Clinical trial NCT04552899
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Hoffmann-La Roche
Start date: 2021-03-19; Completion date: 2023-02-10
Enrollment: 665 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This phase III study will evaluate the efficacy, safety and pharmacokinetics (PK) of recombinant human pentraxin-2 (rhPTX-2; PRM-151) zinpentraxin alfa, compared with placebo in participants with idiopathic pulmonary fibrosis (IPF).

Detailed description:

Arms: arm 1: Participants will receive intravenous (IV) infusions of Zinpentraxin Alfa over 50-70 minutes on Days 1, 3 and 5, then followed by infusions every 4 weeks (Q4W) to Week 48. arm 2: Participants will receive IV infusions of placebo over 50-70 minutes on Days 1, 3 and 5, followed by infusions Q4W to Week 48.
Interventions: intervention 1: PRM-151 (Zinpentraxin Alfa) intervention 2: Placebo
Intervention descriptions: intervention 1: A 10 mg/kg IV infusion of PRM-151 based on the participants weight will be administered on Days 1, 3 and 5 followed by infusions Q4W to Week 48. intervention 2: Placebo matching PRM-151 will be administered by IV infusion on Days 1, 3 and 5, followed by infusions Q4W to Week 48.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
 
A Phase III Randomized, Double-Blind, Placebo-Controlled Trial to 
Evaluate the Efficacy and Safety of PRM-151 in Patients With 
Idiopathic Pulmonary Fibrosis 
NCT Number: NCT04552899 
Document Dates: Protocol Version 5: 28-April-2022 
 
 
 


 
CONFIDENTIAL 
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland.  However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered. 
 
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
Protocol WA42293, Version 5 
PROTOCOL 
TITLE: 
A PHASE III RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED TRIAL TO EVALUATE 
THE EFFICACY AND SAFETY OF PRM-151 IN 
PATIENTS WITH IDIOPATHIC PULMONARY 
FIBROSIS  
PROTOCOL NUMBER: WA42293 (also known as PRM-151-303) 
VERSION NUMBER: 
5  
EUDRACT NUMBER: 
2020-000791-38 
IND NUMBER: 
110,774 
NCT NUMBER: 
NCT04552899 
TEST PRODUCT: 
Recombinant human pentraxin-2 (rhPTX-2; 
PRM-151); Zinpentraxin Alfa 
MEDICAL MONITOR: 
, M.B.B.S. 
SPONSOR NAME AND 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
APPROVAL DATE: 
See electronic signature and date stamp on the final 
page of this document. 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
2/Protocol WA42293, Version 5 
PROTOCOL HISTORY 
Protocol 
Associated Country-Specific Protocols 
Version 
Date Final 
Country 
Version 
Date Final 
5 
See electronic date stamp on the 
final page. 
 
 
 
3 
13 November 2020 
Japan 
4 
27 July 2021 
2 
29 June 2020 
VHP 
2 
12 November 2020 
1 
13 March 2020 
 
 
 
 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
3/Protocol WA42293, Version 5 
PROTOCOL AMENDMENT, VERSION 5: 
RATIONALE 
Protocol WA42293 has been amended to incorporate the changes made to address 
feedback from health authorities during review of clinical trial applications along with 
additional changes initiated by the Sponsor.  Changes to the protocol, along with 
a rationale for each change, are summarized below. 
The following changes were made based on recommendations from the Japan 
Pharmaceuticals and Medical Devices Agency and were implemented in Protocol 
WA42293, Version 4 (Japan): 
 
The exclusion criterion for women who are pregnant or breastfeeding, and women 
of childbearing potential has been added (Sections 4.1.2 and 5.5.3.1).  The inclusion 
criteria (Section 4.1.1) have been updated to reflect the above change.  
 
Serum and urine pregnancy tests for women of childbearing potential have been 
removed from sample collection and schedule of assessments sections 
(Section 4.5.12). 
 
An appendix has been added to clarify the additional pharmacokinetic samples that 
will be collected for some patients enrolling in Japan (Appendix 4). 
 
The following additional changes have been made to Protocol WA42293, Version 5: 
 
Text has been added to describe galectin-1 and galectin-3 host cell protein identified 
within first generation PRM-151 drug product.  It has been further clarified that an 
additional purification step will be applied to the second generation PRM-151 which 
will not contain detectable levels of Chinese hamster ovary cell galectins (Sections 
1.2 and 4.3.1.1). 
 
Text has been added to describe the sugar galactose-α-1,3-galactose identified in 
first and second generation PRM-151 drug product and on the increased risk of 
anaphylaxis or hypersensitivity reaction in patients with a history of tick bites, red 
meat allergy, or IgE antibodies directed against galactose-α-1,3-galactose (Sections 
1.2.2 and 5.1.2). 
 
Text has been added on the potential risk of post-implantation fetal loss associated 
with PRM-151 (Sections 5.1 and 5.1.3) 
 
Text has been added to address assessment of risks related to SARS-CoV-2 
infection (Section 1.3.1). 
 
Text has been updated to clarify how assessments from patients who received lung 
transplant will be analyzed (Section 2.1.1). 
 
“Progression-free survival” has been updated to “Time to disease progression” in 
secondary efficacy objective as per United States Food and Drug Administration 
(FDA) suggestion to better reflect the nature of the endpoint (Section 2.1.2).  
 
Text has been updated to clarify that safety analyses may also be performed for 
subgroups of interest and details of all such analyses will be provided in the 
Statistical Analysis Plan (Section 2.2).  


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
4/Protocol WA42293, Version 5 
• 
Text has been updated to clarify that all sites in Hong Kong and Taiwan can 
contribute to the China cohort regardless of their National Medical Products 
Administration accreditation status (Sections 3.1.1, 4.1, 4.1.1, 4.2.1, 6, and 6.12). 
• 
The exclusion criterion regarding “clinically significant abnormality on 
electrocardiogram or laboratory tests during eligibility assessment” has been split 
into two different criteria for clarity (Section 4.1.2.).   
• 
Testing requirement for tuberculosis has been clarified in the exclusion criteria 
(Section 4.1.2).  
• 
Text has been updated to clarify measuring samples for longitudinal endogenous 
PTX-2 levels in order to evaluate if there is any modulation after rhPTX-2 drug is 
administered (Section 4.2.2). 
• 
It has been clarified that at dosing visits, vital signs should be measured predose 
(within 60 minutes prior to dosing), every 15 minutes during the infusion, and 30−60 
minutes postdose (Section 4.3.2.1). 
• 
It has been clarified that all past anti fibrotic therapy will be recorded in the Prior and 
Concurrent Anti-fibrotic Use form and all COVID-19 vaccines received will be 
recorded on the Concomitant Medications eCRF (Sections 4.4 and 4.5.3). 
• 
Text has been added to include approved vaccination including COVID-19 vaccine 
as a permitted therapy (Section 4.4.1) 
• 
Text has been added to include high-dose corticosteroids (equivalent to prednisone 
> 10 mg daily) as a prohibited therapy unless it is clinically indicated (Section 4.4.2) 
• 
Text has been added to include post-infusion lab samples that are required to be 
collected after infusion of drug (Section 4.5.2). 
• 
Table 2, Sequence of Assessments, has been updated to clarify the break between 
assessment of diffusing capacity for carbon monoxide (DLCO) and 6-Minute Walk 
Test (Sections 4.5.2 and 4.5.7). 
• 
It has been clarified that patients who had high-resolution computed tomography 
(HRCT) at screening, will have further HRCT imaging at Week 52 (Section 4.5.2). 
• 
Text has been added to include family history of Idiopathic pulmonary fibrosis (IPF) 
to gather comprehensive understanding of medical history of patients with IPF 
(Section 4.5.3). 
• 
Text has been added to include tuberculosis as a respiratory infection to gather 
comprehensive understanding of medical history of patients (Section 4.5.3). 
• 
It has been clarified that medical occurrences that begin before the start of study 
treatment but after obtaining informed consent will be recorded on the General 
Medical History and Baseline Conditioned eCRF (Section 4.5.3 and 5.4.1). 
• 
It has been clarified that DLCO assessment will be performed using local equipment 
and only data from acceptable over-read spirometry and DLCO maneuvers will be 
used for eligibility confirmation and data analysis (Section 4.5.6). 
• 
Wording has been added to clarify that the oxygen titration procedure should be 
conducted as per local standard of care (Section 4.5.7). 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
5/Protocol WA42293, Version 5 
• 
It has been clarified that a blood sample for a serum tryptase sample and 
complement C3 test should be collected at the time of a suspected anaphylaxis or 
hypersensitivity event whenever possible, and at the first follow-up visit after the 
event to reflect the management guidelines and to help determine whether tryptase 
and complement C3 levels were elevated during the event (Sections 4.5.12, 5.1.3, 
and Appendix 1).   
• 
Additional information has been provided on sample collection to align with 
infusion-related reaction management guidelines (Table 2) included in the protocol 
(Sections 4.5.12, 5.1.3, and Appendix 1). 
• 
Text has been added to include optional urine sample collection at different 
timepoints (Section 4.5.16.3). 
• 
Text has been added to clarify the difference between study treatment 
discontinuation and study discontinuation.  Additionally, it is expected that if 
a patient discontinues from treatment, they should continue with study visits and 
assessments (Section 4.6). 
• 
Text has been added for better understanding of potential risk associated with 
PRM-151 (Section 5.1). 
• 
Text has been updated in “Abnormal Liver Function Tests” to align with the updated 
Hy’s law calculation (Section 5.4.5.7).  
• 
Text has been updated to clarify that patients diagnosed with idiopathic pulmonary 
fibrosis are the target patient population for this study (Section 6.1).  
• 
As per FDA request, assessments following hospitalization for COVID-19 will be 
collected and analysed, given the likelihood of COVID hospitalization will continue 
for appreciable time (Section 6.1).  
• 
As per the request by FDA, the supplementary estimand has been removed since 
its handling of intercurrent events is not clinically relevant (Section 6.1).  
• 
Text has been deleted since the statement is no longer considered relevant to drug 
compliance with respect to this study (Section 6.4). 
• 
Language has been updated in primary efficacy analysis, sensitivity and 
supplementary analyses of primary and key secondary endpoints (previous section), 
and analyses addressing the effect of missing data to reflect suggestions from 
regulatory agencies, and to improve clarity of the text (Sections 6.4 and 6.41). 
• 
Text has been updated to clarify the interim analyses planned for this study 
(Section 6.11).  
• 
It has been clarified that an external global Steering Committee will provide 
oversight of Studies WA42293 and WA42294 (Section 9.5). 
• 
International non-proprietary name has replaced the RO number throughout the 
protocol and has also been added in the footer of each page.   
 
Additional minor changes have been made to improve clarity and consistency.  
Substantive new information appears in italics.  This amendment represents cumulative 
changes to the original protocol. 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
6/Protocol WA42293, Version 5 
 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 13 
PROTOCOL SYNOPSIS .................................................................................... 14 
1. 
BACKGROUND ............................................................................ 28 
1.1 
Idiopathic Pulmonary Fibrosis .................................................. 28 
1.2 
PRM-151.................................................................................. 29 
1.2.1 
PRM-151 Host Cell Proteins ................................................... 30 
1.2.2 
Galactose--1,3-galactose (α‑Gal) ........................................... 30 
1.3 
Study Rationale and Benefit–Risk Assessment ....................... 31 
1.3.1 
Benefit–Risk Assessment ........................................................ 32 
1.3.2 
Risks Associated with Radiologic Imaging ............................... 34 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 35 
2.1 
Efficacy Objectives .................................................................. 35 
2.1.1 
Primary Efficacy Objective ....................................................... 35 
2.1.2 
Secondary Efficacy Objective .................................................. 35 
2.1.3 
Exploratory Efficacy Objective ................................................. 36 
2.2 
Safety Objective ....................................................................... 37 
2.3 
Pharmacokinetic Objectives..................................................... 38 
2.4 
Immunogenicity Objectives ...................................................... 38 
2.5 
Biomarker Objective ................................................................ 38 
2.6 
Health Status Utility Objective .................................................. 39 
3. 
STUDY DESIGN ........................................................................... 39 
3.1 
Description of the Study ........................................................... 39 
3.1.1 
Overall Study Design and Plan ................................................ 39 
3.2 
End of Study and Length of Study ........................................... 42 
3.3 
Rationale for Study Design ...................................................... 43 
3.3.1 
Rationale for PRM-151 Dose and Schedule ............................ 43 
3.3.2 
Rationale for Key Primary and Secondary Endpoints .............. 44 
3.3.3 
Rationale for Control Group ..................................................... 45 
3.3.4 
Rationale for Biomarker Assessments ..................................... 46 
4. 
MATERIALS AND METHODS ...................................................... 46 


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7/Protocol WA42293, Version 5 
4.1 
Patients .................................................................................... 46 
4.1.1 
Inclusion Criteria ...................................................................... 46 
4.1.2 
Exclusion Criteria ..................................................................... 48 
4.2 
Method of Treatment Assignment and Blinding ....................... 50 
4.2.1 
Treatment Assignment ............................................................. 50 
4.2.2 
Blinding .................................................................................... 51 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 52 
4.3.1 
Study Treatment Formulation and Packaging .......................... 52 
4.3.1.1 
PRM-151 (Zinpentraxin Alfa) ................................................. 52 
4.3.1.2 
Placebo .................................................................................... 52 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 53 
4.3.2.1 
PRM-151 and Placebo ............................................................. 53 
4.3.3 
Investigational Medicinal Product Handling and 
Accountability ........................................................................... 54 
4.3.4 
Continued Access to PRM-151 ................................................ 55 
4.4 
Concomitant Therapy .............................................................. 55 
4.4.1 
Permitted Therapy ................................................................... 56 
4.4.2 
Prohibited Therapy .................................................................. 56 
4.4.3 
Use of Pirfenidone or Nintedanib ............................................. 57 
4.5 
Study Assessments ................................................................. 58 
4.5.1 
Informed Consent Forms and Screening Log .......................... 58 
4.5.2 
Sequence of Assessments ...................................................... 58 
4.5.3 
Medical History, Baseline Conditions, Concomitant 
Medication, and Demographic Data ......................................... 59 
4.5.4 
Physical Examinations ............................................................. 60 
4.5.5 
Vital Signs ................................................................................ 61 
4.5.6 
Pulmonary Function Tests ....................................................... 61 
4.5.7 
Six-Minute Walk Test ............................................................... 62 
4.5.8 
High-Resolution Computed Tomography ................................. 63 
4.5.9 
Lung Biopsy ............................................................................. 63 
4.5.10 
Assessment of Acute Exacerbations of IPF, 
Hospitalizations for Respiratory Causes, and Deaths 
(Adjudicated Events) ................................................................ 63 


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4.5.10.1 
Acute Exacerbations of IPF and Suspected Acute 
Exacerbations of IPF ............................................................... 64 
4.5.10.2 
Hospitalizations for Respiratory Causes .................................. 64 
4.5.10.3 
Deaths Due to Respiratory Causes ......................................... 64 
4.5.11 
Health Care Utilization for Respiratory Events ......................... 65 
4.5.12 
Laboratory, Biomarker, and Other Biological Samples ............ 65 
4.5.13 
Electrocardiograms .................................................................. 67 
4.5.14 
Clinical Outcome Assessments ............................................... 68 
4.5.14.1 
Data Collection Methods for Clinical Outcome 
Assessments ........................................................................... 68 
4.5.14.2 
Description of Clinical Outcome Assessment Instruments ....... 69 
4.5.15 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites) ................ 69 
4.5.16 
Optional Samples for Research Biosample Repository ........... 70 
4.5.16.1 
Overview of the Research Biosample Repository .................... 70 
4.5.16.2 
Approval by the Institutional Review Board or Ethics 
Committee ............................................................................... 71 
4.5.16.3 
Sample Collection .................................................................... 71 
4.5.16.4 
Confidentiality .......................................................................... 72 
4.5.16.5 
Consent to Participate in the Research Biosample 
Repository................................................................................ 72 
4.5.16.6 
Withdrawal from the Research Biosample Repository ............. 73 
4.5.16.7 
Monitoring and Oversight ......................................................... 73 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 74 
4.6.1 
Study Treatment Discontinuation ............................................. 74 
4.6.2 
Patient Discontinuation from the Study .................................... 74 
4.6.3 
Study Discontinuation .............................................................. 75 
4.6.4 
Site Discontinuation ................................................................. 75 
5. 
ASSESSMENT OF SAFETY ......................................................... 75 
5.1 
Potential Risks Associated with PRM-151 ............................... 76 
5.1.1 
Infusion-Related Reactions ...................................................... 77 
5.1.2 
Anaphylactic and Hypersensitivity Reactions........................... 77 
5.1.3 
Post-implantation Fetal Loss ....................................................... 78 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
9/Protocol WA42293, Version 5 
5.1.4 
Management Guidelines for Infusion-Related Reactions, 
Anaphylactic and Hypersensitivity Reactions........................... 78 
5.2 
Management of Patients Who Experience Adverse Events ..... 81 
5.2.1 
Dose Modifications .................................................................. 81 
5.2.2 
Treatment Interruption ............................................................. 81 
5.3 
Safety Parameters and Definitions .......................................... 81 
5.3.1 
Adverse Events ........................................................................ 81 
5.3.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 82 
5.3.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 82 
5.3.4 
Collection of Survival Data ....................................................... 83 
5.3.5 
Lung Transplantation ............................................................... 83 
5.4 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 84 
5.4.1 
Adverse Event Reporting Period .............................................. 84 
5.4.2 
Eliciting Adverse Event Information ......................................... 84 
5.4.3 
Assessment of Severity of Adverse Events ............................. 84 
5.4.4 
Assessment of Causality of Adverse Events............................ 85 
5.4.5 
Procedures for Recording Adverse Events .............................. 86 
5.4.5.1 
Infusion-Related Reactions ...................................................... 86 
5.4.5.2 
Diagnosis versus Signs and Symptoms ................................... 86 
5.4.5.3 
Adverse Events That Are Secondary to Other Events ............. 86 
5.4.5.4 
Persistent or Recurrent Adverse Events .................................. 87 
5.4.5.5 
Abnormal Laboratory Values ................................................... 87 
5.4.5.6 
Abnormal Vital Sign Values ..................................................... 88 
5.4.5.7 
Abnormal Liver Function Tests ................................................ 88 
5.4.5.8 
Deaths ..................................................................................... 89 
5.4.5.9 
Preexisting Medical Conditions ................................................ 89 
5.4.5.10 
Lack of Efficacy or Worsening of Idiopathic Pulmonary 
Fibrosis .................................................................................... 90 
5.4.5.11 
Hospitalization or Prolonged Hospitalization ............................ 90 
5.4.5.12 
Cases of Accidental Overdose or Medication Error ................. 90 
5.5 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 91 


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5.5.1 
Medical Monitors and Emergency Medical Contacts ............... 92 
5.5.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 93 
5.5.2.1 
Events That Occur prior to Study Drug Initiation ...................... 93 
5.5.2.2 
Events That Occur after Study Drug Initiation .......................... 93 
5.5.3 
Reporting Requirements for Pregnancies ................................ 93 
5.5.3.1 
Pregnancies in Female Patients .............................................. 93 
5.5.3.2 
Pregnancies in Female Partners of Male Patients ................... 94 
5.5.3.3 
Abortions.................................................................................. 94 
5.5.3.4 
Congenital Anomalies/Birth Defects ........................................ 95 
5.6 
Follow-Up of Patients after Adverse Events............................. 95 
5.6.1 
Investigator Follow-Up ............................................................. 95 
5.6.2 
Sponsor Follow-Up .................................................................. 95 
5.7 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 95 
5.8 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 96 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 97 
6.1 
Primary efficacy estimand ........................................................ 97 
6.2 
Determination of Sample Size ................................................. 99 
6.2.1 
Assumptions on Treatment Effects for Sample-Size and 
Power Calculations ................................................................ 100 
6.2.1.1 
Robustness of Power and Sample-Size Calculations ............ 101 
6.3 
Summaries of Conduct of Study ............................................ 102 
6.4 
Summaries of Treatment Group Comparability ...................... 102 
6.5 
Efficacy Analyses ................................................................... 103 
6.5.1 
Primary Efficacy Analysis....................................................... 103 
6.5.2 
Key Secondary Efficacy Endpoint .......................................... 104 
6.5.3 
Analyses Addressing the Effect of Missing Data .................... 104 
6.5.4 
Other Secondary Efficacy Analyses ....................................... 104 
6.5.5 
Exploratory Efficacy Analyses ................................................ 105 
6.6 
Safety Analyses ..................................................................... 105 
6.6.1 
Analyses of Exposure, Adverse Event, and Laboratory 
Data ....................................................................................... 105 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
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6.7 
Pharmacokinetic Analyses ..................................................... 105 
6.8 
Immunogenicity Analyses ...................................................... 106 
6.9 
Biomarker Analyses ............................................................... 106 
6.10 
Health Status Utility Analyses ................................................ 107 
6.11 
Interim AnalysEs................................................................... 107 
6.11.1 
Planned Interim Analysis ...................................................... 107 
6.11.2 
Optional Interim Analysis ....................................................... 107 
6.12 
China Subpopulation Analyses .............................................. 108 
7. 
DATA COLLECTION AND MANAGEMENT ............................... 108 
7.1 
Data Quality Assurance ......................................................... 108 
7.2 
Electronic Case Report Forms ............................................... 108 
7.3 
Electronic Patient Reported Outcome Data ........................... 109 
7.4 
Source Data Documentation .................................................. 109 
7.5 
Use of Computerized Systems .............................................. 110 
7.6 
Retention of Records ............................................................. 110 
8. 
ETHICAL CONSIDERATIONS .................................................... 110 
8.1 
Compliance with Laws and Regulations ................................ 110 
8.2 
Informed Consent .................................................................. 111 
8.3 
Institutional Review Board or Ethics Committee .................... 112 
8.4 
Confidentiality ........................................................................ 112 
8.5 
Financial Disclosure ............................................................... 113 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................... 113 
9.1 
Study Documentation ............................................................ 113 
9.2 
Protocol Deviations ................................................................ 113 
9.3 
Management of Study Quality ................................................ 114 
9.4 
Site Inspections ..................................................................... 114 
9.5 
Administrative Structure ......................................................... 114 
9.6 
Dissemination of Data and Protection of Trade Secrets ........ 115 
9.7 
Protocol Amendments ........................................................... 116 
10. 
REFERENCES............................................................................ 117 
 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
12/Protocol WA42293, Version 5 
 
LIST OF TABLES 
Table 1 
Final Assessment and End of Study Visits .................................. 42 
Table 2 
Sequence of Assessments.......................................................... 59 
Table 3 
Actions if an Infusion-Related Reaction (Grade 2) Occurs ........ 79 
Table 4 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 85 
Table 5 
Primary Efficacy Estimand Analysis Strategy for Intercurrent 
Events ......................................................................................... 99 
Table 6 
Results of the PRM-151-202 Study on Planned Primary and 
Key Secondary Endpoints ......................................................... 100 
Table 7 
Results of Power Calculations for Different Effect-Sizes and 
N=658 Patients ......................................................................... 102 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 40 
 
 
LIST OF APPENDICES 
Appendix 1  
Schedule of Activities ................................................................ 123 
Appendix 2  
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for all IPF Patients, Excluding China*, 
Hong Kong*, Taiwan*, and Japan ............................................. 128 
Appendix 3  
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for IPF Patients in China, Hong Kong 
and Taiwan ............................................................................... 131 
Appendix 4 
Schedule of Pharmacokinetic, Immunogenicity, and 
Biomarker Samples for IPF Patients in Japan ........................... 133 
Appendix 5  
Sampson's Criteria for Diagnosing Potential Cases of 
Anaphylaxis ............................................................................... 136 
Appendix 6  
St. George’s Respiratory Questionnaire ................................... 137 
Appendix 7  
University of California, San Diego –  Shortness of Breath 
Questionnaire ............................................................................ 143 
Appendix 8  
EuroQol 5-Dimension Questionnaire, 5-Level Version .............. 147 
Appendix 9  
National Cancer Institute Common Terminology Criteria for 
Adverse Events ......................................................................... 149 
Appendix 10  Method of Eligibility Verification and Implementation of 
Randomization .......................................................................... 150 
Appendix 11  Borg Scale for Rating Dyspnea and Overall Fatigue (CR10) .... 152 
 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
13/Protocol WA42293, Version 5 
PROTOCOL AMENDMENT ACCEPTANCE FORM 
TITLE: 
A PHASE III RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED TRIAL TO EVALUATE 
THE EFFICACY AND SAFETY OF PRM-151 IN 
PATIENTS WITH IDIOPATHIC PULMONARY 
FIBROSIS 
PROTOCOL NUMBER: 
WA42293 (also known as PRM-151-303) 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2020-000791-38 
IND NUMBER: 
110,774 
NCT NUMBER: 
NCT04552899 
TEST PRODUCT: 
Recombinant human pentraxin-2 (rhPTX-2; PRM-
151); Zinpentraxin Alfa 
MEDICAL MONITOR: 
, M.B.B.S. 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
I agree to conduct the study in accordance with the current protocol. 
 
 
 
Principal Investigator's Name  (print) 
 
 
 
 
 
Principal Investigator's Signature 
 
Date 
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by your local study monitor. 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
14/Protocol WA42293, Version 5 
PROTOCOL SYNOPSIS 
TITLE: 
A PHASE III RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED TRIAL TO EVALUATE THE EFFICACY 
AND SAFETY OF PRM-151 IN PATIENTS WITH IDIOPATHIC 
PULMONARY FIBROSIS 
PROTOCOL NUMBER: 
WA42293 (also known as PRM-151-303) 
VERSION NUMBER: 
5 
EUDRACT NUMBER: 
2020-000791-38 
IND NUMBER: 
110,774 
NCT NUMBER: 
NCT04552899 
TEST PRODUCT: 
Recombinant human pentraxin-2 (rhPTX-2; PRM-151); 
Zinpentraxin Alfa 
PHASE: 
Phase III 
INDICATION: 
Idiopathic pulmonary fibrosis 
SPONSOR: 
F. Hoffmann-La Roche Ltd 
 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of PRM-151 compared with 
placebo in patients with idiopathic pulmonary fibrosis (IPF).  Specific objectives and 
corresponding endpoints for the study are outlined below. 
EFFICACY OBJECTIVES 
Primary Efficacy Objective 
The primary efficacy objective is to demonstrate superiority of 10 mg/kg PRM-151 plus standard 
of care treatment as needed (excluding lung transplantation) administered every 4 weeks 
(Q4W) via intravenous (IV) infusion, over matching placebo plus standard of care treatment as 
needed (excluding lung transplantation), on lung function on the basis of the following endpoint: 
 
Absolute change from baseline to Week 52 in forced vital capacity (FVC [mL]) 
 
The primary comparison will be made regardless of whether patients changed or withdrew from 
randomized treatment or changed additional treatment (excluding lung transplantation) during 
the study.  Patients who received a lung transplant will be assessed as if a lung transplant had 
not been available during the study, and all assessments after the transplant will not be 
included in the analysis. 
 
Secondary Efficacy Objective 
The secondary efficacy objective is to demonstrate superiority of 10 mg/kg PRM-151 plus 
standard of care treatment as needed (excluding lung transplantation) administered Q4W via 
IV infusion, over matching placebo plus standard of care treatment as needed (excluding lung 
transplantation) on the basis of the following endpoints: 
 
Absolute change from baseline to Week 52 in 6-minute walk distance (6MWD) (in meters) 
 
Absolute change from baseline to Week 52 in FVC% predicted  
 
Time to disease progression, defined as time to first occurrence of ≥ 10% absolute decline 
in % predicted FVC, ≥ 15% relative decline in 6MWD, or death  


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
15/Protocol WA42293, Version 5 
 
Time to first respiratory-related hospitalizations (defined as non-elective hospitalizations 
due to any respiratory cause, including acute exacerbations of IPF, or suspected acute 
exacerbations of IPF, as determined by the Clinical Adjudication Committee) 
 
Change from baseline to Week 52 in University of California, San DiegoShortness of 
Breath Questionnaire (UCSD-SOBQ) 
 
Change from baseline to Week 52 in St. George Respiratory Questionnaire (SGRQ) Total 
Score  
 
Time to first acute exacerbation of IPF, or suspected acute exacerbation of IPF, as 
determined by the Clinical Adjudication Committee 
 
Change from baseline to Week 52 in carbon monoxide diffusing capacity (DLCO) 
 
Survival, as measured by all-cause mortality 
 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the efficacy of PRM-151 plus 
standard of care treatment as needed (excluding lung transplantation) compared with matching 
placebo plus standard of care treatment as needed (excluding lung transplantation) on the basis 
of the following endpoints: 
 
Change from baseline to Week 52 in FVC% predicted, FVC (mL), by concurrent therapy 
stratum (i.e., with nintedanib treatment vs. with pirfenidone treatment vs. without pirfenidone 
or nintedanib treatment)  
 
Change from baseline to Week 52 in FVC% predicted, FVC (mL), by MUC5B risk allele 
positive or negative status 
 
Change from baseline to Week 52 in 6MWD, by concurrent therapy stratum (i.e., with 
nintedanib treatment vs. with pirfenidone treatment vs. without pirfenidone or nintedanib 
treatment)  
 
Change from baseline to Week 52 in SGRQ Individual Domains (Symptoms, Activity, and 
Impacts) Score 
 
Change from baseline to Week 52 in the 6-minute walk test (6MWT) pre-test to pre-test 
measurements of Borg dyspnea score, fatigue score, and oxygen saturation 
 
Change from baseline to Week 52 in the 6MWT pre-test to post-test measurements of Borg 
dyspnea score, fatigue score, and oxygen saturation 
 
Change from baseline to week 52 in the 6MWT post-test to post-test measurements of Borg 
dyspnea score, fatigue score, and oxygen saturation 
 
Change from baseline to Week 52 in quantitative imaging analysis parameters of HRCT 
scan of the thorax 
 
Length of hospital stay for respiratory-related hospitalizations, total time in intensive care 
units due to respiratory causes, deaths due to respiratory causes, and unscheduled 
outpatient clinic/urgent care/emergency room utilization related to respiratory events 
 
A decline or an increase in FVC% predicted of  5%,  10%, and  15% from baseline to 
Week 52 
 
A decline or an increase in FVC in mL of  100 mL and  200 mL from baseline to Week 52 
 
A decline or an increase in 6MWD  5%,  10%,  15%, and  20% from baseline to 
Week 52 
 
A decline or an increase in 6MWD  25 m, and 50 m from baseline to Week 52 
 
Number of acute exacerbations during the 52 weeks 
 
At least one acute exacerbation during the 52 weeks; as determined by the Clinical 
Adjudication Committee 
 
Survival as measured by IPF-related mortality 
 
Survival as measured by respiratory-related mortality 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
16/Protocol WA42293, Version 5 
 
Disease progression defined as:   10% absolute decline in % predicted FVC; respiratory 
hospitalization; or a decline of 50 m in 6MWD  
 
Disease progression and subsequently start pirfenidone or nintedanib or switch from 
nintedanib to pirfenidone (or vice versa)  
 
Time to worsening on the UCSD-SOBQ, as indicated by a change in score of 10 points or 
greater 
 
Time to worsening on the SGRQ total score, as indicated by a change in score of 7 or 
greater 
 
Time to worsening on the SGRQ Activity domain, as indicated by a change in score of 5 or 
greater 
 
Time to worsening on the SGRQ Symptom Domain, as indicated by a change in score of 
8 or greater 
 
Time to worsening on the SGRQ Impact Domain, as indicated by a change in score of 7 or 
greater 
 
Change in pulmonary function test (PFT) parameters (FVC, 6MWT, or DLCO) from baseline 
to Week 52 between SARS-CoV-2 antibody positive compared with negative patients 
 
Change in PFT parameters (FVC, 6MWT, or DLCO) from baseline to Week 52 in patients 
who develop SARS-CoV-2 antibodies during treatment (not present at baseline) 
 
Efficacy evaluations will be performed for the primary, secondary, and exploratory efficacy 
endpoints as detailed in the protocol.  Exploratory analyses may also be performed for 
additional measures and subgroups of interest.  Details of all such analyses will be provided in 
the Statistical Analysis Plan (SAP). 
SAFETY OBJECTIVE 
The safety objective for this study is to confirm the safety and tolerability of 10 mg/kg of 
PRM-151 administered Q4W via IV infusion plus standard of care treatment as needed relative 
to matching placebo plus standard of care treatment as needed in a population of all dosed 
patients, on the basis of the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to the 5-point 
severity scale (National Cancer Institute Common Terminology Criteria for Adverse Events, 
Version 5.0 [NCI CTCAE, v.5.0]) 
 
Incidence and severity of IRRs and other adverse events of special interest 
 
Proportion of patients permanently discontinuing study treatment due to adverse events 
 
Change from baseline in targeted clinical laboratory test results 
 
Safety analyses may also be performed for subgroups of interest.  Details of such analyses will 
be provided in the SAP. 
PHARMACOKINETIC OBJECTIVES 
The pharmacokinetic (PK) objective for this study is to characterize pharmacokinetics of 
PRM-151 in patients with IPF on the basis of the following: 
 
Plasma concentrations of PRM-151 at specified timepoints  
 
The exploratory PK objectives are to evaluate the potential relationship between drug exposure 
and the efficacy and safety of PRM-151 on the basis of the following: 
 
Relationship between PK for PRM-151 and efficacy endpoints 
 
Relationship between PK for PRM-151 and safety endpoints 
 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to PRM-151 on 
the basis of the following: 
 
Prevalence of ADAs at baseline and incidence of ADAs during the study 
 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
17/Protocol WA42293, Version 5 
The exploratory immunogenicity objective for this study is to evaluate potential effects of ADAs 
on the basis of the following: 
 
Relationship between ADA status and efficacy, safety, or PK endpoints 
 
BIOMARKER OBJECTIVE 
The exploratory biomarker objective for this study is to identify and/or evaluate biomarkers that 
are predictive of response to PRM-151 (i.e., predictive biomarkers), are early surrogates of 
efficacy, are associated with progression to a more severe disease state (i.e., prognostic 
biomarkers), are associated with acquired resistance to PRM-151, are associated with 
susceptibility to developing adverse events or can lead to improved adverse event 
monitoring or investigation (i.e., safety biomarkers), can provide evidence of PRM-151 activity 
(i.e., pharmacodynamic biomarkers), or can increase the knowledge and understanding of 
disease biology and drug safety, on the basis of the following: 
 
Relationship between biomarkers in blood listed in Section 4.5.12 and efficacy, safety, PK, 
immunogenicity, or other biomarker endpoints 
 
HEALTH STATUS UTILITY OBJECTIVE 
The exploratory health status utility objective for this study is to evaluate health status utility 
scores of patients treated with PRM-151 plus standard of care treatment as needed on the 
basis of the following endpoint: 
 
Change from baseline to Week 52 in EuroQol 5-Dimension, 5-Level Questionnaire 
(EQ-5D-5L) index-based, and visual analog scale (VAS) scores 
 
STUDY DESIGN 
DESCRIPTION OF STUDY 
This Phase III, randomized, double-blind, placebo-controlled, pivotal study is designed to 
confirm the efficacy and safety of PRM-151 in the treatment of patients with IPF during 
a 52-week period.  At the end of this 52-week period, patients will be invited to enroll in an 
open-label extension (OLE) study (Study WA42294) to receive treatment with PRM-151.  
Patients who do not enroll in the OLE study will be followed up for an additional 4 weeks (to 
Week 56, for safety monitoring). 
The OLE study will provide patients with further study assessments and PRM-151 treatment on 
an ongoing basis.  However, the OLE study will also consist of a long-term survival cohort, 
where patients who do not want further study assessments or treatment can enroll (for 
long‑term collection of survival data only). 
Patients meeting the eligibility criteria for the study will be randomized to PRM-151 10 mg/kg 
Q4W or placebo.  Efficacy will be evaluated through assessment of functional capacity as 
measured by FVC, 6MWD, other pulmonary function tests (PFTs), and assessment of patients 
with respiratory events leading to hospitalizations, progression of disease, acute IPF 
exacerbations. 
Patient reported outcomes (PROs) will be assessed using the SGRQ, UCSD-SOBQ, and 
EQ-5D-5L. 
Dyspnea, fatigue, and SpO2 will be assessed based on measurements taken during the 6MWT.  
For patients who require a HRCT scan during the screening period, an additional chest HRCT 
scan will be performed at Week 52.  Patients who do not require a HRCT scan during the 
screening period (i.e., they already have a historic HRCT scan of acceptable quality performed 
within 12 months prior to screening) will not be required to perform a scan at Week 52. 
Treated patients will be followed until the end of the 52-week study period unless the patient 
withdraws consent for follow-up or dies. 
Patients will be evaluated for study eligibility during a screening period of up to 4 weeks.  If any 
patient is prevented from completing required screening procedures within the 4-week period 
due to unforeseeable circumstances.  Screening may be extended up to a maximum of 
2 weeks.  Patients who are determined to be eligible based on the screening assessments will 
be randomized into the study and randomly allocated to treatment with PRM-151 or placebo. 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
18/Protocol WA42293, Version 5 
Patients entering the screening period on anti-fibrotic therapy (pirfenidone or nintedanib) should 
have been on treatment for at least 3 months, and on a stable dose for at least 4 weeks prior to 
the screening visit and are expected to remain on their specific dose and regimen throughout 
the study duration unless dose reduction or discontinuation is indicated for safety or tolerability 
reasons. 
Patients entering the screening period of the study NOT on anti-fibrotic treatment (pirfenidone or 
nintedanib), either treatment naive or having previously taken and discontinued, must have 
been off such treatment for at least 4 weeks prior to the screening visit and during screening.  
At the time of consent, if a patient is considering starting treatment with either nintedanib or 
pirfenidone, the patient should be advised of being on treatment for at least 3 months prior to 
screening. 
For all patients receiving anti-fibrotic therapy, the investigator should document the dose, 
frequency, and duration of the anti-fibrotic drug.  For patients not receiving anti-fibrotic therapy 
during the screening period, the investigator should document the reason(s).  
During the study, patients may initiate pirfenidone or nintedanib as rescue, if determined to 
be clinically indicated by the investigator.  The investigator may consider discussing 
changes in anti-fibrotic therapy with the Medical Monitor throughout the study.  The 
investigator is required to document the specific reason for introducing anti-fibrotic therapy in 
patients who were randomized into the study not on anti-fibrotic therapy.  
Approximately 658 patients will be randomly assigned on a 1:1 basis to treatment with PRM-151 
or placebo, as follows: 
 
PRM-151 Group:  PRM-151 10 mg/kg IV infusion over 50–70 minutes on Days 1, 3, and 5, 
then one infusion Q4W for 48 weeks 
 
Placebo Group: Matched placebo IV infusion over 50–70 minutes on Days 1, 3, and 5, then 
one infusion Q4W for 48 weeks 
 
The randomization will be stratified as follows: 
 
Concurrent use of nintedanib treatment versus pirfenidone treatment versus no concurrent 
treatment 
 
Region:  China (including Hong Kong and Taiwan), North America (United States and 
Canada), Europe (including eastern Europe), Latin America, and Rest of World (including 
east Asia, Australia, and New Zealand) 
 
All patients will have a final assessment visit at Week 52 (4 weeks after the final study drug 
infusion).  Patients will be invited to enroll in an OLE study at this point (Study WA42294), and if 
they roll over into that study, the Week 52 visit will be considered their end of study visit.  
Patients who do not enroll in the OLE study will have their end of study visit at Week 56, in 
addition to the Week 52 visit. 
This study will enroll approximately 658 patients globally across all sites.  Enrollment will be 
globally competitive.  After completion of the global enrollment phase, additional patients may 
be enrolled in an extended China enrollment phase at sites in mainland China, Hong Kong, and 
Taiwan  The global population will include all patients enrolled during the global enrollment 
phase and the China subpopulation  will include all patients enrolled in China, Hong Kong and 
Taiwan (i.e., during both the global enrollment phase and the extended China enrollment 
phase). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
eligible for rescreening once for selected reasons.  In addition, the screening period may be 
extended if a patient fails a test due to technical issues with the test and the patient will be 
allowed to repeat the test (e.g., lab sample hemolyzed and not able to be analyzed).   
NUMBER OF PATIENTS 
Approximately 658 patients with IPF will be enrolled during the global enrollment phase of this 
study.  After completion of the global enrollment phase, additional patients may be enrolled in 
China, Hong Kong, and Taiwan in an extended China enrollment phase to ensure a total 
enrollment that is sufficient to support registration in China Target Population 
Inclusion Criteria 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
19/Protocol WA42293, Version 5 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age 40–85 years, inclusive, at time of signing Informed Consent Form 
 
Ability to comply with the requirements of the study protocol, according to the investigator’s 
best judgment 
 
Documented diagnosis of IPF per the 2018 ATS/ERS/JRS/ALAT Clinical Practice Guideline  
 
HRCT pattern consistent with the diagnosis of IPF, confirmed by central review of chest 
HRCT (available HRCT of acceptable quality performed within 12 months prior to screening 
or obtained during the screening period) and central review of lung biopsy (LB), if available 
 
Minimum 6MWD of 150 meters with maximum use of 6 L/min at sea-level and up-to 8 L/min 
at altitude ( 5000 feet [1524 meters] above sea level) of supplemental oxygen while 
maintaining oxygen saturation of  83% during the 6MWT during screening 
 
FVC  45% predicted during screening as determined by the over-reader 
 
Forced expiratory volume in 1 second (FEV1)/FVC ratio  0.70 during screening as 
determined by the over-reader 
 
DLCO  30% and  90% of predicted during screening (Hgb corrected or uncorrected) as 
determined by the over-reader 
 
If receiving pirfenidone or nintedanib treatment for IPF, the patient must have been on 
treatment for at least 3 months and on a stable dose for at least 4 weeks prior to screening, 
and during screening (with no contraindications according to local prescribing information) 
 
If not currently receiving nintedanib or pirfenidone treatment (either treatment naïve or 
having previously taken and discontinued) must have discontinued such treatment 
 4 weeks prior to screening and during screening 
If patient is considering starting treatment with either nintedanib or pirfenidone, patient 
must be on treatment for at least 3 months prior to screening, provided there are no 
contraindications according to local prescribing information. 
 
For women of childbearing potential (excluding patients enrolling in Japan):  agreement to 
remain abstinent (refrain from heterosexual intercourse) or use contraception, as defined 
below: 
Women must remain abstinent or use contraceptive methods with a failure rate of  1% 
per year during the treatment period and for 8 weeks after the final dose of PRM-151. 
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined 
by the investigator (e.g., Müllerian agenesis).  The definition of childbearing potential may 
be adapted for alignment with local guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year include 
bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices. 
Hormonal contraceptive methods must be supplemented by a barrier method. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not adequate methods of contraception.  If required per local guidelines or regulations, 
locally recognized adequate methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form. 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
20/Protocol WA42293, Version 5 
 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or use 
a condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant female partner, men must 
remain abstinent or use a condom during the treatment period and for 8 weeks after the 
final dose of PRM-151 to avoid exposing the embryo.  Men must refrain from donating 
sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are 
not adequate methods of preventing drug exposure.  If required per local guidelines or 
regulations, information about the reliability of abstinence will be described in the local 
Informed Consent Form. 
 
Anticipated life expectancy of at least 12 months at baseline, according to the investigator’s 
judgment 
 
Patient and investigator considered all medicinal treatment options and/or possibly lung 
transplantation prior to considering participation in the study.  If the patient is on a lung 
transplant list, the investigator anticipates the patient will be able to complete the study prior 
to transplant. 
 
For patients enrolled in the extended China enrollment phase:  current resident of mainland 
China, Hong Kong, or Taiwan, and of Chinese ancestry 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Evidence of other known causes of interstitial lung disease (e.g., domestic and occupational 
environmental exposures, connective-tissue disease, and drug toxicity) 
 
FVC% predicted value showing improvement in the 6-month period prior to screening and 
including screening value, as assessed by the investigator 
 
Emphysema present on  50% of the HRCT, or the extent of emphysema is greater than the 
extent of fibrosis, according to central review of the HRCT 
 
Receiving nintedanib in combination with pirfenidone 
 
Received cytotoxic, immunosuppressive, cytokine modulating, or receptor antagonist 
agents (including but not limited to methotrexate, azathioprine, mycophenolate mofetil, 
cyclophosphamide, cyclosporine or other steroid sparing agent) within 4 weeks prior to or 
during screening  screening 
 
Receiving systemic corticosteroids equivalent to prednisone  10 mg/day or equivalent 
within 2 weeks prior to or during screening 
 
Receiving strong inhibitor or inducer of CYP1A2 in patients taking pirfenidone 
 
Receiving potent inhibitor or inducer of P-gp in patients taking nintedanib 
 
Acute respiratory or systemic bacterial, viral, or fungal infection either during screening or 
prior to screening and not successfully resolved 4 weeks prior to screening visit 
 
Positive interferon gamma release assay test for tuberculosis during screening: Patients 
who have completed treatment for tuberculosis within 6 months prior to screening, and have 
no evidence of recurrent disease do not need to be tested. 
 
Resting oxygen saturation of  89% using up to 4 L/min of supplemental oxygen at sea 
level and up-to 6 L/min at altitude ( 5000 feet [1524 meters] above sea level) during 
screening 
 
Co-existing acute or chronic medical condition that, in the investigator’s opinion, would 
substantially limit the ability to comply with study requirements or may influence any of the 
safety or efficacy assessments included in the study 
 
Class IV New York Heart Association chronic heart failure 
 
Historical evidence of left ventricular ejection fraction  35% 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
21/Protocol WA42293, Version 5 
 
Presence of pulmonary hypertension that, in the investigator’s opinion, would substantially 
limit the ability to comply with study requirements or may influence any of the safety or 
efficacy assessments included in the study 
 
Cardiopulmonary rehabilitation program based on exercise training that has been 
completed within 8 weeks prior to screening or planned to start during the patient’s 
enrollment in this trial 
 
History of smoking (including cigarette, cannabis, cigar, pipe and vaping) within 3 months 
prior to or during screening 
 
History of alcohol or substance use disorder  within 2 years prior to or during screening or 
known or suspected active alcohol or substance-use disorder 
 
History of a malignancy within the 5 years prior to screening, with the exception of basal cell 
or squamous cell skin neoplasms. In addition, a malignant diagnosis or condition that 
occurred more than 5 years prior to screening, and any basal cell or squamous cell 
neoplasm must be considered cured, inactive, and not under treatment. 
 
Unable to refrain from use of the following: 
– 
Short acting bronchodilators (SABA) within 4 hours before pulmonary function, DLCO, 
and 6MWT assessments 
– 
Once daily, long-acting bronchodilators within 24 hours before pulmonary function, 
DLCO, and 6MWT assessments 
– 
Twice daily, long-acting bronchodilators within 12 hours before pulmonary function 
testing, DLCO, and 6MWT assessments 
 
Known post-bronchodilator response in FEV1 and/or FVC  12% and  200 mL, respectively 
 
Receipt of an investigational drug within 4 weeks, or 5 half-lives, whichever is longer, prior 
to or during screening 
 
Previous treatment with PRM-151 
 
History of severe allergic reaction or anaphylactic reaction to a biologic agentincluding any 
allergies to the additives of the drug product. 
 
Clinically significant abnormality on ECG during screening that, in the opinion of the 
investigator, may pose an additional risk in administering study drug to the patient  
 
Prolonged corrected QT interval  450 ms (for men) or  470 ms (for women) on ECG 
during screening, based on the Fridericia correction formula 
 
Clinically significant laboratory test abnormalities during screening (hematology, serum 
chemistry, and urinalysis) that, in the opinion of the investigator, may pose an additional risk 
in administering study drug to the patient 
 
Any of the following laboratory abnormalities during screening: 
– 
ALT and/or AST   2.5  upper limit of normal (ULN)  
– 
Total bilirubin  2  ULN  
 
Pregnant or breastfeeding, or become pregnant during the study or within 8 weeks after the 
final dose of PRM-151 
Women of childbearing potential must have a negative serum pregnancy test result within 
30 days prior to initiation of study drug. 
 
Women of childbearing potential (Only for patients enrolling in Japan) 
– 
A woman is considered to be of childbearing potential if she is postmenarchal, has not 
reached a postmenopausal state ( 12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to 
surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis). 
 


PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
22/Protocol WA42293, Version 5 
END OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
(i.e., last patient in the global and extended China enrollment phases combined) or the date at 
which the last data point required for statistical analysis (i.e., Week 52 efficacy assessments) or 
safety follow-up is received from the last patient (global and extended China enrollment phases 
combined), whichever occurs later.  The end of the study is expected to occur 56 weeks after 
the last patient is enrolled. 
LENGTH OF STUDY 
The total length of the study is approximately 2.5 years.  
INVESTIGATIONAL MEDICINAL PRODUCTS 
The investigational medicinal product (IMP) for this study is PRM-151.  Placebo is also 
considered an IMP in this study.   
TEST PRODUCT (INVESTIGATIONAL DRUG) 
Patients randomized to study drug will receive IV infusions of 10 mg/kg PRM-151 over 50 to 70 
minutes, with dose based on the patient’s weight taken at the same clinic visit (for loading or 
reloading doses, the weight taken at the first clinic visit for the first dose can be applied to the 
second and third doses). 
COMPARATOR 
Patients randomized to placebo will receive IV infusions of placebo over 5070 minutes. 
NON-INVESTIGATIONAL MEDICINAL PRODUCTS 
The non-investigational medicinal products (NIMPs) for this study are pirfenidone and 
nintedanib.  The NIMPs are considered background therapy for those patients already receiving 
either product when entering the trial and rescue therapy for any patient who commences 
treatment with either product during the trial. 
STATISTICAL METHODS 
Unless otherwise specified, all baseline and efficacy analyses will be based on the full analysis 
set (FAS) defined as all randomized subjects who received at least one administration (full or 
partial dose) of study drug and will use the grouping as assigned by randomization.  The safety 
evaluable population will include all randomized patients who received at least one 
administration (full or partial dose) of study drug and will be grouped by treatment received. 
The primary analysis will occur when the last enrolled patient has completed the Week 52 study 
visit.  Significance testing of the primary and secondary endpoints will account for multiplicity 
and control family-wise type I error, which is fixed at 0.05 two-sided.  The study has one single 
primary efficacy endpoint (absolute change from baseline to Week 52 in FVC [mL]) and one 
family of secondary efficacy endpoints that have been ordered in a prespecified sequence, 
starting with the key secondary endpoint, absolute change from baseline to Week 52 in 6MWD.  
The planned statistical analysis will control the overall type I error for the testing of these 
efficacy endpoints by applying a fixed-sequence statistical strategy, testing all the endpoints 
according to the pre-specified order.  All hypothesis tests will be two-sided unless otherwise 
specified.  
The global population will include all patients enrolled during the global enrollment phase , and 
the China subpopulation will include all patients enrolled in China, Hong Kong and Taiwan 
(i.e., during both the global enrollment phase and the extended China enrollment phase).  
Separate analyses will be performed for the global population and the China subpopulation. 
PRIMARY ANALYSIS 
The primary estimand will evaluate the effectiveness of PRM-151 plus standard of care 
treatment as needed (excluding lung transplantation) versus matching placebo plus standard of 
care treatment as needed (excluding lung transplantation).  It corresponds to the difference in 
outcome attributable to the randomized study drug, whatever changes in the treatment regimen 
(randomized drug and any associated treatment) occurs afterwards (excluding lung 
transplantation), as described in Mallinckrodt et al. 2017 and Mallinckrodt et al. 2012.  Lung 
transplantation will be handled as a particular intercurrent event (see below).  The attributes of 
the estimand are as follows: 


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 
The treatment regimen of interest is study drug (PRM-151 or placebo) as randomized, in 
combination with any background or additional treatment (i.e., PRM-151 or placebo taken 
alone or as an add-on to standard of care with pirfenidone or nintedanib, dosed as required) 
including all changes in standard of care treatment and all other additional treatments, with 
the exclusion of lung transplantation. 
 
The population is patients diagnosed with idiopathic pulmonary fibrosis as defined 
through the inclusion/exclusion criteria presented in Section 4.1 of the protocol.  All patients 
randomized having received at least one administration (full or partial dose) of the study 
drug (all treated patients) will be included in the analysis (FAS).  
 
The variable is the absolute change from baseline to Week 52 in FVC mL for the primary 
efficacy endpoint. 
 
The population-level summary measure is the between randomized treatments difference in 
mean change from baseline at Week 52 in FVC mL.  
 
Intercurrent events (post-randomization events): 
Any change in initial treatment regimen (change in study drug, change in standard of care, 
use of prohibited medication) will be considered irrelevant in defining the treatment effect of 
interest.  As the primary objective is to assess the effectiveness of PRM-151, the analysis 
will be performed ignoring any such intercurrent event. 
Deaths are expected to be infrequent as the study plans to include patients with a life 
expectancy longer than the study duration.  Assessments following death will be assigned 
with values to designate treatment failure.  Further details will be provided in the SAP. 
Lung transplantation:  Lung transplantation is expected to be rare during the study, as 
patients likely to receive a lung transplantation during the study are excluded. Any data 
recorded after lung transplantation will be censored from the analysis because they are no 
longer an accurate measure of efficacy reflecting the diseased lung(s).  In some instances, 
FVC can improve to over 80% following lung transplantation or even 100% for bilateral lung 
transplantation 612 months after surgery.  
 
The primary efficacy analysis will be performed on the FAS population.  All FVC mL 
measurements that meet the minimal level of quality will be used for this analysis, except those 
recorded after lung transplantation, whatever other intercurrent events might have occurred 
before that were recorded.  Assessments following death will be assigned with values to 
designate treatment failure, and the details will be provided in the SAP.   
The comparison of PRM-151 with placebo will be carried out via a two-sided statistical test.  The 
primary efficacy endpoint will be analyzed using a linear mixed-effect model with random 
intercept and random slope, with FVC mL measured at each timepoint as the dependent 
variable, stratification factors, age, sex, height, and treatment by time interaction as fixed 
effects, and subject and time as random effects.  The random intercept represents deviations 
from the mean baseline FVC mL measure for each subject.  The model will assume an 
unstructured covariance structure.  If there are convergence problems with the model, the 
following covariance structures will be tested:  compound symmetry, first-order autoregressive 
[AR(1)] and Toeplitz.  The covariance structure converging to the best fit, based on Akaike’s 
information criterion (AIC), will be used.  The comparison of PRM-151 with placebo will be 
carried out by computing the estimate of the difference in absolute change from baseline at 
Week 52 between the two treatment arms with 95% CIs and p-value. 
DETERMINATION OF SAMPLE SIZE   
The purpose of this study is hypothesis testing regarding the effect of PRM-151 versus placebo. 
With the planned sample size of 658 patients, the study has a power of 0.89 using a two-sided 
type I error level of 0.05 to detect a standardized effect-size of 0.25 on change from baseline to 
Week 52 in FVC mL. 
Optional Interim Analyses  
No other efficacy interim analyses are planned at this time.  However, in exceptional 
circumstances, when patient enrollment and study conduct is significantly impacted by external 
factors such that study completion does not seem feasible (e.g., ongoing or worsening impact of 
the global COVID-19 pandemic, the availability of compelling clinical trial results for an external 


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competitor molecule, or significant changes in standard of care), the Sponsor may choose to 
conduct one interim efficacy analysis.  Below are the specifications in place to ensure the study 
continues to meet the highest standards of integrity when an optional interim analysis is 
executed. 
If an interim efficacy analysis is conducted, the Sponsor will remain blinded.  The interim 
efficacy analysis will be conducted by an external statistical group and reviewed by the iDMC.  
Interactions between the iDMC and Sponsor will be carried out as specified in the 
iDMC Charter.  If there is a potential for the study to be stopped for positive efficacy as a result 
of the interim analysis, the type I error rate will be controlled to ensure statistical validity is 
maintained.  If the study continues beyond the interim analysis, the critical value at the final 
analysis would be adjusted accordingly to maintain the protocol-specified overall type I error 
rate, per standard Lan-DeMets methodology. 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
6MWD 
6-minute walk distance 
6MWT 
6-minute walk test 
ADA 
anti-drug antibody 
ALAT 
Latin American Thoracic Society 
ATS 
American Thoracic Society 
AUC 
area under the plasma concentration-time curve 
CHO 
Chinese Hamster Ovary Cell 
Cmax 
maximum concentration 
COPD 
chronic obstructive pulmonary disease 
CRO 
contract research organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough concentration 
DAMP 
damage-associated molecular patterns 
DLCO 
diffusing capacity for carbon monoxide 
EC 
Ethics Committee 
ECM 
extracellular matrix 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EQ-5D-5L 
EuroQol 5-Dimension, 5-Level Questionnaire 
ERS 
European Respiratory Society 
FAS 
full analysis set 
FcR 
Fc receptor 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
Hgb 
hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HCP 
Host cell protein 
hPTX-2 
human pentraxin-2 
HRCT 
high-resolution computed tomography 
ICH 
International Council for Harmonisation 
iDMC 
independent Data Monitoring Committee 


 
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Abbreviation 
Definition 
ILD 
interstitial lung disease 
IPF 
idiopathic pulmonary fibrosis 
IL-10 
interleukin-10 
IMP 
investigational medicinal product 
IND 
Investigational New Drug (Application) 
INN 
International Nonproprietary Name 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IxRS 
interactive voice or web-based response system 
JRS 
Japanese Respiratory Society 
LB 
lung biopsy 
LS 
least squares 
MAD 
multiple ascending dose 
MAR 
Missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NGS 
next-generation sequencing 
NIMP 
non-investigational medicinal product 
OLE 
open-label extension 
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamic 
PFT 
pulmonary function test 
PK 
pharmacokinetic 
PRO 
patient-reported outcome 
PRR 
pattern recognition receptor 
PTX-2 
Pentraxin-2 
Q4W 
every 4 weeks 
RBR 
Research Biosample Repository 
rhPTX-2 
recombinant human pentraxin-2 
SAD 
single ascending dose 
SAP 
Statistical Analysis Plan 
SGRQ 
St. George Respiratory Questionnaire 
SOC 
standard of care 
TEDE 
Total Effective Dose Equivalent  
UCSD-SOBQ 
University of California, San Diego-Shortness of 
Breath Questionnaire 


 
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Abbreviation 
Definition 
UIP 
usual interstitial pneumonia 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WES 
whole exome sequencing 
WGS 
whole genome sequencing 
w/v 
weight/volume 


 
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1. 
BACKGROUND 
1.1 
IDIOPATHIC PULMONARY FIBROSIS  
Idiopathic pulmonary fibrosis (IPF) is a rare, specific form of chronic, fibrosing, interstitial 
pneumonia limited to the lung and leads to an irreversible loss of lung function.  It has 
the histopathologic pattern of usual interstitial pneumonia (UIP) upon analysis of 
a surgical lung biopsy.  Historically, patients who received a diagnosis of IPF required 
a surgical lung biopsy; however, the current definition allows for an IPF diagnosis 
through clinical and radiological methods.  The diagnosis of IPF requires the exclusion of 
other known causes of interstitial lung disease (ILD), such as domestic and occupational 
environmental exposures, connective-tissue disease, and drug toxicity (Raghu et al. 
2011).  Patient prognosis is poor with the 5-year survival rate for IPF previously reported 
as being between 20% and 40% (Olson et al. 2007).  In 2015, the incidence of IPF in 
North America and Europe was estimated at 3 to 9 cases per 100,000 person-years, 
with lower incidence in Asia and South America (Hutchinson et al. 2015).  Although rare, 
the incidence of IPF is increasing, likely due to an increasing recognition of the disease 
and the recent development of uniform diagnostic criteria (Raghu et al. 2018).  
IPF disproportionately affects men over the age of 60 (Raghu et al. 2018).   
Pirfenidone and nintedanib are currently the only pharmacologic therapies approved for 
the treatment of IPF (Raghu et al. 2015).  The rate of decline in forced vital capacity 
(FVC) is slower in patients treated with pirfenidone and nintedanib.  However, neither 
treatment halts disease progression or improves any objective measurements of disease 
status (Nathan et al. 2016).  Therefore, disease progression and respiratory decline is 
inevitable.  Thus, a need for additional novel treatment approaches remains. 
Evidence suggests that epithelial damage and abnormal wound repair contribute to the 
pathogenesis of IPF (Richeldi et al. 2017).  Fibrocytes, usually inactive fibroblast-like 
cells derived from peripheral blood monocytes, have been implicated in this process 
(De Biasi et al. 2015).  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 interstitium.  In established disease, pulmonary function tests 
(PFTs) identify restrictive disease (reduced total lung capacity) and abnormal gas 
exchange (reduced carbon monoxide diffusion) (Raghu et al. 2011).  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 (Richeldi et al. 2017). 


 
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IPF is estimated to be the primary cause of death due to respiratory failure in 60% of 
patients with IPF and acute exacerbations of the disease are associated with 
a particularly high risk of respiratory failure (Frankel and Schwarz 2009).  Other common 
causes of death include acute coronary syndromes, congestive heart failure, lung 
cancer, infection, and venous thromboembolic disease (Frankel and Schwarz 2009). 
1.2 
PRM-151 
Pentraxin-2 (PTX-2) is a highly conserved endogenous serum protein and a soluble 
pattern recognition receptor (PRR) of the innate immune system that regulates 
monocyte activation and differentiation (Steel and Whitehead 1994; Gewurz et al. 1995; 
Pepys et al. 1997; Garlanda et al. 2005; Mantovani et al. 2008).    
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 Fcγ receptors (FcγRs) on 
monocytes and promotes their differentiation into regulatory macrophages, 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.  During normal homeostasis, PTX-2 
serves as a naturally circulating regulatory protein that specifically binds to apoptotic or 
necrotic debris in circulation and rapidly removes it through FcγR-mediated phagocytosis 
by monocytes and macrophages within the spleen and liver.  This process suppresses 
a systemic innate activation response to those damage-associated molecular pattern 
(DAMP) signals (Cox et al. 2014). 
PRM-151 is a recombinant human pentraxin-2 (rhPTX-2) protein.  It is produced via 
Chinese hamster ovary cell culture, purified and formulated as a sterile liquid for 
intravenous (IV infusion.  Like the native human protein, PRM-151 is expressed and 
purified as a non-covalent, homo-pentamer.  Each monomer in the pentamer exhibits the 
same 204 amino acid primary sequence.  The theoretical average molecular weight of 
the fully glycosylated, bi-sialylated monomers in each pentamer is 25462.5 Da.  
The theoretical average molecular weight of the corresponding pentamer is 127,313 Da. 
PRM-151 mediates its activity by coupling recognition of DAMPs within injured tissue to 
specific phagocytosis through FcγR on monocytes.  This process both removes the 
inflammatory and fibrotic stimulation provided by the DAMP signals, and actively 
stimulates the generation of a regulatory macrophage population identified through 
increased local expression of interleukin-10 (IL-10).  
Of importance, patients with IPF (in comparison to healthy subjects) have both increased 
fibrocyte numbers in circulation (Moeller et al. 2009) and decreased levels of circulating 
PTX-2 (Murray et al. 2011). 


 
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Supplementing endogenous PTX-2 levels through IV administration of PRM-151 should 
theoretically increase the regulatory capacity of PTX-2 in circulation and at the site of 
disease, thereby promoting healing and reducing fibrosis. 
Robust nonclinical and clinical data exist to support the investigation of PRM-151 in the 
treatment of fibrotic diseases, summaries of which are provided in the following sections.  
Efficacy and safety of PRM-151 is also being investigated in patients with myelofibrosis 
in a Phase II study.  For more information on nonclinical or clinical investigations, please 
refer to the PRM-151 Investigator’s Brochure. 
1.2.1 
PRM-151 Host Cell Proteins 
Mass spectroscopy analysis of PRM-151 was performed to characterize host cell protein 
(HCP) impurities, which led to the identification of Chinese hamster ovary cell 
galectin-1 (CHO Gal-1) and CHO galectin-3 (CHO Gal-3).  It was found that CHO 
Gal-1 and CHO Gal-3 co-purifies with PRM-151, and has been present in Phase 2 and 
Phase 3 batches of investigational medicinal product (IMP). 
The Sponsor performed an assessment of toxicology, safety, and efficacy on the potential 
impact of the presence of CHO Gal-1/3 in the PRM-151 drug product.  Nonclinical 
toxicity data suggest that the overall risk to patients of direct adverse effects due to 
CHO Gal-1/3 at levels present in the drug product is low.  There continues to be 
a favorable benefit/risk assessment based on the clinical data from the Phase 2 study to 
date (which used drug substance that has now been confirmed to have these host cell 
proteins present at the time).  Levels of HCPs in the drug product that  are equal to or 
below the levels identified in batches used to supply the Phase 2 studies, are not 
anticipated to adversely impact the known benefit/risk profile of PRM-151; there are no 
new safety risks, and there is no direct evidence of impact on efficacy.  
In order to control the CHO Gal-1/3 levels, each batch of PRM-151 will be tested for 
the two HCPs by mass spectrometry.  Only batches with levels equal to or lower than 
the threshold level will be released for use in clinical studies.  An additional 
purification step will be applied to the ‘second generation’ drug product and thus it 
will not contain detectable levels of CHO galectins.  Second generation drug will be 
implemented in 2022.  
1.2.2 
Galactose--1,3-galactose (α‑Gal)  
As part of the extended physicochemical characterization, the analysis of N-linked glycan 
profiles has shown the presence of galactose-α-1,3-galactose (α-Gal) at low levels in both 
1st and 2nd generation PRM-151.  The highest level of α-Gal observed was 0.3% in 1st 
generation batches.  For 2nd generation PRM-151, levels  3% of α-Gal have been 
observed.   
 


 
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The Sponsor conducted an assessment of safety regarding the α-Gal glycan and concluded 
that PRM-151 containing α-Gal at the levels found is suitable for use in clinical studies 
with the benefit-risk ratio remaining favorable. More information on the presence of α‑Gal 
is provided in the PRM-151 Investigator’s Brochure (IB). 
1.3 
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT 
The current study is a confirmatory, randomized, double-blind, placebo-controlled, 
Phase III clinical trial to assess the efficacy and safety of PRM-151 in patients with IPF 
with or without concurrent treatment with pirfenidone or nintedanib.  
The primary efficacy endpoint for this study will be the absolute change from baseline 
to Week 52 in FVC (mL), and the key secondary endpoint will be the absolute change in 
6-minute walk distance (6MWD) over the same interval.  Results from previous Phase I 
and Phase II studies have produced robust safety and efficacy data, establishing 
a PRM-151 dose and treatment regimen, and are strongly supportive of conducting 
a Phase III study to confirm efficacy and safety.  Summary of the Phase I and II study 
outcomes are as follows: 
• 
In a Phase I study in healthy participants and patients with pulmonary fibrosis, 
administration of PRM-151 increased circulating pentraxin 2 concentrations 6- to 
13-fold (Dillingh et al. 2013).   
• 
An additional Phase I study in patients with IPF showed improvements in 
predicted percentage of FVC value and 6MWD following treatment with PRM-151 
(Van den Blink et al. 2016). 
 
The randomized, placebo-controlled Phase II efficacy and safety Study PRM-151-202 of 
10 mg/kg of PRM-151 every 4 weeks (Q4W) in patients with IPF revealed clinically and 
statistically significant efficacy outcomes and showed an acceptable safety profile in 
a population of patients predominantly (~80%) receiving standard-of-care anti-fibrotic 
treatment (Raghu et al. 2018): 
• 
The primary endpoint was change in FVC (% predicted) from baseline to Week 28.  
This endpoint was successfully met with a between-group difference in least 
squares (LS) mean change in FVC [% predicted] of + 2.3 in favor of PRM-151 
(95% CI: 0.9 to 3.7; p = 0.0014). 
• 
Although the study was not powered for formal hypothesis testing of secondary 
endpoints, encouraging results were also observed for 6MWD (between-group 
difference in LS mean change from baseline to Week 28 = 31.3 m [95% CI: 14.7 to 
47.8, p = 0.0002]) and FVC (mL) (between-group difference in LS mean change 
from baseline to Week 28 = 114.6 mL [95% CI: 4.4 to 224.8, p = 0.041]). 
• 
Clinically and statistically meaningful changes observed on the two entirely different 
prognostic endpoints (FVC [% predicted] and 6MWD) as outlined above suggest 
that the treatment effect observed for PRM-151 is not due to chance. 


 
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 
The treatment effect for PRM-151 versus placebo was independent of patients 
receiving concurrent pirfenidone or nintedanib, or no concurrent therapy for IPF. 
 
The most common adverse events in the PRM-151 versus placebo group were 
cough (18% vs. 5%), fatigue (17% vs. 10%), and nasopharyngitis (16% vs. 23%). 
 
Serious adverse events occurred in 6 patients (7.8%) in the PRM-151 group and 
4 patients (10.3%) in the placebo group.  None of the serious adverse events were 
considered related to the study treatment.  
 
Three patients (2.6%) experienced adverse events that led to discontinuation from 
the study drug (2 patients in the PRM-151 group and 1 patient in the placebo 
group).  One patient in the placebo group died from pneumonia. 
 
Recently completed analyses of the open-label extension (OLE) of study PRM-151-202 
provided additional evidence for the efficacy and safety of 10 mg/kg of PRM-151 
administered Q4W (Raghu et al. 2019): 
 
The reduction in deterioration of FVC and 6MWD have been retained in the group 
initially randomized to PRM-151, and patients from the placebo group who crossed 
over to PRM-151 treatment show a reduction in the rate of decline for both FVC and 
6MWD upon initiation of active therapy. 
 
Adverse events were consistent with long-term IPF sequelae.  Thirty-one (28%) 
patients had serious adverse events, mostly unrelated to PRM-151.  Those 
occurring in two or more patients were pneumonia (six [5%] of 111), IPF 
exacerbation (four [4%]), IPF progression (four [4%]), and chest pain (two [2%]).  
Twenty-one (19%) patients had severe adverse events, of which IPF exacerbation 
and IPF progression each occurred in two (2%) patients.  Two (2%) patients 
experienced life-threatening adverse events (one had pneumonia and one had 
small-cell lung cancer extensive stage). 
 
Overall, these data further support the efficacy and safety of administration of PRM-151 
10 mg/kg Q4W in patients with IPF, with or without concurrent use of pirfenidone or 
nintedanib. 
The Sponsor believes these are important findings that merit confirmation in a pivotal 
program, with the objective of obtaining registration of PRM-151 for the treatment of 
patients with IPF. 
1.3.1 
Benefit–Risk Assessment 
PRM-151, a recombinant form of an endogenous human protein, was generally well 
tolerated in nonclinical toxicity studies and in Phase I and II clinical studies.  Clinically 
and statistically significant positive effects with PRM-151 were observed in the Phase II 
IPF study, both for change in FVC (% predicted) and 6MWD through 28 weeks of 
treatment.  Based on encouraging Phase I and II data in subjects with IPF, PRM-151 
has the potential to be a well-tolerated, disease modifying treatment for a broad 
spectrum of fibrotic diseases, including IPF. 


 
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In the two Phase I studies of PRM-151 administered intravenously to normal volunteers 
and patients with IPF, no serious adverse events were reported, and no other safety 
signals were 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 serious adverse events noted in 57 days; similar types and number of 
treatment-emergent adverse events were reported in both PRM-151 and placebo 
treated subjects.  
In the Phase II study (PRM-151-202; n  116), PRM-151 was generally well tolerated 
through at least 6 months of treatment as evidenced by the following:  
 
None of the serious adverse events reported during the study were considered 
related to the study treatment.  
 
Treatment-emergent adverse events (serious and non-serious) leading to temporary 
discontinuation of study treatment were more common in the PRM-151 group than 
the placebo group overall (six patients [7.8%] and one patient [2.6%], respectively), 
but these events were distributed across a range of body systems with no single 
preferred term reported in more than one patient and did not appear to indicate 
a safety risk for PRM-151.  
 
The most common adverse event assessed as possibly or probably related to study 
treatment was fatigue (16 events in nine patients from the PRM-151 group [11.7%] 
and three events in three patients from the placebo group [7.7%]).  
 
Adverse events of cough with possible or probable relationship to study treatment 
were reported in seven patients from the PRM-151 group (9.1%; seven events).  
No patient from the placebo group was reported with possibly or probably related 
cough adverse events.  
 
Four infusion-related reactions (IRRs) occurred in three patients, two patients in the 
PRM-151 group (2.6%) and one patient in the placebo group (2.6%).  One patient in 
the PRM-151 group experienced dizziness and another experienced a hypertensive 
crisis event; one patient in the placebo group experienced two hypertensive crisis 
events.  There was no difference between treatment arms in the nature or frequency 
of IRRs.  None of the IRR events was deemed serious.  There were no IRR events 
among the seven patients with anti-drug antibodies (ADAs [six patients in the 
PRM-151 group; one patient in the placebo group]) through Week 28. 
 
Risks associated with PRM-151 are inherent in it being the recombinant form of 
a naturally occurring human protein and consist of potential development of ADA and 
infusion reactions.  PRM-151 has an endogenous counterpart; therefore, ADAs 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.  


 
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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.  Individuals 
who have chronic medical issues may be at higher risk for serious illness from 
COVID-19, including those with pulmonary fibrosis.  However as stated above, it is not 
anticipated that PRM-151 will increase the risk of infection with SARS-CoV-2 or the 
severity of infection.  Based on the mechanism of action of PRM-151, a possible 
interaction between PRM-151 treatment and COVID-19 vaccination is not expected.  
For patients enrolling in this study and receiving PRM-151 treatment, a decision to 
administer the vaccine to a patient should be made on an individual basis by the 
investigator in consultation with the patient.  When administered, COVID-19 vaccines 
must be given in accordance with the approved or authorized vaccine label.  Receipt of 
the COVID-19 vaccine is considered a concomitant medication and should be 
documented as such (see Section 4.4.1). 
As with any protein therapeutic, the potential for reactions exists and safety procedures 
will be implemented, including careful monitoring of patients 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 and the potential benefits of PRM-151 as a therapy 
for IPF remain to be proven in clinical efficacy studies. 
1.3.2 
Risks Associated with Radiologic Imaging 
The high-resolution computed tomography (HRCT) scans performed for this study will 
involve the delivery of small amounts of radiation to the patient.  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 reasonably achievable" (ALARA) to obtain the quality of images necessary 
for imaging of lung abnormalities and quantification by image 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-induced malignancy, is exceedingly small compared to the risk of mortality 
inherent to IPF.  From currently available data, the U.S. Nuclear Regulatory Commission 
has adopted a risk value for an occupational dose of one rem (0.01 Sieverts) Total 
Effective Dose Equivalent (TEDE) of approximately one chance in 2,500 of fatal cancer 
per rem of TEDE received.  For this protocol, the dose will vary, depending on the 
specific HRCT scanner technology available at each site, but the volumetric HRCT dose 
index is estimated to be less than 10 milliGray with effective dose for a standard patient 
of less than 3 milliSieverts (0.003 Sieverts) per scan.  The dose will be adjusted 
appropriately to assure consistent image quality, based on patient 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. 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy, safety, and pharmacokinetics of PRM-151 
compared with placebo in patients with IPF.  Specific objectives and corresponding 
endpoints for the study are outlined below. 
2.1 
EFFICACY OBJECTIVES 
2.1.1 
Primary Efficacy Objective 
The primary efficacy objective is to demonstrate superiority of 10 mg/kg PRM-151 plus 
standard of care treatment as needed (excluding lung transplantation) administered 
Q4W via IV infusion, over matching placebo plus standard of care treatment as needed 
(excluding lung transplantation), on lung function on the basis of the following endpoint: 
 
Absolute change from baseline to Week 52 in forced vital capacity (FVC [mL]) 
 
The primary comparison will be made regardless of whether patients changed or 
withdrew from randomized treatment or changed additional treatment (excluding lung 
transplantation) during the study.  Patients who received a lung transplant will be 
assessed as if a lung transplant had not been available during the study, and all 
assessments after the transplant will not be included in the analysis. 
2.1.2 
Secondary Efficacy Objective 
The secondary efficacy objective is to demonstrate superiority of 10 mg/kg PRM-151 
plus standard of care treatment as needed (excluding lung transplantation) administered 
Q4W via IV infusion, over matching placebo plus standard of care treatment as needed 
(excluding lung transplantation) on the basis of the following endpoints: 
 
Absolute change from baseline to Week 52 in 6MWD (in meters) 
 
Absolute change from baseline to Week 52 in FVC% predicted  
 
Time to disease progression, defined as time to first occurrence of ≥ 10% absolute 
decline in % predicted FVC, ≥ 15% relative decline in 6MWD, or death  
 
Time to first respiratory-related hospitalizations (defined as non-elective 
hospitalizations due to any respiratory cause, including acute exacerbations of IPF, 
or suspected acute exacerbations of IPF, as determined by the Clinical 
Adjudication Committee) 
 
Change from baseline to Week 52 in University of California, San DiegoShortness 
of Breath Questionnaire (UCSD-SOBQ) 
 
Change from baseline to Week 52 in St. George Respiratory Questionnaire (SGRQ) 
Total Score  
 
Time to first acute exacerbation of IPF, or suspected acute exacerbation of IPF, as 
determined by the Clinical Adjudication Committee 
 
Change from baseline to Week 52 in carbon monoxide diffusing capacity (DLCO) 


 
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 
Survival, as measured by all-cause mortality 
 
2.1.3 
Exploratory Efficacy Objective 
The exploratory efficacy objective for this study is to evaluate the efficacy of PRM-151 
plus standard of care treatment as needed (excluding lung transplantation) compared 
with matching placebo plus standard of care treatment as needed (excluding lung 
transplantation) on the basis of the following endpoints: 
 
Change from baseline to Week 52 in FVC% predicted, FVC (mL), by concurrent 
therapy stratum (i.e., with nintedanib treatment vs. with pirfenidone treatment vs. 
without pirfenidone or nintedanib treatment)  
 
Change from baseline to Week 52 in FVC% predicted, FVC (mL), by MUC5B risk 
allele positive or negative status 
 
Change from baseline to Week 52 in 6MWD, by concurrent therapy stratum 
(i.e., with nintedanib treatment vs. with pirfenidone treatment vs. without pirfenidone 
or nintedanib treatment)  
 
Change from baseline to Week 52 in SGRQ Individual Domains (Symptoms, 
Activity, and Impacts) Score 
 
Change from baseline to Week 52 in the 6-minute walk test (6MWT) pre-test to 
pre-test measurements of Borg dyspnea score, fatigue score, and oxygen saturation 
 
Change from baseline to Week 52 in the 6MWT pre-test to post-test measurements 
of Borg dyspnea score, fatigue score, and oxygen saturation 
 
Change from baseline to Week 52 in the 6MWT post-test to post-test measurements 
of Borg dyspnea score, fatigue score, and oxygen saturation 
 
Change from baseline to Week 52 in quantitative imaging analysis parameters of 
HRCT scan of the thorax 
 
Length of hospital stay for respiratory-related hospitalizations, total time in intensive 
care units due to respiratory causes, deaths due to respiratory causes, and 
unscheduled outpatient clinic/urgent care/emergency room utilization related to 
respiratory events 
 
A decline or an increase in FVC% predicted of  5%,  10%, and  15% from 
baseline to Week 52 
 
A decline or an increase in FVC in mL of  100 mL and  200 mL from baseline to 
Week 52 
 
A decline or an increase in 6MWD  5%,  10%,  15%, and  20% from baseline to 
Week 52 
 
A decline or an increase in 6MWD  25 m, and 50 m from baseline to Week 52 
 
Number of acute exacerbations during the 52 weeks 
 
At least one acute exacerbation during the 52 weeks; as determined by the Clinical 
Adjudication Committee 


 
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 
Survival as measured by IPF-related mortality 
 
Survival as measured by respiratory-related mortality 
 
Disease progression defined as:   10% absolute decline in % predicted FVC; 
respiratory hospitalization; or a decline of 50 m in 6MWD  
 
Disease progression and subsequently start pirfenidone or nintedanib or switch from 
nintedanib to pirfenidone (or vice versa)  
 
Time to worsening on the UCSD-SOBQ, as indicated by a change in score of 
10 points or greater 
 
Time to worsening on the SGRQ total score, as indicated by a change in score of 
7 or greater 
 
Time to worsening on the SGRQ Activity domain, as indicated by a change in score 
of 5 or greater 
 
Time to worsening on the SGRQ Symptom Domain, as indicated by a change in 
score of 8 or greater 
 
Time to worsening on the SGRQ Impact Domain, as indicated by a change in score 
of 7 or greater 
 
Change in PFT parameters (FVC, DLCO) or 6MWD from baseline to Week 52 
between SARS-CoV-2 antibody positive compared with negative patients 
 
Change in PFT parameters (FVC, DLCO) or 6MWD from baseline to Week 52 in 
patients who develop SARS-CoV-2 antibodies during treatment (not present at 
baseline)  
 
Efficacy evaluations will be performed for the primary, secondary, and exploratory 
efficacy endpoints as detailed in Section 6.5.  Exploratory analyses may also be 
performed for additional measures and subgroups of interest.  Details of all such 
analyses will be provided in the Statistical Analysis Plan (SAP). 
2.2 
SAFETY OBJECTIVE 
The safety objective for this study is to confirm the safety and tolerability of 10 mg/kg of 
PRM-151 administered Q4W via IV infusion plus standard of care treatment as needed 
relative to matching placebo plus standard of care treatment as needed in a population 
of all dosed patients, on the basis of the following endpoints: 
 
Incidence and severity of adverse events, with severity determined according to the 
5-point severity scale (National Cancer Institute Common Terminology Criteria for 
Adverse Events, Version 5.0 [NCI CTCAE, v.5.0]) 
 
Incidence and severity of IRRs and other adverse events of special interest 


 
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 
Proportion of patients permanently discontinuing study treatment due to 
adverse events 
Change from baseline in targeted clinical laboratory test results 
Safety evaluations will be performed as detailed in Section 6.5.  Safety analyses may 
also be performed for subgroups of interest.  Details of such analyses will be provided in 
the SAP. 
 
2.3 
PHARMACOKINETIC OBJECTIVES 
The pharmacokinetic (PK) objective for this study is to characterize pharmacokinetics of 
PRM-151 in patients with IPF on the basis of the following: 
 
Plasma concentrations of PRM-151 at specified timepoints  
 
The exploratory PK objectives are to evaluate the potential relationship between drug 
exposure and the efficacy and safety of PRM-151 on the basis of the following: 
 
Relationship between PK for PRM-151 and efficacy endpoints 
 
Relationship between PK for PRM-151 and safety endpoints 
 
2.4 
IMMUNOGENICITY OBJECTIVES 
The immunogenicity objective for this study is to evaluate the immune response to 
PRM-151 on the basis of the following: 
 
Prevalence of ADAs at baseline and incidence of ADAs during the study 
 
The exploratory immunogenicity objective for this study is to evaluate potential effects of 
ADAs on the basis of the following: 
 
Relationship between ADA status and efficacy, safety, or PK endpoints 
 
2.5 
BIOMARKER OBJECTIVE  
The exploratory biomarker objective for this study is to identify and/or evaluate 
biomarkers that are predictive of response to PRM-151 (i.e., predictive biomarkers), are 
early surrogates of efficacy, are associated with progression to a more severe disease 
state (i.e., prognostic biomarkers), are associated with acquired resistance to PRM-151, 
are associated with susceptibility to developing adverse events or can lead to improved 
adverse event monitoring or investigation (i.e., safety biomarkers), can provide evidence 
of PRM-151 activity (i.e., pharmacodynamic [PD] biomarkers), or can increase the 
knowledge and understanding of disease biology and drug safety, on the basis of 
the following: 
 
Relationship between biomarkers in blood listed in Section 4.5.12 and efficacy, 
safety, PK, immunogenicity, or other biomarker endpoints 
 


 
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2.6 
HEALTH STATUS UTILITY OBJECTIVE  
The exploratory health status utility objective for this study is to evaluate health status 
utility scores of patients treated with PRM-151 plus standard of care treatment as 
needed on the basis of the following endpoint: 
 
Change from baseline to Week 52 in EuroQol 5-Dimension, 5-Level Questionnaire 
(EQ-5D-5L) index-based, and visual analog scale (VAS) scores 
 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
3.1.1 
Overall Study Design and Plan 
This Phase III, randomized, double-blind, placebo-controlled, pivotal study is designed to 
confirm the efficacy and safety of PRM-151 in the treatment of patients with IPF during 
a 52-week period.  At the end of this 52-week period, patients will be invited to enroll in 
an open-label extension study (Study WA42294) to receive treatment with PRM-151.  
Patients who do not enroll in the OLE study will be followed up for an additional 4 weeks 
(to Week 56, for safety monitoring).   
The OLE study will provide patients with further study assessments and PRM-151 
treatment on an ongoing basis.  However, the OLE study will also consist of a long-term 
survival cohort, in which patients who do not want further study assessments or 
treatment can enroll (for long-term collection of survival data only). 
Figure 1 presents an overview of the study design.  A schedule of activities is provided in 
Appendix 1. 


 
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Figure 1 Study Schema 
 
OLE  open-label extension; Q4W  once every 4 weeks. 
a Patients will have a final assessment visit at Week 52 (4 weeks after the final study drug 
infusion).  For patients enrolling in the OLE study, this will also be their end of study visit.  
b Patients who do not enroll in the OLE study will have their final assessment visit at Week 52, 
followed by an end of study visit at Week 56 (8 weeks after the final study drug infusion). 
 
Patients meeting the eligibility criteria for the study will be randomized to PRM-151 
10 mg/kg Q4W or placebo.  Efficacy will be evaluated through assessment of functional 
capacity as measured by FVC, 6MWD, other PFTs, and assessment of patients with 
respiratory events leading to hospitalizations, progression of disease, acute IPF 
exacerbations. 
Patient reported outcomes (PROs) will be assessed using the SGRQ, UCSD-SOBQ, 
and EQ-5D-5L. 
Dyspnea, fatigue, and SpO2 will be assessed based on measurements taken during the 
6MWT.  For patients who require a HRCT scan during the screening period, an 
additional chest HRCT scan will be performed at Week 52.  Patients who do not require 
a HRCT scan during the screening period (i.e., they already have a historic HRCT scan 
of acceptable quality performed within 12 months prior to screening) will not be required 
to perform a scan at Week 52. 
Treated patients will be followed until the end of the 52-week study period unless the 
patient withdraws consent for follow-up or dies. 
Patients will be evaluated for study eligibility during a screening period of up to 
4 weeks.   If any patient is prevented from completing required screening procedures 


 
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within the 4-week period due to unforeseeable circumstances, screening can be 
extended up to a maximum of 2 weeks.  Patients who are determined to be eligible 
based on the screening assessments will be randomized into the study and randomly 
allocated to treatment with PRM-151 or placebo.  
Patients entering the screening period on anti-fibrotic therapy (pirfenidone or nintedanib) 
should have been on treatment for at least 3 months, and on a stable dose for at least 
4 weeks prior to the screening visit, and are expected to remain on their specific dose 
and regimen throughout the study duration unless dose reduction or discontinuation is 
indicated for safety or tolerability reasons. 
Patients entering the screening period of the study NOT on anti-fibrotic treatment 
(pirfenidone or nintedanib), either treatment naive or having previously taken and 
discontinued, must have been off such treatment for at least 4 weeks prior to the 
screening visit and during screening.  At the time of consent, if a patient is considering 
starting treatment with either nintedanib or pirfenidone, the patient should be advised of 
being on treatment for at least 3 months prior to screening (Section 4.1.1). 
For all patients receiving anti-fibrotic therapy, the investigator should document the dose, 
frequency, and duration of the anti-fibrotic drug.  For patients not receiving anti-fibrotic 
therapy during the screening period, the investigator should document the reason(s).  
During the study, patients may initiate pirfenidone or nintedanib as rescue, if determined 
to be clinically indicated by the investigator.  The investigator may consider discussing 
changes in anti-fibrotic therapy with the Medical Monitor throughout the study.  The 
investigator is required to document the specific reason for introducing anti-fibrotic 
therapy in patients who were randomized into the study not on anti-fibrotic therapy.  
Approximately 658 patients will be randomly assigned on a 1:1 basis to treatment with 
PRM-151 or placebo, as follows: 
 
PRM-151 Group:  PRM-151 10 mg/kg IV infusion over 50–70 minutes on Days 1, 3, 
and 5, then one infusion Q4W for 48 weeks 
 
Placebo Group: Matched placebo IV infusion over 50–70 minutes on Days 1, 3, and 
5, then one infusion Q4W for 48 weeks 
The randomization will be stratified as follows: 
 
Concurrent use of nintedanib treatment versus pirfenidone treatment versus no 
concurrent treatment 
 
Region:  China (including Hong Kong and Taiwan), North America (United States 
and Canada), Europe (including eastern Europe), Latin America, and Rest of World 
(including east Asia, Australia, and New Zealand)  
 




 
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The total length of the study is approximately 2.5 years.  
3.3 
RATIONALE FOR STUDY DESIGN 
3.3.1 
Rationale for PRM-151 Dose and Schedule 
Dose selection for this Phase III trial of PRM-151 in IPF is based on prior nonclinical and 
clinical data demonstrating favorable safety and efficacy at equivalent doses of up to 
10 mg/kg IV.  In summary:  
 
Nonclinical studies and in vitro potency assays indicate that the effective dose range 
in humans is predicted to be 0.210 mg/kg IV.  
 
PRM-151 has demonstrated a decrease in lung fibrosis in preclinical models of IPF 
(TGF-1 overexpression, and bleomycin-induced lung fibrosis); the effect lasted for 
as long as 30 days after dosing (Murray et al. 2011; Murray et al. 2010; Pilling et al. 
2007), which supports Q4W dosing. 
 
The dose of 10 mg/kg IV selected for the current study has a dose-based safety 
margin of 10x and an area under the plasma concentration-time curve (AUC)-based 
safety margin of approximately 5x compared to the rat no-observed-adverse-effect-
level (NOAEL) of 100 mg/kg from a 26-week repeat-dose Good Laboratory Practice 
(GLP) compliant toxicity study. 
 
The dose of 10 mg/kg IV has been identified as an appropriate dose level in patients 
with IPF based on the outcomes of the single ascending dose (SAD) and multiple 
ascending dose (MAD) Phase I studies conducted in healthy subjects and patients 
with IPF (studies PRM151A-11EU [Dillingh et al. 2013], PRM151F-12GL [van den 
Blink et al. 2016]), and further supported by the randomized Phase II efficacy and 
safety study PRM-151-202 with PRM-151 (Raghu et al. 2018) and the interim 
analysis from study PRM-151-202 OLE (Raghu et al. 2019): 
The Phase I MAD study PRM151F-12GL revealed that plasma levels of 
PRM-151 (Cmax and AUC; baseline-corrected) were dose proportional across 
the range of doses from 1 to 10 mg/kg (Dillingh et al. 2013).  Additionally, while 
the study was not designed to support formal hypothesis testing, the mean 
change from baseline to Day 57 (which was 42 days after administration of last 
dose of study drug) in the 6MWD trended upward with increasing dose of IV 
PRM-151 (11 m, +6 m, and +35 m at 1 mg/kg, 5 mg/kg, and 10 mg/kg, 
respectively; and declined in the placebo group: 11 m).  Similar observations 
were noted in mean change from baseline in FVC.  The effects of PRM-151 
were well tolerated at doses up to 10 mg/kg IV by patients with IPF (van den 
Blink et al. 2016).  These preliminary efficacy and safety data in patients with 
IPF supported further evaluation of 10 mg/kg IV administered Q4W. 
In the randomized, placebo-controlled Phase II efficacy and safety study, 
PRM-151-202, 10 mg/kg IV of PRM-151 was administered on Days 1, 3, and 5 
followed by Q4W administration for 24 weeks in patients with IPF.  Data from 
this study demonstrated clinically and statistically significant efficacy outcomes 
and showed an acceptable safety profile (Raghu et al. 2018). 


 
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Additionally, 52-week data on 111 patients enrolled in the 128-week OLE of 
study PRM-151-202 have shown durability of effect of PRM-151 at 10 mg/kg 
Q4W IV in patients randomized to the active arm.  Furthermore, patients in 
the placebo group crossing over to receive PRM-151 (10 mg/kg IV) in the 
extension phase experienced a reduction in the rate of decline for FVC 
(% predicted) and FVC (mL) and no decline in 6MWD upon initiation of active 
therapy (Raghu et al. 2019).  Every 28 weeks, patients in this study received 
PRM-151 on Days 1, 3, and 5. 
 
These data further support the selection of the dose of 10 mg/kg IV PRM-151 Q4W for 
the confirmatory Phase III study in patients with IPF, with or without concurrent use of 
pirfenidone or nintedanib. 
Loading Dose 
Patients with IPF have increased fibrocyte numbers in circulation and decreased levels 
of circulating PTX-2.  PRM-151 mediates its activity by coupling recognition of DAMPs 
within injured tissue to specific phagocytosis through FcR on monocytes.  Loading 
doses were instituted in the preclinical models to increase the exposure of PTX-2 in the 
fibrotic tissue space within the lungs, to increase the likelihood that all local 
monocyte/macrophage lineage cells would be polarized to the pro-resolutive state. 
The Phase I MAD study (PRM151F-12GL) showed that administration of 510 mg/kg in 
humans increased circulating levels of PTX-2 by 58 fold.  This data suggested that 
a dosing regimen that includes a loading dose may have persistent positive biologic 
effects up to 42 days after the last administration.  
Loading doses of PRM-151 on Days 1, 3, and 5 were administered in the Phase II study 
(PRM-151-202) and repeat loading doses were administered in the 128-week OLE 
(PRM-151-202) every 28 weeks.  
Given the duration of this proposed Phase III study (52 weeks), it is expected that there 
may be occasional dose interruptions.  Repeat loading of PRM-151 will be required on 
the resumption of study treatment (three doses administered on alternate days), if any 
dose of study drug is missed (see Section 4.3.2.1).  This is to ensure adequate tissue 
exposure of PRM-151, given the estimated tissue half-life of PTX-2 (2430 days, see 
PRM-151 Investigator’s Brochure for further details). 
3.3.2 
Rationale for Key Primary and Secondary Endpoints 
For the Phase III study, FVC (mL) has been selected as the primary outcome measure 
based on the common clinical use of this reproducible measure to monitor disease 
progression and on the results of Phase II study PRM-151-202.  Change from baseline 
in FVC is the most commonly employed primary endpoint in clinical studies assessing 
treatments for IPF and has been used as the basis of approval for other IPF therapies 
(Nathan and Meyer 2014; Table of Surrogate Endpoints, FDA, 2018).  In addition to the 


 
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advantages of being easy to measure and highly reproducible, FVC is considered to be 
clinically reflective of the burden of the IPF disease process (Nathan and Meyer 2014; 
Saketkoo et al. 2014).  FVC outcomes have been associated with subsequent survival, 
as declines in FVC have been shown to correlate with increased risk of mortality 
(Saketkoo et al. 2014; Collard et al. 2003).   
The Sponsor has selected 6MWD as the key secondary outcome measure for this study 
as this test has the combined attributes of providing a direct measure of patients’ 
functional ability as well as having an association with patient outcomes in IPF (Lederer 
et al. 2006; du Bois et al. 2014; Eaton, et al. 2005; Flaherty, et al. 2006; Caminati et al. 
2009; Nathan et al. 2014; Singh, et al. 2014, Brown and Nathan 2017).  
The 6MWD is a valid and responsive clinical endpoint, which provides objective and 
clinically meaningful information regarding functional status and near-term prognosis 
(Nathan et al. 2015).  A difference of 24 to 45 m has been reported as clinically 
important in the IPF population (du Bois et al. 2011; Nathan et al. 2013; Verma et al. 
2011).  A change of 14 to 30.5 m has been found to be clinically important across 
multiple patient groups (Bohannon and Crouch 2016), and the 6MWD was found to be 
associated with health-related quality of life measures in patients with IPF, representing 
a meaningful outcome for patients (Verma et al., 2011).  Furthermore, a decline of more 
than 25 m has been independently associated with 1-year all-cause mortality in IPF 
(Swigris et al. 2010; du Bois et al. 2014; Brown and Nathan 2017).  Additionally, the 
6MWD has been found to be sufficiently robust to serve as the primary efficacy 
outcome measure for therapies intended to treat pulmonary arterial hypertension 
(Galiè et al. 2009).  
Data from the PRM-151 Phase II study (Raghu et al. 2018) have demonstrated 
stabilization of the decline in 6MWD in the group receiving PRM-151 with 
a placebo-corrected treatment effect of +31.3 m.  These data warrant confirmation of the 
6MWD as an important measure of clinical benefit in this pivotal Phase III study. 
3.3.3 
Rationale for Control Group  
A placebo-treated control group will be used in this study to assess the differences in 
pulmonary function, 6MWD, PROs, and safety in patients who receive PRM-151 
compared with patients who receive placebo.  The use of a control group is necessary 
given the inherent variability in IPF progression in individual patients, IPF exacerbations, 
patients’ lung function, and use of subjective assessments such as the PROs.  Patients 
in the control group will undergo the same study assessments as the patients treated 
with PRM-151.  All patients will be allowed to receive standard of care in addition to 
study drug throughout the study. 


 
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3.3.4 
Rationale for Biomarker Assessments 
IPF is a disease in which circulating levels of PTX-2 are lower in patients relative to 
healthy subjects (Murray et al. 2011) and may reflect retention of PTX-2 in the lung 
tissue due to localized biological activity.  The disease is heterogeneous, with several 
pathways implicated in its pathobiology (Wolters et al. 2018).  The rate at which IPF 
progresses is variable among individuals and potential biomarkers to predict this include 
CCL18 (Neighbors et al. 2018), MUC5B and telomere length (Dressen et al. 2018).  
Therefore, the study will include an exploratory component focused on identification of 
biomarkers that may be prognostic for patients likely to have an accelerated rate of 
disease progression.  PD biomarkers including, but not limited to, CCL18 will be 
assessed to demonstrate evidence of biologic activity of PRM-151 in patients.  As these 
biomarkers may also have prognostic value, their potential association with disease 
progression will also be explored.  Biomarker samples collected during the study may be 
used to assess the relationship between IPF-related biomarkers, disease progression, 
clinical status, and treatment benefit. 
4. 
MATERIALS AND METHODS  
4.1 
PATIENTS 
Approximately 658 patients with IPF will be enrolled during the global enrollment phase 
of this study.  After completion of the global enrollment phase, additional patients may be 
enrolled in China, Hong Kong and Taiwan in an extended China enrollment phase to 
ensure a total enrollment that is sufficient to support registration in China (see 
Section 3.1.1). 
4.1.1 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
Signed Informed Consent Form 
 
Age 40–85 years, inclusive, at time of signing Informed Consent Form 
 
Ability to comply with the requirements of the study protocol, according to the 
investigator’s best judgment 
 
Documented diagnosis of IPF per the 2018 ATS/ERS/JRS/ALAT Clinical Practice 
Guideline (Raghu et al. 2018; Appendix 10)  
 
HRCT pattern consistent with the diagnosis of IPF, confirmed by central review of 
chest HRCT (available HRCT of acceptable quality performed within 12 months 
prior to screening or obtained during the screening period) and central review of 
lung biopsy (LB), if available.  Details provided in Appendix 10. 
 
Minimum 6MWD of 150 meters with maximum use of 6 L/min at sea-level and up to 
8 L/min at altitude ( 5000 feet [1524 meters] above sea level) of supplemental 
oxygen while maintaining oxygen saturation of  83% during the 6MWT during 
screening 


 
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 
FVC  45% predicted during screening as determined by the over-reader  
 
Forced expiratory volume in 1 second (FEV1)/FVC ratio  0.70 during screening as 
determined by the over-reader 
 
DLCO  30% and  90% of predicted during screening (Hgb corrected or 
uncorrected) as determined by the over-reader 
 
If receiving pirfenidone or nintedanib treatment for IPF, the patient must have been 
on treatment for at least 3 months and on a stable dose for at least 4 weeks prior to 
screening and during screening (with no contraindications according to local 
prescribing information) 
 
If not currently receiving nintedanib or pirfenidone treatment (either treatment naïve 
or having previously taken and discontinued) must have discontinued such 
treatment  4 weeks prior to screening and during screening 
If patient is considering starting treatment with either nintedanib or pirfenidone, 
patient must be on treatment for at least 3 months prior to screening, provided 
there are no contraindications according to local prescribing information. 
 
For women of childbearing potential (excluding patients enrolling in Japan):  
agreement to remain abstinent (refrain from heterosexual intercourse) or use 
contraception, as defined below: 
Women must remain abstinent or use contraceptive methods with a failure rate of 
< 1% per year during the treatment period and for 8 weeks after the final dose of 
PRM-151.  
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea 
with no identified cause other than menopause), and is not permanently infertile 
due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or 
another cause as determined by the investigator (e.g., Müllerian agenesis).  
The definition of childbearing potential may be adapted for alignment with local 
guidelines or regulations. 
Examples of contraceptive methods with a failure rate of  1% per year 
include bilateral tubal ligation, male sterilization, hormonal contraceptives 
that inhibit ovulation, hormone-releasing intrauterine devices, and copper 
intrauterine devices. 
Hormonal contraceptive methods must be supplemented by a barrier method. 
The reliability of sexual abstinence should be evaluated in relation to the duration 
of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) 
and withdrawal are not adequate methods of contraception.  If required per local 
guidelines or regulations, locally recognized adequate methods of contraception 
and information about the reliability of abstinence will be described in the local 
Informed Consent Form. 


 
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 
For men:  agreement to remain abstinent (refrain from heterosexual intercourse) or 
use a condom, and agreement to refrain from donating sperm, as defined below: 
With a female partner of childbearing potential or pregnant female partner, men 
must remain abstinent or use a condom during the treatment period and for 
8 weeks after the final dose of PRM-151 to avoid exposing the embryo.  
Men must refrain from donating sperm during this same period. 
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient.  
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation 
methods) and withdrawal are not adequate methods of preventing drug 
exposure.  If required per local guidelines or regulations, information about the 
reliability of abstinence will be described in the local Informed Consent Form. 
 
Anticipated life expectancy of at least 12 months at baseline, according to the 
investigator’s judgment 
 
Patient and investigator considered all medicinal treatment options and/or possibly 
lung transplantation prior to considering participation in the study.  If the patient is 
on a lung transplant list, the investigator anticipates the patient will be able to 
complete the study prior to transplant. 
 
For patients enrolled in the extended China enrollment phase:  current resident of 
mainland China, Hong Kong, or Taiwan, and of Chinese ancestry 
 
4.1.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
Evidence of other known causes of ILD (e.g., domestic and occupational 
environmental exposures, connective-tissue disease, and drug toxicity) 
 
FVC% predicted value showing improvement in the 6-month period prior to 
screening and including screening value, as assessed by the investigator 
 
Emphysema present on  50% of the HRCT, or the extent of emphysema is greater 
than the extent of fibrosis, according to central review of the HRCT 
 
Receiving nintedanib in combination with pirfenidone 
 
Received cytotoxic, immunosuppressive, cytokine modulating, or receptor 
antagonist agents (including but not limited to methotrexate, azathioprine, 
mycophenolate mofetil, cyclophosphamide, cyclosporine or other steroid sparing 
agent) within 4 weeks prior to or during screening 
 
Receiving systemic corticosteroids equivalent to prednisone  10 mg/day or 
equivalent within 2 weeks prior to or during screening  
 
Receiving strong inhibitor or inducer of CYP1A2 in patients taking pirfenidone 
 
Receiving potent inhibitor or inducer of P-gp in patients taking nintedanib 


 
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 
Acute respiratory or systemic bacterial, viral, or fungal infection either during 
screening or prior to screening and not successfully resolved 4 weeks prior to 
screening visit 
 
Positive interferon gamma release assay test for tuberculosis during screening:  
Patients who have completed treatment for tuberculosis within 6 months prior to 
screening, and have no evidence of recurrent disease do not need to be tested. 
 
Resting oxygen saturation of  89% using up to 4 L/min of supplemental oxygen at 
sea level and up to 6 L/min at altitude ( 5000 feet [1524 meters] above sea level) 
during screening 
 
Co-existing acute or chronic medical condition that, in the investigator’s opinion, 
would substantially limit the ability to comply with study requirements or may 
influence any of the safety or efficacy assessments included in the study 
 
Class IV New York Heart Association chronic heart failure 
 
Historical evidence of left ventricular ejection fraction  35% 
 
Presence of pulmonary hypertension that, in the investigator’s opinion, would 
substantially limit the ability to comply with study requirements or may influence any 
of the safety or efficacy assessments included in the study 
 
Cardiopulmonary rehabilitation program based on exercise training that has been 
completed within 8 weeks prior to screening or planned to start during the patient’s 
enrollment in this trial 
 
History of smoking (including cigarette, cannabis, cigar, pipe and vaping) within 
3 months prior to or during screening 
 
History of alcohol or substance use disorder  within 2 years prior to or during 
screening or known or suspected active alcohol or substance-use disorder 
 
History of a malignancy within the 5 years prior to screening, with the exception of 
basal cell or squamous cell skin neoplasms.  In addition, a malignant diagnosis or 
condition that occurred more than 5 years prior to screening, and any basal cell or 
squamous cell neoplasm must be considered cured, inactive, and not under 
treatment. 
 
Unable to refrain from use of the following: 
– 
Short acting bronchodilators (SABA) within 4 hours before pulmonary function, 
DLCO, and 6MWT assessments 
– 
Once daily, long-acting bronchodilators within 24 hours before pulmonary 
function, DLCO, and 6MWT assessments 
– 
Twice daily, long-acting bronchodilators within 12 hours before pulmonary 
function testing, DLCO, and 6MWT assessments 
 
Known post-bronchodilator response in FEV1 and/or FVC  12% and  200 mL, 
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 
Receipt of an investigational drug within 4 weeks, or 5 half-lives, whichever is 
longer, prior to or during screening 
 
Previous treatment with PRM-151 
 
History of severe allergic reaction or anaphylactic reaction to a biologic agent 
including any allergies to the additives of the drug product. 
 
Clinically significant abnormality on ECG during screening that, in the opinion of the 
investigator, may pose an additional risk in administering study drug to the 
patient  
 
Prolonged corrected QT interval  450 ms (for men) or  470 ms (for women) on 
ECG during screening, based on the Fridericia correction formula 
 
Clinically significant laboratory test abnormalities during screening (hematology, 
serum chemistry, and urinalysis) that, in the opinion of the investigator, may pose an 
additional risk in administering study drug to the patient 
 
Any of the following laboratory abnormalities during screening: 
– 
ALT and/or AST   2.5  upper limit of normal (ULN)  
– 
Total bilirubin  2  ULN  
 
Pregnant or breastfeeding, or become pregnant during the study or within 8 weeks 
after the final dose of PRM-151 
Women of childbearing potential must have a negative serum pregnancy test 
result within 30 days prior to initiation of study drug. 
 
Women of childbearing potential (Only for patients enrolling in Japan) 
– 
A woman is considered to be of childbearing potential if she is postmenarchal, 
has not reached a postmenopausal state ( 12 continuous months of 
amenorrhea with no identified cause other than menopause), and is not 
permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, 
and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis). 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT AND BLINDING  
4.2.1 
Treatment Assignment 
This is a randomized, double-blind study.  After initial written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from an interactive voice or web-based 
response system (IxRS). 
Patients will be randomly assigned to one of two treatment arms:  PRM-151 or placebo.  
Randomization will occur in a 1:1 ratio through use of a permuted block randomization 
method to ensure a balanced assignment to each treatment arm and will be stratified 
as follows: 


 
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 
Concurrent use of nintedanib treatment versus pirfenidone treatment versus no 
concurrent treatment 
 
Geographic Region (China [including Hong Kong and Taiwan], North America 
[United States and Canada], Europe [including eastern Europe], Latin America, and 
Rest of World [including east Asia, Australia, and New Zealand]) 
  
4.2.2 
Blinding  
Patients and all study site personnel will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial.  These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, the independent data coordinating center 
(iDCC) and independent Data Monitoring Committee (iDMC) members. 
While PK and immunogenicity samples must be collected from patients assigned to the 
comparator arm to maintain the blinding of treatment assignment, PK and ADA assay 
results for these patients are generally not needed for the safe conduct or proper 
interpretation of the study data.  Laboratories responsible for performing study drug 
PK and ADA assays will be unblinded to patient treatment assignments to identify 
appropriate samples for analysis.  PK samples from patients assigned to the comparator 
arm will not be analyzed for study drug PK concentration except by request (e.g., to 
evaluate a possible error in dosing).  Plasma concentration (i.e., baseline, predose PK 
samples, and some longitudinal sampling) to measure the endogenous level of human 
pentraxin-2 [hPTX-2] will be analyzed from all patients and will include patients from the 
comparator arm.  Baseline immunogenicity samples will be analyzed for all patients.  
Postbaseline immunogenicity samples from patients assigned to the comparator arm will 
not be analyzed for ADAs except by request. 
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations. 
PRM-151 is a human recombinant form of a naturally occurring regulatory protein, 
and there is no known antidote to this protein in the event of a safety event.  If the 
investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  
The investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to patient unblinding, the investigator will be 
able to break the treatment code by contacting the IxRS. 


 
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As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.8) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment. 
4.3 
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN 
The investigational medicinal product (IMP) for this study is PRM-151.  Placebo is also 
considered an IMP in this study.  The non-investigational medicinal products (NIMPs) for 
this study are pirfenidone and nintedanib.  The NIMPs are considered background 
therapy for those patients already receiving either product when entering the trial and 
rescue therapy for any patient who commences treatment with either product during 
the trial. 
4.3.1 
Study Treatment Formulation and Packaging 
4.3.1.1 
PRM-151 (Zinpentraxin Alfa) 
PRM-151 Sterile Solution for Infusion is a 20 mg/mL solution of PRM-151 in 10 mM 
sodium phosphate, 5% (weight/volume [w/v]) sorbitol, and 0.01% (w/v) polysorbate 20 
with a pH of 7.5.  PRM-151 (Zinpentraxin Alfa) is supplied as a sterile concentrate in 
single use vials in clear borosilicate vials.  The solution is clear to opalescent and 
essentially particle free.  Refer to the pharmacy manual for detailed instructions on drug 
preparation, storage, and administration. 
CHO Gal-1 and CHO Gal-3 were identified in the first generation PRM-151 drug 
product.  No new safety risks or no evidence on impact of efficacy were identified.  An 
additional purification step will be applied to the second generation drug product and 
thus it will not contain detectable levels of CHO galectins.  All patients enrolling onto 
the study after 1 June 2022, and randomized to the PRM-151 treatment arm will 
receive second generation PRM-151., whereas patients who enrolled into the study 
prior to 1 June 2022, and were randomized to the PRM-151 treatment arm, will 
continue receiving first generation PRM-151 for the remainder of the study.   
4.3.1.2 
Placebo  
Placebo is a solution of 10 mM sodium phosphate, 5% (w/v) sorbitol, and 0.01% (w/v) 
polysorbate 20 with a pH of 7.5, matched to PRM-151 in total volume.   
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 


 
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4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1. 
Refer to the pharmacy manual for detailed instructions on drug preparation, storage, and 
administration. 
Details on treatment administration (e.g., dose and timing) should be noted on the 
Study Drug Administration electronic Case Report Form (eCRF).  Cases of accidental 
overdose or medication error, along with any associated adverse events, should be 
reported as described in Section 5.4.5.12. 
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.2. 
4.3.2.1 
PRM-151 and Placebo 
Patients will be randomized to receive the study drug PRM-151 or a PRM-151 matching 
placebo.  Patients randomized to study drug will receive IV infusions of 10 mg/kg 
PRM-151 over 50 to 70 minutes, with dose based on the patient’s weight taken at the 
same clinic visit (for loading or reloading doses, the weight taken at the first clinic visit for 
the first dose can be applied to the second and third doses).  Patients randomized to 
placebo will receive IV infusions of placebo over 5070 minutes.  Refer to the pharmacy 
manual for more detail. 
On all dosing days, dosing will occur after all efficacy and predose safety assessments 
scheduled for that visit are completed.  Patients will receive treatment on study Days 1, 
3, and 5, followed by infusions Q4W to Week 48.  If any infusions are missed, repeat 
loading doses will be required at the next scheduled visit (three doses administered on 
alternate days). 
Medical personnel authorized by the investigator will be responsible for the 
administration of study drug and for observation of each patient throughout the study.  
At dosing visits, vital signs should be measured predose (within 60 minutes prior to 
dosing), every 15 minutes during the infusion, and 30−60 minutes postdose.  Patients 
should be observed for 1 hour post infusion to monitor for IRRs.  Investigator, or 
designee, should assess whether any elements of the Sampson criteria were met after 
every infusion, as outlined in Appendix 5. 
In the case of occurrence of signs and symptoms consistent with IRR, follow procedures 
and medication guidelines outlined in Section 5. 


 
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If the patient is not able to adhere to the dosing schedule of any doses, the study 
Medical Monitor should be contacted.  
 
To allow for flexibility around weekends, holidays, etc., the loading dose visits may 
occur over a time span of up to 8 days, with a minimum of 1 full calendar day 
between administration of doses (patients must not be dosed on consecutive days).  
 
Loading doses must be completed within an 8-day window.  If any loading doses are 
missed or cannot be completed within the 8-day window, further doses must not be 
administered outside this period.  In such instances, the patient will be required to 
repeat the loading dose regimen at the next scheduled visit. 
 
If the patient does not receive the scheduled dose within the specified visit window 
for the Week 4 visit or beyond, a protocol deviation will be documented, and the 
patient should be dosed as soon as possible within 3 weeks of the original 
scheduled visit. 
 
If the dose is delayed by  3 weeks beyond the original scheduled visit (within 
1 week of the next scheduled dosing visit), the delayed dose is considered a missed 
dose and should not be administered.  Dosing should resume with the next dose 
(reloading of three doses, as described above) according to schedule.  
 
After a missed or delayed dose, patients should keep following the dates on the 
original dosing schedule, and visit dates should not shift, unless otherwise directed 
by the investigator or study team (additional visits to allow for reloading of three 
doses will need to be scheduled).  
 
In exceptional situations and following consultation with the Medical Monitor, if patients 
cannot attend the study site for a scheduled infusion, administration of study drug may 
be permitted in other settings (e.g., at a different investigational site).  Patient safety 
must be prioritized when utilizing off-site procedures (e.g., ensuring staff are 
appropriately qualified to deliver the infusion and are trained to monitor for and manage 
anaphylaxis and IRRs).  In such circumstances, infusion-related safety data, safety 
laboratory assessments, and PK/PD samples may also be collected off-site.  
4.3.3 
Investigational Medicinal Product Handling and Accountability 
All IMPs required for completion of this study (PRM-151 and placebo) will be provided 
by the Sponsor.  The study site (i.e., investigator or other authorized personnel 
[e.g., pharmacist]) is responsible for maintaining records of IMP delivery to the site, IMP 
inventory at the site, IMP use by each patient, and disposition or return of unused IMP, 
thus enabling reconciliation of all IMP received, and for ensuring that patients are 
provided with doses specified by the protocol. 
The study site should follow all instructions included with each shipment of IMP.  
The study site will acknowledge receipt of IMPs supplied by the Sponsor, using the 
IxRS, to confirm the shipment condition and content.  Any damaged shipments will be 
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conditions have been maintained during transit for all IMPs received and that any 
discrepancies have been reported and resolved before use of the IMPs.  All IMPs must 
be stored in a secure, environmentally controlled, and monitored (manual or automated) 
area in accordance with the labeled storage conditions, with access limited to the 
investigator and authorized staff. 
Only patients enrolled in the study may receive IMPs, and only authorized staff may 
supply or administer IMPs. 
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation.  The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor.  The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form. 
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the drug accountability log. 
Refer to the pharmacy manual and/or the PRM-151 Investigator's Brochure for 
information on IMP handling, including preparation and storage, and accountability.  
4.3.4 
Continued Access to PRM-151 
Patients may be eligible to receive PRM-151 as part of an OLE study planned by the 
Sponsor.  Eligible patients will be able to receive PRM-151 until the drug is commercially 
available in their country for IPF or the Sponsor decides to terminate the trial.  The 
Roche Global Policy on Continued Access to Investigational Medicinal Product is 
available at the following website: 
http://www.roche.com/policy continued access to investigational medicines.pdf 
4.4 
CONCOMITANT THERAPY 
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 30 days 
prior to initiation of study drug to the study completion or discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.  Additionally, all COVID-19 vaccinations received at any time in 
the past (even prior to 30 days before screening) should be recorded on the Concomitant 
Medications eCRF. 
All past anti-fibrotic therapy will be recorded in the Prior and Concurrent Anti-fibrotic 
Use form of the eCRF.   


 
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4.4.1 
Permitted Therapy  
There are no restrictions on the use of any concomitant medication required for the 
treatment of an emerging medical condition (adverse event) while a patient is enrolled in 
the trial.  In such cases, all available therapies should be provided for the optimal 
medical management of the patient, including use of systemic corticosteroids in the 
event of acute exacerbation of IPF if deemed indicated by the treating physician.  
For guidance on the use of pirfenidone or nintedanib, see Section 4.4.3.  Additionally, 
use of the following medications as part of routine care is allowed: 
• 
Chronic maintenance, low-dose oral corticosteroid use (equivalent to prednisone 
≤ 10 mg daily) is permitted.  Short-term, higher doses of corticosteroid may be 
required for acute medical emergencies (e.g., adrenal insufficiency or acute 
exacerbations of IPF) and is permitted, along with subsequent corticosteroid dose 
tapering.  Reasons for corticosteroid use should be clearly documented in the 
eCRF. 
• 
Inhaled bronchodilator agents, except for restricted use in the 12- to 24-hour period 
preceding efficacy assessment measures (see Section 4.5.6) 
• 
Initiation of or change in supplemental oxygen therapy as clinically indicated, except 
when performing the 6MWT, when oxygen usage should be maintained at the 
baseline oxygen flow rate established by the oxygen titration procedure conducted 
during screening (see Section 4.5.7) 
• 
Approved vaccinations,  including COVID-19 vaccinations  
 
4.4.2 
Prohibited Therapy 
To avoid potential interactions of therapeutic agents that may interfere with either the 
safety or efficacy assessments, use of the following medications are prohibited during 
the study: 
• 
All investigational therapies, within 4 weeks (or 5 half-lives, whichever is longer) 
before screening and during study participation 
• 
Any newly approved anti-fibrotic therapy that becomes available during the study 
• 
Short-acting bronchodilator use within 4 hours before pulmonary function, DLCO, and 
6MWT assessments 
• 
Once daily, long-acting bronchodilators within 24 hours before pulmonary function 
testing, DLCO, and 6MWT assessments 
• 
Twice daily, long-acting bronchodilators within 12 hours before pulmonary function 
testing, DLCO, and 6MWT assessment 
• 
Immune-suppressants (e.g., methotrexate, azathioprine, cyclophosphamide, 
cyclosporine, everolimus, or other immune-suppressants, including those used 
after organ transplant) within 4 weeks before baseline (Dosing Day 1) and during 
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 
High-dose corticosteroids (equivalent to prednisone  10 mg daily) unless clinically 
indicated as per Section 4.4.1. 
 
Strong inhibitors or inducers of CYP1A2 in patients taking pirfenidone 
 
Potent inhibitors or inducers of P-gp in patients taking nintedanib 
 
Combined treatment with pirfenidone and nintedanib 
 
In addition, cardiopulmonary rehabilitation programs should not be initiated during 
the study. 
4.4.3 
Use of Pirfenidone or Nintedanib 
Standard-of-care anti-fibrotic therapy (pirfenidone or nintedanib) is permitted during the 
study, if not contraindicated according to local prescribing information.  Patients must 
have been on treatment for at least 3 months and a stable dose for at least 4 weeks prior 
to and during screening, and during the study. 
For all patients receiving anti-fibrotic therapy, the investigator should document the dose 
and regimen of the anti-fibrotic drug.  For patients not receiving anti-fibrotic therapy 
during the study, the investigator should document the reason(s).  All historic and current 
use, including changes in pirfenidone or nintedanib doses and reasons for change must 
be recorded in the eCRF. 
 
Patients are expected to remain on their specific dose and regimen of nintedanib or 
pirfenidone throughout the study duration, although a patient may stop, dose 
reduce, re-start, or dose increase nintedanib or pirfenidone treatment during the 
study for safety or tolerability reasons, in accordance with local prescribing 
information.  All reasons for dose changes must be documented in the eCRF. 
 
In addition, patients may switch from nintedanib to pirfenidone (or vice versa) during 
the study if clinically indicated and if not contraindicated according to local 
prescribing information.  The investigator may consider discussing changes in 
anti-fibrotic therapy with the Medical Monitor throughout the study. 
 
If not on nintedanib or pirfenidone treatment for IPF at study entry, patients must 
have been off treatment for a minimum of 4 weeks before Screening or been 
treatment naive (i.e., never taken the medications).  During the study, patients may 
initiate (naive users) or re-start (prior users) nintedanib or pirfenidone, as rescue, if 
determined to be clinically indicated by the investigator upon follow-up examination 
performed after the Baseline Dosing visit (Day 1), providing there are no 
contraindications according to local prescribing information.  The investigator may 
consider discussing changes in anti-fibrotic therapy with the Medical Monitor 
throughout the study.  Patients who start rescue therapy will be encouraged to 
remain in the study and continue study treatment. 
 
Combination use of pirfenidone and nintedanib is not allowed in the study.  
 


 
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4.5 
STUDY ASSESSMENTS  
The schedules of activities to be performed during the study are provided in Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4.  All activities should be performed and 
documented for each patient. 
Patients will be closely monitored for safety and tolerability throughout the study.  
Patients should be assessed for toxicity prior to each dose; dosing will occur only if the 
clinical assessment and laboratory test values from the previous visit are acceptable. 
4.5.1 
Informed Consent Forms and Screening Log 
Written informed consent for participation in the study must be obtained before 
performing any study-related procedures (including screening evaluations).  Informed 
Consent Forms for enrolled patients and for patients who are not subsequently enrolled 
will be maintained at the study site. 
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  At screening, each patient will be assessed for 
eligibility against the study entrance criteria (Section 4.1).  Screening assessments may 
be performed during one visit or over multiple days during this 4-week period, and 
consideration should be given to the sequence of conducting the screening evaluations, 
with less invasive testing performed first (e.g., medical history review, central laboratory 
tests), followed by more involved testing (e.g., 6MWD, chest HRCT).  From baseline or 
dosing day 1 onwards, the sequence of assessments should be followed as per Table 2.  
Prior to any invasive testing, the site should verify that the historic HRCT scans (if not 
planned to be conducted during screening) and LB (if applicable) have been conducted 
and will be able to be retrieved at the start of the screening period in order to be sent for 
central review.  Site should make sure that test conditions for each test are optimal at 
time of testing.  Patients who do not meet the study entrance criteria will not be allowed 
to participate in the study.  However, for select reasons, patients who do not meet the 
criteria for participation may be eligible for rescreening once.  The reason(s) for the 
patient’s ineligibility for the study will be documented in a site screening log.  Once 
a patient has met all eligibility criteria, they can be randomized immediately (i.e., they do 
not need to wait for the 4-week screening period).  No baseline assessments or 
procedures should be performed until randomization has taken place. 
4.5.2 
Sequence of Assessments 
On dosing days, dosing will occur after all safety and efficacy assessments scheduled 
for that visit are complete.  Assessments should be completed as shown in Table 2.  For 
loading or reloading doses, scheduled efficacy assessments will only be performed on 
the first of the three loading dose days. 


 
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Table 2 
Sequence of Assessments 
 
Sequence 
Assessments 
1 
 
Patient-reported outcomes (PRO) (in following order): 
– 
SGRQ 
– 
UCSD-SOBQ 
– 
EQ-5D-5L 
2 
 
Medical history, review of concomitant medications, vital 
signs, physical examination, and ECG  
3 
 
Pulmonary function tests (in following order): 
– 
Spirometry 
– 
DLCO 
30-60 minute break  
– 
6MWT 
4 
 
HRCT  (when completed on same day as other 
assessments) a 
5 
 
Laboratory samples 
6 
 
Study drug administration b 
7 
 
Post-infusion laboratory samples (see 
Appendix 2Appendix 4) 
6MWT  6-minute walk test; DLCO  diffusing capacity for carbon monoxide; 
eCRF  electronic Case Report Form; EQ-5D-5L  EuroQol 5-Dimension, 5-Level 
Questionnaire; HRCT  high-resolution computed tomography; OLE  open-label 
extension; SGRQ  St. George Respiratory Questionnaire; 
UCSD-SOBQ  University of California, San DiegoShortness of Breath 
Questionnaire. 
a Performed at week 52 for patients who had a HRCT scan as part of screening. 
In order to allow flexibility in scheduling, the HRCT can be performed at an 
earlier time on a different day.  For patients participating in the OLE study, the 
Week 52 HRCT should be performed before any dosing in the OLE study.  
Efficacy measurements should be collected as outlined in the schedule of 
activities. 
b In exceptional circumstances, if the site is unable to perform all study 
assessments on the same day or at the same site, study drug infusion may be 
administered up to 48 hours after the on-site efficacy assessments, provided 
that these are completed within the 5-day visit window.  However, the 
sequence of assessments must be maintained, and all efforts should be made 
to complete study assessments on the same date. 
 
4.5.3 
Medical History, Baseline Conditions, Concomitant Medication, 
and Demographic Data 
Medical history, including number of years since IPF diagnosis, family history of IPF, 
clinically significant diseases, surgeries, cancer history (including prior cancer therapies 
and procedures), reproductive status, smoking history, and alcohol and substance use, 


 
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that occurred prior to time of first dose of study drug should be reported as medical 
history on the General History and Baseline Conditions eCRF, including:  
 
Pulmonary hypertension 
 
Chronic obstructive pulmonary disease (COPD)/Emphysema 
 
Lung cancer 
 
Obstructive sleep apnea  
 
Pulmonary embolism 
 
Respiratory infections (including tuberculosis ) 
 
Cardiovascular disease and risk factors, including arrhythmias, cardiac failure or 
congestive heart failure, ischemic heart disease, cerebrovascular disease and 
stroke, peripheral artery disease systemic arterial hypertension, 
hypercholesterolemia/hyperlipidemia,  
 
Participation in supervised pulmonary or cardiac rehabilitation programs  
 
Past surgical history  
 
All medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the patient within 30 days prior 
to initiation of study treatment will be recorded on the Concomitant Medications eCRF. 
At the time of each follow-up physical examination, an interval medical history should be 
obtained and any changes in medications and allergies should be recorded.  History of 
anti-fibrotic therapy should also be documented since IPF was diagnosed 
(i.e., pirfenidone and nintedanib treatment, dose, duration of therapy, reasons for 
discontinuation, if applicable).  Additionally, history of all COVID-19 vaccinations 
received in the past should be documented. 
Patient demographic information including age, sex, and self-reported race/ethnicity will 
be recorded in the screening period for all patients, where allowed per local regulations. 
4.5.4 
Physical Examinations 
A complete physical examination, performed during screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, and 
neurologic systems.  Any abnormality identified at baseline should be recorded on the 
General Medical History and Baseline Conditions eCRF. 
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  New or worsened clinically significant 
abnormalities should be recorded as adverse events on the Adverse Event eCRF. 
Height will be recorded during screening for all patients.  Weight will be recorded at each 
dosing visit (except for the second and third loading doses). 


 
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4.5.5 
Vital Signs 
Vital signs will include measurements of respiratory rate, pulse rate, systolic and 
diastolic blood pressure while the patient is in a seated position, oxygen saturations, and 
temperature.  Record abnormalities observed at baseline on the General Medical History 
and Baseline Conditions eCRF.  At subsequent visits, record new or worsened clinically 
significant abnormalities on the Adverse Event eCRF. 
At dosing visits, vital signs should be measured predose (within 60 minutes prior to 
dosing), every 15 minutes during the infusion, and 3060 minutes postdose. 
4.5.6 
Pulmonary Function Tests 
Standardized spirometry equipment and procedure guidelines will be provided to all 
study sites.  As some PFTs are considered aerosol-generating procedures, additional 
precautions to reduce potential spread of infection should be taken in accordance with 
local guidance.  Spirometry will be performed according to ATS/ERS guidelines (as 
referenced in the PFT manual) as per the schedule of activities (see Appendix 1).  
Details on PFT procedures are available in the PFT manual.  PFT data will be sent for 
central review.  
DLCO will be measured according to ATS/ERS guidelines (as referenced in the 
PFT manual).  DLCO will be performed using local equipment as this will not be 
provided by the Sponsor to study sites. 
Acceptability of the spirometry and DLCO data from the computerized system (including 
screening assessments) will be determined by over-readers blinded to study drug 
treatment (comprising graphic representations of the maneuvers as well as numerical 
results).  Calculations for the reproducibility of the acceptable maneuvers will be 
performed and reviewed centrally by over-readers blinded to study drug treatment.  
Only data from acceptable over-read spirometry and DLCO maneuvers will be used for 
eligibility confirmation and data analysis. 
The screening spirometry and/or DLCO sessions may be repeated once, if the initial 
session is rejected by the over-reader.  This is the only session during the study that 
may be repeated.  In extenuating circumstances, one further spirometry and/or DLCO 
session may be attempted after discussion with the Medical Monitor.  No more than 
three spirometry and/or DLCO sessions should be performed during the screening 
period.  Repeat sessions are only permitted following rejection of previous sessions by 
the over-reader. 
On visits at which spirometry and DLCO are to be performed spirometry should be 
performed first, followed by DLCO, and then 6MWT.  


 
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Inhaled bronchodilator use in the 12- to 24-hour period prior to PFTs and the 6MWT 
is restricted: 
 
Short-acting bronchodilator should not be used within 4 hours before pulmonary 
function, DLCO, and 6MWT assessments. 
 
Once daily, long-acting bronchodilators should not be used within 24 hours before 
pulmonary function testing, DLCO, and 6MWT assessments. 
 
Twice daily, long-acting bronchodilators should not be used within 12 hours before 
pulmonary function testing, DLCO, and 6MWT assessments. 
 
4.5.7 
Six-Minute Walk Test 
Conduct of the 6MWT will be carefully defined and controlled according to the criteria 
defined and validated by du Bois et al. (2011), with additional control measures 
suggested in the ERS/ATS Guideline for field walking tests (Holland et al. 2014): 
 
The test will be performed indoors on a flat, straight corridor with a hard surface at 
least 30 m in length.  
 
An oxygen titration procedure will be performed at the Screening for patients who 
require supplemental oxygen during the 6MWT (up to 6 L/min of oxygen at sea 
level, and up to 8 L/min at altitude [5000 ft]) to establish a baseline flow rate.  The 
oxygen titration procedure should be conducted as per local standard practice.  
 
Before each 6MWT, patients will be required to have resting oxygen saturation as 
measured by pulse oximetry of at least 89% after 10 minutes of rest breathing room 
air, or at the baseline oxygen flow rate as established during the titration procedure.  
 
Patients will be instructed to walk as far as they can without jogging or running; if 
they need to slow down or stop to rest, they will be permitted to do so and 
encouraged to resume walking as soon as they are able.  
 
The test will be stopped if the patient experiences chest pain, intolerable dyspnea, 
leg cramps, diaphoresis, or desaturation below 83% for at least 10 seconds.  
 
The pre-test conditions for oxygen use will be maintained throughout the study as 
much as possible, as noted at the Day 1 visit prior to first dose. 
 
As previously described, the 6MWT assessment should be performed after completion 
of PRO questionnaires and after PFTs, allowing for a short recovery period from 
the PFTs.  In the rare instance that it is not possible to complete the 6MWT last, allow 
a 30-60 minute recovery time before continuing with the next efficacy assessment.   
A procedure manual and training video (video instructions) detailing the testing method 
recommended by the ATS and the European Respiratory Society (ATS 2002; 
Holland et al. 2014) for the 6MWT will be provided separately.  These materials will 
include detailed instructions for standardized execution of the 6MWT, and describe 
the equipment and personnel required to conduct the assessment as well as the 
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The Borg Scale of Perceived Exertion (Appendix 11) will be assessed just prior to and 
immediately following the completion of the 6MWT.   
4.5.8 
High-Resolution Computed Tomography 
Pulmonary HRCT scans will be reviewed during screening to confirm the IPF diagnosis.  
Good-quality standard of care scans obtained  12 months prior to screening and in 
accordance with study image acquisition guidelines can be used for eligibility 
determination.  If a HRCT scan meeting the image acquisition guidelines is not 
available, a new HRCT scan should be obtained during screening. HRCT scans will be 
reviewed first by the site radiologist and/or investigator to assess for eligibility.  If the site 
determines that the patient’s HRCT meets IPF diagnostic criteria as specified in 
Appendix 10, the HRCT scans will be sent for central review to confirm eligibility.  The 
blinded central review radiologists will evaluate screening images in accordance with the 
2018 IPF Clinical Practice Guidelines by ATS, the ERS, JRS, and the ALAT (Raghu et 
al. 2018), and determine the extent of emphysema on the scan, if present.  Final eligibility 
will be determined by the central review assessments, inclusive of lung biopsy, if 
available. 
Randomized patients who undergo protocol-specified HRCT scan during screening will 
undergo repeat imaging at the Week 52 visit.   
4.5.9 
Lung Biopsy 
Lung biopsies are not required for eligibility into the study and are not required during 
the study.  Patients who have undergone a lung biopsy (including cryobiopsy) to support 
the diagnosis of IPF, should have the relevant slides sent for central review assessment 
to confirm eligibility in accordance with the ATS/ERS/JRS/ALAT IPF Clinical Practice 
Guideline (Raghu et al. 2018).  The central review pathologists will evaluate submitted 
slides for UIP pattern.  The histopathologic assessment criteria are outlined in Appendix 
10. 
4.5.10 
Assessment of Acute Exacerbations of IPF, Hospitalizations 
for Respiratory Causes, and Deaths (Adjudicated Events) 
An independent, blinded Clinical Adjudication Committee will be convened to review all 
available data for all potential cases of acute exacerbations of IPF, hospitalizations for 
respiratory causes, and all deaths.  This Clinical Adjudication Committee will be 
comprised of pulmonary disease physicians familiar with IPF exacerbations.  A charter 
for the Clinical Adjudication Committee will provide further details.  The Clinical 
Adjudication Committee will determine if the reported events meet the criteria of acute 
exacerbation of IPF, hospitalization for respiratory causes, and deaths (including deaths 
related specifically to respiratory causes) as defined in the charter. 


 
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4.5.10.1 
Acute Exacerbations of IPF and Suspected Acute 
Exacerbations of IPF 
Acute exacerbation of IPF is defined as an acute, clinically significant respiratory 
deterioration characterized by evidence of new widespread alveolar abnormality, marked 
by the following diagnostic criteria (Collard et al. 2016): 
 
Previous or concurrent diagnosis of IPF 
 
Acute worsening or development of dyspnea typically  30 days in duration 
 
Computed tomography with new bilateral ground-glass opacity and/or 
consolidation superimposed on a background pattern consistent with usual 
interstitial pneumonia pattern 
 
Deterioration not fully explained by cardiac failure or fluid overload 
 
Acute exacerbations of IPF are further categorized as triggered acute exacerbation or 
idiopathic acute exacerbation, depending on whether an underlying trigger for acute 
exacerbation is found (e.g., infection, post-procedural/postoperative, drug toxicity, 
aspiration). 
Events that are clinically considered to meet the definition of acute exacerbation of IPF 
but fail to meet all four diagnostic criteria owing to missing computed tomography data 
are termed "suspected acute exacerbations of IPF." 
At each study visit, the investigator will ask directed questions and review the patient file 
to assess the possibility that the patient experienced an acute IPF exacerbation since 
the preceding study visit.  An acute IPF exacerbation should be reported as an adverse 
event of special interest (see Section 5.3.3) (or serious adverse event as applicable). 
All relevant adverse event data (summary on clinical course, signs and symptoms; 
laboratory, lung function and imaging results; and treatment provided, including 
hospitalizations) relating to the exacerbation must be collected and entered onto the 
adverse event form.  A charter for the Clinical Adjudication Committee describes the 
process for the data to be reviewed and criteria for defining an IPF exacerbation. 
4.5.10.2 
Hospitalizations for Respiratory Causes 
Hospitalizations for respiratory causes are defined as non-elective hospitalizations due 
to any respiratory cause, including acute exacerbations of IPF, or suspected acute 
exacerbations of IPF.  All investigator-reported hospitalizations for respiratory causes will 
be assessed by an independent Clinical Adjudication Committee, as described in the 
charter. 
4.5.10.3 
Deaths Due to Respiratory Causes 
All deaths occurring during the study must be recorded.  The event or condition that 
caused or contributed to the fatal outcome should be recorded as a single medical 
concept on the Adverse Event eCRF. 


 
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All investigator-reported deaths will be assessed by an independent Clinical 
Adjudication Committee to determine whether each death was related to IPF, another 
respiratory cause, or an alternative (non-respiratory and non-IPF) cause. 
4.5.11 
Health Care Utilization for Respiratory Events 
The following events will be recorded as health care utilization for respiratory events: 
• 
Unscheduled visits to a healthcare professional/clinic for any respiratory event 
• 
Urgent care or emergency room visits for respiratory events  
• 
Hospitalization days for a respiratory cause, including for exacerbation of respiratory 
symptoms 
• 
During hospitalization, any stay in ICU, including ICU days 
 
4.5.12 
Laboratory, Biomarker, and Other Biological Samples   
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis: 
• 
Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, and 
differential count (lymphocytes, eosinophils, neutrophils, monocytes, basophils) 
• 
Serum chemistries and liver function tests (LFTs):  chloride, potassium, BUN, 
creatinine, albumin, AST, total bilirubin, sodium, bicarbonate (CO2), calcium, 
glucose, ALK, ALT, total protein, C-reactive protein (CRP), eGFR 
• 
Coagulation tests:  PT, PTT, INR 
• 
Pregnancy test (Excluding patients enrolled in Japan) 
• 
All women of childbearing potential will have a serum pregnancy test during 
screening.  Urine pregnancy tests will be performed at specified subsequent visits.  
If a urine pregnancy test is positive, it must be confirmed by a serum pregnancy test.  
Urinalysis, including dipstick (pH, specific gravity, glucose, protein, ketones, blood) 
and microscopic examination (sediment, RBCs, WBCs, casts, crystals, epithelial 
cells, bacteria) 
• 
SARS-CoV-2 serology testing (IgM, IgG) 
• 
Tuberculosis test:  interferon gamma release assay 
Patients who have completed treatment for active or latent tuberculosis within 
6 months prior to screening, and have no evidence of recurrent disease, do not 
need to be tested 
 
In exceptional situations, upon Sponsor approval, laboratory samples may be collected 
off-site. 
The following samples will be sent to one or several central laboratories or to the 
Sponsor or a designee for analysis: 
• 
Serum sample for ADA analysis 


 
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• 
Serum sample for tryptase and complement C3 in case of ≥ Grade 2 IRRs or 
suspected anaphylaxis or hypersensitivity reactions 
• 
PRM-151 plasma sample for PK analyses 
Blood samples for determination of PRM-151 concentration are to be collected 
from all IPF patients for PK measurements (see Appendix 2), patients enrolled 
in China and Hong Kong and Taiwan (see Appendix 3), and all patients 
enrolled in Japan (see Appendix 4).   
• 
Serum and plasma samples for biomarker analysis 
• 
Blood PAXgene for RNA biomarker analysis 
PAXgene for RNA biomarker analysis is not applicable for Chinese patients 
enrolled in mainland China.  
Circulating blood biomarkers that may provide information on the course of fibrosis will 
be collected. The IPF-related biomarkers that will be investigated may include, but are 
not limited to, CCL18, osteopontin, CXCL13, periostin, and COMP.  Longitudinal 
samples will be used to assess IPF-related biomarker changes over time.  Screening 
and baseline samples will be used to assess the relationship of IPF-related biomarkers 
with clinical status, disease progression, and treatment benefit.  If novel PTX-2 or 
IPF-related biomarkers are identified, they may be measured from stored blood, serum, 
or plasma.   
Exploratory biomarker research may include, but will not be limited to MUC5B and 
telomere length measurement.  Research may involve extraction of DNA, cell-free DNA, 
or RNA; analysis of mutations, single nucleotide polymorphisms, and other genomic 
variants; and genomic profiling through use of next-generation sequencing (NGS) of 
a comprehensive panel of genes.  Genomic research will be aimed at exploring inherited 
characteristics.  NGS methods may include whole genome sequencing (WGS) or whole 
exome sequencing (WES) of blood samples, but only at participating sites 
(see Section 4.5.15). 
Screening blood samples, including those collected from patients who do not enroll in 
the study, may be used for future research and/or development of disease-related tests 
or tools. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual. 
Unless the patient gives specific consent for his or her leftover samples to be stored for 
optional exploratory research (see Section 4.5.16), biological samples will be destroyed 


 
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no later than the time of completion of the final Clinical Study Report, with the following 
exceptions: 
 
PK or immunogenicity analysis may be needed for additional immunogenicity 
characterization and for PK or immunogenicity assay development and validation; 
PK and ADA samples collected for study-related analyses will be stored for up to 
5 years after the final study results have been reported. 
 
Blood and other samples collected for biomarker research and biomarker assay 
development will be destroyed no later than 5 years after the final Clinical Study 
Report has been completed, unless the patient consents optionally to have leftover 
samples retained as part of the Research Biosample Repository (RBR; see 
Section 4.5.16).  However, the storage period will be in accordance with the 
Institutional Review Board/Ethics Committee (IRB/EC)-approved Informed Consent 
Form and applicable laws (e.g., health authority requirements). 
 
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data. 
Data arising from sample analysis, including data on genomic variants, will be subject to 
the confidentiality standards described in Section 8.4. 
Given the complexity and exploratory nature of exploratory biomarker analyses, the 
results are extremely unlikely to impact any clinical decision making, and data derived 
from these analyses will generally not be provided to study investigators or patients 
unless required by law.  The aggregate results of any conducted research will be 
available in accordance with the effective Sponsor policy on study data publication. 
4.5.13 
Electrocardiograms 
ECG will be collected prior to study drug dosing at selected visits (see Appendix 1).  
Apart from the scheduled assessment, ECG may also be collected in the event of an 
IRR as soon as possible after stabilization of the patient. 
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
ECGs for each patient should be obtained from the same machine whenever possible 
to minimize variability.  Lead placement should be as consistent as possible.  ECG 
recordings must be performed after the patient has been resting in a supine position for 
at least 10 minutes.  Scheduled ECGs are to be obtained prior to other procedures 
scheduled at that same time (e.g., vital sign measurements, blood draws).  
Circumstances that may induce changes in heart rate, including environmental 
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resting period and during ECG recording.  For safety monitoring purposes, the 
investigator must review, sign, and date all ECG tracings.   
Paper copies of ECG tracings will be kept as part of the patient's permanent study file at 
the site.  De-identified copies of all ECGs will be electronically transmitted or mailed for 
storage centrally at a designated contract research organization (CRO).   
Clinically significant ECG abnormalities should be reported as adverse events.  
If considered appropriate by the Sponsor, ECGs may be analyzed retrospectively at 
a central laboratory. 
4.5.14 
Clinical Outcome Assessments  
PRO instruments will be completed to assess the treatment benefit and patient 
experience of PRM-151.  PRO data will be collected through use of the following 
instruments:  SGRQ, UCSD-SOBQ, and EQ-5D-5L (assessed in that order). 
4.5.14.1 
Data Collection Methods for Clinical Outcome Assessments 
PRO instruments will be self-administered at the clinic at specified timepoints during the 
study (see schedule of activities in Appendix 1).  At the clinic, instruments will be 
administered before the patient receives any information on disease status, prior to the 
performance of non‑PRO assessments, and prior to the administration of study 
treatment, unless otherwise specified. 
PRO instruments, translated into the local language as appropriate, will be completed 
through use of an electronic device provided by the Sponsor.  The device will be 
pre‑programmed to enable the appropriate instruments to be administered in the correct 
order at each specified timepoint.  The electronic device and instructions for completing 
the instruments electronically will be provided by the site staff.  The data will be 
transmitted to a centralized database maintained by the electronic device vendor.  
The data will be available for access by appropriate study personnel.  
During clinic visits, instruments should be administered as outlined below: 
 
Patients' health status should not be discussed prior to administration of the 
instruments. 
 
Sites must administer the official version of each instrument, as provided by the 
Sponsor.  Instruments must not be copied from the protocol. 
 
Sites should allow sufficient time for patients to complete the instruments. 
 
Sites should administer the instruments in a quiet area with minimal distractions and 
disruptions. 
 
Patients should be instructed to answer questions to the best of their ability; there 
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 
Site staff should not interpret or explain questions, but may read questions verbatim 
upon request. 
 
Patients should not obtain advice or help from others (e.g., family members or 
friends) when completing the instruments. 
 
4.5.14.2 
Description of Clinical Outcome Assessment Instruments 
St. George’s Respiratory Questionnaire  
The SGRQ is a 50-item respiratory-specific quality-of-life questionnaire initially 
developed and validated for use in COPD (Jones et al. 1992; see Appendix 6).  
It includes questions that assess the impact of disease on symptoms, activity, and 
functionality.  The symptom scale assesses the severity of respiratory symptoms, the 
activity scale examines impairment in patient activity as a result of respiratory symptoms, 
and the impact scale evaluates effects of respiratory symptoms on overall function and 
well-being.  Each scale is scored from 0 to 100, and a total score represents the 
weighted average of these three subscores.  Items are assessed on various response 
scales, including a 5-point Likert scale and a true/false scale.  The SGRQ has a recall 
period of the past 4 weeks. 
University of California, San Diego–Shortness of Breath Questionnaire 
The UCSD-SOBQ is a 24-item questionnaire used to assess dyspnea severity during 
specific activities (21 items) and limitations caused by dyspnea in daily life (4 items) (See 
Appendix 7).  Items are assessed using a 6-point Likert scale and summed to produce 
a total score ranging from 0–120, with higher scores reflecting greater dyspnea severity.  
Respondents are asked to provide their answers based on an average day during the 
past week. 
EuroQol 5-Dimension Questionnaire, 5-Level Version 
The EQ-5D-5L is a validated self-report health status questionnaire that is used to 
calculate a health status utility score for use in health economic analyses (EuroQol 
Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013) (see Appendix 8).  
There are two components to the EQ-5D-5L:  a five-item health state profile that 
assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as 
well as a VAS that measures health state.  The EQ-5D-5L is designed to capture the 
patient's current health status.  Published weighting systems allow for creation of 
a single composite score of the patient's health status.  
4.5.15 
Blood Samples for Whole Genome Sequencing or Whole 
Exome Sequencing (Patients at Participating Sites)  
At participating sites, blood samples will be collected for DNA extraction to enable 
telomere length measurements and WGS or WES to identify variants that are predictive 
of response to study drug, are associated with progression to a more severe disease 
state, are associated with susceptibility to developing adverse events, can lead to 
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and understanding of disease biology and drug safety.  Research will be aimed at 
exploring inherited characteristics.  The samples may be sent to one or more 
laboratories for analysis. 
Collection and submission of blood samples for WGS or WES is contingent upon the 
review and approval of the exploratory research by each site's IRB/EC and, if applicable, 
an appropriate regulatory body.  If a site has not been granted approval for WGS or 
WES, this section of the protocol (Section 4.5.15) will not be applicable at that site. 
Genomics is increasingly informing researcher's understanding of disease pathobiology.  
WGS and WES provide a comprehensive characterization of the genome and exome, 
respectively, and, along with clinical data collected in this study, may increase the 
opportunity for developing new therapeutic approaches or new methods for monitoring 
efficacy and safety or predicting which patients are more likely to respond to a drug or 
develop adverse events.  Data will be analyzed in the context of this study but may also 
be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
Blood samples collected for WGS or WES are to be stored until they are no longer 
needed or until they are exhausted.  However, the storage period will be in accordance 
with the IRB/EC-approved Informed Consent Form and applicable laws (e.g., health 
authority requirements). 
No sites in mainland China will participate in this sample/data collection.  
Refer to Section 4.5.12 for details on use of samples after patient withdrawal, 
confidentiality standards for data, and availability of data from biomarker analyses. 
4.5.16 
Optional Samples for Research Biosample Repository 
4.5.16.1 
Overview of the Research Biosample Repository 
The RBR is a centrally administered group of facilities used for the long-term storage of 
human biological specimens, including body fluids, solid tissues, and derivatives thereof 
(e.g., DNA, RNA, proteins, peptides).  The collection, storage, and analysis of RBR 
samples will facilitate the rational design of new pharmaceutical agents and the 
development of diagnostic tests, which may allow for individualized drug therapy for 
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Samples for the RBR will be collected from patients who give specific consent to 
participate in this optional research.  RBR samples will be analyzed to achieve one or 
more of the following objectives: 
 
To study the association of biomarkers with efficacy or disease progression 
 
To identify safety biomarkers that are associated with susceptibility to developing 
adverse events or can lead to improved adverse event monitoring or investigation 
 
To increase knowledge and understanding of disease biology and drug safety 
 
To study drug response, including drug effects and the processes of drug absorption 
and disposition 
 
To develop biomarker or diagnostic assays and establish the performance 
characteristics of these assays 
 
4.5.16.2 
Approval by the Institutional Review Board or Ethics 
Committee 
Collection, storage, and analysis of RBR samples is contingent upon the review and 
approval of the exploratory research and the RBR portion of the Informed Consent Form 
by each site's IRB/EC and, if applicable, an appropriate regulatory body.  If a site has not 
been granted approval for RBR sampling, this section of the protocol (Section 4.5.16) 
will not be applicable at that site. 
4.5.16.3 
Sample Collection 
The following samples will be stored in the RBR and used for research purposes, 
including, but not limited to, research on biomarkers related to PTX-2 or PRM-151, 
diseases, or drug safety: 
 
Peripheral blood mononuclear cell (PBMC) samples collected during screening and 
12 hours postdose on Days 1 and 5, and on Weeks 4 and 12 
 
Urine samples collected per Appendix 2 and Appendix 4. 
 
Leftover blood, serum, plasma, urine, and PBMC samples and any derivatives 
thereof (e.g., DNA, RNA, proteins, peptides) 
 
An optional DNA sample will be collected once at any visit if site declines 
participating in the collection of blood samples for WGS and WES.  
 
The above samples may be sent to one or more laboratories for analysis of germline or 
somatic variants via WGS, WES, or other genomic analysis methods, including telomere 
length measurements.  Genomics is increasingly informing researcher's understanding 
of disease pathobiology.  WGS and WES provide a comprehensive characterization of 
the genome and exome, respectively, and, along with clinical data collected in this study, 
may increase the opportunity for developing new therapeutic approaches or new 
methods for monitoring efficacy and safety or predicting which patients are more likely to 
respond to a drug or develop adverse events. 


 
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Data generated from RBR samples will be analyzed in the context of this study but may 
also be explored in aggregate with data from other studies.  The availability of a larger 
dataset will assist in identification and characterization of important biomarkers and 
pathways to support future drug development. 
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.   
RBR samples are to be stored until they are no longer needed or until they 
are exhausted.  However, the RBR storage period will be in accordance with the 
IRB/EC-approved Informed Consent Form and applicable laws (e.g., health authority 
requirements). 
RBR samples will not be collected from Chinese patients that are enrolled in the study 
(both in the global and extended China enrollment phases) in mainland China. 
4.5.16.4 
Confidentiality 
RBR samples and associated data will be labeled with a unique patient identification 
number. 
Patient medical information associated with RBR samples is confidential and may be 
disclosed to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Given the complexity and exploratory nature of the analyses of RBR samples, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 
be available in accordance with the effective Sponsor policy on study data publication. 
Data generated from RBR samples must be available for inspection upon request by 
representatives of national and local health authorities, and Sponsor monitors, 
representatives, and collaborators, as appropriate. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of the RBR data will become and remain the exclusive and unburdened property 
of the Sponsor, except where agreed otherwise. 
4.5.16.5 
Consent to Participate in the Research Biosample Repository 
The Informed Consent Form will contain a separate section that addresses participation 
in the RBR.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential hazards of participation in the RBR.  Patients will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
and for any reason during the storage period.  A separate, specific signature will be 


 
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required to document a patient's agreement to provide optional RBR samples.  Patients 
who decline to participate will not provide a separate signature. 
The investigator should document whether or not the patient has given consent to 
participate and (if applicable) the date(s) of consent, by completing the RBR Research 
Sample Informed Consent eCRF. 
In the event of an RBR participant's death or loss of competence, the participant's 
samples and data will continue to be used as part of the RBR research. 
4.5.16.6 
Withdrawal from the Research Biosample Repository 
Patients who give consent to provide RBR samples have the right to withdraw their 
consent at any time for any reason.  After withdrawal of consent, any remaining samples 
will be destroyed.  However, if RBR samples have been tested prior to withdrawal of 
consent, results from those tests will remain as part of the overall research data.  If 
a patient wishes to withdraw consent to the testing of his or her RBR samples during the 
study, the investigator must inform the Medical Monitor in writing of the patient's wishes 
through use of the appropriate RBR Subject Withdrawal Form and must enter the date of 
withdrawal on the RBR Research Sample Withdrawal of Informed Consent eCRF.  If 
a patient wishes to withdraw consent to the testing of his or her RBR samples after 
closure of the site, the investigator must inform the Sponsor by emailing the study 
number and patient number to the following email address: 
global rcr-withdrawal@roche.com 
A patient's withdrawal from this study does not, by itself, constitute withdrawal of consent 
for testing of RBR samples.  Likewise, a patient's withdrawal of consent for testing of 
RBR samples does not constitute withdrawal from this study. 
4.5.16.7 
Monitoring and Oversight 
RBR samples will be tracked in a manner consistent with Good Clinical Practice by 
a quality-controlled, auditable, and appropriately validated laboratory information 
management system, to ensure compliance with data confidentiality as well as 
adherence to authorized use of samples as specified in this protocol and in the Informed 
Consent Form.  Sponsor monitors and auditors will have direct access to appropriate 
parts of records relating to patient participation in the RBR for the purposes of verifying 
the data provided to the Sponsor.  The site will permit monitoring, audits, IRB/EC review, 
and health authority inspections by providing direct access to source data and 
documents related to the RBR samples. 


 
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4.6 
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION 
It should be noted that study treatment discontinuation and patient discontinuation 
from the study are managed differently, as follows: 
 
Patients who discontinue study treatment will continue with study visits and 
assessments (without continuing to receive study drug treatment) 
 
Patients who discontinue from the study will be invited to enroll in the OLE study 
for long-term follow-up of survival data, if they do not wish to continue with study 
drug treatment and other assessments and visits. 
 
4.6.1 
Study Treatment Discontinuation 
Patients must permanently discontinue study treatment if they experience any of 
the following: 
 
Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient's safety if he or she continues to receive study treatment 
 
Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient 
 
Pregnancy 
 
Anaphylaxis or serious hypersensitivity reaction 
 
Grade 4 IRR or two Grade 3 IRRs 
 
Lung transplant 
 
The primary reason for study treatment discontinuation should be documented on 
the appropriate eCRF.  Patients who discontinue study treatment prematurely will not 
be replaced. 
If a patient discontinues study drug treatment prematurely for any reason, the patient will 
be encouraged to complete all planned study visits and assessments (except for IMP 
administration) through to Week 52.  If unable to return for the remaining protocol visits 
through to week 52, patients will return to the clinic for a treatment discontinuation visit 
4 weeks after the final dose of study drug (see Appendix 1 for additional details).  Every 
effort should be made to collect spirometry, 6MWD, safety, and survival data at the time 
of the Week 52 or treatment discontinuation visit. 
4.6.2 
Patient Discontinuation from the Study 
Patients will return to the clinic for a study completion or study discontinuation (end of 
study [see week 56 of Appendix 1]) visit 4 weeks after the treatment completion or 
treatment discontinuation visit (8 weeks after the final dose of study treatment).  
Patients have the right to voluntarily withdraw from the study at any time for any reason.  
In addition, the investigator has the right to withdraw a patient from the study at any time. 


 
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Reasons for patient discontinuation from the study may include, but are not limited to, 
the following: 
 
Patient withdrawal of consent 
 
Study termination or site closure 
 
Adverse event 
 
Loss to follow-up 
 
Every effort should be made to obtain a reason for patient discontinuation from the 
study.  The primary reason for discontinuation from the study should be documented on 
the appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator.  Patients 
who withdraw from the study will not be replaced. 
Patients will be invited to enroll in the OLE study for long-term follow-up of survival data 
if the patient does not wish to continue with study treatments or other assessments and 
visits. 
4.6.3 
Study Discontinuation 
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following: 
 
The incidence or severity of adverse events in this or other studies indicates 
a potential health hazard to patients 
 
Patient enrollment is unsatisfactory 
 
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.   
4.6.4 
Site Discontinuation 
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following: 
 
Excessively slow recruitment 
 
Poor protocol adherence 
 
Inaccurate or incomplete data recording 
 
Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice 
 
No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled) 
 
5. 
ASSESSMENT OF SAFETY  
PRM-151 is not approved, and clinical development is ongoing.  The safety plan for 
patients in this study is based on clinical experience with PRM-151 in completed and 


 
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ongoing studies.  The anticipated important safety risks for PRM-151 are outlined below.  
Please refer to the PRM-151 Investigator's Brochure for detailed safety information.  
Several measures will be taken to ensure the safety of patients participating in this 
study.  Eligibility criteria have been designed to exclude patients at higher risk for 
toxicities.  Patients will undergo safety monitoring during the study, including 
assessment of the nature, frequency, and severity of adverse events.  In addition, 
guidelines for managing adverse events, including criteria treatment interruption or 
discontinuation, are provided below. 
If patients have been prescribed pirfenidone or nintedanib, this should comply with local 
prescribing information.  Patients should adhere to the instructions and 
recommendations stated in the respective local labels.  Investigators should consult local 
prescribing information for management of adverse events, including guidance on dose 
reductions and discontinuation of these treatments. 
In exceptional circumstances, if patients cannot attend a study site for a scheduled visit, 
patients should be followed up ideally by telephone around the time of the scheduled 
visit to collect information on any adverse events and changes to concomitant 
medications. 
Pandemic Preparedness 
Patients with active infection are excluded from study participation.  In the setting of 
a pandemic or epidemic, screening for infections prior to and during study participation 
should be considered according to local or institutional guidelines or those of applicable 
professional societies. 
5.1 
POTENTIAL RISKS ASSOCIATED WITH PRM-151 
Potential risks for PRM-151 include infusion-related reactions (IRRs), anaphylactic 
and hypersensitivity reactions, post-implantation fetal loss, and immunogenicity.  
Outlined below is the safety plan for managing the potential risks of IRRs, anaphylactic 
and hypersensitivity reactions, and post-implantation fetal loss.  Refer to the latest IB 
for further information.  
Infusion-related reaction (see Section 5.4.5.1) is a temporal and causality-based event.  
This is not a clinical syndrome or medical concept and cannot be characterized by 
clinical criterion.  Whereas, hypersensitivity reaction is considered as an immune 
related reaction which can be immediate or delayed.  There is a great degree of overlap 
in signs and symptoms between IRR and hypersensitivity reaction.  Investigators 
should use their medical judgement to assess if an event is immune mediated. 


 
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5.1.1 
Infusion-Related Reactions 
IRR risks associated with PRM-151 are inherent in it being the recombinant form of 
a naturally occurring human protein.  PRM-151 has an endogenous counterpart, and 
ADAs could potentially affect the efficacy of PRM-151 treatment in addition to having the 
potential to cross-react with endogenous hPTX-2.  Patients should be monitored 
for IRRs, which may occur within 24 hours of administration of PRM-151. 
Signs and symptoms of an infusion reaction may include the following:  headache, fever, 
facial flushing, pruritus, 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., anaphylaxis) may occur at any time during the infusion. 
In the Phase II study (PRM-151-202; n  116), 2 patients (2.6%) treated with PRM-151 
experienced IRRs during the randomized period (in Weeks 1 and 8), and 10 patients 
(9.0%) treated with PRM-151 during the OLE period (occurring from Weeks 28 to 108).  
All IRRs were either Grade 1 or 2 except for one Grade 3 IRR. 
5.1.2 
Anaphylactic and Hypersensitivity Reactions 
Anaphylactic and hypersensitivity reactions are considered a potential risk with all 
biologic medications, including PRM-151.  Appropriate precautions should be taken to 
ensure appropriate measures to manage anaphylaxis are available.  PRM-151 was 
found to contain small amounts of the sugar -Gal (Section 1.2.2).  The -Gal epitope 
is present in red meat, the gastrointestinal tract of ticks with long shells, and also in 
some drugs of animal origin (e.g., porcine or bovine gelatin) and therapeutic chimeric 
monoclonal antibodies (e.g., cetuximab).  In patients presenting immunoglobulin E 
(IgE) sensitization to -Gal (e.g., red meat allergy or a history of tick bites), clinical 
allergic reactions having immediate onset may be induced by the first parenteral 
exposure to drugs containing -Gal (Popescu et al. 2019).  As a result, the risk of 
anaphylactic or hypersensitivity reactions may be increased in patients with a history 
of tick bites, red meat allergy, or patients with IgE antibodies directed against -Gal. 
More information on the presence of -Gal in PRM-151 is provided in the PRM-151 
IB. 
In Phase I/II clinical trials of PRM-151 to date, one event was reported as an 
anaphylactic reaction in a patient taking part in the Phase II study (PRM-151G-101) in 
patients with myelofibrosis.  The event occurred 17 days following the fifth dose of 
PRM-151 (for additional details see the PRM-151 Investigator’s Brochure). 
Investigators and health care professionals administering study treatment should be 
trained to recognize and manage the signs and symptoms of a potential anaphylactic, or 
hypersensitivity reaction and should be familiar with Sampson’s criteria for defining 
anaphylaxis (Sampson et al. 2006; Appendix 5).  Investigators and health care 


 
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professionals should also be trained to accurately and appropriately report these events 
immediately to the Sponsor as adverse events of special interest and as serious adverse 
events, if appropriate (see Section 5.5).  Health care professionals should also instruct 
patients on how to recognize the symptoms of any anaphylactic, or hypersensitivity 
reactions, and to contact a health care provider or seek emergency care in case of any 
such symptoms.  Patients will need to be clinically stable prior to each dose of study 
drug as assessed by clinical evaluations, including vital signs and spirometry 
measurements. 
If a patient experiences a suspected and/or non-serious hypersensitivity reaction, the 
case should be discussed with the Medical Monitor prior to continued dosing.  If a patient 
has signs or symptoms of an anaphylactic or serious hypersensitivity reaction, 
administration of the study drug must be discontinued permanently. 
The patient should be treated according to the standard of care for management of 
anaphylaxis or hypersensitivity reaction. 
5.1.3 
Post-implantation Fetal Loss 
In a rabbit dose range finding embryo fetal development study, PRM-151-‑related 
adverse effects at 60 mg/kg/day included a high number of embryo-fetal deaths, 
post‑implantation loss rate, high placental remnant rate, and lower fetal viability rate.  
At 200 mg/kg/day, PRM-151 treatment resulted in complete post-implantation fetal 
loss.   
No pregnancies have been reported across any of the completed Phase 1 and 2 studies 
with PRM-151. 
In this study, women of childbearing potential (WOCBP) must remain abstinent or use 
contraceptive methods with a failure rate of   1% per year during the treatment period 
and for 8 weeks after the final dose of PRM-151.  Additionally, women of childbearing 
potential enrolling from sites in Japan are excluded from the study.  Male subjects with 
a female partner of childbearing potential or pregnant female partner must remain 
abstinent or use a condom during the treatment period and for 8 weeks after the final 
dose of PRM-151. 
5.1.4 
Management Guidelines for Infusion-Related Reactions, 
Anaphylactic and Hypersensitivity Reactions 
If an IRR Grade  2 event occurs, the steps outlined in Table 3 should be followed.  For 
Grade 1 IRRs, investigators should treat as per medical judgement or local procedures. 


 
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Table 3 
Actions if an Infusion-Related Reaction (Grade 2) Occurs 
Event 
Actions 
IRR Event Occurs 
If NCI CTCAE Grade 2 (Section 5.4.3) signs and symptoms 
are present: 
 
Treat per local guidelines. 
 
Reduce rate of study drug infusion (to 120 minutes). 
 
Collect ECG and after patient stabilizes, collect labs 
(serum tryptase a, ADA, PK sample, complement C3). 
 
Capture signs and symptoms per Sampson criteria.  
 
If NCI CTCAE Grade 3 signs and symptoms are present: 
 
Treat per local guidelines.  
 
Stop study drug infusion. 
 
Collect ECG and after patient stabilizes, collect labs 
(serum tryptase a, ADA, PK sample, complement C3).  
 
Capture signs and symptoms per Sampson criteria. 
 
If NCI CTCAE Grade 4 signs and symptoms are present or a 
patient experiences a second occurrence of a Grade 3 IRR, in 
addition to the above guidance for a Grade 3 IRR event: 
 
Permanently discontinue study drug treatment. 
IRR (Grade 2 and Grade 3 
[1st occurrence]) resolved after 
treatment and/or reduced 
infusion rate 
 
Complete study drug infusion at reduced rate 
(120 minutes). 
 
Closely monitor patient. 
IRR not resolved after treatment 
and/or reduced infusion rate  
 
Stop study drug infusion.  
 
Treat and closely monitor patient. 
IRR (Grade 2 and Grade 3 
[1st occurrence])  resolved 
after continued treatment  
 
Restart study drug infusion at reduced rate (120 minutes). 
 
Next study drug infusion should be at reduced rate and 
premedication should be used. b 
 
Subsequent study drug infusions may be at reduced rate 
with premedication. 
 
Please note, if a patient experiences a second occurrence 
of a Grade 3 IRR or a Grade 4 IRR event, study drug 
treatment must be permanently discontinued. 
ADA  anti-drug antibody; IRR  infusion-related reaction; PK  pharmacokinetics; NCI 
CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
a Serum tryptase should be collected between 1 - 6 hours after the event 
 b  Diphenhydramine or clemastine and dexamethasone are recommended (see details in 
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The next study drug infusion after a Grade ≥ 2 IRR or non-serious hypersensitivity 
reactions should be infused over 120 minutes and the following premedications are 
recommended for all subsequent study drug administrations after these events: 
• 
Diphenhydramine 50 mg IV or clemastine 2 mg IV (or an equivalent dose of an 
antihistaminic drug); recommended timing of premedication: 30 minutes prior to 
infusion 
• 
Dexamethasone 10 mg IV (or an equivalent dose of a long-acting corticosteroid)); 
recommended timing of premedication: 60 minutes prior to infusion 
 
If subsequent infusion(s) are uneventful, the investigator may resume 50- to 70-minute 
infusions of study treatment and may discontinue premedication. 
Suspected IRRs (Grade ≥2), anaphylactic, and hypersensitivity (all grades) reactions 
must be reported as an Adverse Event of Special Interest as described in Section 5.3.3.  
See reporting of IRRs discussed in Section 5.4.5.1. 
Assessment of potential anaphylaxis will be conducted at every infusion per the clinical 
criterion for diagnosing anaphylaxis as described by Sampson et al. 2006 NIAID/FAAN 
(Appendix 5).  Patients experiencing suspected anaphylaxis or hypersensitivity 
reaction should be managed as per local guidelines.  If a patient experiences suspected 
anaphylaxis and/or hypersensitivity reaction regardless of seriousness or severity, an 
ECG should be collected after the patient stabilizes.  Blood samples for ADA, serum 
tryptase, complement C3, and PK analysis should be obtained at the time of the event 
whenever possible (serum tryptase should be collected between 1 and 6 hours after the 
event), and a blood sample for ADA, serum tryptase, and complement C3 should be 
obtained at the first follow-up visit after the event. 
All potential anaphylaxis cases reported by investigators to the Sponsor will be 
subsequently submitted for adjudication to a blinded Anaphylaxis Adjudication 
Committee, composed of external experts in allergic diseases.  The committee will 
assess whether the reported event is a true anaphylaxis event (based on Sampson's 
criteria) and whether the reported anaphylaxis event is causally related to study 
treatment. 
If a patient has signs or symptoms of an anaphylactic or serious hypersensitivity reaction 
(including events deemed to have met the criteria as described by Sampson according 
to the blinded Anaphylaxis Adjudication Committee), administration of the study drug 
must be discontinued permanently. 
The anaphylaxis adjudication process has been outlined in the Anaphylaxis Adjudication 
Committee Charter.   


 
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5.2 
MANAGEMENT OF PATIENTS WHO EXPERIENCE ADVERSE 
EVENTS 
5.2.1 
Dose Modifications 
Dose modifications of PRM-151 or matching placebo are not permitted in the study. 
5.2.2 
Treatment Interruption 
Study treatment may be temporarily suspended in patients who experience toxicity 
considered to be related to study drug.  Resumption of study treatment should be 
discussed with the Medical Monitor. 
In the event that one or more doses of PRM-151 or placebo is missed, the patient will be 
required to reload with three doses of study treatment at the next scheduled visit, 
allowing alternate days between infusions.  Reasons for any such dose interruptions 
should be recorded in the eCRF.  The investigator should discuss with the Medical 
Monitor prior to reloading after a dose is missed due to an adverse event. 
5.3 
SAFETY PARAMETERS AND DEFINITIONS 
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol‑specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study. 
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.5. 
5.3.1 
Adverse Events 
According to the International Council for Harmonisation (ICH) guideline for Good 
Clinical Practice, an adverse event is any untoward medical occurrence in a clinical 
investigation subject administered a pharmaceutical product, regardless of causal 
attribution.  An adverse event can therefore be any of the following: 
 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
 
Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Sections 5.4.5.9 
and 5.4.5.10 for more information) 
 
Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline 
 
Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
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 
Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies) 
 
5.3.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) 
A serious adverse event is any adverse event that meets any of the following criteria: 
 
Is fatal (i.e., the adverse event actually causes or leads to death) 
 
Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death) 
 
This does not include any adverse event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death. 
 
Requires or prolongs inpatient hospitalization (see Section 5.4.5.11) 
 
Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient's ability to conduct normal life 
functions) 
 
Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug 
 
Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above) 
 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE; 
see Section 5.4.3); the event itself may be of relatively minor medical significance (such 
as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF. 
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.5.2 for 
reporting instructions). 
5.3.3 
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor) 
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 


 
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Section 5.5.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows. 
Adverse events of special interest related to drug development in general: 
• 
Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by 
Hy's Law (see Section 5.4.5.7) 
• 
Suspected transmission of an infectious agent by the study drug, as defined below 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection 
in a patient exposed to a medicinal product.  This term applies only when 
a contamination of the study drug is suspected. 
Adverse events of special interest relevant to PRM-151: 
• 
Suspected Infusion Related Reaction with NCI CTCAE Grade ≥ 2 
• 
Suspected anaphylactic or hypersensitivity reactions (all grades)  
• 
Acute or suspected exacerbation of IPF (all grades) 
 
5.3.4 
Collection of Survival Data 
All efforts should be made to collect the survival data even if the patient cannot 
physically be present for the visit.  
Survival data collection may be accomplished remotely if necessary (i.e., via telephone 
or electronically), provided these communications are well documented.  
If a patient is lost to follow-up or withdraws from the study, survival status will be 
ascertained through the use of Death Registries, where approved and available 
(unless the patient withdraws consent from such data collection). 
Patients who withdraw consent from the study will be invited to enroll in the OLE study 
for long-term survival follow-up. 
5.3.5 
Lung Transplantation 
Qualification for lung transplant will be assessed by the investigator.  In general, 
qualification for lung transplant may be regarded as the point in time when a patient 
would be referred for evaluation for lung transplantation using local guidelines or 
practice, under ideal circumstances (e.g., no obvious contraindication for lung 
transplant).  When applicable, date of qualification as assessed by investigator will be 
collected.  Date of actual lung transplantation will be collected, when applicable. 


 
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5.4 
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS 
The investigator is responsible for ensuring that all adverse events (see Section 5.3.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Sections 5.55.7. 
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.3.2 for seriousness criteria), severity 
(see Section 5.4.3), and causality (see Section 5.4.4).   
5.4.1 
Adverse Event Reporting Period 
Investigators will seek information on adverse events at each patient contact.  
All adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient's medical record and on the Adverse Event eCRF. 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.5.2 for instructions for reporting serious adverse events).  All other 
medical occurrences that begin before the start of study treatment but after obtaining 
informed consent will be recorded on the General Medical History and Baseline 
Conditions eCRF, and not on the Adverse Event eCRF. 
After initiation of study drug, all adverse events will be reported until 8 weeks after the 
final dose of study drug. 
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.7. 
5.4.2 
Eliciting Adverse Event Information 
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following: 
"How have you felt since your last clinic visit?" 
"Have you had any new or changed health problems since you were last here?"  
 
5.4.3 
Assessment of Severity of Adverse Events 
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity (see Appendix 9).  Table 4 will be used for assessing 
severity for adverse events that are not specifically listed in the NCI CTCAE. 


 
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Table 4 
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE 
Grade 
Severity 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; or intervention not indicated 
2 
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a 
3 
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c 
4 
Life-threatening consequences or urgent intervention indicated d 
5 
Death related to adverse event d 
NCI CTCAE  National Cancer Institute Common Terminology Criteria for Adverse Events. 
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm 
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc. 
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden. 
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.5.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.3.2. 
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.5.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.3.2. 
 
5.4.4 
Assessment of Causality of Adverse Events 
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration: 
 
Temporal relationship of event onset to the initiation of study drug 
 
Course of the event, with special consideration of the effects of discontinuation of 
study drug, or reintroduction of study drug (as applicable) 
 
Known association of the event with the study drug or with similar treatments 
 
Known association of the event with the disease under study 
 
Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event 
 
Presence of non-treatment-related factors that are known to be associated with the 
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5.4.5 
Procedures for Recording Adverse Events 
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations. 
Only one adverse event term should be recorded in the event field on the Adverse 
Event eCRF. 
5.4.5.1 
Infusion-Related Reactions 
Adverse events that occur during or within 24 hours after study drug administration and 
are judged to be related to study drug infusion should be captured as a diagnosis 
(e.g., "infusion-related reaction," or "anaphylactic reaction") on the Adverse Event eCRF.  
If possible, avoid ambiguous terms such as "systemic reaction."  Associated signs and 
symptoms should be recorded on the dedicated Infusion-Related Reaction eCRF.  
If a patient experiences both a local and systemic reaction to the same dose of study 
drug, each reaction should be recorded separately on the Adverse Event eCRF, with 
signs and symptoms also recorded separately on the dedicated Infusion-Related 
Reaction eCRF. 
5.4.5.2 
Diagnosis versus Signs and Symptoms 
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis. 
5.4.5.3 
Adverse Events That Are Secondary to Other Events 
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example: 
 
If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF. 
 
If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF. 
 
If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF. 


 
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 
If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF. 
 
If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF. 
 
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated. 
5.4.5.4 
Persistent or Recurrent Adverse Events 
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.5.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events. 
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as 
a separate event on the Adverse Event eCRF. 
5.4.5.5 
Abnormal Laboratory Values 
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event. 
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., alkaline phosphatase and bilirubin 5  ULN associated with cholestasis), only the 
diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF. 


 
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If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with 
a descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia." 
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.4.5.4 for 
details on recording persistent adverse events). 
5.4.5.6 
Abnormal Vital Sign Values 
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must 
be reported as an adverse event if it meets any of the following criteria: 
 
Is accompanied by clinical symptoms 
 
Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation) 
 
Results in a medical intervention or a change in concomitant therapy 
 
Is clinically significant in the investigator's judgment  
 
It is the investigator's responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event. 
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF. 
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.4.5.4 for 
details on recording persistent adverse events). 
5.4.5.7 
Abnormal Liver Function Tests 
The finding of an elevated ALT or AST ( 3  ULN) in combination with either an 
elevated total bilirubin ( 2  ULN) or clinical jaundice in the absence of cholestasis or 
other causes of hyperbilirubinemia is considered to be an indicator of severe liver injury 
(as defined by Hy’s Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following: 
 
Treatment-emergent ALT or AST  3  ULN in combination with total bilirubin 
 2  ULN 
 
Treatment-emergent ALT or AST  3  ULN in combination with clinical jaundice  


 
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The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.4.5.2) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest 
(see Section 5.5.2).  Any such events should be managed according to local practices 
and guidelines.  No drug-specific management guideline is available, as abnormal liver 
function tests are not a known adverse drug reaction or risk for PRM-151. 
5.4.5.8 
Deaths 
All deaths that occur during the protocol-specified adverse event reporting period 
(see Section 5.4.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.5.2).  
This includes death attributed to progression of IPF. 
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death"). 
If the death is attributed solely to progression of IPF, "Idiopathic pulmonary fibrosis 
progression" should be recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.7. 
5.4.5.9 
Preexisting Medical Conditions 
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF. 
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
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5.4.5.10 
Lack of Efficacy or Worsening of Idiopathic Pulmonary 
Fibrosis 
Medical occurrences or symptoms of deterioration that are anticipated as part of 
idiopathic pulmonary fibrosis should be recorded as an adverse event if judged by the 
investigator to have unexpectedly worsened in severity or frequency or changed in 
nature at any time during the study.  When recording an unanticipated worsening of 
idiopathic pulmonary fibrosis on the Adverse Event eCRF, it is important to convey 
the concept that the condition has changed by including applicable descriptors 
(e.g., "accelerated worsening of idiopathic pulmonary fibrosis"). 
5.4.5.11 
Hospitalization or Prolonged Hospitalization 
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital) 
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.3.2), except as 
outlined below. 
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event: 
 
Hospitalization for a preexisting condition, provided that all of the following criteria 
are met: 
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease 
The patient has not experienced an adverse event 
 
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse 
event instead: 
 
Hospitalization that was necessary because of patient requirement for outpatient 
care outside of normal outpatient clinic operating hours 
 
5.4.5.12 
Cases of Accidental Overdose or Medication Error 
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows: 
 
Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose 
 
Medication error:  accidental deviation in the administration of a drug  
In some cases, a medication error may be intercepted prior to administration of 
the drug. 
 
Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 


 
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separately on the Adverse Event eCRF.  If the associated adverse event 
fulfills seriousness criteria, the event should be reported to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.5.2).  
For PRM-151or matching placebo, adverse events associated with special situations 
should be recorded as described below for each situation: 
 
Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the adverse event 
term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes. 
 
In addition, all special situations associated with PRM-151 or matching placebo, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box. 
 
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details. 
 
Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details. 
 
As an example, an accidental overdose that resulted in a headache would require two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 
entry to report the headache.  The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries. 
5.5 
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR 
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 


 
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of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug: 
 
Serious adverse events (defined in Section 5.3.2; see Section 5.5.2 for details on 
reporting requirements) 
 
Adverse events of special interest (defined in Section 5.3.3; see Section 5.5.2 for 
details on reporting requirements) 
 
Pregnancies (see Section 5.5.3 for details on reporting requirements) 
 
For serious adverse events and adverse events of special interest, the investigator must 
report new significant follow-up information to the Sponsor immediately (i.e., no more 
than 24 hours after becoming aware of the information).  New significant information 
includes the following: 
 
New signs or symptoms or a change in the diagnosis 
 
Significant new diagnostic test results 
 
Change in causality based on new information 
 
Change in the event's outcome, including recovery 
 
Additional narrative information on the clinical course of the event 
 
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and IRB/EC. 
5.5.1 
Medical Monitors and Emergency Medical Contacts 
In the event of an emergency, the investigator or other physician should use their 
medical judgment and do what is best for the patient, 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 patient 
should continue to participate in the study.  All protocol deviations and reasons for such 
deviations must be documented. 
Contact Information  
Medical Monitor/Emergency Medical Contact: 
To be provided by Sponsor 
Telephone No.: 
To be provided by Sponsor 
Mobile Telephone No.: 
To be provided by Sponsor  
Medical Monitor/Emergency Medical Contact: 
To be provided by Sponsor (Secondary)  
Telephone No.: 
To be provided by Sponsor  
 
Mobile Telephone No.: 
To be provided by Sponsor  
  


 
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To ensure the safety of study patients, an Emergency Medical Call Center will be 
available 24 hours per day, 7 days per week, in case the above-listed contacts cannot 
be reached.  The Emergency Medical Call Center will connect the investigator with an 
Emergency Medical Contact, provide medical translation service if necessary, and track 
all calls.  Contact information, including toll-free numbers for the Emergency Medical Call 
Center, will be distributed to investigators.  
5.5.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest 
5.5.2.1 
Events That Occur prior to Study Drug Initiation 
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators. 
5.5.2.2 
Events That Occur after Study Drug Initiation 
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 8 weeks after the final dose of study drug.  Investigators 
should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system. 
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.   
Instructions for reporting serious adverse events that occur  8 weeks after the final dose 
of study treatment are provided in Section 5.7. 
5.5.3 
Reporting Requirements for Pregnancies 
5.5.3.1 
Pregnancies in Female Patients 
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 8 weeks after the final 
dose of study drug.  


 
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Female patients enrolling from site in Japan of childbearing potential are prohibited 
from enrolling in this study.  However, in the unlikely event that any female patients 
enrolling from sites in Japan become pregnant during the study or within 8 weeks after 
the final dose of study drug, they will be instructed to immediately inform the 
investigator.  A paper Clinical Trial Pregnancy Reporting Form should be completed and 
submitted to the Sponsor or its designee immediately (i.e., no more than 24 hours after 
learning of the pregnancy), either by faxing or by scanning and emailing the form using 
the fax number or email address provided to investigators.  Pregnancy should not be 
recorded on the Adverse Event eCRF.  The investigator should discontinue study drug 
and counsel the patient, discussing the risks of the pregnancy and the possible effects 
on the fetus.  Monitoring of the patient should continue until conclusion of the pregnancy.  
Any serious adverse events associated with the pregnancy (e.g., an event in the fetus, 
an event in the mother during or after the pregnancy, or a congenital anomaly/birth 
defect in the child) should be reported on the Adverse Event eCRF.  In addition, the 
investigator will submit a Clinical Trial Pregnancy Reporting Form when updated 
information on the course and outcome of the pregnancy becomes available.   
5.5.3.2 
Pregnancies in Female Partners of Male Patients 
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
8 weeks after the final dose of study drug.  A paper Clinical Trial Pregnancy Reporting 
Form should be completed and submitted to the Sponsor or its designee immediately 
(i.e., no more than 24 hours after learning of the pregnancy), either by faxing or by 
scanning and emailing the form using the fax number or email address provided to 
investigators.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient exposed to study drug.  When 
permitted by the site, the pregnant partner would need to sign an Authorization for Use 
and Disclosure of Pregnancy Health Information to allow for follow-up on her pregnancy.  
If the authorization has been signed, the investigator should submit a Clinical Trial 
Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient or 
his pregnant partner may provide information on the risks of the pregnancy and the 
possible effects on the fetus, to support an informed decision in cooperation with the 
treating physician and/or obstetrician. 
5.5.3.3 
Abortions 
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.5.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 


 
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recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.5.2).  A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event. 
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
Pregnancy Reporting Form.  
5.5.3.4 
Congenital Anomalies/Birth Defects 
Any congenital anomaly/birth defect in a child born to a female patient exposed to study 
drug or the female partner of a male patient exposed to study drug should be classified 
as a serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.5.2). 
5.6 
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS 
5.6.1 
Investigator Follow-Up 
The investigator should follow each adverse event until the event has resolved to 
baseline grade or better, the event is assessed as stable by the investigator, the patient 
is lost to follow-up, or the patient withdraws consent.  Every effort should be made to 
follow all serious adverse events considered to be related to study drug or trial-related 
procedures until a final outcome can be reported. 
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient's medical record to facilitate source data 
verification. 
All pregnancies reported during the study should be followed until pregnancy outcome. 
5.6.2 
Sponsor Follow-Up 
For serious adverse events, adverse events of special interest, and pregnancies, the 
Sponsor or a designee may follow up by telephone, fax, email, and/or a monitoring visit 
to obtain additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case. 
5.7 
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD 
After the end of the adverse event reporting period (defined as 8 weeks after the final 
dose of study drug), if the investigator becomes aware of a serious adverse event that is 
believed to be related to prior exposure to study drug, the event should be reported 
through use of the Adverse Event eCRF.  However, if the EDC system is not available, 
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by faxing or by scanning and emailing the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form using the fax number or email 
address provided to investigators. 
5.8 
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, 
AND ETHICS COMMITTEES 
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation. 
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events through use of the reference safety 
information in the document listed below: 
Drug 
Document 
PRM-151 
PRM-151 Investigator's Brochure  
 
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document. 
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed. 
The suspected unexpected serious adverse reaction (SUSAR) reporting will be as per 
the national regulatory requirements in participating countries in accordance with the 
Sponsor’s internal standard operating procedures. 
An iDMC 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 iDMC will be 
constituted of independent clinicians’ expert in the field of IPF and clinical research and 
a statistician.  A formal charter will be established for the conduct of the iDMC.  The 
Committee is planned to review the safety data in an unblinded manner.  The iDMC may 
also review other data (e.g., PK) according to local health authority requirements.  If 
appropriate, the iDMC may also evaluate benefit and risk by reviewing relevant efficacy 
data together with safety data during the scheduled iDMC meetings. Details regarding 
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6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
Unless otherwise specified, all baseline and efficacy analyses will be based on the full 
analysis set (FAS) defined as all randomized subjects who received at least one 
administration (full or partial dose) of study drug and will use the grouping as assigned 
by randomization.  The safety evaluable population will include all randomized patients 
who received at least one administration (full or partial dose) of study drug and will be 
grouped by treatment received. 
The primary analysis will occur when the last enrolled patient has completed the 
Week 52 study visit.  Significance testing of the primary and secondary endpoints 
will account for multiplicity and control family-wise type I error, which is fixed at 
0.05 two-sided.  The study has one single primary efficacy endpoint (absolute change 
from baseline to Week 52 in FVC [mL]) and one family of secondary efficacy endpoints 
that have been ordered in a prespecified sequence, starting with the key secondary 
endpoint, absolute change from baseline to Week 52 in 6MWD (see Section 3.3.2).  
The planned statistical analysis will control the overall type I error for the testing of these 
efficacy endpoints by applying a fixed-sequence statistical strategy, testing all the 
endpoints according to the pre-specified order.  All hypothesis tests will be two-sided 
unless otherwise specified.  
The SAP will contain full details of the statistical analyses and will be signed before 
the database lock and prior to any unblinded statistical analyses by the Sponsor.  
Any change to the planned statistical methods will be documented in the SAP and in the 
clinical study report. 
The global population will include all patients enrolled during the global enrollment 
phase , and the China subpopulation will include all patients enrolled in China, Hong 
Kong and Taiwan (i.e., during both the global enrollment phase and the extended China 
enrollment phase).  Separate analyses will be performed for the global population and 
the China subpopulation (see Section 6.12 for information on the China subpopulation 
analyses). 
6.1 
PRIMARY EFFICACY ESTIMAND 
The primary estimand will evaluate the effectiveness of PRM-151 plus standard of care 
treatment as needed (excluding lung transplantation) versus matching placebo plus 
standard of care treatment as needed (excluding lung transplantation).  It corresponds to 
the difference in outcome attributable to the randomized study drug, whatever changes 
in the treatment regimen (randomized drug and any associated treatment) occurs 
afterwards (excluding lung transplantation), as described in Mallinckrodt et al. 2017 and 
Mallinckrodt et al. 2012.  Lung transplantation will be handled as a particular intercurrent 
event (see below).  The attributes of the estimand are as follows: 
 
The treatment regimen of interest is study drug (PRM-151 or placebo) as 
randomized, in combination with any background or additional treatment 
(i.e., PRM-151 or placebo taken alone or as an add-on to standard of care with 


 
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pirfenidone or nintedanib, dosed as required) including all changes in 
standard of care treatment and all other additional treatments, with the exclusion 
of lung transplantation. 
 
The population is patients diagnosed with idiopathic pulmonary fibrosis as defined 
through the inclusion/exclusion criteria presented in Section 4.1 of the protocol.  All 
patients randomized having received at least one administration (full or partial dose) 
of the study drug (all treated patients) will be included in the analysis (FAS).  
 
The variable is the absolute change from baseline to Week 52 in FVC mL for the 
primary efficacy endpoint. 
 
The population-level summary measure is the between randomized treatments 
difference in mean change from baseline at week 52 in FVC mL. 
 
Intercurrent events (post-randomization events): 
Any change in initial treatment regimen (change in study drug, change in standard 
of care, use of prohibited medication) will be considered irrelevant in defining the 
treatment effect of interest.  As the primary objective is to assess the effectiveness 
of PRM-151, the analysis will be performed ignoring any such intercurrent event. 
Deaths are expected to be infrequent as the study plans to include patients with 
a life expectancy longer than the study duration.  Assessments following death will 
be assigned with values to designate treatment failure.  Further details will be 
provided in the SAP. 
Lung transplantation:  Lung transplantation is expected to be rare during the study, 
as patients likely to receive a lung transplantation during the study are excluded.  
Any data recorded after lung transplantation will be censored from the analysis 
because they are no longer an accurate measure of efficacy reflecting the diseased 
lung(s).  In some instances, FVC can improve to over 80% following lung 
transplantation or even 100% for bilateral lung transplantation 612 months after 
surgery (Hernandez et al. 2018).  
 
Table 5 below summarizes the handling of intercurrent events for the primary 
efficacy estimand. 


 
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Table 5 
Primary Efficacy Estimand Analysis Strategy for Intercurrent 
Events 
Intercurrent Event (ICE) 
Analysis strategy 
Any change to 
randomized treatment 
Temporary study drug 
discontinuation 
Treatment policy 
 
All measurements post ICE 
analyzed 
Permanent study drug 
discontinuation 
Temporary or permanent 
change in study drug dose 
Missed study drug dose 
Randomized treatment 
switches, if any 
Any change in 
standard of care 
(SOC), with pirfenidone 
or nintedanib therapy 
 
SOC started during study 
Treatment policy 
All measurements post ICE 
analyzed 
Change in dose of SOC 
SOC discontinued 
SOC switch (from pirfenidone 
to nintedanib or vice versa) 
Other concomitant 
treatment 
Use of prohibited concurrent 
medication (Section 4.4.2) 
Treatment policy 
All measurements post ICE 
analyzed 
Hospitalization for 
COVID-19 
 
Treatment policy  
All measurements post ICE 
analyzed 
Terminal events 
Death 
 
 
No measurements available after 
such events  
Composite strategy 
Assessments following death will 
be assigned with values to 
designate treatment failure 
Lung transplantation 
Hypothetical strategy 
Measurements collected after lung 
transplantation deleted from the 
analysis  
Implicit imputation using linear 
mixed-effect model 
ICE  intercurrent event; SOC  standard of care. 
 
6.2 
DETERMINATION OF SAMPLE SIZE 
The purpose of this study is hypothesis testing regarding the effect of PRM-151 
versus placebo.   


 
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6.2.1 
Assumptions on Treatment Effects for Sample-Size and Power 
Calculations 
The hypotheses on treatment effect-sizes used for sample-size and power calculations 
were based on the results of the placebo-controlled period of the PRM-151-202 study, 
summarized in Table 6. 
Table 6 
Results of the PRM-151-202 Study on Planned Primary and Key 
Secondary Endpoints 
LS-Means for change from baseline to Week 28 (Linear Mixed Effect Models) 
Endpoint 
Placebo (N=39) 
Mean (SE) 
PRM-151 (N=77) 
Mean (SE) 
Difference 
Mean (SE) 
Standardized 
effect size 
FVC (mL) 
-242.3 (45.47) 
-127.7 (32.86) 
114.6 (56.10) 
0.40 
6MWD (meters) 
-33.7 (10.52) 
-0.20 (7.59) 
33.5 (12.97) 
0.51 
FVC (% predicted) 
-5.40 (0.96) 
-2.50 (0.69) 
2.80 (1.19) 
0.46 
6MWD  6-minute walk distance; FVC  forced vital capacity.  
 
The effect-sizes observed for the between-group differences in least-square means for 
change from baseline to Week 28 from the linear mixed effect models with random 
intercept and slope adjusted on stratum, were 114.6 mL for FVC mL (common standard 
deviation:  286.9, standardized effect-size:  0.40), 33.5 m for 6MWD (common standard 
deviation:  66.3, standardized effect-size:  0.51), and 2.80% for FVC % predicted 
(common standard deviation:  6.04, standardized effect-size:  0.46).  A greater between 
group difference is expected at Week 52 in the current study, but a greater variability 
might also be observed at Week 52, due to the longer follow-up.  
In the OLE of the PRM-151-202 study, where all patients received PRM-151 from Week 
28 onwards, the Week 52 standard errors from the Random Coefficient Regression 
Model (RCRM) model allowed to compute corresponding standard deviations of 403.5 
mL (FVC mL), 8.77% (FVC %predicted) and 82.3 m (6MWD) in patients who were 
initially randomized to PRM-151, that are indeed larger than those at Week 28 (288.3 
mL, 6.06% and 66.6 m respectively).  
To avoid underestimating the power of the study and to enable the opportunity to explore 
the efficacy in relevant patient subgroups including baseline concomitant IPF medication 
use, smaller standardized effect-sizes than observed in study PRM-151-202 at Week 28 
of 0.25 for FVC mL and FVC % predicted and 0.30 for 6MWD were used for the 
calculations.  In addition, to investigate the impact of increased variability for studies of 
longer duration, the power for this calculated sample size was assessed in the following 
way:  (a) using the placebo-controlled treatment differences observed at Week 28 as 
estimates for the Week 52 treatment effects and (b) using the Week 52 standard 
deviations for the initially randomized PRM-151 arm from study PRM-151-202, as 


 
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estimates for the Week 52 common standard deviations.  This was performed in order to 
confirm that the nominal power is at least 80% under these assumptions. 
With a total of 658 patients (329 in each arm), the nominal power to detect 
a standardized effect size of 0.25 for FVC mL and FVC % predicted, using a two-sided 
type I error level of 0.05 is 0.89 and the nominal power to detect a standardized effect 
size of 0.30 on 6MWD using a two-sided type I error level of 0.05 is 0.97. 
With a total of 658 patients (329 in each arm), the nominal power to detect an effect of 
114.6 mL on FVC mL with common standard deviation of 403.5 (standardized effect size 
of 0.28) using a two-sided type I error of 0.05 is 0.95.  The nominal power to detect an 
effect of 33.5 meters on 6MWD with common standard deviation of 82.3 (standardized 
effect size of 0.41) using a two-sided type I error level of 0.05 is > 0.99.  For FVC % 
predicted, the nominal power to detect an effect of 2.80% with common standard 
deviation of 8.77 (standardized effect size of 0.32) using a two-sided type I error of 0.05 
is 0.98.  
6.2.1.1 
Robustness of Power and Sample-Size Calculations 
In Table 7, power calculations for alternative values of the effect-sizes of the first three 
endpoints in the fixed-sequence testing are provided. 
With the planned sample size of 658 patients, a standardized effect-size of 0.220 on 
FVC, both mL and % predicted (corresponding to absolute between group differences of 
89 mL and 1.92%, respectively) will be detected with a power of 80%. 
For 6MWD, the study has a high power (0.973) to detect an absolute between group 
difference of 25 m (considered the minimal clinically relevant difference), corresponding 
to a standardized effect-size of 0.30.  A smaller effect-size of 0.25, corresponding to an 
absolute difference of 20.8 m will be detected with a power of 90%.  


 
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Table 7 
Results of Power Calculations for Different Effect-Sizes and 
N=658 Patients 
 
alpha 
 
Hypothesized 
absolute 
difference 
Power with  
N=658 patients 
FVC (mL) 
H0: difference = 0 
0.05 
2-sided 
114.6 
0.953 
107.0 
0.925 
102.0 
0.899 
95.0 
0.854 
89.0 
0.806 
6MWD (meters) 
H0: difference = 0 
0.05 
2-sided 
33.5 
>0.999 
27.5 
0.990 
25.0 
0.973 
23.0 
0.947 
20.8 
0.899 
18.0 
0.800 
FVC (% predicted) 
H0: difference = 0 
0.05 
2-sided 
2.80 
0.983 
2.45 
0.947 
2.33 
0.925 
2.22 
0.900 
2.05 
0.849 
1.92 
0.800 
Standard deviation of 403.5 mL (FVC mL), 82.3 m (6MWD) and 8.77 
(FVC %predicted) based on Week 52 standard errors from the MMRM model 
in patients who were initially randomized to PRM-151 in Study PRM-151-202. 
6MWD  6-minute walk distance; FVC  forced vital capacity. 
 
6.3 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients randomized will be tabulated by study site and treatment group.  
Patient disposition (the number of patients who enroll, discontinue, or complete the 
study) will be summarized by treatment group.  Reasons for premature study 
discontinuation will be listed and summarized.  Enrollment and major protocol 
deviations will be listed and evaluated for their potential effects on the interpretation of 
study results. 
6.4 
SUMMARIES OF TREATMENT GROUP COMPARABILITY 
Unless otherwise specified, the baseline value for each variable will be considered the 
assessment collected on Treatment Day 1, prior to administration of study drug. 


 
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Demographic and baseline characteristics such as age, sex, race/ethnicity, concomitant 
IPF medication use, comorbid illnesses, and pulmonary function, will be summarized for 
the FAS population overall and by treatment group using means, standard deviations, 
medians, and ranges for continuous variables and proportions for categorical variables, 
as appropriate.  Exposure to study treatment (number of study drug treatments and 
duration of treatment) will be summarized overall and by treatment group. 
Proportions of patients taking each concomitant medication will be provided. 
6.5 
EFFICACY ANALYSES 
The study endpoints comprise one primary endpoint, one key secondary endpoint, and 
a series of other secondary endpoints (see Section 2).  All the primary and secondary 
efficacy analyses will be performed on the FAS population.  Relying on the analytical 
strategy presented in Section 6, the planned statistical analysis will control the 
study-wise type I error at the planned 0.05 two-sided level despite multiple endpoints.  
A fixed-sequence testing strategy will be used for statistical testing of first the primary 
endpoint then the secondary endpoints according to the prespecified order to control the 
study-wise type I error rate at 0.05 two-sided.  See Section 6 for details. 
In addition to the analyses described in Sections 6.5.1 and 6.5.2, the following analyses 
will be performed for the primary efficacy endpoint and key secondary efficacy 
endpoints.  Details of these analyses will be described in the SAP: 
 
Subgroup analyses to evaluate the consistency of results across prespecified 
subgroups (e.g., concurrent use of IPF treatment, geographic region, first and 
second generation PRM-151) 
 
6.5.1 
Primary Efficacy Analysis 
All FVC mL measurements that meet the minimal level of quality will be used for this 
analysis, except those recorded after lung transplantation, whatever other intercurrent 
events might have occurred before that were recorded.  Assessments following death 
will be assigned with values to designate treatment failure, and the details will be 
provided in the SAP.  
The comparison of PRM-151 with placebo will be carried out via a two-sided statistical 
test.  The primary efficacy endpoint will be analyzed using a linear mixed-effect model 
with random intercept and random slope, with FVC mL measured at each timepoint as 
the dependent variable, stratification factors, age, sex, height and treatment by time 
interaction as fixed effects, and subject and time as random effects.  The random 
intercept represents deviations from the mean baseline FVC mL measure for each 
subject.  The model will assume an unstructured covariance structure.  If there are 
convergence problems with the model, the following covariance structures will be tested:  
compound symmetry, first-order autoregressive [AR(1)] and Toeplitz.  The covariance 


 
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structure converging to the best fit, based on Akaike’s information criterion (AIC), will be 
used. 
The comparison of PRM-151 with placebo will be carried out by computing the estimate 
of the difference in absolute change from baseline at Week 52 between the two 
treatment arms with 95% CIs and p-value. 
6.5.2 
 Key Secondary Efficacy Endpoint 
If the primary efficacy test on FVC mL is found significant at the alpha level of 
0.05 two-sided then the fixed sequence testing procedure will continue by testing 6MWD 
at the alpha level of 0.05 two-sided. 
The key secondary endpoint (6MWT) will be analyzed using the same methodology as 
the primary endpoint with specifics for models and summaries detailed in the SAP. 
6.5.3 
Analyses Addressing the Effect of Missing Data 
All efforts will be made to minimize missing data.  Assessments following death and 
lung transplantation will be imputed for the primary and key secondary endpoints.  No 
other imputation for missing data is planned to be performed for the primary analysis, as 
the planned analysis model is capable of handling missing data when the data are 
assumed to be missing at random (MAR).  Various sensitivity analyses to support the 
primary analysis will use alternative methods of handling missing values.  Details will 
be provided in the SAP 
6.5.4 
Other Secondary Efficacy Analyses 
As mentioned in Section 6.5, and conditional to significant results being obtained first on 
the primary endpoint and then the key secondary endpoint, the remaining secondary 
endpoints will be tested using the fixed-sequence strategy in the predefined order 
presented in Section 2.1.2, each at the same significance level of 0.05 two-sided and the 
testing sequence will stop as soon as a non-significant result is observed. 
In case a non-significant test occurs during this testing sequence, the tests for the 
remaining endpoints in the sequence will nevertheless be computed as 
sensitivity/exploratory analyses but will not allow any formal claim of efficacy on 
these endpoints. 
All continuous secondary endpoints will be analyzed using the same methodology as the 
primary endpoint.  The SAP will detail specifics for models and summaries. 
For time to event endpoints, the log-rank test will be used for the comparison between 
the two treatment arms.  The hazard ratio will be estimated using a Cox regression 
model.  Descriptive statistics and Kaplan-Meier curves will be provided.  Details on 
model specifications will be provided in the SAP. 


 
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6.5.5 
Exploratory Efficacy Analyses 
Exploratory efficacy analyses will be described in detail in the SAP.  
6.6 
SAFETY ANALYSES 
Safety analyses will consist of all randomized patients who received at least one 
administration (full or partial dose) of study drug, with patients grouped according to 
treatment received.  Safety summaries will be presented by treatment arm for all treated 
patients. Details of supplemental subgroup analyses comparing the safety of first and 
second generation PRM-151 will be provided in the SAP. 
Safety will be assessed through summaries of exposure to study treatment, adverse 
events, SAEs, AESIs, and changes in laboratory test results. 
6.6.1 
Analyses of Exposure, Adverse Event, and Laboratory Data 
Study treatment exposure (such as treatment duration, total dose received) will be 
summarized with descriptive statistics. 
All verbatim adverse event terms will be mapped using the most current version of the 
MedDRA thesaurus terms, and adverse event severity will be graded according to 
NCI CTCAE v5.0 scale.  A by-patient adverse event data listing including onset and 
resolution dates, verbatim term, preferred term, treatment, severity, relationship to 
treatment, action taken, and outcome will be provided.  All adverse events, serious 
adverse events, adverse events leading to death, adverse events of special interest, and 
adverse events leading to study treatment discontinuation that occur on or after the first 
dose of study treatment (i.e., treatment-emergent adverse events) will be summarized by 
mapped term, appropriate thesaurus level, timing from first and last dose of PRM-151, 
and severity grade.  For events of varying severity, the highest grade will be used in the 
summaries.  Deaths and cause of death will be summarized. 
Relevant laboratory data will be displayed by time, with grades identified where 
appropriate.  Additionally, a shift table of selected laboratory tests will be used to 
summarize the baseline and maximum post-baseline severity grade. 
6.7 
PHARMACOKINETIC ANALYSES  
The PK analysis population will consist of patients with sufficient data to determine 
concentrations of PRM-151 at specified timepoints, unless major protocol deviations or 
unavailability of information (e.g., exact blood sampling time) occurred which may 
interfere with PK evaluation, with patients grouped according to treatment received.  
Individual and mean PRM-151 concentration versus time data will be tabulated and 
summarized descriptively.  The pharmacokinetics of PRM-151 will be summarized by 
one or more key PK parameters (as appropriate for data collected).  Estimates for these 


 
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parameters will be tabulated and summarized (mean, standard deviation, coefficient of 
variation, median, minimum, and maximum).   
Additional exploratory PK analyses will be conducted as appropriate. 
6.8 
IMMUNOGENICITY ANALYSES  
The immunogenicity analysis population will consist of all patients with at least one ADA 
assessment.  Patients will be grouped according to treatment received or, if no treatment 
is received prior to study discontinuation, according to treatment assigned.  
Supplemental subgroup analyses will be performed to compare first and second 
generation PRM-151. 
The numbers and proportions of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (post-baseline incidence) 
will be summarized by treatment group.  When determining post-baseline incidence, 
patients are considered to be ADA positive if they are ADA negative or have missing 
data at baseline but develop an ADA response following study drug exposure 
(treatment-induced ADA response), or if they are ADA positive at baseline and the titer 
of one or more post-baseline samples is at least 0.60 titer unit greater than the titer of 
the baseline sample (treatment-enhanced ADA response).  Patients are considered to 
be ADA negative if they are ADA negative or have missing data at baseline and all 
post‑baseline samples are negative, or if they are ADA positive at baseline but do not 
have any post-baseline samples with a titer that is at least 0.60 titer unit greater than the 
titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy and PK, may be analyzed and 
reported via descriptive statistics. 
6.9 
BIOMARKER ANALYSES 
Biomarkers will be assessed at baseline and subsequent timepoints following 
administration of PRM-151.  Biomarkers will be presented as absolute value over time 
and/or percent change relative to baseline over time.  Biomarker levels at baseline or 
over time may be compared with efficacy or safety measurements to assess prognostic 
or predictive properties.  Samples taken during screening and baseline before first 
PRM-151 dose may be averaged to better normalize postdose endpoints taking into 
account normal variability. 
Genetic assessments may include genotype-outcome comparisons to assess prognostic 
or predictive properties. 
Descriptive or summary statistics will be used to describe biomarker and genetic 
assessments.  


 
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6.10 
HEALTH STATUS UTILITY ANALYSES 
Change from baseline in EQ-5D-5L health utility index-based and VAS scores will be 
calculated at specified timepoints. 
6.11 
INTERIM ANALYSES 
6.11.1 
Planned Interim Analysis 
An interim futility analysis will be performed after at least 40% of patients have 
completed their Week 28 visits.  The futility boundary for this analysis is calculated to 
correspond approximately to 25% Bayesian Predictive Power, assuming a linear 
extrapolation between Week 28 and Week 52 visits. 
This interim futility analysis will be conducted by an external statistical group and 
reviewed by the iDMC.  The Sponsor will remain blinded.  Interactions between the 
iDMC and Sponsor will be carried out as specified in the iDMC charter.  
The details regarding this futility analysis will be documented in the SAP and 
will be submitted to FDA at least 2 months prior to the conduct of the interim 
analysis. The SAP may also be submitted to other health authorities upon 
request. The iDMC charter will document potential recommendations the iDMC 
can make to the Sponsor as a result of the futility analysis (e.g., stop the study 
for futility, continue the study), and the iDMC charter will be made available to 
health authorities upon request.  
6.11.2 
Optional Interim Analysis 
No other efficacy interim analyses are planned at this time.  However, in exceptional 
circumstances, when patient enrollment and study conduct is significantly impacted by 
external factors such that study completion does not seem feasible (e.g., ongoing or 
worsening impact of the global COVID-19 pandemic, the availability of compelling 
clinical trial results for an external competitor molecule, or significant changes in 
standard of care), the Sponsor may choose to conduct one interim efficacy analysis.  
Below are the specifications in place to ensure the study continues to meet the highest 
standards of integrity when an optional interim analysis is executed. 
If an interim efficacy analysis is conducted, the Sponsor will remain blinded.  The interim 
efficacy analysis will be conducted by an external statistical group and reviewed by the 
iDMC.  Interactions between the iDMC and Sponsor will be carried out as specified in 
the iDMC Charter. If there is a potential for the study to be stopped for positive efficacy 
as a result of the interim analysis, the type I error rate will be controlled to ensure 
statistical validity is maintained. If the study continues beyond the interim analysis, the 
critical value at the final analysis would be adjusted accordingly to maintain the 
protocol-specified overall type I error rate, per standard Lan-DeMets methodology. 


 
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6.12 
CHINA SUBPOPULATION ANALYSES  
The China subpopulation will include all patients enrolled in China, Hong Kong and 
Taiwan (i.e., during both the global enrollment phase and the extended China enrollment 
phase).  Results from these analyses will be summarized in a separate Clinical Study 
Report.  
7. 
DATA COLLECTION AND MANAGEMENT 
7.1 
DATA QUALITY ASSURANCE 
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system. 
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data, spirometry, 
HRCT, DLCO and other non-eCRF data will be sent directly to the Sponsor, using the 
Sponsor's standard procedures to handle and process the electronic transfer of 
these data. 
eCRFs and correction documentation will be maintained in the EDC system's audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor's standard procedures. 
PRO data will be collected through the use of an electronic device provided by a vendor 
(see Section 7.3 for details). 
7.2 
ELECTRONIC CASE REPORT FORMS  
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor. 
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee. 
At the end of the study, the investigator will receive patient data for his or her site in 
a readable format that must be kept with the study records.  Acknowledgement of receipt 
of the data is required. 


 
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7.3 
ELECTRONIC PATIENT REPORTED OUTCOME DATA 
An electronic device will be used to capture PRO data.  The device is designed for entry 
of data in a way that is attributable, secure, and accurate, in compliance with U.S. FDA 
regulations for electronic records (21 CFR Part 11).  The data will be transmitted to 
a centralized database maintained by the electronic device vendor. 
The electronic data will be available for view access only, via a secure web server.  Only 
identified and trained users may view the data, and their actions will become part of the 
audit trail.  The Sponsor will have view access only.  System backups for data stored by 
the Sponsor and records retention for the study data will be consistent with the 
Sponsor's standard procedures. 
Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats that must be kept with the study records as source data.  
Acknowledgement of receipt of the data is required.  In addition, the Sponsor will receive 
all data in a machine-readable format. 
7.4 
SOURCE DATA DOCUMENTATION 
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents.  
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial. 
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6. 
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for trial-


 
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related monitoring, Sponsor audits, and IRB/EC review.  The study site must also allow 
inspection by applicable health authorities. 
7.5 
USE OF COMPUTERIZED SYSTEMS 
When clinical observations are entered directly into a study site's computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  
An acceptable computerized data collection system allows preservation of the original 
entry of data.  If original data are modified, the system should maintain a viewable audit 
trail that shows the original data as well as the reason for the change, name of the 
person making the change, and date of the change. 
7.6 
RETENTION OF RECORDS 
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic PRO and clinician-reported outcome data 
(if applicable), Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 15 years after 
completion or discontinuation of the study or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations.   
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location. 
Roche will retain study data for 25 years after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer. 
8. 
ETHICAL CONSIDERATIONS 
8.1 
COMPLIANCE WITH LAWS AND REGULATIONS 
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union or 
European Economic Area will comply with the E.U. Clinical Trial Directive (2001/20/EC) 
and applicable local, regional, and national laws. 


 
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8.2 
INFORMED CONSENT 
The Sponsor's sample Informed Consent Form (and ancillary sample Informed Consent 
Forms such as an Assent Form or Mobile Nursing Informed Consent Form, if applicable) 
will be provided to each site.  If applicable, it will be provided in a certified translation of 
the local language.  The Sponsor or its designee must review and approve any proposed 
deviations from the Sponsor's sample Informed Consent Forms or any alternate consent 
forms proposed by the site (collectively, the "Consent Forms") before IRB/EC 
submission.  The final IRB/EC−approved Consent Forms must be provided to the 
Sponsor for health authority submission purposes according to local requirements. 
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature. 
The Consent Forms must be signed and dated by the patient or the patient's legally 
authorized representative before his or her participation in the study.  The case history or 
clinical records for each patient shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study. 
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes. 
If the Consent Forms are revised (through an amendment or an addendum) while 
a patient is participating in the study, the patient or a legally authorized representative 
must re-consent by signing the most current version of the Consent Forms or the 
addendum, in accordance with applicable laws and IRB/EC policy.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study. 
A copy of each signed Consent Form must be provided to the patient or the patient's 
legally authorized representative.  All signed and dated Consent Forms must remain in 
each patient's study file or in the site file and must be available for verification by study 
monitors at any time. 
For sites in the United States, each Consent Form may also include patient authorization 
to allow use and disclosure of personal health information in compliance with the U.S. 


 
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Health Insurance Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes 
a separate Authorization Form for patient authorization for use and disclosure of 
personal health information under the HIPAA regulations, the review, approval, 
and other processes outlined above apply except that IRB review and approval may not 
be required per study site policies. 
8.3 
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE 
This protocol, the Informed Consent Forms, any information to be given to the patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC.  
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC.  Investigators are 
also responsible for promptly informing the IRB/EC of any protocol amendments (see 
Section 9.6). 
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC and 
archived in the site's study file.  
8.4 
CONFIDENTIALITY 
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location. 
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
patient, unless permitted or required by law. 
Medical information may be given to a patient's personal physician or other appropriate 
medical personnel responsible for the patient's welfare, for treatment purposes. 
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 


 
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be available in accordance with the effective Sponsor policy on study data publication 
(see Section 9.5). 
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate. 
Study data, which may include data on genomic variants, may be submitted to 
government or other health research databases or shared with researchers, government 
agencies, companies, or other groups that are not participating in this study.  These data 
may be combined with or linked to other data and used for research purposes, to 
advance science and public health, or for analysis, development, and commercialization 
of products to treat and diagnose disease.  In addition, redacted Clinical Study Reports 
and other summary reports will be provided upon request (see Section 9.5). 
8.5 
FINANCIAL DISCLOSURE 
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2). 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION 
9.1 
STUDY DOCUMENTATION 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data. 
9.2 
PROTOCOL DEVIATIONS 
The investigator should document and explain any protocol deviations.  The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed. 


 
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9.3 
MANAGEMENT OF STUDY QUALITY 
The Sponsor or delegate contract research organization (CRO) will implement a system 
to manage the quality of the study, focusing on processes and data that are essential to 
ensuring patient safety and data integrity.  Prior to study initiation, the Sponsor or CRO 
will identify potential risks associated with critical trial processes and data and will 
implement plans for evaluating and controlling these risks.  Risk evaluation and control 
will include the selection of risk-based parameters (e.g., adverse event rate, protocol 
deviation rate) and the establishment of quality tolerance limits for these parameters 
prior to study initiation.  Detection of deviations from quality tolerance limits will trigger an 
evaluation to determine if action is needed.  Details on the establishment and monitoring 
of quality tolerance limits will be provided in a Quality Tolerance Limit Management Plan. 
9.4 
SITE INSPECTIONS 
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study. 
9.5 
ADMINISTRATIVE STRUCTURE 
This study is sponsored and managed by F. Hoffmann-La Roche Ltd.  A CRO will 
manage clinical site operations and medical monitoring.  
Approximately 400 sites globally will participate to enroll approximately 658 patients.  An 
IxRS will be used for study drug inventory management and to enroll patients in 
this study.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests, biomarker and PK analyses, PFTs), as specified in 
Section 4.5. 
Samples for urine pregnancy tests will be analyzed at site locally. Samples for PD, PK, 
biomarker, and ADA tests will be sent to the Sponsor or a designee for storage and 
analysis.  
PRO data will be recorded electronically via devices supplied by a PRO vendor.  
HRCT imaging and lung biopsy slides (if available) will be read centrally and managed 
by a central reading vendor(s). 
An iDMC will be employed to monitor and evaluate patient safety throughout the study.  
The iDMC may also monitor other data (e.g., PK).  Details regarding the iDMC data 
evaluation and monitoring will be specified in the iDMC charter.   


 
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A Clinical Adjudication Committee, an independent and blinded expert clinician panel, 
will adjudicate potential cases of acute exacerbations of IPF, hospitalizations for 
respiratory causes and all deaths.  The definition of events for independent assessment, 
criteria for adjudication of events and details of the adjudication process will be provided 
in a charter.  The clinical expert panel's composition and a description of its 
responsibilities will also be provided in the charter. 
An Anaphylaxis Adjudication Committee, an independent and blinded committee 
composed of external experts in allergic diseases, will adjudicate all potential 
anaphylaxis cases reported by investigators to the Sponsor.  The committee will assess 
whether the reported event is a true anaphylaxis event (based on Sampson's criteria) 
and whether the reported anaphylaxis event is causally related to study treatment.  
Further details will be provided in the Anaphylaxis Adjudication Charter. 
An external global Steering Committee, comprised of recognized experts in IPF, will 
provide oversight of Study WA42293 and Study WA42294.  Their roles and 
responsibilities will be outlined in the Steering Committee Charter. 
9.6 
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS 
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries, and in peer-reviewed journals.  The Sponsor will 
comply with all requirements for publication of study results.  Study data may be shared 
with others who are not participating in this study (see Section 8.4 for details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request.  For more information, refer to the Roche Global Policy on Sharing of Clinical 
Trials Data at the following website: 
www.roche.com/roche global policy on sharing of clinical study information.pdf 
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound. 
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 


 
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proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel. 
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise. 
9.7 
PROTOCOL AMENDMENTS 
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements. 
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information). 


 
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10. 
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Appendix 1: Schedule of Activities 
  
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126/Protocol WA42293, Version 5 
ADA = anti-drug antibody; AE = adverse event; Discon. = discontinuation; DLCO = diffusing capacity for carbon monoxide; eCRF = electronic Case 
Report Form; EQ-5D-5L = EuroQol 5-Dimension, 5-Level Questionnaire; HRCT = high-resolution computed tomography; IPF = idiopathic pulmonary 
fibrosis; OLE = open-label extension; PCR = polymerase chain reaction; PD = pharmacodynamic; PK = pharmacokinetic; SGRQ = St. George 
Respiratory Questionnaire; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; TB = tuberculosis; 
Treat. = treatment, UCSD-SOBQ = University of California, San Diego-Shortness of Breath Questionnaire. 
a Screening period is up to 4 weeks.  Eligible patients can be randomized as soon as their screening assessments have been completed and all 
eligibility criteria have been confirmed.  Randomization must occur prior to any baseline assessments being conducted on Visit 2.  
b Patients will have their final safety and efficacy assessments, including HRCT if applicable, at Week 52. 
c Patients not enrolling in the OLE study will return for an end-of-study visit at Week 56.  
d Treatment discontinuation visit should occur 4 weeks after final dose of study drug.  Study discontinuation visit should occur 4 weeks after the 
treatment discontinuation visit (8 weeks after the final dose of study drug). 
e To allow for flexibility around weekends, holidays, and so on, the loading dose visits may occur over a time span of up to 8 days, with a minimum 
of 1 full calendar day between administration of doses (patients must not be dosed on consecutive days).  In case one or more loading doses 
have been missed or delayed beyond the 8-day loading phase window, loading doses should be administered again at the next scheduled visit.  
No loading doses should be administered outside of the 8-day loading phase window. 
f Patients who discontinue study drug early will have ± 2-week window to complete study visits.  
g Testing for active or latent TB should be conducted with an interferon gamma release assay during screening.  Patients who have completed 
treatment for active or latent tuberculosis within 6 months prior to screening, and have no evidence of recurrent disease, do not need to be 
tested. 
h On dosing days, vital signs should be completed predose (within 60 minutes prior to dosing), every 15 minutes during infusion, and 
30−60 minutes postdose. 
i Full physical exam during screening and baseline, and an abbreviated physical exam thereafter. 
j Patients will have an assessment for SARS-CoV-2 serology at baseline, then every 3 months, and at the Week 52 visit.  In the event of an acute 
respiratory exacerbation or infection during the study, additional SARS-CoV-2 serology or PCR testing may be performed according to local 
guidelines as needed.  
k Blood samples for ADA, serum tryptase, complement C3, and PK analyses should be obtained at the time of the events of ≥ Grade 2 
infusion-related reactions, or suspected anaphylaxis, or hypersensitivity reactions whenever possible.  Serum tryptase should be collected 
between 1 and 6 hours after the event and a blood sample for ADA, serum tryptase, complement C3, should be obtained at the first follow-up 
visit after the events of suspected anaphylaxis, or hypersensitivity reactions. 
l For PK, /PD biomarker and ADA sampling schedule, see Appendix 2.  For China-specific schedule, see Appendix 3.  For Japan-specific 
schedule, see Appendix 4. 


Appendix 1: Schedule of Activities 
  
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
127/Protocol WA42293, Version 5 
m SGRQ, UCSD-SOBQ, and EQ-5D-5L are to be completed in this order and prior to any other trial-related procedures. 
n If an HRCT of adequate quality for confirmation of eligibility is not available within 12 months prior to screening, an HRCT must be obtained 
during screening for eligibility verification.  Only patients who have HRCT performed as part of screening are required to have a repeat HRCT 
scan at Week 52.  
o Repeat loading doses will be required if patients miss infusions of study treatment.  Following a missed infusion, the patient should receive three 
doses on alternate days at the next scheduled visit; scheduled efficacy assessments will only be performed on the first of the three loading dose 
days.  Additional PK/PD samples may be taken in such cases (see Appendix 2, unscheduled visits).  
p In exceptional circumstances, if the site is unable to perform all study procedures on the same day or at the same site, study drug infusion may 
be administered up to 48 hours after the on-site efficacy assessments, provided that these are completed within the 5-day visit window.  
However, the sequence of procedures must be maintained, and all efforts should be made to complete study assessments and procedures on 
the same date. 
q At each visit, the investigator should assess the patient’s use of pirfenidone or nintedanib since the last visit.  Any change in dose should be 
recorded on the eCRF. 






Appendix 2: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples for 
all IPF Patients, Excluding China 
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
130/Protocol WA42293, Version 5 
d The urine samples are optional and should be obtained only from patients who sign the 
separate RBR Informed Consent Form to collect residual samples at assigned clinical visits. 
e PK samples will be collected as plasma, and ADA samples will be collected as serum. 
f If starting the extension study at Week 52, PRM-151 PK, ADA, and PD biomarker samples 
should be collected prior to dosing.  In circumstances when drug reloading is required, if the 
first day of the start of reloading does not coincide with the planned sample collection dates, 
PK, ADA, and PD biomarker samples should be taken prior to the start of the first loading 
dose.  










Appendix 4: Schedule of Pharmacokinetic, Immunogenicity, and Biomarker Samples for 
IPF Patients in Japan 
  
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
135/Protocol WA42293, Version 5 
c The PBMC samples are optional and should be obtained only from patients who sign the separate RBR 
Informed Consent Form.  
d The urine samples are optional and should be obtained only from patients who sign the separate RBR 
Informed Consent Form to collect residual samples at assigned clinical visits. 
e PK samples will be collected as plasma, and ADA samples will be collected as serum.  
f If starting the extension study at Week 52, PRM-151 PK, ADA, and PD biomarker samples should be 
collected prior to dosing.  In circumstances when drug reloading is required, if the first day of the start of 
reloading does not coincide with the planned sample collection dates, PK, ADA, and PD biomarker samples 
should be taken prior to the start of the first loading dose. 


 
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Appendix 5 
 
Sampson's Criteria for Diagnosing Potential Cases of 
Anaphylaxis 
Anaphylaxis is highly likely when any one of the following three criteria is fulfilled: 
1) Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen 
lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
a) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow [PEF], hypoxemia) 
b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(e.g., hypotonia [collapse], syncope, incontinence) 
 
2) Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
a) Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, 
swollen lips-tongue-uvula) 
b) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia) 
c) Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence) 
d) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting) 
 
3) Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
a) Adults:  systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that person's baseline 
 
REFERENCE 
Sampson HA, Munoz-Furlong A, Campbell RL, et al: Second symposium on the 
definition and management of anaphylaxis: summary report: Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
Symposium. J Allergy Clin Immunol 2006;117: 3917. 
 
 


  
137/Protocol WA42293, Version 5 
Appendix 6 
 
St. George’s Respiratory Questionnaire  
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study. 
 
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd


Appendix 6:  St. George’s Respiratory Questionnaire 
  
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
138/Protocol WA42293, Version 5 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Appendix 6:  St. George’s Respiratory Questionnaire 
  
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
139/Protocol WA42293, Version 5 
 
 
 


Appendix 6:  St. George’s Respiratory Questionnaire 
  
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
140/Protocol WA42293, Version 5 
 


Appendix 6:  St. George’s Respiratory Questionnaire 
  
141/Protocol WA42293, Version 5 
 
 
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd


Appendix 6:  St. George’s Respiratory Questionnaire 
  
142/Protocol WA42293, Version 5 
 
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd


 
143/Protocol WA42293, Version 5 
Appendix 7 
 
University of California, San Diego –  
Shortness of Breath Questionnaire  
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study. 
 
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd


Appendix 7:  University of California, San Diego–Shortness of Breath Questionnaire 
  
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
144/Protocol WA42293, Version 5 
 
 


Appendix 7:  University of California, San Diego–Shortness of Breath Questionnaire 
  
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
145/Protocol WA42293, Version 5 


Appendix 7:  University of California, San Diego–Shortness of Breath Questionnaire 
 
 
146/Protocol WA42293, Version 5 
 
 
 
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd


 
 
147/Protocol WA42293, Version 5 
Appendix 8 
 
EuroQol 5-Dimension Questionnaire, 5-Level Version 
Do not reproduce or distribute.  The Sponsor will provide 
sites with all instruments to be completed in this study. 
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd


Appendix 8:  EuroQol 5-Dimension Questionnaire, 5-Level Version 
 
 
148/Protocol WA42293, Version 5 
  
 
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd


 
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
149/Protocol WA42293, Version 5 
Appendix 9 
 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
The United States of America (USA) National Cancer Institute Common Terminology 
Criteria for Adverse Events, version 5.0 (NCI CTCAE, v.5.0) can be found on the 
following website. 
https://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm#ctc 50 
[Accessed: 21 September 2019] 
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 v5.0 includes 811 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. 
 
 
 


 
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Appendix 10 
 
Method of Eligibility Verification and Implementation of 
Randomization 
Screening 
Patients who are candidates for screening into the study will be evaluated for eligibility 
by the investigator to ensure that all eligibility criteria have been satisfied for 
randomization.  The Screening period starts once Informed Consent is signed and ends 
at randomization.  
Additional guidance on specific eligibility criteria follows.  
 
Inclusion Criterion: Idiopathic pulmonary fibrosis (IPF) diagnosis is made by the site, 
per the 2018 IPF Clinical Practice Guidelines by American Thoracic Society (ATS), 
the European Respiratory Society (ERS), Japanese Respiratory Society (JRS) and 
the Latin American Thoracic Society (ALAT) (Raghu et al. 2018).  For purposes of 
this trial patients with a clinical context suggestive of IPF and with high-resolution 
computed tomography (HRCT) pattern of usual interstitial pneumonia (UIP) or 
probable UIP are considered to have a diagnosis of IPF when biopsy is not available 
(Raghu et al. 2019). 
 
An HRCT of adequate quality, as determined by the central reviewer, obtained 
within 12 months prior to Screening is required for confirmation of eligibility.  If an 
HRCT of adequate quality is not available within 12 months prior to Screening, an 
HRCT must be obtained during Screening for eligibility verification.  All HRCT scans 
intended for eligibility verification will be sent for central radiology review.  Please 
refer to the relevant study document for details on quality criteria and transmission 
of HRCT.  
 
The reference set for spirometry is GLI2012 (Quanjer et al. 2012).  
  




 
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Appendix 11 
 
Borg Scale for Rating Dyspnea and Overall Fatigue (CR10) 
 
 
 
 
 
 
 


Signature Page for: System identifier:RIM-CLIN-438677
Protocol - WA42293 - ZINPENTRAXIN ALFA - v5 - Published
Approval Task
Company Signatory
28-Apr-2022 08:59:34 GMT+0000

SAP_001.pdf: 
 
Official Title: 
 
A Phase III Randomized, Double-Blind, Placebo-Controlled Trial to 
Evaluate the Efficacy and Safety of PRM-151 in Patients With 
Idiopathic Pulmonary Fibrosis 
NCT Number: NCT04552899 
Document Dates: SAP Version 1: 18-October-2022 
 
 
 


 
 
 
STATISTICAL ANALYSIS PLAN APPROVAL 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
DATE FINAL: 
See electronic signature on the last page of this 
document. 
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
PRM-151 (Zinpentraxin Alfa)—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WA42293 
 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: A PHASE III RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED TRIAL TO EVALUATE THE EFFICACY 
AND SAFETY OF PRM-151 IN PATIENTS WITH IDIOPATHIC 
PULMONARY FIBROSIS 
STUDY NUMBER: 
WA42293 (also known as PRM-151-303) 
STUDY NAME:  
STARSCAPE 
VERSION NUMBER: 
1  
ROCHE COMPOUND(S): 
Recombinant human pentraxin-2 (rhPTX-2; PRM-151; 
RO7490677) [Zinpentraxin Alfa] 
EUDRACT NUMBER: 
2020-000791-38 
IND NUMBER: 
110,774 
NCT NUMBER: 
NCT04552899 
PLAN PREPARED BY: 
, M.Sc. 
, Ph.D. 


 
PRM-151 (Zinpentraxin Alfa) — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WA42293 
2 
 
STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This Statistical Analysis Plan (SAP) was developed based on Roche SAP model 
document Version 2, 26 October 2020. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
1 
See electronic signature on 
the last page of this 
document 
Version 5, 28 April 2022 


 
PRM-151 (Zinpentraxin Alfa) — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WA42293 
3 
 
 
TABLE OF CONTENTS 
1. 
INTRODUCTION ............................................................................. 8 
1.1 
Objectives, Endpoints and Estimands ....................................... 8 
1.2 
Study Design ........................................................................... 14 
1.2.1 
Treatment Assignment and Blinding ........................................ 15 
1.2.1.1 
Treatment Assignment ............................................................. 15 
1.2.1.2 
Blinding .................................................................................... 16 
1.2.2 
Central Review and Adjudication ............................................. 17 
1.2.2.1 
Pulmonary Function Tests ....................................................... 17 
1.2.2.2 
High-Resolution Computed Tomography ................................. 18 
1.2.2.3 
Lung Biopsy ............................................................................. 18 
1.2.2.4 
Assessment of Acute Exacerbations of IPF, 
Hospitalizations for Respiratory Causes, and Deaths 
(Adjudicated Events) ................................................................ 18 
1.2.2.5 
Assessment for Suspected Anaphylaxis .................................. 19 
1.2.3 
Data Monitoring ....................................................................... 19 
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION ........................................................................ 19 
2.1 
Statistical Hypotheses ............................................................. 19 
2.2 
Sample Size Determination ..................................................... 20 
2.2.1 
Assumptions on Treatment Effects for Sample-Size and 
Power Calculations .................................................................. 20 
2.2.2 
Robustness of Power and Sample-Size Calculations .............. 21 
2.2.3 
Sample Size for the China Subpopulation ............................... 22 
3. 
ANALYSIS SETS .......................................................................... 23 
4. 
STATISTICAL ANALYSES ........................................................... 23 
4.1 
General Consideration ............................................................. 24 
4.2 
Participant Disposition ............................................................. 24 
4.3 
Primary Endpoint(s) Analysis ................................................... 24 
4.3.1 
Definition of Primary Endpoint(s) ............................................. 24 
4.3.2 
Main Analytical Approach for Primary Endpoint ....................... 25 
4.3.3 
Sensitivity Analyses for Primary Endpoint ............................... 26 


 
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4.3.3.1 
Sensitivity Analysis Addressing the Effect of Missing Data 
After Death due to IPF ............................................................. 26 
4.3.3.1.1 
Sensitivity Analysis Addressing the Effect of Missing Data 
After Treatment Discontinuation .............................................. 26 
4.3.3.1.2 
Sensitivity Analysis Addressing Non-linearity .......................... 27 
4.3.4 
Supplementary Analyses for Primary Endpoint(s) ................... 27 
4.3.4.1 
Subgroup Analyses for Primary Endpoint(s) ............................ 27 
4.4 
Secondary Endpoints Analyses ............................................... 28 
4.4.1 
Key/Confirmatory Secondary Endpoint .................................... 29 
4.4.2 
Supportive Secondary Endpoint(s) .......................................... 29 
4.4.2.1 
Other Continuous Secondary Endpoints .................................. 29 
4.4.2.2 
PRO Secondary Endpoints ...................................................... 30 
4.4.2.3 
Time-to-Event Secondary Endpoints ....................................... 31 
4.5 
Exploratory Endpoint(s) Analysis ............................................. 33 
4.6 
Safety Analyses ....................................................................... 35 
4.6.1 
Extent of Exposure .................................................................. 35 
4.6.2 
Adverse Events ........................................................................ 36 
4.6.3 
Adjudicated Anaphylactic and Hypersensitivity Reactions ....... 39 
4.6.4 
Laboratory Data ....................................................................... 39 
4.6.5 
Vital Signs ................................................................................ 40 
4.6.6 
ECGs ....................................................................................... 40 
4.6.7 
Other Safety Endpoints ............................................................ 40 
4.7 
Other Analyses ........................................................................ 40 
4.7.1 
Summaries of Conduct of Study .............................................. 40 
4.7.2 
Summaries of Treatment Group Comparability ........................ 40 
4.7.3 
Pharmacokinetic Analyses ....................................................... 41 
4.7.4 
Biomarker Analyses ................................................................. 41 
4.7.5 
Immunogenicity Analyses ........................................................ 41 
4.7.6 
Analyses of China and Japan Subpopulations ........................ 42 
4.7.7 
Other Analyses ........................................................................ 43 
4.8 
Interim Analyses ...................................................................... 43 
4.8.1 
Planned Interim Analysis ......................................................... 43 
4.8.2 
Optional Interim Analysis ......................................................... 44 


 
PRM-151 (Zinpentraxin Alfa) — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WA42293 
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5. 
SUPPORTING DOCUMENTATION .............................................. 45 
6. 
REFERENCES.............................................................................. 46 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ..................................... 8 
Table 2 
Primary Estimand Analysis Strategy for Intercurrent Events ....... 13 
Table 3 
Results of the PRM-151-202 Study on Planned Primary and 
Key Secondary Endpoints ........................................................... 20 
Table 4 
Results of Power Calculations for Different Effect-Sizes and 
N  658 Patients .......................................................................... 22 
Table 5 
Analysis Populations ................................................................... 23 
Table 6 
Subgroup Definitions ................................................................... 28 
Table 7 
Estimand Analysis Strategy for Intercurrent Events: 
Time-to-Event Secondary Endpoints .......................................... 32 
 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 15 
 
 
LIST OF APPENDICES 
Appendix 1 
Changes to Protocol-Planned Analyses ...................................... 46 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Description 
6MWD 6-minute walk distance 
6MWT 
6-minute walk test 
ADA 
anti-drug antibody 
AE 
adverse event 
ANCOVA 
analysis of covariance 
ALAT 
Latin American Thoracic Society 
ATS 
American Thoracic Society 
BMI 
body mass index 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DLCO 
carbon monoxide diffusing capacity 
EQ-5D-5L 
EuroQol 5-Dimension, 5-Level Questionnaire 
EuroQol 
European Quality of Life Scale 
ERS 
European Respiratory Society 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
Hgb 
hemoglobin 
HR 
hazard ratio 
HRCT 
high-resolution computed tomography 
HRQoL 
health-related quality of life 
IA 
interim analysis 
ICH 
International Council on Harmonization 
iDMC 
independent Data Monitoring Committee 
IPF 
idiopathic pulmonary fibrosis 
ITT 
intent to treat 
IV 
intravenous 
IxRS 
interactive voice/web-based response system 
JRS 
Japanese Respiratory Society 
LLoQ 
lower limit of quantification 
MAR 
missing at random 
MDD 
minimally detectable difference 


 
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MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
NCI 
National Cancer Institute 
NMPA 
National Medical Products Administration 
OLE 
open-label extension 
PD 
pharmacodynamic 
PFT 
pulmonary function test 
PK 
pharmacokinetic 
PRO 
patient-reported outcomes 
Q4W 
every 4 weeks 
zinpentraxin alfa 
recombinant human pentraxin 2; PRM-151 
SAE 
serious adverse events 
SAP 
Statistical Analysis Plan 
SGRQ 
St. George Respiratory Questionnaire 
SOC 
standard of care 
SMQs 
standardized MedDRA queries 
UCSD-SOBQ 
University of California, San Diego-Shortness of Breath 
Questionnaire 
UIP 
usual interstitial pneumonia 
VAS 
visual analog scale 
 
 


 
PRM-151 (Zinpentraxin Alfa) — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WA42293 
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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides details on the study design, outcome 
measures, and statistical analysis plan for Study WA42293.  The analyses and 
endpoints specified in this document supersede the analysis plan described in the study 
protocol.  The International Nonproprietary Name (INN) zinpentraxin alfa is now the 
preferred name of the study drug under investigation (rather than PRM-151 or rhPTX-2); 
it will be used throughout this SAP. 
1.1 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
This study will evaluate the efficacy, safety, and pharmacokinetics of zinpentraxin alfa 
compared with placebo in participants with idiopathic pulmonary fibrosis (IPF).  Specific 
objectives and corresponding endpoints for the study are outlined in Table 1.  The 
Clinical Adjudication Committee mentioned in the table below and the rest of the SAP 
(with the exception of the Anaphylaxis Adjudication Committee introduced in 
Section 1.2.2.5) refers to the Clinical Adjudication Committee reviewing acute or 
suspected exacerbation of IPF, hospitalization due to respiratory causes, and death. 
Table 1 
Objectives and Corresponding Endpoints 
Primary Efficacy Objective 
Corresponding Endpoint 
 
To evaluate the efficacy of 
zinpentraxin alfa plus SOC treatment 
as needed compared with placebo 
plus SOC treatment as needed 
 
Absolute change from baseline at Week 52 in 
FVC (mL) 
Key Secondary Efficacy Objective 
Corresponding Endpoint 
 
To evaluate the efficacy of 
zinpentraxin alfa plus SOC treatment 
as needed compared with placebo 
plus SOC treatment as needed 
 
Absolute change from baseline at Week 52 in 
6MWD (in meters) 
Secondary Efficacy Objective 
Corresponding Endpoints 
 
To evaluate the efficacy of 
zinpentraxin alfa plus SOC treatment 
as needed compared with placebo 
plus SOC treatment as needed 
 
Absolute change from baseline at Week 52 in 
FVC% predicted 
 
Time to disease progression, defined as time 
to first occurrence of   10% absolute decline in 
FVC% predicted,   15% relative decline in 
6MWD, or death 
 
Time to first respiratory-related hospitalization 
(defined as non-elective hospitalization due to 
any respiratory cause, including acute 
exacerbations of IPF, or suspected acute 
exacerbations of IPF, as determined by the 
Clinical Adjudication Committee) 
 
Absolute change from baseline at Week 52 in 
UCSD-SOBQ score 


 
PRM-151 (Zinpentraxin Alfa) — F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan WA42293 
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 
Absolute change from baseline at Week 52 in 
SGRQ Total Score 
 
Time to first acute exacerbation of IPF, or 
suspected acute exacerbation of IPF, as 
determined by the Clinical Adjudication 
Committee 
 
Absolute change from baseline at Week 52 in 
Hgb-corrected carbon monoxide diffusing 
capacity (DLCO) % predicted  
 
Survival, as measured by all-cause mortality 
Exploratory Efficacy Objective 
Corresponding Endpoints 
 
To evaluate the efficacy of 
zinpentraxin alfa plus SOC treatment 
as needed compared with placebo 
plus SOC treatment as needed 
 
Absolute change from baseline at Week 52 in 
FVC% predicted and FVC (mL), by baseline 
concomitant medication stratum 
 
Absolute change from baseline at Week 52 in 
FVC% predicted and FVC (mL), by mucin 5B 
(MUC5B) risk allele positive or negative status 
 
Absolute change from baseline at Week 52 in 
6MWD (m), by baseline concomitant 
medication stratum 
 
Proportion of patients who progress on the 
UCSD-SOBQ, as indicated by an increase in 
score of 10 points or greater 
 
Proportion of patients who progress on the 
SGRQ total score, as indicated by an increase 
in score of 7 or greater 
 
Change from baseline to Week 52 in SGRQ 
Individual Domains (Symptoms, Activity, and 
Impacts) Score 
 
Proportion of patients who progress on the 
SGRQ Symptoms Domain, as indicated by an 
increase in score of 8 or greater 
 
Proportion of patients who progress on the 
SGRQ Activity Domain, as indicated by an 
increase in score of 5 or greater 
 
Proportion of patients who progress on the 
SGRQ Impacts Domain, as indicated by an 
increase in score of 7 or greater 
 
Absolute change from baseline at Week 52 in 
quantitative imaging analysis parameters of 
HRCT scan of the thorax 
 
Length of hospital stay for respiratory-related 
hospitalizations 
 
Total time in intensive care units due to 
respiratory causes 
 
Unscheduled outpatient clinic/urgent 
care/emergency room utilization related to 
respiratory events 


 
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Statistical Analysis Plan WA42293 
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 
Number of acute exacerbations during the 
52 weeks; as determined by the Clinical 
Adjudication Committee 
 
Survival as measured by IPF-related mortality 
 
Survival as measured by respiratory-related 
mortality 
 
Disease progression and subsequent start of 
oxygen supplementation 
 
Change in PFT parameters (FVC, DLCO) or 
6MWD from baseline at Week 52 between 
SARS-CoV2 antibody positive compared with 
negative patients (present at baseline) 
 
Change in PFT parameters (FVC, DLCO) or 
6MWD from baseline at Week 52 in patients 
who develop SARS-CoV2 antibodies during 
treatment (not present at baseline) 
 
Absolute change from baseline at Week 52 in 
FVC (mL) by selected countries 
Safety Objective 
Corresponding Endpoints 
 
To evaluate the safety of zinpentraxin 
alfa plus SOC treatment as needed 
compared with placebo plus SOC 
treatment as needed 
 
Incidence and severity of adverse events, with 
severity determined according to the 5-point 
severity scale (NCI CTCAE v.5.0) 
 
Incidence and severity of IRRs and other 
adverse events of special interest 
 
Proportion of patients permanently 
discontinuing study treatment due to 
adverse events 
 
Change from baseline in targeted clinical 
laboratory test results 
Pharmacokinetic Objective 
Corresponding Endpoint 
 
To characterize the PK profile of 
zinpentraxin alfa  
 
Plasma concentrations of zinpentraxin alfa at 
specified timepoints 
Exploratory Pharmacokinetic Objective 
Corresponding Endpoints 
 
To evaluate potential relationships 
between drug exposure and the 
efficacy and safety of zinpentraxin alfa 
 
Relationship between PK for zinpentraxin alfa 
and efficacy endpoints 
 
Relationship between PK for zinpentraxin alfa 
and safety endpoints 


 
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Immunogenicity Objective 
Corresponding Endpoints 
 
To evaluate the immune response to 
zinpentraxin alfa  
 
Prevalence of ADAs at baseline  
 
Incidence of ADAs during the study 
Exploratory Immunogenicity 
Objective 
Corresponding Endpoint 
 
To evaluate potential effects of ADAs 
 
Relationship between ADA status and efficacy, 
safety, or PK endpoints 
Exploratory Biomarker Objective 
Corresponding Endpoint 
 
To identify and/or evaluate biomarkers 
that are predictive of response to 
zinpentraxin alfa (i.e., predictive 
biomarkers), are early surrogates of 
efficacy, are associated with 
progression to a more severe disease 
state (i.e., prognostic biomarkers), are 
associated with acquired resistance to 
zinpentraxin alfa, are associated with 
susceptibility to developing adverse 
events or can lead to improved 
adverse event monitoring or 
investigation (i.e., safety biomarkers), 
can provide evidence of zinpentraxin 
alfa activity (i.e., PD biomarkers), or 
can increase the knowledge and 
understanding of disease biology and 
drug safety 
 
Relationship between biomarkers in blood and 
efficacy, safety, PK, immunogenicity, or other 
biomarker endpoints 
 
Exploratory Health Status Utility 
Objective 
Corresponding Endpoint 
 
To evaluate health status utility scores 
of participants treated with 
zinpentraxin alfa plus SOC treatment 
as needed compared with placebo 
plus SOC treatment as needed 
 
Absolute change from baseline in EuroQol 
EQ-5D-5L index-based, and VAS scores at 
Week 52 
6MWD    6-minute walk distance; 6MWT   6-minute walk test; ADA anti-drug antibody; 
CTCAE  Common Terminology Criteria for Adverse Events; DLCO    carbon monoxide 
diffusing capacity; EQ-5D-5L   EuroQol 5-Dimension, 5-Level Questionnaire; FVC    forced 
vital capacity; Hgb  hemoglobin; HRCT    high-resolution computed tomography; 
HRQol  health‑related quality of life; NCI  National Cancer Institute; PD  pharmacodynamic; 
PFT    pulmonary function test; PK  pharmacokinetic; SGRQ    St. George Respiratory 
Questionnaire; SOC    standard of care; UCSD-SOBQ    University of California, San 
Diego‑Shortness of Breath Questionnaire; VAS  visual analogue scale.  


 
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Primary Estimand 
The primary efficacy objective is to evaluate the effect of zinpentraxin alfa plus standard 
of care (SOC) treatment as needed compared with the matching placebo plus SOC 
treatment as needed on disease progression at Week 52, regardless of changes to the 
initial treatment regimen (including randomized drug and any associated treatment) and 
in the absence of lung transplantation.  The primary estimand is the difference in mean 
absolute change from baseline at Week 52 in forced vital capacity (FVC) mL between 
zinpentraxin alfa and placebo treated patients.  The primary estimand is further 
described by the following attributes: 
 
Population:  adults diagnosed with IPF who meet the inclusion/exclusion criteria 
presented in Section 4.1 of the protocol. 
 
Treatment:  study drug (zinpentraxin alfa or placebo) as randomized, in combination 
with any background or additional treatment (i.e., zinpentraxin alfa or placebo taken 
alone or as an add-on to SOC with pirfenidone or nintedanib, dosed as required) 
including all changes in SOC treatment and all other additional treatments, with the 
exclusion of lung-transplantation. 
 
Variable:  absolute change from baseline at Week 52 in FVC mL.  
 
Population-level summary measure:  between randomized treatment difference in 
mean change from baseline at Week 52 in FVC mL.  
 
Intercurrent events: 
– 
Change to initial treatment regimen:  The treatment effect of interest is 
irrespective of changes to the initial treatment regimen, which include changes 
to study drug (including treatment discontinuation), changes to standard of 
care, and the use of prohibited medication.  Therefore, all data collected after 
changes to the initial treatment regimen will be included in the analysis.  Any 
data missing after changes to the initial treatment regimen will be assumed to 
be missing at random (MAR).  A sensitivity analysis described in 
Section 4.3.3.1 will assess the impact of assuming that data missing after 
treatment discontinuation is MAR. 
– 
Death:  Deaths are expected to be rare as the study plans to include patients 
with a life expectancy longer than the study duration.  Given that deaths are 
expected to be rare, and the observation that conservative imputation of 
missing, post-death data for continuous FVC (mL) outcomes introduces highly 
influential outliers, deaths will be treated with a hypothetical strategy.  
A sensitivity analysis described in Section 4.3.3.1.1 will assess the impact of 
this strategy on treatment effect estimation and inference. 
– 
Lung transplantation:  Lung transplantation is expected to be rare during the 
study, as patients likely to receive a lung transplantation during the study are 
excluded.  Furthermore, the treatment effect of interest is in the hypothetical 
scenario that lung transplantations are unavailable, since assessments 
following lung transplantation are no longer reflective of diseased lung(s).  


 
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In some instances, FVC can improve to over 80% following lung 
transplantation, or even 100% for bilateral lung transplantation 6-12 months 
after surgery (Hernandez et al. 2018).  Therefore, any data recorded after lung 
transplantation will be excluded from the analysis and treated as missing data 
because such data is not compatible with this hypothetical strategy. 
– 
Hospitalization for COVID-19:  The treatment effect of interest is irrespective of 
COVID-19 hospitalization, given that COVID-19 hospitalizations will likely 
continue for the population of interest for the foreseeable future.  Therefore, all 
data recorded after COVID-19 hospitalization will be included in the analysis.  
Any missing data after COVID-19 hospitalizations will be assumed to be MAR. 
 
In general, with the exception of data collected after lung transplantation, all observed 
outcome data will be included in the analysis.  All missing data, including data excluded 
after lung transplantations and missing data due to death, will be considered similar to 
data from other patients in the same treatment group with the same baseline 
characteristics with no such missing data (compatible with MAR assumption).  Sensitivity 
analyses addressing missing data assumptions are described in Section 4.3.3. 
Table 2 below summarizes the handling of intercurrent events for the primary estimand. 
Table 2 
Primary Estimand Analysis Strategy for Intercurrent Events 
Intercurrent Event (ICE) 
Analysis strategy 
Any change to randomized 
treatment 
Temporary study drug 
discontinuation 
Treatment policy 
 
All measurements post 
ICE analyzed 
Permanent study drug 
discontinuation 
Temporary or permanent 
change in study drug dose 
Missed study drug dose 
Randomized treatment 
switches, if any 
Any change in standard of care 
(SOC), with pirfenidone or 
nintedanib therapy 
SOC started during study 
Treatment policy 
 
All measurements post 
ICE analyzed 
Change in dose of SOC 
SOC discontinued 
SOC switch (from pirfenidone 
to nintedanib or vice-versa) 


 
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Table 2 Primary Estimand Analysis Strategy for Intercurrent Events (cont.) 
Intercurrent Event (ICE) 
Analysis strategy 
Other concomitant 
treatment 
Use of prohibited concurrent 
medication (Section 4.4.2 in the 
Protocol) 
Treatment policy 
 
All measurements post ICE analyzed 
Terminal events 
 
 
 
Death 
 
Hypothetical strategy 
 
Deaths are expected to be rare 
 
Lung 
transplantation 
 
Hypothetical Strategy 
 
Measurements collected after lung 
transplantation are excluded from the 
analysis 
Hospitalization for 
COVID-19 
 
 
Treatment policy strategy 
 
All measurements post ICE analyzed 
COVID-19 Coronavirus disease 2019; ICE  intercurrent event; IPFidiopathic pulmonary 
fibrosis, SOC  standard of care. 
  
1.2 
STUDY DESIGN 
Study WA42293 is a Phase III, randomized, double-blind, placebo-controlled, pivotal 
clinical trial designed to confirm the efficacy and safety of zinpentraxin alfa in the 
treatment of IPF patients with or without concurrent treatment with pirfenidone or 
nintedanib. 
Approximately 658 patients will be randomly assigned on a 1:1 basis to treatment with 
zinpentraxin alfa at a dose of 10 mg/kg or matched placebo on Days 1, 3, and 5, then 
one infusion every 4 weeks (Q4W) for 48 weeks.  Patients will be evaluated for study 
eligibility during a screening period of up to 4 weeks.  Study treatment will be 
administered by intravenous (IV) infusion over 50–70 minutes every 4 weeks.  If any 
infusions are missed, repeat loading doses will be required at the next scheduled visit 
(three doses administered on alternate days).  During the placebo-controlled treatment 
period (defined as Day 1 to Week 52), patients will continue to receive blinded study 
treatment every 4 weeks to Week 48 and have a final assessment visit at Week 52.  
This study will enroll approximately 658 patients globally across all sites.  Enrollment will 
be globally competitive.  After completion of the global enrollment phase, additional 
patients may be enrolled in an extended China enrollment phase at sites in mainland 
China, Hong Kong, and Taiwan.  The global population will include all patients enrolled 
during the global enrollment phase and the China subpopulation will include all patients 
enrolled at sites in mainland China, Hong Kong, and Taiwan (i.e., during both the global 


 
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enrollment phase and the extended China enrollment phase).  Separate analyses will be 
performed for the global population and the China subpopulation (see Section 4.7.6 for 
China subpopulation analyses). 
Following participation in this study, patients may be eligible to participate in a separate 
open-label extension (OLE) study (Study WA42294) to receive treatment with 
zinpentraxin alfa and further study assessments.  Patients who do not enroll in the OLE 
study will be followed up for an additional 4 weeks (to Week 56, for safety monitoring).  
The OLE study will also consist of a long-term survival cohort, where patients who do not 
want further study assessments or treatment can enroll (for long-term collection of 
survival data only). 
The study schema is shown in Figure 1. 
Figure 1 Study Schema 
 
IVintravenous; OLEopen-label extension; Q4Wonce every 4 weeks. 
a Patients will have a final assessment visit at Week 52 (4 weeks after the final study drug 
infusion).  For patients enrolling into the OLE study, this will also be their end of study visit.  
b Patients who do not enroll in the OLE study will have their final assessment visit at Week 52, 
followed by an end of study visit at Week 56 (8 weeks after the final study drug infusion). 
  
1.2.1 
Treatment Assignment and Blinding 
1.2.1.1 
Treatment Assignment 
This is a randomized, double-blind study.  After initial written informed consent has been 
obtained, all screening procedures and assessments have been completed, and 
eligibility has been established for a patient, the study site will obtain the patient's 
identification number and treatment assignment from an interactive voice or web-based 
response system (IxRS). 


 
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Patients will be randomly assigned to one of two treatment arms:  zinpentraxin alfa or 
placebo.  Randomization will occur in a 1:1 ratio through use of a permuted block 
randomization method to ensure a balanced assignment to each treatment arm and will 
be stratified as follows: 
 
Concurrent use of nintedanib treatment versus pirfenidone treatment versus no 
concurrent treatment 
 
Geographic Region (China [including Hong Kong and Taiwan, if applicable], 
North America [United States and Canada], Europe [including eastern Europe], 
Latin America, and Rest of World [including east Asia, Australia, and New Zealand]) 
 
The randomization method implemented in the China extension cohort will be the same 
as that implemented in the global population, except for the stratification factor for 
geographic region. 
1.2.1.2 
Blinding 
Patients and all study site personnel will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill 
their job roles during a clinical trial.  These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, the independent data coordinating center 
(iDCC) and independent Data Monitoring Committee (iDMC) members. 
While pharmacokinetic (PK) and immunogenicity samples must be collected from 
patients assigned to the comparator arm to maintain the blinding of treatment 
assignment, PK and anti-drug antibody (ADA) assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of the study data.  
Laboratories responsible for performing study drug PK and ADA assays will be 
unblinded to patient treatment assignments to identify appropriate samples for analysis.  
PK samples from patients assigned to the comparator arm will not be analyzed for study 
drug PK concentration except by request (e.g., to evaluate a possible error in dosing).  
Plasma concentration (i.e., baseline, predose PK samples) to measure the endogenous 
level of human pentraxin-2 (hPTX-2) may be analyzed from all patients including 
patients from the comparator arm.  Baseline immunogenicity samples will be analyzed 
for all patients.  Post-baseline immunogenicity samples from patients assigned to the 
comparator arm will not be analyzed for ADAs except by request. 
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event (AE) for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations. 


 
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Zinpentraxin alfa is a human recombinant form of a naturally occurring regulatory 
protein, and there is no known antidote to this protein in the event of a safety event.  If 
the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  
The investigator should document and provide an explanation for any non-emergency 
unblinding.  If the Medical Monitor agrees to patient unblinding, the investigator will be 
able to break the treatment code by contacting the IxRS. 
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.8 in Protocol) that are considered by the investigator or Sponsor to be 
related to study drug.  The patient may continue to receive treatment, and the 
investigator, patient, and Sponsor personnel, with the exception of the Drug Safety 
representative and personnel who must have access to patient treatment assignments to 
fulfill their roles (as defined above), will remain blinded to treatment assignment. 
1.2.2 
Central Review and Adjudication 
Central review and adjudication will be performed for clinical and safety data as needed, 
prior to the efficacy or safety analyses.  The membership and procedures of each central 
review or adjudication will be detailed in a charter or requirements document.  
1.2.2.1 
Pulmonary Function Tests 
Standardized spirometry equipment and procedure guidelines will be provided to all 
study sites.  As some pulmonary function tests (PFTs) are considered 
aerosol‑generating procedures, additional precautions to reduce potential spread of 
infection should be taken in accordance with local guidance.  Spirometry will be 
performed according to American Thoracic Society (ATS) / European Respiratory 
Society (ERS) guidelines (as referenced in the PFT manual) as per the schedule of 
activities (see Appendix 1 of the protocol).  Details on PFT procedures are available in 
the PFT manual.  PFT data will be sent for central review.  
Carbon monoxide diffusing capacity (DLCO) will be measured according to ATS/ERS 
guidelines (as referenced in the PFT manual).  DLCO will be performed using local 
equipment, as this will not be provided to study sites. 
Acceptability of the spirometry and DLCO data from the computerized system (including 
screening assessments) will be determined by over-readers blinded to study drug 
treatment (comprising graphic representations of the maneuvers as well as numerical 
results).  Calculations for the reproducibility of the acceptable maneuvers will be 
performed and reviewed centrally by over-readers blinded to study drug treatment.  Only 
acceptable spirometry and DLCO data will be used.  


 
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The screening spirometry and/or DLCO sessions may be repeated once, if the initial 
session is rejected by the over-reader.  This is the only session during the study that 
may be repeated.  In extenuating circumstances, one further spirometry and/or DLCO 
session may be attempted after discussion with the Medical Monitor.  No more than 
three spirometry and/or DLCO sessions should be performed during the screening period.  
Repeat sessions are only permitted following rejection of previous sessions by the 
over-reader. 
1.2.2.2 
High-Resolution Computed Tomography 
Pulmonary high-resolution computed tomography (HRCT) scans will be reviewed during 
screening to confirm the IPF diagnosis.  Good-quality standard of care scans obtained 
 12 months prior to screening and in accordance with study image acquisition 
guidelines can be used for eligibility determination.  If scans meeting these conditions 
are not available, an HRCT scan may be conducted during screening.  HRCT scans will 
be reviewed first by the site radiologist and/or investigator to assess for eligibility.   
If the site determines that the patient’s HRCT meets IPF diagnostic criteria as specified 
in the Protocol, the HRCT scans will be sent for central review to confirm eligibility.  The 
blinded central review radiologists will evaluate screening images in accordance with the 
2018 Clinical Practice Guidelines by ATS, the ERS, Japanese Respiratory Society 
(JRS), and the Latin American Thoracic Society (ALAT) (Raghu et al. 2018).  Final 
eligibility will be determined by the central review assessments, inclusive of lung biopsy, 
if available. 
1.2.2.3 
Lung Biopsy 
Lung biopsies are not required for eligibility into the study.  Patients who have 
undergone a lung biopsy (including cryobiopsy) to aid in the diagnosis of IPF, should 
have slides sent for central review assessment to confirm eligibility in accordance with 
the ATS/ERS/JRS/ALAT Clinical Practice Guideline (Raghu et al. 2018).  The central 
review pathologists will evaluate submitted slides for usual interstitial pneumonia (UIP) 
pattern.  The histopathologic assessment criteria are outlined in the Protocol. 
1.2.2.4 
Assessment of Acute Exacerbations of IPF, Hospitalizations 
for Respiratory Causes, and Deaths (Adjudicated Events) 
An independent, blinded Clinical Adjudication Committee will be convened to review all 
available data for all potential cases of acute or suspected exacerbations of IPF, 
hospitalizations for respiratory causes, and all deaths.  This Clinical Adjudication 
Committee will be comprised of pulmonary disease physicians familiar with IPF 
exacerbations.  A charter for the Clinical Adjudication Committee will provide further 
details.  The Clinical Adjudication Committee will determine if the reported events meet 
the criteria of acute or suspected exacerbation of IPF, hospitalization for respiratory 
causes, and deaths (including deaths related specifically to respiratory causes) as 
defined in the charter. 


 
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1.2.2.5 
Assessment for Suspected Anaphylaxis 
Assessment of potential anaphylaxis will be conducted at every infusion per the clinical 
criterion for diagnosing anaphylaxis as described by Sampson et al. (2006) NIAID/FAAN. 
All potential anaphylaxis cases reported by investigators to the Sponsor will be 
subsequently submitted for adjudication to a blinded Anaphylaxis Adjudication 
Committee, composed of external experts in allergic diseases.  The committee will 
assess whether the reported event is a true anaphylaxis event (based on Sampson's 
criteria) and whether the reported anaphylaxis event is causally related to study 
treatment. 
If a patient has signs or symptoms of an anaphylactic or serious hypersensitivity reaction 
(including events deemed to have met the criteria as described by Sampson according 
to the blinded Anaphylaxis Adjudication Committee), administration of the study drug 
must be discontinued permanently. 
Further details will be provided in the Anaphylaxis Adjudication Charter. 
1.2.3 
Data Monitoring 
An iDMC will be established to review safety data from this study, thereby better 
ensuring the safety of study participants.  If appropriate, the iDMC may also evaluate 
benefit and risk by reviewing relevant efficacy data together with safety data during the 
scheduled iDMC meetings.  Consistent with US Food and Drug Administration (FDA) 
recommendations (FDA Guidance for Industry, Establishment and Operation of Clinical 
Trial Data Monitoring Committees 2006), the iDMC will be constituted of independent 
clinician’s expert in the field of IPF and clinical research and a statistician.  A formal 
charter will be established for the conduct of the iDMC.  The Committee is planned to 
review the safety data in an unblinded manner.  The iDMC may also review other data 
(e.g., PK) according to local health authority requirements.  Details regarding the iDMC 
data evaluation will be specified in the iDMC charter.  
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATION 
2.1 
STATISTICAL HYPOTHESES 
The following statistical hypotheses will be tested to demonstrate superiority of 
zinpentraxin alfa plus standard of care treatment as needed (excluding lung 
transplantation) compared with placebo plus standard of care treatment as needed 
(excluding lung transplantation), on lung function for the primary efficacy endpoint: 
Null hypothesis H0: the mean change from baseline at Week 52 in FVC mL for patients 
in the placebo arm is the same as the mean change from baseline at Week 52 in 
FVC mL for patients in the respective zinpentraxin alfa arm. 


 
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Alternative hypothesis H1: the mean change from baseline at Week 52 in FVC mL for 
patients in the placebo arm is not the same as the mean change from baseline at 
Week 52 in FVC mL for patients in the respective zinpentraxin alfa arm. 
Similar statistical hypotheses will be tested for the key secondary efficacy endpoint: 
change from baseline at Week 52 in 6-minute walk distance (6MWD). 
A fixed-sequence testing strategy will be used for statistical testing of first the primary 
endpoint then the secondary endpoints in a hierarchical manner to control the overall 
type I error rate at 0.05 two-sided.  See Section 4 for details. 
2.2 
SAMPLE SIZE DETERMINATION 
The purpose of this study is hypothesis testing regarding the effect of zinpentraxin alfa 
versus placebo.  
2.2.1 
Assumptions on Treatment Effects for Sample-Size and Power 
Calculations 
The hypotheses on treatment effect-sizes used for sample-size and power calculations 
were based on the results of the placebo-controlled period of the PRM-151-202 study, 
summarized in Table 3.  
Table 3 
Results of the PRM-151-202 Study on Planned Primary and Key 
Secondary Endpoints 
LS-Means for change from baseline at Week 28 (linear mixed effect models) 
Endpoint 
Placebo (N=39) 
Mean (SE) 
zinpentraxin alfa 
(N=77) 
Mean (SE) 
Difference 
Mean (SE) 
Standardized 
effect size 
FVC (mL) 
-242.3 (45.47) 
-127.7 (32.86) 
114.6 (56.10) 
0.40 
6MWD (meters) 
-33.7 (10.52) 
-0.20 (7.59) 
33.5 (12.97) 
0.51 
FVC (% predicted) 
-5.40 (0.96) 
-2.50 (0.69) 
2.80 (1.19) 
0.46 
6MWD  6-minute walk distance; FVC  forced vital capacity; SE  standard error.  
  
The effect-sizes observed for the between-group differences in least-square means for 
change from baseline at Week 28 from the linear mixed effect models with random 
intercept and slope adjusted on stratum, were 114.6 mL for FVC mL (common standard 
deviation:  286.9, standardized effect-size:  0.40), 33.5 m for 6MWD (common standard 
deviation:  66.3, standardized effect-size:  0.51), and 2.80% for FVC % predicted 
(common standard deviation:  6.04, standardized effect-size:  0.46).  A greater between 
group difference is expected at Week 52 in the current study, but a greater variability 
might also be observed at Week 52, due to the longer follow-up.  


 
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In the OLE of the PRM-151-202 study, where all patients received zinpentraxin alfa from 
Week 28 onwards, the Week 52 standard errors from the mixed model for repeated 
measures (MMRM) model allowed to compute corresponding standard deviations of 
403.5 mL (FVC mL), 8.77% (FVC %predicted) and 82.3 m (6MWD) in patients who were 
initially randomized to zinpentraxin alfa, that are indeed larger than those at Week 28 
(288.3 mL, 6.06% and 66.6 m respectively).  
To avoid underestimating the power of the study and to enable the opportunity to explore 
the efficacy in relevant patient subgroups including baseline concomitant IPF medication 
use, smaller standardized effect-sizes than observed in study PRM-151-202 at Week 28 
of 0.25 for FVC mL and FVC % predicted and 0.30 for 6MWD were used for the 
calculations.  In addition, to investigate the impact of increased variability for studies of 
longer duration, the power for this calculated sample size was assessed in the following 
way: (a) using the placebo-controlled treatment differences observed at Week 28 as 
estimates for the Week 52 treatment effects and (b) using the Week 52 standard 
deviations for the initially randomized zinpentraxin alfa arm from study PRM-151-202, as 
estimates for the Week 52 common standard deviations.  This was performed in order to 
confirm that the nominal power is at least 80% under these assumptions. 
With a total of 658 patients (329 in each arm), the nominal power to detect a 
standardized effect size of 0.25 for FVC mL and FVC% predicted, using a two-sided 
type I error level of 0.05 is 0.89 and the nominal power to detect a standardized effect 
size of 0.30 on 6MWD using a two-sided type I error level of 0.05 is 0.97. 
With a total of 658 patients (329 in each arm), the nominal power to detect an effect of 
114.6 mL on FVC mL with common standard deviation of 403.5 (standardized effect size 
of 0.28) using a two-sided type I error of 0.05 is 0.95.  The nominal power to detect an 
effect of 33.5 meters on 6MWD with common standard deviation of 82.3 (standardized 
effect size of 0.41) using a two-sided type I error level of 0.05 is  0.99.  For FVC% 
predicted, the nominal power to detect an effect of 2.80% with common standard 
deviation of 8.77 (standardized effect size of 0.32) using a two-sided type I error of 0.05 
is 0.98.  
2.2.2 
Robustness of Power and Sample-Size Calculations 
In Table 4, power calculations for alternative values of the effect-sizes of the first three 
endpoints in the fixed-sequence testing are provided. 
With the planned sample size of 658 patients, a standardized effect-size of 0.220 on 
FVC, both mL and % predicted (corresponding to absolute between group differences of 
89 mL and 1.92%, respectively) will be detected with a power of 80%. 
For 6MWD, the study has a high power (0.973) to detect an absolute between group 
difference of 25 m (considered the minimal clinically relevant difference), corresponding 


 
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to a standardized effect-size of 0.30.  A smaller effect-size of 0.25, corresponding to an 
absolute difference of 20.8 m will be detected with a power of 90%.  
Table 4 
Results of Power Calculations for Different Effect-Sizes and 
N=658 Patients 
 
alpha 
Hypothesized absolute difference 
Power with  
N=658 patients 
FVC (mL) 
H0: difference = 0 
0.05 
2-sided 
114.6 
0.953 
107.0 
0.925 
102.0 
0.899 
95.0 
0.854 
89.0 
0.806 
6MWD (meters) 
H0: difference = 0 
0.05 
2-sided 
33.5 
>0.999 
27.5 
0.990 
25.0 
0.973 
23.0 
0.947 
20.8 
0.899 
18.0 
0.800 
FVC (% predicted) 
H0: difference = 0 
0.05 
2-sided 
2.80 
0.983 
2.45 
0.947 
2.33 
0.925 
2.22 
0.900 
2.05 
0.849 
1.92 
0.800 
6MWD = 6-minute walk distance; FVC = forced vital capacity. 
Standard deviation of 403.5 mL (FVC mL), 82.3 m (6MWD) and 8.77 (FVC% predicted) based 
on Week 52 standard errors from the MMRM model in patients who were initially 
randomized to zinpentraxin alfa in Study PRM-151-202. 
  
2.2.3 
Sample Size for the China Subpopulation 
This study will initially enroll approximately 658 participants across all sites during the 
global enrollment phase.  After completion of the global enrollment phase, additional 
participants may be enrolled in an extended China enrollment phase at sites in China, 
Hong Kong and Taiwan to ensure a total enrollment that is sufficient to 
support registration in China.  The global population will include all participants enrolled 
during the global enrollment phase (including participants enrolled at National Medical 
Products Administration (NMPA)-recognized sites during that phase), and the China 
subpopulation will include all participants enrolled at NMPA-recognized sites (during 
both the global enrollment phase and the extended China enrollment phase). 


 
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3. 
ANALYSIS SETS 
The analysis populations presented in this section are based on patients enrolled during 
the global enrollment phase of the study and will not include the China extension, unless 
otherwise specified.  The analysis plan for the China extension is presented in 
Section 4.7.6. 
The analysis populations are defined in Table 5. 
Table 5 
Analysis Populations 
Population 
Definition 
Randomized 
All randomized patients 
Full analysis set  
All randomized patients who received at least one administration 
(full or partial dose) of study drug and will use the grouping 
according to the treatment assignment at randomization. 
Safety-evaluable 
All randomized patients who received at least one administration 
(full or partial dose) of study drug and will be grouped according 
to the actual treatment received. 
Pharmacokinetic-evaluable  
All randomized patients who received at least one administration 
(full or partial dose) of zinpentraxin alfa and have at least one 
evaluable postdose PK sample that is above the LLOQ. 
Immunogenicity-evaluable  
All randomized patients with at least one postdose ADA 
assessment and will be grouped according to treatment received 
or, if no treatment is received prior to study discontinuation, 
according to treatment assigned. 
Biomarker-evaluable  
All randomized patients who received at least one administration 
(full or partial dose) of zinpentraxin alfa and have genetic data to 
enable assessment of MUC5B status. The analysis will group 
patients according to treatment actually received. 
LLOQ  lower limit of quantification; MUC5B  mucin 5B; PRO  patient‑reported outcomes. 
  
4. 
STATISTICAL ANALYSES 
The primary analysis will occur when the last enrolled patient from the global enrollment 
phase has completed the study.  Significance testing of the primary and secondary 
endpoints will account for multiplicity and control family-wise type I error, which is fixed 
at 0.05 two-sided.  The study has one single primary efficacy endpoint (absolute change 
from baseline at Week 52 in FVC [mL]) and one family of secondary efficacy endpoints 
that have been ordered in a prespecified sequence, starting with the key secondary 
endpoint, absolute change from baseline at Week 52 in 6MWD (see Section 4.4).  
The planned statistical analysis will control the overall type I error for the testing of these 
efficacy endpoints by applying a fixed-sequence multiple testing strategy, testing all the 
endpoints according to the pre-specified order.  All hypothesis tests will be two-sided 
unless otherwise specified. 


 
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4.1 
GENERAL CONSIDERATION 
The efficacy endpoints comprise one primary endpoint (FVC [mL]), one key secondary 
endpoint (6MWD [m]), a series of other secondary endpoints and other exploratory 
endpoints.  All efficacy analyses will be performed on the FAS population, unless 
otherwise specified. Participants will be analyzed according to the treatment assigned at 
randomization by IxRS.  Significance testing of the primary and secondary endpoints 
will account for multiplicity and control family-wise type I error, which is fixed at 
0.05 two-sided.  All safety analyses will be performed in the safety-evaluable population, 
unless otherwise specified.  Participants will be analyzed according to the treatment they 
actually received. 
In safety analyses, all deaths are included, from all sources, regardless of completeness 
of death date; participants who died with only a partial death date available will be 
included.  In efficacy analyses, death data from adjudication will be used.  If the death 
date is only partially available, the missing part of the date will be imputed.  
For hospitalization in efficacy analyses, the adjudicated date of hospitalization will be 
used and a partial date will be imputed using the same approach as for death.  
4.2 
PARTICIPANT DISPOSITION 
The number of patients randomized will be tabulated by region, country, study site and 
treatment arm.  The FAS, safety-evaluable, PK-evaluable and PRO-evaluable 
populations, including numbers of patients in each population, will be summarized.  
Patient disposition (the number of patients treated and have completed the study) will be 
tabulated by the treatment arm.  Premature treatment discontinuation and study 
discontinuation, as well as reasons for discontinuations, will be summarized. 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS 
4.3.1 
Definition of Primary Endpoint(s) 
The primary efficacy endpoint is the between-group difference in the mean absolute 
change from Baseline (Dosing Day 1) at Week 52 in FVC (mL).  The comparison of 
zinpentraxin alfa with placebo will be analyzed at a 0.05 two-sided significance level.   
All FVC mL measurements that meet the minimal level of quality will be used for the 
primary analysis, except those recorded after lung transplantation, whatever other 
intercurrent events might have occurred before that were recorded.  No imputation for 
missing data is planned to be performed for the primary analysis since the primary 
analysis assumes missing data are MAR and the planned analysis model is unbiased 
under this assumption. 


 
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4.3.2 
Main Analytical Approach for Primary Endpoint 
Descriptive statistics for the raw values at each visit and the change from baseline at 
each visit through Week 52 in FVC mL will be computed by treatment group for the FAS 
population.  
The comparison of zinpentraxin alfa with placebo will be carried out via a linear mixed 
(random coefficient) model at a 0.05 two-sided significance level. Each subject’s vector 
of responses is independent of the other subjects, and within-subject responses are 
correlated.  
The statistical model can be written as follows: 
𝑌𝑖𝑗 =  (β0 +  𝛽0𝑖) +   (𝛽1  + β𝑣 𝑇𝑟𝑡𝑖 +  𝛽1𝑖) ∗ 𝑡𝑖𝑗 + 𝛽𝑠 𝑆𝑒𝑥𝑖  +   𝛽𝑎 𝐴𝑔𝑒𝑖 +   𝛽ℎ 𝐻𝑒𝑖𝑔ℎ𝑡𝑖 
+ 𝛽𝑐 𝑆𝑡𝑟𝑎𝑡𝑎𝐶𝑖 + 𝛽𝑟 𝑆𝑡𝑟𝑎𝑡𝑎𝑅𝑖 +   𝜖𝑖𝑗 
where  
 
𝑌𝑖𝑗 is the FVC (mL) value for subject 𝑖 at visit 𝑗 (including baseline);  
 
β0 and 𝛽1 are the intercept and the slope;  
 
𝛽0𝑖 and 𝛽1𝑖 are the random subject effects for intercept and slope;  
 
𝑇𝑟𝑡𝑖= 0 if subject 𝑖 is in the Placebo group and 𝑇𝑟𝑡𝑖= 1 if subject 𝑖 is in the 
zinpentraxin alfa group; 
 
β𝑣 is the coefficient for the interaction term of treatment effect and assessment time;  
 
𝑡𝑖𝑗 is the assessment time (continuous in days) for subject 𝑖 at visit 𝑗;  
 
𝛽𝑠, 𝛽𝑎 and 𝛽ℎ are the coefficients for subject specific demographic variables;  
 
𝑆𝑒𝑥𝑖, 𝐴𝑔𝑒𝑖 , and 𝐻𝑒𝑖𝑔ℎ𝑡𝑖are the sex (male as the class of reference), baseline age 
(years) and baseline height (cm) for patient 𝑖; 
 
βc and βr are the coefficients for subject specific stratification variables;  
 
𝑆𝑡𝑟𝑎𝑡𝑎𝐶𝑖 and 𝑆𝑡𝑟𝑎𝑡𝑎𝑅𝑖 are the stratification factors on concurrent IPF treatment (no 
concurrent IPF treatment as the class of reference) and region (Rest of World as the 
class of reference) for subject 𝑖; 
 
𝜖𝑖𝑗 is the within-subject random error for subject 𝑖 at visit 𝑗;  
 
𝛽0𝑖 and 𝛽1𝑖 are assumed to have a multivariate normal distribution with mean 0 and 
unstructured covariance matrix; 
 
𝜖𝑖𝑗 are assumed to be independent and normally distributed with mean 0 and 
variance 𝜎𝜖2 
 
If there are convergence problems with the model, the following covariates will continue 
to be removed from the model (in this order) until convergence is met (1) stratification 
factor for region, (2) stratification factor for concurrent IPF treatment (3) age, sex, and 
height.  If the model still fails to converge, a random intercept model will be used (no 
random slope). 


 
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The comparison of zinpentraxin alfa with placebo will be carried out by estimating the 
difference in mean absolute change from baseline at Week 52 between the two 
treatment arms with 95% CI and p-value. 
4.3.3 
Sensitivity Analyses for Primary Endpoint 
4.3.3.1 
Sensitivity Analysis Addressing the Effect of Missing Data 
After Death due to IPF 
To analyze the effect of missing data after death, a rank analysis of covariance 
(ANCOVA) model will be fit, where patients who die are assigned the worst rank.  
Specifically, for each patient who survives the duration of the trial, a slope will be 
calculated from a line fit through their observed FVC assessments.  The slopes will then 
be ranked, assigning the worst rank to patients who die.  The rank ANCOVA model will 
include age, sex, height and ranked baseline score as covariates. 
4.3.3.1.1 
Sensitivity Analysis Addressing the Effect of Missing Data 
After Treatment Discontinuation 
Patients are expected to continue with study assessments after permanent treatment 
discontinuation. However, it is possible that patients who discontinue treatment fail to 
return for their follow-up assessments or discontinue the study, in which case some 
post-discontinuation data would be missing.  Analysis under MAR will implicitly impute 
these missing values based on all observed data without distinguishing between 
on‑treatment and off-treatment data and may therefore overestimate the treatment 
effect.  Furthermore, the ICE strategy for treatment discontinuation would be a hybrid 
between a hypothetical and treatment policy strategy, and it becomes unclear what 
treatment effect is actually being estimated.  
More conservative imputation approaches will be implemented to assess the sensitivity 
of treatment effect estimation and inference to missing data assumptions.  The first 
approach will be to use conditional mean imputation for reference-based imputation of 
missing data (Wolbers et al. 2022).  The imputation model will be an MMRM with 
baseline outcome, age, sex, height, treatment group, visit and treatment-by-visit 
interactions as covariates.  Missing data for patients in the placebo arm will be imputed 
under MAR, and missing data for patients in the zinpentraxin alfa arm will be imputed 
under copy increments in reference.  Under this reference-based assumption, patients in 
the intervention arm who discontinue treatment do not get any further benefit from 
treatment after discontinuation.  The imputed, complete data will be analyzed via 
ANCOVA, with FVC (mL) slope as the outcome and baseline FVC, age, sex, height and 
treatment as covariates.  Re-sampling based inference for the treatment effect estimate 
will be obtained via the jackknife. 
In addition to the reference-based imputation, a tipping point analysis will be 
implemented by applying different delta-adjustments for each treatment group to the 
imputed data to see which combination of delta values tip the primary analysis result. 


 
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4.3.3.1.2 
Sensitivity Analysis Addressing Non-linearity 
To evaluate the impact of assuming a linear disease trajectory, a repeated measures 
mixed-effects model (MMRM) will be used to estimate the difference in mean change 
from baseline in FVC (mL) at Week 52.  For this sensitivity analysis, only data from 
scheduled assessments will be used to fit the MMRM.  The response variable for the 
model is change from baseline in FVC (mL).  The following variables will be included as 
model terms: baseline FVC (mL), stratification factors, treatment group, visit and 
treatment-by-visit interaction.  Subject, treatment, and visit will be class variables and the 
within-subject errors will be assumed to have an unstructured variance-covariance 
matrix.  If the analysis fails to converge, the following covariance structures will be 
tested:  compound symmetry, first-order autoregressive [AR(1)], and Toeplitz.  The 
covariance structure converging to the best fit, based on Akaike’s information criterion 
(AIC), will be used. 
The difference in the least squares mean change from baseline between the 
zinpentraxin alfa and placebo groups will be estimated at each post-baseline visit, as 
well as 95% CI’s and p-values.  The MMRM LS means plot with CI’s will be made to 
visualize the estimates. 
4.3.4 
Supplementary Analyses for Primary Endpoint(s) 
4.3.4.1 
Subgroup Analyses for Primary Endpoint(s) 
The generalizability of primary endpoint results when comparing zinpentraxin alfa to 
placebo will be investigated by estimating the treatment effect in subgroups based on 
stratification factors and key baseline demographics, disease characteristics, etc., as 
listed in Table 6.  
Descriptive summaries including number and proportion of patients in each category will 
be provided overall and by treatment group as appropriate.  Summaries of primary 
endpoint by these subgroups will be provided in forest plots. 


 
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Table 6 
Subgroup Definitions 
Patient Characteristics 
Categories 
Baseline concomitant medications 
– 
Concurrent use of either nintedanib or pirfenidone 
treatment 
– 
Concurrent use of nintedanib treatment 
– 
Concurrent use of pirfenidone treatment 
– 
No concurrent treatment 
Geographic region 
China 
North America  
Europe 
Latin America 
Rest of World 
Age 
  65 years 
65 to  75 years 
  75 years 
Sex 
Female 
Male 
zinpentraxin alfa generation 
First Generation 
Second Generation 
 
4.4 
SECONDARY ENDPOINTS ANALYSES 
If the primary efficacy test on FVC mL is found significant at the alpha level of 
0.05 two-sided then the fixed-sequence testing procedure will continue by testing the 
secondary endpoints in a hierarchical manner as specified below: 
1. 
Absolute change from baseline at Week 52 in 6MWD (m) 
2. 
Absolute change from baseline at Week 52 in FVC% predicted  
3. 
Time to disease progression, defined as time to first occurrence of   10% absolute 
decline in % predicted FVC,   15% relative decline in 6MWD, or death  
4. 
Time to first respiratory-related hospitalization  
5. 
Absolute change from baseline at Week 52 in University of California, San 
Diego‑Shortness of Breath Questionnaire (UCSD-SOBQ) 
6. 
Absolute change from baseline at Week 52 in St. George Respiratory Questionnaire 
(SGRQ) Total Score  
7. 
Time to first acute exacerbation of IPF, or suspected acute exacerbation of IPF, as 
determined by the Clinical Adjudication Committee 
8. 
Absolute change from baseline at Week 52 in hemoglobin (Hgb)-corrected DLCO % 
predicted 
9. 
Survival, as measured by all-cause mortality  
 


 
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4.4.1 
Key/Confirmatory Secondary Endpoint 
The assessment of the key secondary endpoint (6MWD [m]) using the 6MWT is 
described in Section 4.5.7 of Protocol.  
It will be analyzed using the same estimand strategy, descriptive statistics, and model as 
the primary endpoint (FVC [mL]) in Section 1.1 and Section 4.3.2 and will be analyzed at 
a 0.05 two-sided significance level. 
Subgroup analyses for the primary efficacy endpoint described in Section 4.3.4.1 will be 
performed for the key/confirmatory secondary endpoint as well using the same 
descriptive summaries and summaries of treatment effect in forest plots. 
4.4.2 
Supportive Secondary Endpoint(s) 
4.4.2.1 
Other Continuous Secondary Endpoints 
The other continuous secondary endpoints include: 
 
absolute change from baseline at Week 52 in FVC% predicted  
 
absolute change from baseline at Week 52 in Hgb-corrected DLCO % predicted  
 
FVC% predicted will be analyzed using the same estimand strategy, descriptive 
statistics and model (excluding age, sex and height as covariates) as the primary 
endpoint (FVC [mL]) in Section 1.1 and Section 4.3.2 and will be analyzed at a 
0.05 two-sided significance level. 
Visit summary and change from baseline analyses will be performed for Hgb-corrected 
DLCO % predicted values.  Summary statistics (number of patients, mean, standard 
deviation, median, minimum, maximum) of absolute values and changes from baseline 
at each time point will be presented by treatment arm. Hgb-corrected DLCO % predicted 
will be analyzed using the same estimand strategy as the primary endpoint (FVC [mL]) in 
Section 1.1. 
A MMRM will be used for comparing the least squares mean change from baseline at 
Week 52 in Hgb-corrected DLCO % predicted values between treatment arms at a 
0.05 two‑sided significance level.  The model will include baseline value as a covariate, 
and treatment, time, stratification variables and treatment by time interaction as 
explanatory variables.  Repeated measures over time will be accounted for by an 
unstructured covariance structure.  


 
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The statistical model is as follows: 
        𝐶ℎ𝑔𝑖𝑗  =   𝛽0 +    𝛽𝑡 𝑇𝑟𝑡𝑖 + 𝛽𝑣 𝑉𝑖𝑠𝑖𝑡𝑗 + 𝛽𝑟 𝑇𝑟𝑡𝑖 ∗ 𝑉𝑖𝑠𝑖𝑡𝑗 + 𝛽𝑏 𝐵𝑎𝑠𝑒𝑖 + 𝛽𝑐 𝑆𝑡𝑟𝑎𝑡𝑎𝐶𝑖 
+ 𝛽𝑟 𝑆𝑡𝑟𝑎𝑡𝑎𝑅𝑖 +  𝜀𝑖𝑗 
where  
 
𝐶ℎ𝑔𝑖𝑗 is the change from baseline for subject 𝑖 at visit 𝑗; 
 
𝛽0 is the intercept;  
 
𝛽𝑡 is the coefficient for the treatment effect and 𝑇𝑟𝑡𝑖 is the planned treatment for 
subject 𝑖: 𝑇𝑟𝑡𝑖 =0 if subject 𝑖 is assigned to the Placebo group (k = Placebo) and 
𝑇𝑟𝑡𝑖=1 if subject 𝑖 is assigned to the zinpentraxin alfa group; 
 
𝛽𝑣 is the coefficient for the visit effect and 𝑉𝑖𝑠𝑖𝑡𝑗 is the categorical visit; 
 
𝛽𝑟 is the coefficient for the interaction term between treatment and categorical visit 
and 𝑇𝑟𝑡𝑖 ∗ 𝑉𝑖𝑠𝑖𝑡𝑗  is the interaction term between treatment and categorical visit;   
 
𝛽𝑏 is the coefficient for the baseline measure and 𝐵𝑎𝑠𝑒𝑖 is the baseline measure for 
subject 𝑖; 
 
𝛽𝑐 and 𝛽𝑟 are the coefficients for subject specific stratification variables;  
 
𝑆𝑡𝑟𝑎𝑡𝑎𝐶𝑖 and 𝑆𝑡𝑟𝑎𝑡𝑎𝑅𝑖 are the stratification factors on concurrent IPF treatment (no 
concurrent IPF treatment as the class of reference) and region (Rest of World as the 
class of reference) for subject 𝑖; 
 
𝜀𝑖𝑗 is the random error for subject 𝑖 at visit 𝑗. 
 
If the analysis fails to converge, the following covariance structures will be tested:  
compound symmetry, first-order autoregressive [AR(1)], and Toeplitz.  The covariance 
structure converging to the best fit, based on Akaike’s information criterion (AIC), will be 
used. 
The least squares mean estimates of the mean change from baseline and the difference 
between the two treatment arms at each post-baseline visit will be provided with 
95% CIs and p-values.  
4.4.2.2 
PRO Secondary Endpoints 
The PRO secondary endpoints are listed below: 
 
Change from baseline at Week 52 in UCSD-SOBQ score 
 
Change from baseline at Week 52 in SGRQ total score 
 
The PRO secondary endpoints will be analyzed using the same estimand strategy, 
descriptive statistics and model as Hgb-corrected DLCO % predicted in Section 4.4.2.1 
and will be analyzed at a 0.05 two‑sided significance level. 


 
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4.4.2.3 
Time-to-Event Secondary Endpoints 
The time-to-event secondary endpoints are listed below: 
 
Time to disease progression, defined as time to first occurrence of  10% absolute 
decline in % predicted FVC, 15% relative decline in 6MWD, or death  
 
Time to first respiratory-related hospitalizations (defined as non-elective 
hospitalizations due to any respiratory cause, including acute exacerbations of IPF, 
or suspected acute exacerbations of IPF, as determined by the Clinical Adjudication 
Committee) 
 
Time to first acute exacerbation of IPF, or suspected acute exacerbation of IPF, as 
determined by the Clinical Adjudication Committee 
 
Survival, as measured by all-cause mortality  
 
Descriptive statistics for the frequency of each type of event will be provided.  The 
stratified log rank test (on stratification factors) will be used to compare the time to event 
endpoints between two treatment arms at a 0.05 two-sided significance level.  The 
Kaplan-Meier plot, median time to event, and their 95% CIs, and a p-value from the 
log‑rank test will be presented. The hazard ratio and its 95% CI will be estimated using a 
Cox proportional hazards model, adjusting for sex, age, and height. In fitting the 
Cox model, ties will be handled with the approximate likelihood method of Efron (1977). 
Time-to-event will be measured in reference to Baseline Day 1 through the end of study. 
Patients are considered to be in the placebo-controlled period even if they have 
discontinued study treatment, if they would still be receiving placebo-controlled study 
treatment had they not discontinued.  For time to first respiratory-related hospitalizations 
and time to first acute exacerbation of IPF, patients not experiencing an event will be 
censored at the earliest of the last day known alive, or the last date during the placebo-
controlled period (see Section 1.2).  For disease progression and survival (all-cause 
mortality), patients without an event will be censored at the last clinic assessment during 
the placebo-controlled period.  
The estimand strategy for the time-to-event endpoints are summarized below in Table 7. 
 
 


 
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Table 7 
Estimand Analysis Strategy for Intercurrent Events: 
Time-to-Event Secondary Endpoints 
Endpoints 
Estimand 
 
Time to disease progression, defined 
as time to first occurrence of   10% 
absolute decline in % predicted 
FVC,  15% relative decline in 6MWD, 
or death  
Population: see primary endpoint 
Treatment: see primary endpoint 
Population-level summary measure: log rank test 
and hazard ratio 
Intercurrent events: 
 
Any patients who undergo lung transplantation 
will be censored at the date of the transplant 
(hypothetical strategy) 
 
Survival, as measured by all-cause 
mortality  
Population: see primary endpoint 
Treatment: see primary endpoint 
Population-level summary measure: log rank test 
and hazard ratio 
Intercurrent events: 
● 
Any patients who undergo lung transplantation 
will be censored at the date of the transplantation 
(hypothetical strategy) 
 
Time to first respiratory-related 
hospitalizations (defined as 
non-elective hospitalizations due to any 
respiratory cause, including acute 
exacerbations of IPF, or suspected 
acute exacerbations of IPF, as 
determined by the Clinical Adjudication 
Committee) 
Population: see primary endpoint 
Treatment: see primary endpoint 
Population-level summary measure: log rank test 
and hazard ratio 
Intercurrent events: 
 
Deaths are expected to be infrequent, but in 
case of occurrence, they will be treated as 
disease progression and counted as event of 
interest (composite strategy)  
 
Any patients who undergo lung transplantation 
will be censored at the date of the transplantation 
(hypothetical strategy) 
 
Time to first acute exacerbation of IPF, 
or suspected acute exacerbation of 
IPF, as determined by the Clinical 
Adjudication Committee 
Population: see primary endpoint 
Treatment: see primary endpoint 
Population-level summary measure: log rank test 
and hazard ratio 
Intercurrent events: 
 
Deaths are expected to be infrequent, but in 
case of occurrence, they will be treated as 
disease progression and counted as event of 
interest (composite strategy)  
 
Any patients who undergo lung transplantation 
will be censored at the date of the transplantation 
(hypothetical strategy) 
6MWD   6-minute walk distance; FVC  forced vital capacity; IPF   idiopathic pulmonary fibrosis. 
 


 
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4.5 
EXPLORATORY ENDPOINT(S) ANALYSIS 
The exploratory efficacy endpoints are: 
 
Absolute change from baseline at Week 52 in FVC% predicted and FVC (mL), by 
baseline concomitant medication stratum 
 
Absolute change from baseline at Week 52 in FVC% predicted and FVC (mL), by 
mucin 5B (MUC5B) risk allele positive or negative status 
 
Absolute change from baseline at Week 52 in 6MWD (m), by baseline concomitant 
medication stratum 
 
Proportion of patients who progress on the UCSD-SOBQ, as indicated by an 
increase in score of 10 points or greater 
 
Proportion of patients who progress on the SGRQ total score, as indicated by an 
increase in score of 7 or greater 
 
Change from baseline to Week 52 in SGRQ Individual Domains (Symptoms, 
Activity, and Impacts) Score 
 
Proportion of patients who progress on the SGRQ Symptoms Domain, as indicated 
by an increase in score of 8 or greater 
 
Proportion of patients who progress on the SGRQ Activity Domain, as indicated by 
an increase in score of 5 or greater 
 
Proportion of patients who progress on the SGRQ Impacts Domain, as indicated by 
an increase in score of 7 or greater 
 
Absolute change from baseline at Week 52 in quantitative imaging analysis 
parameters of HRCT scan of the thorax 
 
Length of hospital stay for respiratory-related hospitalizations 
 
Total time in intensive care units due to respiratory causes 
 
Unscheduled outpatient clinic/urgent care/emergency room utilization related to 
respiratory events 
 
Number of acute exacerbations during the 52 weeks, as determined by the Clinical 
Adjudication Committee 
 
Survival as measured by IPF-related mortality 
 
Survival as measured by respiratory-related mortality 
 
Disease progression and subsequent start of oxygen supplementation 
 
Change in PFT parameters (FVC, DLCO) or 6MWD from baseline at Week 52 
between SARS-CoV2 antibody positive compared with negative patients (present at 
baseline) 
 
Change in PFT parameters (FVC, DLCO) or 6MWD from baseline at Week 52 in 
patients who develop SARS-CoV2 antibodies during treatment (not present at 
baseline) 
 
Absolute change from baseline at Week 52 in FVC (mL) by selected countries 


 
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In addition, the following endpoint will be explored to evaluate health status utility scores 
of patients treated with zinpentraxin alfa plus standard of care treatment: 
 
Absolute change from baseline at Week 52 in EuroQol 5-Dimension, 5-Level 
Questionnaire (EQ-5D-5L) index-based, and visual analog scale (VAS) scores 
 
Change-from-Baseline Exploratory Endpoints: FVC, 6MWD, DLCO, EQ-5D-5L 
VAS 
The endpoints on FVC, 6MWD and DLCO will be analyzed and summarized with use of 
the same methods as the change from baseline endpoints in Section 4.3.2, 
Section 4.4.1, and Section 4.4.2.1, unless otherwise specified. 
The EQ-5D-5L VAS endpoint will be analyzed and summarized with use of the same 
methods as the change from baseline endpoints in Section 4.4.2.2. 
Change-from-Baseline Exploratory Endpoints: HRCT 
Descriptive statistics for the raw values at each visit and the change from baseline to 
Week 52 will be computed by the treatment group for the quantitative HRCT imaging 
analysis parameters. 
Proportion of progressors: SGRQ, UCSD-SOBQ  
The proportion of progressors at Week 52 will be estimated by treatment group with 95% 
CIs using a standardized regression estimator, adjusting for baseline score and baseline 
concurrent IPF treatment. 
Acute Exacerbation of IPF Endpoints 
Descriptive statistics for continuous variables will be prepared by treatment group for the 
total number and rate (per year) of acute or suspected exacerbations during the 
52 weeks. 
Time-to-Event Exploratory Endpoints 
These endpoints will be analyzed and summarized with use of the same methods for the 
time-to-event secondary endpoints, unless otherwise specified.  
Healthcare Utilization Exploratory Endpoints 
Descriptive statistics for continuous variables will be prepared for: 
 
Length of hospital stay in days for respiratory-related hospitalizations 
 
Total time in intensive care units in days due to respiratory causes 


 
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 
Unscheduled outpatient clinic/urgent care/emergency room utilization related to 
respiratory events 
 
Impact of SARS-CoV2 Antibody 
Descriptive statistics will be prepared for: 
 
Change in PFT parameters (FVC, DLCO) or 6MWD from baseline at Week 52 
between SARS-CoV2 antibody positive compared with negative patients (present at 
baseline) 
 
Change in PFT parameters (FVC, DLCO) or 6MWD from baseline at Week 52 in 
patients who develop SARS-CoV2 antibodies during treatment (not present at 
baseline)  
 
4.6 
SAFETY ANALYSES 
Safety analyses will be based on all patients who received at least one administration 
(full or partial dose) of randomized study drug, with patients grouped according to the 
actual treatment received.  Safety summaries will be presented by the treatment arm for 
all treated patients.  
Safety will be assessed through descriptive summary of exposure to study treatment, 
seriousness and severity of AEs and adverse events of special interest (AESIs), 
changes in laboratory test results, death, discontinuation from study treatment, ECG and 
vital signs.  These summaries will be produced for the entire study period 
(placebo‑controlled study treatment period and safety follow-up period for patients not 
entering the open label extension study). 
4.6.1 
Extent of Exposure 
Extent of exposure to study drug (zinpentraxin alfa or placebo) will be summarized 
descriptively (mean, standard deviation, median, range, and proportions where 
appropriate) for the following measures: 
 
Number of patients exposed  
 
Treatment duration (weeks), measured from date of first administration at Baseline 
Day 1 
 
Cumulative number of infusions    total number of non-zero infusions 
 
Cumulative volume of infusion received    total volume of non-zero infusions 
 
Number of missed infusions 
 
Number of patients receiving reloading infusions 
 
Number of infusion cycles, defined as either up to 3 loading or reloading infusion or 
1 regular infusion 
 
Extent of exposure to zinpentraxin alfa will also be summarized by drug generation using 
the above measures. 


 
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Exposure to concurrent use of pirfenidone or nintedanib will also be summarized 
descriptively by treatment group.  
4.6.2 
Adverse Events 
All verbatim (“investigator-reported”) AE terms will be assigned a standardized term (the 
“preferred term”) and a superclass term using the most current version of the Medical 
Dictionary for Regulatory Activities (MedDRA) thesaurus terms, and AE severity will be 
graded according to National Cancer Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0 scale.  A by-patient AE data listing including onset study 
day, duration, preferred term, treatment, severity, relationship to treatment, treatment for 
AE, action taken, and outcome will be provided.  
All AEs, serious adverse events (SAEs), AEs leading to death, AESIs, and AEs leading 
to study treatment discontinuation that occur during or after the first dose of study 
treatment (i.e., treatment-emergent adverse events) will be summarized by preferred 
term and severity grade as appropriate.  An exacerbation or worsening of a pre-existing 
condition will be considered treatment-emergent only if the most extreme intensity is 
greater than the intensity at baseline (i.e., the intensity for a given AE increases and its 
end date is on or after the date of the first dose).  For events of varying severity, the 
highest grade will be used in the summaries.  Listings of AEs, SAEs, and AESIs will also 
be produced.  Any non-treatment emergent SAEs will also be listed separately. 
Summary tables of the cumulative incidence of safety outcomes will be provided for the 
treatment and placebo arms independently. Safety outcomes of interest include, but are 
not limited to: 
 
AEs and SAEs of any grade 
 
AEs (any grade) with a difference in incidence between the treatment and placebo 
arm 
 
AEs by highest NCI CTCAE v.5.0 grade 
 
Severe AEs (NCI CTCAE v.5.0 Grade 3 or above) 
 
AEs leading to death  
 
AEs leading to study treatment discontinuation 
 
AEs leading to drug interruption 
 
AEs leading to withdrawal from study 
 
Treatment related AEs and SAEs 
 
AESIs 
 
Common AEs, i.e., those occurring in at least 5% of patients in either arm 
 
Suspected Infusion Related Reaction (all grades) 
 


 
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Summaries of safety data by baseline concurrent anti-fibrotic therapy and zinpentraxin 
alfa drug generation will be provided as appropriate. 
The within-arm cumulative incidence and the difference in cumulative incidence between 
arms, along with the 95% CIs, will be summarized in a forest plot for the following safety 
outcomes: all AEs, all severe AEs, all SAEs, all AEs leading to treatment 
discontinuation, all AEs determined to be related to study drug, deaths, and the most 
frequent individual AEs (by preferred term). 
Deaths and cause of death will be summarized and a listing of patients who died during 
the study will be provided. 
Summaries of confirmed or suspected COVID-19 AEs and AEs associated with 
COVID-19 will also be provided. 
A listing of all pregnancies will be presented. 
AESIs for this study are as follows: 
AESIs related to drug development in general: 
 
Cases of potential drug-induced liver injury that include an elevated alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with 
either an elevated bilirubin or clinical jaundice, as defined by Hy's Law (see 
Section 5.4.5.7 of the Protocol) or if the patient is reported to have the preferred 
term of ‘drug-induced liver injury’ 
 
Suspected transmission of an infectious agent by the study drug, as defined below: 
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only 
when a contamination of the study drug is suspected. Such events will be 
retrieved if a patient is reported to have the MedDRA preferred term of 
‘suspected transmission of an infectious agent via product’ or ‘transmission of 
an infectious agent via product’ 
  
AESIs relevant to zinpentraxin alfa: 
 
Suspected Infusion Related Reaction with NCI CTCAE Grade  2:  The risk of IRR 
associated with zinpentraxin alfa is inherent in it being the recombinant form of a 
naturally occurring human protein. The subset of the potential risk of IRR 
(Grade  2) has been categorized as drug specific AESI for close monitoring. 
Infusion Related Reaction includes all the cases if meet both the following criteria: 
(i) any events onset during the infusion or within 24 hours from the end of study 
infusion (ii) causality: not unrelated (related or missing).  However, further analysis 


 
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will be performed to identify true cases of IRR based on medical judgement and 
confirmation provided by the investigators.  
 
Suspected anaphylactic or hypersensitivity reactions (all grades):  Anaphylactic and 
hypersensitivity reactions are considered potential risk for all biologic medications 
including zinpentraxin alfa.  Potential cases of anaphylactic, anaphylactoid, and 
hypersensitivity reactions will be identified and sent for adjudication by an 
independent Anaphylaxis Adjudication Committee (see Section 1.2.2.5).  Events will 
be identified using the Standardized MedDRA Query (SMQ Wide) ‘Anaphylactic 
reaction’ and MedDRA gastrointestinal symptoms event terms consistent with 
Sampson criteria.  In addition, all cases flagged by the investigator as an AESI 
under the criterion ‘Suspected anaphylactic or hypersensitivity reactions’ or with an 
AE term of “anaphylaxis”, “hypersensitivity” or for which an investigator has 
assessed that the event represents “known or suspected” anaphylaxis will be 
considered for adjudication. Members of the AAC review blinded data to adjudicate 
cases as anaphylaxis per Sampson’s Criteria and for relatedness to study drug.  A 
detailed description of the process for identification of potential events and data flow 
is provided in the AAC Charter.  Events adjudicated by the AAC as meeting 
Sampson’s Criteria for anaphylaxis and relatedness to study drug will be 
summarized.  Additionally, a listing of all possible cases of anaphylaxis will be 
produced. 
 
Acute or suspected exacerbation of IPF (all grades):  Acute exacerbation of IPF is 
defined as an acute, clinically significant respiratory deterioration characterized by 
evidence of new widespread alveolar abnormality, marked by the following 
diagnostic criteria (Collard et al. 2016):  
– 
Previous or concurrent diagnosis of IPF  
– 
Acute worsening or development of dyspnea typically   30 days in duration  
– 
Computed tomography with new bilateral ground-glass opacity and/or 
consolidation superimposed on a background pattern consistent with UIP 
pattern  
– 
Deterioration not fully explained by cardiac failure or fluid overload  
 
 
Acute exacerbations of IPF are further categorized as triggered acute exacerbation 
or idiopathic acute exacerbation, depending on whether an underlying trigger for 
acute exacerbation is found (e.g., infection, post-procedural/postoperative, drug 
toxicity, aspiration).  There is no evidence to suggest acute or suspected 
exacerbation of IPF is a risk associated with zinpentraxin alfa.  This was categorized 
as an AESI based on the feedback received through the Voluntary Harmonization 
Procedure.  
 
An independent, blinded Clinical Adjudication Committee review all available data 
for all potential cases of acute exacerbations of IPF.  The committee determines if 
the reported events meet the criteria of an acute exacerbation of IPF or a suspected 
acute exacerbation.  Events that are clinically considered to meet the definition of 
acute exacerbation of IPF but fail to meet all four diagnostic criteria owing to the 


 
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missing computed tomography data are termed “suspected acute exacerbations of 
IPF”. 
 
The data collected from the already completed Phase I and Phase II trials of 
zinpentraxin alfa do not suggest that the frequency or nature of the AESIs listed above 
are serious enough to potentially impact regulatory decision-making. 
4.6.3 
Adjudicated Anaphylactic and Hypersensitivity Reactions 
Anaphylaxis and hypersensitivity events as adjudicated by the Anaphylaxis Adjudication 
Committee will be summarized descriptively.  Listing of treatment emergent adverse 
events of anaphylaxis and hypersensitivity as defined above and their assessment by an 
Independent Anaphylaxis Adjudication Committee as per the Anaphylaxis Adjudication 
Committee charter will be produced.  
4.6.4 
Laboratory Data 
Descriptive summaries of laboratory values at baseline, by visit, and change from 
baseline throughout the study will be tabulated by each treatment arm.  Highest 
NCI CTCAE v.5.0 grade post-baseline will also be reported and shift tables from 
baseline to worst value during the study post-baseline will be presented by each 
treatment arm.  
Summaries will be analyzed for the following parameters: hematology (hemoglobin, 
hematocrit, platelet count, RBC count, WBC count, and differential counts [lymphocytes, 
eosinophils, neutrophils, monocytes, and basophils]), serum chemistries and liver 
function tests (LFTs) (sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine, calcium, total and direct bilirubin, total protein, albumin, alanine 
aminotransferase, aspartate aminotransferase, alkaline phosphatase, C-reactive protein 
[CRP], eGFR) and urinalysis (pH, specific gravity, glucose, protein, ketones, blood, 
sediment, RBCs, WBCs, casts, crystals, epithelial cells, bacteria). 
Proportion of patients experiencing clinically significant changes relative to baseline will 
be summarized by treatment arm as appropriate for the parameters listed above. 
A Hy’s law analysis will be provided.  The potential Hy’s law quadrant is defined as ALT 
or AST increases above 3-fold the upper limit of normal (ULN) with concomitant total 
bilirubin increases above 2-fold the ULN or clinical jaundice in the absence of 
cholestasis or other causes of hyperbilirubinemia is considered as an indicator of severe 
liver injury (as defined by Hy’s Law).  
Visual plots (box plots or line plots) will be used to display selected laboratory 
parameters over time/by visit where appropriate.  


 
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4.6.5 
Vital Signs 
Values, along with change from baseline, will be summarized using descriptive statistics 
for each vital sign parameter. 
Summary statistics on absolute values and their change from baseline for all observed 
vital signs (respiratory rate, pulse rate, systolic and diastolic blood pressure while the 
patient is in a seated position, oxygen saturations, and temperature) will be presented 
over time by treatment group.  Baseline is defined as the last assessment prior to 
treatment.  
4.6.6 
ECGs 
A shift table of qualitative ECG assessments will be produced. 
4.6.7 
Other Safety Endpoints 
Summaries of safety data by ADA status will be provided as appropriate.  See 
Section 4.7.5 for more details on ADA status. 
4.7 
OTHER ANALYSES 
4.7.1 
Summaries of Conduct of Study 
Eligibility criteria deviations and other major protocol deviations will be summarized.  
The impact of COVID-19 will be assessed by including major protocol deviations related 
to COVID-19 and by summarizing COVID-19 related intercurrent events by treatment 
arm. 
Compliance analysis will be performed for the overall UCSD-SOBQ and SGRQ 
questionnaires.  Compliance rates will be summarized by number and proportion of 
patients among those expected to complete the UCSD-SOBQ or SGRQ at each time 
point. 
4.7.2 
Summaries of Treatment Group Comparability 
Unless otherwise specified, the baseline value for each variable will be considered the 
assessment collected on Baseline Day 1, prior to administration of study drug. 
Demographic and baseline characteristics (including, but not limited to, age, sex, 
race/ethnicity, concomitant IPF medication use, comorbid illnesses, and pulmonary 
function) will be summarized overall for the FAS population and by treatment group 
using descriptive statistics as appropriate.  
Compliance with study drug will be computed for each patient as the proportion of 
prescribed study drug actually taken for the safety population. 


 
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Proportions of patients taking each concomitant medication will be provided for the 
safety population. 
Medical history will be summarized using summary statistics, reporting the proportion of 
patients with at least one medical condition and the total number of medical conditions 
based on the safety population. 
4.7.3 
Pharmacokinetic Analyses 
Summary tables for plasma concentration of zinpentraxin alfa (mean, standard 
deviation, %CV, geometric mean, % CV of geometric mean, median, minimum, and 
maximum) will be produced by visit, treatment arm, and drug generation.  As more 
intensive PK data are collected in patients enrolled in China (and Hong Kong and 
Taiwan, if applicable) and Japan, summary tables will be produced for these patients 
separately (see Section 4.7.6 for details on the analyses of China and Japan 
subpopulations).  
Individual patient data and descriptive statistics (i.e., median and interquartile range) will 
be plotted by visit for each treatment arm. 
Exploratory PK analyses to evaluate potential relationships between drug exposure and 
the efficacy and safety of zinpentraxin alfa will be performed.  These analyses will be 
presented in a separate report and the results will be reported separately as appropriate. 
4.7.4 
Biomarker Analyses 
Exploratory biomarker analyses will be performed to identify and/or evaluate biomarkers 
in the context of drug activity, efficacy, PK, safety, and/or immunogenicity endpoints.  
These analyses will be detailed in the Biomarker Analysis Plan and the results will be 
reported separately. 
4.7.5 
Immunogenicity Analyses 
The following summaries will be provided by the treatment group: 
 
Number and proportion of ADA-positive patients and ADA-negative patients at 
baseline (baseline prevalence) and after drug administration (post-baseline 
incidence)  
 
Number and percentage of patients with treatment-induced, treatment‑enhanced 
and treatment unaffected ADAs 
 
Drug concentration at ADA collection timepoints 
 
A by-patient listing of ADA status will be provided.  
When determining post-baseline incidence, patients are considered to be ADA positive if 
they are ADA negative or have missing data at baseline but develop an ADA response 
following study drug exposure (treatment-induced ADA response), or if they are ADA 


 
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positive at baseline and the titer of one or more post-baseline samples is at least 
0.60 titer unit greater than the titer of the baseline sample (treatment-enhanced ADA 
response).  Patients are considered to be ADA negative if they are ADA negative or 
have missing data at baseline and all post-baseline samples are negative, or if they are 
ADA positive at baseline but do not have any post-baseline samples with a titer that is at 
least 0.60 titer unit greater than the titer of the baseline sample (treatment unaffected). 
The relationship between ADA status and safety, efficacy, and PK, will be analyzed and 
reported via descriptive statistics.  ADA status will also be reported by drug generation.  
4.7.6 
Analyses of China and Japan Subpopulations 
If applicable, a separate analysis will be performed for the China subpopulation, where 
data from all participants enrolled at sites in mainland China, Hong Kong, and Taiwan 
(during both the global enrollment phase and the extended China enrollment phase) will 
be combined and summarized.  Similar analysis will be conducted for the Japan 
subpopulation.  These analyses will be detailed in a separate analysis plan.  Data from 
the China extension cohort will not be included in the primary analysis of the main study.  
All analyses described in this section will include data from the Japan subpopulation and 
all data from the China subpopulation collected up to the clinical cutoff date for the China 
subpopulation analysis as defined in Section 1.2. 
The analysis population for the China subpopulation analyses includes all participants 
enrolled at sites in mainland China, Hong Kong, and Taiwan.  The Japan subpopulation 
includes all participants enrolled in Japan.  Data for the China and Japan subpopulations 
will be analyzed using the same statistical methods as described in Section 4.1 to 
Section 4.6 when data allow.  In addition, key PK and ADA data for the China and Japan 
subpopulations will be summarized. 
The PK parameters for zinpentraxin alfa in plasma will be estimated as appropriate for 
each subject profile in the China and Japan subpopulations by non-compartmental 
analysis methods using Phoenix WinNonlin software (v8.3 or later, Certara USA, Inc.).   
Plasma PK parameters definitions are as below: 
 
Cmax:  maximum observed concentration 
 
Tmax:  time to maximum observed concentration 
 
AUC0-t:  area under the concentration-time curve from hour 0 to the last measurable 
concentration, calculated using the linear trapezoidal rule for increasing 
concentrations and the logarithmic rule for decreasing concentrations 
 
AUC0-∞:  area under the concentration-time curve extrapolated to infinity, calculated 
using the formula: 
AUC0-∞    AUC0-t +Ct/z 


 
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where Ct is the last measurable concentration and z is the terminal elimination rate 
constant 
 
%AUCextrap:  percentage of area under the concentration-time curve that is due to 
extrapolation from the last measurable concentration to infinity 
 
z:  terminal elimination rate constant, where z is the magnitude of the slope of the 
linear regression of the log concentration versus time profile during the terminal 
phase 
 
t1/2:  terminal elimination half-life (whenever possible), where t1/2    (ln 2)/z 
 
CL:  systemic clearance 
 
V:  volume of distribution 
 
Other parameters may be added as appropriate.  PK parameters analysis will use actual 
times as recorded on the eCRF. 
Estimates for PK parameters will be listed and summarized (mean, standard deviation, 
coefficient of variation mean, geometric mean, coefficient of variation geometric mean, 
median, minimum, and maximum). 
Additional exploratory PK analyses will be conducted as appropriate.  Exploratory PK 
analyses to evaluate potential relationships between drug exposure and the efficacy and 
safety of zinpentraxin alfa might be described in a separate document and presented in 
a separate report. 
4.7.7 
Other Analyses 
SARS-CoV-2 serology will be summarized descriptively by time point and treatment 
group. 
4.8 
INTERIM ANALYSES 
4.8.1 
Planned Interim Analysis 
An interim futility analysis will be performed after at least 40% of patients have 
completed their Week 28 visit.  The futility boundary for this analysis is calculated to 
correspond approximately to 25% Bayesian Predictive Power, assuming a linear 
extrapolation between Week 28 and Week 52 visits.  
This interim futility analysis will be conducted by an external statistical group and 
reviewed by the iDMC.  The Sponsor will remain blinded.  Interactions between the 
iDMC and Sponsor will be carried out as specified in the iDMC charter.  
The futility analysis will be based on the following endpoint:  
 
Absolute change from baseline to Week 28 in FVC (mL)  
 


 
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The difference in mean absolute change from baseline to Week 28 in FVC (mL) between 
the two treatment arms will be estimated using a linear mixed-effect model with random 
intercept and random slope, with FVC mL measured at each timepoint (including 
baseline) as the dependent variable, stratification factors, age, sex, height, and 
treatment by time interaction as fixed effects, and subject and time as random effects. 
The full analysis set (FAS) is defined as all randomized patients who received at least 
one administration (full or partial) of study drug.  A subset of the FAS will be used for the 
interim futility analysis.  Only patients in the FAS with an expected Week 28 visit by the 
data cutoff date will be used for the futility analysis and will be grouped according to their 
treatment assignment at randomization.  Patients contributing data to the futility analysis 
may have assessments beyond Week 28.  Assessments collected after Week 28 will 
also be included in the futility analysis.  No missing data will be imputed for the interim 
analysis.  Measurements collected after lung transplantation will be excluded from the 
analysis. 
The criterion to declare futility will be based on the estimated difference in FVC decline 
between PRM-151 and placebo.  In particular, the iDMC will declare the study futile if the 
following condition is met:  
 
The estimated difference in mean absolute change from baseline at Week 28 in 
FVC (mL) between rhPTX-2 and placebo treated patients is less than 10 mL  
 
The data cutoff date (the date by which assessments that have occurred will be included 
in the futility analysis) is the date by which 40% of patients (according to planned total 
sample size) are scheduled to have completed their Week 28 visit.  For these first 40% 
of patients, all assessments that occur before or on the data cutoff date will be included 
in the analysis, including assessments collected after the Week 28 visit. 
All outputs for the futility analysis will be produced by the iDCC on unblinded data and 
will be reviewed during the futility analysis meeting by the iDMC only. 
4.8.2 
Optional Interim Analysis 
No other efficacy interim analyses are planned at this time.  However, in exceptional 
circumstances, when patient enrollment and study conduct is significantly impacted by 
external factors such that study completion does not seem feasible (e.g., ongoing or 
worsening impact of the global COVID-19 pandemic, the availability of compelling 
clinical trial results for an external competitor molecule, or significant changes in 
standard of care), the Sponsor may choose to conduct one interim efficacy analysis. 
Below are the specifications in place to ensure the study continues to meet the highest 
standards of integrity when an optional interim analysis is executed.  
If an interim efficacy analysis is conducted, the Sponsor will remain blinded.  The interim 
efficacy analysis will be conducted by an external statistical group and reviewed by the 


 
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iDMC.  Interactions between the iDMC and Sponsor will be carried out as specified in 
the iDMC Charter.  If there is a potential for the study to be stopped for positive efficacy 
as a result of the interim analysis, the type I error rate will be controlled to ensure 
statistical validity is maintained.  If the study continues beyond the interim analysis, the 
critical value at the final analysis would be adjusted accordingly to maintain the 
protocol‑specified overall type I error rate, per standard Lan-DeMets methodology 
(DeMets and Lan 1994).  
5. 
SUPPORTING DOCUMENTATION 
Refer to Appendix 1 below for details. 


 
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Appendix 1 Changes to Protocol-Planned Analyses 
The following are the major changes to the planned analyses specified in the 
Study WA42293 protocol, Version 5.  These are captured in the following sections of this 
SAP: 
 
Section 1.1 and Section 4.5 were updated to simplify exploratory endpoints and to 
clarify primary and secondary endpoints. 
 
Section 1.1 was updated to amend the ICE strategy for death for the primary 
endpoint analysis. 
 
Section 4.3.2 was updated to show approaches used in case of model 
non‑convergence. 
 
Section 4.4.2 was updated for the analysis method for Hgb-corrected DLCO % 
predicted. 
 
6. 
REFERENCES 
Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary 
fibrosis. An international working group report. Am J Respir Crit Care Med 
2016;194:265–75. 
DeMets DL, Lan G. Interim analysis: the alpha spending function approach. Stat Med 
1994;13:1341-52. 
Efron B. The Efficiency of Cox's Likelihood Function for Censored Data. Journal of the 
American Statistical Association 1977; 72(359), 557-65. 
FDA Guidance for Industry 2006. U.S. Food and Drug Administration. (2006 [cited: 
12 March 2020]). Guidance for clinical trial sponsors: establishment and operation 
of clinical trial data monitoring [resource on the internet]. Available from: 
https://www.gmp-compliance.org/guidelines/gmp-guideline/fda-guidance-for-
clinicaltrial-sponsorson-the-establishment-and-operationof-clinical-trial-data-
monitoringcommittees. 
Hernandez RL, Perez MA, Carrasco MT, et al. Lung transplantation in idiopathic 
pulmonary fibrosis. Med Sci 2018;6:68. 
Raghu G, Remy-Jardin M, Myers JL, et al. Diagnosis of idiopathic pulmonary fibrosis. 
An official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care 
Med 2018;199:A2636. 
Sampson HA, Munoz-Furlong A, Campbell RL, et al: Second symposium on the 
definition and management of anaphylaxis: summary report: Second National 
Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network 
Symposium. J Allergy Clin Immunol 2006;117: 3917. 
Wolbers M, Noci A, Delmar P, et al. Standard and reference-based conditional mean 
imputation. Pharmaceutical Statistics 2022;1-12. 


Signature Page for Statistical Analysis Plan WA42293  Version 1-Zinpentraxin Alf
System identifier: RIM-CLIN-455199
Approval Task
Scientific content approver
18-Oct-2022 16:18:11 GMT+0000