Conditions: Idiopathic Pulmonary Fibrosis
Keywords: Idiopathic Pulmonary Fibrosis IPF pulmonary fibrosis antimicrobial therapy doxycycline co-trimoxazole
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 513
Healthy volunteers: no

Brief summary:
The purpose of this study is to compare the effect of standard care, versus standard of care plus antimicrobial therapy (co-trimoxazole or doxycycline), on clinical outcomes in patients diagnosed with idiopathic pulmonary fibrosis (IPF).

Detailed description:
This is a randomized, un-blinded, phase III, multi-center clinical trial of an antimicrobial therapy strategy in idiopathic pulmonary fibrosis patients. Our overall hypothesis is that reducing harmful microbial impact with antimicrobial therapy will reduce the risk of non-elective, respiratory hospitalization or death in patients with Idiopathic Pulmonary Fibrosis (IPF).

Subjects will be randomized 1:1 to either receive a prescription drug voucher for oral antimicrobial therapy in the form of one double strength 160 milligrams (mg) trimethoprim/800mg sulfamethoxazole (double strength co-trimoxazole) twice daily plus folic acid 5 mg daily OR doxycycline 100mg once daily if weight \< 50 kilograms (kg) or 100mg twice daily if weight \> 50 kg. Patients randomized to receive antimicrobial therapy will be given co-trimoxazole unless they have an allergy, contraindication to co-trimoxazole, renal insufficiency (glomerular filtration rate (GFR) \< 30 milliliters (ml)), are hyperkalemic (potassium \> 5 milliequivalents(mEq)/liter(L)), or are concomitantly taking an angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or potassium sparing diuretic in which case they will receive doxycycline.

Participation in this study will be between 12 months and 36 months depending on time of enrollment.

Arms:
arm 1: Co-trimoxazole OR doxycycline arm 2: Standard of care for patients with IPF for comparison

Interventions: intervention 1: Antimicrobial therapy: Co-trimoxazole or Doxycycline intervention 2: No Intervention: Standard of Care
Intervention descriptions: intervention 1: 160mg trimethoprim/800mg sulfamethoxazole (double strength co-trimoxazole) twice daily plus folic acid 5 mg daily OR doxycycline 100mg once daily if weight \< 50 kilograms or 100mg twice daily if weight \> 50 kilograms for up to 36 months intervention 2: Standard of care

Protocol document:
Prot_001.pdf: 
ClinicalTrials.gov Uploaded Document Cover Page 
 
 
 
Study Title: 
Study of Clinical Efficacy of Antimicrobial Therapy Strategy Using 
Pragmatic Design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) 
NCT Number:   
 
NCT02759120 
Document Description:  
Study Protocol 
Document Date:  
 
March 2, 2018 
 
 
 
 
Previous Protocol Versions:  
Protocol Amendment 1, April 15, 2017 
Protocol Initial, April 7, 2016 
 


CleanUP-IPF Protocol Amendment 2 
 
Version Date: March 2, 2018 
1 | P a g e  
 
Study Protocol 
 
 
 
 
Study of Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic 
Design in Idiopathic Pulmonary Fibrosis  
(CleanUP-IPF) 
 
 
Protocol Amendment 2 
 
Protocol Version Date: March 2, 2018 
ClinicalTrials.gov ID:  NCT02759120 
 
 


CleanUP-IPF Protocol Amendment 2 
 
Version Date: March 2, 2018 
2 | P a g e  
 
TABLE OF CONTENTS 
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CleanUP-IPF Protocol Amendment 2 
 
Version Date: March 2, 2018 
3 | P a g e  
 
 
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CleanUP-IPF Protocol Amendment 2 
 
Version Date: March 2, 2018 
4 | P a g e  
 
1. EXECUTIVE SUMMARY 
 
Title: 
Study of Clinical Efficacy of Antimicrobial Therapy Strategy Using Pragmatic 
Design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) 
Location: 
Approximately 30-40 clinical sites in the United States 
Objectives: 
To compare the impact of an antimicrobial therapy strategy on clinical 
outcomes (hospitalization or death) 
Study Design: 
500-patient, randomized, un-blinded, phase III, multicenter clinical trial of an 
antimicrobial therapy strategy in idiopathic pulmonary fibrosis patients 
Treatment 
Regimens: 
1:1 randomization to either oral antibiotic (co-trimoxazole or doxycycline) in 
addition to standard-of-care or standard-of-care alone.  
The subject randomized to antimicrobial therapy will be treated with 
trimethoprim 160mg/800mg sulfamethoxazole (double strength co-
trimoxazole) twice a day plus folic acid 5 mg daily unless there is a 
contraindication to this therapy.   
If the subject develops an intolerance to co-trimoxazole the dosage can be 
decreased to once a day 160mg trimethoprim/800mg sulfamethoxazole (one 
double strength co-trimoxazole) three times weekly plus folic acid 5 mg 
daily.   
If intolerance continues with co-trimoxazole then the antimicrobial agent 
can be changed to doxycycline (without folic acid).   
Subjects with a contraindication to co-trimoxazole will be treated with 
doxycycline (without folic acid).  Doxycycline will be dosed at 100 mg once 
daily if body weight is < 50 kg and 100 mg twice daily if ≥ 50 kg.  
Primary 
Endpoint: 
Time to first non-elective, respiratory hospitalization or all-cause mortality 
Secondary 
Endpoints: 
 Time to death from any cause 
 Time to first non-elective, respiratory hospitalization 
 Time to first non-elective, all-cause hospitalization 
 Total number of non-elective respiratory hospitalizations 
 Total number of non-elective all-cause hospitalizations 
 Change in FVC from randomization to 12 months 


CleanUP-IPF Protocol Amendment 2 
 
Version Date: March 2, 2018 
5 | P a g e  
 
 Change in DLCO from randomization to 12 months 
 Total respiratory infections 
 Change in UCSD-Shortness of Breath Questionnaire and Fatigue Severity 
Scale score from randomization to 12 months 
 Change in Leicester Cough Questionnaire score from randomization to 12 
months 
 Change in EQ-5D score and SF-12 score from randomization to 12 
months 
 Change in ICEpop CAPability measure for Older people (ICECAP-O) score 
from randomization to 12 months 
 
 
 


CleanUP-IPF Protocol Amendment 2 
 
Version Date: March 2, 2018 
6 | P a g e  
 
Overview of the Pulmonary Trials Cooperative and the CleanUP-IPF study 
The CleanUP-IPF trial is a collaborative effort involving the following groups: 
1. National Institutes of Health 
2. National Heart, Lung, and Blood Institute 
3. University of Pittsburgh 
4. Weill Cornell University 
5. Duke Clinical Research Institute 
6. Clinical Sites 
The CleanUP-IPF leadership team shall be referred to as the “CleanUP-IPF Protocol Leadership 
Group” (PLG). The CleanUP-IPF PLG is one of multiple PLGs which comprise the Pulmonary 
Trials Cooperative (PTC). The following flow chart depicts each group which makes up the PTC: 
 
 
 
 
 
 
 
 
 
 
 
 
 
Organizational Components 
 Protocol Leadership Groups (PLGs) – design and carry out clinical studies 
 Network Management Core (NEMO) – facilitate the research conducted by the PTC 
 Operations Committee – primary responsibility for the implementation, oversight, and 
continuing evaluation of PTC studies 
 Executive Committee – provide leadership and oversight to the PTC at large 
 Clinical Sites – recruit and enroll participants, deliver the study intervention, complete 
clinic visits and phone calls, collect and enter data, and carry out procedures as defined 
by each study’s protocol 
DSMB 
Clinical 
Sites 
NHLBI 
NEMO 
PLGs 
Operations 
Committee
Executive 
Committee


CleanUP-IPF Protocol Amendment 2 
 
Version Date: March 2, 2018 
7 | P a g e  
 
 Data and Safety Monitoring Board (DSMB) – review the design of each study, monitor 
patient safety, and review progress 
 NHLBI Project Office – oversight for the whole endeavor 
 
More information about the PTC and CleanUP-IPF can be found at … 
 
http://www.pulmonarytrials.org/ 
 
https://clinicaltrials.gov/ct2/show/NCT02759120 
 
 


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The primary objective of the CleanUP-IPF study is to compare the effect of standard care vs. 
standard care plus antimicrobial therapy (co-trimoxazole or doxycycline) on clinical outcomes in 
patients diagnosed with idiopathic pulmonary fibrosis. 
Our overall hypothesis is that reducing harmful microbial impact with antimicrobial therapy will 
reduce the risk of non-elective, respiratory hospitalization or death in patients with IPF. 
 6HFRQGDU\2EMHFWLYHV
Secondary objectives of this protocol will be to examine the effect of this treatment strategy for 
the following endpoints: 
x Time to death from any cause 
x Time to first non-elective, respiratory hospitalization 
x Time to first non-elective, all-cause hospitalization 
x Total number of non-elective respiratory hospitalizations 
x Total number of non-elective all-cause hospitalizations 
x Change in FVC from randomization to 12 months 
x Change in DLCO from randomization to 12 months 
x Total number of respiratory infections 
x Change in UCSD-Shortness of Breath Questionnaire from randomization to 12 months 
x Change in Fatigue Severity Scale score from randomization to 12 months 
x Change in Leicester Cough Questionnaire score from randomization to 12 months 
x Change in EQ-5D score and SF-12 score from randomization to 12 months 
x Change in ICEpop CAPability measure for Older people (ICECAP-O) score from 
randomization to 12 months 
 
 


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3. BACKGROUND AND RATIONALE 
Idiopathic pulmonary fibrosis (IPF), a fibrotic interstitial lung disease characterized by the 
histopathologic pattern of usual interstitial pneumonia (UIP), has a median survival of 3-5 years’ 
post-diagnosis but exhibits heterogeneous longitudinal disease progression.  Recent studies of 
pirfenidone and nintedanib confirm beneficial effects on longitudinal change in forced vital 
capacity but inconsistent benefits on clinical endpoints or health status.  Both of these agents 
can be difficult to tolerate and are expensive.   
A recent study showed that an abnormal lung microbial community is independently associated 
with disease progression in IPF subjects (COMET)1; this has been confirmed by a second 
investigative group2.  Similarly, it has been demonstrated that polymorphisms in the TOLLIP 
gene are associated with impaired outcome in IPF patients3.  Additional preliminary data 
suggest that a systemic marker of inflammatory cell activation is associated with IPF disease 
progression4.  Lastly, preliminary data from COMET suggest that a circulating gene expression 
signature of altered host response is associated with the aberrant lung microbial community. 
Intriguingly, other investigative groups have suggested improved clinical outcomes in IPF 
patients treated with co-trimoxazole or doxycycline compared to matched placebo5-7.  The 
totality of these data suggests that an abnormal lung microbiome interacting with genetic 
susceptibility in host response may be associated with impaired clinical outcomes in IPF.  
Our principal hypothesis is that antimicrobial therapy in IPF patients will improve clinical 
outcomes in a pragmatic therapeutic trial.  The study aims are: 
Aim 1.  To determine if antimicrobial therapy (co-trimoxazole or doxycycline) in addition to 
standard care compared to standard care alone improves the time to non-elective respiratory 
hospitalization or death. 
Aim 2.  To determine if response to antimicrobial therapy is a function of genetic susceptibility 
to impaired host response in IPF patients. 
We propose to examine the potential of precision medicine by examining the interaction of 
antimicrobial therapy with baseline genotype.  Our long-term goal is to define patient-specific 
therapy in IPF.   
 
 
 
 


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1. ≥ 40 years of age 
2. Diagnosed with IPF by enrolling investigator 
3. Signed informed consent 
 ([FOXVLRQ&ULWHULD
1. Received antimicrobial therapy in the past 30 days for treatment purposes (antibiotic 
prophylaxis for procedures do not meet criteria, nor do antivirals) 
2. Contraindicated for antibiotic therapy, including but not exclusive to: 
a. Allergy or intolerance to BOTH tetracyclines AND trimethoprim, sulfonamides or 
their combination 
b. Allergy or intolerance to tetracyclines AND known potassium level > 5 mEq/L in 
the past 90 days.   
i. If the enrolling physician feels the potassium level has normalized, 
documentation to that effect must be provided. 
c. Allergy or intolerance to tetracyclines AND concomitant use of angiotensin 
converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), potassium 
sparing diuretic, dofetilide, methotrexate, azathioprine, mycophenolate mofetil, 
cyclophosphamide  
d. Allergy or intolerance to tetracyclines AND known glucose-6-phosphate 
dehydrogenase deficiency 
e. Allergy or intolerance to tetracyclines AND untreated folate or B12 deficiency 
f. Allergy or intolerance to tetracyclines AND known renal insufficiency (defined as 
a GFR < 30 ml/min within the previous 90 days) 
i. If the enrolling physician feels the renal dysfunction has resolved, 
documentation to that effect must be provided. 
 
g. Seizure disorder on antiepileptic therapy.  
3. Pregnant (as determined by urine dipstick pregnancy test at randomization), or anticipate 
becoming pregnant 
4. Use of an investigational study agent for IPF therapy within the past 30 days, or an IV 
infusion with a half-life of four (4) weeks  
5.  Concomitant immunosuppression with azathioprine, mycophenolate, cyclophosphamide, 
or cyclosporine. 
 
Participation in other IPF clinical trials or registries, while participating in the CleanUP-IPF trial, is 
not exclusionary assuming the participant meets all other eligibility criteria. 




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5. TREATMENT INTERVENTIONS 
This will be an unblinded, randomized clinical trial comparing the following treatment strategies 
 Standard care 
 Standard care + oral antimicrobial therapy  
 
Patients randomized to receive antimicrobial therapy will receive a prescription drug voucher 
for the medication (and folic acid if given co-trimoxazole) during the enrollment visit.  To 
minimize risk to the participating subject and to maximize a positive outcome we have created 
an algorithm for antimicrobial therapy that encourages use of co-trimoxazole but allows 
doxycycline use.   
Figure 1 illustrates the proposed antimicrobial therapy algorithm. Contraindications to co-
trimoxazole at enrollment include: 
 allergy to sulfa products or trimethoprim 
 renal insufficiency (GFR < 30 mL/min, defined as estimated from the blood urea nitrogen 
and creatinine) 
 hyperkalemic (potassium > 5 mEq/L) 
 concomitantly taking an ACEI, ARB, potassium sparing diuretic, dofetilide, methotrexate, 
azathioprine, mycophenolate mofetil, cyclophosphamide  
 Other contraindication to co-trimoxazole in the investigator’s opinion 
Subjects meeting any of the above and randomized to antibiotic therapy will take doxycycline 
instead. Subjects on vitamin A or retinoids will need to stop these medications if randomized to 
doxycycline. 
Co-trimoxazole intolerance is defined by the investigator. Mild intolerance (e.g. nausea, 
abdominal pain, headaches, anorexia) may require a dose adjustment to half dose.  Moderate 
intolerance (e.g. decreased leukocytes, mild increase in potassium) require a dose adjustment 
or a switch to doxycycline at the investigator’s discretion. A significant intolerance (e.g. 
leukopenia, hyperkalemia, decrease in GFR by more than 50% or to less than 30 ml/min, rash) 
requires stopping the co-trimoxazole and providing medical treatment as appropriate. 
Doxycycline should be started when medically appropriate in the opinion of the investigator 
after moderate or significant intolerance. All dose adjustments will be at the discretion of the 
treating physician(s) with the medical monitor available for consultation if needed. Dosing 
adjustments, and/or switching of co-trimoxazole to doxycycline, will be documented within the 
eCRFs, as well as the reason for the adjustment. 
 
 


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Figure 1 
 
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All patients will be randomized using the study electronic data capture (EDC) system.  Patients 
will be randomized to treatment in a 1:1 allocation ratio using a simple randomization scheme. 
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This study will be unblinded.  Blinding would add substantial additional complexity without 
commensurate incremental benefit related to testing the primary hypothesis of a treatment 
strategy trial. 
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This study will evaluate and compare treatment strategies of standard care and standard care + 
antimicrobial therapy in patients with IPF.  
Although investigators are encouraged to follow the assigned treatment strategy for the study 
duration, in all cases the patient’s safety based on the clinical judgment of the treating 
physician will take priority over the specific treatment assignment.   


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There is the potential of adverse cardiovascular events secondary to co-trimoxazole therapy; 
this is felt to possibly reflect a drug interaction with trimethoprim resulting in hyperkalemia8,9.  
Review of older literature suggests that the major risk factors for trimethoprim related 
hyperkalemia are higher trimethoprim dose and renal insufficiency with hypoaldosteronism, 
and potassium altering medications and age as probable risk factors10.  Our inclusion/exclusion 
criteria should mitigate this risk as will monitoring for hyperkalemia early after the introduction 
of co-trimoxazole therapy10. 
If a subject randomized to the antimicrobial strategy group develops an intolerance to co-
trimoxazole the dosage should first be decreased to one double strength 160mg trimethoprim/ 
800mg sulfamethoxazole (co-trimoxazole) three times weekly plus folic acid 5 mg daily.  If 
intolerance continues with co-trimoxazole then the antimicrobial agent can be changed to 
doxycycline (with no 5mg folic acid).  
Doxycycline will be dosed at 100 mg once daily if body weight is < 50 kg and 100 mg twice daily 
if > 50 kg, and no 5mg folic acid will be prescribed.   
 
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All patients diagnosed at the participating centers with IPF will be screened by a study 
coordinator.  Patients meeting eligibility criteria will be approached regarding participation in 
this study. 
 (VWLPDWHG(QUROOPHQW3HULRG
This study will enroll approximately 500 patients at 20-40 study sites. The projected enrollment 
timeline for enrollment is approximately 30 months. 
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A complete schedule of assessments throughout the study is given in Appendix A. 
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After providing informed consent and signing the informed consent form (ICF), patients will be 
evaluated (via a physical examination) for eligibility into the study by ensuring that they: 
x Are the appropriate age 
x Have been diagnosed at the site with idiopathic pulmonary fibrosis 
x Are not currently on antibiotic therapy, for treatment purposes (antibiotic prophylaxis for 
procedures do not meet criteria, nor do antivirals), and do not have any contraindications 
to antibiotic therapy.  


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Prior to randomization, the coordinator will document the following: 
x Date of consent 
x Patient characteristics (sex, race, ethnicity, age, height, weight) 
x Information on how IPF diagnosis was made 
x Known co-morbidities 
x Details on patient history of gastroesophageal reflux disease (GERD) 
x Physical exam findings 
x Current concomitant medications 
x Urine dipstick pregnancy test (for pre-menopausal female participants only) 
x In recipients randomized to co-trimoxazole and taking digoxin, these recipients should 
be notified of a possible drug interaction and have additional digoxin monitoring by the 
provider monitoring digoxin levels for the patient.  
x In recipients randomized to co-trimoxazole and taking warfarin, these recipients should 
be notified of a possible drug interaction and have additional coagulation (defined as 
PT/PTT/INR) monitoring by the provider monitoring coagulation labs for the patient.  
x In recipients randomized to doxycycline and Vitamin A or retinoids, patients should be 
notified of a drug interaction and must stop these medications prior to starting 
doxycycline.  
x Evaluation of seizure disorder and need for antiepileptic therapy.  Antiepileptic therapy 
is a contraindication for enrollment. 
The following procedures will be performed prior to randomization, if results are not available 
from recent clinically indicated testing: 
x Spirometry and DLCO assessments, if not done within 90 days of randomization for 
clinical purposes.. The results of these tests will be recorded by the coordinator into the 
EDC system. 
x Quality of life questionnaires 
x Buccal and fecal sample collection for microbial ecology. Subjects will be given a fecal 
collection sample kit and instructions to take home.  
x Urine pregnancy test for females who are able to become pregnant 
x Blood draw for the following lab tests (Described in Appendix B):  
o Genotype  
o Gene expression  
o Chemistry panel and liver function tests– defined as minimum of sodium, 
potassium, chloride, bicarbonate, blood urea nitrogen (BUN), and creatinine, 
total bilirubin, direct bilirubin, alkaline phosphatase (ALP), alanine transaminase 
(ALT), and aspartate aminotransferase (AST) 
o Complete Blood Count (CBC) 


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If a subject does not meet the eligibility criteria due to a condition that subsequently resolves 
(e.g., infection or renal insufficiency), they may be considered for enrollment once the 
condition resolves if they meet the all eligibility criteria at the time of randomization.  
 5DQGRPL]DWLRQ
After providing informed consent and signing the ICF, all eligible study subjects will be 
randomized in a 1:1 allocation ratio to either receive or not receive a prescription drug voucher 
for daily antimicrobial therapy.  Folic acid will also be included within the prescription drug 
voucher, for subjects randomized to co-trimoxazole therapy.  Subjects should begin 
administration of drug without delay following randomization. 
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All study participants will continue to be followed on a usual care basis.  Refer to the schedule 
of assessments for more details.  Study participants will be followed for up to a maximum of 36 
months.  It is anticipated that the overall study will end once the final enrolled patient 
completes their 12-month visit.  Subjects randomized to antimicrobial therapy will remain on 
the assigned therapy until the end of the study or their 36-month study visit.  Study participants 
are encouraged to contact their treating pulmonologist regarding their use of anti-microbial 
therapy after their study participation has ended.  At the completion of the 36-month phone 
contact data collection will cease. To gain a better understanding of the long-term 
consequences of treatment, patients may be contacted up to 5 years after the end of their 
study participation.  The primary analyses will be based on data collected until the end of the 
active treatment portion of the study. 
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Approximately 1 week (visit window of 1 week +/- 3 days) after enrollment (and the beginning 
of administration of drug), subjects assigned to the antimicrobial therapy arm will return to the 
enrolling site or a local laboratory for the following: 
x Blood drawn for electrolytes (Described in Appendix B) 
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Approximately 1 month (visit window of 1 month +/- 7 days) after enrollment, all subjects will 
be contacted by the site coordinator to document the following: 
x Any issues related to drug assignment 
x Vital status assessment 
x Medication adherence 
x Hospitalization and respiratory infection assessment 


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Approximately 3 months (visit window of 3 months +/-+/- 7 days) after enrollment, subjects 
assigned to the antimicrobial therapy arm will return to the enrolling site or a local laboratory 
for the following:  
x Blood draw for the following safety labs (Described in Appendix B):   
o Chemistry panel and liver function tests– defined as minimum of sodium, 
potassium, chloride, bicarbonate, BUN, and creatinine, total bilirubin, direct 
bilirubin, alkaline phosphatase, ALT, and AST 
o Complete blood count (CBC) 
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Approximately 6 months (visit window of 6 months +/- 7 days) after enrollment, subjects 
assigned to the antimicrobial therapy arm will return to the enrolling site or a local laboratory 
for the following:  
x Blood drawn for the following safety labs (Described in Appendix B): 
o Chemistry panel and liver function tests– defined as minimum of sodium, 
potassium, chloride, bicarbonate, BUN, and creatinine, total bilirubin, direct 
bilirubin, alkaline phosphatase, ALT, and AST 
o Complete blood count (CBC) 
x Vital status Assessment 
x Medication adherence 
x Hospitalization and respiratory infection information 
 6L[PRQWKSKRQHFRQWDFWIRUVWDQGDUGFDUHDUP
Approximately 6 months (visit window of 6 months +/- 4 weeks) after enrollment, subjects 
randomized to the standard care arm ONLY will be contacted by the site coordinator to 
document the following:  
x Vital status assessment 
x Medication adherence 
x Hospitalization and respiratory infection information 
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All subjects will return to the enrolling site approximately 12 months (visit window of 12 
months +/- 4 weeks) after enrollment and will complete the following: 
x Quality-of-life questionnaires   
x Spirometry and DLCO assessment 
*If a spirometry (with DLCO) assessment is available within 90 days of the in-person 
visit it may be used as the study assessment.  Otherwise the spirometry assessment 
with DLCO should be conducted at the in-person visit.   
x Blood draw for the following safety labs (for antimicrobial arm only): 


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o Chemistry panel and liver function tests– defined as minimum of sodium, 
potassium, chloride, bicarbonate, BUN, and creatinine, total bilirubin, direct 
bilirubin, alkaline phosphatase, ALT, and AST  
x Complete Blood Count (CBC) (for antimicrobial arm only) 
x Blood draw for gene expression  
x Buccal and fecal samples collection for microbial ecology  
 (LJKWHHQPRQWKSKRQHFRQWDFW
Approximately 18 months (visit window of 18 months +/- 4 weeks) after enrollment, all subjects 
will be contacted by the site coordinator to document the following: 
x Vital status 
x Medication adherence 
x Hospitalization and respiratory infection information 
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All subjects will return to the enrolling site approximately 24 months (visit window of 24 
months +/- 4 weeks) after enrollment and will complete the following: 
x Quality-of-life questionnaires   
x Spirometry and an DLCO assessment 
*If a spirometry (with DLCO) assessment is available within 90 days of the in-person 
visit it may be used as the study assessment.  Otherwise the spirometry assessment 
with DLCO should be conducted at the in-person visit.   
x Blood draw for the following safety labs (for antimicrobial arm only): 
o  Chemistry panel and liver function tests– defined as minimum of sodium, 
potassium, chloride, bicarbonate, BUN, and creatinine, total bilirubin, direct 
bilirubin, alkaline phosphatase, ALT, and AST  
x Complete Blood Count (CBC) (for antimicrobial arm only) 
x Blood draw for gene expression  
x Buccal and fecal samples collection for microbial ecology  
 7KLUW\PRQWKSKRQHFRQWDFW
Approximately 30 months (visit window of 30 months +/- 4 weeks) after enrollment, subjects 
will be contacted by the site coordinator to document the following:  
x Vital status 
x Medication adherence 
x Hospitalization and respiratory infection information 
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Approximately 36 months (visit window of 36 months +/- 4 weeks) after enrollment, subjects 
will be contacted by the site coordinator to document the following:  


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x Vital status 
x Medication adherence 
x Hospitalization and respiratory infection information 
 
Participants randomized to the antimicrobial arm who are still taking study drug at this visit 
should consult with their treating pulmonologist about continuing any prescriptions for 
antimicrobial therapies, as prescription drug voucher coverage will cease after completion of 
the 36 month phone contact. Data collection for study purposes will cease after completion of 
the 36-month phone contact. 
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The primary endpoint of this study will be the time to first non-elective, respiratory 
hospitalization or all-cause mortality. 
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x Time to death from any cause 
x Time to first non-elective respiratory hospitalization 
x Time to first non-elective all-cause hospitalization 
x Total number of non-elective respiratory hospitalizations 
x Total number of non-elective all-cause hospitalizations 
x Change in FVC from randomization to 12 months 
x Change in DLCO from randomization to 12 months 
x Total number of respiratory infections 
x Change in UCSD-Shortness of Breath Questionnaire from randomization to 12 months 
x Change in Fatigue Severity Scale score from randomization to 12 months 
x Change in Leicester Cough Questionnaire score from randomization to 12 months 
x Change in EQ-5D score and SF-12 score from randomization to 12 months 
x Change in ICEpop CAPability measure for Older people (ICECAP-O) score from 
randomization to 12 months 
 5ROHRIWKH&OHDQ83,3)$GMXGLFDWLRQ&RPPLWWHH
An Adjudication Committee will classify all hospitalization events.  The Adjudication Committee 
will follow procedures described in the Adjudication Charter.  Briefly, medical records from 
inpatient hospitalizations will be obtained by the data coordinating center through an 
established, secure process which will be detailed in the informed consent document.  Non-
elective respiratory hospitalizations will be defined as any unplanned inpatient hospitalizations 
for which the primary cause was a pulmonary condition, in the opinion of the blinded 
adjudicators and based on all available clinical data. Examples include, but are not limited to, 
the following: 


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-acute exacerbation of IPF (definite or suspected) 
-pulmonary infection/pneumonia 
-pulmonary embolus 
-pneumothorax 
-pulmonary aspiration 
-ARDS of identifiable cause 
These causes will be adjudicated by review of admission history and physical and discharge 
summary from the hospitalization.  These documents will be obtained (with patient consent) by 
the DCC from the hospital where the encounter occurred.  Documents will be made available to 
adjudicators in PDF form via the secure and integrated data management system (IBM Clinical 
Development Endpoint Adjudication Module) at the DCC.  Each hospitalization event will be 
adjudicated by one of the study pulmonologists from the adjudication committee, ensuring that 
the adjudicator is independent from the study site at which the event occurred.  If this 
adjudication is in agreement with the site investigator’s assessment (with regard to date of 
event, elective vs. non-elective and respiratory vs. non-respiratory), this assessment will serve 
as the final event adjudication.  In the event of the independent adjudicator’s assessment 
disagreeing with the site investigator’s assessment, a second blinded member of the 
adjudication committee, also independent of the involved site, will serve as a “tiebreaker”. 
Hospitalizations occurring primarily for lung transplantation will be considered “elective,” as the 
timing of lung transplant events is unpredictable because of donor lung availability rather than 
occurrence of acute or worsening illness.  On the other hand, hospitalizations initially caused by 
an acute pulmonary condition but during which lung transplantation later occurs will be 
considered non-elective.  Non-pulmonary causes of dyspnea, such as cardiac disease, will not 
be considered respiratory causes of hospitalizations. 
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All CleanUP-IPF sites will submit the study protocol, informed consent form, and other study 
documents to their IRB for approval—the approval letter for each clinical center will be stored 
at the CC. Any amendments to the protocol, other than minor administrative changes, must be 
approved by each IRB before they are implemented.  
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All patients will have the purpose of the study, the study interventions and evaluations, and the 
potential risks and benefits of participation explained to them and their questions answered.  If 
they consent to participation in this study, they will review and sign the informed consent form.  


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6XPPDU\RIWKH5LVNVDQG%HQHILWV
This study will evaluate an antimicrobial therapy strategy in patients with IPF.  These agents are 
currently used in clinical practice.  We therefore do not anticipate that participation in this 
study will be associated with increased risks beyond that of standard IPF therapy.  We have 
added limited exclusionary criteria to minimize risk of antimicrobial therapy. 
Potential benefits to study participants include the possibility of improvements in clinical 
outcomes.  
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Adverse events (AEs) of special interest ONLY will be collected for the CleanUP-IPF trial. These 
AEs include: 
x Arrhythmia 
x Vomiting 
x Diarrhea 
x Rash 
x Hyperkalemia 
These adverse events of special interest will be collected via data entry into the eCRF within the 
electronic data capture system. Start and stop dates will also be collected for these events, as 
well as any concomitant medications prescribed (with start and stop dates of the concomitant 
medication) for treatment of such events.  
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Any adverse Event that meets any of the following criteria: (1) results in death; (2) is life-
threatening (i.e. places a participant at immediate risk of death from the event as it occurred); 
(3) requires inpatient hospitalization or prolongation of existing hospitalization; (4) results in a 
persistent or significant disability/incapacity; (5) results in a congenital anomaly/birth defect; 
OR (6) any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the participant’s health and may require medical or surgical intervention to prevent 
one of the other outcomes listed in this definition (e.g. allergic bronchospasm requiring 
intensive treatment in the emergency room or at home). 
 
Information about all serious adverse events, whether volunteered by the subject, discovered by 
investigator questioning, or detected through physical examination, laboratory test or other 
means, will be collected and recorded on the Serious Adverse Event eCRF. 
 
For this study, all SAEs occurring from the time of drug administration to 30 days post-study 
completion visit will be captured on the SAE eCRF.  As the Month 36 Visit is a Phone Call Visit, 
review of subjects’ medical records is required, in order to evaluate any SAEs within 30 days 
post-study completion visit. Unless exempted as described below, all SAEs, whether or not 
deemed drug-related, must be reported by the investigator or qualified designee within 1 


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business day of first becoming aware of the event. The investigator/qualified designee will 
enter the required information regarding the SAE into the appropriate module of the IBM 
Clinical Development, which will automatically result in distribution of the information to the 
Duke Clinical Research Institute Medical Monitor and Clinical Operations team, and the 
Network Management Core (NEMO). If IBM Clinical Development is temporarily unavailable, 
the event, including the investigator-determined causality to study drug, should be reported via 
a paper back-up SAE form to the DCRI Medical Monitor and Clinical Operations team, and the 
NEMO. Upon return of the availability of EDC system, the SAE information must be entered into 
the eCRF.  
 
Follow-up: When additional relevant information becomes available, the Investigator will 
record follow-up information according to the same process used for reporting the initial event 
as described above. The Investigator will follow all reportable events until resolution, 
stabilization or the event is otherwise explained.  
 
Investigators are also responsible for promptly reporting SAEs to their reviewing IRB/EC in 
accordance with local requirements. 
 
The DCRI Medical Monitor and Clinical Operations team, and NEMO will follow all SAEs until 
resolution, stabilization, until otherwise explained or until the last subject completes the final 
follow-up, whichever occurs first. The DCRI Medical Monitor and Clinical Operations team will 
report all SAEs to the CleanUP-IPF trial team within 1-2 business day(s) of receipt and notify the 
Data Safety Monitoring Board (DSMB) chair monthly. If no events have occurred, the DCRI 
Clinical Operations team will notify the NEMO, and NEMO will notify the DSMB chair as such. 
 
An independent DSMB will review composite data at regular intervals throughout the study. 
The DSMB will be empowered to stop the study for evidence of efficacy or harm. 
 
Events Relatedness refers to the extent to which an adverse event is considered to be related 
to the intervention or study procedures. An adverse event is considered related if there is a 
reasonable possibility that the event may have been caused by the procedure. The following 
definitions apply to relatedness, per the Pulmonary Trials Cooperative’s Manual of Operations:  
1) Unrelated: adverse event is clearly due to extraneous causes (e.g., underlying disease, 
environment) 
2) Unlikely: (adverse event must meet 2 of the following criteria): 
 Does not have temporal relationship to intervention 
 Could readily have been produced by the participant’s clinical state 
 Could have been due to environmental or other interventions 
 Does not follow known pattern of response to intervention 
 Does not reappear or worsen with reintroduction of intervention 
 
3) Possible: (adverse event must meet 2 of the following criteria): 


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22 | P a g e  
 
x Has a reasonable temporal relationship to intervention 
x Could not readily have been produced by the participant’s clinical state 
x Could not readily have been due to environmental or other interventions 
x Follows a known pattern of response to intervention 
 
4) Probable: (adverse event must meet 3 of the following criteria): 
x Has a reasonable temporal relationship to intervention 
x Could not readily have been produced by the participant’s clinical state or have 
been due to environmental or other interventions 
x Follows a known pattern of response to intervention 
x Disappears or decreases with reduction in dose or cessation of intervention 
 
5) Definite: (adverse event must meet 4 of the following criteria): 
x Has a reasonable temporal relationship to intervention 
x Could not readily have been produced by the participant’s clinical state or have 
been due to environmental or other interventions 
x Follows a known pattern of response to intervention 
x Disappears or decreases with reduction in dose or cessation of intervention and 
recurs with re-exposure 

3UHJQDQF\
Pregnancy occurring during a clinical investigation, although not considered a serious adverse 
event, must be reported to DCRI within the same timelines as a SAEs.  The pregnancy will be 
recorded on the appropriate paper pregnancy tracking form.  The pregnancy will be followed 
until final outcome.  Any associated SAEs that occur to the mother or fetus/child will be 
recorded in the SAE eCRF, within IBM Clinical Development. 
All pre-menopausal female participants will have a urine sample collected at their 
screening/baseline visit, and a urine dipstick pregnancy test will be completed.  
In an effort to prevent pregnancies from occurring during a subject’s participation in the study, 
women of child-bearing potential must use two acceptable methods of contraception at the 
same time unless the subject has had a surgical sterilization, in which case no additional 
contraception is required. Medically acceptable contraceptives include: (1) documented 
surgical sterilization (such as a hysterectomy, tubal ligation), (2) barrier methods (such as a 
condom or diaphragm) used with a spermicide, (3) hormonal contraception (combination oral 
contraceptives, transdermal patch, injectables, implantables, or vaginal ring) or (4) an 
intrauterine device (IUD) or intrauterine system (IUS).  Abstinence is not an acceptable form of 
contraception in this study. 
Male participants must also agree to take all necessary measures to avoid causing pregnancy in 
their sexual partners during the study.  Medically acceptable contraceptives include: (1) surgical 


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23 | P a g e  
 
sterilization (such as a vasectomy), or (2) a condom used with a spermicidal.  Contraceptive 
measures such as Plan B (TM), sold for emergency use after unprotected sex, are not acceptable 
methods for routine use. 
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Means, standard deviations, medians, 25th and 75th percentiles will be presented for continuous 
variables; the number and frequency of patients in each category will be presented for nominal 
variables.  Statistical tests with a two-sided p value <0.05 will be considered statistically 
significant, unless otherwise stated.  Analyses will be performed using SAS software (SAS 
Institute, Inc., Cary, NC). 
$QDO\VLVRI3ULPDU\(QGSRLQW
Detailed description of the plan for statistical analysis of each endpoint will be detailed in a 
Statistical Analysis Plan.  The primary analysis will be based on intention to treat.  Crossovers 
will be tracked and we will have an alternate analysis cohort based on these data.  Subjects 
receiving lung transplantation will be censored for all endpoints at the time of transplantation. 
The statistical comparison of the two randomized arms with respect to the primary endpoint 
will be a time-to-event analysis, and therefore will be based on the time from randomization to 
first non-elective, respiratory hospitalization or death from any cause.  The Cox proportional 
hazards regression model will be the primary tool to analyze and assess outcome differences 
between the two treatment arms.  The Cox model will include an indicator variable for 
treatment group, age, sex, baseline DLCO (pp), baseline FVC (pp), use of NAC at enrollment, and 
choice of antimicrobial agent prior to randomization.  Hazard ratios and 95% confidence 
intervals will summarize the differences between treatment arms. 
For the primary analysis, subjects without any respiratory hospitalization or death event at the 
time of analysis will be censored at their last visit or lung transplantation.  The censoring 
mechanism is assumed to be non-informative.  Supportive analyses will be performed to assess 
the impact of a potential informative censoring. 
6DPSOH6L]H-XVWLILFDWLRQ
Based on prior work from the study team using IPFnet data, it is anticipated that the event rate 
in the placebo arm will be highly dependent on the proportion of patients enrolled at the 
different GAP scores.  Given the availability of two FDA-approved drugs for IPF, it is our belief 
that the study population will be heavily weighted toward GAP scores of 3.  In Table 1, the 
statistical power is determined for designs enrolling 500 patients with placebo group events 
rates varying from 24% to 36% and (12-month) treatment effects varying from 30% to 35%. In 


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24 | P a g e  
 
general, the proposed design provides adequate power expect when the 12-month standard-
of-care group event rate is 24% and the reduction in events is less than 30%. 
Table 1. Statistical Power Assuming a Sample Size of 500 Randomized Patients 
Standard-of-care 
event rate* 
Antimicrobial therapy 
strategy event rate* 
One-year Event Rate 
Reduction 
Power 
24% 
16.8% 
30% 
78% 
30% 
21.0% 
30% 
87% 
36% 
25.2% 
30% 
93% 
24% 
16.0% 
33.3% 
86% 
30% 
20.0% 
33.3% 
93% 
36% 
24.0% 
33.3% 
97% 
24% 
15.6% 
35% 
89% 
30% 
19.5% 
35% 
95% 
36% 
23.4% 
35% 
98% 
*12-month event rates. Calculations assume a 2-sided Type-I error rate of 0.05. The minimum follow-up is planned 
to be 12 months and the maximum follow-up is 42 months.  Drop-out rates are assumed to be approximately 2% 
per year. Power calculations were based on a log-rank test with assumed event rates were exponentially 
distributed. Calculations were computing using nQuery 7.0 software. 
We plan to enroll 500 patients over a 30 month window with a minimum of 12 months of 
follow-up on all patients. Table 2 shows the required number of endpoint events to have 80% 
to 90% power with hazard ratios varying from 0.50 to 0.75.  
 
Table 2. Required number of events 
 
HR=0.50 
HR=0.55 
HR=0.60 
HR=0.65 
HR=0.70 
HR=0.75 
80% power 
65 
88 
120 
169 
247 
379 
85% power 
75 
100 
138 
194 
282 
434 
90% power 
87 
118 
161 
226 
330 
508 
Calculations performed using nQuery 7.0 and assume a 0.05 type I error rate (two-sided) with 1:1 randomization. 
$QDO\VLVRI6HFRQGDU\(QGSRLQWV
The analyses for the time-to-event secondary endpoints will be similar to those outlined for the 
primary endpoint using the time from randomization through the first occurrence of any 
component of a specific secondary endpoint (or censoring) as the response variable, and 


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25 | P a g e  
 
assessing group differences using the Cox proportional hazards model. Analyses of continuous 
secondary outcome variables will rely on a repeated measures approach, using mixed models 
and incorporating all available assessments. The analyses of all study endpoints will be detailed 
in the Statistical Analysis plan.  
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The DCRI will have primary responsibility for data management, including the development of 
data collection systems, data monitoring processes, and data storage and back up.  State-of-
the-art technology will be used for the management of the network’s data.  
'HVLJQDQG'HYHORSPHQW
The DCC will be responsible for development of the electronic case report forms (eCRFs), 
development and validation of the clinical study database, ensuring data integrity, and training 
clinical center staff on applicable data management procedures.  A web-based distributed data 
entry model will be implemented.  This system will be developed to ensure that guidelines and 
regulations surrounding the use of computerized systems used in clinical trials are upheld.  
'DWD&ROOHFWLRQ)RUPV
The data collection process consists of direct data entry at the study clinical centers into the 
IBM Clinical Development study database.  Data entry should be completed according to the 
instructions provided and project specific training.  The investigator is responsible for 
maintaining accurate, complete and up-to-date records, and for ensuring the completion of the 
data collection forms for each research participant.  
'DWD$FTXLVLWLRQDQG(QWU\
Data entry into eCRFs shall be performed by authorized individuals.  Selected eCRFs may also 
require the investigator’s written signature or electronic signature, as appropriate.  Electronic 
CRFs will be monitored for completeness, accuracy, and attention to detail during the study.  
'DWD(GLWLQJ
Completed data will be entered into the IBM Clinical Development system.  If incomplete or 
inaccurate data are found, a data clarification request will be generated and distributed to 
clinical centers for a response.  Clinical centers will resolve data inconsistencies and errors and 
enter all corrections and changes into data management system and will adhere to the data 
entry and query response timelines specified by the CleanUP-IPF PLG. 
'DWD6HFXULW\
Access to databases will be controlled centrally by the DCRI through user passwords linked to 
appropriate privileges.  This protects the data from unauthorized changes and inadvertent loss 


CleanUP-IPF Protocol Amendment 2 
 
Version Date: March 2, 2018 
26 | P a g e  
 
or damage.  Database and web servers will be secured by a firewall and through controlled 
physical access.  Database back up will be performed daily using standard procedures in place 
at the DCRI.  All disk drives that provide network services, and all user computers, will be 
protected using virus-scanning software.  
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A DSMB will be appointed by the NHLBI for this trial.  It will include individuals with pertinent 
expertise in IPF and clinical trials.  The DSMB will advise the Steering Committee regarding the 
continuing safety of current participants and those yet to be recruited.  It is anticipated that the 
DSMB will meet approximately 2 times per year to review safety and overall study progress. 
6WDWLVWLFDO0RQLWRULQJ3ODQ
Safety and efficacy data will be periodically assessed by the DSMB.  Safety and efficacy data will 
be periodically assessed by the DSMB.  For ethical reasons, an interim examination of key safety 
and endpoint data will be performed at regular intervals during the course of the trial.  The 
interim monitoring will also involve a review of the control arm event rates, patient 
recruitment, compliance with the study protocol, status of data collection, and other factors 
that reflect the overall progress and integrity of the study.  An NHLBI-appointed DSMB will 
carefully and confidentially review the results of the interim analyses and status reports.  If 
protocol modifications are warranted, close consultation among the DSMB, the NHLBI staff, and 
the study leadership will be required.  A separate DSMB charter outlining the operating 
guidelines for the committee and the protocol for evaluation of data will be created prior to 
study enrollment and agreed upon during the initial meeting of the DSMB.  
It is anticipated that the DSMB will meet at 6-month intervals to review the accumulating data. 
The DCRI will create regular reports to track patient enrollment reports, rates of compliance 
with the assigned testing strategy, and frequency of protocol violations.  Prior to each meeting, 
the data coordinating center will conduct any requested statistical analyses and prepare a 
summary report along with the following information: patient enrollment reports, rates of 
compliance with the assigned testing strategy, frequency of protocol violations, and description 
of SAEs (statistical comparisons of the randomized arms with respect to these SAEs will use chi-
square or other appropriate 2-sample methods).  
There will be one planned interim review for efficacy.  The efficacy review will focus on the 
composite endpoint of respiratory hospitalization or all-cause death and should occur once 300 
enrolled subjects have been followed for 12 months.  The Lan-DeMets alpha spending function 
with O'Brien-Fleming type boundaries will be used for the interim analysis. 


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27 | P a g e  
 
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Clinical sites participating in this study will be trained in the following aspects of the study 
including a protocol overview covering: 
x Good Clinical Practice (GCP) overview 
x Inclusion / exclusions 
x Protocol activities 
x Telephone contact methodology 
x SAE reporting expectations 
x Blood draw requirements 
x Sample processing, storage, and shipping 
x Electronic data capture 
x Accessing the EDC 
x Data entry requirements and scheduling expectations 
x Query resolution procedures 
x Uploading documentation for outcome event classification 
 
 


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28 | P a g e  
 
 
14. REFERENCES 
1. 
Han MK, Zhou Y, Murray S, et al. Lung microbiome and disease progression in idiopathic 
pulmonary fibrosis: an analysis of the COMET study. Lancet Respir Med 2014;2:548-56. 
2. 
Molyneaux PL, Cox MJ, Willis-Owen SA, et al. The role of bacteria in the pathogenesis and 
progression of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2014;190:906-13. 
3. 
Noth I, Zhang Y, Ma SF, et al. Genetic variants associated with idiopathic pulmonary fibrosis 
susceptibility and mortality: a genome-wide association study. Lancet Respir Med 2013;1:309-17. 
4. 
Moore BB, Fry C, Zhou Y, et al. Inflammatory leukocyte phenotypes correlate with disease 
progression in idiopathic pulmonary fibrosis. Front Med 2014;1. 
5. 
Shulgina L, Cahn AP, Chilvers ER, et al. Treating idiopathic pulmonary fibrosis with the addition 
of co-trimoxazole: a randomised controlled trial. Thorax 2013;68:155-62. 
6. 
Bhattacharyya P, Nag S, Bardhan S, et al. The role of long-term doxycycline in patients of 
idiopathic pulmonaryfibrosis: The results of an open prospective trial. Lung India 2009;26:81-5. 
7. 
Mishra A, Bhattacharya P, Paul S, Paul R, Swarnakar S. An alternative therapy for idiopathic 
pulmonary fibrosis by doxycycline through matrix metalloproteinase inhibition. Lung India 2011;28:174-
9. 
8. 
Fralick M, Macdonald EM, Gomes T, et al. Co-trimoxazole and sudden death in patients receiving 
inhibitors of renin-angiotensin system: population based study. BMJ 2014;349:g6196. 
9. 
Scheper H, Lijfering WM. Link between co-trimoxazole and sudden death in patients receiving 
inhibitors of renin-angiotensin system could be due to confounding. BMJ 2014;349:g6899. 
10. 
Perazella MA. Trimethoprim-induced hyperkalaemia: clinical data, mechanism, prevention and 
management. Drug Saf 2000;22:227-36. 
 
 


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15. APPENDIX A – Schedule of Assessments  
VISIT 
V1 
V1A2 
V2 
V2A3 
V2B3 
V3 
V4 
V5 
V6 
V7 
V8 
 
Screening/ 
Enrollment 
1 Week (+/- 
3 days) 
1 Month 
(+/- 7 days) 
3 Month 
(+/-7 days) 
6 Month (+/-
4 weeks) 
6 Month 
(+/- 4 
weeks) 
12 Month 
(+/- 4 
weeks) 
18 Month 
(+/- 4 
weeks) 
24 Month 
(+/- 4 
weeks) 
30 Month 
(+/- 4 
weeks) 
36 Month 
(+/- 4 
weeks) 
Task 
 
 
Phone Call 
 
 
Phone Call 
 
Phone Call 
 
Phone Call 
Phone Call 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
IPF Diagnosis 
Checklist 
X 
 
 
 
 
 
 
 
 
 
 
Spirometry 
(if not available 
in last 90 days) 
X 
  
 
 
 
 
 
X 
 
X 
 
 
DLCO  
(if not available 
in last 90 days) 
X  
 
 
 
 
 
 
X 
 
X 
 
 
Concomitant 
Medication 
Review 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant 
Medication 
Update 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 


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30 | P a g e  
 
 
1. Patient reported questionnaires include: UCSD-SoBQ, Fatigue Severity Scale, Leicester Cough, EQ-5D, SF-12, ICECAP-O  
2. For subjects receiving co-trimoxazole, a blood sample to document electrolytes will be drawn at week 1, Visit 1A. 
3. For subjects assigned to the antimicrobial therapy arm, a blood sample to document complete blood count, liver function tests, and chemistry panel, 
will be drawn at 3 months, 6 months, 12 months, and 24 months to be obtained at Visit 2A, Visit 2B, Visit 4, and Visit 6, respectively. 
Complete Blood 
Count (CBC)  
X  
(if not 
available in 
last 90 days) 
 
 
X3 
X3 
 
X3 
 
X3 
 
 
Chemistry panel 
w/liver function 
tests 
X  
(if not 
available in 
last 90 days) 
 
 
X3 
X3 
 
X3 
 
X3 
 
 
Electrolytes 
only 
 
X2 
 
 
 
 
 
 
 
 
 
Genotype 
X 
 
 
 
 
 
 
 
 
 
 
Gene 
expression 
X 
 
 
 
 
 
X 
 
X 
 
 
Buccal Swab, 
Fecal samples  
X 
 
 
 
 
 
X 
 
X 
 
 
Patient 
Reported 
Outcomes 
Questionnaires1 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
Clinical Events  
Mortality     
Hospitalization  
Resp. infection      
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


CleanUP-IPF Protocol Amendment 2 
 
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16. APPENDIX B – CleanUP-IPF Laboratory Schedule 
 
Antimicrobial Arm (Co-trimoxazole and Doxycycline Arms) 
  
CBC 
Electrolytes 
Chemistry plus liver 
function tests 
Gene 
expression 
Genotype 
Buccal 
sample 
Fecal 
sample 
Approx. total Blood 
Amount 
Baseline 
x 
 
x 
x 
x 
x 
x 
28.5 ml 
Week 1 
  
x* 
 
  
  
  
  
6 ml 
3 month 
x 
 
x 
  
  
  
  
8.5 ml 
6 month 
x 
 
x 
  
  
  
  
8.5 ml 
12 month 
x 
 
x 
x 
  
x 
x 
18.5 ml 
24 month 
x 
 
x 
x 
  
x 
 x 
18.5 ml 
*only in co-trimoxazole treated patients 
88.5 ml 
 
Standard of Care Arm 
  
CBC 
Chemistry plus liver 
function tests 
Gene 
expression 
Genotype 
Buccal 
sample 
Fecal 
sample 
Approx. total Blood 
Amount  
Baseline 
x 
x 
x 
x 
x 
x 
28.5 ml 
12 month 
  
  
x 
  
x 
x 
10 ml 
24 month 
  
  
x 
  
 x 
 x  
10 ml 
48.5 ml 
Safety Labs  
Complete Blood Count (CBC): WBC, RBC, hemoglobin, hematocrit, mean corpuscular volume (MCV), Platelets, mean platelet volume (MPV) 
Electrolytes: Sodium, Potassium, Chloride, Carbon Dioxide (CO2) 
Chemistry: Sodium, Potassium, Chloride, Carbon Dioxide (CO2), Urea Nitrogen (BUN) and Creatinine 
Liver Function Studies: Alkaline Phosphatase, Total Bilirubin, Direct bilirubin, Aspartate Aminotransferase (AST), and Alanine Aminotransferase (ALT) 
 
 

SAP_000.pdf: 
Statistical Analysis Plan (CleanUP-IPF) 
Page 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan 
 
 
 
Date: 28NOV2016 
 
 
 ClinicalTrials.gov ID: NCT02759120 


Statistical Analysis Plan (CleanUP-IPF) 
Page 2 
 
 
 
 
Table of Contents 
I. 
OVERVIEW ........................................................................................................................................................ 3 
II. 
STUDY DESIGN ................................................................................................................................................. 3 
RANDOMIZATION ....................................................................................................................................................... 3 
DATA SOURCES .......................................................................................................................................................... 3 
III. 
ANALYSIS POPULATION AND MISSING DATA ................................................................................... 3 
IV. 
GENERAL METHODOLOGY ..................................................................................................................... 4 
V. 
PRIMARY ENDPOINT ..................................................................................................................................... 4 
VI. 
SECONDARY ENDPOINTS ......................................................................................................................... 5 
VII. 
ENDPOINT DESCRIPTIONS ....................................................................................................................... 5 
PRIMARY ENDPOINT ................................................................................................................................................... 5 
VIII. 
SECONDARY ENDPOINT DESCRIPTIONS ............................................................................................. 6 
SECONDARY ENDPOINT #1 ......................................................................................................................................... 6 
SECONDARY ENDPOINT #2 ......................................................................................................................................... 7 
SECONDARY ENDPOINT #3 ......................................................................................................................................... 8 
SECONDARY ENDPOINT #4 ......................................................................................................................................... 8 
SECONDARY ENDPOINT #5 ......................................................................................................................................... 9 
SECONDARY ENDPOINT #6 ....................................................................................................................................... 10 
SECONDARY ENDPOINT #7 ....................................................................................................................................... 11 
SECONDARY ENDPOINT #8 ....................................................................................................................................... 11 
SECONDARY ENDPOINT #9 ....................................................................................................................................... 12 
SECONDARY ENDPOINT #10 ..................................................................................................................................... 13 
SECONDARY ENDPOINT #11 ..................................................................................................................................... 13 
SECONDARY ENDPOINT #12 ..................................................................................................................................... 14 
SECONDARY ENDPOINT #13 ..................................................................................................................................... 15 
IX. 
SAFETY ENDPOINTS ................................................................................................................................ 16 
SERIOUS ADVERSE EVENTS ....................................................................................................................................... 16 
CONCOMITANT MEDICATION ................................................................................................................................... 16 
X. 
TRIAL CONDUCT ........................................................................................................................................... 17 
COMPLIANCE ............................................................................................................................................................ 17 
THERAPY CROSSOVER .............................................................................................................................................. 17 
XI. 
EXPLORATORY ANALYSES ................................................................................................................... 17 
SIX MINUTE WALK TEST ............................................................................................................................................ 17 
XII. 
INTERIM ANALYSES ................................................................................................................................ 18 
XIII. 
SUBGROUP OF INTEREST ....................................................................................................................... 18 
XIV. 
REFERENCES ............................................................................................................................................. 19 
XV. 
TABLES/LISTING/GRAPH MOCK-UPS ................................................................................................. 19 


Statistical Analysis Plan (CleanUP-IPF) 
Page 3 
 
 
I. 
Overview 
 
 
CleanUP-IPF is a randomized, unblinded, multi-center clinical trial of patients with a 
diagnosis of idiopathic pulmonary fibrosis (IPF). A total of approximately 500 patients 
will be enrolled in the trial. Eligible patients will be randomized to the following 
treatment strategies: 
 Standard care 
 Standard care + oral antimicrobial therapy 
 
Patients randomized to receive antimicrobial therapy will be given co-trimoxazole 
unless they have an allergy, contraindication to co-trimoxazole, renal insufficiency 
(GFR < 30 ml), are hyperkalemic (potassium > 5 mEq/L), or are concomitantly taking 
an angiotensin converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), 
or potassium sparing diuretic in which case they will receive doxycycline. 
 
II. 
Study Design 
 
 
 
Randomization 
 
Eligible patients will be randomized 1:1 to either receive or not receive a prescription 
drug voucher for oral antimicrobial therapy in the form of one double strength 160mg 
trimethoprim/800mg sulfamethoxazole (double strength co-trimoxazole) twice daily 
plus folic acid 5 mg daily OR doxycycline 100mg once daily if weight < 50 kilograms or 
100mg twice daily if weight > 50 kilograms. 
 
Data Sources 
 
A database of case report form and biomarker core lab data will be created in 
eClincalOS (eCOS), and the data then transferred to SAS for analysis. The randomized 
treatment assignment will be provided through data collected by the eCOS system. 
 
III. 
Analysis Population and Missing Data 
 
 
 
The primary analysis will be based on intention to treat. 
All randomized patients will 
be included in the analysis population for assessing the primary and secondary 
endpoints. Extensive efforts being made in connection with the clinical sites to ensure 
data quality and completeness, it is expected that exclusion of patients for any 
endpoint analysis will be minimal. 
 
For the primary endpoint patients without any observed non-elective, respiratory 
hospitalization or all-cause mortality will be censored at their last visit or lung 
transplantation. For the adjustment variables in the primary model the imputation 
method will be dictated by the amount of missingness. If all the adjustment variables 


Statistical Analysis Plan (CleanUP-IPF) 
Page 4 
 
 
 
 
have a missing data rate of 2% or below (approximately 10 or less out of 500) then a 
simple imputation mehod will implemented. If any one of the adjustment variables has 
a missing data rate over 2% (approximately more than 10 out of 500) then multiple 
imputation mehod will implemented. For the simple approach categorical adjustment 
variables will be imputed to the mode and continuous adjustment variables              
will be imputed to the median value. For the multiple imputation the full conditional 
specification method (FCS) method wil be used and assume an arbitrary missing     
data pattern [Berglund and Heeringa 2014]. The multiple imputation scenario (20 
planned iterations) will be constructed which includes the treatment group indicator 
variable and the adjustment variables planned for the primary model. 
 
IV. 
General Methodology 
 
 
 
Definition of Statistical Significance: The statistical plan will test non-directional 
hypotheses, i.e., all tests will be 2-sided. The level of significance for all efficacy and 
safety analyses will be 0.05. 
Statistical Tests: For situations were one observation per patient is observed, (e.g. 
safety comparisons at individual time points), a general analysis convention will be 
used unless otherwise specified. For continuous and ordinal variables, treatment 
group differences will be tested using the Wilcoxon rank-sum test for two groups and 
Kruskal-Wallis one-way analysis of variance for comparisons of more than two groups. 
For censored data, like time to event, treatment group differences will be tested using 
the log rank test. For discrete variables, treatment group differences will be tested 
using the chi-square test. In the situation of low cell counts the treatment group 
differences will be tested using Fisher’s exact method. 
Descriptive Statistics: For continuous and ordinal variables the number of 
observations, number of missing values, mean, standard deviation, median, twenty- 
fifth percentile, and seventy-fifth percentile will be given. For binary (e.g. yes/no), 
categorical, and/or ordinal variables a simple count and percent will be provided. 
Other statistics may be considered if necessary. 
Descriptive Plots: Descriptive plots may replace or produced in addition to descriptive 
statistics if deemed appropriate. If deemed necessary plots of descriptive statistics 
such as spaghetti, mosaic, box, cumulative distribution, and loess curves will be 
provided. 
Study Listings: Study data will be listed by treatment group, visit if applicable, and 
patient where appropriate. 
Software and Validation Procedures: All data presented in interim and final analyses 
will be generated and validated under the guidance of the DCRI Clinical Trials 
Statistical SOPs. 
 
V. 
Primary Endpoint 
 
 
 
The primary endpoint of this study will be the comparison of “Standard care + oral 
antimicrobial therapy” and “Standard care” for the time to first non-elective, 
respiratory hospitalization or all-cause mortality. 


Statistical Analysis Plan (CleanUP-IPF) 
Page 5 
 
 
 
 
VI. 
Secondary Endpoints 
 
 
 
Secondary goals of this study are to assess differences between treatment groups for 
the following: 
1. Time to death from any cause 
2. Time to first non-elective respiratory hospitalization 
3. Time to first non-elective all-cause hospitalization 
4. Total number of non-elective respiratory hospitalizations 
5. Total number of non-elective all-cause hospitalizations 
6. Change in FVC from randomization to 12 months 
7. Change in DLCO from randomization to 12 months 
8. Total number of respiratory infections 
9. Change in UCSD-Shortness of Breath Questionnaire from randomization to 12 months 
10. Change in Fatigue Severity Scale score from randomization to 12 months 
11. Change in Leicester Cough Questionnaire score from randomization to 12 months 
12. Change in EQ-5D score and SF-12 score from randomization to 12 months 
13. Change in ICEpop CAPability measure for Older people (ICECAP-O) score from 
randomization to 12 months 
 
VII. Endpoint Descriptions  
 
 
 
Primary Endpoint 
 
Endpoint Description: Time to first non-elective, respiratory hospitalization or all- 
cause mortality. 
 
Response Variable Definition: Time to first respiratory hospitalization or all-cause 
mortality (primary endpoint) will be defined as the time to first observed event 
respiratory hospitalization or all-cause mortality. All patients will have some 
information regarding mortality and last visit of follow-up. Patients without any 
observed respiratory hospitalization or death event at the time of analysis will be 
censored at their last visit or lung transplantation. The respiratory hospitalizations 
will be reviewed and adjudicated by a clinical events committee (CEC). 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. Note that the baseline DLCO and baseline 
FVC will be added to regression models using the % predicted versions for all 
endpoints. 
 
Handling of Dropouts and Missing Data: 
The censoring mechanism is assumed to be non-informative. Supportive analyses will 
be performed to assess the impact of a potential informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection of 
restricted cubic spline plots. If a departure is observed then a suitable transformation 


Statistical Analysis Plan (CleanUP-IPF) 
Page 6 
 
 
 
 
will be explored. In addition the proportional hazard assumptions will be explored by 
inspection of Martingale residuals plots for all model covariates. If a major departure 
is observed then the variable will added to the model as a stratification variable. 
 
Statistical Tests: The Cox proportional hazards regression model will be used to 
estimate outcome differences between the two treatment arms: “Standard care + oral 
antimicrobial therapy” and “Standard care”. The outcome is the time to first non- 
elective, respiratory hospitalization or all-cause mortality with model terms for 
treatment arm, baseline measurement, and covariates. Hazard ratios and 95% 
confidence intervals will summarize the differences between treatment arms. 
 
Interpretation of Results: For Cox regression models a hazard ratio below 1.00 will 
indicate a reduction in events for “Standard care + oral antimicrobial therapy” arm. 
A 
hazard ratio above 1.00 will indicate increase in events for “Standard care + oral 
antimicrobial therapy” arm. 
 
Alternative Analysis: To explore therapy crossovers an alternative analysis scenario 
with be constructed. Therapy crossover will be defined as patients assigned “Standard 
care” and receiving after randomization “oral antimicrobial therapy”. The previous 
presented primary analysis model will be used and moditified. Specifucally the 
response variable definition for the “Standard care” assigned patients (with crossover) 
will be changed such that the time to event and event indicator variables will be 
censored at the time of therapy crossover. The same statistical model and 
interpretation will be used as the primary analysis. 
 
VIII. Secondary Endpoint Descriptions  
 
 
 
Secondary Endpoint #1 
 
Endpoint Description: Time to death from any cause. 
 
Response Variable Definition: Time to death will be defined as the time to all-cause 
mortality. All patients will have some information regarding mortality and last visit of 
follow-up. Patients without any observed death at the time of analysis will be censored 
at their last visit or lung transplantation. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: The censoring mechanism is assumed to be 
non-informative. Supportive analyses will be performed to assess the impact of a 
potential informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection of 
restricted cubic spline plots. If a departure is observed then a suitable transformation 
will be explored. In addition the proportional hazard assumptions will be explored by 


Statistical Analysis Plan (CleanUP-IPF) 
Page 7 
 
 
 
 
inspection of Martingale residuals plots. If a major departure is observed then the 
variable will added to the model as a stratification variable. 
 
Statistical Tests: The Cox proportional hazards regression model will be used to 
estimate outcome differences between the two treatment arms: “Standard care + oral 
antimicrobial therapy” and “Standard care”. The outcome is the time to death from any 
cause with model terms for treatment arm, baseline measurement, and covariates. 
Hazard ratios and 95% confidence intervals will summarize the differences between 
treatment arms. 
 
Interpretation of Results: For Cox regression models a hazard ratio below 1 will 
indicate a reduction in events for “Standard care + oral antimicrobial therapy” arm. 
A 
hazard ratio above 1.00 will indicate increase in events for “Standard care + oral 
antimicrobial therapy” arm. 
 
Secondary Endpoint #2 
 
Endpoint Description: Time to first non-elective respiratory hospitalization 
 
Response Variable Definition: Time to first non-elective respiratory hospitalization will 
be defined as the time to first non-elective respiratory hospitalization. The 
hospitalizations will be reviewed and adjudicated by a CEC as non-elective respiratory 
hospitalizations. All patients will have some information regarding mortality and last 
visit of follow-up. Patients without any observed event at the time of analysis will be 
censored at their last visit, death, or lung transplantation. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: The censoring mechanism is assumed to be 
non-informative. Supportive analyses will be performed to assess the impact of a 
potential informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection of 
restricted cubic spline plots. If a departure is observed then a suitable transformation 
will be explored. In addition the proportional hazard assumptions will be explored by 
inspection of Martingale residuals plots. If a major departure is observed then the 
variable will added to the model as a stratification variable. 
 
Statistical Tests: The Cox proportional hazards regression model will be used to 
estimate outcome differences between the two treatment arms: “Standard care + oral 
antimicrobial therapy” and “Standard care”. The outcome is the time to first non- 
elective respiratory hospitalization with model terms for treatment arm, baseline 
measurement, and covariates. Hazard ratios and 95% confidence intervals will 
summarize the differences between treatment arms. 
 
Interpretation of Results: For Cox regression models a hazard ratio below 1.00 will 
indicate a reduction in events for “Standard care + oral antimicrobial therapy” arm. 
A 


Statistical Analysis Plan (CleanUP-IPF) 
Page 8 
 
 
 
 
hazard ratio above 1.00 will indicate increase in events for “Standard care + oral 
antimicrobial therapy” arm. 
 
Secondary Endpoint #3 
 
Endpoint Description: Time to first non-elective all-cause hospitalization 
 
Response Variable Definition: Time to first non-elective hospitalization will be defined 
as the time to first non-elective hospitalization. The hospitalizations will be reviewed 
and adjudicated by a CEC as non-elective all-cause hospitalizations. All patients will 
have some information regarding mortality and last visit of follow-up. Patients without 
any observed event at the time of analysis will be censored at their last visit, death, or 
lung transplantation. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: The censoring mechanism is assumed to be 
non-informative. Supportive analyses will be performed to assess the impact of a 
potential informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection of 
restricted cubic spline plots. If a departure is observed then a suitable transformation 
will be explored. In addition the proportional hazard assumptions will be explored by 
inspection of Martingale residuals plots. If a major departure is observed then the 
variable will added to the model as a stratification variable. 
 
Statistical Tests: The Cox proportional hazards regression model will be used to 
estimate outcome differences between the two treatment arms: “Standard care + oral 
antimicrobial therapy” and “Standard care”. The outcome is the time to first non- 
elective all-cause hospitalization with model terms for treatment arm, baseline 
measurement, and covariates. Hazard ratios and 95% confidence intervals will 
summarize the differences between treatment arms. 
 
Interpretation of Results: For Cox regression models a hazard ratio below 1.00 will 
indicate a reduction in events for “Standard care + oral antimicrobial therapy” arm. 
A 
hazard ratio above 1.00 will indicate increase in events for “Standard care + oral 
antimicrobial therapy” arm. 
 
 
Secondary Endpoint #4 
 
Endpoint Description: Total number of non-elective respiratory hospitalizations 
 
Response Variable Definition: The hospitalizations will be reviewed and adjudicated by 
a clinical events committee (CEC) as non-elective respiratory hospitalizations. 


Statistical Analysis Plan (CleanUP-IPF) 
Page 9 
 
 
 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, and choice of antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: All patients will have some information 
regarding mortality and last visit of follow-up. Lung transplantation will be additional 
censoring variable in this analyses. The censoring mechanism is assumed to be non- 
informative. Supportive analyses will be performed to assess the impact of a potential 
informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection 
scatter plots with LOESS curves. If a departure is observed then a suitable 
transformation will be explored. The validity of this model in terms of meeting 
modeling assumptions will be assessed via standard modeling diagnostics and 
goodness-of-fit measures. 
 
Statistical Tests: A Poisson regression model will be used to estimate outcome ratio 
between the two treatment arms: “Standard care + oral antimicrobial therapy” and 
“Standard care”. The outcome is the total number of non-elective respiratory 
hospitalizations with model terms for treatment arm, baseline measurement, and 
covariates. Rates and 95% confidence intervals will summarize the differences 
between treatment arms. 
 
Interpretation of Results: For poisson regression models a ratio below 1.00 will indicate 
a reduction in events for “Standard care + oral antimicrobial therapy” arm. 
A 
hazard ratio above 1.00 will indicate increase in events for “Standard care + oral 
antimicrobial therapy” arm. 
 
 
Secondary Endpoint #5 
 
Endpoint Description: Total number of non-elective all-cause hospitalizations 
 
Response Variable Definition: The hospitalizations will be reviewed and adjudicated by 
a CEC as non-elective all-cause hospitalizations. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: All patients will have some information 
regarding mortality and last visit of follow-up. Lung transplantation will be additional 
censoring variable in this analyses. The censoring mechanism is assumed to be non- 
informative. Supportive analyses will be performed to assess the impact of a potential 
informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection 
scatter plots with LOESS curves. If a departure is observed then a suitable 
transformation will be explored. The validity of this model in terms of meeting 


Statistical Analysis Plan (CleanUP-IPF) 
Page 10 
 
 
 
 
modeling assumptions will be assessed via standard modeling diagnostics and 
goodness-of-fit measures. 
 
Statistical Tests: The Poisson regression model will be used to estimate outcome ratio 
between the two treatment arms: “Standard care + oral antimicrobial therapy” and 
“Standard care”. The outcome is the total number of non-elective all-cause 
hospitalizations with model terms for treatment arm, baseline measurement, and 
covariates. Rates and 95% confidence intervals will summarize the differences 
between treatment arms. 
 
Interpretation of Results: For Poisson regression models a ratio below 1.00 will indicate 
a reduction in events for “Standard care + oral antimicrobial therapy” arm. 
A 
ratio above 1.00 will indicate increase in events for “Standard care + oral antimicrobial 
therapy” arm. 
 
Secondary Endpoint #6 
 
Endpoint Description: Change in FVC (L) from randomization to 12 months 
 
Response Variable Definition: The FVC data will be collected at baseline and 12 
months. The change from baseline will be calculated for the 12 month values by 
subtracting the baseline result. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: All patients will have some information 
regarding mortality and last visit of follow-up. Lung transplantation will be additional 
censoring variable in this analyses. The censoring mechanism is assumed to be non- 
informative. Supportive analyses will be performed to assess the impact of a potential 
informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection 
scatter plots with LOESS curves. If a departure is observed then a suitable 
transformation will be explored. The validity of this model in terms of meeting 
modeling assumptions will be assessed via standard modeling diagnostics and 
goodness-of-fit measures. 
 
Statistical Tests: The linear regression model will be used to estimate outcome 
differences between the two treatment arms: “Standard care + oral antimicrobial 
therapy” and “Standard care”. The outcome is the measured result at 12 months with 
model terms for treatment arm, baseline measurement, and covariates. Descriptive 
statistics will be calculated at baseline and 12 months by treatment group. 
 
Interpretation of Results: For linear models a difference below 0.00 will indicate a 
reduction in score for “Standard care + oral antimicrobial therapy” arm. 
A difference 
above 0.00 will indicate increase in score for “Standard care + oral antimicrobial 
therapy” arm. 


Statistical Analysis Plan (CleanUP-IPF) 
Page 11 
 
 
 
 
 
Secondary Endpoint #7 
 
Endpoint Description: Change in DLCO from randomization to 12 months 
 
Response Variable Definition: The DLCO data will be collected at baseline and 12 
months. The change from baseline will be calculated for the 12 month values by 
subtracting the baseline result. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: 
All patients will have some information regarding mortality and last visit of follow-up. 
Lung transplantation will be additional censoring variable in this analyses. The 
censoring mechanism is assumed to be non-informative. Supportive analyses will be 
performed to assess the impact of a potential informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection 
scatter plots with LOESS curves. If a departure is observed then a suitable 
transformation will be explored. The validity of this model in terms of meeting 
modeling assumptions will be assessed via standard modeling diagnostics and 
goodness-of-fit measures. 
 
Statistical Tests: The linear regression model will be used to estimate outcome 
differences between the two treatment arms: “Standard care + oral antimicrobial 
therapy” and “Standard care”. The outcome is the measured result at 12 months with 
model terms for treatment arm, baseline measurement, and covariates. Descriptive 
statistics will be calculated at baseline and 12 months by treatment group. 
 
Interpretation of Results: For linear models a difference below 0.00 will indicate a 
reduction in score for “Standard care + oral antimicrobial therapy” arm. 
A difference 
above 0.00 will indicate increase in score for “Standard care + oral antimicrobial 
therapy” arm. 
 
 
Secondary Endpoint #8 
 
Endpoint Description: Total number of respiratory infections 
 
Response Variable Definition: all lower respiratory tract infection(s) treated with 
antibiotic treatment will be collected in follow-up. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 


Statistical Analysis Plan (CleanUP-IPF) 
Page 12 
 
 
 
 
Handling of Dropouts and Missing Data: The censoring mechanism is assumed to be 
non-informative. Supportive analyses will be performed to assess the impact of a 
potential informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection 
scatter plots with LOESS curves. If a departure is observed then a suitable 
transformation will be explored. The validity of this model in terms of meeting 
modeling assumptions will be assessed via standard modeling diagnostics and 
goodness-of-fit measures. 
 
Statistical Tests: A Poisson regression model will be used to estimate outcome ratio 
between the two treatment arms: “Standard care + oral antimicrobial therapy” and 
“Standard care”. The outcome is the total number of respiratory infections with model 
terms for treatment arm, baseline measurement, and covariates. Rates and 95% 
confidence intervals will summarize the differences between treatment arms. 
 
Interpretation of Results: For Poisson regression models a ratio below 1.00 will indicate 
a reduction in events for “Standard care + oral antimicrobial therapy” arm. 
A 
ratio above 1.00 will indicate increase in events for “Standard care + oral antimicrobial 
therapy” arm. 
 
 
Secondary Endpoint #9 
 
Endpoint Description: Change in UCSD-Shortness of Breath Questionnaire from 
randomization to 12 months 
 
Response Variable Definition: The UCSD-Shortness of Breath Questionnaire data will 
be collected at baseline and 12 months. For the collect questionnaire data the UCSD- 
Shortness of Breath score will be calculated. The change from baseline will be 
calculated for the 12 month values by subtracting the baseline result. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: 
The censoring mechanism is assumed to be non-informative. Supportive analyses will 
be performed to assess the impact of a potential informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection 
scatter plots with LOESS curves. If a departure is observed then a suitable 
transformation will be explored. The validity of this model in terms of meeting 
modeling assumptions will be assessed via standard modeling diagnostics and 
goodness-of-fit measures. 
 
Statistical Tests: The linear regression model will be used to estimate outcome 
differences between the two treatment arms: “Standard care + oral antimicrobial 


Statistical Analysis Plan (CleanUP-IPF) 
Page 13 
 
 
 
 
therapy” and “Standard care”. The outcome is the measured result at 12 months with 
model terms for treatment arm, baseline measurement, and covariates. Descriptive 
statistics will be calculated at baseline and 12 months by treatment group. 
 
Interpretation of Results: For linear models a difference below 0.00 will indicate a 
reduction in score for “Standard care + oral antimicrobial therapy” arm. 
A difference 
above 0.00 will indicate increase in score for “Standard care + oral antimicrobial 
therapy” arm. 
 
Secondary Endpoint #10 
 
Endpoint Description: Change in Fatigue Severity Scale score from randomization to 
12 months 
 
Response Variable Definition: The Fatigue Severity Scale Questionnaire data will be 
collected at baseline and 12 months. For the collect questionnaire data the Fatigue 
Severity Scale score will be calculated. The change from baseline will be calculated for 
the 12 month values by subtracting the baseline result. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: The censoring mechanism is assumed to be 
non-informative. Supportive analyses will be performed to assess the impact of a 
potential informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection 
scatter plots with LOESS curves. If a departure is observed then a suitable 
transformation will be explored. The validity of this model in terms of meeting 
modeling assumptions will be assessed via standard modeling diagnostics and 
goodness-of-fit measures. 
 
Statistical Tests: The linear regression model will be used to estimate outcome 
differences between the two treatment arms: “Standard care + oral antimicrobial 
therapy” and “Standard care”. The outcome is the measured result at 12 months with 
model terms for treatment arm, baseline measurement, and covariates. Descriptive 
statistics will be calculated at baseline and 12 months by treatment group. 
 
Interpretation of Results: For linear models a difference below 0.00 will indicate a 
reduction in score for “Standard care + oral antimicrobial therapy” arm. 
A difference 
above 0.00 will indicate increase in score for “Standard care + oral antimicrobial 
therapy” arm. 
 
Secondary Endpoint #11 
 
Endpoint Description: Change in Leicester Cough Questionnaire score from 
randomization to 12 months 


Statistical Analysis Plan (CleanUP-IPF) 
Page 14 
 
 
 
 
Response Variable Definition: The Leicester Cough Questionnaire data will be collected 
at baseline and 12 months. For the collect questionnaire data the Leicester Cough 
Questionnaire score will be calculated. The change from baseline will be calculated for 
the 12 month values by subtracting the baseline result. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: 
The censoring mechanism is assumed to be non-informative. Supportive analyses will 
be performed to assess the impact of a potential informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection 
scatter plots with LOESS curves. If a departure is observed then a suitable 
transformation will be explored. The validity of this model in terms of meeting 
modeling assumptions will be assessed via standard modeling diagnostics and 
goodness-of-fit measures. 
 
Statistical Tests: The linear regression model will be used to estimate outcome 
differences between the two treatment arms: “Standard care + oral antimicrobial 
therapy” and “Standard care”. The outcome is the measured result at 12 months with 
model terms for treatment arm, baseline measurement, and covariates. Descriptive 
statistics will be calculated at baseline and 12 months by treatment group. 
 
Interpretation of Results: For linear models a difference below 0.00 will indicate a 
reduction in score for “Standard care + oral antimicrobial therapy” arm. 
A difference 
above 0.00 will indicate increase in score for “Standard care + oral antimicrobial 
therapy” arm. 
 
Secondary Endpoint #12 
 
Endpoint Description: Change in EQ-5D score and SF-12 score from randomization to 
12 months 
 
Response Variable Definition: The SF-12 questionnaire data will be collected at 
baseline and 12 months. The EQ-5D questionnaire data will be collected at baseline 
and 12 months. For the collect questionnaire data the EQ-5D score and SF-12 score 
will be calculated. The change from baseline will be calculated for the 12 month 
values by subtracting the baseline result. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: 
The censoring mechanism is assumed to be non-informative. Supportive analyses will 
be performed to assess the impact of a potential informative censoring. 


Statistical Analysis Plan (CleanUP-IPF) 
Page 15 
 
 
 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection 
scatter plots with LOESS curves. If a departure is observed then a suitable 
transformation will be explored. The validity of this model in terms of meeting 
modeling assumptions will be assessed via standard modeling diagnostics and 
goodness-of-fit measures. 
 
Statistical Tests: The linear regression model will be used to estimate outcome 
differences between the two treatment arms: “Standard care + oral antimicrobial 
therapy” and “Standard care”. The outcome is the measured result at 12 months with 
model terms for treatment arm, baseline measurement, and covariates. Descriptive 
statistics will be calculated at baseline and 12 months by treatment group. 
 
Interpretation of Results: For linear models a difference below 0.00 will indicate a 
reduction in score for “Standard care + oral antimicrobial therapy” arm. 
A difference 
above 0.00 will indicate increase in score for “Standard care + oral antimicrobial 
therapy” arm. 
 
Secondary Endpoint #13 
 
Endpoint Description: Change in ICEpop CAPability measure for Older people 
(ICECAP-O) score from randomization to 12 months 
 
Response Variable Definition: The ICECAP-O questionnaire data will be collected at 
baseline and 12 months. For the collect questionnaire data the ICECAP-O score will 
be calculated. The change from baseline will be calculated for the 12 month values by 
subtracting the baseline result. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: The censoring mechanism is assumed to be 
non-informative. Supportive analyses will be performed to assess the impact of a 
potential informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection 
scatter plots with LOESS curves. If a departure is observed then a suitable 
transformation will be explored. The validity of this model in terms of meeting 
modeling assumptions will be assessed via standard modeling diagnostics and 
goodness-of-fit measures. 
 
Statistical Tests: The linear regression model will be used to estimate outcome 
differences between the two treatment arms: “Standard care + oral antimicrobial 
therapy” and “Standard care”. The outcome is the measured result at 12 months with 
model terms for treatment arm, baseline measurement, and covariates. Descriptive 
statistics will be calculated at baseline and 12 months by treatment group. 


Statistical Analysis Plan (CleanUP-IPF) 
Page 16 
 
 
 
 
Interpretation of Results: For linear models a difference below 0.00 will indicate a 
reduction in score for “Standard care + oral antimicrobial therapy” arm. 
A difference 
above 0.00 will indicate increase in score for “Standard care + oral antimicrobial 
therapy” arm. 
 
IX. 
Safety endpoints 
 
 
Serious adverse events 
 
Endpoint Description: Frequency and types of serious adverse events (SAEs) during 
the following-up period of the trial. 
 
Response Variable Definition: SAEs will be identified by the site PI and coded into the 
MEDRA medical dictionary. 
 
Statistical Tests: The number of patients with one or move SAEs will be tabulated along 
with the total number of distinct SAEs. Comparison of the “Standard care + oral 
antimicrobial therapy” and “Standard care” arms will be done with a chi-square test, 
i.e. the number of patient with one or more events. Other groupings of SAEs maybe 
generated as deemed necessary. 
 
Interpretation of Results: For cases where “Standard care + oral antimicrobial therapy” 
rate is less than “Standard care” rate will indicate a reduction for “Standard care + oral 
antimicrobial therapy” arm. 
For cases where “Standard care + oral antimicrobial 
therapy” rate is greater than “Standard care” rate will indicate an increase for 
“Standard care + oral antimicrobial therapy” arm. 
 
Concomitant Medication 
 
Endpoint Description: Frequency and types of concomitant medication usage during 
the following-up period of the trial. 
 
Response Variable Definition: Concomitant medication will be collected each visit and 
phone contact with the site. 
 
Statistical Tests: The number of patients with one or more given concomitant 
medication will be tabulated. Shift tables from baseline will be generate also. 
Comparison of the “Standard care + oral antimicrobial therapy” and “Standard care” 
arms will be done with a chi-square test, i.e. the number of patient with one or more 
occurrences. Other groupings of concomitant medication maybe generated as deemed 
necessary. 
 
Interpretation of Results: For cases where “Standard care + oral antimicrobial therapy” 
rate is less than “Standard care” rate will indicate a reduction for “Standard care + oral 
antimicrobial therapy” arm. 
For cases where “Standard care + oral antimicrobial 
therapy” rate is greater than “Standard care” rate will indicate an increase for 
“Standard care + oral antimicrobial therapy” arm. 


Statistical Analysis Plan (CleanUP-IPF) 
Page 17 
 
 
 
 
X. 
Trial conduct 
 
 
 
Compliance 
 
Endpoint Description: Rates of thearpy distribution and adherence within the 
assigned testing strategy: Standard care + oral antimicrobial therapy. 
 
Response Variable Definition: Data related to the distribution (payment system for 
prescriptions called TRIALCARD) of the assigned therapy will be collected during 
patient follow-up. Patient response to thearpy adherence in weeks prior to contact will 
be collect at 6 months intervals 
 
Statistical Tests: No statistical tests are planned. The rates of thearpy distribution 
and adherence are to be estimated at 6 and 12 months for the Standard care + oral 
antimicrobial therapy assigned patients. 
 
Therapy crossover 
 
Endpoint Description: Rates of oral antimicrobial therapy crossover for the “Standard 
care” assigned patients. 
 
Response Variable Definition: Time to first crossover will be defined as the time to first 
oral antimicrobial therapy usage in the patients randomized to “Standard care” 
 
Statistical Tests: No statistical tests are planned. Kaplan-meier event rates will be 
calculated at representative intervals for ther standard care therapy assigned patients. 
Time to event plots will be generated also. The rates of thearpy crossover are to be 
estimated at 6 and 12 months for the standard care therapy assigned patients. 
 
XI. 
Exploratory analyses 
 
 
 
Six minute walk test 
 
Endpoint Description: Change in six minute walk test and pre/post walk Borg 
assessment from randomization to 12 months 
 
Response Variable Definition: The six minute walk test data will be collected at 
baseline and 12 months. The change from baseline will be calculated for the 12 
month values by subtracting the baseline result. 
 
Additional Covariates: Age, sex, baseline DLCO, baseline FVC, use of NAC at 
enrollment, use of standard of care medications at enrollment, and choice of 
antimicrobial agent prior to randomization. 
 
Handling of Dropouts and Missing Data: All patients will have some information 
regarding mortality and last visit of follow-up. Lung transplantation will be additional 


Statistical Analysis Plan (CleanUP-IPF) 
Page 18 
 
 
 
 
censoring variable in this analyses. The censoring mechanism is assumed to be non- 
informative. Supportive analyses will be performed to assess the impact of a potential 
informative censoring. 
 
Diagnostic tests: The additional continuous covariates to be used in the primary 
analysis model will be assessed for major departures from linearity by inspection 
scatter plots with LOESS curves. If a departure is observed then a suitable 
transformation will be explored. The validity of this model in terms of meeting 
modeling assumptions will be assessed via standard modeling diagnostics and 
goodness-of-fit measures. 
 
Statistical Tests: The linear regression model will be used to estimate outcome 
differences between the two treatment arms: “Standard care + oral antimicrobial 
therapy” and “Standard care”. The outcome is the measured result at 12 months with 
model terms for treatment arm, baseline measurement, and covariates. Descriptive 
statistics will be calculated at baseline and 12 months by treatment group. 
 
Interpretation of Results: For linear models a difference below 0.00 will indicate a 
reduction in score for “Standard care + oral antimicrobial therapy” arm. 
A difference 
above 0.00 will indicate increase in score for “Standard care + oral antimicrobial 
therapy” arm. 
 
XII. Interim Analyses  
 
 
 
There will be one planned interim review for efficacy. The efficacy review will focus on 
the composite endpoint of respiratory hospitalization or all-cause death and should 
occur once 300 enrolled subjects have been followed for 12 months. The information 
time will be computed by dividing the observed number of primary endpoint events by 
the projected number of primary endpoint events. To conserve the overall type I error 
rate of 0.05 the O’Brien-Fleming Spending Function will be used to allow for stopping 
if large treatment effects are observed while allowing the final significance level to be 
conserved at the nominal level (Lan and DeMets 1983). 
 
 
XIII. Subgroup of Interest  
 
 
The following subgroups of interest will be based on information available prior to 
randomization: 
 
Use of standard of care medications at enrollment 
 
Antimicrobial therapy determined prior to randomization 
 
Use of NAC at enrollment 
 
The subgroups of interest will be assess sepereately for the primary endpoint within 
the framework of cox proportional hazards regression model. The subgroup variable 
and subgroup by treatment arm intereaction will be added to the model. If the 
interaction is significant then the hazard ratios and 95% confidence intervals will be 


Statistical Analysis Plan (CleanUP-IPF) 
Page 19 
 
 
 
 
estimated for the difference in treatment arms for the separate levels of the subgroup 
variable. 
 
The antimicrobial therapy determined prior to randomization is made up to 2 groups: 
1) Co-trimoxazole and 2) Doxycycline. The baseline and primary/secondary analyses 
will be repeated for these 2 groups seperately. 
 
XIV. References  
 
 
Berglund, Patricia and Heeringa, Steven. Multiple Imputation of Missing Data Using 
SAS®. SAS Institute, July 2014, pp83-89. 
Lan, KK Gordan, Demets, David L, Discrete sequential boundaries for clinical trials, 
Biometrika Volume 70, Issue 3Pp. 659-663 
 
XV. Tables/Listing/Graph Mock-ups  
 
 
The tables, listings, and figures shown below are the template versions and may be 
modified as needed. It is planned that there will be separate sets of tables based on 
the subgroups of interest listed above. 


Statistical Analysis Plan (CleanUP-IPF) 
Page 20 
 
 
 
 
CLEANUP-IPF Study 
Final Analysis Table 1.1 
Enrollment and Patient Follow-up 
Patient Enrollment by Site 
Investigational Site 
Enrolled 
(101) <<Site name>> 
(102) <<Site name>> 
N/N (xx.x%) 
N/N (xx.x%) 
(103) <<Site name>> 
(104) <<Site name>> 
… 
(140) <<Site name>> 
N/N (xx.x%) 
N/N (xx.x%) 
… 
N/N (xx.x%) 
Total 
N/N (xx.x%) 


Page 21 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 1.2 
Enrollment and Patient Follow-up 
Completed and Withdrawn Patients 
 
 
Event 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
P-Value 
Started Study 
Completed 
N 
N/N (xx.x%) 
N 
N/N (xx.x%) 
N 
N/N (xx.x%) 
Study Termination due to Death 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Withdrawal 
6 Months 
# of Events/# of Patients 
N/N 
N/N 
N/N 
x.xxx 
Kaplan-Meier Event Rate (95% CI) 
12 Months 
# of Events/# of Patients 
xx.x (xx.x, xx.x) 
N/N 
xx.x (xx.x, xx.x) 
N/N 
xx.x (xx.x, xx.x) 
N/N 
x.xxx 
Kaplan-Meier Event Rate (95% CI) 
18 Months 
# of Events/# of Patients 
xx.x (xx.x, xx.x) 
N/N 
xx.x (xx.x, xx.x) 
N/N 
xx.x (xx.x, xx.x) 
N/N 
x.xxx 
Kaplan-Meier Event Rate (95% CI) 
24 Months 
# of Events/# of Patients 
xx.x (xx.x, xx.x) 
N/N 
xx.x (xx.x, xx.x) 
N/N 
xx.x (xx.x, xx.x) 
N/N 
x.xxx 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Reasons for Withdrawal 
Reason #1 
N 
N 
N 
Reason #2 
… 
Reason #X 
N 
… 
N 
N 
… 
N 
N 
… 
N 
Therapy Distribution 
6 Months 
N/N (xx.x%) 
12 Months 
N/N (xx.x%) 
Thearpy adherence (7 Days Prior) 
6 Months 
N/N (xx.x%) 
12 Months 
N/N (xx.x%) 
 
Therapy crossover 
 


Page 22 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 1.2 
Enrollment and Patient Follow-up 
Completed and Withdrawn Patients 
 
 
Event 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
P-Value 
 
 
6 Months 
# of Events/# of Patients 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
12 Months 
# of Events/# of Patients 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
18 Months 
# of Events/# of Patients 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
24 Months 
# of Events/# of Patients 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
 
 


Page 23 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
CLEANUP-IPF Study 
Final Analysis Graph 1.2.1 
Enrollment and Patient Follow-up 
Completed and Withdrawn Patients 
Withdrawal Rate, Kaplan-Meier Estimates 
 
100% 
 
90% 
 
 
80% 
 
70% 
 
60% 
 
50% 
 
40% 
 
30% 
 
20% 
 
10% 
 
0% 
Weeks 
Oral 
antimicrobial 
therapy 
Standard care 
Log-rank P-Value at XX Weeks 
x.xxx 
0 


Page 24 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 2.1 
Baseline 
Demographic and Risk Factor Summary 
 
 
Parameter 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
P-Value 
 
 
 
Age (Years) 
x.xxx 
N 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
Median (Q1, Q3) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
Min, Max 
x.xx, x.xx 
x.xx, x.xx 
x.xx, x.xx 
Female 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Weight (kg) 
x.xxx 
N 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
Median (Q1, Q3) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
Height (cm) 
x.xxx 
N 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
Median (Q1, Q3) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
BMI 
x.xxx 
N 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
Median (Q1, Q3) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
Ethnicity (Hispanic or Latino ) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Race 
American Indian or Alaska Native 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Asian 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Black or African American 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Native Hawaiian or other Pacific Islander 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
White 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Other 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Minorities 1 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
BP (systolic)(mmHg) 
N 
Mean (SD) 
Median (Q1, Q3) 
 
xx 
xx.x (xx.x) 
xx.x (xx.x., xx.x) 
 
xx 
xx.x (xx.x) 
xx.x (xx.x., xx.x) 
 
xx 
xx.x (xx.x) 
xx.x (xx.x., xx.x) 
x.xxx 
BP (diastolic)(mmHg) 
x.xxx 


Page 25 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 2.1 
Baseline 
Demographic and Risk Factor Summary 
 
 
Parameter 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
P-Value 
 
 
 
N 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
Median (Q1, Q3) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
Heart rate (bpm) 
x.xxx 
N 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
Median (Q1, Q3) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
SpO2 (%) 
x.xxx 
N 
xx 
xx 
xx 
Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
Median (Q1, Q3) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
xx.x (xx.x., xx.x) 
Marital Status 
Single 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Married 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Divorced 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Domestic 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Partner 
Widowed 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
1. Any patient whose ethnicity is Hispanic or Latino, or whose race is non-white 


Page 26 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 2.2 
Baseline 
Medical History 
 
 
Parameter 
 
 
 
Coronary artery disease 
Acute MI 
Valvular heart disease 
Congestive Heart failure 
Atrial fibrillation 
Intermittent claudication 
Peripheral vascular disease 
Cerebrovascular disease 
Dementia 
Chronic pulmonary disease 
Connective tissue disease 
Ulcer disease 
Mild liver disease 
Diabetes 
Hemiplegia 
Moderate or severe renal disease 
Diabetes with end organ damage 
Any tumor 
Leukemia 
Lymphoma 
Moderate or severe liver disease 
Metastatic solid tumor 
AIDS 
Lung cancer 
Other cancer 
Gastroesophageal reflux (GER) 
 
 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
P-Value 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
x.xxx 
x.xxx 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
x.xxx 
x.xxx 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
x.xxx 
x.xxx 
x.xxx 


Page 27 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 2.3 
Baseline 
Prior Medications 
 
 
Parameter 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
P-Value 
 
 
Proton Pump Inhibitors (PPI) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
H2 Blockers (H2 Receptor Antagonists) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Chronic prednisone (>1month) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Azathioprine 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
N-acetylcystteine (NAC) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Cotrimoxazole 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Albuterol/ atrovent/ other metered-dose 
inhaler (MDI) 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Pirfenidone 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
Nintedanib 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
x.xxx 
 
 


Page 28 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 2.4 
Baseline 
6 Minute Walk Test 
 
 
Parameter 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
Resting SpO2 (%) 
x.xxx 
N 
Mean (SD) 
Median (Q1, Q3) 
Borg Scale Pre-Walk Rating (0-10 Range) 
N 
Mean (SD) 
Median (Q1, Q3) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
 
 
x.xxx 
Borg Scale Post-Walk Rating (0-10 Range) 
x.xxx 
N 
Mean (SD) 
Median (Q1, Q3) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
Six Minute Walk Distance (m) 
x.xxx 
N 
Mean (SD) 
Median (Q1, Q3) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 


Page 29 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
CLEANUP-IPF Study 
Final Analysis Table 2.5 
Baseline 
Spirometry and Lung Diffusion Testing 
 
 
Parameter 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
FEV1 (Liters) 
N 
Mean (SD) 
Median (Q1, Q3) 
FEV1% Predicted 
N 
Mean (SD) 
Median (Q1, Q3) 
FEV1/FVC Percentage 
N 
Mean (SD) 
Median (Q1, Q3) 
FVC (liters) 
N 
Mean (SD) 
Median (Q1, Q3) 
FVC % Predicted 
N 
Mean (SD) 
Median (Q1, Q3) 
DLCO (mL/min/mmHg) 
N 
Mean (SD) 
Median (Q1, Q3) 
DLCO Corrected (mL/min/mmHg) 
N 
Mean (SD) 
Median (Q1, Q3) 
DLCO % Predicted 
N 
Mean (SD) 
Median (Q1, Q3) 
 
 
xx 
xx 
xx 
x.xxx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
x.xxx 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xxx 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xxx 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 


Page 30 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
 
 
CLEANUP-IPF Study 
Final Analysis Table 2.6 
Baseline 
Quality of Life 
 
 
Parameter 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
UCSD Shortness of Breath Questionnaire 
Total Score (0*-120 Range) 
N 
Mean (SD) 
Median (Q1, Q3) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xxx 
EuroQoL Score(0-1* Range) 
x.xxx 
N 
Mean (SD) 
Median (Q1, Q3) 
EuroQoL Thermometer Response (0-100* 
Range) 
N 
Mean (SD) 
Median (Q1, Q3) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
 
x.xxx 
ICECAP-O: Summary Score (0-1* Range) 
x.xxx 
N 
Mean (SD) 
Median (Q1, Q3) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
SF-12 Score 
x.xxx 
N 
Mean (SD) 
Median (Q1, Q3) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
Fatigue Severity Scale score 
x.xxx 
N 
Mean (SD) 
Median (Q1, Q3) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
Leicester Cough Questionnaire score 
x.xxx 
N 
Mean (SD) 
Median (Q1, Q3) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
*Indicates better health score 


Page 31 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 3.1 
Primary Efficacy 
Summary of Events 
 
 
Event 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
P-Value 
Primary Endpoint 
1st Respiratory hospitalization 
Death 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
x.xxx 
At 6 Months 
# of events/# of Patients 
N/N 
N/N 
N/N 
x.xxx 
Kaplan-Meier Event Rate (95% CI) 
At 12 Monthss 
# of events/# of Patients 
xx.x (xx.x, xx.x) 
N/N 
xx.x (xx.x, xx.x) 
N/N 
xx.x (xx.x, xx.x) 
N/N 
x.xxx 
Kaplan-Meier Event Rate (95% CI) 
At 18 Months 
# of events/# of Patients 
xx.x (xx.x, xx.x) 
N/N 
xx.x (xx.x, xx.x) 
N/N 
xx.x (xx.x, xx.x) 
N/N 
x.xxx 
Kaplan-Meier Event Rate (95% CI) 
At 24 Months 
# of events/# of Patients 
xx.x (xx.x, xx.x) 
N/N 
xx.x (xx.x, xx.x) 
N/N 
xx.x (xx.x, xx.x) 
N/N 
x.xxx 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Mortality 
# of events 
N/N 
N/N 
N/N 
 
Cause of Death 
 
Reason #1 
Reason # 
N 
N 
N 
… 
… 
… 
… 
Reason #X 
N 
N 
N 
 
At 6 Months 
x.xxx 
# of events/# of Patients 
N/N 
N/N 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
At 12 Monthss 
x.xxx 
# of events/# of Patients 
N/N 
N/N 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
At 18 Months 
x.xxx 
# of events/# of Patients 
N/N 
N/N 
N/N 


Page 32 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 3.1 
Primary Efficacy 
Summary of Events 
 
 
Event 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
P-Value 
 
 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
At 24 Months 
x.xxx 
# of events/# of Patients 
N/N 
N/N 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
 
Non-elective hospitalization 
Patients with one of more 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
Number per patient 
0 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
1 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
2 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
3 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
 
At 6 Months 
x.xxx 
# of events/# of Patients 
N/N 
N/N 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
At 12 Monthss 
x.xxx 
# of events/# of Patients 
N/N 
N/N 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
At 18 Months 
x.xxx 
# of events/# of Patients 
N/N 
N/N 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
At 24 Months 
x.xxx 
# of events/# of Patients 
N/N 
N/N 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Respiratory hospitalization 
 
Patients with one of more 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
Number per patient 
0 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
1 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
2 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
3 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
 
 


Page 33 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 3.1 
Primary Efficacy 
Summary of Events 
 
 
Event 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
P-Value 
 
 
At 6 Months 
x.xxx 
# of events/# of Patients 
N/N 
N/N 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
At 12 Monthss 
x.xxx 
# of events/# of Patients 
N/N 
N/N 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
At 18 Months 
x.xxx 
# of events/# of Patients 
N/N 
N/N 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
At 24 Months 
x.xxx 
# of events/# of Patients 
N/N 
N/N 
N/N 
Kaplan-Meier Event Rate (95% CI) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
xx.x (xx.x, xx.x) 
Respiratory infections 
 
Patients with one of more 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
Number per patient 
0 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
1 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
2 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
3 
N (xx.x%) 
N (xx.x%) 
N (xx.x%) 
 
 


Page 34 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
CLEANUP-IPF Study 
Final Analysis Table 3.1.1 
Primary Efficacy 
Time to first 1st Respiratory hospitalization or Death 
Kaplan-Meier Plot 
 
100% 
 
90% 
 
80% 
 
70% 
 
60% 
 
50% 
 
40% 
 
30% 
 
20% 
 
10% 
 
0% 
 
 
OAT 
N 
N 
N 
N 
N 
SOC 
N 
N 
N 
N 
N 
Oral antimicrobial 
therapy 
Standard Care 
Log-rank P-Value at 24 Months 
x.xxx 
0 


Page 35 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
CLEANUP-IPF Study 
Final Analysis Table 3.1.2 
Primary Efficacy 
Time to Death 
Kaplan-Meier Plot 
 
CLEANUP-IPF Study 
Final Analysis Table 3.1.3 
Primary Efficacy 
Time to first 1st Respiratory hospitalization 
Kaplan-Meier Plot 
 
CLEANUP-IPF Study 
Final Analysis Table 3.1.4 
Primary Efficacy 
Time to first 1st Non-elective hospitalization 
Kaplan-Meier Plot 


Page 36 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
CLEANUP-IPF Study 
Final Analysis Table 3.2 
Primary Efficacy 
Model Analysis 
 
 
 
Comparison 
Estimate with 95% Confidence 
Interval 
Test Statistic 
Nominal 
P-Value 
 
 
Time to 1st Respiratory hospitalization or Death 
Hazard ratio of Oral antimicrobial therapy vs. Standard 
Care 
Time to first 1st Respiratory hospitalization 
Hazard ratio of Oral antimicrobial therapy vs. Standard 
Care 
Time to first 1st Non-elective hospitalization 
Hazard ratio of Oral antimicrobial therapy vs. Standard 
Care 
Total Respiratory hospitalizations 
 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
Rate of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
Rate of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
Ratio of Oral antimicrobial therapy vs. Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
Total Non-elective hospitalizations 
 
Rate of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Rate of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Ratio of Oral antimicrobial therapy vs. Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
Total Respiratory infections 
 
Rate of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Rate of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Ratio of Oral antimicrobial therapy vs. Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
 


Page 37 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 4.1.1 
Secondary Efficacy 
FVC and DLCO 
Descriptive Summary 
 
 
Parameter 
Visit 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
FVC (liters) 
Baseline 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
x.xxx 
 
 
 
x.xxx 
 
 
 
x.xxx 
 
FVC % Predicted 
Baseline 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
x.xxx 
 
 
 
x.xxx 
 
 
 
x.xxx 
 
 


Page 38 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 4.1.1 
Secondary Efficacy 
FVC and DLCO 
Descriptive Summary 
 
 
Parameter 
Visit 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
DLCO (mL/min/mmHg) 
Baseline 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
DLCO Corrected (mL/min/mmHg) 
Baseline 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
DLCO % Predicted 
Baseline 
x.xxx 
x.xxx 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
xx 
xx 
x.xxx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
xx 
xx 
x.xxx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xxx 
xx 
xx 
xx 
x.xxx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xxx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
xx 
xx 
x.xxx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xxx 
x.xxx 


Page 39 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 4.1.1 
Secondary Efficacy 
FVC and DLCO 
Descriptive Summary 
 
 
Parameter 
Visit 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
 
x.xxx 
 
 
 
x.xxx 
 
 


Page 40 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 4.1.2 
Primary Efficacy 
FVC and DLCO 
Change from Baseline Summary 
 
 
Parameter 
Visit 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
FVC (liters) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
x.xxx 
 
 
 
x.xxx 
 
FVC % Predicted 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
x.xxx 
 
 
 
x.xxx 
 
DLCO (mL/min/mmHg) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
 
x.xxx 
 
 
 
x.xxx 
 


Page 41 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 4.1.2 
Primary Efficacy 
FVC and DLCO 
Change from Baseline Summary 
 
 
Parameter 
Visit 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
Median (Q1, Q3) 
DLCO Corrected (mL/min/mmHg) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
Week 12 
x.xxx 
N 
Mean (SD) 
xx 
x.xx (xx.x) 
xx 
x.xx (xx.x) 
xx 
x.xx (xx.x) 
Median (Q1, Q3) 
Week 24 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xxx 
N 
Mean (SD) 
xx 
x.xx (xx.x) 
xx 
x.xx (xx.x) 
xx 
x.xx (xx.x) 
Median (Q1, Q3) 
DLCO % Predicted 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
Week 12 
N 
xx 
xx 
xx 
x.xxx 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xxx 
 
 


Page 42 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
CLEANUP-IPF Study 
Final Analysis Table 4.1.3 
Secondary Efficacy 
FVC and DLCO 
Model Analysis 
 
 
Comparison 
Estimate with 95% Confidence Interval 
Test Statistic 
Nominal 
P-Value 
 
 
FVC (liters) 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
FVC % Predicted 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
DLCO (mL/min/mmHg) 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
DLCO Corrected (mL/min/mmHg) 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 


Page 43 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
 
 
DLCO % Predicted 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
 


Page 44 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
CLEANUP-IPF Study 
Final Analysis Table 4.2.1 
Secondary Efficacy 
Quality of Life Measures 
Descriptive Summary 
 
 
Parameter 
Visit 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
UCSD Shortness of Breath 
Questionnaire Total Score (0*-120 
Range) 
Baseline 
N 
Mean (SD) 
Median (Q1, Q3) 
12 Months 
N 
Mean (SD) 
Median (Q1, Q3) 
24 Months 
N 
Mean (SD) 
Median (Q1, Q3) 
EuroQoL Score(0-1* Range) 
EuroQoL Thermometer Response 
(0-100* Range) 
ICECAP-O: Summary Score (0-1* 
Range) 
SF-12 Score 
Fatigue Severity Scale score  
Leicester Cough Questionnaire score 
 
 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
 
x.xxx 
 
 
 
x.xxx 
 
 
 
x.xxx 
 
 


Page 45 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 4.2.2 
Secondary Efficacy 
Quality of Life Measures 
Change from Baseline Summary 
 
 
Parameter 
Visit 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
UCSD Shortness of Breath 
Questionnaire Total Score (0*-120 
Range) 
12 Months 
N 
Mean (SD) 
Median (Q1, Q3) 
24 Months 
N 
Mean (SD) 
Median (Q1, Q3) 
EuroQoL Score(0-1* Range) 
EuroQoL Thermometer Response 
(0-100* Range) 
ICECAP-O: Summary Score (0-1* 
Range) 
SF-12 Score 
Fatigue Severity Scale score  
Leicester Cough Questionnaire score 
 
 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
 
x.xxx 
 
 
 
x.xxx 
 
 


Page 46 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
CLEANUP-IPF Study 
Final Analysis Table 4.2.3 
Secondary Efficacy 
Quality of Life Measures 
Model Analysis 
 
 
Comparison 
Estimate with 95% Confidence Interval 
Test Statistic 
Nominal 
P-Value 
 
 
UCSD Shortness of Breath Questionnaire Total Score 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
EuroQoL Thermometer Response 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
ICECAP-O: Summary Score 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
SF-12 Score 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 


Page 47 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
 
 
Fatigue Severity Scale score 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
Leicester Cough Questionnaire score 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
 


Page 48 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
CLEANUP-IPF Study 
Final Analysis Table 5.1 
Safety 
Serious Adverse Events 
 
 
Body System 
Event Name 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
P-Value 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Summarization format NPAT (xx.x%) NSAE, where NPAT is the number of patient with at least one SAE, xx.x% = NPAT divided by the total number of randomized patients times 100, 
and NSAE is the number of SAEs observed 
Any Body System and Event 
1st Body System Name 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
x.xxx 
1st Event Name 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
2nd Event Name 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
… 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
Xth Event Name 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
2nd Body System Name 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
1st Event Name 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
2nd Event Name 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
… 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
Xth Event Name 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
Xth Body System Name 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
1st Event Name 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
2nd Event Name 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
… 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 
Xth Event Name 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
NPAT (xx.x%) NSAE 
x.xxx 


Page 49 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 5.2 
Safety 
Concomitant Medications Shift Table 
 
 
Parameter 
Baseline 
Usage 
Post-Baseline 
Usage 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
 
 
PPI 
H2 Blocker 
No 
 No 
N/N (xx.x%) 
N/N (xx.x%) 
 N/N 
(xx.x%) Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
 No 
N/N (xx.x%) 
N/N (xx.x%) 
 N/N 
(xx.x%) Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Overall 
 No 
N/N (xx.x%) 
N/N (xx.x%) 
 N/N 
(xx.x%) Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
No 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Overall 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Chronic prednisone 
No 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Overall 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Azathioprine 
No 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Overall 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
NAC 


Page 50 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 5.2 
Safety 
Concomitant Medications Shift Table 
 
 
Parameter 
Baseline 
Usage 
Post-Baseline 
Usage 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
 
 
No 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Overall 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Cotrimoxazole 
No 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Overall 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
MDI 
No 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Overall 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Pirfenidone 
No 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Overall 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 


Page 51 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 5.2 
Safety 
Concomitant Medications Shift Table 
 
 
Parameter 
Baseline 
Usage 
Post-Baseline 
Usage 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N= NEVAL 
 
 
Nintedanib 
No 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Overall 
No 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
Yes 
N/N (xx.x%) 
N/N (xx.x%) 
N/N (xx.x%) 
 
 


Page 52 
Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 6.1.1 
Exploratory Endpoint  
Six Minute Walk Test 
Descriptive Summary 
 
 
Parameter 
Visit 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
Resting SpO2 (%) 
Baseline 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
x.xxx 
 
 
 
x.xxx 
 
 
 
x.xxx 
 
Borg Scale Pre-Walk Rating (0-10 Range) 
Baseline 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
x.xxx 
 
 
 
x.xxx 
 
 
 
x.xxx 
 
 


Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 6.1.1 
Exploratory Endpoint  
Six Minute Walk Test 
Descriptive Summary 
Page 53 
 
 
Parameter 
Visit 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
Borg Scale Post-Walk Rating (0-10 
Range) 
Baseline 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
Six Minute Walk Distance (m) 
Baseline 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
x.xxx 
x.xxx 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
xx 
xx 
x.xxx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
xx 
xx 
xx 
x.xxx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xxx 
xx 
xx 
xx 
x.xxx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xxx 
xx 
x.xx (xx.x) 
xx 
x.xx (xx.x) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xxx 
xx 
x.xx (xx.x) 
xx 
x.xx (xx.x) 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 
x.xx (x.xx, x.xx) 


Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 6.1.2 
Exploratory Endpoint  
Six Minute Walk Test 
Change from Baseline Summary 
Page 54 
 
 
Parameter 
Visit 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
Resting SpO2 (%) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
x.xxx 
 
 
 
x.xxx 
 
Borg Scale Pre-Walk Rating (0-10 Range) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
x.xxx 
 
 
 
x.xxx 
 
Borg Scale Post-Walk Rating (0-10 
Range) 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xxx 
 
x.xxx 
 
 
 
x.xxx 
 


Statistical Analysis Plan (CleanUP-IPF) 
CLEANUP-IPF Study 
Final Analysis Table 6.1.2 
Exploratory Endpoint  
Six Minute Walk Test 
Change from Baseline Summary 
Page 55 
 
 
Parameter 
Visit 
Statistic 
Oral antimicrobial therapy 
N= NEVAL 
Standard Care 
N= NEVAL 
All Patients 
N=NEVAL 
P-Value 
 
 
Six Minute Walk Distance (m) 
x.xxx 
Week 12 
N 
Mean (SD) 
Median (Q1, Q3) 
Week 24 
N 
Mean (SD) 
Median (Q1, Q3) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
 
xx 
x.xx (xx.x) 
x.xx (x.xx, x.xx) 
x.xxx 
 
 
 
x.xxx 
 
 


Page 56 
Statistical Analysis Plan (CleanUP-IPF) 
 
 
 
CLEANUP-IPF Study 
Final Analysis Table 6.1.3 
Exploratory Endpoint  
Six Minute Walk Test 
Model Analysis 
 
 
Comparison 
Estimate with 95% Confidence Interval 
Test Statistic 
Nominal 
P-Value 
 
 
Borg Scale Pre-Walk Rating (0-10 Range) 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
Borg Scale Post-Walk Rating (0-10 Range) 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
Six Minute Walk Distance (m) 
Slope of Oral antimicrobial therapy 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
Slope of Standard Care 
xx.xx (xx.xx, xx.xx) 
xxx.xx 
x.xxx 
 
Difference of Oral antimicrobial therapy vs. 
Standard Care 
xx.xx (xx.xx, xx.xx) 
xx.xx 
x.xxx 
 
 


Addendum to the CleanUP-IPF Analysis Plan (signed 28NOV2016) 
 
Fernando J. Martinez, Principal Investigator 
Imre Noth, Principal Investigator 
Kevin Anstrom, Principal Investigator 
Jerry Kirchner, Project Leader 
Eric Yow, Statistician 
29MAY2020 
On 19DEC2019 the DCC received a memorandum from the Executive Secretary of 
CleanUP-IPF DSMB regarding the recommendations for investigators of the CleanUP-IPF 
study following DSMB meeting 18DEC2019 meeting conference call. 
The 
recommendations were to terminate the trial and proceed with an orderly study close-out. 
Study PIs and DCC developed and implemented a plan to complete patient visits and 
follow-up in March 2020 and database lock by May 2020. 
 
Beginning in mid-March across the United States stay at home orders were issued due to the 
COVID19 pandemic.  The stay at home orders limited site PIs and coordinators access to 
medical records and other key patient data.  The impact of limited access was the following: 
 Entry of some visit data 
 Responses to database queries 
 Collecting and submitting patients records for endpoint adjudication 
 Collecting and submitting patients records for medical monitor review of serious 
adverse events and MedDRA coding 
 
The impact of COVID19 on the data lock and reporting the primary results for publication 
are the following: 
 Unable to complete all adjudication of primary endpoint components: death and 
hospitalization 
 Entry of serious adverse events and associated term in database to allow MedDRA 
system organ class coding 
 
Given the need to report timely results in the public domain and the unknown end of 
COVID19 pandemic, the deviation of the primary statistical analysis reporting would be as 
follows: 
 According to the Statistical Analysis Plan (SAP), the primary analysis of the primary 
endpoint was to be based on CEC adjudicated endpoints.  Now, the plan is to use 
adjudicated results if available.  If the CEC adjudicated result is not available then the 
site reported result would be used for the endpoint. 
 For serious adverse events, the summary of MedDRA system organ class coding was 
planned for the primary statistical  analysis and reporting of results.  The serious 
adverse event analysis would be altered as follows: 
o For events with serious adverse event term entry in the database and 
MedDRA system organ class coding, we will use MedDRA coding. 
o For events without serious adverse event term entry in the database and 
without MedDRA system organ class coding, the medical monitor would 


review the available documentation and if reasonable information is available 
to classify to MedDRA system organ class, then the medical monitor result 
will be used. 
o For events without serious adverse event term entry in the database, and no 
MedDRA system organ class coding, and no documentation to support a 
classification by the medical monitor, then the result will not be coded. 
 
The primary analysis is based on the final locked dataset and events collected.  A sensitivity 
analysis of the primary results will be constructed to explore possible differences in 
snapshots or timeframes of the data. The results would be censored at date of the DSMB 
meeting on 17DEC2019 and again at 01MAR2020 (associated with the COVID 19 
pandemic) to understand any differences in the data collection affected the results. 


 
 


 
The NHL.BI carefully reviewed the DSMB reconunendations. On December 19,2019, Dr.Lora 
Reineck notified you of the intent of the Instirute to concur with the DSMB reconunendation for 
early tennination. 
 
The NHL.BI is hopeful that we can achieve our shared goal of maximizing the information and 
generalizable knowledge gained from the srudy. 
 
Thank you for your leadership on this important study. 
 
Sincerely, 
 
 
James P. Kiley, Ph.D. 
Director,Division of LungDiseases 
National Heart, Lung, and Blood In'ilitute, NIH 
 
cc: 
Dr.Frank Sciurba 
Dr.Stephen Wisniewski 
Dr.Tony Punturieri 
Ms.Lisa Viviano 
Mr.Andre Walker 
Dr.Ton1Croxton 
Dr.Lora Reineck 
Dr.Amy Patterson 
Dr.Nakela Cook