria, 
along with a provision for free-text comments, as they apply to the individual subject, by text 
mail and email (the redundancy will preclude missed enrollments if one or more cellphone 
batteries are discharged, or a PI(s) is off-line). The randomization will proceed after confirmation 
of the diagnoses, and edibility is attested by at least one PI (or one of more Co-investigator if all 
the other PIs are unavailable).  In the event of disagreement, the randomization will not 
progress until a clear majority of PIs concur, either for or against randomization.  In these 
challenged cases, which are expected to be rare, the consensus (either for or against 
randomization) can be obtained by telephone conversation, cellular texts, or emails, after careful 
review of pertinent data, that could including radiology reports or deidentified images or other 
necessary information. Clinical co-Investigators will "vote" only if there is no other participating 
PI available, or in cases of otherwise unresolvable ties among the PIs.     
 
All patients enrolled in both cohorts will receive a standardized steroid dosing regimen (for 19 
days), as well as empiric antibiotics for 8 days (to follow), as per clinical standards. The empiric 
broad-spectrum antibiotics will be initiated soon after admission, and the will be reassessed and 
tailored based on the subsequent cultures and sensitivity results. Subsequent treatments with 
steroids and antibiotics will be at the discretion of the attending physicians, based on their 
clinical assessments.  
 
Patients will be monitored carefully for occurrence of adverse events, laboratory test 
abnormalities, and changes in vital signs.  Adverse events will be evaluated according to criteria 
outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.   
 
The treatment protocol will last for 19 days.  Enrolled patients may be discharged from the 
hospital prior to the completion of the 19 day therapy, if medically indicated per their attending 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
_________________________________________________________________________________________________________ 
 
15 
 
 
physicians, and if they can still receive their study treatments and maintain protocol compliance 
as outpatients.  Conversely, enrolled subjects still hospitalized on day 20 will be followed for the 
duration of their hospital stay.  Patients removed from the study for unacceptable adverse 
events will be followed until resolution or stabilization of the adverse event. Subjects discharged 
from the hospital will be encouraged to return as outpatients for observations and specimen 
acquisitions on days 60, 90, 180, 270, and 365.  Telephone interview to detect potential late 
complications and outcomes will be conducted by study coordinators at other monthly intervals. 
 
2.3 STUDY TREATMENTS 
Following confirmation that patients meet all inclusion/exclusion criteria (Section 3.2) and have 
completed the informed consent process and baseline screening assessments, participants will 
be randomly assigned to receive one of the two following treatments, starting on Day 1, in a 
ratio of 2:1. 
 
1.) EXPERIMENTAL TREATMENT (n=34): Subjects will be treated with 60 mg prednisone 
p.o. on day 1, followed by 20 mg prednisone/day p.o. thru day 19, except on days 6 and 15.  
Methylprednisolone (Solumedrol) i.v. at equivalent doses may be used in lieu of prednisone.  On 
days 6 and 15 subjects will receive 100 mg Solumedrol i.v., as a premedication for rituximab.  
Steroid dosing after day 19 will be at the discretion of the attending physician.  There is no 
evidence that any steroid regimen has efficacy for AE-IPF.1-4 Nonetheless, these agents are 
standard of practice (SOP) for AE-IPF patients with widely varying dosing regimens.1  
 
In addition:  The experimental trial subjects will also have a dialysis/pheresis catheter 
placed in a central vein, followed by therapeutic plasma exchanges (TPE), rituximab, and IVIG.  
 
-TPE consist of 1x estimated plasma volume exchanges for 3 successive days (days 1,2, 
and 3), followed by two more daily treatments on days 5 and 6, and then four more q.o.d. (days 
9,11,13, and 15).  Initial daily TPE is intended to promptly decrease autoantibody titers in these 
rapidly progressive subjects.  Subsequent interrupted scheduling will allow equilibration of 
tissue-bound autoantibodies into the circulation, thereby increasing TPE efficacy.  The 48 hour 
interruption (days 7-8) is to enable the first dose of slow-onset rituximab to be administered 
early, rather than later (after all TPE). Spacing of 48 hrs between rituximab and the next TPE 
prevents removal of the anti-B-cell agent (Dr. Paul Brunetta, Genentech, pers. comm.).  
Plasma fluid volume will be replaced during TPE with 5% albumin, to maintain a net fluid 
balance of 95-100%.  In the event a subject’s fibrinogen is <120 mg/dL at the initiation of a 
TPE, as may occur in later treatments, either (1) cryoprecipitated antihaemophilic factor (AHF) 
(two 5-pooled units) will be given prior to the procedure to raise the fibrinogen level or (2) the 
replacement fluid will be 50% plasma and 50% 5% albumin, in order to maintain post-
procedural fibrinogen >50 mg/dL and thus, minimize bleeding risks.  The use of 
cryoprecipitated AHF prior to the procedure or plasma as the replacement fluid during the 
procedure will be at the discretion of the attending apheresis physician.  Calcium 
supplementation, either by po or by IV, may be given to reduce citrate toxicity related to TPE.  
Dialysis catheters are removed after the last TPE, when the fibrinogen level is >100 mg/dL.   
 
-Rituximab: One gm i.v. will be administered on day 6 (after completion of that day’s TPE) 
and again on day 15, after the last TPE.  This regimen was adopted from the protocol of an 
ongoing IPF trial (ART-IPF) and has been well tolerated.  Subjects will be premedicated with 
acetaminophen, diphenhydramine, and methylprednisolone 100 mg i.v., to obviate reactions.     
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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16 
 
 
-IVIG:  Doses of 0.5 gm/kg will be administered on days 16-19, after the last TPE.  Subjects 
who have mild reactions will be premedicated, as for rituximab, prior to subsequent doses. This 
is also SOP for lung transplant recipients treated with IVIG for antibody-mediated allograft 
rejection in our hospitals.  
 
-Empiric Antibiotics: All subjects, at all sites, in both treatment arms, will receive 
antibiotics for 8 days, a SOP for empiric therapy of patients with exacerbations of chronic lung 
diseases, based on recognition that bronchoalveolar lavage (BAL) and transtracheal aspiration 
(TTA) have poor diagnostic accuracy.  Empiric antibiotic therapy for AE-IPF is widely accepted. 
The 8 day duration is based on data in other seriously ill patients. Our SOP regimen is: 
azithromycin (until Legionella DFA is negative) plus piperacillin/tazobactam + vancomycin.  
Substitutions for allergies are ciprofloxacin and linezolid, respectively.  Antibiotics will be 
administered as specified by package inserts.  Subjects intubated after enrollment will be 
managed using standard ARDS Network guidelines. 
The duration of this antibiotic regimen can be shortened, at the discretion of the attending 
physician, among patients who have been treated with an identical (or clinically comparable) 
regimen, at the time of or immediately prior to enrollment in STRIVE-IPF (e.g., patients who 
were getting antibiotics at an outside hospital prior to transfer to the study site).  Given 
difficulties in diagnosing infections in these often critically ill patients (see Infectious 
Considerations Section 3.3), the AE-IPF subjects in this trial should receive appropriate 
antibiotics, but consideration for adjustment is necessary in cases in which the total duration of 
antibiotic therapy would be excessive and potentially deleterious.       
 
2.) TREATMENT AS USUAL (TAU) Controls (n=17):  The subjects in this arm will receive 
the same steroid regimen at the Experimental Arm Subjects:  60 mg prednisone p.o. on day 1, 
followed by 20 mg prednisone/day p.o. thru day 19, except on days 6 and 15.  
Methylprednisolone i.v. at equivalent doses may be used in lieu of prednisone.  On days 6 and 
15 subjects will receive 100 mg Solumedrol i.v.  Steroid dosing after day 19 will be at the 
discretion of the attending physician.  
All TAU subjects will also receive the identical empiric antibiotic regimen as the 
Experimental Treatment Arm subjects (see details above).   
 
2.4 RANDOMIZATION  
A randomization list, (2:1 experimental arm to controls) will be generated in advance by the 
Data Coordinating Center (DCC) and programmed into the web-based data entry and 
management system.  Subjects will be stratified by disease severity as either A.) Mild (In order 
maintain SaO2 >93%, supplemental O2 requirement are less than or equal to either 5L/min by 
nasal cannula or 50% O2 by face mask) or B.) Severe (Supplemental O2 requirements > either 
5L/min or >50% O2 per face mask).  Subjects will also be stratified based on their use or nonuse 
of any/both antifibrotic medications (nintenanab and/ pirfenidone), with 2 to 1 randomization 
within strata.  Due to the small sample size, stratification by site will not be attempted. 
 
 
 
 
 
 
 
 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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17 
 
 
2.5 STUDY TREATMENT SCHEMATIC 
The experimental interventions (days 1-19) are outlined below in Table 1: 
Days on 
Intervention 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
Prednisone or 
equivalent (p.o. 
dose per day) 
 
 60 mg 
20 mg each day 
none 
20 mg each day 
none 
20 mg each day 
Therapeutic 
Plasma 
Exchange (TPE) 
 
TPE, each of these 
days 
 
 
TPE, each 
of these 
days 
 
 
 
TPE 
 
TPE 
 
TPE 
 
TPE 
 
 
 
 
Rituximab 
 
 
 
 
 
 
1 gm 
IV 
 
 
 
 
 
 
 
 
1gm 
IV 
 
 
 
 
Acetaminophen 
(prior to Rituximab) 
 
 
 
 
 
650 
mg 
Oral 
 
 
 
 
 
 
 
 
650 
mg 
Oral 
 
 
 
 
Solumedrol 
(prior to Rituximab) 
 
 
 
 
 
100 
mg 
IV 
 
 
 
 
 
 
 
 
100 
mg 
IV 
 
 
 
 
Benadryl -
diphenhydramine 
(prior to Rituximab) 
 
 
 
 
 
50 mg 
Oral 
 
 
 
 
 
 
 
 
50 mg 
Oral 
 
 
 
 
Antibiotics 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
IVIG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0.5 gm/kg/day 
Experimental 
Blood 
Specimens 
Before therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
O2 requirement 
assessment 
Before therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After 
therapy 
TPE Collection 
500 ml + 50 ml 
 
50 
ml 
 
 
 
 
 
50 ml 
 
 
 
 
 
50 ml 
 
 
 
 
6 minute walk 
distance 
Before therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
After 
therapy 
 
Table 1.  Outline of Experimental Arm Procedures.  Notes: Maintenance steroid doses after 
Day 19 are at discretion of attending physician(s).  Later surveillance, endpoint measures, (and 
specimen acquisitions) are not shown here (days 60, 90, 180, 270, 365), or telephone contacts 
(end of months 1, 4, 5, 7, 8, 10, 11). Adverse events are prospectively recorded at these time 
points too, and at any time they may arise.  
 
2.6 RELAPSES AMONG SUBJECTS 
The duration of a single treatment course will almost certainly be finite, although several 
subjects have had prolonged remissions after the experimental therapy (Fig. 2, see also27).  
Patients with other autoantibody diseases who respond to analogous therapy often get 
consolidation therapy to sustain their remissions.  We do not believe consolidation therapy can 
be incorporated into this trial.  The first principle here is to assess benefits of autoantibody-
targeted therapy.  If so, later trials can focus on prolonging remission durations with 
consolidation therapies (if necessary).  Nonetheless, patients who respond to their therapies in 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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either treatment arm may be given the benefit of comparable therapies if their AE-IPF flares 
again.   
 
Two patients to date responded well to the experimental regimen and were discharged from the 
hospital with much lower O2 requirements and ambulatory abilities, but again developed 
recurrent symptoms of increasing dyspnea and hypoxemia about 3 months later.  Both 
responded to an abbreviated treatment protocol, adopted from analogous regimens used to 
treat other relapsing autoimmune disorders, consisting of five TPE administered every other day 
followed by four successive doses of IVIG (0.5 g/kg/day).  Both subjects again responded, and 
were discharged and have had prolonged remissions.  Another subject experienced a relapse 
within a few days of a successful initial treatment, while he was awaiting hospital discharge, and 
he too responded to the abbreviated treatment protocol.    
 
Hence, subjects in either arm that had a favorable clinical response lasting for at least 5 days 
after completion of their initial treatment, will be eligible for retreatment one time during their 6 
month participation in this trial.   
 
For purposes here, a relapse is defined as a recrudescence of AE-IPF symptoms and physical 
findings, i.e., new or increased shortness of breath or hypoxemia during the last 30 days, 
without other explicable etiology.  The presence of a relapse will be confirmed by adjudication 
among the PIs, following the same communication and survey procedures used to adjudicate 
and confirm the initial diagnoses of AE-IPF (see page 14).   
 
The definition of a "favorable clinical response" is based on our clinical secondary endpoints, 
and consists of either a reduction in requirement for supplemental oxygen by 50% or an 
improvement of 6MWD by 30 m (see page 24).    
 
The treatment of an AE-IPF relapse in a participant is based on their initial randomization.   
 
 
All subjects will again be treated with 60 mg prednisone p.o. (or methylprednisolone 
equivalent) on day 1, followed by 20 mg/day for the duration of their therapy, and the specified 
empiric antibiotic regimen.  In addition: 
 
 
A.) Experimental arm subjects who relapse will receive TPE x 5, administered every 
 
other day, followed by four successive doses of IVIG (0.5 g/kg/day). A 50 ml aliquot 
 
from the first TPE discard will be collected, stored, and used in experimental assays. 
 
 
B.) TAU subjects will again be treated with the steroids and antibiotics.  
 
Second relapses, if they occur within the 6-month trial participation, will be treated with standard 
therapy (i.e., TAU).   
 
All subjects with relapses will have 20 ml blood obtained for experimental purposes prior to 
beginning their respective "salvage" therapies.  Assays (e.g., HEp-2 titers, IgG levels, particular 
autoantibody levels, or other immune mediators) in these specimens could be especially 
valuable to identify immune parameters that are associated with, and possible predict, AE-IPF 
recurrences. 
   
 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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19 
 
 
2.7 STUDY PROCEDURES  
Routine clinical care for seriously ill patients with respiratory insufficiency will be followed as 
ordered by the primary physician.  The study will log the results of specific screening-baseline 
measures, coagulation assays (which are mandated by this protocol in conjunction with TPE).  
The results of other selected tests that may be obtained during the routine provision of clinical 
care will also be logged.  These may include: complete blood count (CBC), electrolytes, 
glucose, BUN, serum creatinine, ionized calcium, magnesium, phosphorus, albumin, liver 
function tests consisting of total bilirubin, aspartate alanine transaminase (ALT), and aspartate 
glutamine transaminase (AST).  
 
The first batch of removed plasma from the day 1 TPE (as well as every third TPE thereafter 
(33,6,9) ) will be aliquoted and stored frozen (-20o or below) for later experimental studies.   
 
An extra 39 ml of blood needed for experimental immunologic research studies will be obtained 
pretreatment.  These and all other blood draws will utilize phlebotomy tubes with K2-EDTA 
anticoagulant Subsequently, 29 ml of blood for testing will be procured on days 60, 90, 180, 
270, and 365 after the start of therapy.    
 
Enrolled subjects will be visited by study personnel on each day of their hospitalization.   
 
The following information will be collected and entered into the study case report forms (CRFs) 
and/or web-based data collection system.  All clinical and laboratory data are initially obtained 
for routine clinical care, and will be collected from medical records. 
 
1. Physician names and contact information, general medical and surgical histories, co-
morbidities, concurrent medications, and allergies.  
2. Recording of vital signs, demographics, and medication regimen. 
3. Review of medications 
4. Brief assessment of symptoms. 
5. Recording of laboratory and clinical testing results. 
 
The schedule for patient assessment and data collection is outlined as follows. 
 
2.7.1 Screening 
Screening (one or more days prior to randomization):  Patients will undergo screening 
assessments to determine that all inclusion/exclusion criteria are met prior to receiving the study 
drug treatments. The screening assessment may take place over more than one day.  Eligible 
patients will adjudicated by review and if concurred to be eligible will have the study explained in 
detail and asked to provide Informed Consent. 
 
The following tests and procedures will be performed after providing informed consent, but prior 
to randomization:  
• Detailed medical history and demographics. 
• Physical exam and inpatient progress assessment to include vital signs and blood pressure. 
• Laboratory evaluations specific for Inclusion/Exclusion Criteria to include: hepatitis B surface 
 antigen (HBsAg), hepatitis B core antibody (HBcAb) and hepatitis C virus antibody (HCV 
 Ab). tests, IgA, ANA, RF, anti-SSA, anti-CCP, pregnancy test, either urine or blood (if 
 applicable). ANCA will also be performed at this time, but are not used to determine 
 eligibility.  If HCV Ab are positive, HCV nucleic acid PCR will be performed.  A positive result 
 with the HCV PCR is an exclusion criterion, whereas negative results of this test do not 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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20 
 
 
 preclude randomization.   
  
2.7.2 Experimental procedures 
Day 1 (Initiation of therapy): 
Randomization should occur as soon as possible after meeting confirmed eligibility, but within a 
maximum of 48 hours after meeting all inclusion/exclusion criteria.  Confirmation of eligibility by 
other study clinicians, as detailed in Section 2.2 Study Design (page 14) will be necessary prior 
to randomization.  Patients that meet all inclusion/exclusion criteria (and confirmation as above) 
will be randomized to receive one of the study treatments described above in Section 2.3.  In 
addition, the following data will be obtained (if not already obtained during screening): 
 
• Physical exam and inpatient progress assessment to include vital signs and blood pressure. 
• Laboratory evaluations (routine clinical care) that may include: complete blood count (CBC), 
electrolytes, glucose, BUN, serum creatinine, ionized calcium, magnesium, phosphorus, 
INR, albumin, liver function tests including of total bilirubin, aspartate alanine transaminase 
(ALT) 
• Experimental immunologic assays with blood samples to be processed and stored frozen,   
   for later batch shipment (while frozen) to the Clinical Coordinating Center (CCC) 
• Initiation of common steroid therapy, if not already started (see Section 2.3) 
• Initiation of common antibiotic regimen, if not already started (see Section 2.3) 
• Record O2 requirement 
• Six minute walk distance (6MWD).  6MWD = 0 among subjects unable to ambulate. 
• Adverse Event (AE) assessment.  
 
For subjects randomized to TPE: 
• Laboratory evaluations: complete blood count (CBC), INR, electrolytes, ionized calcium level   
 (at the discretion of the attending physician), fibrinogen level 
• Dialysis catheter placement in a central vein among subjects randomized to experimental  
   therapy 
• First TPE (with collection of a discarded 500 ml and 50 ml plasma aliquots from this 
procedure) 
• AE assessment 
 
Day 2 (for subjects randomized to TPE): 
• Laboratory evaluations: complete blood count (CBC), INR, electrolytes, ionized calcium level   
 (at the discretion of the attending physician), fibrinogen level 
• Second TPE 
• AE assessment 
 
Day 3 (for subjects randomized to TPE): 
• 
Laboratory evaluations: complete blood count (CBC), INR, electrolytes, ionized calcium level  
(at the discretion of the attending physician), fibrinogen level 
• Third TPE (with collection of a 50 ml discarded plasma aliquot from this procedure) 
• AE assessment 
 
Day 5 (for subjects randomized to TPE): 
• 
Laboratory evaluations: complete blood count (CBC), INR, electrolytes, ionized calcium level  
(at the discretion of the attending physician), fibrinogen level 
• Fourth TPE 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
_________________________________________________________________________________________________________ 
 
21 
 
 
• AE assessment 
 
Day 6 (for subjects randomized to TPE): 
• 
Laboratory evaluations: complete blood count (CBC), INR, electrolytes, ionized calcium level  
(at the discretion of the attending physician), fibrinogen level 
• Fifth TPE 
• Following completion of TPE: premedications and rituximab 
• AE assessment 
 
Day 9 (for subjects randomized to TPE): 
• 
Laboratory evaluations: complete blood count (CBC), INR, electrolytes, ionized calcium level  
(at the discretion of the attending physician), fibrinogen level 
• Sixth TPE (with collection of a discarded 50 ml plasma aliquot from this procedure) 
• AE assessment 
 
Day 11 (for subjects randomized to TPE): 
• 
Laboratory evaluations: complete blood count (CBC), INR, electrolytes, ionized calcium level  
(at the discretion of the attending physician), fibrinogen level 
• Seventh TPE 
• AE assessment 
 
Day 13 (for subjects randomized to TPE): 
• 
Laboratory evaluations: complete blood count (CBC), INR, electrolytes, ionized calcium level  
(at the discretion of the attending physician), fibrinogen level 
• Eighth TPE 
• AE assessment 
 
Day 15 (for subjects randomized to TPE): 
• 
Laboratory evaluations: complete blood count (CBC), INR, electrolytes, ionized calcium level  
(at the discretion of the attending physician), fibrinogen level 
• Ninth and final TPE (with collection of a discarded 50 ml plasma aliquot from this procedure) 
• Following completion of TPE: premedications and rituximab 
• AE assessment 
 
Days 16-19 (for subjects randomized to TPE): 
• IVIG each day at 0.5 gm/kg 
• AE assessment 
 
Day 19 (All Subjects): 
• Record O2 requirement 
• Six minute walk distance (6MWD).  6MWD = 0 among subjects unable to ambulate. 
 
2.7.3 Follow-up monitoring 
A variance of 5 days will be allowed for the telephone contacts to account for weekends or 
holidays.  A variance of 10 days will be allowed for each outpatient follow-up visit for similar 
reasons, as well as potential logistic/transportation problems.  If subjects remain hospitalized at 
these later dates, an identical evaluation and procedures will be performed (as feasible): 
 
Day 30 (1st month): 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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22 
 
 
• Telephone call (if discharged from the hospital, or personal visit if an inpatient) to access 
status (brief assessment of symptoms, and a review of medical or surgical histories). 
• AE assessment 
 
Day 60 (2nd month): 
• Outpatient or inpatient evaluation, if admitted to the hospital for other reasons, to include 
directed physical exam, assessment of symptoms, and a review of interval medical or 
surgical histories 
• Experimental immunologic assays (blood samples to be processed and stored frozen),   
   for later batch shipment (while frozen) to the Coordinating Center 
• O2 requirement 
• 6MWD 
• AE assessment 
 
Day 90 (3rd month):  
• Outpatient or inpatient evaluation, if admitted to the hospital for other reasons, to include 
directed physical exam, assessment of symptoms, and a review of interval medical or 
surgical histories 
• Experimental immunologic assays (blood samples to be processed and stored frozen),   
   for later batch shipment (while frozen) to the Coordinating Center 
• O2 requirement 
• 6MWD 
• AE assessment 
 
Day 120 (4th month): 
• Telephone call (if discharged from the hospital, or personal visit if an inpatient) to access 
status (brief assessment of symptoms, and a review of medical or surgical histories). 
• AE assessment 
 
Day 150 (5th month): 
• Telephone call (if discharged from the hospital, or personal visit if an inpatient) to access 
status (brief assessment of symptoms, and a review of medical or surgical histories). 
• AE assessment 
 
Day 180 (6th month):  
• Outpatient or inpatient evaluation, if admitted to the hospital for other reasons, to include 
directed physical exam, assessment of symptoms, and a review of interval medical or 
surgical histories 
• Experimental immunologic assays (blood samples to be processed and stored frozen),   
   for later batch shipment (while frozen) to the Coordinating Center 
• O2 requirement 
• 6MWD 
• AE assessment 
 
Day 210 (7th month): 
• Telephone call (if discharged from the hospital, or personal visit if an inpatient) to access 
status (brief assessment of symptoms, and a review of medical or surgical histories). 
• AE assessment 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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23 
 
 
Day 240 (8th month): 
• Telephone call (if discharged from the hospital, or personal visit if an inpatient) to access 
status (brief assessment of symptoms, and a review of medical or surgical histories). 
• AE assessment 
 
Day 270 (9th month):  
• Outpatient or inpatient evaluation, if admitted to the hospital for other reasons, to include 
directed physical exam, assessment of symptoms, and a review of interval medical or 
surgical histories 
• Experimental immunologic assays (blood samples to be processed and stored frozen),   
   for later batch shipment (while frozen) to the Coordinating Center 
• O2 requirement 
• 6MWD 
• AE assessment 
 
Day 300 (10th month): 
• Telephone call (if discharged from the hospital, or personal visit if an inpatient) to access 
status (brief assessment of symptoms, and a review of medical or surgical histories). 
• AE assessment 
 
Day 330 (11th month): 
• Telephone call (if discharged from the hospital, or personal visit if an inpatient) to access 
status (brief assessment of symptoms, and a review of medical or surgical histories). 
• AE assessment 
 
Day 365 (12th month)- final assessment:  
• Outpatient or inpatient evaluation, if admitted to the hospital for other reasons, to include 
directed physical exam, assessment of symptoms, and a review of interval medical or 
surgical histories 
• Experimental immunologic assays (blood samples to be processed and stored frozen),   
   for later batch shipment (while frozen) to the Coordinating Center 
• O2 requirement 
• 6MWD 
• AE assessment 
 
Every effort will be made to ascertain status among those seemingly lost to follow up by 
contacting patient or next of kin, conducting internet searches for obituaries, etc. 
 
2.7.4  Specimen Collection and Management 
Specimen Collection / Documentation:  An extra 29 ml of blood for experimental immunologic 
research studies will be obtained pretreatment, and on days 60, 90, 180, 270, and 365 after the 
start of therapy.   The peripheral blood will be processed to separate mononuclear cells, 
plasma, and sera, which will be aliquoted, and frozen (at -20o or below) until used in batched 
assays.  The apheresis waste bag (plasma removed from the patient) during the first TPE and 
the last TPE will also be aliquoted and stored frozen, for additional assays.  These assays will 
be carried out in the laboratories of Dr. Steven Duncan at the Clinical Coordinating Center 
(UAB) after batched overnight shipment of the specimens. 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
_________________________________________________________________________________________________________ 
 
24 
 
 
Each research sample will be labeled with subject’s unique identifier, sample date, and sample 
collection time.  The code number and date on which the specimen is frozen, all other 
information about the specimen, and subsequent processing will be entered on a specimen 
processing worksheet. 
 
Covariate information, e.g., concomitant medications, laboratory values, etc., will be obtained at 
each time point. 
 
Specimen Handling and Labeling (De-Identification) 
All research specimens and all records associated with the samples will be labeled only with a 
unique code that links to the trial data, but contains no personal identifiers. The information 
linking these code numbers to the corresponding subject’s identity will be kept in a secure 
location in the PI’s office at each participating center, and will not be available to staff managing 
samples at the research laboratories.  
 
Specimen Management and Storage: Specimens in excess of immediate assay requirements 
may be stored indefinitely in a secured freezer under the control of the responsible PI.  The 
coding information linking patient identifiers to the stored samples will be maintained in a locked, 
secure area that will be accessible only to the study investigator. Subjects may request to have 
their samples destroyed at any time. These samples will be destroyed immediately upon receipt 
of the subjects’ written request to do so.  
 
Restrictions to Direct Access of Specimens:  Specimens will be kept in the responsible study 
investigators’ laboratories indefinitely and will be under the control of the PI.  Investigators or 
other personnel not involved with the management or operations of the study are not permitted 
direct access to the specimens.  
 
2.8  STUDY ENDPOINTS 
 
2.8.1. The Primary End-Point 
The primary endpoint of this trial is six-month survival.  Patient survival is unequivocally 
important, objective, and accurately ascertained from observations, patient or family phone 
interviews, and internet obituary searches. The uncensored event will be death from any cause, 
with lung transplantations tabulated as censored events.  Lung transplantations, or institution of 
extracorporeal membrane oxygenation (ECMO) will be used as events in sensitivity analyses to 
ensure the consistency of the outcome results, since these are likely informative censorings. 
 
2.8.2. Secondary End-Points  
General:  O2 requirements and six minute walks will be assessed immediately prior to treatment 
and after completion of therapy on day 19, as well as on days 60, 90, 180, 270, and 365.  
Subjects discharged from the hospital after completion of the protocol will be instructed to return 
to our clinics for these scheduled assessments.  These visits and endpoint measures are 
already SOP in many IPF clinics.  Adverse events and relapses that occur anytime during the 
subjects participation in this study will be recorded and compared.  
 
A.) Supplemental O2 requirements: are a reflection of lung function, and clinically important. 
O2 measures, at the times specified above, will be tabulated as the flow rate (or concentration) 
necessary to maintain resting arterial oxygen saturations (per oximeter) at >93% (this gives 
some safety margin), as we used in the pilot trial.27 Many air-hungry AE-IPF cannot tolerate a 
tight-fitting face mask, nor breathe thru a mouthpiece.  Thus, we cannot systematically measure 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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25 
 
 
FIO2, which precludes analyses of PaO2:FIO2.27 Supplemental O2 requirements over the various 
intervals will be dichotomously categorized into one of two groups for comparison: 1.) Improved 
(reduced by >50%) or 2.) Unimproved (reduced <50%, unchanged or worsened).  
 
B.) Six minute walk distance (6MWD): will also be performed at those times described above.  
6MWD are simple, inexpensive, reproducible, and SOP in IPF patients. 6MWD will be 
performed per ATS/ ERS guidelines, by trained nursing staff in hospital or clinic hallways (our 
SOP).  Values for 6MWD can be obtained in all patients, even those who are bedbound (value = 
0)(Fig. 1B).  Only one AE-IPF so far could tolerate spirometry at enrollment, precluding 
systematic analyses of PFTs. 6MWD results over the various intervals will also be dichotomized 
into either 1.) Improved (by >30 meters) or 2.) Unimproved (improved <30 m., same, or 
worsened).  The cutoff value of 30 m. ~corresponds to 6MWD minimal clinically important 
differences.  
 
C.) Adverse events: The NCI Common Toxicity Criteria Scale will be used to define grades 
(severity) of adverse events and toxicities.  An adverse event is defined as any untoward 
medical occurrence in a subject, regardless of its relationship to these treatments.  Toxicity is an 
adverse event with a direct relationship to the study drug.  All toxicities are adverse events, but 
not all adverse events are toxicities.  Computer data entry (and case report forms- [CRF]) will 
require responses to all adverse events, with a particular focus on infections (including location 
and organism), catheter-related problems (e.g., bleeding, clot), apheresis-related complications 
(e.g., hypotension, citrate toxicity, etc), metabolic or hemodynamic perturbations (e.g., 
hyperglycemia, hypotension, etc.) and other, less frequent complications (e.g., neurologic 
symptoms), as well as having provision for free text entries.  Recording all AEs in pre-specified 
checklists (and free text entries), will guard against unintended bias in this unblinded trial.  
 
D.) AE-IPF Relapses.  The number of relapses that occur in subjects in either study arm will be 
compared adjusted for duration of exposure (i.e. deaths have potentially less time in which to 
have a relapse and thus this will be used in the analyses).  The definition of an AE-IPF relapse 
and the adjudication process used to confirm these diagnoses has been detailed on page 18.     
 
2.8.3 Additional Studies That are Not Formal Endpoints  
All these assays will be performed in the laboratory of Dr. Duncan, using stored (frozen) 
plasma specimens, batch-shipped from all sites: 
 
A.) Anti-HEp-2 IFA Titers:  Pretreatment autoantibody titers will be compared to results at the 
post-treatment time points described previously.  Among subjects who are evidently not going to 
survive, or will dropout for other reasons, measures will be made immediately prior to these 
events, if feasible.   
 
HEp-2 IFA are a simple Gold Standard for autoantibody detection that have been used for 
decades in research and clinical labs.  We have described these IFA in prior studies, with 
corroborations by independent groups. HEp-2 IFA are also the primary endpoint of the ongoing 
ART-IPF trial.   
 
In brief, commercial slides with fixed, permiabilized HEp-2 cells are incubated with plasma 
specimens at serial titrations from 1:20 to 1:320, along with negative control (normal IgG) and 
positive control standards.  Plasma is washed off, and replaced with FITC-conjugated anti-
human IgG, followed by fluorescence microscopy and imaging.  Images are scored by replicate 
blinded observers to determine the highest (most dilute) titer wherein specimen 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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26 
 
 
fluorescence is greater than the concurrent negative controls.  Note:  IFA for diagnoses of 
conventional autoimmune syndromes depend on finding specific abnormal fluorescence 
patterns, whereas we use these assays to detect nonspecific patterns that are not 
diagnostic for SLE, scleroderma, etc.   Subjects with positive tests for known autoimmune 
disorders, per hospital clinical laboratories (e.g., ANA, RF, Anti-SSA, etc.), are ineligible 
(Exclusion Criterion #15).   
 
B.) Anti-HEp-2 IFA Patterns:  An analysis of HEp-2 IFA results to date in all AE-IPF (including 
the initial series treated with a less aggressive regimen27) indicates the pre-treatment immuno-
fluorescence patterns may be associated with responses to therapy.  All nine (9) AE-IPF who 
had nucleoli sparing (Figure 7A) responded promptly to TPE with early and significant reductions 
of their O2 requirements, and their 6 month survival is 56%.  In contrast, no treatment responses 
were evident among the five (5) patients with enhanced nucleoli staining (Fig. 7B); their median 
survival was 11 days, and all were dead within 6 months.  The hazard ratio for nucleoli sparing 
vs enhanced staining is 15.2, with 95%CI = 1.7-142.9 (p=0.001).  Responses were mixed, and 
outcomes intermediate, among the 6 AE-IPF who had neither nucleoli sparing nor enhanced 
nucleoli staining.  Their median survivals were 23 days, and 33% were alive at 6 months.   
 
Figure 7. HEp-2 Staining Patterns of AE-IPF Plasma Specimens.  HEP-2 IFA were invariably 
positive in AE-IPF patients, with highly varied patterns.  A.) Nucleoli sparing; B.) Enhanced 
nucleoli staining; and C.) Other (nucleoli staining is not enhanced, and not spared.  All IFA here 
were at 1:40 plasma dilutions.  
 
Given these interesting preliminary results, we plan to prospectively ascertain the HEp-2 
staining patterns of all subjects in both treatment arms, to test the ability of these assays to 
predict survival, and treatment responsiveness.  Other studies now in progress will attempt to 
identify particular HEp-2 nucleoli autoantigens among the AE-IPF, for potential use as 
mechanistic biomarkers to personalize treatment 
 
C.) Autoantibody repertoires in AE-IPF will be defined using modifications of a nonbiased 
discovery assay that we've previously detailed.24 In brief, water soluble lysates are made from 
explanted normal lungs that were not used as donor organs.20 We already have >20 normal 
lungs banked from prior studies.20 Immunoglobulins within the lysates are removed with protein 
A/G, and albumin is removed by depleting resin (ThermoFisher, Rockport, IL).  The lysates are 
adsorbed on normal IgG bound to protein G (to minimize nonspecific binding).  The eluants are 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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27 
 
 
next run thru columns of IPF plasma IgG covalently bound to protein G.  The proteins that 
specifically bind to this IPF IgG (putative autoantigens) are eluted by acidification and 
electrophoresed on 2-D gels. Individual proteins are spot picked and sequenced by mass 
spectrometry (MALDI-TOF/TOF).   
 
Three assays using pooled plasmas from several stable IPF patients have been performed.24 
Pooling was necessary given the small volumes of plasma available from individual phlebotomy 
specimens.  HSP70 was identified in all three, along with >30 other potential autoantigens. 
Preliminary studies indicate several of these other identified proteins may also be autoantigens 
of IPF, including HSP90, HSP27, and annexin.39 
 
The availability of large volume plasma specimens from the TPEs (3-5L/subject) will enable us 
to now determine the number and specificities of autoantibodies among individual AE-IPF 
patients.    
 
The presence of a particular autoantibody, or panel of autoantibodies, in many or (hopefully) all 
AE-IPF, will be validated in homemade ELISA assays (to quantify these particular 
autoantibodies) 24 using plasmas from the AE-IPF subjects enrolled in this trial (phlebotomy 
yields are adequate for ELISA), the previously treated AE-IPF patients , and specimens 
collected in earlier investigations.20-28  Prevalence(s) and concentrations (OD values) of specific 
autoantibodies discovered in the AE-IPF patients will be compared to findings in already 
collected plasma specimens from stable IPF (>200 at UPMC + UAB), >50 normal controls, and 
>150 COPD patients (disease controls), as detailed in prior studies. 24,28    
 
D.) Circulating Immunoglobulin Concentrations: Levels of IgA, IgM, total IgG and IgG 
isotypes will be quantified by ELISA among pre-treatment specimens and plasmas obtained 60, 
90, 180, 270, and 365 days after the start of therapy. Pretreatment IgG levels could conceivably 
correlate with clinical responsiveness, and later measures would exclude the presence of 
hypogammaglobulinemia in long-term survivors.  However, we do not believe IgG measures 
during the actual experimental therapy, or for some time thereafter (e.g., <60 days) will be 
helpful, since these determinations will be confounded by infusions of exogenous 
immunoglobulins in fresh frozen plasma (used to reverse TPE reductions of clotting factors) and 
the IVIG administrations during days 16-19.   
 
E.) B Lymphocyte Stimulating Factor (BLyS, aka BAFF), measured by ELISA25, may 
rebound after rituximab and presage clinical relapses.62 Serial assays could find BLyS is a 
prognostic biomarker in treated AE-IPF patients, or indicate adjunct therapy with an anti-BlyS 
agent (belimumab) may be helpful in this population.  
 
F.) Quality of Life (QoL) Measures:  Patients will complete a King's Brief Interstitial Lung 
Disease health status questionnaire (K-BILD) at 3 and 6 months.  This instrument was specifically 
developed for and validated in patients with interstitial lung disease, is brief, simple to administer, 
easy for patients to complete, measures health status in three domains, and is reproducible.80 
 
2.9 DATA AND POWER ANALYSES 
 
2.9.1 Primary Endpoint Data Analyses (6 month survival):  The statistical hypothesis is: 
H0:  pTAU < pE 
HA:  pTAU > pE 
Where pE = mortality rate in the experimental arm and pTAU = mortality rate in the treated as usual 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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28 
 
 
arm.  TAU = treatment as usual. 
 
Baseline demographic and clinical data of participants will be summarized using means (with 
standard deviations) and medians (with inter-quartile ranges) for continuous variables, and 
counts and percentages for discrete variables, stratified by treatment group.  Differences among 
groups (to examine the randomization effectiveness), will be assessed by t-tests, or by Fisher’s 
exact test for discrete data.  Deaths will be tabulated based on the actual day they occur, relative 
to the date of randomization.  Survival analyses will use an exponential survival model and be 
summarized using Kaplan-Meier plots via product-limit estimation and log-rank tests, with lung 
transplantations treated as censored events in the primary analysis.  Even though trial 
subjects are selected to not be eligible for lung transplants at enrollment, we anticipate some 
may occur, especially in the experimental arm, will improve enough to have later transplant 
evaluations and be listed for these procedures.  Only one subject in each arm of the pilot study 
had lung transplants during their 6-month observations (Fig. 2). Since transplants are few and 
will occur relatively late, the power of our actuarial analyses will be minimally, if at all, affected.   
 
Analysis will be based on intention-to-treat and deaths at any time will be counted against the 
treatment arm assigned.   We expect few dropouts or cross-overs although we have budgeted 
for 10% dropouts in each group (see Power Analyses).  TAU participants will not be permitted to 
cross-over to the treatment group because of the intent-to-treat analysis.   
 
2.9.2 Primary Endpoint Power Analyses: A one-sided log-rank test with an overall sample 
size of 51 subjects (17 in the control group and 34 in the treatment group) achieves 97.6% 
(94.6% two-tailed) power at a 0.05 significance level to detect a hazard ratio of 0.3 when the 
control group hazard rate is 1.00. The subject accrual (entry) occurs over 40 months. The 
accrual pattern across time periods is assumed to be uniform (all periods equal). The proportion 
dropping out of the control group is 0.10. The proportion dropping out of the treatment group is 
0.10. The proportion switching from the control group to another group with a hazard rate equal 
to the treatment group is 0. The proportion switching from the treatment group to another group 
with a hazard rate equal to the control group is 0. 
 
2.9.3 Interim Analysis:  A formal interim analysis for safety as required by the DSMB will occur 
when 30/51 = 59% of the overall study information should be available, approximately 6 months 
after the 30th patient is randomized.  The safety analysis will be based on serious adverse 
events, as defined by the NCI Common Toxicity Criteria Scale, that are treatment-related or 
possibly treatment-related, as well as AE-IPF relapses.  Other adverse events of lesser 
severities, and/or not directly related to the treatments, are also routinely recorded per protocol, 
and will provide additional information for consideration by the DSMB at the interim analysis.   
The formal interim safety analysis will be conducted when 30 patients have completed treatment 
(20 experimental and 10 controls) using a lower boundary of a nominal 0.05 level with no 
adjustments for Type I errors since this is a safety assessment.  The DSMB will monitor the 
incidence of mortality in the cohort and no formal stopping rules are proposed for mortality.   
More  precisely,  adverse event rates between groups  will be  compared  by employing 
negative  binomial  regression (proc genmod procedure  in  SAS)  and  person months  of  
exposure will be  used as an offset  variable to control for unequal exposure time (i.e., time to 
death and/or relapse). The 6 month adverse event rate will be assessed using the person 
months of exposure concept, since it is expected that there will be greater mortality in the TAU 
group and thus, unequal exposure times will need to be controlled.  We will continue to enroll 
participants during the period while the safety interim is being conducted, but if a safety signal is 
observed, the DSMB will decide the benefit versus risk of continuing.  If there is a safety 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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29 
 
 
difference at the interim analysis that reaches nominal statistical significant, the DSMB may 
consider stopping the trial, depending on the direction and the outcome of mortality after 
examining all evidence, including overall safety and efficacy.  
 
2.9.4 Secondary Endpoint Data Analyses: O2 requirements and six minute walks will be 
assessed immediately prior to treatment and after completion of therapy on day 19, as well as 
on days 60, 90, 180, 270, and 365.  Subjects discharged from the hospital after completion of 
the protocol will be instructed to return to our clinics for these scheduled assessments. These 
visits, visit intervals, and actual endpoint measures are already standard of practice in our IPF 
clinics.   Adverse events and relapses that occur anytime during the subjects participation in this 
study will be recorded and compared (Table 4).  
 
 
Baseline 
Day 19 
Day 60 
Day 90 
Day 180 
O2 Required 
X 
X 
X 
X 
X 
6MWD 
X 
X 
X 
X 
X 
Adverse events 
---Anytime---- 
Relapses 
---Anytime---- 
Table 4.  Schedule of secondary endpoint assessments.  Tabulations of adverse events will 
occur not only on those scheduled times denoted here, but will also include any adverse events 
that have occurred at intervals in between those visits.   
 
Although each participant's formal involvement with the study lasts 6 months (180 days), we 
intend to continue to collect periodic data on these patients at their subsequent routine and 
standard medical visits (e.g., at 270 and 365 days after the start of treatment),   Based on 
observations to date, we believe the majority of those subjects who had clinical benefits evident 
at 6 months will continue in remission for a more prolonged, if as-of-yet undefined, period.  
Thus, additional longitudinal observations after treatment will help us to determine the practical 
duration of treatment effects.  These data will, in turn, be invaluable to develop subsequent 
maintenance regimens (and/or design follow-on studies) that could optimize the care of AE-IPF 
patients.    
 
We anticipate many TAU subjects will deteriorate rapidly, and secondary endpoint measures 
will often be infeasible at later time points.  Nonetheless, the analyses proposed here will still 
enable early intergroup comparisons that will confirm treatment effects.  Later measures 
(probably mostly among surviving experimental arm subjects) will provide information about the 
durability of therapy. Analyses will follow intention to treat principles. 
 
For the secondary analyses, we will use repeated measures mixed effects models to utilize the 
maximum data from each participant, in addition to the dichotomized (improved vs. otherwise) 
assessments for oxygen requirements and walk distance (to follow).  The proportion of subjects 
with significant O2 and 6MWD changes in each arm will be compared by Fisher's exact test.  
For sensitivity analyses, we will use the worst O2 from a completing patient for any deaths 
within each treatment group.  Similarly for the 6 minute walk we will impute the worst time 
within the treatment arm surviving to complete the walk.  For the AEs and Relapses, we will 
use Poisson regression with an offset for the time under study. 
 
2.10 DATA COORDINATING CENTER (DCC):  
The DCC, under the direction of Dr. Fazlur  (Co-Invest), will be responsible for data management 
and analyses. The DCC includes experienced research methodologists and data base 
managers, in addition to data and IT support staff (see also Resources and Facilities).  The DCC 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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30 
 
 
will provide full service electronic data capture, participant tracking, automated SAE notification, 
QA/QC reporting, other study reports and data management services with a secure password 
protected system that is consistently backed up. The extent of these data management services 
include: database specification, edit check programming, management plan development and 
maintenance, ongoing manual data review and query management, medical coding and data 
cleaning and locking.  Serving as the repository of all study data collected, the DCC will interface 
with the various investigators for their specialized data and results.  The DCC will also provide 
programming, statistical analysis and medical writing services, which include the programming of 
data summaries, tables, and statistical analyses.  The DCC will also provide requested data to 
the DSMB and assist with the interim monitoring meeting(s), study progress tracking, and safety 
monitoring.  In addition, the DCC will be responsive to requests from the IRBs at the clinical sites 
or the NHLBI.   
 
Each clinical site will be audited to assure that they are collecting data and treatment is being 
provided in accordance with the protocol.  Audits of a random selection of data, and all protocol 
consents will also be reviewed.  A report will be sent to the Clinical Sites, DSMB, and NHLBI 
after each site visit. 
 
2.11 ANTICIPATED RESULTS AND PITFALLS 
 
2.11.1 Specific Aim 1 (Primary Endpoint).   
 
Anticipated Results and Potential Pitfalls: We predict survival will be greater in the 
experimental arm (Fig. 2).   
 
Insertion of large bore dialysis (TPE) catheters has risks and discomforts.  We chose not to have 
a placebo arm since insertions in TAU controls for no benefit (these are NOT routinely used for 
i.v. infusions) may be problematic for subject recruitment.  Further, TPE is dynamic (blood in; 
blood out; plasma out; albumin in, etc.), and the machine is large, complex, and does not have 
sham provisions.  Many patients will be too ill to safely transport for non-essential reasons.  We 
cannot devise a way to blind observers, staff and TPE techs. Thus, this study is unblinded. 
Inadvertent bias should be minimal, however, given the unequivocal primary endpoint. 
 
It is possible, albeit unlikely, the benefit of TPE in AE-IPF could be due to removal of mediators 
other than autoantibodies.  However, we found plasma levels of matrix metalloproteinase 7 
(MMP7), an enzyme involved in degradation of extracellular matrix, and a representative soluble 
mediator of IPF, were not associated with TPE, or clinical responses.27  Furthermore, the 
duration of TPE effects on soluble factors is limited.17,18 and cannot readily account for the 
prolonged remissions of several trial subjects (Fig. 2).  
 
The experimental regimen is unlikely to reverse the lung fibrosis that afflicted these patients prior 
to their AE.  Nonetheless, easing symptoms and prolonging survival is a worthwhile goal, and a 
focus of much effort in other serious diseases (e.g., oncology, pulmonary artery hypertension, 
etc).  Moreover, prolonging survival will enable patients to have transplant evaluations, and live 
long enough to procure a donor organ.27 
 
The duration of a single treatment course will almost certainly be finite, although several subjects 
have had prolonged remissions (Fig. 2, see also27).  Patients with other autoantibody diseases 
who respond to analogous therapy may get consolidation therapy to sustain their remissions.  
We do not believe consolidation therapy can be incorporated into this trial.  The first principle 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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31 
 
 
here is to assess benefits of autoantibody-targeted therapy.  If so, later trials can focus on 
further prolonging remission durations with consolidation therapies (if necessary).  Proposing a 
consolidation now, prior to first proving our hypothesis, is premature, and would require a 
complex trial design with more subject groups (and much larger “n”).  
 
2.11.2 Specific Aim 2 (Secondary Endpoints) Anticipated Results and Pitfalls 
O2 need assessments and 6MWD are simple and standard of practice (SOP) in our medical 
centers. Our dichotomous categorizations will highlight clinically relevant treatment effects (with 
practical meanings for patients) as opposed to lesser (and perhaps even trivial) simple 
mathematical changes. The large changes necessary to qualify as treatment effects here are 
also more reliably tabulated, and less subject to unintentional bias than entry of small interval 
values.  A potential downside is loss of power (given dichotomous rather than continuous 
variable comparisons), but after witnessing therapy effects, we anticipate treated subjects will 
more often show large endpoint improvements, compared to TAU (Fig. 1).  
 
Serial measures up to 1 year after treatment will help us determine duration of effects, as we 
anticipate many experimental arm subjects will be remission-free for >6 months (Fig 2. and 
citation27).  Many TAU subjects will likely deteriorate, and their secondary endpoint measures 
will often be infeasible at later time points.  Nonetheless, analyses of the early time points will 
still enable us to prove treatment benefits.   
 
Based on multiple studies involving thousands of patients treated with analogous regimens, and 
our experiences (Figs. 1, 2),27 we anticipate adverse events will not be significantly greater 
among experimental arm subjects, and the trial regimen will have an acceptable risk:benefit 
ratio in these high-risk patients.  
 
Based on experiences to date, we anticipate a greater proportion of TAU patients who improve  
and are discharged from their initial hospitalization will have relapses, compared to experimental 
arm subjects.  
 
2.12 STUDY TIMELINES AND MILESTONES 
Timelines and Milestones: Infrastructure and regulatory requirements should be completed by 
<9 months after funding is awarded (Figure 8).  This consortium has considerable clinical trial 
experience.  Our clinical experience with this therapy will let us “hit the ground running”.  Our 
creative plan for funding patient care costs enables us to study many more subjects at many 
more centers than if the NIH had to assume the entire financial burden (see Budget 
Justification). Our potential subject population is greater than the necessary study numbers that 
we will easily meet this conservative target enrollment, and assuming reasonable consent, we 
anticipate doing so ahead of schedule, which would save even more money (see Feasibility- 
above).  
   
 
Year 1 
Year 2 
Year 3 
Year 4 
Year 5 
                      Month:      1-4 
5-8 
9-12 
1-4 
5-8 
9-12 
1-4 
5-8 
9-12 
1-4 
5-8 
9-12 
1-4 
5-8 
9-12 
Regulatory and Logistic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Enrollment (n) 
 
 
5 
5 
5 
5 
5 
5 
6 
6 
6 
3 
 
 
 
Data Analyses 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 8.  Projected timeline and milestones, relative to the Notice of Award date. 
 
 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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32 
 
 
3 HUMAN SUBJECTS 
 
3.1 SUBJECT POPULATION 
Human Subject Characteristics: 
Fifty-one (51) adult IPF subjects with acute exacerbations of their lung disease, of both genders 
and all ethnic backgrounds, who are hospitalized at any of the four participating medical centers, 
will be eligible for enrollment.  Subjects must provide written informed consent prior to 
participation.  Surrogate consent will not be allowed.  No special vulnerable populations will be 
studied. 
 
Participating Centers: 
Each participating center is expected to comply with appropriate regulatory, protocol, and data 
collection requirements. 
 
1.  University of Alabama at Birmingham (UAB).  
2.  Brigham and Women's Hospital (BMH) -No Longer Active 
3.  Temple University Hospital (TUH)  
4.  University of Pittsburgh Medical Center (UPMC) 
5.  Baylor University (BU) 
6.  University of Utah (UU) 
7. Thomas Jefferson University (TJU) 
 
The study-specific identifying numbers for these centers are: 
  
01 (UAB) 
02 (BWH) 
03 (TUH) 
04 (UPMC)  
05 (BU) 
06 (UU) 
07 (TJU) 
 
Clinical Coordinating Center (CCC): 
The Clinical Coordinating Center and the Lead Institution is UAB.  The CCC will be responsible for 
coordination, development, and monitoring the submission, and approval of the protocol and 
consent documents, as well as any subsequent amendments per the individual institution IRB’s 
and applicable regulatory guidelines. The CCC will ensure that all participating centers in the 
multi-center protocol demonstrate their intent and capability of complying with Federal 
Regulations, Good Clinical Practices (GCP) and HIPAA requirements. 
 
3.1.1 Inclusion of Women and Minorities 
Women who meet the inclusion criteria, and have none of the exclusion criteria, will be enrolled 
without restriction as dictated by the study protocols.  Because of the use of a study medication, 
woman of child bearing potential must meet specialized inclusion/exclusion criteria to minimize 
this risk. We will make efforts to enroll participants in this research in a distribution which mirrors 
the study populations of the participating medical centers.   
 
3.1.2 Inclusion of Children 
Children under 18 years of age will not be enrolled because they do not develop this disease.  
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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33 
 
 
3.2  INCLUSION AND EXCLUSION CRITERIA 
The inclusion criteria have been selected to isolate a patient population with idiopathic pulmonary 
fibrosis with acute disease exacerbations.  The exclusion criteria are selected to not enroll 
patients with an alternative cause for a respiratory decompensation and to exclude patients with 
increased risk for the associated interventions.   
 
Inclusion Criteria 
1.)  Age between 40-85 years old.   
 
2.)  A diagnosis of IPF that fulfills ATS/ERS Consensus Criteria.1   
 
3.)  Hospitalized patient with a diagnosis of AE-IPF, as ascertained by the responsible Primary 
Investigator, with findings that include 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 
UIP pattern on locally read chest CT scan.  
 
5.) Ability and willingness to give informed consent 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 serological evidence of hepatitis B, or current hepatitis C infection.   
 
4.) Coagulopathy, defined as an INR >1.6, PTT > 2x control, fibrinogen <100 mg/dL, or platelet 
count <50K 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.  
 
8.) Active malignancy or undergoing treatment 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, or other considerations, that the responsible physician-
investigators believe should disqualify subjects, or are expected to interfere with study 
participation.  
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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34 
 
 
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.) Presence of a condition or ongoing treatment with a medication that precludes 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: ANA, RF, Anti-SSA, and Anti-
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.  ANCA will continue to be tested during screening but negative results are 
no longer a requirement for randomization.  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.  
 
17.) Listed with the United Network for Organ Sharing for lung transplant at the time of 
enrollment.  
 
18.) Patients who are intubated at time of STRIVE enrollment. 
 
19.) Prior use of rituximab within the year preceding enrollment. 
 
20.) Clinical or Morphologic Domain criteria of IPAF.2   
 
Clinical Domain Criteria include: distal digital fissuring (i.e., "mechanic hands"), distal 
digital tip ulceration, inflammatory arthritis or polyarticular morning stiffness >60 min, plamar 
telangiectasia, Raynaud's phenomenon, unexplained digital edema, unexplained fixed rash on 
the digital extensor surfaces (Gottron's  sign). 
 
Morphological Domain Criteria include: any radiographic or histopathological finding 
other than UIP (e.g., NSIP, LIP, etc.), or multi-compartment involvement of unexplained pleural 
or pericardial effusions or thickening.  
 
3.3  INFECTIOUS CONSIDERATIONS 
 
Infectious Considerations:  AE-IPF is infrequently complicated by occult bacteria or viral 
pulmonary infections and, in the absence of treatment with cellular immunosuppressants, rarely 
(if ever) complicated by occult opportunists.1-7 BAL are not SOP prior to administration of 
rituximab to autoimmune populations, many of whom have lung diseases that resemble IPF.5-18  
Invasive diagnostic procedures to exclude occult pulmonary infection are also not SOP for AE-
IPF evaluations at our hospitals due to the rarity of infections, poor diagnostic yields, and 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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35 
 
 
potential risks.   A detailed review of 35 AE-IPF admissions to UPMC revealed that BAL was 
performed in only 9 (26%), was uniquely productive in only 2 (6%), and our SOP antibiotic 
regimen covered those organisms.  Most subjects will have tenuous respiratory function at 
entry,27 and BAL or TTA will result in gratuitous intubations, while providing questionably useful 
data. All physician investigators believe that requiring mandatory invasive procedures for AE-IPF 
subjects is contraindicated, and refuse to participate if this becomes an enrollment criterion.   
Instead, procedures will be performed in potential subjects when they are safe and are 
indicated in the judgment of the attending physician.27 However, potential subjects recently 
treated with immunosuppressants MUST have a prior negative BAL (Exclusion Criterion #15).  
Rituximab decreases autoantibody titers, but total immunoglobulins are less reduced (if at 
all).  Infection rates after rituximab therapy are minimally if at all different than those of placebo 
controls  TPE only transiently reduces immunoglobulins, and is not usually associated with 
serious infections.  Potential effects of TPE and rituximab on immunoglobulins should also be 
mitigated by IVIG therapy.   
 
Given the ongoing profusion of highly sensitive viral detection assays, which in many cases 
have unspecified clinical significances, the putative identification of a virus in respiratory or 
other specimens among potential subjects will need to be interpreted by attending and study 
physicians in the appropriate clinical context.  As an example, the identification of a rhinovirus 
in a nasal swab may have triggered the AE-IPF, but seems unlikely (given current information) 
to primarily account for the pulmonary infiltrates and respiratory compromise.  On the other 
hand, the frequent association of influenza (A and B), adenovirus, and respiratory syncytia 
virus (RSV) with pulmonary disease will exclude recruitment of AE-IPF patients who have 
positive tests for these viruses.  Other viral identifications with questionable significance in non-
immunocompromised patients (e.g., parainfluenza, metapneumovirus) will be considered on a 
case-by-case basis.  
 
 
4  RECRUITMENT AND INFORMED CONSENT PROCEDURES 
 
4.1  RECRUITMENT METHODS 
Subjects will be recruited from the inpatient population among the participating institutions.  The 
primary care physician/clinical care team, who may be study investigators or colleagues of the 
study investigators, will first identify potential research subjects.  The clinician investigators will 
discuss the research project with the potential subjects.  
 
4.2  INFORMED CONSENT PROCEDURES 
The consent process will begin via one of two possible pathways:  
  
 
1) Referral of the prospective participant to the investigators/research coordinator by a physician 
who has knowledge of the proposed research, and obtains patient consent for the research 
team to approach the patient/surrogate. 
 
2) Individuals who have provided signed IRB-approved HIPPA compliant consent for 
participation in clinical trial research registries.   
 
Subjects must provide informed consent prior to performing any of the study procedures.  The 
information about this study will be given to subjects in language understandable to subjects.  
Only physician investigators will present the study to the potential subjects. The physician 
investigator will verbally present a general outline of the research plan, including inclusion and 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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36 
 
 
exclusion criteria, to the prospective participant. The consent form, outlining the design of the 
study, will include the risks and benefits of participating, and will be reviewed and the 
investigator will answer any questions. Prospective participants may take as much time as 
required to make an informed decision. Written informed consent will be obtained from each 
participant prior to performing any research study procedures. 
 
In addition, older potential study participants whose competency to consent is in question will be 
tested for sufficient comprehension and recall of the information presented. Prospective 
subjects who do not remember the important facts about participation in the research study after 
repeated testing will not be included in the study. The investigators will also assess whether a 
participant understands experimental procedures over time, including assessment throughout 
the full duration of participation in the study.  
 
 
5 POTENTIAL RISKS AND BENEFITS 
 
5.1 POTENTIAL RISKS 
 
5.1.1 General Risks of Study Protocol and Procedures 
The potential subject risks specifically related to the study protocol procedures could include 
loss of confidentiality or actual physical harm due to experimental procedures. 
 
5.1.2 Potential Risks of Experimental Intervention 
The potential subject risks specifically related to the study protocol procedures could 
include: 
 
Insertion of a central venous catheter for plasma exchange:  
Common Risks: Bleeding at the insertion site, pneumothorax, catheter-associated blood 
clots, internal hemorrhage/hemothorax, and infections. 
 
Plasma Exchange:  
Common Risks: A drop in blood pressure that may be associated with symptoms of 
dizziness or light-headedness, and mild/transient citrate toxicity (perioral tingling or 
numbness, paraesthesia, nausea, vomiting). 
 
Other Risks: Unusual complications include extracorporeal anticoagulation, severe 
hypocalcemia leading to muscle irritability, cardiac arrhythmias, and seizures, infections by 
blood products (plasma and/or cryoprecipitated AHF), transfusion reactions, allergic 
reactions to the replacement solutions or sterilizing agents for the tubing, and adverse 
effects of immunosuppression produced by the associated hypogammaglobulinemia 
(although this will be mitigated by the IVIG therapy). 
 
Corticosteroid (methylprednisolone- premedication for rituximab): 
Common Risks: Insomnia, nausea, vomiting, upset stomach; fatigue or dizziness; muscle 
weakness or joint pain; problems with diabetes control; or increased hunger or thirst.  
Nonetheless, corticosteroids are SOP for acute exacerbations of IPF, despite an absence of 
supporting data.   
 
Other Risks: Acne, increased hair growth, thinning of the skin, cataracts, glaucoma, 
osteoporosis, roundness of the face, and changes in behavior. 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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37 
 
 
 
Rituximab:  
Common Risks: Fever, chills, headache, pain, rash, pruritus, angioedema, nausea, 
abdominal pain, cytopenias, weakness, cough, rhinitis. Infusion related reactions: 
angioedema, bronchospasm, chills, dizziness, fever, headache, hyper-/hypotension, 
myalgia, nausea, pruritus, rash, rigors, urticaria, and vomiting.  
 
Infrequent Risks: Hypotension, peripheral edema, hypertension, flushing, edema, dizziness, 
anxiety, agitation, depression, hypoesthesia, insomnia, malaise, nervousness, neuritis, 
somnolence, vertigo, migraine, urticaria, hyperglycemia, hypoglycemia, hyper-
cholesterolemia, diarrhea, vomiting, dyspepsia, anorexia, weight loss, anemia, pain at the 
injection site, back pain, myalgia, arthralgia, paresthesia, arthritis, hyperkinesia, hypertonia, 
neuropathy, conjunctivitis, lacrimation disorder, throat irritation, bronchospasm, dyspnea, 
upper respiratory tract infection, sinusitis, LDH increases.  
 
Other Risks: Rare events associated with rituximab include severe mucocutaneous 
reactions, progressive multifocal leukoencephalopathy due to LC virus reactivation, 
hepatitis B reactivations, and other infections. 
 
Intravenous Immunoglobulin (IVIG): 
Serious risks include renal insufficiency, venous or arterial thrombotic events, and anti-IgA-
mediated anaphylaxis.  Adverse events in >5% of subjects include headache, chills, fever, 
shaking, fatigue, malaise, anxiety, back pain, muscle cramps, abdominal cramps, blood 
pressure changes, chest tightness, palpitations, nausea, tachycardia, vomiting, cutaneous 
reactions, wheezing, rash, arthralgias, and edema.   
 
Venipuncture:  
Common Risks: temporary, minor discomfort, bruising. 
 
Other Risks: infection, bleeding and phlebitis. 
 
5.2 ALTERNATIVE TREATMENTS 
 
The alternative treatments for the subjects participating in this investigation are to continue their 
TAU medical care under the direction of their attending physician. 
 
5.3 POTENTIAL BENEFITS 
 
Participation in the proposed research may or may not provide a direct benefit to the subjects.  
Potential benefits from the participation in this protocol include enhanced survival, improved 
respiratory symptoms, and decreased exacerbation severity. Identification of the mechanism(s) 
mediating these outcomes will facilitate risk-stratification for these adverse outcomes, and 
development of targeted treatment strategies for the future.   
 
Based on the preceding assessment of risks and potential benefits, the risks to subjects are 
reasonable in relation to anticipated benefits.  The research presents a balance of risks and 
expected direct benefits similar to that available in the clinical setting.  
 
Importance of the Knowledge to be Gained 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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38 
 
 
The preliminary data in this application outline a hypothesis for the progressive clinical 
deterioration in patients with acute IPF exacerbations.  The protocol specifically seeks to 
address that hypothesis.  If the study intervention is found to be both safe and effective in the 
study population, the treatment of IPF would be altered significantly, and ultimately could lead to 
a change in the disease natural history.  Completion of these protocols will begin to address 
important questions related to disease. 
 
5.4 DATA SAFETY MONITORING PLAN 
      
5.4.1 Data Safety Monitoring Board 
A Data and Safety Monitoring Board (DSMB), independent of the study investigators, will monitor 
the clinical trial outlined in this proposal for the duration of this proposal.  The DSMB will be 
appointed by the sponsoring agency (NHLBI), from among experts in the field.  The Food and Drug 
Administration has already provided an exemption from IND requirements for this protocol.  Each 
participating site will complete local Institutional Review Board (IRB) approval. The specifics of the 
DSMB structure and function are outlined below. 
 
The DSMB will be expected to meet as needed, but not less than every six months, to review 
the progression of the study including patient enrollment, protocol compliance, and adverse 
event reports. The DSMB will conduct interim monitoring of accumulating data from research 
activities to assure the continue safety of human subjects, relevance and appropriateness of the 
study, and the integrity of research data. 
 
5.4.1.2 Clinical Coordinating Center (CCC) 
The CCC is the UAB study team, led by the Contact PI and the Protocol Chair, Dr. Steven 
Duncan.  The CC will ensure that all participating institutions within the multi-center protocol 
demonstrate their intent and capability of complying with Federal Regulations, GCPs and HIPAA 
requirements.  
 
Each study site will be subject to on-going monitoring.  Study sites will be evaluated for meeting 
enrollment criteria and for the accurate and timely submission of data forms, and timely 
response to data queries from the study monitors or data coordinating center. 
 
The UAB study team will assume the following general responsibilities: 
• 
Assist in protocol review. 
• 
Maintain copies of FWA and Institutional Review Board (IRB) approvals from all 
Participating Institutions. 
• 
Maintain updated roster of participants.  
• 
Verify eligibility. 
• 
Verify response. 
• 
Collect data on protocol specific CRFs. 
• 
Prepare all submitted data for review by the Protocol Chair. 
• 
Maintain documentation of Serious Adverse Event reports submitted by Participating 
Institutions and submit to Protocol Chair for timely review.   
• 
Distribute Serious Adverse Event safety reports.  
• 
Monitor participating institutions either by on-site inspection of selected participant 
records and/or with source documents and research records submitted to the 
Coordinating center.  
 
5.4.1.3 Data Coordination Center (DCC) 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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39 
 
 
 
The DCC will provide methods for data entry, management, quality control, and analyses, and 
provide administration and maintenance of a comprehensive database.   The DCC, based in the 
UAB Department of Biostatistics in the School of Public Health, is directed by Dr. Rahman 
Fazlur  (Co-Investigator).  The School of Public Health is adjacent to the UAB Hospital complex.   
 
In conjunction with the clinical trial PIs, the DCC will establish a data collection protocol and 
mechanism.  Data will be collected on paper Case Report forms.  The data on these forms will 
then be entered into a database at the Clinical Site by manually typing the data into the 
database, through the Web-based system.  All data are loaded into a central database and can 
be managed using the online data management system.  Numerous data quality checks, such 
as duplicate entry checks, double-entry verification, and real-time data checking (e.g., ID 
verification, range checks) will be implemented to ensure that the data are accurate, complete 
and secure.  Data entry personnel will be trained and certified in the correct use of the system.   
 
5.4.1.4 Participating Institutions 
Each Participating Institution will provide to the CCC a list of the key personnel assigned to the 
role for oversight of data management at their site. The general responsibilities for each 
Participating Institution are as follows: 
 
• 
Commit to accrual to the multi-center protocol. 
• 
Submit protocol and/or amendments to their local IRB. 
• 
Maintain a regulatory binder. 
• 
Update Coordinating Center with research staff changes on a timely basis. 
• 
Submit source documents, research records, and CRFs per protocol specific submission 
guidelines to the CCC. 
• 
Submit Serious Adverse Event reports to local IRB and provide copies to the CCC.  
• 
Submit deviations and violations to their local IRB and the CCC. 
 
5.4.1.5. Adverse Events: The National Cancer Institute Common Toxicity Criteria Scale will be 
used to define grades (severity) of adverse events and toxicities.  An adverse event is any 
untoward medical occurrence in a participant who received study drug, regardless of its 
relationship to the study drug.  Toxicity is an adverse event with a direct relationship to the study 
drug.  All toxicities are adverse events, but not all adverse events are toxicities.  This is a 
determination made by the study investigator.  The study investigators will classify adverse 
events as “definitely", "most likely,” “possibly,” “unlikely” or "clearly not" due to the study drug.  
Toxicity will be defined as an adverse event that is definitely, most likely, or possibly caused by 
a study drug or procedure. 
 
The severity of adverse changes in physical signs or symptoms will be classified as follows: 
 
• 
Grade 1 (Mild): asymptomatic or mild symptoms; clinical or diagnostic observation only; 
intervention not indicated. 
 
• 
Grade 2 (Moderate): minimal, local or noninvasive intervention indicated; limiting age-
appreciate instrumental ADL (Activities of Daily Living). 
 
• 
Grade 3 (Severe): medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL. 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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40 
 
 
 
• 
Grade 4 (Life-threatening): consequences; urgent intervention indicated. 
 
• 
Grade 5 (Death): event is a direct cause of death. 
 
Assuring patient safety is an essential component of this protocol.  The contact PI has primary 
responsibility for the oversight of the data and safety monitoring.  The study investigators will 
evaluate all adverse events.  All subjects who have adverse events, whether considered 
associated with the use of the study medication or not, must be monitored to determine the 
outcome.   
 
The study coordinators must view patient records for possible adverse event on a daily basis, 
while subjects are hospitalized. All untoward medical occurrences observed in subjects will be 
recorded on the participants’ adverse event case report forms (CRF) by the study coordinator 
under the supervision of the PI, with a particular focus on infections (including location and 
organism), catheter-related problems (e.g., bleeding, clot), apheresis-related complications 
(e.g., hypotension, citrate toxicity, etc), metabolic or hemodynamic perturbations (e.g., 
hyperglycemia, hypotension, etc.) and other, less frequent complications (e.g., neurologic 
symptoms), as well as having provision for free text entries.  Recording all adverse events in 
pre-specified checklists (and free text entries), will guard against unintended bias.  The CRFs 
will then be reviewed for completeness and internal consistency. Subsequently, the CRFs will 
be recorded on an electronic password-guarded study database.  In addition to internal 
safeguards built into a computerized system, external safeguards will be put in place to ensure 
that access to the computerized system and to the data is restricted to authorized personnel. 
Training conducted by qualified individuals on a continuing basis will be provided to individuals 
in the specific operations with regard to computerized systems that they are to perform during 
the course of the study.  
 
The clinical course of the adverse event will be followed up according to accepted standards of 
medical practice, even after the end of the period of observation, until a satisfactory explanation 
is found or the PI considers it medically justifiable to terminate follow-up. 
 
The contact PI will work with the reporting investigators and DCC to prepare a detailed written 
summary of serious, unexpected, and treatment related adverse events, and will compare, and 
contrast the event with prior events. The detailed written summary will be provided to the DSMB 
and the IRB.  
 
In addition, the DSMB Report addressed the following information will be submitted to the IRB at 
the time of continuing review annually or more often as required: 
 
• 
A list of the research personnel who participated in the data and safety monitoring. 
 
• 
The frequency of monitoring that took place during the renewal intervals and/or the dates 
that data and safety monitoring was conducted. 
 
• 
A summary of cumulative data related to unanticipated problems (including adverse 
events) including a determination of causality and whether the risk to benefit assessment 
has changed. 
 
• 
If appropriate, a summary of pertinent scientific literature reports, therapeutic 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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41 
 
 
developments, or results of related studies that may have an impact on the safety of 
study participants or the ethics of the research study. 
 
• 
A summary of the outcome of reviews conducted to ensure subject privacy and research 
data confidentiality. 
 
• 
Final conclusions regarding changes to the anticipated benefit-to-risk assessment of the 
study participation and final recommendations related to continuing, changing, or 
terminating the study. 
 
 
 
5.4.2 STOPPING RULE: 
 
Individual subject specific stopping rules: 
A study participant will be discontinued from further study drug treatment/Intervention(s) 
administration if any of the following occur: 
 
• 
Any clinical adverse event, laboratory abnormality, intercurrent illness, other medical 
condition or situation occurs such that continued participation in the study would not 
be in the best interest of the participant. 
• 
Development of any exclusion criteria may be cause for discontinuation (eg: 
hemodynamic instability, defined as a vasopressor requirement that would 
contraindicate the use of plasmapheresis).   
• 
Intercurrent illness or an unexpected fatal or life-threatening adverse event, which 
requires discontinuation of study treatment 
• 
Request by the subject to withdraw from the study 
• 
Investigator discretion 
 
5.4.3 Trial Termination due to Efficacy or Inefficiency:  See Section 2.9.4.  
 
5.4.4 Parameters to be Monitored 
The following progress will be monitored throughout the course of the research to ensure the 
safety of subjects as well as the integrity and confidentiality of their data. 
 
• 
An evaluation of the progress of the research study, including subject recruitment and 
retention, and an assessment of the timeliness and quality of the data. 
 
• 
A review of collected data (including adverse events, unanticipated problems, and 
subject withdrawals) to determine whether there is a change to the anticipated benefit-
to-risk assessment of study participation and whether the study should continue as 
originally designed, should be changed, or should be terminated. 
 
• 
An assessment of external factors or relevant information (eg. Pertinent scientific 
literature reports or therapeutic development, results of related studies) that may have 
an impact on the safety and study participants or the ethics of the research study. 
 
• 
A review of study procedures designed to protect the privacy of the research subjects 
and the confidentiality of their research data. 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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42 
 
 
5.4.5 Frequency of Monitoring 
 
The contact PI will review subject safety data as it generated. The principal investigators, co-
principle investigators, and the research staff will meet or converse bi-monthly when the study is 
being initiated, and then thereafter at least at monthly intervals, or more frequently if necessary, 
to re-evaluate study goals, subject recruitment, data coding and retention, documentation and 
identification of adverse events, complaints, and confidentiality of subjects. There will be an 
evaluation of the progress of the research study, including assessments of data quality, time 
lines, participant recruitment, accrual, and retention. The PIs will also review the outcome and 
adverse event data to determine whether there is any change to the anticipated benefit-to-risk 
ratio of study participation and whether the study should continue as originally designed or 
should it be re-evaluated and changed. 
  
The DSMB is expected to meet as needed, but not less than every 6 months, to review the 
progression of the study including patient enrollment, protocol compliance, and adverse event 
reports. An emergency meeting of the DSMB may be called at any time by the Chair should 
participant safety questions or other unanticipated problems arise. 
 
5.4.6 Reportable Adverse Events 
For this study, a Serious Adverse Event is any untoward clinical event that is thought by the 
responsible investigator to be study-related, that is also: 
 
1. Fatal or immediately life threatening 
2. Permanently disabling, or severely incapacitating. 
3. Requires, or prolongs, inpatient hospitalization.   
4. Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered serious adverse events when, based upon 
appropriate medical judgment, they may jeopardize the patient, or subject, and may 
require medical, or surgical intervention to prevent one of the serious outcomes listed 
above. 
 
If clinically important and unexpected adverse experiences, or clinically important study-related 
adverse experiences occur, they will be recorded on the adverse event case report form.  
   
5.4.7 Adverse Events Reporting Timeline 
The investigators will report life-threatening or fatal unexpected adverse events associated with 
the use of the study drug or procedures to the contact PI, DCC, NHLBI, DSMB, the local IRB, 
and central IRB (for the CCC) within seven (7) calendar days of discovery of the incident 
 
Serious (but not fatal or life-threatening) and unexpected adverse events associated with the 
use of the study drugs or procedures must be reported to the DCC, NHLBI, DSMB, the local 
IRB, and central IRB (for the CCC) within 15 calendar days. 
 
5.5  RISK MANAGEMENT PROCEDURES 
 
5.5.1 Protection Against Loss of Confidentiality  
 
All research interventions/activities will be conducted in private patient care areas. The 
collection of sensitive information about subjects is limited to the amount necessary to achieve 
the aims of the research, so that no unneeded sensitive information is being collected. 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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43 
 
 
 
To avoid any violation of subject confidentiality, all data will be stored in a password-protected 
database, identified only by study ID number at the DCC.   A confidential database linking 
patient identifying information with study ID number will be maintained at each clinical site; the 
CCC or DCC will not be in possession of patient identifying information.   
 
All demographic and clinical information about the subject will be stored on an electronic 
password-guarded study database under the supervision of the PIs for this protocol. All staff will 
sign confidentiality statements. Access to the database will be limited to the data manager and 
staff under the supervision of the PIs. 
 
Specimens will be stripped of subject identifiers and stored according to a similar coding 
protocol as described above. These specimens will be stored safely in the custody of the 
Principal Investigator responsible for the individual assays. These Investigators will limit future 
access to any remaining sample to only those investigators with prior IRB approval for their 
studies. 
 
The PIs will retain the data for the entire period of this study. The investigators may continue to 
use and disclose subjects de-identified information for the purpose of this study for a minimum 
of seven years after final reporting or publication of the study. If the subject and/or legal 
representative decide to withdraw or be withdrawn from study participation, they may request 
that the study data and samples be destroyed. 
 
All staff involved in this study are properly credentialed and instructed in the areas of testing, 
confidentiality, and safety.  All principal and co-investigators, coordinators, and other Key 
Personnel are required to participate in courses and be certified as mandated by local IRBs 
regarding Education and Certification Programs in Research & Practice Fundamentals (RPF).   
 
5.5.2 Protection Against Potential Risks of Experimental Intervention 
 
Despite the documented safety profile of plasma exchange, rituximab, and IVIG in other human 
disorders of abnormal immune regulation, the study has been designed with a focus on 
protecting patients against risk including: 
 
Selection of a target patient population with a very high risk of morbidity and mortality due to the 
absence of a defined treatment for the disorder. 
 
Involvement of trained staff in central venous access placement for the provision of 
plasmapheresis and utilization of ultrasound guidance for placement of all catheters 
Involvement of trained hospital staff for the provision of plasmapheresis in patients with 
advanced medical illness 
 
Involvement by trained staff / investigators with experience in the administration of Rituximab 
 
Prior human experience with the study medication in similar conditions with an autoimmune 
hypothesis including rheumatoid arthritis and myositis 
 
Exclusion of all patients with conditions which might simulate IPF exacerbations such as 
congestive heart failure, pneumonia, and pulmonary thromboembolism 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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44 
 
 
Continuous monitoring by an independent DSMB 
 
Particular Risk Mitigations for: 
 
Therapeutic Plamsa Exchange:  The subjects will undergo routine monitoring of coagulation 
parameters (fibrinogen) with correction of acquired defects during the procedure consistent with 
existing medical practice.  Patients with contraindications to the use of this modality (e.g, use of 
angiotensin converting enzymes [ACE]) will be excluded from participation, until and unless the 
ACE can be discontinued or replaced with other anti-hypertensives.  The TPE protocols and 
practices for each site will be reviewed by a Co-Investigator (Dr. Pham) with particular expertise, 
to ensure safety and uniformity. 
 
Rituximab:  The patient population will receive pre-treatment with acetaminophen (650mg), 
diphenhydramine (50mg), and methylpredisolone (100mg IV) prior to drug administration.  This 
regimen will significantly lessen the risk of general reactions to the medication.  Patients with 
contraindications to use of this agent (e.g., past or current hepatitis B or current hepatitis C) will 
be excluded from participating.   
 
IVIG:   Risks of renal injury or anaphylaxis, and other serious side effects (e.g., thrombosis) are 
obviated by prior hydration, slow IVIG infusions, and excluding patients with IgA deficiency.79 
 
Medical treatment for conditions that arise as a result of study participation will not be treated by 
study personnel. The volunteer will be informed of the problems identified, and this information will 
be transmitted to the responsible attending physician or physician designated for the subject. In the 
event of physical injury resulting from the research procedures, medical treatment will be available 
but not offered free of charge. In addition, financial compensation is not available for wages lost 
because of injury related to the research protocol. This will be emphasized at the time of consent. 
 
 
6 
STUDY ADMINSTRATION 
 
6.1 REGULATORY AND ETHICAL CONSIDERATIONS 
The clinical study will be conducted in accordance with the current IRB-approved clinical 
protocol; International Conference of Harmonization (ICH) guidelines on Good Clinical Practice, 
and relevant policies, requirements, and regulations of the IRBs, and applicable federal 
regulations, including those required under an IND exemption. 
 
The clinical trial will be registered with ClinicalTrials.gov to comply with Section 801 of Public 
Law 110-85. 
 
The investigators will make certain that appropriate processes and procedures are in place to 
ensure that ongoing questions and concerns of enrolled subjects are adequately addressed and 
that the subjects are informed of any new information that may affect their decision to continue 
participation in the clinical study.  In the event of substantial changes to the clinical study or the 
risk-to-benefit ratio of study participation, the investigators will obtain the informed consent of 
enrolled subjects for continued participation in the clinical study. 
 
6.2  PROTOCOL DEVELOPMENT 
 
6.2.1 Activation of a protocol 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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The Protocol Chair (Dr. Duncan) is responsible for the coordination, development, and approval 
of the protocol as well as its subsequent amendments, and reporting serious adverse events, 
violations and deviations per IRB guidelines.  . 
 
To meet these requirements, the Protocol Chair will be responsible for the following minimum 
standards: 
• 
Identify, qualify and initiate participating institutions and obtain accrual commitments.  
• 
Commit to the provision that the protocol will not be rewritten or modified by anyone 
other than the Protocol Chair. 
• 
Ensure that there is only one version of the protocol and that all participating institutions 
use the correct version.  
• 
Oversee the development of data collection forms (case report forms) that are of 
common format for use at all the participating institutions.  
 
 6.2.2 Coordinating Center Support Function 
The UAB study team will provide administrative and clerical support to the Protocol Chair for the 
development and distribution of the protocol.  
 
The tasks to be performed by the UAB study team include: 
• 
Maintain Regulatory documents for all participating institutions.  
• 
Review of the protocol and consent to check for logistics, spelling, and 
consistency.  Provide the Protocol Chair a list of queries related to any 
inconsistencies. 
• 
Provide necessary administrative sections, including paragraphs related to 
randomization, data management schedules, and multi-center guidelines.  
• 
Maintenance of contact list of all participating institutions in the multi-center 
protocol and the distribution of updates to the sites as needed.  
• 
Assistance in preparation and maintenance of case report forms. 
• 
Conduct regular communications with all participating institutions (conference 
call, emails, etc)   
• 
Maintain documentation of all communications.  
 
6.3 PROTOCOL MANAGEMENT 
 
The CCC is responsible for assuring that each participating institution has the appropriate 
assurance on file with the Office of Human Research Protection (OHRP).   Additionally, the 
CCC must maintain copies of all IRB approvals, for each participating institution.  
 
6.3.1 Protocol distribution 
 
The CCC will distribute the final approved protocol and any subsequent amended protocols to 
all participating institutions.    
 
6.3.2  Protocol revisions and closures 
 
The participating institutions will receive phone, fax, mail or e-mail notification of protocol 
revisions from the CCC or designee.  It is the individual participating institution’s responsibility to 
notify its IRB of these revisions. 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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Non life-threatening revisions: Participating institutions will receive written notification of protocol 
revisions regarding non life-threatening events from the CCC or designee. Non-life-threatening 
protocol revisions should be IRB approved and implemented within 90 days from receipt of the 
notification. 
 
Revisions for life-threatening causes: Participating institutions will receive telephone notification 
from the CCC or designee concerning protocol revisions required to protect lives with follow-up 
by fax, mail or e-mail.  Life-threatening protocol revisions will be implemented immediately 
followed by IRB request for approval 
 
Protocol closures and temporary holds: Participating institutions will receive fax, e-mail, or 
phone notification of protocol closures and temporary holds from the CCC or designee. 
Closures and holds will be effective immediately.  In addition, the CCC or designee will update 
the participating institutions on an ongoing basis about protocol accrual data so that they will be 
aware of imminent protocol closures. 
 
6.3.4. Protocol deviations and violations:  These events are defined here as: 
 
Protocol Deviation:  An accidental or unintended study activity that diverges from the IRB-
approved protocol, e.g., missing a study window because the subject is traveling, or test that 
cannot be performed because of scheduling conflicts, etc.  Implicit to this definition is the lack 
of serious consequences that typically does not render a subject ineligible or require their 
discontinuation from the study. 
 
Protocol Violation: A serious non-compliance or protocol divergence that materially reduces 
the quality or completeness of the data, or makes the ICF inaccurate, or impacts a subject's 
safety, rights, or welfare.  Violations may require exclusion of patients from eligibility analysis 
or discontinuation from the study.  Examples include inadequate informed consent, use of 
prohibited medication, multiple visits outside permissible windows, etc.   
 
Protocol deviations will continue to be routinely reported to the DCC using eCRF (Form F14). 
Protocol violations should, in addition, be reported directly to the CCC PI (Dr. Duncan) within  7 
working days.  Equivocal cases will in turn be presented by the CCC PI to other site PIs for 
adjudication.  Unequivocal or adjudicated protocol violations will be reported by the DCC and/or CCC 
PI to the DSMB within two weeks.  These reporting requirement do not supplant or modify pre-
existing requirements for AE reporting (see Section 5.4.7) 
 
6.4 INFORMED CONSENT REQUIREMENTS 
 
 
 
The CCC-approved informed consent document will serve as a template for the informed 
consent from participating institutions. Participating sites are to send their version of the 
informed consent document and HIPAA authorization, if a separate document, to the CCC for 
their revision prior to submission to the participating site's IRB.  
 
The Principal Investigator at each participating institution will identify the physician members of 
the study team who will be obtaining consent and signing the consent form for therapeutic 
protocols.  
 
All study participants in this study will be provided a consent form describing the study and 
providing sufficient information for participants to make informed decisions about their 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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47 
 
 
participation in this study.  This consent form will be submitted along with the protocol for review 
and approval by the IRB at each participating center.  The study participant MUST be consented 
with the IRB approved consent form before the participant is subjected to any study procedures.  
The approved consent form MUST be signed and dated by the study participant and the 
investigator obtaining the consent. 
 
 
6.5 IRB DOCUMENTATION 
 
Sites must obtain local IRB initial approval.  The following must be on file with the CCC or 
designee and must be submitted and approved by the Coordinating Center prior to initiation of 
the study: 
 
• 
Approval Letter of the institution's IRB  
• 
Copy of the Informed Consent Form approved by the participating institution’s IRB  
• 
IRB approval for all amendments 
 
It is the participating institution's responsibility to notify its IRB of protocol amendments.  
Participating institutions will have 90 days from receipt to provide the CCC their IRB approval for 
amendments to a protocol.    
 
6.5.1 IRB Renewal Approval 
Annual IRB renewal approval from the participating institution is required in order to continue 
research and recruit participants onto a protocol.  There is no grace period for continuing 
approvals. 
 
6.6  QUALITY CONTROL AND QUALITY ASSURANCE  
To ensure the human subject protection, study procedures, laboratory, study intervention 
administration, and data collection processes are of high quality and meet GCP and, when 
appropriate, regulatory guidelines, the DCC may conduct a quality assurance audit (site 
monitoring) of the site records at any time during or after completion of the study.  Audits of a 
random selection of data, and all protocol consents will also be reviewed.   
 
Monitoring will be scheduled periodically throughout the conduct of the study to assure compliance 
with the approved protocol, and to verify the completeness and accuracy of study data.  Monitoring 
also aids in identifying any research-related problems for the investigator to correct.  A brief written 
report on each audit or site visit will be prepared by the DCC and sent to the clinical center, DSMB, 
and NHLBI after each site visit. 
 
6.7  DATA HANDLING AND RECORD-KEEPING 
 
6.7.1 Data recording/Case Report Forms    
Case report forms (CRFs) are the primary data collection instruments for the study.  All data 
requested on the CRFs must be recorded, and any missing data must be explained.  If a space is 
left blank because the procedure was not done or the question was not asked, “N/D” must be 
noted.  If the item is not applicable to the individual case “N/A” must be noted.  All entries must be 
printed legibly in black ink on the paper case report forms.  In the event of any entry errors, 
corrections must be made by drawing a single straight line through the incorrect entry, writing the 
initials of the person making the correction, recording the date when the correction is being made, 
and entering the correct data above the strike through.    
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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48 
 
 
Data elements that are extracted from the medical record (such as participant history or official 
clinical interpretations of images, pathology, or surgery results) and recorded on the case report 
forms (CRFs) will be audited against the appropriate component of the medical record.  The 
investigator will review, approve and sign/date each completed CRF; the investigator’s signature 
serving as attestation of the investigator’s responsibility for ensuring that all clinical and 
laboratory data entered on the CRF are complete, accurate and authentic.  
Source Data are the clinical findings and observations, laboratory and test data, and other 
information contained in Source Documents.  Source Documents are the original records (and 
certified copies of original records); including, but not limited to, hospital medical records,  
physician or office charts, physician or nursing notes, subject diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, x-rays, etc.  
Information recorded on the CRF must be consistent with the Source Data recorded on the 
Source Documents or discrepancies must be explained. 
 
Source data are found in all information, original records of findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Source documents represent the first recording of any 
observations made or data generated about a study participant while he or she is enrolled in a 
clinical trial. Source documents for each study participant substantiate the data that are 
submitted to DCC. 
 
Research records for each case should contain copies of the source documents for the data 
reported to DCC.  If data is abstracted from medical charts that are not filed at the investigative 
sites (e.g. hospital charts), copies of these records should be filed in the research chart.  
However, every attempt must be made to obtain all records/charts that were used to abstract 
any study data for this protocol at the time of the audit visit.  This will prevent any discrepancies 
and the inability to verify the document and the data reported.   
 
The CRFs must be kept current to reflect subject status at each phase during the course of the 
trial. In all cases, subjects must not be identified on the CRF by name. Appropriate coded 
identifications (i.e. Subject ID number) will be used. Every effort will be made to collect complete 
data for each study visit. Causes of missing data will be fully documented. With respect to safety 
evaluation, it is not planned to impute missing data. 
 
6.7.1 Record maintenance and retention   
Following closure of the study, the investigator must maintain all site study records in a safe and 
secure location. The records must be easily accessible when needed (e.g., for the DCC audit or 
regulatory inspection) and must be available for review in conjunction with assessment of the 
facility, supporting systems, and relevant site staff. 
 
Where permitted by local laws/regulations or institutional policy, some or all of the records may 
be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, 
caution must be exercised before such action is taken. The investigator must ensure that all 
reproductions are legible and are a true and accurate copy of the original. In addition, they must 
meet accessibility and retrieval standards, including regeneration of a hard copy, if required. 
The investigator must also ensure that an acceptable back-up of the reproductions exists and 
that there is an acceptable quality control procedure in place for creating the reproductions. 
 
The minimum retention time will meet the strictest standard applicable to each participating site, 
as dictated by local laws/regulations, and/or institutional requirements. 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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49 
 
 
7  COSTS AND PAYMENTS 
 
7.1  COSTS 
Salaries and costs of the research physicians and staff conducting this study will be borne by 
the NIH grant.  The cost of the autoantibody reduction therapy, items and services required to 
provide these treatments, and items or services required to prevent, diagnose, or treat 
complications of the therapy will be paid by the subject’s insurance. This is necessary given the 
nature of the interventions, size of the trial, and the structure of and resources available from the 
FOA (PAR-13-128).   
The following, from the Centers for Medicare and Medicaid Services website is apropos:  
(https://www.cms.gov/CCIIO/Resources/FAct-Sheets-and FAQs/aca_ implementation_ 
faqs15.html), that reads in part:  
 
Coverage for Individuals Participating in Approved Clinical Trials: In general, PHS Act 
section 2709(a), as added by the Affordable Care Act, states that if a group health plan or health 
insurance issuer in the group and individual health insurance market provides coverage to a 
qualified individual (as defined under PHS Act section 2709(b)), then such plan or issuer: (1) may 
not deny the qualified individual participation in an approved clinical trial with respect to the 
treatment of cancer or another life-threatening disease or condition; (2) may not deny (or limit or 
impose additional conditions on) the coverage of routine patient costs for items and services 
furnished in connection with participation in the trial [see definition of routine patient costs below]; 
and (3) may not discriminate against the individual on the basis of the individual’s participation in 
the trial.  A qualified individual under PHS Act section 2709(b) is generally a participant or 
beneficiary who is eligible to participate in an approved clinical trial according to the trial protocol 
with respect to the treatment of cancer or another life-threatening disease or condition; and 
either: (1) the referring health care professional is a participating provider and has concluded that 
the individual’s participation in such trial would be appropriate; or (2) the participant or 
beneficiary provides medical and scientific information establishing that the individual’s 
participation in such trial would be appropriate.  
 
Moreover, Medicare is expressly mandated to pay for costs of care in clinical trials, and our 
potential study population is predominantly covered by Medicare.  The population of potential 
subjects in our tertiary referral Centers is so much greater than that needed for this study that we 
could easily meet enrollment targets if we had to using only Medicare patients (but again, this is 
not anticipated).  The relevant mandate follows:   
 
The Medicare National Coverage Determination (NCD) for Routine Costs in Clinical Trials 
(310.1) stipulates that Medicare covers the routine costs of qualifying clinical trials, defined as 
follows: Routine costs include all items and services that “are generally available to Medicare 
beneficiaries that are provided in the experimental or the control arm of a clinical trial” and that 
are needed for “the provision of the investigational item or service, the clinically appropriate 
monitoring of the effects of the item or service, or the prevention of complications” and for 
“reasonable and necessary care arising from the provision of an investigational item or service in 
particular, for the diagnosis and treatment of complications.” Clinical trials are deemed 
automatically qualified for this coverage if they are funded by the NIH or selected other 
government organizations.   
 
The proposed clinical trial meets the three major requirements for Medicare coverage:  1.) The 
subject or purpose of the trial must be the evaluation of an item or service that falls within a 
Medicare benefit category (e.g., physicians' service, durable medical equipment, diagnostic test) 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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and is not statutorily excluded from coverage (e.g., cosmetic surgery, hearing aids); 2.) The trial 
must not be designed exclusively to test toxicity or disease pathophysiology. It must have 
therapeutic intent; and 3.) Trials of therapeutic interventions must enroll patients with diagnosed 
disease rather than healthy volunteers. Trials of diagnostic interventions may enroll healthy 
patients in order to have a proper control group. Additional relevant information is available on:  
 https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=1&ncdver= 
2&bc=BAABAAAAAAAA 
 
All TAU medications, other routine lab tests, and any other clinical diagnostic or treatment 
procedures will be considered routine medical care and will be billed to the subjects’ health 
insurance company. Subjects will be responsible for paying any deductibles, co-payments or co-
insurance that are a normal part of their health insurance plan. Subjects who do not have health 
insurance will be responsible for these costs.   
 
Costs for shipping experimental specimens and performing ancillary experimental tests (see 
Section 2.8.3), such as anti-HEp-2 titers and fluorescent patterns, autoantibody repertoires, 
serum Ig levels, BLyS concentrations, and others, will be borne by the research grant 
(UO1HL133232). 
 
7.2  PAYMENTS 
Participation in this protocol is completely voluntary. Subjects will not be compensated for their 
participation in this research study.  Travel costs, for subjects returning for serial outpatient 
assessments, may be provided on an as-needed basis, based on Federal mileage rates 
and to a maximum per visit of $200. Parking will be provided at no cost while at the 
research clinic.   
 
 
8  QUALIFICATIONS AND SOURCES OF SUPPORT 
 
8.1 QUALIFICATIONS OF THE PRINCIPLE INVESTIGATORS 
 
Steven R. Duncan, M.D., Principal Investigator. Professor of Medicine, Division of 
Pulmonary, Allergy and Critical Care Medicine (PACCM), University of Alabama at 
Birmingham (UAB). Dr. Duncan is the contact PI of this proposal.  He is an attending physician 
on the pulmonary medicine service at UAB Hospital and clinics, and has been trained in cellular 
and molecular immunology.  Dr. Duncan directs the Program in Immunology of Chronic Lung 
Diseases at UAB.  He will have primary responsibility for protocol development, founding of the 
coordinating center, fulfillment of administrative, regulatory and legal requirements, 
development of data acquisition methods in conjunction with the DCC, and interface with the PIs 
at the collaborating centers, the DSMB and IRB, etc.  Dr. Duncan will also participate in direct 
clinical care of research subjects at UAB.  Dr. Duncan will also supervise and direct the end-
point immunologic assays, collation of clinical and research findings, data analyses, and 
manuscript preparation.  
 
Gerard (Jerry) Criner, M.D., Principle Investigator. Professor of Medicine, Temple 
University.  Dr. Criner is an attending physician on the pulmonary medicine services at Temple 
University hospitals and clinics.  He is the Pulmonary and Critical Care Medicine Director, 
Chairman of the Thoracic Medicine and Surgery Department at Temple, and Director of the 
Temple Lung Institute.  He is the author or co-author of numerous studies of chronic lung 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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disease, including IPF, and PI or Co-PI of previous and ongoing clinical trials involving patients 
with IPF and other chronic lung disease. 
 
Daniel J. Kass, M.D., Principal Investigator.  Associate Professor of Medicine, Division of 
Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of 
Medicine. Dr. Kass is an attending physician on pulmonary medicine services at the University 
of Pittsburgh Medical Center (UPMC), and Director of the Dorothy P. and Richard P. Simmons 
Center for Interstitial Lung Disease at UPMC.  Dr. Kass has an active, NIH-funded basic 
research program in IPF, and considerable expertise in conducting clinical trials in this disease 
population. 
 
Ivan O. Rosas, M.D., Principle Investigator. Professor of Medicine, Baylor  University.  Dr. 
Rosas is the Pulmonary Division Chief, and an attending physician on the pulmonary medicine 
services at Baylor University Medical Center. He is a highly regarded researcher in the field of 
interstitial lung disease and IPF, having authored or co-authored dozens of relevant papers, and 
he is the PI or Co-Investigator of numerous clinical trials.    
 
8.2 SOURCE OF SUPPORT  
National Heart, Lung, and Blood Institute (UO1HL133232) 
 
 
 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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9   REFERENCES 
1. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, 
Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho 
C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Müller 
NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ; 
ATS/ERS/JRS /ALAT Committee on Idiopathic Pulmonary Fibrosis.  An official ATS/ERS/ 
JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and 
management. Am J Respir Crit Care Med. 2011; 183:788-824 PMID: 21471066 
2. Fischer A, Antoniou KM, Brown KK, Cadranel J, Corte TJ, du Bois RM, Lee JS, Leslie KO, 
Lynch DA, Matteson EL, Mosca M, Noth I, Richeldi L, Strek ME, Swigris JJ, Wells AU, West SG, 
Collard HR, Cottin V; “ERS/ATS Task Force on Undifferentiated Forms of CTD-ILD”. An official 
European Respiratory Society/American Thoracic Society research statement: interstitial 
pneumonia with autoimmune features. Eur Respir J. 2015; 46:976-87. PMID:26160873 
3. Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King, Jr. TE, 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, Mueller-Quernheim J, 
Myers JL, Nicholson AG, Selman M, Toews GB, Wells AU, Martinez FJ, with the Idiopathic 
Pulmonary Fibrosis Clinical Research Network Investigators. Acute exacerbations of idiopathic 
pulmonary fibrosis. Am J Respir Crit Care Med, 2007; 176. 636–643 PMID: 17585107  
4. Mallick S. Outcome of patients with idiopathic pulmonary fibrosis (IPF) ventilated in intensive 
care unit.  Resp Med 2008; 102:1355-1359 PMID 18635345 PMCID  
5. Rangappa P, Moran JL.  Outcomes of patients admitted to the intensive care unit with 
idiopathic pulmonary fibrosis.  Crit Care Resusc 2009; 11:102-9. PMID:19485873 
6. Al-Hameed FM, Sharma S. Outcome of patients admitted to the intensive care unit for acute 
exacerbation of idiopathic pulmonary fibrosis. Can Respir J 2004; 11:117-22. PMID:15045042 
7. Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King TE, Flaherty KR, Schwartz 
DA, Noble PW, Raghu G, Brown KK.  The clinical course of patients with idiopathic pulmonary 
fibrosis.  Ann Intern Med 2005; 142:963-67. PMID:15968010 
8. Erickson SB, Kurtz SB, Donadio JV, Holley KE, Wilson CB, Pineda AA.  Use of combined 
plasmapharesis and immunosuppression in the treatment of Goodpasture’s syndrome.  Mayo Clin 
Proc 1979; 54:714-720 PMID: 491763 
9. Sem M, Molberg O, Lund MB, Gran JT. Rituximab treatment of the anti-synthetase syndrome: 
a retrospective case series. Rheumatology (Oxford) 2009; 48:968-971 PMID: 19531628  
10. Martinu T, Howell DN, Palmer SM. Acute cellular rejection and humoral sensitization in lung 
transplant recipients.  Semin Resp Crit Care Med 2010; 31:179-188 PMID: 20354931 
11. Borie R, Debray MP, Laine C, Aubier M, Crestani B.  Rituximab therapy in autoimmune 
pulmonary alveolar proteinosis. Eur Respir J. 2009; 33,1503-1506 .PMID: 19483052 
12. Keir GJ, Maher TM, Hansell DM, Denton CP, Ong VH, Singh S, Wells AU, Brezoni EA.  
Severe interstitial lung disease in connective tissue disease: rituximab as rescue therapy.  Eur 
Resp J. 2012; 40:641-648 PMID: 22282550 
13. Stone JH, Merkel PA, Spiera R, Seo P, Langford CA, Hoffman GS, Kallenberg CG, St Clair 
EW, Turkiewicz A, Tchao NK, Webber L, Ding L, Sejismundo LP, Mieras K, Weitzenkamp D, Ikle 
D, Seyfert-Margolis V, Mueller M, Brunetta P, Allen NB, Fervenza FC, Geetha D, Keogh KA, Kissin 
EY, Monach PA, Peikert T, Stegeman C, Ytterberg SR, Specks U; RAVE-ITN Research Group.  
RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. 
N Engl J Med 2010; 363:221-232 PMID: 20647199 
14. Jordan SC, Reinsmoen N, Peng A, Lai CH, Cao K, Villicana R, Toyoda M, Kahwaji J, Vo 
AA. Advances in diagnosing and managing antibody-mediated rejection. Pediatr Nephrol. 2010; 
25:2035-45.  PMID: 200771221 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
_________________________________________________________________________________________________________ 
 
53 
 
 
15. Hachem RR, Yusen RD, Meyers BF, Aloush AA, Mohanakumar T, Patterson A, Trulock EP. 
Anti-HLA antibodies and preemptive antibody directed therapy after lung transplantation.  J Heart 
Lung Transplant. 2010; 29:973–980.  PMID: 20558084 
16. Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N 
Eng J Med. 2012; 367:2015-2025. PMID: 23171098 
17. Orlin JB, Berkman EM. Partial plasma exchange using albumin replacement: removal and 
recovery of normal plasma constituents.  Blood 1980; 56: 1055-1059. PMID: 6159932 
18. Reverberi R, Reverberi L.  Removal kinetics of therapeutic apheresis. Blood Transfus 2007; 
5:164-74. PMID: 19204770 
19. Dau PC.  Immunologic rebound.  J Clin Apher 1995; 10:210-17. PMID: 8770715 
20. 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; 179:2592-2599 PMID: 17675522  
21. Gilani SR, Vuga LJ, Lindell KO, Gibson KF, Xue J, Lindsay EK, Kaminski N, Valentine VG, 
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 One 2010; 5:e8959 PMID: 
20126467 
22. Xue J, Gochuico BR, Kahloon RA, Bhargava A, Alawas AS, Feghali-Bostwick CA, Nathan 
SD, Rosen GD, Rosas IO, Csizmadia E, Dacic S, Ocak I, Fuhrman CR, Cuenco KT, Smith MA, 
Jacobs SS, Zeevi A, Morel PA, Pilewski JM, Sciurba FC, Zhang Y, Duncan SR. The HLA allele 
DRB1*15 is over-represented in patients with idiopathic pulmonary fibrosis. PLoS One 2011; 
6:e14715, PMID: 21373184 
23. 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. Idiopathic pulmonary fibrosis patients with antibodies to heat 
shock protein 70 have poor prognoses.  Am J Resp Crit Care Med 2013; 187:768-775 
24. ibid, Online Data Supplement. http://www.atsjournals.org/doi/suppl/10.1164/rccm.201203-
0506OC/suppl_file/kahloon.pdf. Accessed June 12, 2016 
25. Xue J, Kass DJ, Bon JM, 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 (BLyS) and B-cell differentiation in idiopathic pulmonary fibrosis.  J Immunol 
2013; 191:2089-95. PMID: 23872052 
26. Herazo-Maya JD, Noth I, Duncan SR, SungHwan K, Scwu-Fan M, Tseng GC, Feingold E, 
Juan-Guardela BM, Richards TJ, Lussier Y, Huang Y, Rekha V, Lindell O, Xue J, Gibson KF. 
Shapiro SD, Garcia JGN, Kaminski N.  Peripheral blood mononuclear cell gene expression profiles 
may predict poor outcome in idiopathic pulmonary fibrosis. Sci Translat. 2013; 5(205):205ra136. 
doi: 10.1126/scitranslmed.3005964. PMID:24089408 
27. Donahoe M, Chien N, Raval JS, Gibson KF, Saul M, Zhang Y, Duncan SR. Autoantibody-
targeted treatments for acute exacerbations of idiopathic pulmonary fibrosis. PLoS One. 
2015;10(6):e0127771. doi: 10.1371/journal.pone.0127771. PMCID:PMC4470587 
28. Vuga LJ, Tedrow JR, Pandit KV, Kass DJ, Xue J, Leader JK, Gibson KF, Kaminski N, 
Sciurba FC, Duncan SD. C-X-C motif chemokine 13 (CXCL13) is a prognostic biomarker of 
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2014; 189:966-974.  PMID:24628285 
29. Nydegger UE, Sturzenegger M.  Treatment of autoimmune disease: synergy between 
plasma exchange and intravenous immunoglobulin.  Therap Apher 2001; 5:186-192. PMID: 
11467755 
30. Campbell DA, Poulter LW, Janossy G, du Bois RM. Immunohistological analysis of lung 
tissue from patients with cryptogenic fibrosing alveolitis suggesting local expression of immune 
hypersensitivity. Thorax 1985;40:405-11. PMID: 3875162 PMCID: PMC460088 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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31. Marchal-Somme J, Uzunhan Y, Marchand-Adam S, Valeyre D, Soumelis V, Crestani B, 
Soler P. Cutting edge: non-proliferating mature immune cells form a novel type of organizing 
lymphoid structure in idiopathic pulmonary fibrosis. J Immunol 2006; 176:5735-5739 PMID: 
16670278 
32. Parra ER, Kairalla RA, Ribeiro de Carvalho CR, Eher E, Capelozzi VL. Inflammatory cell 
phenotyping of the pulmonary interstitium in idiopathic interstitial pneumonia.  Respiration 2007, 
74:159-69 PMID: 17108669 
33. DePianto DJ, Chandriani S, Abbas AR, Jia G, N'Diaye EN, Caplazi P, Kauder SE, Biswas S, 
Karnik SK, Ha C, Modrusan Z, Matthay MA, Kukreja J, Collard HR, Egen JG, Wolters PJ, Arron 
JR. Heterogeneous gene expression signatures correspond to distinct lung pathologies and 
biomarkers of disease severity in idiopathic pulmonary fibrosis. Thorax. 2015; 70:48-56. 
PMID:25217476 
34. Balestro E, Calabrese F, Turato G, Lunardi F, Bazzan E, Marulli G, Biondini D, Rossi E, 
Sanduzzi A, Rea F, Rigobello C, Gregori D, Baraldo S, Spagnolo P, Cosio MG, Saetta M. Immune 
inflammation and disease progression in idiopathic pulmonary fibrosis.  PLoS One 2016; 11(5): 
e0154516, doi: 10.1371/journal.pone.0154516. PMID:27159038 
35. Aloisi F, Pujol-Borrell R. Lymphoid neogenesis in chronic inflammatory disease. Nature Rev, 
2006; 6:205-11. PMID 16498451 
36. Browning JL. B cells move to center stage: novel opportunities for autoimmune disease 
treatment.  Nature Rev 2006; 5:564-75. PMID:16816838 
37. Dobashi N, Fujita J, Murota M, Ohtsuki Y, Yamadori I, Yoshinouchi T, Ueda R, Bandoh S, 
Kamei T, Nishioka M, Ishida T, Takahara J. Elevation of anti-cytokeratin 18 antibody and 
circulating cytokeratin 18: anti-cytokeratin 18 antibody immune complexes in sera of patients with 
idiopathic pulmonary fibrosis. Lung 2000;178:171-9 PMID: 10871435 
38. Ogushi F, Tani K, Endo T, Tada H, Kawano T, Asano T, Huang L, Ohmoto Y, Muraguchi M, 
Moriguchi H, Sone S. Autoantibodies to IL-1 in sera from rapidly progressive idiopathic pulmonary 
fibrosis. J Med Invest 2001; 48:181-9 PMID: 11694958 
39. Kurosu K, Takiguchi Y, Okada O, Yumoto N, Sakao S, Tada Y, Kasahara Y, Tanabe N, 
Tatsumi K, Weiden M, Rom WN, Kuriyama T.  Identification of annexin 1 as a novel autoantigen in 
acute exacerbation of idiopathic pulmonary fibrosis. J Immunol 2008; 181:756–767 PMID: 
18566442 
40. Taillé C, Grootenboer-Mignot S, Boursier C, Michel L, Debray MP, Fagart J, Barrientos L, 
Mailleux A, Cigna N, Tubach F, Marchal-Sommé J, Soler P, Chollet-Martin S, Crestani B. 
Identification of periplakin as a new target for autoreactivity in idiopathic pulmonary fibrosis. Am J 
Respir Crit Care Med 2011; 183:759-66. PMID: 20935114 
41. Magro CM, Waldman WJ, Knight DA, Allen JN, Nadasdy T, Frambach GE, Ross P, Marsh 
CB. Idiopathic pulmonary fibrosis related to endothelial injury and antiendothelial cell antibodies. 
Hum Immunol 2006; 67:284-97. PMID 16720208 
42. Wallace WHH, Howie SM. Upregulation of tenascin and TGF- production in a type II 
alveolar epithelial cell line by antibody against a pulmonary auto-antigen.  J Pathol 2001; 195:251-
6. PMID: 11592106 
43. Grigolo B, Mazzetti I, Borzì RM, Hickson ID, Fabbri M, Fasano L, Meliconi R, Facchini A. 
Mapping of topoisomerase II alpha epitopes recognized by autoantibodies in idiopathic pulmonary 
fibrosis. Clin Exp Immunol 1998; 114:339-46. PMID: 9844041  
44. Yang Y, Fujita J,  Bandho S,  Ohtsuki Y, Yamadori I, Yoshinouchi T, Ishida T. Detection of 
antivimentin antibody in sera of patients with idiopathic pulmonary fibrosis and non-specific 
interstitial pneumonia. Clin Exp Immunol 2002; 128:169-74. PMID 11982605  
45. Vittal R, Mickler EA, Fisher AJ, Zhang C, Rothhaar K, Gu H, Brown KM, Emtiazdjoo A, Lott 
JM, Frye SB, Smith GN, Sandusky GE, Cummings OW, Wilkes DS. Type V collagen induced 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
_________________________________________________________________________________________________________ 
 
55 
 
 
tolerance suppresses collagen deposition, TGF-β and associated transcripts in pulmonary fibrosis. 
PLoS One. 2013; 8:e76451. doi: 10.1371/journal.pone.0076451. PMCID:PMC3804565 
46. Shum AK, Alimohammadi M, Tan CL, Cheng MH, Metzger TC, Law CS, Lwin W, 
Perheentupa J, Bour-Jordan H, Carel JC, Husebye ES, De Luca F, Janson C, Sargur R, Dubois N, 
Kajosaari M, Wolters PJ, Chapman HA, Kämpe O, Anderson MS. BPIFB1 is a lung-specific 
autoantigen associated with interstitial lung disease. Sci Transl Med 2013; 5:1–10. PMCID: 
PMC3882146 
47. Solomon DH, Kavanaugh AJ, Schur PH.  American College of Rheumatology Ad Hoc 
Committee on Immunologic Testing Guidelines.  Evidence-based guidelines for the use of 
immunologic tests: antinuclear antibody testing. Arthritis Rheum.2002; 47, 434-44 PMID:12382306  
48. Naparstek Y, Plotz PH. The role of autoantibodies in autoimmune disease. Annu Rev 
Immunol 1993; 11:79-104 PMID: 8476578 
49. Katsumata Y, Kawaguchi Y, Baba S, Hattori S, Tahara K, Ito K, Iwasaki T, Yamaguchi N, 
Oyama M, Kozuka-Hata H, Hattori H, Nagata K, Yamanaka H, Hara M. Identification of three new 
autoantibodies associated with systemic lupus erythematosus using two proteomic approaches. 
Mol Cell Proteomics. 2011;10:M110.005330. PMID: 21474795 
50. Chung L, Utz PJ.  Antibodies in scleroderma: direct pathogeneicity and phenotypic 
associations.  Curr Rheum Reports 2004; 6:156-63. PMID:15016347 
51. Mayadas TN, Tsokos GC, Tsuboi N. Mechanisms of immune complex-mediated neutrophil 
recruitment and tissue injury. Circulation 2009; 120:2012-24. PMID: 19917895  
52. Feghali-Bostwick CA, Gadgil AS, Otterbein LE, Pilewski JM, Stoner MW, Csizmadia E, 
Zhang Y, Sciurba FC, Duncan SR.  Autoantibodies in patients with chronic obstructive pulmonary 
disease.  Am J Resp Critical Care Med 2008;177:156-163. PMID: 17975205 
53. Eikon KB, Santer DM. Complement, interferon and lupus.  Curr Opin Immunol. 2012; 
24:665-70. PMID: 22999705 
54.  Lech M, Anders HJ.  The pathogenesis of lupus nephritis.  J Am Soc Nephrol 2013; 
24:1357-66. PMID: 23929771 
55. Dreisin RB, Schwarz MI, Theofilopoulos AN, Stanford RE.  Circulating immune complexes in 
the idiopathic interstitial pneumonias. N Engl J Med. 1978;298:353-357. PMID:146160 
56. Dall Aglio PP, Pesci A, Bertorelli G, Brianti E, Scarpa S. Study of immune complexes in 
broncholaveolar lavage fluids.  Respiration 1988; 54:36-41 PMID: 3231904 
57. Thériault JR, Adachi H, Calderwood SK. Role of scavenger receptors in the binding and 
internalization of heat shock protein 70. J Immunol. 2006; 177:8604-11. PMID: 17142759 
58. Fong JJ, Sreedhara K, Deng L, Varki NM, Angata T, Liu Q, Nizet V, Varki A. 
Immunomodulatory activity of extracellular Hsp70 mediated via paired receptors Siglec-5 
and Siglec-14. EMBO J. 2015;34:2775-88.  PMID: 26459514 
59. Kong F, Wang H, Guo J, Peng M, Ji H, Yang H, Liu B, Wang J, Zhang X, Li S. Hsp70 
suppresses apoptosis of BRL cells by regulating the expression of Bcl-2, cytochrome C, and 
caspase 8/3. In Vitro Cell Dev Biol Anim. 2016; 52:568-75   PMID:26969466 
60. Giffard RG, Han RQ, Emery JF, Duan M, Pittet JF. Regulation of apoptotic and inflammatory 
cell signaling in cerebral ischemia: the complex roles of heat shock protein 70. Anesthesiology. 
2008;109:339-48. PMID:18648242 
61. Bagnato G, Harari S. Cellular interactions in the pathogenesis of interstitial lung diseases. 
Eur Respir Rev. 2015; 24:102-14 PMID: 25726561 
62. Cancro MP, D’Cruz DP, Khamashta MA. The role of B lymphocyte stimulator (BLyS) in 
systemic lupus erythematosus. J. Clin. Invest. 2009; 119:1066–1073. PMID:19411764 
63. Bossen C, Schneider P. BAFF, APRIL and their receptors: structure, function and signaling. 
Semin. Immunol. 2006; 18:263–275. PMID 16914324 
64. Dillon SR, Harder B, Lewis KB, Moore MD, Liu H, Bukowski TR, Hamacher NB, Lantry MM, 
Maurer M, Krejsa CM, Ellsworth JL, Pederson S, Elkon KB, Wener MH, Dall'Era M, Gross JA. B-

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
_________________________________________________________________________________________________________ 
 
56 
 
 
lymphocyte stimulator/a proliferation-inducing ligand heterotrimers are elevated in the sera of 
patients with autoimmune disease and are neutralized by atacicept and B-cell maturation antigen-
immunoglobulin.  Arthrtitis Res Ther 2010; 12:R48. PMID:20302641 
65. François A, Gombault A, Villeret B, Alsaleh G, Fanny M, Gasse P, Adam SM, Crestani B, 
Sibilia J, Schneider P, Bahram S, Quesniaux V, Ryffel B, Wachsmann D, Gottenberg JE, Couillin I.  
B cell activating factor is central to bleomycin- and IL-17-mediated experimental pulmonary 
fibrosis. J Autoimmun. 2015; 56:1-11. PMID:25441030 
66. Rioja I, Hughes FJ, Sharp CH, Warnock LC, Montgomery DS, Akil M, Wilson AG, Binks MH, 
Dickson MC. Potential novel biomarkers of disease activity in rheumatoid arthritis patients: 
CXCL13, CCL23, transforming growth factor alpha, tumor necrosis factor receptor superfamily 
member 9, and macrophage colony-stimulating factor. Arthritis Rheum 2008; 58:2257–67 PMID: 
18668547 
67. Brettschneider J, Czerwoniak A, Senel M, Fang L, Kassubek J, Pinkhardt E, Lauda F, 
Kapfer T, Jesse S, Lehmensiek V, Ludolph AC, Otto M, Tumani H. The chemokine CXCL13 is a 
prognostic marker in clinically isolated syndrome (CIS). PLoS ONE 2010; 5:e11986 PMID: 
20700489. 
68. Lee HT, Shiao YM, Wu TH, Chen WS, Hsu YH, Tsai SF, Tsai CY. Serum BLC/CXCL13 
concentrations and renal expression of CXCL13/CXCR5 in patients with systemic lupus 
erythematosus and lupus nephritis.  J Rheum 2010; 37:45-52 PMID 19955043. 
69. Meraouna M, Cizeron-Clairac G, Le Panse R, Bismuth J, Truffault F, Tallaksen C, Berrih-
Aknin S. The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravis. Blood 
2006; 108:432–40. PMID: 16543475  
70. Nelson PJ, Krensky AM. Chemokines, chemokine receptors, and allograft rejection. 
Immunity 2001; 14:377–86. PMID: 11602841 
71. Parker DC. T-cell dependent B-cell activation.  Annu Rev Immunol 1993; 11:331-340.PMID: 
8476565 
72. McKinney EF, Lee JC, Jayne DR, Lyons PA, Smith KG. T-cell exhaustion, co-stimulation 
and clinical outcome in autoimmunity and infection. Nature. 2015; 523:612-616. PMID: 2612302 
73. Sollid LM, Pos W, Wucherpfennig KW.  Molecular mechanisms for contribution of MHC 
molecules to autoimmune diseases. Curr Opin Immunol. 2014;31:24-30. PMID:25216261 
74. Pordeus V, Szyper-Kravitz M, Levy RA, Vaz NM, Shoenfeld Y.  Infections and 
Autoimmunity: A panorama.  Clinic Rev Allerg Immunol 2008; 34:283-299. PMID: 18231878 
75. Franks AL, Slansky JE.  Multiple associations between a broad spectrum of autoimmune 
diseases, chronic inflammatory diseases and cancer.  Anticancer Res 2012; 32:1119-1136. PMID: 
22493341 
76. Hoshida S, Nishion M, Tanouchi J, Kishimoto T, Yamad Y.  Acute Chlamydia pneumonia 
infection with heat shock protein 60-related response in patients with acute coronary syndromes. 
Atherosclerosis 2005; 183:109-112.  PMID: 16216593 
77. Purcell AW, Todd A, Kinoshita G, Lynch TA, Keech CL, Gething MJ, Gordon TP.  
Association of stress proteins with autoantigens: a possible mechanism for triggering 
autoimmunity.  Clin Exp Immunol 2003; 132:193-200. PMID 12699405 
78. Vanderlugt CL, Miller SD. Epitope spreading in immune mediated diseases: implications for 
immunotherapy. Nat Rev Immunol 2002, 2:85-94 PMID: 11910899 
79. Oldstone MB. Molecular mimicry, microbial infection and autoimmune disease: evolution of 
the concept.  Curr Top Microbiol Immunol 2005, 296:1-17 PMID: 16329189 
80. Patel AS, Siegert RJ, Brignall K, Gordon P, Steer S, Desai SR, Maher TM, Renzoni EA, 
Wells AU, Higginson IJ, Birring SS. The development and validation of the King's Brief Interstitial 
Lung Disease (K-BILD) health status questionnaire. Thorax 2012; 67:804-10 PMID:22555278 
 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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Modifications as of June 4, 2018 
 
Amendments and Modifications to Earlier Versions of STRIVE-IPF 
 
Protocol Modifications  
Note:  an asterisk (*) denotes changes recommended or mandated by DSMB 
 
1) The date and version number were updated on header and Synopsis (now v2.2 June 
4, 2018). 
2) The NCT number, which was assigned during the interval, has been added to the 
Synopsis. 
3) Personnel changes include substitution of Dr. Williams for Dr. Pham, and Dr. 
Valentine for Dr. Stigler (Synopsis). 
4) The number of acute exacerbations of IPF (AE-IPF) has been added as a secondary 
endpoint (Synopsis and Section 2.8.2).* 
5) An independent adjudication process has been added, in which diagnoses prior to 
randomization are confirmed by another study investigator (Synopsis, Section 2.2 and 
2.7.2).* 
6) Changes to Inclusion Criteria include specifications that potential participants need to 
be hospitalized and diagnoses confirmed by site PI (see also modification #5) (Synopsis 
and Section 3.2).* 
7) Requirement that participants have to have ability and willingness to give informed 
consent and adhere to study requirements (Inclusion criteria #5) supplants formal 
prohibition of surrogate consent (Synopsis and Section 3.2).* 
8) Prior exclusion of any participant who received rituximab at any previous time has 
been modified to only exclude if this drug was given within the last year (Synopsis and 
Section 3.2).* 
9) Former prohibition that precluded enrollment of any participant with a prior history of 
malignancy (excepting low grade skin and prostate cancers) was replaced with 
exclusion limited to those with active malignancy (again, excepting low grade skin and 
prostate cancer) (Synopsis and Section 3.2).* 
10) Slight re-wording, without sustentative changes, to exclusions of those whom the PI 
believes other considerations preclude safe study or who have contraindications to TPE 
(Synopsis and Section 3.2).* 
11) Addition of anti-neutophil cytoplasmic autoantibody (ANCA) to list of autoimmune 
tests that preclude randomization (Synopsis and Section 3.2).* 
12) Addition of formal requirement that intubation precludes enrollment (this is 
redundant with modification #7 above, since intubation effectively prevents giving 
informed consent) (Synopsis and Section 3.2).* 
13) Formal addition of clinical and morphological features of idiopathic pneumonitis with 
autoimmune features to exclusion criteria (Synopsis and Section 3.2).* 
14) Altered requirement for prophylactic antibiotic use in those patients who were 
already treated with same at time of enrollment, so as to prevent over-treatment 
(Section 2.3).   
15) The usual antibiotic course has been added to the Treatment schema (Section 2.5). 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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16) An aliquot of the collected plasma of the first therapeutic plasma exchange (TPE) 
from patients who are undergoing repeat treatment for relapses will be collected, stored 
and used in experimental assays.  These plasma specimens are normally discarded 
(Section 2.6). 
17) Aliquots of the therapeutic plasma exchange (TPE), which are otherwise discarded, 
will also be procured from TPE#3 and #6, in addition to the first and last TPE (#9) that 
were previously described (Section 2.7).   
18) Blood collection has been modified to include 39 ml during the baseline evaluation, 
an increase of 10 ml, from the previous 29 ml collection.  The increase will enable us to 
perform all protocol-specific qualifying tests (e.g., autoimmune serologies, viral studies, 
etc.), as well as the experimental immunology tests.  The blood draw (of 29 ml) that had 
been scheduled for day 19 has now been omitted, so total blood procured for this 
protocol is lessened (Section 2.7).    
19) Quality of life (QOL) measures, specifically the K-BILD questionnaire, have been 
added for 3 month and 6 month assessments (Section 2.8.2).* 
20) Added stipulations that TAU cannot cross-over to experimental arm therapies during 
the observation period, given the analyses here being based on intent-to-treat (Section 
2.9.1).*  
21) Modified description of primary endpoint analysis (Section 2.9.2)* 
22) Changed interim analysis from efficacy analysis to safety (Section 2.9.3)* 
23) Changed timelines of reporting adverse events to NHLBI standards: Those that are 
life-threatening or fatal unexpected adverse events associated with the use of the study 
drug or procedures will be reported to the contact PI, DCC, NHLBI, DSMB, the local 
IRB, and central IRB (for the CCC) within seven (7) calendar days of discovery of the 
incident.  Serious (but not fatal or life-threatening) and unexpected adverse events 
associated with the use of the study drugs or procedures must be reported to the DCC, 
NHLBI, DSMB, the local IRB, and central IRB (for the CCC) within 15 calendar days. 
(Section 5.4.7).* 
 
 
Modifications as of June 4, 2018 
 
Informed Consent Form (ICF) Modifications to Earlier Versions 
Note:  an asterisk (*) denotes changes recommended or mandated by DSMB 
 
1) The date and version number were updated on footer (now v3.1 June 4, 2018). 
2) Personnel changes include substitution of Dr. Williams for Dr. Pham, and Dr. 
Valentine for Dr. Stigler (face page). 
3) Text changes, ostensibly to make this easier to understand, are made throughout this 
ICF (each page- see tracked changes)* 
4) The Explanation of Procedures (starting on page 4) have been summarized with 
redundancies removed, again at the request of a DSMB member to "make this easier to 
understand" (starting on Page 5).* 
5) Blood collection has been modified to include 39 ml during the baseline evaluation, 
an increase of 10 ml, from the previous 29 ml collection.  The increase will enable us to 
perform all protocol-specific qualifying tests (e.g., autoimmune serologies, viral studies, 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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59 
 
 
etc.), as well as the experimental immunology tests.  The blood draw (of 29 ml) that had 
been scheduled for day 19 has now been omitted, so total blood procured for this 
protocol is lessened (Explanation of Procedures- Screening and Baseline).    
6) Little boxes that enclose the first description of the particular procedures have been 
added.* 
7) Tables that schematize the tests and procedures have been added (pages 4 and 7).* 
8) The blood draw for experimental lab assays on day 19 has been omitted (page 6). 
9) Quality of life (QOL) measures, specifically the K-BILD questionnaire, have been 
added for 3 month and 6 month assessments (page 6).* 
10) The possibility of fatal reactions to rituximab has been added.  To our knowledge 
these only occur in lymphoma patients, are probably related to tumor lysis, and do not 
occur in patients getting the drug to treat antibody-mediated diseases, but this warning 
is nonetheless added here (page 11).* 
11) The study termination criterion of "…if approved by the FDA" was removed (page 
15)* 
 
 
Protocol Modifications:  Modifications made that resulted in version 3.1 (dated 
Jan. 21, 2019) 
  
Note:  an asterisk (*) denotes changes recommended or mandated by DSMB 
 
1) The date and version number were updated on header and Synopsis (now becoming 
v3.1, Jan 21, 2019). 
 
2) Residual and incorrect references to acquiring blood specimens for experimental 
immunology assays on day 19 have been omitted throughout the protocol (e.g., pages 
15 and  23). 
 
3) A series of further clarifications to the protocol regarding treatments of AE-IPF 
relapses* These are located now on pages 18 and 25.  They include: 
 
 
a) a more detailed definition of what constitutes an AE-IPF relapse 
 
 
 
b) omission of the former stipulation that required hospital discharge, after 
 
interval improvement with therapy, in order to be eligible for rescue re-treatment. 
 
 
c) a stipulation that 5 days need to elapse between completion of the initial 
 
treatment and the AE-IPF relapse, in order to re-implement rescue therapy. 
 
 
d) addition of a consensus adjudication process among the majority of PIs to  
 
substantiate the diagnoses of AE-IPF relapses, prior to rescue re-treatment. 
 
4) Various typo's and mis-spelled words have been corrected throughout this document 
 
5) The TPE collection schedule has been added to Table 1 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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60 
 
 
 
Informed Consent Form (ICF) Modifications (becoming V4. Jan 21. 2019) 
 
Note:  an asterisk (*) denotes changes recommended or mandated by DSMB 
 
1) The date and version number were updated on the ICF face page footer. 
 
2) The ICF now clearly states participants randomized to the experimental treatment 
arm will be eligible for one re-treatment with an AE-IPF relapse that occurs during their 
6-month participation in the trial.  A second relapse occurring in this subpopulation, or 
relapses occurring in TAU arm participants, will be treated with the TAU protocol.* 
 
3) The protocol for experimental treatment of AE-IPF relapses has been clarified to 
describe five TPE at every other day intervals, followed by the IVIG.* 
 
4) The supplemental ICF to allow genetic testing has been modified to mention some 
possible uses.* 
 
 
 
Protocol Modifications to v. 3.1 (Jan 21, 2019) that resulted in Version 4.0 (dated 
August 18, 2019) 
 
 
1) The potential for thrombotic complications of IVIG is now described on pages 38 and 45 
 
2) ANCA has been removed as an exclusion criterion (pages 8, 20, 35) 
 
3) Hepatitis C antibody (HCV Ab) tests will continue to be used in screening, but positive results 
will lead to testing by HCV nucleic acid PCR tests.  Patients who are merely HCV Ab+ but have 
negative PCR assays will be eligible for further consideration and possible randomization 
(pages  7,20,35) 
 
4) Ionized calcium measures are no longer an absolute requirement prior to TPE, but can 
continue to be obtained at the discretion of attending physicians (pages 20-22) 
 
5) A section has been added to the protocol (Section 6.3.4) to define, distinguish, and 
standardize Protocol Violations and Protocol Deviations, as well as detail reporting requirements 
for the former (pages 47 and 48) 
 
6) We've added two items to the Table of Contents, to make it easier to locate appropriate 
Protocol sections and page numbers for AE reporting timelines, and Protocol violation and 
deviation definitions.  
 
7) Interval personnel changes are noted.  Dr. Cutter's position as DCC head has been assumed 
by Dr. Fazlur.  Dr. De Andrade has relocated and is no longer a STRIVE Co-Invest.  
 
 
 

STRIVE-IPF V.6.0 May 7, 2020                                                                                           Contact PI: Steven R. Duncan, MD 
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61 
 
 
Protocol Modifications to v. 4.0 (August 18, 2019) that resulted in Version 5.0 
(dated September 3, 2019). 
 
The ICF Modification describing potential thrombotic and bleeding AE with IVIG was corrected.  
 
 
 
 
Informed Consent Form (ICF) Modifications to V4.0 dated Jan 21, 2019  (becoming 
V5. August 18. 2019) 
 
 
1) The potential for thrombotic complications of IVIG is now described on page 12 
 
2) The potential maximal number of subject recruitments at UAB during the duration of this trial 
has been increased to 24. 
 
 
 
 
Informed Consent Form (ICF) Modifications to V5.0 dated August 18, 2019  
(becoming V5.1. September 3. 2019) 
 
Six words missing from the description of potential bleeding and clotting AE with IVIG, originally 
approved, have been re-added (page 12) 
 
 
 
 
Protocol Modifications to V.5.0 dated September 3, 2019, that resulted in Version 
6.0 (dated May 7, 2020) 
 
1)  Dates and version numbers have been updated throughout 
 
2) The participating sites currently active have been updated 
 
3) The current Co-Investigator list has been updated 
 
4) A typo has been corrected to clarify collection of plasma discards during AE-IPF relapses (pg 
21)