A Phase 2 Trial to Evaluate the Efficacy of PRM-151 in Subjects With Idiopathic Pulmonary Fibrosis (IPF)
Phase: PHASE2
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Hoffmann-La Roche

PRM-151
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Clinical Trial Protocol:  Study PRM-151-202 
 
Study Title: 
A Phase 2 Trial to Evaluate the Efficacy of PRM-151 in Subjects with 
Idiopathic Pulmonary Fibrosis (IPF) 
Study Number: 
PRM-151-202 
Study Phase: 
2 
Product Name: 
PRM-151 
IND Number: 
110,774 
EUDRACT 
Number: 
Indication: 
 
2014-004782-24 
Idiopathic Pulmonary Fibrosis (IPF) 
 
 
 
Sponsor: 
Promedior, Inc 
101 Hartwell Ave. 
Lexington, MA 02421 
Tel: 1-781-538-4200 
Fax:  1-781-538-4300 
 
Sponsor Contact: 
Karen Carroll, RN 
Medical Director: 
Medical Monitor: 
Bernt van den Blink, MD, PhD 
Mohamed El Malt, MD, PhD 
 
 
Date  
Original Protocol: 
Version 1.0  11 November 2014 
Amendment # 1: 
Version 2.0  26 February 2015 
Amendment # 2: 
Version 3.0 11 March 2015 
Amendment # 3: 
Version 4.0 3 February 2016 
 
Confidentiality Statement 
The information contained herein is confidential and the proprietary 
property of Promedior, Inc and any unauthorized use or disclosure of 
such information without the prior written authorization of Promedior 
is expressly prohibited. 
Karen Carroll, RN
Bernt van den Blink, MD, PhD
Mohamed El Malt, MD, PhD

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SYNOPSIS 
Sponsor: 
Promedior, Inc 
Name of Finished Product: 
Recombinant human Pentraxin-2; PRM-151 
Study Title: 
A Phase 2 Trial to Evaluate the Efficacy of PRM-151 in Subjects with Idiopathic Pulmonary 
Fibrosis (IPF) 
Study Number: 
PRM-151-202 
Study Phase:  Phase 2 
Investigational Product; Dose; and Mode of Administration:  
PRM-151 10 mg/kg every 4 weeks via intravenous infusion over 60 minutes.   
On all dosing days, dosing will occur after all safety and efficacy assessments scheduled for 
that visit are completed. 
Comparator Dose; and Mode of Administration: 
Placebo will be administered via IV infusion over 60 minutes. 
Primary Objective:  
 Determine the effect size of PRM-151 relative to placebo in change from Baseline to 
Week 28 in mean FVC% predicted, pooling subjects on a stable dose of pirfenidone or 
nintedanib with subjects not on other treatment for IPF. 
Secondary Objective(s): 
 Determine the effect size of PRM-151 relative to placebo in change from Baseline to 
Week 28 in normal lung parenchyma as quantified on high- resolution CT (HRCT) 
imaging analysis, pooling subjects on a stable dose of pirfenidone or nintedanib with 
subjects not on other treatment for IPF. 
 Determine the effect size of PRM-151 relative to placebo in change from Baseline to 
Week 28 in mean FVC% predicted, separately in subjects on a stable dose of 
pirfenidone or nintedanib and separately in subjects not on other treatments for IPF. 
 Determine the effect size of PRM-151 relative to placebo in change from Baseline to 
Week 28 in normal lung parenchyma as quantified on HRCT imaging analysis, 
separately in subjects on a stable dose of pirfenidone or nintedanib and in subjects not 
on other treatments for IPF. 
 Assess the tolerability and safety of PRM-151 in subjects with IPF through Week 28 
 Assess the ability of PRM-151 to reduce disease-related events associated with 
mortality. 
 Determine the effect size of PRM-151 relative to placebo on pulmonary function in 
addition to mean change in FVC% predicted. 
 Determine the effect size of PRM-151 relative to placebo on 6-minute walk distance. 
 Assess the effect size of PRM-151 relative to placebo on Hb-corrected DLCO. 

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Exploratory Objective(s): 
 Evaluate the efficacy and estimate the size of effect of PRM-151 relative to 
placebo in change from baseline to weeks 4, 8, 12, 16, 20, 24 and 28 in 
FVC % predicted and 6-minute walking distance, pooling subjects on a 
stable dose of pirfenidone or nintedanib with subjects not on other 
treatment for IPF, and separately in subjects on a stable dose of pirfenidone 
or nintedanib and in subjects not on other treatments for IPF. 
 
Assess the impact of PRM-151 on disease related symptoms. 
 Assess the impact of PRM-151, disease pathogenesis and disease progression on 
exploratory serum, cellular and genetic biomarkers. 
 
 
Exploratory Objective(s):

Evaluate the efficacy and estimate the size of effect of PRM-151 relative to
placebo in change from baseline to weeks 4, 8, 12, 16, 20, 24 and 28 in
FVC % predicted and 6-minute walking distance, pooling subjects on a 
stable dose of pirfenidone or nintedanib with subjects not on other 
treatment for IPF, and separately in subjects on a stable dose of pirfenidone
or nintedanib and in subjects not on other treatments for IPF.
Assess the impact of PRM-151 on disease related symptoms.


Assess the impact of PRM-151, disease pathogenesis and disease progression on 
exploratory serum, cellular and genetic biomarkers.

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Study Endpoints:  
Primary:   
 The primary endpoint is the mean change in FVC % predicted from Baseline to Week 
28. 
Secondary:   
 Structural Imaging: 
 Mean change from Baseline to Week 28 in total lung volume and volume of 
parenchymal features on HRCT (in ml and % of total lung volume) 
representative of interstitial lung abnormalities (ILA) including ground glass 
density, reticular changes, and honeycombing, using quantitative imaging 
software. 
 Mean change from Baseline to Week 28 in volume of parenchymal features on 
HRCT (in ml and % of total lung volume) representative of normal lung (non-
ILA), including normal and mild low attenuation areas, using quantitative 
imaging software. 
 Correlation between mean change from Baseline to Week 28 in FVC % 
predicted and mean change from Baseline to Week 28 in total lung volume and 
volume of parenchymal features on HRCT (in ml and % of total lung volume) 
representative of interstitial lung abnormalities (ILA), including ground glass 
density, reticular changes, and honeycombing by quantitative imaging software. 
 Safety: Tolerability/safety will be assessed over the 28-week study period by the 
following parameters: 
 Incidence of AEs. 
 Incidence of serious adverse events (SAEs). 
 Incidence of respiratory AEs and SAEs. 
 Proportion of subjects discontinuing study drug due to AEs. 
 Change from Baseline in hematology and serum chemistries. 
 All-cause mortality. 
 Mortality due to respiratory deterioration. 
 Disease related events associated with mortality:  The number of “respiratory 
decline” events over the 28-week study period as defined below: 
 Unscheduled visits to a healthcare professional for respiratory status 
deterioration. 
 Urgent care visits for respiratory status deterioration. 
 Hospitalization due to a worsening or exacerbation of respiratory symptoms. 
All “respiratory decline” events will be further characterized according to the 
definitions of IPF-related acute exacerbation, as proposed by an expert committee 
sponsored by the IPF Clinical Research Network and the National Heart Lung and 
Blood Institute (NHLBI) (Collard, Moore et al. 2007) and applied by (Collard, Yow et 
al. 2013) 
 Acute onset of symptoms (< 30 days in duration) 
 New radiographic abnormalities (bilateral ground glass or consolidation on 
HRCT with no pneumothorax or pleural effusion) 
 The absence of an identified infectious etiology by routine clinical practice 

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 Exclusion of alternative causes by routine clinical practice, including: 
a. Left heart failure 
b.Pulmonary embolism 
c. Identifiable cause of acute lung injury 
 Pulmonary Function Tests 
 Proportion (%) of subjects with a decline in FVC% predicted of ≥ 5% and ≥ 
10% from Baseline to Week 28. 
 Proportion (%) of subjects with a decline in FVC in ml of ≥ 100 ml and ≥ 200 
ml from Baseline to Week 28. 
 Proportion of subjects with an increase in FVC % predicted of ≥ 5% and ≥ 10% 
from Baseline to Week 28. 
 Proportion of subjects with an increase in FVC in ml of ≥100 ml and ≥ 200 ml 
from Baseline to Week 28. 
 Proportion of subjects with stable disease by FVC %, defined as a change in 
FVC % predicted of <5% from Baseline to Week 28. 
 Proportion of subjects with stable disease by FVC in ml, defined as a change in 
FVC of < 100ml from Baseline to Week 28. 
 Mean change from Baseline to Week 28 in % predicted Hb-corrected diffusion 
capacity of carbon monoxide (DLCO). 
 Change in 6-minute walk distance, in meters, from Baseline to Week 28. 
Exploratory: 
 Other Weeks 
 Examine the change from Baseline at Weeks 4, 8, 12, 16, 20, 24 and 28 for the 
FVC % predicted, FVC in ml, and 6MWT distance 
 Structural Imaging 
 Transitions from Baseline to Week 28 between all categories of lung features 
(normal, ground glass density, reticular changes, honeycombing, and mild, 
moderate, and severe low attenuation areas) by quantitative imaging software. 
 Correlation of transitions between categories of lung features by quantitative 
imaging and changes in FVC% predicted. 
 Correlation of transitions between categories of lung features by quantitative 
imaging and changes in Hb-corrected DLCO. 
 Impact of inspiratory effort on results of HRCT quantitative imaging. 
 Patient Reported Outcomes 
 Change in Patient Reported Outcomes as measured by King’s Brief Interstitial 
Lung Disease Questionnaire (K-BILD) and Leicester Cough Questionnaire 
(LCQ) from Baseline to Week 28. 
 Biomarkers 
 Changes in serum and cellular biomarkers and response according to baseline 
genetic characteristics: including but not limited to TLR3, L412F 
polymorphism, and MUC5B promoter polymorphism. 
Study Design: 
This study is a Phase 2, randomized, double-blind, placebo controlled, pilot study designed to 
evaluate the efficacy and safety of PRM-151 administered through Week 24 to subjects with 
Biomarkers

Changes in serum and cellular biomarkers and response according to baseline
genetic characteristics: including but not limited to TLR3, L412F
polymorphism, and MUC5B promoter polymorphism.

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IPF. Subjects meeting the eligibility criteria for the study will be randomized with a 2:1 ratio 
to PRM-151 at a dose of 10 mg/kg every 4 weeks or placebo. The randomization will be 
stratified according to other treatments for IPF (subjects receiving pirfenidone or nintedanib 
and subjects with no other treatment for IPF, with a minimum of 25% of subjects on no other 
treatment). Efficacy will be evaluated through pulmonary function tests (PFTs) including 
spirometry, Hb-corrected Diffusion Capacity (DLco) and Total Lung Capacity by Nitrogen 
washout method, quantitative imaging analysis of high resolution CT (HRCT), 6-minute walk 
test (6MWT), and subject reported outcomes (PROs). 
Subjects will be evaluated for study eligibility during Screening within 4 weeks before 
enrollment and Baseline assessments.  Subjects who are determined to be eligible, based on 
Screening assessments, will be enrolled in the study and randomly allocated to treatment with 
PRM-151 or placebo.  Subjects will receive study drug treatment for at least 24 weeks. 
Approximately 117 subjects will be randomly assigned on a 2:1 basis to treatment with 
PRM-151 or placebo, as follows: 
 PRM-151 10 mg/kg IV infusion over 60 minutes days 1, 3, and 5, then one infusion 
every 4 weeks  
 Placebo IV infusion over 60 minutes on days 1, 3, and 5, then one infusion every 4 
weeks 
After completion of study treatment through Week 24, all subjects may receive PRM-151 10 
mg/kg IV infusion over 60 minutes Days 1, 3, and 5, then once every 4 weeks for an indefinite 
period of time in an open label study extension.  Dosing on Days 1, 3 and 5 will be repeated 
once every 28 weeks. 
Study Duration: 
Subjects will receive study drug for a minimum of 24 weeks. 
Subjects will participate in the study for an indefinite period of time, including a 4-week 
screening period, 24-week treatment period, and an open-label treatment extension period,and 
a 4-week follow up visit. 
Study Inclusion and Exclusion Criteria: 
Inclusion Criteria: 
1. Subject is aged 40-80 years. 
2. Subject has IPF satisfying the ATS/ERS/JRS/ALAT diagnostic criteria (Raghu, 
Collard et al. 2011).   
In the absence of a surgical lung biopsy, HRCT must be “consistent with UIP” 
defined as meeting either criteria A, B, and C, or criteria A and C, or criteria B and 
C below: 
A. Definite honeycomb lung destruction with basal and peripheral 
predominance. 
B. Presence of reticular abnormality AND traction bronchiectasis consistent 
with fibrosis, with basal and peripheral predominance. 
C. Atypical features are absent, specifically nodules and consolidation.  
Ground glass opacity, if present, is less extensive than reticular opacity 
pattern.  
3. If on pirfenidone or nintedanib, subject must have been on a stable dose of 
pirfenidone or nintedanib for at least 3 months prior to screening without increase in 

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FVC% predicted on two consecutive PFTs, including screening PFTs. Subjects may 
not be on both pirfenidone and nintedanib. 
4. If not currently receiving pirfenidone or nintedanib, subject must have been off 
pirfenidone or nintedanib for ≥ 4 weeks before baseline. 
5. Subject has a FVC ≥ 50% and ≤ 90% of predicted. 
6. Subject has an Hb corrected and/or Hb uncorrected DLCO  ≥ 25% and ≤ 90% of 
predicted. 
7. Minimum distance on 6MWT of 150 meters.  
8. Subject has a forced expiratory volume in 1 second (FEV1)/FVC ratio > 0.70. 
9. Women of child bearing potential (WCBP), defined as a sexually mature woman not 
surgically sterilized or not post-menopausal for at least 24 consecutive months if ≤ 
55 years or 12 months if > 55 years, must have a negative serum pregnancy test 
within four weeks prior to the first dose of study drug and must agree to use highly 
effective methods of birth control throughout the study.  Highly effective methods 
of contraception include combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation by oral, intravaginal, or 
transdermal administration; progestogen-only hormonal contraception associated 
with inhibition of ovulation by oral, injectable, or implantable administration; 
intrauterine device (IUD); intrauterine hormone-releasing system (IUS); bilateral 
tubal occlusion; partner vasectomy, and total abstinence (only if total abstinence is 
the preferred method and usual lifestyle of the subject). Adequate contraceptive use 
should be continued until 28 days after the final dose of the study drug.  
10. Subject has a life expectancy of at least 9 months 
11. Subject, according to the investigator’s best judgment, can comply with the 
requirements of the protocol. 
12. Subject and the treating physician considered all medicinal treatment options and / 
or possibly a lung transplantation prior to considering participation in the study.  If 
the subject is on a lung transplant list, the investigator anticipates the subject will 
complete the study prior to transplant. 
13. Subject has provided written informed consent to participate in the study. 
Exclusion Criteria: 
1. Subject has emphysema ≥ 50% on HRCT or the extent of emphysema is greater 
than the extent of fibrosis according to reported results from the most recent 
HRCT. 
2. Subject has a history of cigarette smoking within the previous 3 months. 
3. Subject has received investigational therapy for IPF within 4 weeks before 
baseline. 
4. Subject is receiving systemic corticosteroids equivalent to prednisone > 10 mg/day 
or equivalent within 2 weeks of baseline. 
5. Subject received Immuno-suppressants (e.g. azathioprine, cyclophosphamide, or 
cyclosporine or other  immunosuppressants including those used after 
organ transplant) within 4 weeks of baseline. Subject has a history of a malignancy 
within the previous 5 years, with the exception of basal cell skin neoplasms.  In 
addition, a malignant diagnosis or condition first occurring prior to 5 years must be 
considered cured, inactive, and not under current treatment.  

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6. Subject has any concurrent condition other than IPF that, in the Investigator’s 
opinion, is unstable and/or would impact the likelihood of survival for the study 
duration or the subject’s ability to complete the study as designed, or may influence 
any of the safety or efficacy assessments included in the study. 
7. Subject has baseline resting oxygen saturation of < 89% on room air or 
supplemental oxygen. 
8. Subjects that are unable to refrain from use of the following:  
a) Short acting bronchodilators on the day of and within 12 hours of 
pulmonary function, DLCO, and 6-minute walk assessments.   
b) Long acting bronchodilators on the day of and within 24 hours of these 
assessments. 
9. Subject has a known post-bronchodilator (short-acting beta agonist [SABA] – 
albuterol or salbutamol) increase in FEV1 of >10% and in FVC of >7.5%. 
10. Female Pregnant and/or lactating subject. 
Efficacy Assessments: 
Treatment Period: Efficacy related Assessments 
Subjects undergo testing on an every 4-week basis after randomization (occurring at Weeks 4, 
8, 12, 16, 20, 24 and 28) for efficacy and safety.   
During treatment, PFTs, 6MWT, and PROs will be performed on an every 4-week basis.  
HRCT will be performed on Day 1 as the Baseline assessment and again at the completion of 
treatment at Week 24.  HRCT and PFTs must be done on the same day.  PFTs will be 
reviewed centrally by reviewers blinded to treatment group and time point. 
Schedule of Events 
On assessment days, the schedule of events will include the following: 
 Vital Signs and PROs 
 Full physical exam at Screening and an abbreviated physical exam thereafter 
 Pulmonary function 
o Spirometry 
o Diffusion capacity, only at Screening, Baseline and Week 28 
o TLC by nitrogen washout method, only at Screening, Baseline and Week 28 
 HRCT only at Baseline and Week 28.  HRCT will be performed with spirometry at 
selected sites. 
 ECG and Cytokines completed at baseline, prior to PRM-151 dosing.  ECG and 
cytokines will only be repeated in the event of an infusion-related reaction (IRR), as 
soon as possible once the subject is stable.  
 6MWT 
 Blood draw for tolerability/safety assessments and optional blood draw for exploratory 
biomarkers 
 PRM-151 dosing 
On loading dose days (3 and 5 of Week 0), the schedule of events will be as follows: 
 Vitals signs and adverse event assessment 
 PRM-151 dosing 
Open Label Post-Study Treatment Extension 
After completing 24 weeks of treatment, all subjects will be offered the option to receive 
PRM-151 in an open-label PRM-151 treatment extension period for an indefinite period of 
On assessment days, the schedule of events will include the following:

Vital Signs and PROs

Full physical exam at Screening and an abbreviated physical exam thereafter

Pulmonary function
Spirometry
o
Diffusion capacity, only at Screening, Baseline and Week 28
o
TLC by nitrogen washout method, only at Screening, Baseline and Week 28
o

HRCT only at Baseline and Week 28.  HRCT will be performed with spirometry at 
selected sites.

ECG and Cytokines completed at baseline, prior to PRM-151 dosing.  ECG and 
cytokines will only be repeated in the event of an infusion-related reaction (IRR), as
soon as possible once the subject is stable.

6MWT

Blood draw for tolerability/safety assessments and optional blood draw for exploratory 
biomarkers

PRM-151 dosing
Schedule of Events
On loading dose days (3 and 5 of Week 0), the schedule of events will be as follows:

Vitals signs and adverse event assessment

PRM-151 dosing

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time.  All subjects will receive PRM-151 10 mg/kg IV Days 1, 3, 5 and every 4 weeks in the 
extension. Dosing on Days 1, 3 and 5 will be repeated once every 24weeks in the extension.  
PROs, PFTs, and 6MWT will be done every 4 weeks for the first 24 weeks and then every 12 
weeks and DLco, FRC & TLC by nitrogen washout method and HRCT will be done at 1.5 
years (Week 76) and 2.5 years (Week 128). 
Safety Assessments: 
Treatment Period: Tolerability/Safety-Related Assessments 
Safety will be evaluated from reported adverse events (AEs), scheduled physical 
examinations, vital signs, and clinical laboratory test results.  Adverse events and concomitant 
medications will be assessed at all study visits. In addition, information regarding 
hospitalizations, emergency department visits, and unscheduled or urgent care visits to a 
health care provider due to a deterioration in respiratory status or symptoms will be collected 
at all study visits.   
Statistical Methods:  
The primary analysis is planned after last subject completed W28 assessment.   Continuous 
variables will be summarized by dose group with descriptive statistics (e.g., number of 
observations, number of missing observations, mean, SD, median, interquartile range, 
maximum, and minimum). Categorical variables will be tabulated by frequency of subjects per 
dose group, and percentages will be calculated using the number of available observations as 
the denominator (i.e. excluding missing values). Efficacy evaluations will be performed using 
the Full Analysis Set (FAS), defined as all subjects with a Baseline and at least 1 post-Baseline 
observation for the primary efficacy endpoint.  A per-protocol analysis will also be carried out 
on the Per Protocol (PP) set, a subset of the FAS composed of all subjects treated with the 
IMP, having received at least the planned IMP infusions on days 1, 3, 5, and weeks 4, 8 and 12 
and who did not present any major protocol deviations.  
 
The per-protocol set will be used for secondary analyses of the primary efficacy criterion and 
for the analysis of some selected secondary efficacy criteria.  Safety evaluations will be based 
on the Safety Population, defined as all subjects who receive at least 1 dose of study drug and 
have a post-Baseline safety observation.  Demographic data will be summarized for all 
subjects entering the study, and if material differences exist, for the FAS and Safety analysis 
datasets.  (Additional details will be included in the SAP.) 
 
This study is randomized with a 2:1 randomization ratio. A central randomization system will 
be used. The randomization will be stratified according to the subject’s baseline treatment 
status: baseline pirfenidone or baseline nintedanib or no other therapy for IPF at baseline. The 
randomization system will also ensure that at least 25% of the subjects in the final study 
population are on no other therapy for IPF at baseline. 
 
The comparison of PRM-151 with placebo will be carried out via 2-sided statistical tests at 
alpha=0.10. The primary endpoint will be tested with analysis of variance (ANOVA), with 
change from Baseline to week 28 in FVC% predicted as dependent variable (outcome), and 
treatment and stratum, as explanatory variables. FVC% predicted will also be analyzed 
separately for each level of the stratum variable (in subjects on a stable dose of pirfenidone or 
nintedanib and in subjects not on other treatments for IPF) using analysis of variance 

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(ANOVA), with change from Baseline to week 28 in FVC% predicted as dependent variable 
(outcome), and treatment as the explanatory variable.  In case of missing Week 28 assessment 
of FVC% predicted, the last available observation will be carried forward. 
 
A similar analysis will be done for the secondary and exploratory endpoints, replacing FVC % 
predicted with the other endpoints as appropriate.  Analyses over time will use a three-way 
ANCOVA with time (nominal study week) as the third factor, including all interactions.  The 
analysis will adjust for correlated errors over time. 
For all secondary and exploratory efficacy endpoints, the analyses will be based on observed 
data only; no data will be imputed. 
 
AEs will be coded by using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by system organ class, preferred term, and treatment 
group for the number and percent of AEs reported, the number of subjects reporting each AE, 
and the number of subjects with any AE.  A by-subject AE data listing including onset and 
resolution dates, verbatim term, preferred term, treatment, severity, relationship to treatment, 
action taken, and outcome will be provided.   
 
Safety data, including laboratory evaluations and vital signs assessments, will be summarized 
by time of collection and by treatment group.  In addition, change from Baseline to any 
post-dose values will be summarized for vital signs and clinical laboratory results.  The 
frequency of subjects with abnormal safety laboratory results will be tabulated by treatment. 
 
Sample Size Considerations: 
The primary objective is not to formally demonstrate the superiority of PRM-151 over 
placebo, but to provide a reliable estimate of the size of the effect of PRM-151 on change from 
baseline to 28 weeks in mean FVC% predicted, hereafter referred to as the primary endpoint. 
Nevertheless, the sample-size has been calculated to ensure a sufficient power to demonstrate 
the efficacy of PRM-151 over placebo on the primary endpoint under a set of hypotheses on 
effect sizes in the two groups and on the variability of the primary endpoint. The primary 
endpoint will be tested in a model taking into account the stratification variable (two types of 
subjects: subjects on a stable dose of pirfenidone, and subjects not on other treatment for IPF). 
The sample size calculation is based on the following assumptions: 
 Primary endpoint is normally distributed. 
 Homogeneity of variance, i.e. the standard deviation is the same in both arms, and 
for both types of subjects. 
 Randomization ratio PRM-151: placebo equals 2:1. 
 Expected value of the primary endpoint for subjects on pirfenidone or nintedanib 
will be -1.5. 
 Expected value of the primary endpoint for subjects on no other treatment will be -
3. 
 Expected value of the primary endpoint for subjects on PRM-151 will be ≥ 0.75. 
 Standard deviation of the primary endpoint is 5. 
 75% of subjects will be on a stable dose of pirfenidone or nintedanib. 

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 25% of subjects will not be on other treatment for IPF. 
 Significance level (α) = 0.10. 
 Desired power to demonstrate superiority is 80%. 
A sample size of one hundred and two (102) evaluable subjects in total (68 PRM-151 and 34 
placebo) is enough to demonstrate superiority at p < 0.10 with a power of 80% under the 
above assumptions. Assuming a non-evaluability rate of about 15%, 117 subjects in total (78 
PRM-151 and 39 placebo) are to be enrolled. Stratified randomization will ensure a balance of 
PRM-151: placebo in subjects on pirfenidone or nintedanib and not on any other therapy. 
Date of Original Protocol:  Version 1.0  11 November 2014 

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TABLE OF CONTENTS 
 
Synopsis ............................................................................................................ 2 
TABLE OF CONTENTS ............................................................................. 12 
1. 
Introduction and Study rationale .................................................... 19 
1.1. 
Idiopathic Pulmonary Fibrosis ............................................ 19 
1.2. 
PRM-151 ................................................................................ 20 
1.2.1. 
Preclinical Pharmacology ........................................ 21 
1.2.2. 
Nonclinical Metabolism and Pharmacokinetics ...... 21 
1.2.3. 
Toxicology ............................................................... 21 
1.2.4. 
Clinical Experience in Healthy Subjects and Subjects 
with IPF and Myelofibrosis (MF) ............................ 22 
1.3. 
Quantitative Imaging ............................................................ 24 
1.3.1. 
Imbio Lung Texture Analysis .................................. 25 
1.3.2. 
Retrospective Quantitative Imaging Analysis of 
PRM-151 Data ......................................................... 25 
1.4. 
Rationale for Current Study ................................................ 26 
1.5. 
Risk/Benefit Assessment ....................................................... 26 
2. 
Study Objectives................................................................................ 29 
2.1. 
Primary Objectives ............................................................... 29 
2.2. 
Secondary Objectives............................................................ 29 
2.3. 
Exploratory Objectives ......................................................... 29 
3. 
Study Endpoints ................................................................................ 30 
3.1. 
Primary Endpoint ................................................................. 30 
3.2. 
Secondary Endpoints ............................................................ 30 
3.3. 
Exploratory Endpoints ......................................................... 31 
4. 
Investigational Plan .......................................................................... 33 
4.1. 
Overall Study Design and Plan ............................................ 33 
4.1.1. 
Treatment Period: Efficacy-related Assessments .... 33 
4.1.2. 
Treatment Period: Tolerability/Safety-Related 
Assessments ............................................................. 33 
4.1.3. 
Open Label Post-Study Treatment Extension .......... 34 
4.1.4. 
Study Duration ......................................................... 34 

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5. 
Selection of Study Population .......................................................... 35 
5.1. 
Study Population ................................................................... 35 
5.1.1. 
Inclusion Criteria ..................................................... 35 
5.1.2. 
Exclusion Criteria .................................................... 36 
5.2. 
Withdrawal and Replacement of Subjects ......................... 37 
5.3. 
Study Termination ................................................................ 37 
5.4. 
Subject Management ............................................................ 37 
5.5. 
Investigator Compliance ...................................................... 38 
5.6. 
Subject Adherence ................................................................ 38 
5.7. 
Data Monitoring Committee ................................................ 38 
6. 
Study Treatment(s) ........................................................................... 39 
6.1. 
Investigational Product ........................................................ 39 
6.2. 
Treatment(s) Administered .................................................. 39 
6.3. 
Method of Assigning Subjects to Treatment Groups ........ 40 
6.4. 
Blinding .................................................................................. 40 
6.4.1. 
Procedures for Breaking the Blind........................... 40 
6.5. 
Study Drug Supply ................................................................ 40 
6.6. 
Packaging and Labeling ....................................................... 41 
6.7. 
Storage and Accountability .................................................. 41 
6.8. 
Rationale for the Dose(s) Selected ....................................... 41 
7. 
Study procedures .............................................................................. 42 
7.1. 
Informed Consent ................................................................. 42 
7.2. 
Study Entrance Criteria ....................................................... 42 
7.3. 
Demographics ........................................................................ 42 
7.4. 
Past Medical History............................................................. 42 
7.5. 
Height and Weight ................................................................ 42 
7.6. 
Laboratory Variables ........................................................... 42 
7.6.1. 
Hematology and Clinical Chemistries ..................... 43 
7.6.2. 
ECG and Cytokines ................................................. 43 
7.6.3. 
Pregnancy Testing.................................................... 43 
7.7. 
Physical Examination ........................................................... 43 

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7.8. 
Vital Signs .............................................................................. 44 
7.9. 
Concurrent Medications ....................................................... 44 
7.9.1. 
Prohibited Concurrent Medications ......................... 45 
7.10. Efficacy Measurements ........................................................ 45 
7.10.1. 
Pulmonary Function Tests ....................................... 45 
7.10.2. 
Six-minute Walk Test .............................................. 45 
7.10.3. 
High-resolution Computed Tomography ................. 46 
7.10.4. 
Patient Reported Outcomes ..................................... 46 
7.10.5. 
Pentraxin-2 Levels ................................................... 46 
7.10.6. 
Anti-Pentraxin 2 antibodies / Anti-Drug Antibodies 
(ADA) ...................................................................... 46 
7.11. Biomarker Assessments ........................................................ 46 
7.11.1. 
Baseline Genetic Status ........................................... 46 
7.11.2. 
Optional Blood Sample Collection for Biomarker 
Assessment............................................................... 47 
7.12. Safety Measurements ............................................................ 47 
7.12.1. 
Adverse Events ........................................................ 47 
7.12.2. 
Adverse Event Assessment ...................................... 49 
7.12.3. 
Recording Adverse Events....................................... 50 
7.12.4. 
Reporting Serious Adverse Events .......................... 51 
7.12.5. 
Reporting Pregnancies ............................................. 52 
7.12.6. 
Reporting of SAEs to METC (The Netherlands 
only) ......................... Error! Bookmark not defined. 
8. 
Statistical Analyses............................................................................ 53 
8.1. 
Statistical Basis for Sample Size .......................................... 53 
8.2. 
General considerations for statistical analysis ................... 53 
8.2.1. 
Statistical Analysis Plan........................................... 53 
8.2.2. 
Descriptive statistics ................................................ 54 
8.2.3. 
Inferential statistics .................................................. 54 
8.2.4. 
Interim Analyses ...................................................... 54 
8.2.5. 
Software used for statistical analyses ...................... 54 

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8.3. 
Protocol deviations ................................................................ 54 
8.4. 
Analysis datasets ................................................................... 55 
8.5. 
Planned Statistical analyses ................................................. 55 
8.5.1. 
Efficacy Analyses .................................................... 55 
8.5.2. 
Safety Analyses........................................................ 57 
8.5.3. 
Other Analyses ......................................................... 57 
9. 
Ethical, Legal, and Administrative Considerations ....................... 58 
9.1. 
Good Clinical Practice .......................................................... 58 
9.2. 
Informed Consent ................................................................. 58 
9.3. 
Institutional Review Board/Ethics Committee ................... 58 
9.4. 
Amending the Protocol ......................................................... 59 
9.5. 
Confidentiality ....................................................................... 59 
9.6. 
Publication Policy.................................................................. 59 
10. 
Study Management ........................................................................... 60 
10.1. Case Report Forms and Source Documentation ................ 60 
10.2. Monitoring ............................................................................. 60 
10.3. Inspections ............................................................................. 60 
10.4. Financial Disclosure Reporting Obligations ....................... 60 
10.5. Archiving Study Records ..................................................... 60 
11. 
REFERENCES .................................................................................. 62 
12. 
APPENDIX A      Schedule of events ............................................... 64 
13. 
APPENDIX B      Six-minute Walk Test ......................................... 70 
14. 
APPENDIX C      Borg Scale ............................................................ 74 
15. 
APPENDIX D       The King’s Brief Interstitial Lung  Disease 
Questionnaire (K-BILD) .................................................................. 75 
16. 
APPENDIX E       Summary of changes ......................................... 76 
17.       APPENDIX F       National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) 
18. 
APPENDIX G         Leicester Cough Questionnaire (LCQ) ......... 84 
 

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 LIST OF ABBREVIATIONS 
Abbreviation 
Term 
6MWD 
6-Minute walk distance 
6MWT 
Six-minute walk test 
ADL 
Activities of daily living 
ADA 
Anti-Drug Antibodies/Anti-Pentraxin 2 antibodies 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse Event of Special Interest 
ALAT 
Latin American Thoracic Association 
ALK 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC0-24 
Area under the curve from time 0 to 24 hours 
AUC0-∞ 
Area under the curve from time 0 extrapolated to infinity 
BAL 
Bronchoalveolar lavage 
BID 
Twice daily 
BRT 
Bronchodilator reversibility testing 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
CRA 
Clinical Research Associate 
CTGF 
Connective tissue growth factor 
DLCO 
Diffusion Capacity of Carbon Monoxide 
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
ECM 
Extracellular matrix 
eCRF 
Electronic case report form 
ERS 
European Respiratory Society  
EU 
European Union 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
hPTX-2 
Human pentraxin-2 
HRCT 
High-resolution computed tomography 

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Abbreviation 
Term 
hSAP 
Human serum amyloid P(synonymous with hPTX-2) 
IC 
Inspiratory capacity 
ICAM-1 
Intercellular adhesion molecule-1 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IL 
Interleukin 
ILA 
Interstitial Lung Abnormality 
ILD 
Interstitial Lung Disease 
IND 
Investigational New Drug Application 
IPF 
Idiopathic pulmonary fibrosis 
IRB 
Institutional Review Board 
IV 
Intravenous 
JRS 
Japanese Respiratory Society 
LAA 
Low Attenuatino Areas 
LOXL2 
Lysyl oxidase-like 2 protein 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Myelofibrosis 
Mreg 
Regulatory macrophages 
mRNA 
Messenger ribonucleic acid 
O2 
Oxygen 
PDGF 
Platelet-derived growth factor 
PFT 
Pulmonary function test 
PK 
Pharmacokinetics 
pp 
Percentage points 
PRO 
Patient Reported Outcome 
PTX-2 
Pentraxin-2 
q2w 
Every 2 weeks 
q4w 
Every 4 weeks 
RBC 
Red blood cell 
SABA 
Short-acting beta agonist 
SAE 
Serious adverse event 
SAP 
Serum amyloid protein, also 
Statistical Analysis Plan 
SD 
Standard deviation 
SD-SOBQ 
San Diego-Shortness of Breath Questionnaire 
SGRQ 
St. George Respiratory Questionnaire 

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Abbreviation 
Term 
SP-D 
Surfactant protein D 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
TGF-β 
Transforming growth factor-beta 
TK 
Toxicokinetic 
TWA 
Time-weighted average 
UK 
United Kingdom 
US 
United States 
VCAM-1 
Vascular cell adhesion molecule 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 

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1. 
INTRODUCTION AND STUDY RATIONALE 
1.1. 
Idiopathic Pulmonary Fibrosis 
Idiopathic pulmonary fibrosis (IPF) is a rare, specific form of chronic, fibrosing, 
interstitial pneumonia limited to the lung.  In the United States (US), IPF is estimated to 
affect up to 135,000 individuals, with approximately 50,000 cases being diagnosed 
annually (Raghu, Weycker et al. 2006). It is estimated that each year, 40,000 people in 
the US die due to IPF or complications thereof (Raghu, Weycker et al. 2006), the same as 
for breast cancer.  There is limited information regarding the incidence and prevalence of 
IPF in the European Union (EU); however, it is estimated that up to 40,000 individuals 
are affected, with 5,000 cases diagnosed annually in the United Kingdom (UK) alone 
(Navaratnam, Fleming et al. 2011). IPF incidence and prevalence increase with age and 
are higher among males (Nalysnyk, Cid-Ruzafa et al. 2012).  Overall, it is estimated that 
worldwide, 5 million individuals may be affected(Meltzer and Noble 2008).  Although 
rare, the incidence of IPF is increasing, likely due to an increasing understanding of the 
disease and the recent development of uniform diagnostic criteria (Nalysnyk, Cid-Ruzafa 
et al. 2012) 
IPF is a progressive disease with significant morbidity and mortality. The precise 
initiating injury is unknown, and the clinical course of IPF is variable.  The fibrosis that 
develops in IPF follows a similar path to normal wound healing, but is progressive and 
without resolution.  A loss of control of the mechanisms halting the normal wound 
healing process leads to persistence of inflammatory cells (particularly monocyte-derived 
cell populations such as macrophages and fibrocytes), elevated levels of cytokines, 
chemokines, growth factors and other signaling molecules, excessive deposition of 
collagen types 1 and 3, and inhibition of enzymes that degrade extracellular matrix 
(ECM) proteins (Lupher and Gallatin 2006).  Over time, continuing insults result in 
progressive lung fibrosis (pathologic accumulation of excessive ECM), and increasingly 
compromised lung function due to thickening/stiffening of the alveoli.  Signs and 
symptoms that develop over time include exertional dyspnea and cough as well as 
fatigue, weight loss, myalgia, and clubbing of the fingers and toes. 
Ultimately, IPF leads to death, with a median survival after diagnosis of 3 years and a 
5-year survival rate of 20% to 40% (Gomer and Lupher 2010). Estimates are that IPF is 
the primary cause of death for 60% of subjects with IPF, with death commonly occurring 
after an acute exacerbation of the disease. When an acute exacerbation of IPF is not the 
cause of death, other common causes include acute coronary syndromes, congestive heart 
failure, lung cancer, infection, and venous thromboembolic disease (Frankel and Schwarz 
2009). 
No cure currently exists for IPF. There are two approved therapies in the United States 
and one in Europe. Pirfenidone was approved in the EU on February 28, 2011, for 
treatment of mild to moderate idiopathic pulmonary fibrosis (IPF), based on a statistically 
significant reduction in the decline of percent predicted FVC from Baseline at Week 72 
(p=0.001) in subjects receiving pirfenidone compared with subjects receiving placebo. 

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Pirfenidone received approval in the US on October 15, 2014, for treatment of Idiopathic 
Pulmonary Fibrosis, based on the previous data and a new Phase 3 study, which 
demonstrated a statistically significant treatment effect of pirfenidone compared to 
placebo in change in % FVC from baseline to Week 52, with the proportion of subjects 
declining being lower on pirfenidone than on placebo.  Nintedanib was approved in the 
US on October 15, 2014, for Idiopathic Pulmonary Fibrosis, based on a statistically 
significant reduction in the annual rate of decline of FVC (in mL) in subjects receiving 
nintedanib compared to subjects receiving placebo in 3 clinical trials. 
As effective treatment options for IPF have been limited until recently, affected subjects 
also receive supportive therapies and palliative care.  As the clinical course of IPF is 
variable, strategies to treat the disease are individualized, based on the subject’s medical 
history and clinical condition.  Such treatments may include long-term oxygen (O2) 
therapy; pulmonary rehabilitation; opiates; anti-reflux therapy; and low dose 
corticosteroids to treat cough.  Although such therapies may ameliorate subjects’ 
symptoms and improve comfort, they do not slow the progression of the disease or 
prolong survival.  One exception is lung transplantation, which may be considered for 
subjects at increased risk of mortality, leads to an improvement in 5-year survival post-
transplantation to 50 to 56% (Raghu, Collard et al. 2011).However, transplantation is 
generally recommended for subjects aged <60 years and, given that IPF is primarily a 
disease of the elderly with a mean age at diagnosis of 74 years (Fernandez Perez, Daniels 
et al. 2010), most subjects do not fall into a group for which transplant is a likely option. 
1.2. 
PRM-151 
Pentraxin-2 (PTX-2), also called serum amyloid P (SAP), is an endogenous protein that 
circulates in the bloodstream.  Recent discoveries about the biology of tissue repair and 
fibrosis have elucidated the important role that PTX-2 plays biologically in regulating 
processes that relate to scar prevention and healing. PTX-2 is an agonist that binds to Fc 
gamma receptors on monocytes and promotes their differentiation into regulatory 
macrophages (Mreg), which function to promote epithelial healing and resolution of 
inflammation and scarring.  PTX-2 also prevents the differentiation of monocytes into 
M2 pro-fibrotic macrophages and fibrocytes, preventing the formation of fibrosis.  Both 
increased fibrocyte numbers in circulation (Moeller, Gilpin et al. 2009) and decreased 
levels of circulating PTX-2 (Murray, Chen et al. 2011) have been characterized in IPF 
subjects relative to healthy subjects. 
PRM-151 is a recombinantly-expressed version of human pentraxin-2 (hPTX-2). Like the 
native human protein, PRM-151 is expressed and purified as a non-covalent, homo-
pentameric glycoprotein. Each monomer in the pentamer is comprised of 204 amino 
acids with one N-linked glycosylation site at Asn32 possessing a typical complex 
biantennary structure. There is one intramolecular disulfide bond between the only 2 
cysteine residues in each monomer: Cys36-Cys95. The average molecular weight of the 
fully glycosylated, sialylated pentamer is 127313 Da. 

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Preclinical and clinical data exist to support the investigation of PRM-151 in the 
treatment of fibrotic diseases.  
1.2.1. 
Preclinical Pharmacology 
Following the initial in vitro discovery by Gomer and Pilling suggesting that PTX-2 may 
regulate monocyte differentiation into spindle shaped fibrocytes (Pilling, Buckley et al. 
2003), they, with others, published several studies on the activity of species-specific 
serum-derived PTX-2 in preventing fibrosis in models of bleomycin-induced lung 
fibrosis in rats and mice and also in a model of ischemia reperfusion injury to mouse 
heart (Pilling, Roife et al. 2007),(Haudek, Xia et al. 2006). Promedior and its 
collaborators have expanded the animal fibrosis model data using human serum-derived 
PTX-2 and PRM-151 to demonstrate potent anti-fibrotic activity in models of lung injury, 
skin injury, kidney injury, liver injury, radiation-induced injury, and a rabbit 
trabeculectomy model of eye injury. 
1.2.2. 
Nonclinical Metabolism and Pharmacokinetics 
The half-life (t1/2) of IV-dosed PTX-2/PRM-151 (2-7 mg/kg) has been calculated for 
multiple species, with the following results: mouse (4-8 hr) < rabbit (7.3 hr) < monkey 
(6-15 hr) < rat (13-23 hr) < human (30 hr, [human t1/2 from Promedior single, ascending 
dose study, PRM151A-11EU; 10 mg/kg dose in healthy volunteers])(Hawkins, Wootton 
et al. 1990). 
Toxicokinetics (TK) in the rat and monkey 14-day repeat IV-dose studies showed dose-
proportional increases in systemic exposure, with slight to moderate increases in 
exposure with multiple dosing. Anti- PRM-151 antibodies were detected following 
multiple doses, but did not appear to affect the TK parameters in these studies.  In a 6 
month toxicology study in rats, Cmax and AUC were dose proportional at baseline but 
not at later time points.  Investigation of this phenomenon indicates that AUC at later 
time points is falsely low due to interference by Anti-Drug Antibodies/ Anti-Pentraxin 2 
antibodies (ADA) in the PK assay. 
Following IV administration of radiolabeled PRM-151, the highest percentage of the 
administered dose was measured in the systemic tissues at 1 hr post-dose; the highest 
values were in the liver, kidneys, lung, and spleen. A CYP450 inhibition/stimulation 
study showed no inhibition of the 5 enzymes tested. 
1.2.3. 
Toxicology 
No adverse toxicological effects were observed in 14-day IV daily dose studies in 
Sprague Dawley rats at doses ranging from 10 to 200 mg/kg/day or in cynomolgus 
monkeys at doses ranging from 12 to 120 mg/kg/day.  The no observed adverse effect 
level (NOAEL) of 14 daily IV doses of PRM-151 was set at ≥ 200 mg/kg in rats and 
≥ 120 mg/kg in cynomolgus monkeys.  Six-month toxicology studies were initiated in 
Sprague Dawley rats and cynomolgus monkeys employing weekly dosing, and acute 
infusion reactions, some resulting in death, occurred in both studies beginning on Day 15. 
.
Toxicokinetics (TK) in the rat and monkey 14-day repeat IV-dose studies showed dose-
proportional increases in systemic exposure, with slight to moderate increases in 
exposure with multiple dosing. Anti- PRM-151 antibodies were detected following 
multiple doses, but did not appear to affect the TK parameters in these studies.  In a 6
month toxicology study in rats, Cmax and AUC were dose proportional at baseline but 
not at later time points.  Investigation of this phenomenon indicates that AUC at later 
time points is falsely low due to interference by Anti-Drug Antibodies/ Anti-Pentraxin 2 
antibodies (ADA) in the PK assay. 
Following IV administration of radiolabeled PRM-151, the highest percentage of the
administered dose was measured in the systemic tissues at 1 hr post-dose; the highest 
values were in the liver, kidneys, lung, and spleen. A CYP450 inhibition/stimulation 
study showed no inhibition of the 5 enzymes tested.
1.2.3.
Toxicology
No adverse toxicological effects were observed in 14-day IV daily dose studies in
Sprague Dawley rats at doses ranging from 10 to 200 mg/kg/day or in cynomolgus 
monkeys at doses ranging from 12 to 120 mg/kg/day.  The no observed adverse effect 
level (NOAEL) of 14 daily IV doses of PRM-151 was set at ≥200 mg/kg in rats and 
≥120 mg/kg in cynomolgus monkeys. Six-month toxicology studies were initiated in 
Sprague Dawley rats and cynomolgus monkeys employing weekly dosing, and acute
infusion reactions, some resulting in death, occurred in both studies beginning on Day 15.

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The infusion reactions in rats were managed by slowing the rate of infusion and reducing 
the highest dose from 200 to 150 mg/kg, and the study continued to completion, with a 
NOAEL of 100 mg/kg based on a death of one rat unrelated to an acute infusion reaction 
at the 150/200 mg/kg dose.  There were also adverse findings of liver fibrosis at the 
150/200 mg/kg dose level.  The monkey study was terminated early after a death at the 
lowest dose level due to an infusion reaction.  The acute infusion reactions were 
determined to be secondary to complement activation by anti-drug antibodies to PRM-
151, a human protein foreign to both test species. 
Reproductive and developmental toxicity studies have not been conducted with 
PRM-151.  Increased testes weights were observed in a mouse dose range-finding study, 
but the relationship to test article administration could not be determined due to the small 
number of animals in the study.  However, no treatment-related findings (organ weights 
or histopathology) were identified in the reproductive organs of rats or cynomolgus 
monkeys in the 14-day or rats in the 6-month IV dose toxicology studies.  Women of 
childbearing potential will be required to take precautions to prevent pregnancy in the 
current study. 
As noted above, PRM-151 is immunogenic in non-human species.  Phenotypes of 
deficient or knockout mice may identify potential consequences of PRM-151-induced 
neutralizing or depleting antibodies to hPTX-2. To date, there has been no toxicity 
associated with complete deficiency of PTX-2 in mice (Gillmore, Hutchinson et al. 
2004), and therefore the toxicity risks due to generation of depleting or neutralizing 
antibodies to PRM-151 or hPTX-2 are considered low. 
PRM-151 is dose equivalent in humans and non-human species, and the dose of 10 
mg/kg selected for the current study has a safety margin of 10 compared to the rat 
NOAEL of 100 mg/kg.  Moreover, the NOAEL in rats was based on 10 mg/kg every 
week with a total of 2600 mg/kg in 26 weeks, whereas humans are being dosed at 10 
mg/kg days 1, 3, and 5 and then every 4 weeks for a total of 90 mg/kg in 24 weeks. 
1.2.4. 
Clinical Experience in Healthy Subjects and Subjects with IPF and 
Myelofibrosis (MF) 
PRM-151 administered IV has been investigated in 18 healthy subjects and in 18 subjects 
with IPF.  PRM-151 is being investigated in an ongoing Phase 2 study in subjects with 
MF in which 27 subjects enrolled, 20 subjects completed 24 weeks of treatment, and 10 
subjects have received at least 36 weeks of treatment in a study extension.  
In a single ascending dose study (PRM151A-11EU), there were no dose limiting 
toxicities and no serious adverse events (SAEs) were noted. The most frequent (≥15%) 
treatment-emergent adverse events (TEAE) for the PRM-151-treated subjects were 
fatigue (38%) and headache (19%). Overall, the data indicate that single doses of 0.1, 
0.25, 0.5, 1, 2, 5, 10, and 20 mg/kg were safe and well tolerated. The t1/2 of IV 
administered PRM-151 was approximately 30 hours. The PK profile of PRM-151 was 
linear and similar in healthy subjects and subjects with IPF. 
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The infusion reactions in rats were managed by slowing the rate of infusion and reducing
the highest dose from 200 to 150 mg/kg, and the study continued to completion, with a 
NOAEL of 100 mg/kg based on a death of one rat unrelated to an acute infusion reaction
at the 150/200 mg/kg dose.  There were also adverse findings of liver fibrosis at the
150/200 mg/kg dose level.  The monkey study was terminated early after a death at the
lowest dose level due to an infusion reaction.  The acute infusion reactions were
determined to be secondary to complement activation by anti-drug antibodies to PRM-
151, a human protein foreign to both test species. 
Reproductive and developmental toxicity studies have not been conducted with
PRM-151.  Increased testes weights were observed in a mouse dose range-finding study, 
but the relationship to test article administration could not be determined due to the small
number of animals in the study.  However, no treatment-related findings (organ weights
or histopathology) were identified in the reproductive organs of rats or cynomolgus
monkeys in the 14-day or rats in the 6-month IV dose toxicology studies.  Women of 
childbearing potential will be required to take precautions to prevent pregnancy in the
current study.
As noted above, PRM-151 is immunogenic in non-human species.  Phenotypes of 
deficient or knockout mice may identify potential consequences of PRM-151-induced 
neutralizing or depleting antibodies to hPTX-2. To date, there has been no toxicity 
associated with complete deficiency of PTX-2 in mice (Gillmore, Hutchinson et al.
2004), and therefore the toxicity risks due to generation of depleting or neutralizing 
antibodies to PRM-151 or hPTX-2 are considered low. 
PRM-151 is dose equivalent in humans and non-human species, and the dose of 10 
mg/kg selected for the current study has a safety margin of 10 compared to the rat 
NOAEL of 100 mg/kg. Moreover, the NOAEL in rats was based on 10 mg/kg every 
week with a total of 2600 mg/kg in 26 weeks, whereas humans are being dosed at 10
mg/kg days 1, 3, and 5 and then every 4 weeks for a total of 90 mg/kg in 24 weeks. 
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In a multiple ascending dose study (PRM151F-12GL), 21 subjects with IPF were 
enrolled in successive cohorts of 7 subjects each, randomized 5:2 to receive either 
PRM-151 or placebo. Each cohort was assigned a progressively increasing dose level of 
PRM-151: 1, 5, or 10 mg/kg administered IV on Days 1, 3, 5, 8 and 15.  Subjects in all 3 
PRM-151 dose groups demonstrated improvement in FVC% predicted at Day 57 after 
receiving PRM-151 on Days 1, 3, 5, 8 and 15.  Mean change from Baseline in FVC% 
predicted at Day 57 was + 2.4 (standard deviation [SD] 3.8) for all PRM-151-treated 
subjects versus -1.5 (SD 3) for placebo-treated subjects (p=0.0524). Furthermore, 6 out of 
14 PRM-151 treated subjects experienced a relative increase from Baseline of at least 5% 
in FVC % predicted.  Review of other pulmonary function tests (PTFs) showed an 
increase from Baseline in forced expiratory volume in 1 second (FEV1) in all 3 dose 
groups, whereas a decrease from Baseline was seen in the placebo group; none of the 
between group differences was statistically significant.  Mean PFTs at Baseline and 
change from Baseline on Day 57 are summarized in Table 1-1. 
Table 1-1: 
Mean (SD) Pulmonary Function Tests at Baseline and Change from 
Baseline to Day 57:  Study PRM-151F-12GL 
Parameter 
Placebo 
(N=6) 
PRM-151 
1 mg/kg 
(N=5) 
5 mg/kg 
(N=5) 
10 mg/kg 
(N=4) 
All Doses 
(N=14) 
FVC (liters) 
 
 
 
 
 
Baseline  
2.2 (0.64) 
3.0 (0.85) 
2.8 (0.73) 
3.0 (0.71) 
2.9 (0.71) 
∆ from 
Baseline 
-0.06 
(0.116) 
0.06 
(0.164) 
0.06 
(0.074) 
0.08 
(0.210) 
0.06 
(0.142) 
FVC % predicted 
(%) 
 
 
 
 
 
Baseline 
63 (16.7) 
82 (15.5) 
80 (7.8) 
73 (14.3) 
79 (12.5) 
∆ from 
Baseline 
-1.5 (3.3) 
2.4 (4.6) 
2.8 (3.0) 
1.8 (5.3) 
2.4 (4.0) 
DLCO (%) 
 
 
 
 
 
Baseline 
35 (8.4) 
41 (10.5) 
53 (9.8) 
46 (7.2) 
47 (10.1) 
∆ from 
Baseline 
-2.3 (2.1) 
0.2 (3.3) 
-4.0 (6.8) 
-1.5 (3.8) 
-1.8 (4.9) 
FEV1 (%) 
 
 
 
 
 
Baseline 
69 (17.7) 
86 (16.8) 
87 (11.9) 
73 (12.1) 
83 (14.3) 
∆ from 
Baseline 
-1.7 (4.3) 
2.6 (4.3) 
2.4 (1.1) 
0.3 (3.8) 
1.9 (3.2) 
 
Results of the 6-minute walk test (6MWT) showed that on Day 57, the distance walked 
was decreased from Baseline by a mean of -11 (SD, 51) meters in the placebo group 
compared with a numerical improvement in each of the 5 mg/kg, 10 mg/kg, and all dose 
combined groups [+6 (SD, 43), +35 (SD, 45), and +8 (SD, 51) meters, respectively], 

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although these differences were not statistically significant.   No infusion reactions, no 
dose-limiting toxicity and no serious adverse events were observed. In addition, no 
antibodies to PRM-151 were measured. In the PRM-151-treated subjects, the most 
common adverse events recorded during the study were cough (n = 7; 47%), productive 
cough (n=4; 27%) followed by fatigue (n = 3; 20%) and headache (n = 3; 20%). The 
incidence of these events was comparable in the placebo group [cough, 33% (n = 2); 
productive cough, 33% (n = 2); fatigue, 17% (n = 1) and headache, 17% (n = 1)]. Neither 
the nature nor the frequency of these reported adverse events increased with ascending 
PRM-151 dose levels. One subject in the 1 mg/kg dose group experienced an episode of 
moderate hypotension and dizziness just before administration of the third dose of PRM-
151. These symptoms were considered possibly related to PRM-151 administration, and 
resulted in discontinuation of PRM-151 treatment for that specific subject. 
In a Phase 2 study in subjects with myelofibrosis treated with PRM-151 either weekly or 
every 4 weeks, either alone or added to a stable dose of ruxolitinib, data on all 20 subjects 
who completed 24 weeks of treatment and 10 who have completed at least 36 weeks of 
treatment as of Sept. 29, 2014 have demonstrated reduction in bone marrow fibrosis in 9 
subjects and improvement in anemia and/or thrombocytopenia in 9 subjects, 5 of whom 
also had bone marrow improvement.  Treatment emergent adverse events have been 
mostly mild (Grade 1 or 2 by the CTCAE criteria) and unrelated to PRM-151.  There 
were 2 instances of infusion reactions (Grade 2); in each case, subsequent treatments 
were uneventful with diphenhydramine and dexamethasone administered prior to 
treatment.  There were 5 serious adverse events (SAEs) considered possibly related, 
including 1 death.  These included abdominal pain (recovered), sialadenitis (recovered), 
respiratory syncytial virus (recovered), and gastroenteritis (norovirus documented in 
entire family) and pneumonia (death).  There were two unrelated deaths including 
pneumonia (subject voluntarily discontinued all medications including antibiotics and 
subsequently died) and multi-organ failure and cardiac arrest (automatic implantable 
cardioverter defibrillator failed) after bone marrow biopsy site hematoma in a subject 
with a pre-existing arrhythmia.  In summary, reported adverse events have been 
consistent with morbidity and mortality expected in this subject population and with 
adverse events reported in the treatment and placebo arms of ruxolitinib clinical trials 
(Verstovsek, Mesa et al. 2012).  
Based on these encouraging data, Promedior has planned the current study to investigate 
the effects of PRM-151administered through Week 24 to a population of subjects with 
IPF. 
1.3. 
Quantitative Imaging 
This study incorporates quantitative imaging to assess the degree of change in pulmonary 
fibrosis.  Background information for the technique is provided below: 

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1.3.1. 
Imbio Lung Texture Analysis 
Imbio Lung Texture Analysis classifies each voxel of lung parenchyma based on 
morphology, texture and density characteristics.  The quantitative results label each 
region as normal parenchyma, interstitial lung abnormality (ILA: with ground glass 
opacity, reticular densities, and honeycombing texture types) and Low Attenuation Areas 
(LAA; with mild, moderate, and severe types).  It quantifies these characteristics by total 
volume (cm³) or % total lung volume.  Requirements for optimal use of Imbio Lung 
Texture Analysis software include inspiratory non-contrast enhanced HRCT (images 
obtained at TLC), volumetric scans with slice thickness ≤ 5mm (ideally less than 2mm), 
and CT data that has not been modified by edge enhancement filters as part of the 
reconstruction process.  Previous studies have shown that quantification of lung 
parenchyma by Imbio Lung Texture Analysis is comparable to but more reproducible 
than radiologist assessment (Zavaletta, Bartholmai et al.), that these parameters correlate 
with known markers of disease severity such as  FVC%, DLCO, 6MWT² and GOLD 
classification (Raghunath 2014) and that changes in ILA features over time are predictive 
of mortality in UIP (Maldonado, Moua et al.). The Lung Texture Analysis software was 
previously utilized for quantitative evaluation of HRCT data in greater than 4000 ILD 
and COPD subjects within the NHLBI/NIH-funded Lung Tissue Research Consortium 
effort. This technique was used in a retrospective analysis of PRM-151 data as described 
below and will be used prospectively in this study as a secondary endpoint. 
1.3.2. 
Retrospective Quantitative Imaging Analysis of PRM-151 Data 
Imbio Lung Texture Analysis was applied retrospectively to HRCT obtained at screening 
and Day 57 in Study PRM151f-12GL.  Limitations of retrospective analysis included, the 
fact that the datasets contained reconstructed images of variable slice thickness, 
reconstruction kernel and temporal correlation with the physiologic tests were available.  
In particular, the slice thicknesses for some CT scans were ≥ 5 mm for some subjects and 
volumetric HRCT was not available at both time points for any of the subjects.  In 
addition, validation of the inspiratory volume was not prospectively controlled, with full 
inspiration of the subjects during the scan assumed but not specifically coached by the 
performing technologist or measured by spirometry.  Lung Texture Analysis results were 
reported as change from screening to Day 57 in % total lung volume occupied by any of 
the ILA texture types (ground glass, reticular or honeycombing) and non-ILA (normal 
parenchyma or mild LAA).  Areas of moderate or severe LAA that are characteristic of 
emphysema were excluded from the analysis.  Quantitative imaging data was analyzed in 
16 subjects who had ≤ 36 days between screening CT and Day 1 PFTs. There was a 
strong negative correlation between baseline FVC % predicted and percent of lung 
volume identified as ILA by Imbio Lung Texture Analysis software. Non-ILA lung 
decreased in all placebo subjects and was stable or increased in 5 PRM-151 treated 
subjects, all of whom had stable or increased FVC % predicted. There was no clear 
correlation between the magnitude of change in FVC% predicted and %Non-ILA, 
possibly due the limitations inherent to retrospective analysis of the HRCT data.  The 
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atelectasis and increase in overall lung density for the HRCT series that should have been 
performed at TLC on the Day 57.  
1.4. 
Rationale for Current Study 
IPF is a progressive disease that leads to significant morbidity and mortality, with a 
median survival after diagnosis of 3 years and a 5-year survival rate of 20 to 40% (Gomer 
and Lupher 2010).  Despite the two recently approved therapies, no therapies have yet 
been developed for IPF that meaningfully reverse the progressive lung fibrosis that is the 
basic pathologic feature of the disease and no therapies have reproducibly demonstrated 
an improvement in lung function. IPF remains a progressive disease with no cure other 
than lung transplant in selected subjects. Thus, there is still a significant unmet medical 
need for subjects with IPF, particularly those with severe disease (Nalysnyk, Cid-Ruzafa 
et al. 2012). 
As summarized previously, encouraging efficacy data were obtained in a Phase 1 study of 
PRM-151 in a relatively small number of subjects with IPF (n=15) who received 
PRM-151 administered via 30-minute IV infusion at doses of 1, 5, and 10 mg/kg on 
Days 1, 3, 5, 8, and 15, with all 3 groups demonstrating improvement in FVC % 
predicted at Day 57.  Furthermore, 6 out of 14 PRM-151 treated subjects experienced a 
relative improvement of at least 5% from Baseline in FVC % predicted.  These results 
seen at 8 weeks post-Baseline after 5 PRM-151 doses administered over 2 weeks are 
encouraging, particularly considering that the best result with pirfenidone and nintedanib 
is a reduction in the rate of decline rather than improvement in FVC (King, Bradford et 
al.; Richeldi, du Bois et al.).  Improvements from Baseline were also observed in FVC 
measured in milliliters and in 6MWT distance for PRM-151-treated subjects.  Review of 
safety data from this study demonstrated that PRM-151at doses up to 10 mg/kg were safe 
and well tolerated in subjects with IPF. No SAEs were observed over 57 days, and 
similar types and number of TEAEs were reported in both PRM-151- and placebo-treated 
subjects. 
Based on these encouraging data in a small cohort of subjects with IPF, Promedior has 
planned to investigate the effects of PRM-151 in the proposed study involving a larger 
population of subjects with this condition. 
1.5. 
Risk/Benefit Assessment 
PRM-151, a recombinant form of an endogenous human protein, has been well tolerated 
in preclinical toxicology studies and Phase 1 and 2 clinical studies, and has shown an 
early trend towards efficacy in subjects with IPF.  Based on encouraging Phase 1 data in 
subjects with IPF, PRM-151 has the potential to be a safe, disease modifying treatment 
for a broad spectrum of fibrotic diseases, including IPF. 
PRM-151 represents the recombinant version of an endogenous human serum protein, 
and as such was predicted to have a very favorable safety index.  This prediction has been 
confirmed in multiple preclinical and clinical studies to date.  Two Phase 1 studies of 

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PRM-151 administered IV to normal volunteers and IPF subjects have been completed, 
with no SAEs reported and no other safety signals seen. The single ascending dose study 
(PRM151A-11EU) tested dose levels as high as 20 mg/kg. The multiple ascending dose 
study (PRM151F-12GL) demonstrated that PRM-151 administered by 30-minute IV 
infusion on Days 1, 3, 5, 8 and 15 at up to 10 mg/kg was safe and well tolerated in 
subjects with IPF, with no SAEs noted in 57 days; similar types and number of TEAEs 
were reported in both PRM-151 and placebo treated subjects.  Safety data from 27 
subjects with MF, including 24 weeks of safety data in 20 subjects and an additional 12 
weeks of safety data in 10, confirms the excellent safety profile of PRM-151 to date. 
Most adverse events have been Grade 1 or 2 and unrelated to PRM-151, and 5 possibly 
related SAEs, including one death, have been reported in a group of older subjects 
(median age 67 years) with a serious, life threatening disease. 
Risks associated with PRM-151 are inherent in its being the recombinant form of a 
naturally occurring human protein, and consist of potential development of anti-drug 
antibodies and infusion reactions.  PRM-151 has an endogenous counterpart, and, 
therefore, anti-drug antibodies could develop that could potentially affect the efficacy of 
PRM-151 treatments in addition to having the potential to cross-react with endogenous 
hPTX-2.  Anti-drug antibodies were detected in 3 subjects in the MF trial, with no 
apparent impact on pharmacokinetics, safety, or efficacy.  Two subjects had mild 
infusion reactions which were easily managed and prevented in the one subject that was 
rechallenged; anti-drug antibody was detected in one of them. 
PRM-151 is not a general immunosuppressant, and treatment with PRM-151 is not 
expected to increase rates of infection or adversely affect wound healing. 
As with any protein therapeutic, the potential for reactions exists and safety procedures 
will be implemented including careful monitoring of subjects during infusions and of 
infusion sites.  Appropriate personnel, medication, and other requirements for the 
treatment of potential infusion reactions will be required by the protocol.   
PRM-151 is an investigational agent. Subjects are not anticipated to derive direct benefit 
from participation in studies; the potential benefits of PRM-151 as a therapy for IPF 
remain to be proven in clinical efficacy studies.  
The CT scans performed for this study will involve the delivery of small amounts of 
radiation to the subject.   The dose of radiation expected for the chest HRCT in this 
protocol has not been found to harm most healthy adults. The amount of radiation 
received has a low risk of harmful effects, and evaluation of IPF with HRCT is typical in 
clinical practice to monitor disease or response to therapy.   The protocol's radiation dose 
is "as low as reasonable achievable" (ALARA) to obtain the quality of images necessary 
for imaging of lung abnormalities and quantification by Lung Texture Analysis software.  
The main potential risk from exposure to radiation is cancer. The relative risk of 
developing adverse effects from radiation, such as future development of radiation-
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IPF.  From currently available data, the U.S. Nuclear Regulatory Commission (NRC) has 
adopted a risk value for an occupational dose of 1 rem (0.01 Sieverts) Total Effective 
Dose Equivalent (TEDE) of approximately 1 chance in 2,500 of fatal cancer per rem of 
TEDE received. For this protocol, the dose will vary, depending on the specific CT 
scanner technology available at each site, but the volumetric CT dose index is estimated 
to be less than 10milliGrey with effective dose for a standard subject of less than 3 
milliSieverts (0.003 Sieverts) per scan.  Dose will be adjusted appropriately to assure 
consistent image quality, based on subject size.  No populations at potentially higher risk 
for radiation exposure such as young children or pregnant women will be involved in the 
study. 

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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
The primary objective of this study is: 
 To determine the effect size of PRM-151 relative to placebo in change from Baseline 
to Week 28 in mean FVC% predicted, pooling subjects on a stable dose of 
pirfenidone or nintedanib and subjects not on other treatment for IPF. 
2.2. 
Secondary Objectives 
The secondary objectives of this study are: 
 Determine the effect size of PRM-151 relative to placebo in change from Baseline to 
Week 28 in normal lung parenchyma as quantified on high- resolution CT (HRCT) 
imaging analysis, pooling subjects on a stable dose of pirfenidone or nintedanib with 
subjects not on other treatment for IPF. 
 Determine the effect size of PRM-151 relative to placebo in change from Baseline to 
Week 28 in mean FVC% predicted, separately in subjects on a stable dose of 
pirfenidone or nintedanib and in subjects not on other treatments for IPF. 
 Determine the effect size of PRM-151 relative to placebo in change from Baseline to 
Week 28 in normal lung parenchyma as quantified on HRCT imaging analysis, 
separately in subjects on a stable dose of pirfenidone or nintedanib and in subjects not 
on other treatments for IPF. 
 Assess the tolerability and safety of PRM-151 in subjects with IPF through Week 28. 
 Assess the ability of PRM-151 to reduce disease-related events associated with 
mortality 
 Determine the effect size of PRM-151 relative to placebo on pulmonary function in 
addition to mean change in FVC% predicted 
 Determine the effect size of PRM-151 relative to placebo on 6-minute walk distance 
 Determine the effect size of PRM-151 relative to placebo on Hb-corrected DLCO. 
2.3. 
Exploratory Objectives 
The exploratory objectives of this study are: 
 Evaluate the efficacy and estimate the size of effect of PRM-151 relative to placebo 
in change from baseline to weeks 4, 8, 12, 16, 20, 24 and 28 in FVC % predicted and 
6-minute walking distance, pooling subjects on a stable dose of pirfenidone or 
nintedanib with subjects not on other treatment for IPF and separately in subjects on a 
stable dose of pirfenidone or nintedanib and in subjects not on other treatments for 
IPF. 
 To assess the impact of PRM-151 on disease related symptoms. 
 Assess the impact of PRM-151, disease pathogenesis and disease progression on 
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3. 
STUDY ENDPOINTS 
3.1. 
Primary Endpoint 
The primary endpoint for the study is: 
 Mean change in FVC % predicted from Baseline to Week 28. 
3.2. 
Secondary Endpoints 
The secondary endpoints for the study are: 
1. Structural Imaging: 
 Mean change from Baseline to Week 28 in total lung volume and volume of 
parenchymal features on HRCT (in ml and % of total lung volume) 
representative of interstitial lung abnormalities (ILA), including ground glass 
density, reticular changes, and honeycombing, using quantitative imaging 
software. 
 Mean change from Baseline to Week 28 in volume of parenchymal features 
on HRCT (in ml and % of total lung volume) representative of normal lung 
(non-ILA), including normal and mild low attenuation areas, using 
quantitative imaging software. 
 Correlation between mean change from Baseline to Week 28 in FVC % 
predicted and mean change from Baseline to Week 28 in total lung volume 
and volume of parenchymal features on HRCT (in ml and % of total lung 
volume) representative of interstitial lung abnormalities (ILA), including 
ground glass density, reticular changes, and honeycombing by quantitative 
imaging software. 
2. Safety: Tolerability/safety will be assessed over the 28-week study period by the 
following parameters: 
 Incidence of AEs. 
 Incidence of serious adverse events (SAEs). 
 Incidence of respiratory AEs and SAEs. 
 Proportion of subjects discontinuing study drug due to AEs. 
 Change from Baseline in hematology and serum chemistries. 
 All-cause mortality. 
 Mortality due to respiratory deterioration. 
3. Disease related events associated with mortality:  The number of “respiratory 
decline” events over the 28-week study period as defined below: 
 Unscheduled visits to a healthcare professional for respiratory status 
deterioration. 
 Urgent care visits for respiratory status deterioration. 
 Hospitalization due to a worsening or exacerbation of respiratory 
symptoms. 
All “respiratory decline” events will be further characterized according to the 
definitions of IPF-related acute exacerbation, as proposed by an expert committee 
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Blood Institute (NHLBI) (Collard, Moore et al. 2007) and applied by (Collard, Yow 
et al. 2013) 
 Acute onset of symptoms (< 30 days in duration) 
 New radiographic abnormalities (bilateral ground glass or consolidation 
on HRCT with no pneumothorax or pleural effusion) 
 The absence of an identified infectious etiology by routine clinical practice 
 Exclusion of alternative causes by routine clinical practice, including: 
a.Left heart failure 
b.Pulmonary embolism 
c.Identifiable cause of acute lung injury 
4. Pulmonary Function Tests 
 Proportion (%) of subjects with a decline in FVC% predicted of ≥ 5% and 
≥ 10% from Baseline to Week 28. 
 Proportion (%) of subjects with a decline in FVC in ml of ≥ 100ml and ≥ 
200ml from Baseline to Week 28. 
 Proportion of subjects with an increase in FVC % predicted of ≥ 5% and 
≥10% from Baseline to Week 28. 
 Proportion of subjects with an increase in FVC in ml of ≥ 100 ml and ≥ 
200 ml from Baseline to Week 28. 
 Proportion of subjects with stable disease by FVC %, defined as a change 
in FVC % predicted of < 5% from Baseline to Week 28. 
 Proportion of subjects with stable disease by FVC in ml, defined as a 
change in FVC of < 100ml from Baseline to Week 28. 
 Mean change from Baseline to Week 28 in % predicted Hb-corrected 
diffusion capacity of carbon monoxide (DLCO). 
 Change in 6-minute walk distance, in meters, from Baseline to Week 28. 
3.3. 
Exploratory Endpoints 
The exploratory endpoints for the study include:   
1. Other Weeks 
 Examine the change from Baseline at Weeks 4, 8, 12, 16, 20, 24 and 28for 
the FVC % predicted, FVC in ml, and 6MWT distance. 
2. Structural Imaging 
 Transitions from Baseline to Week 28 between all categories of lung 
features (normal, ground glass density, reticular changes, honeycombing, 
and mild, moderate, and severe low attenuation areas) by quantitative 
imaging software. 
 Correlation of transitions between categories of lung features by 
quantitative imaging and changes in FVC% predicted. 
 Correlation of transitions between categories of lung features by 
quantitative imaging and changes in Hb-corrected DLCO. 
 Impact of inspiratory effort on results of HRCT quantitative imaging. 
 

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3. Patient Reported Outcomes 
 Change in Patient Reported Outcomes as measured by King’s Brief 
Interstitial Lung Disease Questionnaire (K-BILD) and Leicester 
Cough Questionnaire (LCQ) from Baseline to Week 28. 
4. Biomarkers 
 Changes in serum and cellular biomarkers and response according to 
baseline genetic characteristics: including but not limited to TLR3, L412F 
polymorphism, and MUC5B promoter polymorphism. 

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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design and Plan 
The current study is a Phase 2, randomized, double-blind, placebo-controlled, pilot study 
designed to evaluate the efficacy and safety of PRM-151 administered through Week 24 
to subjects with IPF. Subjects meeting the eligibility criteria for the study will be 
randomized to PRM-151 10 mg/kg every 4 weeks or placebo.  Efficacy will be evaluated 
through pulmonary function tests (PFTs), high resolution CT (HRCT), 6-minute walk test 
(6MWT), and Patient Reported Outcomes (PROs). 
 
Subjects will be evaluated for study eligibility during Screening within 4 weeks before 
enrollment and Baseline assessments.  Subjects who are determined to be eligible, based 
on Screening assessments, will be enrolled in the study and randomly allocated to 
treatment with PRM-151 or placebo.  Subjects will receive study drug treatment for 24 
weeks. 
Approximately 117 subjects will be randomly assigned on a 2:1 basis to treatment with 
PRM-151 or placebo, as follows: 
 PRM-151 10 mg/kg IV infusion over 60 minutes on days 1, 3, and 5, then one 
infusion every 4 weeks  
 Placebo IV infusion over 60 minutes on Week days 1, 3, and 5, then one infusion 
every 4 weeks 
The randomization will use a 2:1 ratio (PRM-151: placebo). The randomization will also 
be stratified according to other treatments for IPF (subjects receiving pirfenidone or 
nintedanib and subjects with no other treatment for IPF). 
After completion of study treatment through Week 24, all subjects may receive PRM-151 
10 mg/kg IV infusion over 60 minutes Days 1, 3, and 5, then once every 4 weeks for an 
indefinite period of time in an open label study extension.  Dosing will be administered 
on Days 1, 3, and 5 will be repeated once every 28weeks during the extension. 
4.1.1. 
Treatment Period: Efficacy-related Assessments 
Subjects undergo testing on an every 4-week basis after randomization (occurring at 
Weeks 4, 8, 12, 16, 20, 24 and 28) for efficacy and safety.   
During treatment, PFTs, 6MWT, and PROs will be performed on an every 4-week basis.  
HRCT will be performed on Day 1 as the Baseline assessment and again at Week 28.  
HRCT and PFTs must be done on the same day.  PFTs will be reviewed centrally by 
reviewers blinded to treatment group and time point. 
4.1.2. 
Treatment Period: Tolerability/Safety-Related Assessments 
Adverse events (AEs) and concomitant medications will be assessed at all study visits.  In 
addition, information regarding hospitalizations, emergency department visits, and 
unscheduled or urgent care visits to a health care provider due to a deterioration in 
respiratory status or symptoms will be collected at all study visits.   

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4.1.3. 
Open Label Post-Study Treatment Extension 
4.1.4. 
After completing 24 weeks of treatment, all subjects will be offered the 
option to receive PRM-151 in an open-label PRM-151 treatment 
extension period for an indefinite period of time.. All subjects will receive 
PRM-151 10 mg/kg IV Days 1, 3, 5 then every 4 weeks in the extension. 
Dosing on days 1, 3 and 5 will be repeated every 28 weeks during the 
extension.  PROs, PFTs, spirometry and 6MWT will be done every 4 
weeks for the first 24 weeks and then every 12 weeks. DLco, FRC &TLC 
by nitrogen washout method will be done every 12 weeks. HRCT will be 
done at 1.5 years (Week 76) and 2.5 years (Week 128) on the same day as 
DLco and FRC & TLC by nitrogen washout.  Subjects are allowed to 
begin treatment with, restart treatment with  or increase the dose of 
pirfenidone or nintedanib after the week 28 visit have been   performed   
4.1.5. 
 
4.1.6. 
Study Duration 
Subjects will receive study drug for a minimum of 24 weeks.  Subjects will participate in 
the study for up to 128 weeks, including a 4-week screening period, 24 week treatment 
period, an open-label treatment extension period for an indefinite period of time, and a 4 
week follow up period. 

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5. 
SELECTION OF STUDY POPULATION 
5.1. 
Study Population 
5.1.1. 
Inclusion Criteria 
Each subject must meet all of the following inclusion criteria to be enrolled in the study: 
1. Subject must be 40-80 years of age at the time of signing the Informed 
Consent Form (ICF); 
2. Subject has well documented IPF satisfying the ATS/ERS/JRS/ALAT 
diagnostic criteria (Raghu, Collard et al. 2011).  In the absence of a surgical 
lung biopsy, HRCT must be “consistent with UIP” defined as meeting either 
criteria A, B, and C, or criteria A and C, or criteria B and C below: 
A. Definite honeycomb lung destruction with basal and peripheral 
predominance. 
B. Presence of reticular abnormality AND traction bronchiectasis 
consistent with fibrosis with basal and peripheral predominance. 
C. Atypical features are absent, specifically nodules and consolidation.  
Ground glass opacity, if present, is less extensive than reticular opacity 
pattern.  
3. If on pirfenidone or nintedanib, subject must have been on a stable dose of 
pirfenidone or nintedanib for at least 3 months prior to screening without 
increase in FVC% predicted on two consecutive PFTs, including screening 
PFTs.  Subjects may not be on both pirfenidone and nintedanib. 
4. If not currently receiving pirfenidone or nintedanib, subject must have been 
off pirfenidone or nintedanib for ≥4 weeks prior to screening 
5. Subject has a FVC ≥ 50% and ≤ 90% of predicted. 
6. Subject has an Hb corrected and/or Hb uncorrected DLCO ≥ 25% and ≤ 90% 
of predicted. 
7. Minimum distance on 6MWT of 150 meters.  
8. Subject has a forced expiratory volume in 1 second (FEV1)/FVC ratio > 0.70. 
9. Women of child bearing potential (WCBP), defined as a sexually mature 
woman not surgically sterilized or not post-menopausal for at least 24 
consecutive months if ≤55 years or 12 months if >55 years, must have a negative 
serum pregnancy test within four weeks prior to the first dose of study drug and 
must agree to use highly effective methods of birth control throughout the study 
and up to 30 days after the study for WOCBP and up to 90 days for partners of 
child bearing potential of male participants.  Highly effective methods of 
contraception include combined (estrogen and progestogen containing) 
hormonal contraception associated with inhibition of ovulation by oral, 
intravaginal, or transdermal administration; progestogen-only hormonal 
contraception associated with inhibition of ovulation by oral, injectable, or 
implantable administration; intrauterine device (IUD); intrauterine hormone-
releasing system (IUS); bilateral tubal occlusion; partner vasectomy, and total 
abstinence (only if total abstinence is the preferred method and usual lifestyle 
of the subject). Adequate contraceptive use should be continued until 28 days 
after the final dose of the study drug. 

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10. Subject has a life expectancy of at least 9 months 
11. Subject, according to the investigator’s best judgment, can comply with the 
requirements of the protocol. 
12. Subject and the treating physician considered all medicinal treatment options 
and / or possibly a lung transplantation prior to considering participation in the 
study  
13. If the subject is on a lung transplant list, the Investigator anticipates the 
subject will complete the study prior to transplant. 
14. Subject has provided written informed consent to participate in the study. 
5.1.2. 
Exclusion Criteria 
Subjects meeting any of the following exclusion criteria are not to be rolled in the study:   
1. Subject has emphysema ≥ 50% on HRCT or the extent of emphysema is 
greater than the extent of fibrosis according to the reported results of the most 
recent HRCT. 
2. Subject has a history of cigarette smoking within the previous 3 months. 
3. Subject has received investigational therapy for IPF within 4 weeks before 
baseline. 
4. Subject is receiving systemic corticosteroids equivalent to prednisone > 10 
mg/day or equivalent within 2 weeks of baseline. 
5. Subject received Immuno-suppressants (e.g. azathioprine, cyclophosphamide, 
or cyclosporine or other  immunosuppressants including those used after 
organ transplant) within 4 weeks of baseline. Subject has a history of a 
malignancy within the previous 5 years, with the exception of basal cell skin 
neoplasms. In addition, a malignant diagnosis or condition first occurring 
prior to 5 years must be considered cured, inactive, and not under current 
treatment.  
6. Subject has any concurrent condition other than IPF that, in the Investigator’s 
opinion, is unstable and/or would impact the likelihood of survival for the 
study duration or the subject’s ability to complete the study as designed, or 
may influence any of the safety or efficacy assessments included in the study. 
7. Subject has baseline resting oxygen saturation of < 89% on room air or with 
supplemental oxygen. 
8. Subjects that are unable to refrain from use of the following: 
a. Short acting bronchodilators on the day of and within 12 hours of 
pulmonary function, DLco, and 6-minute walk assessments. 
b. Long acting bronchodilators on the day of and within 24 hours of these 
assessments. 
9. Subject has a known post-bronchodilator (short-acting beta agonist [SABA] – 
albuterol or salbutamol) increase in FEV1 of >10% and in FVC of >7.5%. 
10. Female pregnant and/or lactating subject. 

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5.2. 
Withdrawal and Replacement of Subjects 
The Investigator may withdraw a subject from the study for any of the following reasons: 
 Subject, Investigator, or Sponsor request. 
 Protocol violation. 
 AE. 
 Pregnancy (mandatory). 
 Progression of disease that, in the opinion of the Investigator, precludes further 
study drug treatment. 
 Subject decision.  A subject may withdraw consent to participate in the study at 
any time. 
The reason for study withdrawal is to be documented in the subject’s source documents 
and electronic case report form (eCRF). 
5.3. 
Study Termination 
If the Sponsor or Investigator discovers conditions arising during the study that suggest 
the study should be halted, then this can happen only after appropriate consultation 
between the Sponsor and Investigator.  Conditions that may warrant study termination 
include, but are not limited to: 
 The discovery of any unexpected, significant, or unacceptable risk to the subjects 
enrolled in the study. 
 Site-specific inability of an Investigator to enter subjects at an acceptable rate. 
 Insufficient adherence to the protocol requirements. 
 A decision on the part of the Sponsor to suspend or discontinue development of 
study drug. 
 A decision on the part of the Sponsor to suspend or discontinue the study for 
administrative reasons. 
5.4. 
Subject Management 
This study will be conducted on an out-patient basis. 
Subjects will be evaluated for study eligibility during the Screening period within 4 
weeks before the first study drug dose.  All subjects must provide written informed 
consent before any study specific samples are collected or evaluations performed in this 
study.   
Subjects who are determined to be eligible for the study will be enrolled and randomly 
assigned to treatment at Baseline (Week 0).  For the purposes of this study, enrollment is 
defined as randomization.  
Subjects are allowed to begin treatment on pirfenidone or nintedanib after week 28 visit 
is performed.  . 
During the 24-week treatment period, subjects are to attend study center visits on Days 1, 
3 and 5 then an every 4-week basis at Weeks 4, 8, 12, 16, 20, and 24 (±3 days) for study-
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After completing treatment through week 24, subjects will be offered the option to 
continue PRM-151 in an open-labeled treatment extension for an indefinite period of 
time.  
An End of Study visit is to be conducted 4 weeks (±3 days) after the last dose of study 
drug (Week 28 for the main study and upon completion for the open label extension). 
5.5. 
Investigator Compliance 
Study centers that deviate significantly from the protocol without prior approval from the 
Sponsor and regulatory authorities may be discontinued from the study.  The Investigator 
at each study center is responsible for ensuring the accuracy and completeness of all 
research records, the accountability of study drug, and the conduct of clinical and 
laboratory evaluations as outlined in the protocol. 
5.6. 
Subject Adherence 
All subjects are required to adhere to the protocol-specified visit schedule.  If a subject 
misses a scheduled visit, attempts should be made to reschedule the visit within the visit 
windows described above.  Failure to attend scheduled study visits may result in 
discontinuation from the study. 
5.7. 
Data Monitoring Committee 
A blinded DMC will be established to review safety data from this study, thereby better 
ensuring the safety of study participants. Consistent with US Food and Drug 
Administration (FDA) recommendations (FDA Guidance for Industry, Establishment and 
Operation of Clinical Trial Data Monitoring Committees, 2006), the DMC will be 
constituted of independent clinicians’ expert in the field of IPF and clinical research.  A 
formal charter will be established for the conduct of the DMC. 
The committee is planned to review the safety data in a blinded manner, but a procedure 
will be in place to allow the committee an immediate unblinding of either specific cases 
or of the whole study in case of detection of a potential safety signal necessitating an 
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6. 
STUDY TREATMENT(S) 
6.1. 
Investigational Product 
All study drugs are for investigational use only and are to be used only within the context 
of this study.  All study drugs will be supplied by Promedior.   
6.2. 
Treatment(s) Administered 
Subjects will be randomized to receive the study drug PRM-151 or placebo.  Subjects 
randomized to placebo will receive intravenous (IV) infusions of sterile saline solution 
over 60 minutes. Please refer to the Pharmacy Manual for more detail. 
Subjects randomized to study drug will receive intravenous (IV) infusions of 10 mg/kg 
PRM-151 over 60 minutes, with dose based on the subject’s baseline weight.  Refer to 
the Pharmacy Manual and the Investigator’s Brochure for detailed instructions on special 
precautions and handling and requirements for weight based dose recalculations.  
On all dosing days, dosing will occur after all safety and efficacy assessments scheduled 
for that visit are completed 
Medical personnel authorized by the Investigator will be responsible for the 
administration of study drug and for observation of each subject throughout the study. 
Subjects should be observed for one-hour post infusion to monitor for infusion related 
reactions. 
In the case of occurrence of signs and symptoms consistent with infusion related reaction, 
follow institutional protocol and reduce the rate of infusion of PRM-151 to half the initial 
rate; consider discontinuing infusion of PRM-151 if symptoms do not respond 
immediately to medical intervention.  If signs and symptoms do not resolve immediately 
by slowing the infusion, discontinue infusion of PRM-151. If signs and symptoms resolve 
with intervention including discontinuation of PRM-151, PRM-151 infusion may be 
restarted at half the initial rate. 
In the event of an infusion related reaction (IRR) beginning after treatment on Baseline, 
an ECG is performed and a blood sample for cytokines is  collected as soon as possible 
after stabilization of the subject. 
If PRM-151 resulted in an infusion related reaction, during a prior administration, use the 
following premedication for all subsequent PRM-151 administration: 
 Diphenhydramine 50 mg IV or clemastine 2 mg IV or an equivalent dose of an 
antihistaminic drug 
 Dexamethasone 10 mg IV or an equivalent dose of long-acting corticosteroid 
No other dose modifications are required per protocol.  The investigator should use 
his/her medical judgment in the case of adverse events that may require a dose 
interruption. If the subject is not able to adhere to the original dosing schedule, the 
subject should be dosed as soon as possible within 2 weeks of the scheduled visit.  If the 
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6.3. 
Method of Assigning Subjects to Treatment Groups 
Subjects who are candidates for screening into the study will be evaluated for eligibility 
by the Investigator to ensure that the inclusion and exclusion criteria initially have been 
satisfied.  The Unblinded Pharmacist will register the subject in the IVRS system, and the 
IVRS system will assign a sequential and unique subject number.  Once a subject number 
has been assigned, it cannot be reused. 
Prior to randomization, the Investigator will ensure that the subject continues to meet the 
inclusion and exclusion criteria and is eligible for study participation.   
Once a subject is deemed by the Investigator to be eligible, the unblinded pharmacist will 
access the IVRS system for randomization and study drug assignment.   
6.4. 
Blinding 
All study personnel, with the exception of the unblinded site pharmacist, will be blinded 
to the treatment allocation a subject is randomized to. It is imperative that this blinding be 
maintained during the dispensing of investigational product. 
6.4.1. 
Procedures for Breaking the Blind 
The treatment assignment must not be broken during the study except in emergency 
situations where the identification of study drug is required for further treatment of the 
subject.  Unblinding of the individual subject's treatment by the investigator will be 
limited to medical emergencies or urgent clinical situations in which knowledge of the 
subject's study treatment is necessary for clinical management. In such cases, the 
Investigator should use his/her best judgment as to whether to unblind without first 
attempting to contact the Medical Monitor to discuss and agree to the need for 
unblinding. If the Investigator determines that it is not necessary to unblind immediately, 
he/she will first attempt to contact the Medical Monitor to discuss and agree to the need 
for unblinding. If the Investigator has tried but is unable to reach the Medical Monitor, 
he/she should use his/her best judgment, based on the nature and urgency of the clinical 
situation, and may proceed with unblinding without having successfully reached and 
discussed the situation with the Medical Monitor. 
6.5. 
Study Drug Supply 
PRM-151 Solution for Injection is a 20 mg/mL solution of PRM-151 in 10 mM sodium 
phosphate, 5% (w/v) sorbitol, and 0.01% (w/v) polysorbate 20 with a pH of 7.5. Each vial 
of PRM-151 Solution for Injection contains 160 mg of PRM-151 in 8.0 mL of solution. 
Placebo consists of an infusion of sterile physiologic saline, matched to PRM-151 in total 
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6.6. 
Packaging and Labeling 
PRM-151 is supplied in 10 ml single use vials as a clear to opalescent, sterile 20.0 
mg/mL solution 10 mM sodium phosphate, 5% (w/v) sorbitol, and 0.01% (w/v) 
polysorbate 20 with a pH of 7.5.  Each vial contains 8 ml PRM-151 (160 mg of PRM-
151). 
Study drug will be labeled investigational.  Study drug labels will not bear any statement 
that is false or misleading in any manner or represents that the study drug is safe or 
effective for the purposes for which it is being investigated. 
6.7. 
Storage and Accountability 
PRM-151 will be provided to the clinical site in a temperature controlled, monitored 
container.  Investigational product should be stored under refrigerated conditions (2C-
8C [35.6F-46.4F]) and protected from light.  Vigorous mixing or vortexing should be 
avoided. 
Investigational product will be dispensed at the study site and stored in a locked storage 
area.  The disposition of all investigational product delivered to a Principal Investigator 
must be recorded on a subject-by-subject basis by completing the Clinical Trial Material 
Accountability Log.  The date and time of administration of the investigational product 
must be documented on the appropriate eCRF. 
The unblinded pharmacist must ensure that all documentation regarding investigational 
product receipt, storage, dispensing, loss/damaged and return of used/unused product is 
complete, accurate, and ready for review at each monitoring visit and/or audit.  The sites 
must ensure that the investigational product is available for the monitor to inventory and 
prepare for return shipment to the Sponsor or designee, if required. 
All packing slips and other shipment documentation must be retained as well as any 
investigational product return forms.  See the Pharmacy Manual for additional details. 
6.8. 
Rationale for the Dose(s) Selected 
In a multiple ascending dose study (PRM151F-12GL), PRM-151 administered IV on 
Days 1, 3, 5, 8, and 15 to subjects with IPF was well tolerated at doses up to 10 mg/kg.  
Plasma levels of PRM-151 (Cmax and AUC) were dose proportional across the range of 
doses from 1 to 10 mg/kg.  PRM-151 had a half-life of 21 to 44 hours.  The study did not 
demonstrate a dose response, but was not intended to do so.  Based on these findings, a 
PRM-151 dose of 10 mg/kg was selected for investigation in the current study.  
Preclinical dose ranging studies and in vitro potency assays indicate that the effective 
dose range in humans may be .2-10 mg/kg.  Ten mg/kg was selected for this study 
because it was safe and resulted in a reduction in bone marrow fibrosis in 11 out of 24 
subjects with myelofibrosis treated with PRM-151 10 mg/kg either weekly or every 4 
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7. 
STUDY PROCEDURES 
Detailed descriptions of subject evaluations required for this protocol are described in this 
section.  These evaluations will be performed during the indicated days and weeks of the 
study as described in Section 7 and in the Schedule of Events (Appendix A).  
All data collected are to be recorded on source documents and entered into the 
appropriate eCRF page. 
The Investigator at the clinical trial site is responsible for maintaining a record of all 
subjects pre-screened, screened, and enrolled into the study. 
All subjects must provide written informed consent before the performance of any study 
procedures. 
7.1. 
Informed Consent 
Prior to conducting any study-related procedures, written informed consent must be 
obtained from the subject or the subject’s legally authorized representative. 
The nature, scope, and possible consequences, including risks and benefits, of the study 
will be explained to the subject by the Investigator or designee in accordance with the 
guidelines described in Section 9.1.  Documentation and filing of informed consent 
documents should be completed according to Section 10.5. 
7.2. 
Study Entrance Criteria 
At Screening, each subject assessed for eligibility against the study entrance criteria.  
Subjects who do not meet the study entrance criteria will not be allowed to participate in 
the study.  The reason(s) for the subject’s ineligibility for the study will be documented. 
7.3. 
Demographics 
Subject demographic information including gender, age, date of birth, race, ethnicity and 
number of years since diagnosis of IPF will be collected prior to the subject receiving the 
first dose of PRM-151.   
7.4. 
Past Medical History 
Medical history will be recorded in the eCRF.  Any relevant and/or significant previous 
or existing medical condition(s) that occurred within 5 years prior to time of informed 
consent) should be reported as medical history. Prior and current therapies for IPF will be 
recorded in the eCRF.   
7.5. 
Height and Weight 
Height will be recorded at Screening for all subjects. Weight will be recorded at all 
dosing visits for all subjects.   
7.6. 
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7.6.1. 
Hematology and Clinical Chemistries 
Blood samples for hematology, clinical chemistries and coagulation are to be collected as 
per the schedule of events (Appendix A).   
The following laboratory variables are to be measured: 
 
Hematology; Hematocrit, Platelet count, White blood cell (WBC) count, Red blood cell 
(RBC) count, Hemoglobin, Lymphocytes, Eosinophils, Neutrophils, Monocytes, 
Basophils. 
 
Serum Chemistries and Liver Function Tests; Chloride, Potassium, Blood urea 
nitrogen (BUN), Creatinine, Albumin, Aspartate aminotransferase (AST), Total bilirubin, 
Sodium, Bicarbonate (CO2), Calcium, Glucose, Alkaline phosphatase (ALK), Alanine 
aminotransferase (ALT), Total protein. 
 
Coagulation Tests: Prothrombin time (PT), Partial Thromboplastin time (PTT), 
International Normalized Ratio (INR) 
 
7.6.2. 
ECG and Cytokines 
 
ECG and cytokines will be collected at baseline prior to PRM-151 dosing.  Following the 
baseline assessment, ECG and cytokines will only be collected in the event of an infusion 
related reaction (IRR) as soon as possible after stabilization of the subject. 
 
7.6.3. 
Pregnancy Testing 
Serum pregnancy testing is required for female subjects of child-bearing potential.  A 
female of childbearing potential is a sexually mature woman who has not undergone a 
hysterectomy, bilateral oophorectomy, or tubal ligation or is not naturally 
postmenopausal (i.e., has had menses at any time within the previous 24 months). 
Pregnancy testing is to be performed during Screening.  Pregnancy testing should be 
repeated during treatment any time pregnancy is suspected.   
During Screening, results must be reviewed and confirmed to be negative for the subject 
to be eligible for enrollment in the study.  If positive pregnancy test results are obtained 
after the start of study drug treatment, study drug is to be unblinded and discontinued.  
Pregnancies are to be reported and followed as described above. 
7.7. 
Physical Examination 
A complete physical examination is to be performed during Screening and an abbreviated 
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of height during Screening.  Weight is to be measured throughout the study for use in 
weight based dose calculations. 
Complete physical examinations also will include a review of the following body 
systems: 
 General appearance. 
 Head, eyes, ears, nose, and throat. 
 Respiratory. 
 Cardiovascular. 
 Abdomen. 
 Neurologic. 
 Extremities. 
 Dermatologic. 
Full physical examinations are to be performed at screening; Abbreviated physical exams 
are to be performed thereafter. 
The findings of each examination are to be documented in the eCRF. 
If an abnormality noted on physical examination is considered by the Investigator to be 
clinically significant, then the abnormality is to be recorded as part of the subject’s 
medical history if occurring prior to start of dosing and as an AE occurring if after the 
start of study drug administration at Week 0, where the finding represents a change from 
Baseline.  Any worsening of a baseline medical condition during the study should be 
recorded as an adverse event. 
7.8. 
Vital Signs 
Vital signs, including measurement of systolic and diastolic blood pressure, pulse, heart 
rate, and O2 saturation, are to be measured in the sitting position as per the schedule of 
events (Appendix A). At dosing visits, vital signs will be measured pre-dose as well as 1 
hour post-dose and entered into the eCRF.  Vitals signs should be monitored every 15 
minutes during the infusion and captured on the source document. 
If a vital sign abnormality is considered by the Investigator to be clinically significant, 
then the abnormality is to be recorded as part of the subject’s medical history if occurring 
prior to start of dosing and as an AE occurring if after the start of study drug 
administration at Week 0, where the finding represents a change from Baseline. 
7.9. 
Concurrent Medications 
All prescription and non-prescription medications including pharmacologic doses of 
vitamins, herbal medicines, or other non-traditional medicines, taken from 4 weeks prior 
to the first dose of PRM-151 through the last study visit must be recorded in the eCRF. 

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If on pirfenidone or nintedanib, subject must have been on a stable dose of pirfenidone or 
nintedanib for at least 3 months prior to screening without increase in FVC% predicted 
on two consecutive PFTs, including screening PFTs.  If subjects are currently on a stable 
dose of pirfenidone they are allowed to stop taking pirfenidone while remaining in the 
study but are not allowed to start dosing with nintedanib.  If subjects are currently on a 
stable dose of nintedanib they are allowed to stop taking nintedanib while remaining in 
the study but are not allowed to start dosing with pirfenidone.  
7.9.1. 
Prohibited Concurrent Medications 
The following medications are prohibited during the study: 
 All investigational therapies other than PRM-151for any indication, including 
therapies that are approved in other indications that are being investigated in IPF, 
are prohibited within 4 weeks before Screening and during study participation. 
 Inhaled or systemic corticosteroids.  (Low dose [≤10 mg daily] corticosteroids are 
permissible, provided the dose has been stable for 30 days prior to Baseline.) 
 Bronchodilators: 
 Short-acting bronchodilator use within 12 hours of pulmonary function, DLco, 
and 6MWT assessments. 
 Long acting bronchodilators are disallowed the day of and within 24 hours of 
pulmonary function testing, DLco, and 6MWT assessments. 
 The use of inhaled bronchodilator agents at times outside these windows is 
permissible.  
 Immuno-suppressants (e.g. methotrexate, azathioprine, cyclophosphamide, 
cyclosporine, everolimus or other  immunosuppressants including those used after 
organ transplant) are prohibited within 4 weeks of baseline and during the study.  
7.10. 
Efficacy Measurements 
On all dosing days, dosing will occur after all safety and efficacy assessments scheduled 
for that visit are complete.   
7.10.1. 
Pulmonary Function Tests 
Spirometry will be measured according to ATS guidelines (Miller, Crapo et al. 2005a), as 
per the schedule of events (Appendix A). 
DLCO is to be measured using the single-breath technique according to ATS/ERS 
guidelines (MacIntyre, Crapo et al. 2005) at Screening, Baseline and at Week 28, and 
weeks 76 and 128 visits for subjects continuing treatment in the extension. Diffusion 
capacity should be done on the same day as HRCT. 
Lung volumes (TLC and FRC) using Nitrogen washout method (Wanger, Clausen et al. 
2005) will be performed at Screening, Baseline and Week 28, and weeks 76 and 128 
visits for subjects continuing treatment in the extension. 
PFTs will be reviewed centrally by reviewers blinded to treatment group and time point. 
7.10.2. 
Six-minute Walk Test 
Exercise tolerance will be evaluate during the 6MWT according to ATS guidelines (ATS 
2002) (Appendix B) as per the schedule of events (Appendix A). If possible, 6MWT 

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should be the last efficacy assessment completed, by the subject.  If it is not possible to 
complete the 6MWT last, then allow a 30-minute recovery time before continuing with 
the next efficacy assessment.  During the open-labeled extension, subjects will have 
6MWT measured every twelve weeks.   
7.10.3. 
High-resolution Computed Tomography 
High-resolution Computed Tomography (HRCT) will be performed at the Baseline and 
Weeks 28, and weeks 76 and 128 visits for subjects continuing treatment in the extension.  
Spirometry will be performed at selected sites to ensure that full inspiration HRCT is at 
Total Lung Capacity (TLC). 
HRCT is to be performed with the subject in the supine position and at full inspiration.  
Contiguous CT volumetric acquisition will be obtained according to a specified protocol.  
HRCT scans will be compared using a standardized reading protocol and software to 
assess treatment-related changes in lung fibrosis. 
7.10.4. 
Patient Reported Outcomes 
Kings Brief Interstitial Lung Disease questionnaire (K-BILD) (Patel, Siegert et 
al.)(Appendix D) is a disease specific questionnaire validated to look at the health status 
of subjects with a variety of forms of interstitial lung disease (ILD). It consists of 15 
items.  The K-BILD questionnaire will be performed as per the schedule of events 
(Appendix A). If possible, the questionnaire should be the first assessment completed by 
the subjects.   
Leicester Cough Questionnaire (Birring, Prudon et al. 2003) (Appendix E) a self-
completed health related quality of life measure of chronic cough. The LCQ total score 
ranges from 3 to 21 and from 1 to 7 for physical, psychological and social domains; a 
higher score indicates a better health-related quality of life. The LCQ questionnaire will 
be performed as per the schedule of events (Appendix A). If possible, the questionnaire 
should be the first assessment completed by the subjects.   
7.10.5. 
Pentraxin-2 Levels 
Blood samples for determination of pentraxin-2 levels are to be collected pre-dose as per 
the schedule of events (Appendix A).  
7.10.6. 
Anti-Pentraxin 2 antibodies / Anti-Drug Antibodies (ADA) 
Blood samples for determination of ADA levels are to be collected pre-dose as per the 
schedule of events (Appendix A). 
7.11. 
Biomarker Assessments 
7.11.1. 
Baseline Genetic Status 
The subject’s baseline genetic status for TLR3, L412F polymorphism, and MUC5B 
promoter polymorphism will be collected at Baseline, if available.  If the subject has not 
previously been tested for these genetic characteristics, a blood sample for this analysis 
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7.11.2. 
Blood Sample Collection for Biomarker Assessment 
Blood samples to study exploratory serum and cellular biomarkers are to be collected 
pre-dose at Baseline, Week 28 and at Week 128 of the open label extension. 
7.12. 
Safety Measurements 
7.12.1. 
Adverse Events 
An AE is any untoward medical occurrence in a subject administered a pharmaceutical 
product and that does not necessarily have a causal relationship with this treatment.  An 
AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of study 
drug, whether or not related to study drug.  
All AEs from signing of informed consent until last study visit will be entered in the 
database. For those subjects prematurely withdrawn, TEAEs will be monitored until, at 
least, 4 weeks from last study treatment dose or resolution of AE, whichever is earlier 
7.12.1.1. 
Respiratory Decline Events 
For the purposes of this study, such “respiratory decline” events are defined as follows: 
 Unscheduled visits to a healthcare professional for respiratory status deterioration. 
 Urgent care visits for respiratory status deterioration. 
 Hospitalization due to a worsening or exacerbation of respiratory symptoms. 
 
All “respiratory decline” events will be further characterized according to the definitions 
of IPF-related acute exacerbation, as proposed by an expert committee sponsored by the 
IPF Clinical Research Network and the National Heart Lung and Blood Institute 
(NHLBI) (Collard, Moore et al. 2007) and applied by (Collard, Yow et al. 2013) 
 Acute onset of symptoms (< 30 days in duration) 
 New radiographic abnormalities (bilateral ground glass or consolidation on HRCT 
with no pneumothorax or pleural effusion) 
 The absence of an identified infectious etiology by routine clinical practice 
 Exclusion of alternative causes by routine clinical practice including: 
a. Left heart failure 
b. Pulmonary embolism 
c. Identifiable cause of acute lung injury 
7.12.1.2. 
Infusion related reactions 
In the event of acute hypersensitivity or other infusion reaction, institutional protocol 
should be initiated, ECG should be performed, and a blood sample drawn for cytokines. 
Signs and symptoms of an infusion reaction may include the following: headache, fever, 
facial flushing, pruritis, myalgia, nausea, chest tightness, dyspnea, vomiting, erythema, 
abdominal discomfort, diaphoresis, shivers, hypertension, hypotension, lightheadedness, 
palpitations, urticaria and somnolence.  Although unlikely, serious allergic reactions (e.g., 
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In the case of Grade 2 occurrence of signs and symptoms consistent with infusion related 
reaction, follow institutional protocol and reduce the rate of infusion of PRM-151 to half 
the initial rate; consider discontinue infusion of PRM-151 if symptoms do not respond to 
medical intervention.  If signs and symptoms resolve with intervention including 
discontinuation of PRM-151, PRM-151 infusion may be restarted at half the initial rate. 
In the case of Grade 3 or greater occurrence of signs and symptoms consistent with 
infusion related reaction, discontinue infusion of PRM-151. 
In the event of an infusion related reactions, an ECG should be performed and a blood 
sample for cytokines should be collected as soon as possible after stabilization of the 
subject. 
If PRM-151 resulted in signs and symptoms consistent with Grade 2 or 3 Infusion related 
reaction, infuse PRM-151 over 120 minutes and use the following premedication for all 
subsequent PRM-151 administration: 
 Diphenhydramine 50 mg IV or clemastine 2 mg IV (or an equivalent dose of an 
antihistaminic drug) 
 Dexamethasone 10 mg IV (or an equivalent dose of a long acting corticosteroid) 
 
Infusion related reactions must be reported to Promedior as described in section 7.12.4.1, 
Reporting of Adverse Events of Special Interest. 
7.12.1.3. 
Adverse Drug Reaction 
A suspected adverse drug reaction (ADR) is any AE for which there is a reasonable 
possibility that the drug caused the AE. For the purposes of Health Authority safety 
reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship 
between the drug and the AE. A suspected adverse reaction implies a lesser degree of 
certainty about causality than adverse reaction, which means any AE caused by a drug. 
7.12.1.4. 
Unexpected Adverse Event 
An unexpected AE or suspected adverse reaction is considered “unexpected” if it is not 
listed in the Investigator Brochure or is not listed at the specificity or severity that has 
been observed; or, if an Investigator Brochure is not required or available, is not 
consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended.  
7.12.1.5. 
Serious Adverse Event 
An AE or suspected ADR is considered “serious” if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes:  
 Death. 
 A life-threatening AE.  Life-threatening means that the subject was at immediate 
risk of death from the reaction as it occurred, i.e., it does not include a reaction 

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which hypothetically might have caused death had it occurred in a more severe 
form. 
 In-subject hospitalization or prolongation of existing hospitalization.  
Hospitalization admissions and/or surgical operations scheduled to occur during 
the study period, but planned prior to study entry are not considered AEs if the 
illness or disease existed before the subject was enrolled in the study, provided 
that it did not deteriorate in an unexpected manner during the study (e.g., surgery 
performed earlier than planned). 
 Persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions.   
 Is a congenital anomaly/birth defect. 
An important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, it may jeopardize the subject or may require medical or surgical intervention to 
prevent one of the outcomes listed in the definitions for SAEs.  Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in -subject 
hospitalization, or the development of drug dependency or drug abuse.   
7.12.2. 
Adverse Event Assessment 
All AEs from signing of informed consent until last study visit will be entered in the 
database, but only AEs occurred from the time of first study treatment dose administered 
to the subject (TEAEs) until last study visit will be analysed (see 7.12.1). This includes 
AEs the subject reports spontaneously, those observed by the Investigator, and those 
elicited by the Investigator in response to open-ended questions during scheduled study 
center visits. 
Each AE is to be assessed by the Investigator with regard to the following categories. 
Serious/Non-Serious 
Adverse events that meet the criteria specified above are to be considered serious. 
Relationship to Study Drug 
Relationship of an AE or SAE to investigational product is to be determined by the 
Investigator based on the definitions in Table 7-1. 

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Table 7-1: 
Adverse Event Relatedness 
Relationship to Study 
Drug 
Definition 
Not Related 
Unrelated to investigational product 
Possibly Related 
A clinical event or laboratory abnormality with a 
reasonable time sequence to administration of 
investigational product, but which could also be 
explained by concurrent disease or other drugs or 
chemicals. 
Probably Related 
A clinical event or laboratory abnormality with a 
reasonable time sequence to administration of 
investigational product, unlikely to be attributable to 
concurrent disease or other drugs and chemicals and 
which follows a clinically reasonable response on de-
challenge.  The association of the clinical event or 
laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds. 
 
Intensity 
The Investigator is to determine the intensity of the AE according to the criteria in Table 
7-2. 
Table 7-2: 
Adverse Event Grading 
Severity 
Definition 
Grade 1 (Mild): 
Mild; asymptomatic or mild symptoms; 
clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 (Moderate): 
Moderate; minimal, local or noninvasive 
intervention indicated; limiting age-
appropriate instrumental ADL. 
Grade 3 (Severe): 
Severe or medically significant but not 
immediately life-threatening; 
hospitalization or prolongation of 
hospitalization indicated; disabling; 
limiting self-care ADL.  
Grade 4 (Life-threatening): 
Life-threatening consequences; urgent 
intervention indicated. 
Grade 5 (Death): 
Death related to AE. 
 
7.12.3. 
Recording Adverse Events 
Only TEAEs will be recorded (see 7.12.1).  All AEs, regardless of relationship to study 
drug, are to be recorded in the Adverse Events eCRF.  All AE reports are to contain the 

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following details regarding the AE:  a brief description, onset date, duration, intensity, 
treatment required, relationship to study drug, study drug action taken, outcome, and 
whether the event is classified as serious. 
7.12.4. 
Reporting Serious Adverse Events 
Only serious TEAEs will be recorded (see 7.12.1). The Investigator must report all SAEs 
to the Safety Unit of Pivotal S.L. within 24 hours of discovery either by e-mail or fax to: 
 e-mail: drugsafety@pivotal.es 
 Fax (US SAEs): +1 877 853 3275 
 Fax (non-US SAEs): +34 91 307 60 47  
A completed SAE report is to be sent to Pivotal’s Safety Unit within 24 hours of 
discovering the event.  The initial report should include at least the following 
information: 
 Subject’s study number; 
 Description and date of the event; 
 Criterion for serious; and 
 Preliminary assignment of causality to study drug. 
The Safety unit will contact the Investigator either by email or telephone for follow-up 
information regarding the SAE, as appropriate. 
7.12.4.1. 
Reporting Adverse Events of Special Interest 
The Investigator must report suspected Infusion Related Reaction, regardless of severity, 
on an Adverse Event of Special Interest (AESI) form. This form must be completed and 
submitted, either by e-mail or fax to Pivotal’s Drug Safety Unit, immediately but no later 
than 24 hours of the Investigator’s learning of the event to Pivotal’s Safety Unit: 
 e-mail: drugsafety@pivotal.es 
 Fax (US SAEs): +1 877 853 3275 
 Fax (non- US SAEs): +34 91 307 60 47  
 
7.12.4.2. 
Follow-Up of Adverse Events 
The Investigator must continue to follow all SAEs and non-serious AEs considered to be 
reasonably or possibly related to study drug either until resolution or the Investigator 
assesses them as chronic or stable.  This follow-up may extend after the end of the study. 
7.12.4.3. 
Reporting Safety Information 
The Investigator must promptly report to his or her IRB/EC all unanticipated problems 
involving risks to subjects.  This includes death from any cause and all SAEs reasonably 
or possibly associated with the use of study drug according to the IRB/EC’s procedures.   

e-mail: drugsafety@pivotal.es

Fax (US SAEs): +1 877 853 3275 

Fax (non-US SAEs): +34 91 307 60 47 
of Pivotal S.L. w
Pivotal’s S
Pivotal’s D
e-mail: drugsafety@pivotal.es

Fax (US SAEs): +1 877 853 3275 

Fax (non- US SAEs): +34 91 307 60 47 
Pivotal’s S

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7.12.4.4. 
Protocol Deviations Due to an Emergency or Adverse Event 
In the event of an emergency, the investigator or other physician should use their medical 
judgment and do what is best for the subject, regardless of protocol requirements. The 
Investigator or other physician in attendance in such an emergency must contact the 
Medical Monitor as soon as possible to discuss the circumstances of the emergency. 
The Medical Monitor, in conjunction with the Investigator, will decide whether the 
subject should continue to participate in the study.  All protocol deviations and reasons 
for such deviations must be documented.  
7.12.5. 
Reporting Pregnancies 
Pregnancy itself is not considered an AE. If a subject becomes pregnant or the partner of 
a subject participating in the study becomes pregnant during the study or within 28 days 
of discontinuing any study drug, The Investigator should report the pregnancy on a 
separate pregnancy report form provided to the sites. Only pregnancies occurring from 
the time of first study treatment dose administered to the subject will be reported and 
documented. The study treatment will be immediately discontinued for any female 
subject who becomes pregnant during study participation, if study treatment is ongoing at 
that time.  
The subject/partner should be followed by the Investigator until completion of the 
pregnancy. If the pregnancy ends for any reason before the anticipated date, the 
Investigator should notify the Sponsor. At the completion of the pregnancy, the 
Investigator will document the outcome of the pregnancy.  
This pregnancy report form must be completed and submitted, either by e-mail or fax, 
immediately but no later than 24 hours of the Investigator’s learning of the event to 
Pivotal’s Safety Unit: 
 e-mail: drugsafety@pivotal.es 
 Fax (US SAEs): +1 877 853 3275 
 Fax (non- US SAEs): +34 91 307 60 47  
However, any pregnancy complication, spontaneous or elective abortion, still birth, 
neonatal death, or congenital anomaly will be recorded as an AE or SAE, and reported, as 
applicable. 
 
Pivotal’s S
e-mail: drugsafety@pivotal.es

Fax (US SAEs): +1 877 853 3275 

Fax (non- US SAEs): +34 91 307 60 47 

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8. 
 STATISTICAL ANALYSES 
8.1. 
Statistical Basis for Sample Size 
The primary objective is not to formally demonstrate the superiority of PRM-151 over 
placebo, but to provide a reliable estimate of the size of the effect of PRM-151 on 
absolute change from baseline to 28 weeks in mean FVC% predicted, hereafter referred 
to as the primary endpoint. Nevertheless, the sample-size has been calculated to ensure a 
sufficient power to demonstrate the efficacy of PRM-151 over placebo on the primary 
endpoint under a set of hypotheses on effect sizes in the two groups and on the variability 
of the primary endpoint.  
 
The primary endpoint will be tested in a model with two types of subjects: subjects on a 
stable dose of pirfenidone or nintedanib, and subjects not on other treatment for IPF. 
The sample size calculation is based on the following assumptions: 
 Primary endpoint is normally distributed 
 Homogeneity of variance, i.e. the standard deviation is the same in both arms, 
and for both types of subjects. 
 Randomization ratio PRM-151: placebo equals 2:1. 
 Expected value of the primary endpoint for subjects on pirfenidone or 
nintedanib will be -1.5. 
 Expected value of the primary endpoint for subjects on no other treatment will 
be -3. 
 Expected value of the primary endpoint for subjects on PRM-151 will be ≥ 
0.75. 
 Standard deviation of the primary endpoint is 5 
 75% of subjects will be on a stable dose of pirfenidone or nintedanib 
 25% of subjects will not be on other treatment for IPF 
 Significance level (α)=0.10 two-sided. 
 Desired power to demonstrate superiority is 80% 
A sample size of one hundred and two (102) evaluable subjects in total (68 PRM-151 and 
34 placebo) is enough to demonstrate superiority at p<0.10 with a power of 80% under 
the above assumptions. Assuming a non-evaluability rate of about 15%, 117 subjects in 
total (78 PRM-151 and 39 placebo) are to be enrolled. Stratified randomization will 
ensure a balance of PRM-151: placebo in subjects on pirfenidone or nintedanib and not 
on any other therapy, with at least 25% of subjects on no other therapy. 
8.2. 
General considerations for statistical analysis 
8.2.1. 
Statistical Analysis Plan 
The statistical section of the protocol presents the main features of the planned statistical 
analysis. A detailed statistical analysis plan (SAP) will be prepared by the Venn Life 
Sciences statistician, validated by the sponsor and signed before the database lock prior to 
any unblinded statistical analysis. 
Any change to the planned statistical methods will be documented in the clinical study 
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8.2.2. 
Descriptive statistics 
Quantitative variables will be described by treatment group using the following statistics: 
number of available data, number of missing values, mean, standard deviation, median, 
Q1, Q3, minimum and maximum values. When relevant, confidence intervals will also be 
computed. 
Qualitative variables will be described by treatment group using number of available 
data, number of missing values, frequency counts for each category and corresponding 
percentage. Percentages will be calculated using the number of available data as the 
denominator (i.e. not including missing values). When relevant, confidence intervals will 
also be computed. 
8.2.3. 
Inferential statistics 
For the primary efficacy analysis, the overall type-one error rate will be set to 0.10 two-
sided. There will be one single primary efficacy analysis, from which the conclusions on 
efficacy will be drawn.  Consequently, there is no issue of multiplicity of primary 
analyses and no need to adjust the significance level. 
Additional inferential tests will be computed for secondary efficacy analyses. No 
adjustment of the type-one error rate will be conducted. As a consequence, the results of 
these tests will have to be interpreted bearing in mind the issue of multiplicity and the 
increased risk of erroneously obtaining statistically significant results. Missing, Unused, 
and Spurious Data 
Except for the use of LOCF for the analysis of the primary criterion as described below in 
Sections 8.5.1.1 and 8.5.1.2, all other analyses will be based on observed data only; no 
data will be imputed. 
8.2.4. 
Interim Analyses 
There is no interim analysis planned. 
8.2.5. 
Software used for statistical analyses 
The SAS software, version 9.2 or higher, will be used for the statistical analysis. 
8.3. 
Protocol deviations 
Major protocol deviations are defined as deviations liable to prevent or change the 
interpretation of the results of the primary efficacy analysis of the study. The following 
deviations will be considered as major (this list is not exhaustive and will be reviewed at 
the time of the blind review meeting): 
 noncompliance with the inclusion or non-inclusion criteria 
 noncompliance with study treatment 
 no post-baseline data for the primary efficacy endpoint 
 intake of forbidden medication 

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All other deviations will be considered as minor deviations. However, all deviations will 
be reviewed and adjudicated as either major or minor during the blind review meeting 
before database lock and code break. 
8.4. 
Analysis datasets 
The statistical analysis will be conducted on the following subject data sets: 
The Full Analysis Set (FAS) will consist in all randomized subjects having received at 
least one administration of the study medication with at least one post-baseline 
assessment of FVC% predicted (primary efficacy criterion) available 
The full analysis set will be the primary population for the efficacy analyses in this trial. 
The Per Protocol (PP) set: a subset of the FAS composed of all subjects treated with the 
IMP, having received at least the planned IMP infusions on days 1, 3, 5, and weeks 4, 8 
and 12 and who did not present any major protocol deviations.  
The per-protocol set will be used for secondary analyses of the primary efficacy criterion 
and for the analysis of some selected secondary efficacy criteria. 
The Safety (SAF) dataset: composed of all randomized subjects having received at least 
one dose of study drug. This data set will be used to perform the analysis of safety. 
8.5. 
Planned Statistical analyses 
8.5.1. 
Efficacy Analyses 
8.5.1.1. 
Primary analysis of efficacy 
The primary efficacy criterion is change from baseline to Week 28 in FVC% predicted 
The comparison of PRM-151 with placebo will be carried out via a 2-sided statistical test 
with a type-one error rate of 0.10.  
The two treatment arms will be compared using analysis of variance (ANOVA), with 
change from baseline to Week 28 in FVC% predicted as dependent variable (outcome), 
and treatment and stratum, as explanatory variables.  
In case of missing measurement of FVC% predicted at week 28, the last available post 
baseline measurement will be carried forward. 
The following statistical hypotheses will be tested: 
•H0:Absence of difference between the treatment groups. 
•H1:A difference exists between the treatment groups. 
Least square means for changes from baseline to Week 28 in FVC% predicted, together 
with their 2-sided 95% confidence interval will be presented for both treatment groups. 
The mean difference between the two groups will also be presented with its 2-sided 90% 
confidence interval. 
Due to the number of sites planned to recruit and randomize subjects in the study, it is 
expected that each site will include too few subjects to allow the inclusion of study site as 
a covariate in the stratification and the analysis,  

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8.5.1.2. 
Sensitivity analyses on the primary endpoint: 
Sensitivity analyses on the FAS: 
The mean changes from baseline to Week 28 in FVC% predicted will be compared 
between treatment groups on the FAS using an ANOVA model with treatment group and 
stratum as main effects and with a treatment by stratum interaction term as explanatory 
variables. This analysis will use the same method of data imputation for missing data 
(Last Observation Carried Forward, LOCF) as described in Section 8.5.1.1. 
In case of a significant qualitative treatment by stratum interaction, the data will be 
carefully examined searching for a potential explanation and the conclusions of the 
primary efficacy analysis will have to be interpreted cautiously. 
Potential differences in treatment effect according to study site will be addressed by 
tabulating the results on the primary criterion by treatment site, but it is expected that due 
to the small number of subjects within each site no precise estimates of within site 
treatment effect will be obtained for most of the sites. 
Sensitivity analyses on the PP set: 
The ANOVA model described above (see Section 8.5.1.1) for the primary efficacy 
analysis will be used for the analysis of the primary efficacy endpoint on the PP analysis 
set. 
8.5.1.3. 
Secondary efficacy analyses: 
8.5.1.3.1. Analyses of quantitative secondary and exploratory efficacy endpoints: 
A similar analysis as described for the primary endpoint in Section 8.5.1.1 will be done 
for the secondary and exploratory efficacy variables, replacing FVC % predicted with the 
other variables as appropriate.  These analyses will be conducted on the FAS and Per 
Protocol set.  
FVC% predicted will also be analysed separately for each level of the stratum variable (in 
subjects on a stable dose of pirfenidone or nintedanib and in subjects not on other 
treatments for IPF) using analysis of variance (ANOVA), with change from Baseline to 
week 28 in FVC% predicted as dependent variable (outcome), and treatment as the 
explanatory variable. 
8.5.1.3.2. Analyses of quantitative primary, secondary and exploratory efficacy 
endpoints evolution over time: 
The evolution of each efficacy variable with time will be compared between the two 
groups using a likelihood-based Mixed effects Model for Repeated Measures (MMRM) 
including treatment, stratum and time as fixed factors, the time by treatment interaction, 
the baseline (Day 1) measurement as covariate and the subject effect as a random effect 
to adjust for correlated errors over time. This analysis will be conducted on the FAS for 
all secondary and exploratory efficacy endpoints and on both the FAS and PP set for 
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8.5.1.3.3. Analyses of categorical secondary and exploratory efficacy endpoints: 
Percentages of subjects in each category will be computed per treatment group.  
The two treatment groups will be compared using a stratified statistical test (Cochran-
Mantel-Haenszel general association test in SAS Freq procedure), adjusting for the 
Stratum effect.  If the assumptions underlying the use of the asymptotic test are not met, 
the exact version of the test will be used. 
8.5.2. 
Safety Analyses 
AEs will be coded by using the most current version of Medical Dictionary for 
Regulatory Activities (MedDRA) and summarized by system organ class, preferred term, 
and treatment group for the number and percent of AEs reported, the number of subjects 
reporting each AE, and the number of subjects with any AE.  A by-subject AE data 
listing including onset and resolution dates, verbatim term, preferred term, treatment, 
severity, relationship to treatment, action taken, and outcome will be provided.   
Safety data, including laboratory evaluations and vital signs assessments, will be 
summarized by time of collection and by treatment group.  In addition, change from 
Baseline to any post-dose values will be summarized for vital signs and clinical 
laboratory results.   
The frequency of subjects with abnormal safety laboratory results will be tabulated by 
treatment. 
8.5.3. 
Other Analyses 
8.5.3.1. 
Subject Disposition 
A listing and table of proportions of subjects discontinuing the study for each reason will 
be provided by treatment / dose group.  Details will be included in the Statistical Analysis 
Plan. 
8.5.3.2. 
Demographic and Baseline Characteristics 
Summary statistics will be provided for the demographic and baseline characteristics; 
details will be in the Statistical Analysis Plan. 
8.5.3.3. 
Subject Adherence 
Compliance with study drug will be computed for each subject as proportion of 
prescribed study drug actually taken.  Details will be included in the Statistical Analysis 
Plan. 
8.5.3.4. 
Concomitant Medications 
A listing and table of proportions of subjects taking each concomitant medication will be 
provided.  Details will be included in the Statistical Analysis Plan. 
 

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9. 
ETHICAL, LEGAL, AND ADMINISTRATIVE 
CONSIDERATIONS 
9.1. 
Good Clinical Practice 
This study will be conducted according to the protocol and in compliance with GCP, the 
ethical principles stated in the Declaration of Helsinki, and other applicable regulatory 
requirements. 
The Investigator confirms this by signing the protocol. 
9.2. 
Informed Consent 
Written informed consent in compliance with 21 Code of Federal Regulations (CFR) § 50 
and/or ICH will be obtained from each subject prior to undergoing any protocol-specific 
tests or procedures that are not part of routine care. 
Promedior will provide an informed consent form (ICF) template to the Investigator for 
use in developing a study center-specific ICF.  Prior to submission of the study center-
specific ICF to the IRB/EC, the study center-specific ICF must be reviewed and approved 
by Promedior.  Any changes requested by the IRB/EC must also be approved by 
Promedior.  The final IRB/EC-approved ICF must be provided to Promedior.  Revisions 
to the ICF required during the study must be approved by Promedior, and a copy of the 
revised ICF provided to Promedior. 
Before recruitment and enrollment, each prospective subject (or legal guardian) will be 
given a full explanation of the study and be allowed to read the ICF.  After the 
Investigator or Sub-investigator is assured that the subject/legal guardian understands the 
commitments of participating in the study, the subject/legal guardian will be asked to sign 
and date the ICF.   
A copy of the fully signed and dated ICF will be given to the subject.  The original will 
be maintained in the subject’s medical record at the study center.  All active subjects will 
sign an updated ICF if revisions are made to the ICF during the course of the study. 
9.3. 
Institutional Review Board/Ethics Committee 
The IRB/EC will review all appropriate study documentation in order to safeguard the 
rights, safety, and well-being of the subjects. The study will only be conducted at study 
centers where IRB/EC approval has been obtained. The protocol, Investigator’s 
Brochure, informed consent, advertisements (if applicable), written information given to 
the subjects (including diary cards), safety updates, annual progress reports, and any 
revisions to these documents will be provided to the IRB/EC by the Investigator. 
The final study protocol, including the final version of the Informed Consent Form, must 
be approved or given a favorable opinion in writing by an IRB/EC as appropriate. The 
Investigator must submit written approval to Promedior or designee before he or she can 
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The Investigator is responsible for informing the IRB/EC of any amendment to the 
protocol in accordance with local requirements. In addition, the IRB/EC must approve all 
advertising used to recruit subjects for the study. The protocol must be re-approved by 
the IRB / EC upon receipt of amendments and annually, as local regulations require. 
The Investigator is also responsible for providing the IRB/EC with reports of any 
reportable serious ADRs from any other study conducted with the investigational 
product. Promedior will provide this information to the Investigator. 
Progress reports and notifications of reportable serious ADRs will be provided to the 
IRB/EC according to local regulations and guidelines. 
To ensure compliance with GCP and all applicable regulatory requirements, Promedior or 
designee may conduct a quality assurance audit.  
9.4. 
Amending the Protocol 
Any changes in this research activity, except those to remove an apparent immediate 
hazard to the subject, must be reviewed and approved by Promedior and the IRB/EC that 
approved the study.  Amendments to the protocol must be submitted in writing to the 
Investigator’s IRB/EC for approval prior to subjects being enrolled into the amended 
protocol. 
Promedior may make administrative changes (i.e., changes that do not significantly affect 
subject safety or the study’s scope or scientific quality) without any further approvals.   
9.5. 
Confidentiality 
All study findings and documents will be regarded as confidential.  The Investigator and 
other study personnel must not disclose such information without prior written approval 
from Promedior. 
Subject confidentiality will be strictly maintained to the extent possible under the law.  
Subject names must not be disclosed.  Subjects will be identified in the eCRFs and other 
documents submitted to Promedior or its designated representative, by their initials, birth 
date, and/or assigned subject number.  Documents that identify the subject (e.g., the 
signed ICF) should not to be submitted to Promedior or its designated representative, and 
must be maintained in confidence by the Investigator. 
9.6. 
Publication Policy 
It is anticipated that the results of this study will be presented at scientific meetings 
and/or published in a peer reviewed scientific or medical journal.  A Publications 
Committee comprised of Investigators participating in the study and representatives from 
Promedior, as appropriate, will be formed to oversee the publication of the study results, 
which will reflect the experience of all participating study centers.  Subsequently, 
individual Investigators may publish results from the study in compliance with their 
agreement with the Sponsor. 

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10. 
STUDY MANAGEMENT 
10.1. 
Case Report Forms and Source Documentation 
The Sponsor or designee will provide the study centers with eCRFs for each subject. 
eCRFs will be completed for each study subject.  It is the Investigator’s responsibility to 
ensure the accuracy, completeness, and timeliness of the data reported in the subject’s 
eCRF.  Source documentation supporting the eCRF data should indicate the subject’s 
participation in the study and should document the dates and details of study procedures, 
AEs, and subject status.   
The Investigator, or designated representative, should complete the eCRF as soon as 
possible after information is collected.  An explanation should be given for all missing 
data. 
The Investigator must electronically sign and date the Investigator’s Statement at the end 
of the eCRF to endorse the recorded data.   
10.2. 
Monitoring 
During the course of the study, the CRA will make study center visits to review protocol 
compliance, compare eCRFs and individual subject’s medical records, assess drug 
accountability, and ensure that the study is being conducted according to pertinent 
regulatory requirements in respect to Good Clinical Practice.  eCRFs will be verified with 
source documentation.  The review of medical records will be performed in a manner to 
ensure that subject confidentiality is maintained. 
10.3. 
Inspections 
Regulatory authorities and/or quality assurance personnel from Promedior or its 
designated representative may wish to carry out such source data checks and/or in-center 
audit inspections.  The investigator assures Promedior of the necessary support at all 
times.  In the event of an audit, the Investigator agrees to allow the Sponsor’s 
representatives and any regulatory agencies access to all study records.  
10.4. 
Financial Disclosure Reporting Obligations 
Investigators and Sub-investigators are required to provide financial disclosure 
information to the Sponsor to permit the Sponsor to fulfill its regulatory obligation.  
Investigators and Sub-investigators must commit to promptly updating the information if 
any relevant changes occur during the study and for a period of one year after the 
completion of the study. 
10.5. 
Archiving Study Records 
Essential documents should be retained for a minimum of two years after the last 
approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region or at least two years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  

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However, these documents should be retained for a longer period if required by the 
applicable local requirements. 
ICH requires that subject identification codes be retained for at least 15 years after the 
completion or discontinuation of the study. 
 

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Richeldi, L., R. M. du Bois, et al. "Efficacy and Safety of Nintedanib in Idiopathic 
Pulmonary Fibrosis." New England Journal of Medicine 370(22): 2071-2082. 
Verstovsek, S., R. A. Mesa, et al. (2012). "A double-blind, placebo-controlled trial of 
ruxolitinib for myelofibrosis." N Engl J Med 366(9): 799-807. 
Wanger, J., J. L. Clausen, et al. (2005). "Standardisation of the measurement of lung 
volumes." Eur Respir J 26(3): 511-522. 
Zavaletta, V. A., B. J. Bartholmai, et al. "High Resolution Multidetector CT-Aided 
Tissue Analysis and Quantification of Lung Fibrosis." Academic Radiology 
14(7): 772-787. 
 
 
 
 

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12. 
APPENDIX A      SCHEDULE OF EVENTS 
 

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Study Protocol PRM-151-202 
 
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65 
 
 
  
Week 0  
W4, W8, W12, W28/ EOS 
W28  
W32 
W36 
W40 
W44 
W48 
W52 
Week 56 
  
  
(+/-1day)  
W16, 
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/-3days)  
  
  
  
W20,W24 
  
  
  
  
  
  
  
  
  
  
  
  
(+/- 3d) 
  
  
  
  
  
  
  
  
  
  
  
Baseline  
Dosing 
Dosing  Day 1  
  
Dosing  
Day 1  
Dosing  
Dosing  
Day 1  
Dosing  
Day 1  
Dosing  
Day 1  
Dosing  
Day 1  
Dosing  
Day 1  
Dosing  
Day 1  
Baseline  
Dosing  
  
  
Dosing  
Days   
Days   
Dosing  
Days   
  
  
Day 1  
3, 5  
3, 5  
Day 1  
3, 5  
Informed Consent  
x  
  
  
  
   
  
  
  
  
  
  
  
  
  
  
Demographics  
x  
  
  
   
   
  
  
  
  
   
  
  
   
  
  
Past Medical History  
x  
  
  
   
   
  
  
  
  
   
  
  
   
  
  
Inclusion/Exclusion  
x  
x  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital Signs (pre and 
post dose and every 
15 minutes for the 
duration of the 
infusion 
x  
x  
x  
x   
x   
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Physical Exam[1]  
x  
x  
  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Height (cm)  
x  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Weight (kg)  
x  
x  
  
x   
  
x  
x 
x   
x   
x   
x   
x   
x   
x  
  
Prior/Concomitant 
Medications  
x  
x  
x  
x  
x   
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Special list of 
excluded medications 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
AE/SAE Assessment  
  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
ECG & Cytokines 
(ONLY in the event 
of an IRR after 
Baseline)  
  
x  
x  
x  
  
  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Efficacy 
Assessment[2]  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Patient Reported 
Outcomes; K-BILD 
& LCQ  
x  
x  
  
x  
x  
x  
  
x  
x  
x  
x  
x  
x  
  
  

PRM-151 
Study Protocol PRM-151-202 
 
Version 4.0 
 
66 
 
Pulmonary Function 
Tests (PFTs)   
x  
x  
  
x  
x  
x  
  
x  
x  
x  
x  
x  
x  
  
  
DLCO[3]  
x  
x  
  
  
x  
x  
  
  
  
  
  
  
  
  
  
FRC &TLC by 
nitrogen washout 
method[4]  
x  
x  
  
  
x  
x  
  
  
  
  
  
  
  
  
  
HRCT (with 
spirometry at select 
sites)[5]  
  
x  
  
  
x  
x  
  
  
  
  
  
  
  
  
  
6-minute walk test  
x   
x  
  
x   
x  
x  
  
x   
x   
x   
x   
x   
x   
  
  
Pregnancy test Each 
visit after V4 for all 
WOCBP 
x  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Complete Blood 
Count  
x  
x  
  
x  
x  
x  
  
  
  
x  
  
  
x  
  
  
Chemistry, 
BUN/creatinine  
x  
x  
  
x  
x  
x  
  
  
  
x  
  
  
x  
  
  
Coagulation  
x  
x  
  
x  
x  
x  
  
  
  
x  
  
  
x  
  
  
Status of baseline 
genetic 
characteristics[6]  
  
x  
  
  
  
  
  
  
  
  
  
  
  
  
  
Anti-pentraxin 2 
antibodies (ADA), 
Pre-dose  
  
x  
  
x  
x  
x  
  
  
  
x  
  
  
x  
  
  
Pentraxin-2 levels, 
Pre-dose  
  
x  
  
x  
x  
x  
  
  
  
x  
  
  
x  
  
  
Exploratory 
laboratory 
assessments 
(optional)[7]  
  
x  
  
  
x  
x  
  
  
  
  
  
  
  
  
  
PRM-151 dosing[8]  
  
x  
x  
x  
  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
 
 

PRM-151 
Study Protocol PRM-151-202 
 
Version 4.0 
 
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W60 
W64 
W68 
W72 
W76 
W80 
Week 84 
W88 
W92 
W96 
W100 
W104 
W108 
W
  
  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/-3days)  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(+/- 3d)  
(
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Dosing  
Day 1  
Dosing  
Day 1  
Dosing  
Day 1  
Dosing  
Day 1  
Dosing  
Day 1  
Dosing  
Day 1  
Baseline  
Dosing  
Dosing  
Day 1  
Dosing  
Day 1  
Dosing  
Day 1  
Dosing  
Day 1  
Dosing  
Day 1  
Dosing  
Day 1  
Baseli
  
  
Dosing  
Days   
Dosin
  
  
Day 1  
3, 5  
Day 
Informed Consent  
x  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Demographics  
x  
   
   
  
  
   
   
  
  
   
  
  
   
  
  
  
Past Medical History   
x  
   
   
  
  
   
   
  
  
   
  
  
   
  
  
  
Inclusion/Exclusion  
x  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital Signs (pre and 
post dose and every 15 
minutes for the duration 
of the infusion 
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Physical Exam[1]  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Height (cm)  
x  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Weight (kg)  
x  
x   
x   
x   
x   
x   
x   
x  
  
x   
x   
x   
x   
x   
x   
x  
Prior/Concomitant 
Medications  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Special list of excluded 
medications  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
AE/SAE Assessment   
  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
ECG & Cytokines 
(ONLY in the event of 
an IRR after Baseline)  
  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
Efficacy Assessment[2] 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Patient Reported 
Outcomes; K-BILD & 
LCQ  
x  
  
x  
  
  
x  
  
  
  
x  
  
  
x  
  
  
x  

PRM-151 
Study Protocol PRM-151-202 
 
Version 4.0 
 
68 
 
Pulmonary Function 
Tests (PFTs)   
x  
  
x  
  
  
x  
  
  
  
x  
  
  
x  
  
  
x  
DLCO[3]  
x  
  
  
  
  
x 
  
  
  
  
  
  
  
  
  
  
FRC &TLC by nitrogen 
washout method[4]  
x  
  
  
  
  
x 
  
  
  
  
  
  
  
  
  
  
HRCT (with spirometry 
at select sites)[5]  
  
  
  
  
  
x 
  
  
  
  
  
  
  
  
  
  
6-minute walk test  
x   
  
x   
  
  
x   
  
  
  
x   
  
  
x   
  
  
x  
Pregnancy test Each 
visit after V4 for all 
WOCBP 
x  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Complete Blood Count  
x  
  
x  
  
  
x  
  
  
  
x  
  
  
x  
  
  
x  
Chemistry, 
BUN/creatinine  
x  
  
x  
  
  
x  
  
  
  
x  
  
  
x  
  
  
x  
Coagulation  
x  
  
x  
  
  
x  
  
  
  
x  
  
  
x  
  
  
x  
Status of baseline 
genetic 
characteristics[6]  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Anti-pentraxin 2 
antibodies (ADA), Pre-
dose  
  
  
x  
  
  
x  
  
  
  
x  
  
  
x  
  
  
x  
Pentraxin-2 levels, Pre-
dose  
  
  
x  
  
  
x  
  
  
  
x  
  
  
x  
  
  
x  
Exploratory laboratory 
assessments 
(optional)[7]  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
PRM-151 dosing[8]  
  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
x  
 
 

PRM-151
Study Protocol PRM-151-202 
Version 4.0 
69 
 
 
[1] Full physical exam at screening and an abbreviated physical exam thereafter.  
[2] PROs should be done first before PFTs and 6MWT and 6MWT should be done last after PROs 
and PFTs if possible. During open-label extension, subjects will have PROs, PFTs and 6MWT 
every 4 weeks for the first 24 weeks, then every 12 weeks.    
[3] Diffusion capacity should be done on the same day as HRCT. 
[4] FRC &TLC by nitrogen washout method should be done on the same day as HRCT .  
[5] During open-labeled extension, subjects will have DLco and FRC & TLC by nitrogen washout 
and HCRT at 1.5 years (W76) and 2.5 years (W128). The subjects are able to continue in the open-
label extension for an indefinite period of time. 
[6] TLR3 L412F polymorphism, MUC5B promoter polymorphism 
[7] During open label extension, subjects will have optional exploratory labs at Week 128.  
[8] Dosing on Days 1, 3, and 5 will be repeated every 28 weeks during the extension study. If the 
subject is not able to adhere to the original dosing schedule, the subject should be dosed as soon as 
possible within 2 weeks of the scheduled visit.  If the subject dosing is >2 weeks sponsor should be 
consulted. 
PROs should be done first before PFTs and 6MWT and 6MWT should be done last after PROs 
and PFTs if possible. During open-label extension, subjects will have PROs, PFTs and 6MWT
every 4 weeks for the first 24 weeks, then every 12 weeks. 
[3] Diffusion capacity should be done on the same day as HRCT.
[4] FRC &TLC by nitrogen washout method should be done on the same day as HRCT .
[5] During open-labeled extension, subjects will have DLco and FRC & TLC by nitrogen washout
and HCRT at 1.5 years (W76) and 2.5 years (W128). The subjects are able to continue in the open-
label extension for an indefinite period of time.
[6] TLR3 L412F polymorphism, MUC5B promoter polymorphism
[7] During open label extension, subjects will have optional exploratory labs at Week 128. 

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Study Protocol PRM-151-202 
 
Version 4.0 
 
70 
 
13. 
APPENDIX B      SIX-MINUTE WALK TEST 
TECHNICAL ASPECTS OF THE 6MWT 
(ATS 2002) 
Location 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled. If the weather is comfortable, the test may be performed 
outdoors. The walking course must be 30 m in length. A 100ft hallway is, therefore, required. 
The length of the corridor should be marked every 3 m. The turnaround points should be marked 
with a cone (such as an orange traffic cone). A starting line, which marks the beginning and end 
of each 60-m lap, should be marked on the floor using brightly colored tape. 
 
REQUIRED EQUIPMENT 
1.  Countdown timer (or stopwatch) 
2.  Mechanical lap counter 
3.  Two small cones to mark the turnaround points 
4.  A chair that can be easily moved along the walking course 
5.  Worksheets on a clipboard 
6.  A source of oxygen 
7.  Sphygmomanometer 
8.  Telephone 
9.  Automated electronic defibrillator 
 
PATIENT PREPARATION 
1.  Comfortable clothing should be worn. 
2.  Appropriate shoes for walking should be worn. 
3.  Patients should use their usual walking aids during the test (cane, walker, etc.). 
4.  The patient’s usual medical regimen should be continued. 
5.  A light meal is acceptable before early morning or early afternoon tests. 
6.  Patients should not have exercised vigorously within 2 hours of beginning the test. 
 
MEASUREMENTS 
1. Repeat testing should be performed about the same time of day to minimize intraday 
variability. 
2. A “warm-up” period before the test should not be performed. 

PRM-151 
Study Protocol PRM-151-202 
 
Version 4.0 
 
71 
 
3. The patient should sit at rest in a chair, located near the starting position, for at least 10 
minutes before the test starts. During this time, check for contraindications, measure pulse 
and blood pressure, and make sure that clothing and shoes are appropriate.  Complete the 
first portion of the worksheet. 
4. Pulseoximetry is optional. If it is performed, measure and record baseline heart rate and 
oxygen saturation (SpO2) and follow manufacturer’s instructions to maximize the signal and 
to minimize motion artifact (56, 57). Make sure the readings are stable before recording. 
Note pulse regularity and whether the oximeter signal quality is acceptable.  The rationale for 
measuring oxygen saturation is that although the distance is the primary outcome measure, 
improvement during serial evaluations may be manifest either by an increased distance or by 
reduced symptoms with the same distance walked (39). The SpO2 should not be used for 
constant monitoring during the exercise.  The technician must not walk with the patient to 
observe the SpO2. If worn during the walk, the pulse oximeter must be lightweight (less than 
2 pounds), battery powered, and held in place (perhaps by a “fanny pack”) so that the patient 
does not have to hold or stabilize it and so that stride is not affected. Many pulseoximeters 
have considerable motion artifact that prevents accurate readings during the walk.  
5. Have the patient stand and rate their baseline dyspnea and overall fatigue using the Borg 
scale (see APPENDIX E for the Borg scale and instructions). 
6. Set the lap counter to zero and the timer to 6 minutes. Assemble all necessary equipment (lap 
counter, timer, clipboard, Borg Scale, worksheet) and move to the starting point. 
7. Instruct the patient as follows: 
“The object of this test is to walk as far as possible for 6 minutes. You will walk back and 
forth in this hallway.  Six minutes is a long time to walk, so you will be exerting yourself. 
You will probably get out of breath or become exhausted. You are permitted to slow 
down, to stop, and to rest as necessary. You may lean against the wall while resting, but 
resume walking as soon as you are able. 
You will be walking back and forth around the cones. You should pivot briskly around 
the cones and continue back the other way without hesitation. Now I’m going to show 
you. Please watch the way I turn without hesitation.” 
Demonstrate by walking one lap yourself. Walk and pivot around a cone briskly. 
“Are you ready to do that? I am going to use this counter to keep track of the number of 
laps you complete. I will click it each time you turn around at this starting line. 
Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don’t run 
or jog. 
Start now or whenever you are ready.” 
8. Position the patient at the starting line.  You should also stand near the starting line during 
the test. Do not walk with the patient. As soon as the patient starts to walk, start the timer. 
9. Do not talk to anyone during the walk. Use an even tone of voice when using the standard 
phrases of encouragement.  Watch the patient. Do not get distracted and lose count of the 
laps. Each time the participant returns to the starting line, click the lap counter once (or mark 

PRM-151 
Study Protocol PRM-151-202 
 
Version 4.0 
 
72 
 
the lap on the worksheet). Let the participant see you do it. Exaggerate the click using body 
language, like using a stop- watch at a race. After the first minute, tell the patient the 
following (in even tones): “You are doing well.  You have 5 minutes to go.” When the timer 
shows 4 minutes remaining, tell the patient the following: “Keep up the good work. You 
have 4 minutes to go.” When the timer shows 3 minutes remaining, tell the patient the 
following:  “You are doing well. You are halfway done.” When the timer shows 2 minutes 
remaining, tell the patient the following: “Keep up the good work. You have only2 minutes 
left.” When the timer shows only 1 minute remaining, tell the patient:  “You are doing well.  
You have only 1 minute to go.”Do not use other words of encouragement (or body language 
to speed up). 
If the patient stops walking during the test and needs a rest, say this:  “You can lean against 
the wall if you would like; then continue walking whenever you feel able.”  Do not stop the 
timer.  If the patient stops  before the 6 minutes are up  and  refuses to continue (or  you  
decide   that  they should  not continue), wheel the chair over for the patient to sit on, 
discontinue the walk, and note on the  worksheet the distance, the time stopped, and the 
reason for stopping pre- maturely. 
When the timer is 15 seconds from completion, say this: “In a moment I’m going to tell you 
to stop.  When I do, just stop right where you are and I will come to you.” 
When the timer rings (or buzzes), say this: “Stop!” Walk over to the patient. Consider taking 
the chair if they look exhausted. Mark the spot where they stopped by placing a bean bag or a 
piece of tape on the floor. 
10. Post-test: Record the post walk Borg dyspnea and fatigue levels and ask this: “What, if 
anything, kept you from walking farther?” 
11. If using a pulse oximeter, measure SpO2 and pulse rate from the oximeter and then remove 
the sensor. 
12. Record the number of laps from the counter (or tick marks on the worksheet). 
13. Record the additional distance covered (the number of meters in the final partial lap) using 
the markers on the wall as distance guides. Calculate the total distance walked, rounding to 
the nearest meter, and record it on the worksheet. 
14. Congratulate the patient on good effort and offer a drink of water. 
 
 

PRM-151 
Study Protocol PRM-151-202 
 
Version 4.0 
 
73 
 
 
Note: start and stop time collection is not required 
 

PRM-151 
Study Protocol PRM-151-202 
 
Version 4.0 
 
74 
 
14. 
APPENDIX C      BORG SCALE 
Borg Scale for Rating Dyspnea and Overall Fatigue (ATS 2002) 
Score 
Definition 
0 
Nothing at all 
0.5 
Very, very slight (just noticeable) 
1 
Very slight 
2 
Slight (light) 
3 
Moderate 
4 
Somewhat severe 
5 
Severe (heavy) 
6 
 
7 
Very severe 
8 
 
9 
 
10 
10Very, very severe (maximal) 
 
 
 

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Study Protocol PRM-151-202 
 
Version 4.0 
 
75 
 
15. 
APPENDIX D      THE KING’S BRIEF INTERSTITIAL LUNG  
DISEASE QUESTIONNAIRE (K-BILD) 
(Patel, Siegert et al.) 
 

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Study Protocol PRM-151-202 
 
Version 4.0 
 
76 
 
16. 
APPENDIX E       SUMMARY OF CHANGES 
Changes from Version 3.0 to Version 4.0 
Section(s) 
Change 
Inclusion 
As there is no information available at the moment on the effect 
of PRM-151 on sperm and your partner might become pregnant 
you must use effective methods forms of contraception during 
this study. Effective methods of birth control include the use of 
oral contraceptives or Depo-Provera, with an additional barrier 
method (diaphragm with spermicidal gel or condoms with 
spermicide), double barrier methods (diaphragm with 
spermicidal gel and condoms with spermicide), partner 
vasectomy and total abstinence (only if total abstinence is the 
preferred method and usual lifestyle of the subject). Adequate 
contraceptive use should be continued until 28 days after the 
final dose of the study drug. 
 
Clarified WOCBP birth control. 
Inclusion 
Added: Subject and the treating physician considered all medicinal 
treatment options and / or possibly a lung transplantation prior to 
considering participation in the study. 
Efficacy 
Assessments/Schedule 
of Events 
Added:  ECG and Cytokines completed at baseline, prior to PRM-151 
dosing.  ECG and cytokines will only be repeated then in the event of an 
infusion-related reaction (IRR) afterBaseline. 
Schedule Of Events 
Added note for pre and post vitals collection  
Throughout 
Formatting updates and minor corrections/clarifications to text to 
harmonize with PRM-151-101 
Infusion Reaction 
Changed: Infuse over 1 hour to infuse over 120 minutes 
 
 
Changes from Version 2.0 to Version 3.0 
Section(s) 
Change 
7.10.3 
Removed the requirement to obtain a spirometry guided HRCT at full 
expiration (FRC) 
Throughout 
Formatting updates and minor corrections/clarifications to text. 
 
Changes from Version 1.0 to Version 2.0 

PRM-151 
Study Protocol PRM-151-202 
 
Version 4.0 
 
77 
 
Section(s) 
Change 
Cover page 
Added Amendment 1 version information. 
Study Title 
Modified title of the protocol from “Pilot Trial” to “A Phase 2 Trial”. 
Synopsis: 
(Primary 
Objective);  
2.1 
Modified the Primary Objective from “demonstrating the superiority” to 
“determining the effect size of change”.   
Clarified that the changes will be in normal lung “parenchyma”.   
Updated “by structural” to “on high-resolution CT”.   
Added subject can be on a dose of nintedanib. 
Synopsis: 
(Secondary 
Objective(s);  
2.2 
Modified from “demonstrating superiority” to “determine effect size” and 
from “preservation or increase” to “change”.   
Clarified that change in normal lung “parenchyma” will be quantified “on 
high-resolution CT (HRCT) imaging analysis, pooling subjects on a stable 
dose of pirfenidone with subjects not on other treatment for IPF”.  
Modified the duration of treatment subjects will be assessed for tolerability 
and safety from “24 weeks” to “28 weeks”. 
Added subject can be on a dose of nintedanib. 
Modified an assessment of “6 minute walk distance” to “gas exchange 
(DLCO)”. 
Added Secondary Objectives: 
 
Determine the effect size of PRM-151 relative to placebo in change 
from Baseline to Week 28 in mean FVC% predicted, separately in 
subjects on a stable dose of pirfenidone and separately in subjects not on 
other treatments for IPF. 
 
Determine the effect size of PRM-151 relative to placebo in change 
from Baseline to Week 28 in normal lung parenchyma as quantified on 
HRCT imaging analysis, separately in subjects on a stable dose of 
pirfenidone and in subjects not on other treatments for IPF. 
 
Determine the effect of PRM-151 on pulmonary function in addition to 
mean change in FVC% predicted. 
 
Determine the effect size of PRM-151 relative to placebo on 6 minute 
walk distance. 

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Synopsis: 
(Exploratory 
Objective(s);  
2.3 
Removed Exploratory Objectives: 
 
Assess the ability of PRM-151 to preserve or increase gas exchange 
 
Assess the impact of PRM-151 on functional respiratory imaging 
parameters 
 Added Exploratory Objective: 
 Evaluate the efficacy and estimate the size of effect of PRM-151 
relative to placebo in change from baseline to weeks 4, 8, 12, 16, 
20, and 24 in FVC % predicted and 6 minute walking distance, 
pooling subjects on a stable dose of pirfenidone with subjects not 
on other treatment for IPF, and separately in subjects on a stable 
dose of pirfenidone and in subjects not on other treatments for IPF 
Added subject can be on a dose of nintedanib. 
Synopsis: (Study 
Endpoints) 
Secondary: 
Structural 
Imaging; 
2.2 
Clarified total lung measurements using HRCT (in ml and % of total lung 
volume) using quantitative imaging software.   
Modified “Transitions between all categories of lung features (normal, 
ground glass density, reticular changes, honeycombing, and mild low 
attenuation areas) by quantitative imaging software.”  to “Mean change from 
Baseline to Week 28 in volume of parenchymal features on HRCT (in ml 
and % of total lung volume) representative of normal lung (non-ILA), 
including normal and mild low attenuation areas, using quantitative imaging 
software.” 
Added Secondary Endpoint: 
 
Correlation between mean change from Baseline to Week 28 in FVC % 
predicted and mean change from Baseline to Week 28 in total lung 
volume and volume of parenchymal features on HRCT (in ml and % of 
total lung volume)  representative of interstitial lung abnormalities 
(ILA), including ground glass density, reticular changes, and 
honeycombing by quantitative imaging software. 
Synopsis: (Study 
Endpoints) 
Secondary: 
Safety; 
2.2 
Modified the duration of assessment of tolerability and safety from “24 
weeks” to “28 weeks”. 
 
Synopsis: (Study 
Endpoints) 
Secondary: 
Disease related 
events associated 
with mortality. 
2.2;  7.12.1.1 
Modified the duration of assessment from “24 weeks” to “28 weeks”. 
Modified the definition of respiratory decline based on the definitions of 
IPF-related acute exacerbation proposed by an expert committee sponsored 
by the Clinical Research Network and the National Heart Lung and Blood 
Institute (NHLBI). 

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Synopsis: (Study 
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Secondary: 
Pulmonary 
Function Tests; 
2.2 
Removed PFTs: 
 
Time-weighted average (TWA) of change in FVC% predicted from 
Baseline to Week 28. 
 
TWA of change in FVC in ml from Baseline to Week 28. 
Added PFTs: 
 
Proportion of subjects with stable disease by FVC %, defined as a 
change in FVC % predicted of <5% from Baseline to Week 28. 
 
Proportion of subjects with stable disease by absolute FVC, defined as a 
change in FVC of < 100ml from Baseline to Week 28. 
Synopsis: (Study 
Endpoints) 
Secondary: 
Exploratory; 
2.3 
Added Other Weeks 
 
Examine the change from baseline at Weeks 4, 8, 12, 16, 20, and 24 for 
the FVC % predicted, FVC (l), and 6MWT distance 
Added Structural Imaging 
 
Transitions from Baseline to Week 28 between all categories of lung 
features (normal, ground glass density, reticular changes, 
honeycombing, and mild, moderate, and severe low attenuation areas) 
by quantitative imaging software. 
 
Correlation of transitions between categories of lung features by 
quantitative imaging and changes in FVC% predicted. 
 
Correlation of transitions between categories of lung features by 
quantitative imaging and changes in DLCO. 
 
Impact of inspiratory effort on results of HRCT quantitative imaging. 
Removed Quantitative Functional Respiratory Imaging 
 
Change from baseline to 28 weeks in regional lung volumes, specific 
airway volumes and resistance as measured by quantitative imaging 
software (FluidDA). 
Synopsis: Study 
Design;  
4.1 
Clarification on randomization 2:1 ratio.  The randomization will be 
stratified according to other treatments for IPF (subjects receiving 
pirfenidone and subjects with no other treatment for IPF).  
Modified the evaluation of the Total Lung Capacity by “Helium dilution 
method (TLC by He),” to “Nitrogen washout method”. 
Modified the number of subjects enrolled from “60” to “117”.  
Added dosing on Days 1, 3 and 5 will be repeated once every 24 weeks for 
the open label study extension. 
Added subject can be on a dose of nintedanib. 
Synopsis: Study 
Inclusion 
Criteria; 
5.1.1 
Removed “post-bronchodilator” from Inclusion Criteria 8.  
Added subject can be on a dose of nintedanib. 

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Synopsis: Study 
Exclusion 
Criteria; 
5.1.1 
Removed Exclusion Criteria 8. Subjects has received nintedanib within the 
4 weeks before baseline. 
Synopsis:  
Efficacy 
Assessments; 
4.1.3 
Modified from “Order of Events” to “Schedule of Events”.   
Modified pulmonary function from “TLC by helium dilution” to “TLC by 
nitrogen washout”. 
Clarified that HRCT will be performed with spirometry at selected sites. 
Added dosing on Days 1, 3 and 5 will be repeated once every 24 weeks for 
the open label study extension. 
Synopsis: Safety 
Assessments 
Added “Safety will be evaluated from reported adverse events (AEs), 
scheduled physical examinations, vital signs, and clinical laboratory test 
results.” 
Synopsis: 
Statistical 
Methods: 
Clarified the analysis plan for the study. 
Synopsis: 
Sample Size 
Considerations; 
8.1 
Clarified the sample size calculations and provided rationalization based on 
updated subject enrollment numbers. 
Added that the randomization system will ensure that at least 25% of the 
subjects in the final study population are on no other therapy for IPF at 
baseline. 
List of 
Abbreviations 
Added: 
ADA, AESI, ILA, ILD, and LAA 
1. 
Modified the title from “Introduction” to “Introduction and Study Rational” 
1.3.1 
Modified the title from “Imbio” to “Imbio Lung Texture Analysis” 
Clarified the use of Imbio Lung Texture Analysis and how it will be used 
for analysis in the study. 
1.3.2 
Clarified the retrospective quantitative imaging analysis of PRM-151 data in 
Study PRM151f-12GL.   
1.5 
Added rational for using HRCT and explanation of the low risk of radiation 
to the subjects. 
4.1.1 
Clarified the duration of assessments are to occur weeks, 4, 8, 12, 16, 20, 24 
and 28 weeks for efficacy and safety  

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5.1.2 
Updated Exclusion Criteria 10. to be consistent with the Synopsis. 
Subjects that are unable to refrain from use of the following:  
 
Short acting bronchodilators on the day of and within 12 hours of 
pulmonary function, DLCO, and 6 minute walk assessments.   
 
Long acting bronchodilators on the day of and within 24 hours of these 
assessments. 
5.7 
Modified the procedure for the Data Monitoring Committee. The DMC to 
review the safety data in a blinded manner, but a procedure will be in place 
to allow the committee an immediate unblinding of either specific cases or 
of the whole study in case of detection of a potential safety signal 
necessitating an unblinded review of some (or all) subjects. 
6.2; 7.12.1.2; 
Appendix A 
Clarified that if a subject experiences an infusion related reaction, an ECG 
and a blood sample for cytokines should be collected as soon as possible 
after stabilization of the subject. 
6.8  
Clarified rational for dose selection based on data collected on subjects with 
myelofibrosis treated with PRM-151.   
7.9 
Added subject can be on a dose of nintedanib. 
Clarified that subjects currently on a stable dose of pirfenidone or nintedanib 
they are allowed to stop taking pirfenidone or nintedanib while remaining in 
the study but they are not allowed to start dosing with the other. 
7.10.1 
Modified lung volumes to be done with “Nitrogen washout method” and 
removed “according to ATS guidelines”. 
7.10.2 
Clarified that the 6MWT should be the last efficacy assessment completed, 
by the subject.  If it is not possible to complete the 6MWT last, then allow a 
30 minute recovery time before continuing with the next efficacy 
assessment 
7.10.4 
 
Clarified that if possible, the questionnaires should be the first assessments 
completed by the subjects.   
7.12.1;  7.12.2 
Clarified when AEs should be recorded. 
7.12.4 
Updated the contact information for reporting Serious Adverse Events 
7.12.4.1 
Updated the information for reporting Adverse Events for Special Interest 
7.12.4.5 
Added information regarding reporting pregnancies. 
8.2, 8.3, 8.4, 8.5 
Updated the General Considerations of Statistical Analysis, Protocol 
Deviations, Analysis Datasets, Planned Statistical Analyses section in the 
protocol.   

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9. 
Updated Section numbers for Ethical, Legal, and Administrative 
Considerations.  From Section 8.4 to Section 9. 
References 
Two new references were added. 
Appendix A 
Added a footnote to clarify the dosing on Days 1, 3 and 5 will be repeated 
once every 24 weeks for the open label study extension. 
Appendix B, C 
and G 
Removed Appendix B; Pulmonary Function Tests, Appendix C; Diffusion 
Capacity and Appendix G; Common Terminology Criteria for Adverse 
Events 
Throughout 
Formatting updates and minor corrections/clarifications to text. 
 
 
 
 

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17. 
APPENDIX F:  NATIONAL CANCER INSTITUTE COMMON 
TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (NCI 
CTCAE) 
 
The United States of America (USA) National Cancer Institute Common Terminology Criteria 
for Adverse Events, version 4.0 (NCI CTCAE, v.4.0) can be found on the following website. 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40  
[Accessed: 13 February 2013] 
 
This version of CTCAE is compatible at the AE (Adverse Event) term level where each CTCAE 
term is a Medical Dictionary for Regulatory Activities Terminology (MedDRA) LLT (Lowest 
Level Term).  CTCAE v4.0 includes 764 AE terms and 26 'Other, specify' options for reporting 
text terms not listed in CTCAE.  Each AE term is associated with a 5-point severity scale.  
MedDRA v12.0. 
 

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18. 
G. APPENDIX LEICESTER COUGH QUESTIONNAIRE (LCQ)           
 
 
(Birring, Prudon et al. 2003) 
 
 
 
 
 
 
 
 
 
 
 

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