Conditions: Dilated Cardiomyopathy Lamin A/C Gene Mutation
Keywords: cardiomyopathy Lamin Type A heart failure ARRY-797 C4411002
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 77
Healthy volunteers: no

Brief summary:
This is a randomized, double-blind, placebo-controlled study in patients with dilated cardiomyopathy (DCM) due to a mutation of the gene encoding the lamin A/C protein (LMNA). The study will further evaluate a dose level of study drug (ARRY-371797) that has shown preliminary efficacy and safety in this patient population. After the primary analysis has been performed, eligible patients may receive open-label treatment with ARRY-371797.

Detailed description:

Arms:
arm 1: ARRY-371797 (PF-07265803) tablet orally OR matching placebo tablet orally arm 2: ARRY-371797 (PF-07265803) tablet orally

Interventions: intervention 1: ARRY-371797 (PF-07265803) intervention 2: Placebo
Intervention descriptions: intervention 1: 400 mg twice daily (BID) intervention 2: BID

Protocol document:
Prot_000.pdf: 
ARRY-371797 (PF-07265803) 
Protocol C4411002 (Array-797-301) 
Final Protocol Amendment 8, 09Feb2022 
 
PFIZER CONFIDENTIAL 
Page 1 
 
 
 
 
 
 
 
A PHASE 3, MULTINATIONAL, RANDOMIZED, PLACEBO-CONTROLLED 
STUDY OF ARRY-371797 (PF-07265803) IN PATIENTS WITH SYMPTOMATIC 
DILATED CARDIOMYOPATHY DUE TO A LAMIN A/C GENE MUTATION 
(REALM-DCM) 
 
Study Intervention Number: 
ARRY-371797 (PF-07265803) 
Study Intervention Name: 
p38 MAP Kinase Inhibitor 
US IND Number: 
CCI  
EudraCT Number: 
2017-004310-25 
Protocol Number: 
C4411002 (Array-797-301) 
Phase: 
3 
 
 
 
This document and accompanying materials contain confidential information belonging to Pfizer. Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes. In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified. 


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Protocol Amendment Summary of Changes Table 
 
Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
Amendment 8 
09Feb2022 
Modified protocol sections to include a change 
in the number of participants randomized into 
the study and updated the Section 9.2 Sample 
Size Determination. Rationale: Following a 
planned interim futility analysis, a blinded 
sample size re-estimation was performed for the 
primary efficacy endpoint of change from 
baseline in 6MWT at Week 24 to maintain 
sufficient study power to detect a clinically 
meaningful treatment effect for the primary 
efficacy endpoint. 
Updated Section 9, Statistical Considerations, to 
include the following changes: 1) Section 9.3, 
Analysis Sets, modified the definition of 
Efficacy Analysis Dataset and NYHA Class IV 
Analysis dataset by removing the inclusion 
criterion “with a LMNA gene mutation that is 
pathogenic, likely pathogenic or VUS”. 
Rationale: A correction was made to clarify that 
all randomized participants will be included in 
the respective analyses. 2) Section 9.2, Sample 
Size Determination, added results of the blinded 
sample size re-estimation. Rationale: A planned 
sample size re-estimation was completed 
following the interim futility analysis. 3) 
Section 9.4.5.1, Hierarchical Testing, updated 
the hierarchical testing procedure to move NT- 
proBNP after the composite endpoint of time of 
all-cause mortality or worsening heart failure. 
Rationale: Updates were made based on 
regulatory feedback. 4) deleted the text 
specifying that fifty-two (52) events are required 
to assess the composite endpoint of time to first 
occurrence of all-cause mortality or worsening 
of heart failure. Rationale: The event rate will 
be continually monitored throughout the course 
of the study and further details will be included 
in the SAP on the assessment of the composite 
endpoint. 5) Removed duplicate sentences in the 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
primary efficacy analysis section. Rationale: To 
align with the Statistical Analysis Plan. 
Modified Section 6.1, Study Intervention(s) 
Administered, to include direct-to-participant 
shipment of study intervention if permitted by 
local regulations. Rationale: To allow the option 
of study intervention to be shipped to the 
participant’s home between study visits that are 
every 24 weeks. 
Modified Section 6.6.1, Dose Interruptions, 
Reductions, and Discontinuations 1) to specify 
that if an AE occurs and it’s not considered 
related to study intervention, dosing does not 
have to be reduced or modified, if in the 
investigator’s opinion the AE is due to the 
underlying disease. Rationale: To allow the 
investigator to use clinical judgment not to 
reduce dose if an AE is caused by the 
participants underlying disease. 2) to specify that 
dose reduction should be considered as an option 
before permanently discontinuing study 
intervention. Rationale: Dose reductions are 
allowed per protocol and this sentence was 
added to provide additional clarification. 
Updated Section 4.3 Justification for Dose to 
state the 400 mg BID dose of ARRY-371797 
(PF-07265803) appeared to be associated with 
larger favorable changes in NT-proBNP levels 
than the 100 mg BID dose in an analysis of 
aggregated mean change from baseline at all 
time points. Rationale: To align text with the 
Phase 2 (Array-797-001 [C4411001] final CSR 
and IB. 
Updated Section 10, Appendix 8: Cautionary 
Concomitant Medications. Rationale: The list of 
medications with known TdP risks was accessed 
and updated on 07Jan2022. 
Updated Section 2.1 Study Rationale and 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
Section 2.2 Background. Rationale: To include 
data from the completed Phase 2, long-term 
rollover extension study ARRAY-797-001 
(C4411001). 
Modified Section 6.1.3, Administration. 
Rationale: To clarify that participants should 
abstain from all food 2 hours prior and 2 hours 
after dosing. 
Updated Section 6.4, Study Intervention 
Compliance. Rationale: To clarify study 
intervention dosing compliance must be 
reviewed by the site personnel at each visit using 
the participant diary and discussed with the 
participant at each visit. 
Modified Section 9.4.3.7.1, Population 
Pharmacokinetic/Pharmacodynamic Analyses, to 
indicate that early unblinding is planned when 
≥90% of participants have reached 24 weeks 
post-randomization (or discontinued prior to the 
Week 24 visit). The unblinding will be limited to 
the PK data (ie, no efficacy data). Rationale: 
For PK modeling purposes. 
Modified Section 1.3 and Section 4.1.2 to 
specify that following the Week 60 visit, all 
subsequent on-site clinic visits will be every 24 
weeks. Added the footnote “aa” to specify that 
starting at Week 72, a phone contact visit must 
be performed every 24 weeks to assess 
pregnancy (at-home urine pregnancy test), 
SAE/AEs, HF-related hospitalizations, HF- 
related urgent care visits, assess any changes to 
concomitant medications and assess status of 
study intervention and ensure the participant 
dosing diary is completed. Rationale: A site 
visit every 12 weeks is no longer required in 
efforts to reduce the burden on participants 
remaining on study intervention after 
approximately 1 year after randomization. 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
Modified the open-label SoA to reflect: 1) for 
participants randomized to ARRY-371797 (PF- 
07265803) in the double-blind period visits will 
be every 24 weeks; 2) for participants 
randomized to placebo during the double-blind 
period clinic visits will be every 24 weeks 
following the week 24 visit. Rationale: To 
reduce the burden on participants. 
Removed CRT from Section 7.1, 
Discontinuation of Study Intervention and 
Participant Discontinuation/Withdrawal. 
Rationale for Change: CRT may be part of 
standard of care for some participants with 
dilated cardiomyopathy. CRT initiation and 
adjustment is now permitted for enrolled 
participants. 
Updated Section 1.1, Synopsis and Section 4.1.1, 
Prescreening and Screening for Randomized 
Double-blind Treatment Period to clarify that 
participants who have multiple LMNA variants 
identified by an accredited local laboratory will 
be enrolled on the variant with the highest 
classification tier. Rationale: There is a potential 
for a participant to have multiple LMNA variants. 
Updated the Pfizer protocol number in the 
document header and title page; updated 
footnote “a” and “m” in Section 1.3 SoA; and 
Section 5.1.1.1, Prescreening for Participants, 
with Pre-Identified (P/LP)/VUS LMNA 
mutation. Rationale: Implemented changes 
documented in the PACL dated 14Apr21. 
Section 2.2.3.2, Nonclinical Drug Metabolism, 
was updated to include results from nonclinical 
studies completed. Rationale: Nonclinical drug 
metabolism was finalized and additional data 
were generated to inform potential DDI. 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
Section 2.2.3.3 Nonclinical Toxicity and Safety, 
was updated to include phototoxicity results and 
text was updated to align with IB. Rationale: 
provide most current nonclinical data results. 
Section 2.2.4.3 Clinical Efficacy and 2.2.4.4 
Clinical Safety sections were updated to include 
final study results from the Phase 2 rollover 
extension study (Array-797-001). Rationale: 
The Clinical Study Report for study Array-797- 
001 was finalized on 29-Jun-2021. 
Updated Section 8.4 Adverse Events and Serious 
Adverse Events and Section 10.3. Appendix 3: 
Adverse Events Definition and Procedures for 
Recording, Evaluating, Follow-up, and 
Reporting. Rationale: To align with Pfizer’s 
required protocol template language. 
Updated Section 1.1 Synopsis and Section 3 
Objectives, estimands and Endpoints. Rationale: 
Simplified by removing each specified timepoint 
given that the measurement will be assessed 
throughout the double-blind period. 
Updated Section 1.3, SoA, adding footnote “y” 
and added Appendix 10.10.1 country specific 
requirements in Japan. Rationale: Implemented 
changes documented in the PACL dated 31- 
May-2021. 
Updated bilirubin criterion in Section 5.1.2, 
5.1.3, and 5.1.4. Rationale: To align with 
Pfizer’s required protocol template language. 
Added the study name (REALM-DCM) to the 
title page. Rationale: Study name and branding 
were implemented after protocol version 7 
approval. 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
Typos and inconsistencies were corrected, minor 
clarifications were added, sections were 
harmonized, language that is not applicable has 
been removed throughout the protocol. 
Rationale: Editorial updates. 
 
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs. 


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TABLE OF CONTENTS 
LIST OF TABLES ................................................................................................................... 15 
LIST OF FIGURES .................................................................................................................. 15 
1. PROTOCOL SUMMARY ................................................................................................... 16 
1.1. Synopsis ................................................................................................................... 16 
1.2. Schema..................................................................................................................... 25 
1.3. Schedule of Activities .............................................................................................. 26 
2. INTRODUCTION ................................................................................................................ 33 
2.1. Study Rationale ........................................................................................................ 33 
2.1.1. Rationale for Selection of the Primary Efficacy Endpoint.......................... 33 
2.1.2. Rationale for Selection of the Secondary Endpoint - Composite 
Endpoint of All-Cause Mortality or Worsening Heart Failure (HF- 
related hospitalization or HF-related urgent care visits) .................................. 34 
2.2. Background .............................................................................................................. 34 
2.2.1. LMNA-Related Dilated Cardiomyopathy .................................................... 34 
2.2.3. Nonclinical Studies with ARRY-371797 (PF-07265803) .......................... 36 
2.2.3.1. Nonclinical Pharmacology ......................................................... 36 
2.2.3.2. Nonclinical Drug Metabolism ................................................... 37 
2.2.3.3. Nonclinical Toxicity and Safety ................................................ 38 
2.2.4. Clinical Experience with ARRY-371797 (PF-07265803) .......................... 39 
2.2.4.1. Clinical Pharmacokinetics ......................................................... 39 
2.2.4.2. Clinical Pharmacodynamics ...................................................... 40 
2.2.4.3. Clinical Efficacy ........................................................................ 40 
2.2.4.4. Clinical Safety ........................................................................... 42 
2.3. Benefit/Risk Assessment ......................................................................................... 44 
2.3.1. Risk Assessment ......................................................................................... 44 
2.3.2. Benefit Assessment ..................................................................................... 44 
2.3.3. Overall Benefit/Risk Conclusion ................................................................ 44 
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ............................................................ 45 
4. STUDY DESIGN ................................................................................................................. 47 
4.1. Overall Design ......................................................................................................... 47 
CCI 


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4.1.1. Prescreening and Screening for Randomized Double-Blind 
Treatment Period ..............................................................................................48 
4.1.2. Randomized Double-Blind Treatment Period ............................................48 
4.1.3. ARRY-371797 (PF-07265803) Open-Label Treatment Period ..................49 
4.1.3.1. Open-Label Period for Participants Randomized to 
ARRY-371797 (PF-07265803) ..........................................................50 
4.1.3.2. Open-Label Period for Participants Randomized to 
Placebo ...............................................................................................50 
4.2. Scientific Rationale for Study Design .....................................................................50 
4.3. Justification for Dose ...............................................................................................50 
4.4. End of Study Definition ...........................................................................................51 
5. STUDY POPULATION ......................................................................................................51 
5.1. Inclusion Criteria .....................................................................................................52 
5.1.1. Prescreening Eligibility Criteria for LMNA Mutation Testing ....................52 
5.1.1.1. Prescreening for Participants with Pre-Identified 
P/LP/VUS LMNA Mutation by an Accredited Clinical 
Laboratory ..........................................................................................52 
5.1.1.2. Prescreening for Participants with Unknown LMNA 
Mutation Status or with an Identified LMNA Mutation Result 
not Performed by an Accredited Clinical Laboratory ........................53 
5.1.2. Inclusion Criteria for NYHA Functional Class II and III Participants........53 
5.1.3. Inclusion Criteria for NYHA Functional Class IV Participants ..................55 
5.1.4. Inclusion Criteria for Participants Who Cross Over From Placebo to 
ARRY-371797 (PF-07265803) Treatment in the Open-Label Period .............56 
5.2. Exclusion Criteria ....................................................................................................57 
5.2.1. Exclusion Criteria for NYHA Functional Class II and III Participants .......57 
5.2.2. Exclusion Criteria for NYHA Functional Class IV Participants .................59 
5.2.3. Exclusion Criteria for Participants Who Cross Over From Placebo to 
ARRY-371797 (PF-07265803) Treatment in the Open-Label Period .............60 
5.3. Lifestyle Considerations ..........................................................................................60 
5.3.1. Contraception ..............................................................................................60 
5.3.2. Meals and Dietary Restrictions ...................................................................61 
5.3.3. Restrictions on Physical Activity ................................................................61 
5.4. Screen Failures .........................................................................................................61 
6. STUDY INTERVENTION ..................................................................................................61 


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6.1. Study Intervention(s) Administered .........................................................................61 
6.1.1. Manufacturing and Formulation .................................................................62 
6.1.2. Packaging and Labeling ..............................................................................62 
6.1.3. Administration .............................................................................................63 
6.2. Preparation/Handling/Storage/Accountability ..........................................................63 
6.2.1. Preparation and Dispensing .........................................................................64 
6.3. Measures to Minimize Bias: Randomization and Blinding .....................................65 
6.3.1. Allocation to Study Intervention .................................................................65 
6.3.2. Breaking the Blind ......................................................................................66 
6.4. Study Intervention Compliance ...............................................................................66 
6.5. Concomitant Therapy ..............................................................................................66 
6.5.1. Prohibited Therapies/Treatment ..................................................................66 
6.5.2. Cautionary Use of Concomitant Medications while on Study 
Intervention ......................................................................................................67 
6.6. Dose Modification ...................................................................................................67 
6.6.1. Dose Interruptions, Reductions, and Discontinuations ...............................67 
6.7. Intervention After the End of the Study ..................................................................75 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................................75 
7.1. Discontinuation of Study Intervention .....................................................................75 
7.2. Participant Discontinuation/Withdrawal From the Study ........................................76 
7.2.1. Withdrawal of Consent ...............................................................................76 
7.2.2. Replacement of Participants ........................................................................77 
7.3. Lost to Follow-up ....................................................................................................77 
8. STUDY ASSESSMENTS AND PROCEDURES ...............................................................77 
8.1. Screening Assessments ............................................................................................78 
8.1.1. Participant Demographics and Other Baseline Characteristics .................. 78 
8.1.2. Follicle-Stimulating Hormone ....................................................................78 
8.1.3. Human Immunodeficiency Virus, Hepatitis B, and Hepatitis C 
Serology ...........................................................................................................79 
8.2. Efficacy Assessments ..............................................................................................79 
8.2.1. 6-Minute Walk Test ....................................................................................79 
8.2.2. Activity Monitoring ....................................................................................80 


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8.2.3. N-Terminal Pro-Brain Natriuretic Peptide .................................................. 80 
8.2.4. Echocardiogram .......................................................................................... 80 
8.2.5. Patient-Reported Outcomes ........................................................................ 80 
8.2.5.1. Kansas City Cardiomyopathy Questionnaire (KCCQ) .............. 80 
8.2.5.2. Patient Global Impression .......................................................... 81 
8.2.5.3. EuroQoL EQ-5D-5L .................................................................. 81 
8.2.6. Assessment of Composite Endpoint of All-Cause Mortality or 
Worsening Heart Failure (HF-Related Hospitalization or HF-Related 
Urgent Care Visits) .......................................................................................... 81 
8.3. Safety Assessments .................................................................................................. 82 
8.3.1. Medical History .......................................................................................... 82 
8.3.2. Physical Examinations ................................................................................ 82 
8.3.3. Vital Signs ................................................................................................... 83 
8.3.4. Arrhythmia Assessment .............................................................................. 83 
8.3.5. Electrocardiograms ...................................................................................... 83 
8.3.6. Clinical Safety Laboratory Assessments ..................................................... 84 
8.3.7. Pregnancy Testing ....................................................................................... 85 
8.4. Adverse Events and Serious Adverse Events .......................................................... 85 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information ....... 86 
8.4.1.1. Reporting SAEs to Pfizer Safety ............................................... 87 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF ................... 87 
8.4.2. Method of Detecting AEs and SAEs ........................................................... 87 
8.4.3. Follow-up of AEs and SAEs ....................................................................... 87 
8.4.4. Regulatory Reporting Requirements for SAEs ........................................... 88 
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure ..................................................... 88 
8.4.5.1. Exposure During Pregnancy ...................................................... 88 
8.4.5.2. Exposure During Breastfeeding ................................................. 90 
8.4.5.3. Occupational Exposure .............................................................. 90 
8.4.6. Cardiovascular and Death Events ................................................................ 90 
8.4.7. Disease -Related Events and/or Disease -Related Outcomes Not 
Qualifying as AEs or SAEs .............................................................................. 91 
8.4.8. Adverse Events of Special Interest ............................................................. 91 


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8.4.8.1. Lack of Efficacy ........................................................................ 91 
8.4.9. Medical Device Deficiencies ...................................................................... 91 
8.5. Treatment of Overdose ............................................................................................ 92 
8.6. Pharmacokinetics ..................................................................................................... 92 
CCI 
 
8.8. Genetics ................................................................................................................... 94 
8.8.1. Lamin A/C Genetic Testing ........................................................................ 94 
8.9. Biomarkers ............................................................................................................... 94 
8.10. Immunogenicity Assessments ............................................................................... 94 
8.11. Health Economics .................................................................................................. 94 
8.12. Survival Follow-up ................................................................................................ 94 
9. STATISTICAL CONSIDERATIONS ................................................................................. 95 
9.1. Estimands and Statistical Hypotheses...................................................................... 95 
9.1.1. Estimands .................................................................................................... 95 
9.2. Sample Size Determination ..................................................................................... 95 
9.3. Analysis Sets ............................................................................................................ 97 
9.4. Statistical Analyses .................................................................................................. 97 
9.4.1. General Considerations ............................................................................... 97 
9.4.2. Primary Endpoint(s) .................................................................................... 98 
9.4.2.1. Primary Efficacy Analysis of Change From Baseline in 
6MWT at Week 24 ............................................................................ 98 
9.4.2.2. Sensitivity Analyses................................................................. 100 
9.4.3. Secondary Endpoint(s) .............................................................................. 100 
9.4.3.1. Kansas City Cardiomyopathy Questionnaire Domains of 
TSS and PL ...................................................................................... 100 
9.4.3.2. Patient Global Impression Scores ............................................ 100 
9.4.3.3. Change From Baseline in N-terminal Pro-Brain 
Natriuretic Peptide at Weeks 4, 12, and 24 ...................................... 100 
9.4.3.4. The Composite Endpoint of Time to First Occurrence of 
All-Cause Mortality or Worsening Heart Failure (HF-related 
hospitalization or HF-related urgent care visit) ............................... 101 
9.4.3.5. Overall Survival ....................................................................... 101 
9.4.3.6. Safety Analysis ........................................................................ 101 


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9.4.3.7. Pharmacokinetic Analysis ....................................................... 102 
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CCI 
 
9.4.5. Other Analyse(s) .......................................................................................103 
9.4.5.1. Hierarchical Testing ................................................................103 
9.5. Interim Analyses ....................................................................................................103 
9.6. Data Monitoring Committee or Other Independent Oversight Committee ...........104 
9.6.1. Data Monitoring Committee .....................................................................104 
9.6.2. Steering Committee ...................................................................................105 
9.6.3. Clinical Events Committee .......................................................................105 
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.........................................................................................................106 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ..............106 
10.1.1. Regulatory and Ethical Considerations ...................................................106 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP .......................................................................106 
10.1.2. Financial Disclosure ................................................................................107 
10.1.3. Informed Consent Process ......................................................................107 
10.1.4. Data Protection ........................................................................................108 
10.1.5. Dissemination of Clinical Study Data .....................................................108 
10.1.6. Data Quality Assurance ...........................................................................109 
10.1.7. Source Documents ..................................................................................111 
10.1.8. Study and Site Start and Closure .............................................................111 
10.1.9. Publication Policy ...................................................................................112 
10.1.10. Sponsor’s Qualified Medical Personnel ................................................112 
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................113 
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow--up, and Reporting ....................................................................114 
10.3.1. Definition of AE ......................................................................................114 
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10.3.2. Definition of SAE ...................................................................................115 
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs During 
the Active Collection Period ..........................................................................117 
10.3.4. Reporting of SAEs ..................................................................................120 
10.4. Appendix 4: Contraceptive Guidance ..................................................................121 
10.4.1. Male Participant Reproductive Inclusion Criteria ..................................121 
10.4.2. Female Participant Reproductive Inclusion Criteria ...............................121 
10.4.3. Woman of Childbearing Potential ...........................................................122 
10.4.4. Contraception Methods ...........................................................................123 
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow--up Assessments......125 
10.6. Appendix 6: ECG Findings of Potential Clinical Concern ..................................127 
10.7. Appendix 7: Alternative Measures During Public Emergencies .........................129 
10.8. Appendix 8 Cautionary Concomitant Medications while on Study 
Intervention ..............................................................................................................131 
10.9. Appendix 9: Definitions of Heart Failure Events ................................................135 
10.10. Appendix 10: Country Specific Requirements ..................................................137 
10.10.1. Japan .....................................................................................................137 
10.10.2. France ....................................................................................................138 
10.11. Appendix 11: Abbreviations ..............................................................................139 
10.12. Appendix 12: Protocol Amendment History .....................................................144 
11. REFERENCES .................................................................................................................158 


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LIST OF TABLES 
Table 1. 
Summary of Adverse Events, Regardless of Causality, Reported in 
>1 Participant or Reported as Grade 3/4 (Study ARRAY-797-231) ........43 
Table 2. 
Dose Levels of Study Intervention ............................................................62 
Table 3. 
Guidelines for ARRY-371797 (PF-07265803) Dose Modifications 
for Adverse Events ....................................................................................68 
Table 4. 
Protocol -Required Safety Laboratory Assessments ...............................113 
 
 
LIST OF FIGURES 
Figure 1. 
Mean NT-proBNP Over Time from Study ARRAY-797-231 ..................40 
Figure 2. 
Mean Change in 6MWT Over Time From Studies 
ARRAY-797-231 and ARRAY-797-001 – Combined Dose Groups .......41 


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Rationale 
In the completed Phase 2 study ARRAY-797-231, treatment with ARRY-371797 
(PF-07265803) resulted in rapid (<4 weeks), sustained increases in functional capacity in 
participants with lamin A/C gene mutation (LMNA)-related DCM. Improvements on the 
6MWT compared to baseline, the primary endpoint, were mirrored by favorable changes in 
NT-proBNP levels, LVEF and RV fractional area. ARRY-371797 (PF-07265803) was 
generally well tolerated. The AEs for most participants were mild to moderate, and only 
1 participant discontinued the study because of a treatment-related AE. In the completed 
long-term rollover extension study ARRAY-797-001 (C4411001), ARRY-371797 (PF- 
07265803) was generally well tolerated, with evidence suggesting preserved exercise 
capacity over an extended period of follow-up. Preserved exercise capacity was mirrored by 
favorable trends in NT-proBNP levels. 
 
Based on these clinical data, inhibition of p38 MAPK with the selective p38α inhibitor 
ARRY-371797 (PF-07265803) may provide a novel therapeutic approach and has the 
potential to fill an unmet medical need for the treatment of symptomatic LMNA-related DCM 
and merits further clinical investigation. 
 
Objectives, Estimands, and Endpoints 
 
The primary objective of the study is to evaluate the effect of ARRY-371797 (PF-07265803) 
on functional capacity as measured by the 6-minute walk test (6MWT) compared to placebo 
in patients with symptomatic DCM due to a LMNA gene mutation. The table below 
describes the study objectives including secondary and CCI   objectives and 
corresponding endpoints. 
 
Participants who discontinue study treatment prior to Week 24 will continue to have all 
assessments performed as scheduled through the Week 24 Visit. All data collected during 
the study will be included for the analyses of efficacy regardless of discontinuation of study 
treatment. 
 
Objectives 
Endpoints 
Primary: 
Primary: 
Evaluate the effect of ARRY-371797 (PF-07265803) on 
functional capacity (as measured by the 6 Minute Walk 
Test [6MWT]) compared to placebo. 
New York Heart Association Class (NYHA) II/III 
participants only: Change from baseline in 6MWT at Week 
24. 
Secondary: 
Secondary: 
Evaluate additional measures of efficacy of ARRY-371797 
(PF-07265803) compared to placebo in the randomized 
period. 
NYHA Class II/III patients only: Change from baseline in 
6MWT at Weeks 4 and 12. 


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Objectives 
Endpoints 
NYHA Class II/III participants only: Change from baseline 
in Kansas City Cardiomyopathy Questionnaire (KCCQ) 
Physical Limitation (PL) and Total Symptom Score (TSS) 
domains at Weeks 12 and 24. 
 
NYHA Class II/III participants only: Change from baseline 
in Patient Global Impression (PGI) scores at Weeks 12 and 
24: 
• 
Patient Global Impression of Severity (PGI-S); 
• 
Patient Global Impression of Change (PGI-C). 
 
 
 
 
Evaluate the impact of ARRY-371797 (PF-07265803) on 
composite endpoint of all-cause mortality, or worsening 
heart failure (WHF). 
 
Evaluate the impact of ARRY-371797 (PF-07265803) on 
overall survival (OS). 
Evaluate the safety of ARRY-371797 (PF-07265803) 
compared to placebo. 
 
 
 
 
 
 
 
CCI 
NYHA Class II/III participants: Change from baseline in 
N-terminal pro-brain natriuretic peptide (NT‑proBNP) at 
Weeks 4, 12, and 24. 
Defined as the time from randomization to the first 
occurrence of any event of death due to any cause, or 
worsening heart failure (HF-related hospitalization or HF- 
related urgent care visit). 
OS 
 
Safety as determined by: 
• 
Incidence and severity of Adverse Events (AEs); 
• 
Changes in clinical safety laboratory tests, vital 
signs, and 12 lead electrocardiography (ECGs); 
• 
Incidence and severity of ventricular or atrial 
arrhythmias detected using existing ICD/cardiac 
resynchronization therapy defibrillator (CRT-D) 
or other applicable device interrogations. 


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CCI 
Objectives 
Endpoints 
 
CCI 
 
 
 
 
 
 
 


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Overall Design 
 
This multinational Phase 3 study will evaluate the efficacy, safety, and PK following 
treatment with ARRY-371797 (PF-07265803) compared with placebo (1:1 randomization) in 
at least 160 participants with LMNA-related DCM in NYHA functional Class II and III . 
Additional LMNA-related DCM NYHA functional Class IV participants (up to 40) may be 
randomized (1:1) and will be assessed for overall safety and time from randomization to HF- 
related hospitalization, HF-related urgent care visits or death due to any cause, in addition to 
PK and efficacy, if feasible. 
 
The study will be conducted in 2 parts: a randomized, double-blind treatment period, 
followed by an ARRY-371797 (PF-07265803) open-label treatment period. During the 
randomized, double-blind period, participants, investigators, site personnel, and the sponsor 
personnel directly involved with the conduct of the study will remain blinded to assigned 
treatment. The double-blind period will continue until the primary analysis which includes 
an assessment of the primary efficacy endpoint and completion of an evaluation of a 
composite endpoint consisting of all-cause mortality or worsening heart failure (HF-related 
hospitalization or HF-related urgent care visits). Following the primary analysis, a seamless 
transition to the open-label phase may begin and ongoing treatments will be unblinded and 
participants receiving placebo may initiate treatment with ARRY-371797 (PF-07265803) 
provided eligibility criteria are met. The end of the study is reached once the last participant 
has had the opportunity to be followed for at least 24 weeks in the open-label period of the 
study or has discontinued from the study. 
 
Prescreening and Screening: 
 
All participants with DCM who meet the prescreening eligibility criteria for the study will be 
assessed for the presence of eligible LMNA mutation(s) using an assay performed by an 
accredited clinical laboratory. 
 
The central accredited clinical laboratory will be used to assess LMNA mutation status if the 
LMNA mutation status is unknown at time of prescreening or if the genetic test was not 
performed by an accredited clinical laboratory. The LMNA mutation test results from the 
central accredited clinical laboratory must be available and confirmed prior to entering the 
screening period. 
 
Participants with an identified pathogenic (P), likely pathogenic (LP) or variant of uncertain 
significance (VUS) LMNA mutation status documented by results from an accredited clinical 
laboratory can enter the screening period. Participants who have multiple LMNA variants 
identified will be enrolled on the variant with the highest classification tier and the variant 
with the highest classification will be reported in the eCRF. 
Randomized Double-Blind Treatment Period: 
 
All eligible participants will return to the clinic for assessment at the baseline visit (Day 1) 
prior to randomization. Randomization will be initially stratified based on NYHA class: 
Class II/III or Class IV. Randomization for the NYHA Class II/III participants will be further 


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stratified by the average of the Day -1 and Baseline Visit (Day 1) 6MWT (<320 m or ≥320 
m), and mutation type (pathogenic, likely pathogenic or VUS). On Day 1, eligible 
participants will be randomized (1:1) to 400 mg BID ARRY-371797 (PF-07265803) or 
placebo. 
 
Participants will continue on study intervention (eg, study treatment) as long as the 
participant has not met predefined criteria for treatment discontinuation. All participants 
should have a treatment discontinuation visit as soon as possible after the final dose of study 
treatment. A safety follow-up visit will occur approximately 30 days after the last dose of 
study intervention. Participants who discontinue study treatment prior to Week 24 should 
continue to have all assessments performed as scheduled through the Week 24 visit. Every 
effort should be made to obtain these data. All participants will subsequently be followed for 
HF-related hospitalization, HF-related urgent care visits and OS until death or initiation of 
the open-label treatment period, whichever occurs first (see Section 8.2.6). Every effort 
should be made to obtain these data. 
 
ARRY-371797 (PF-07265803) Open-Label Treatment Period: 
 
After the primary analysis has been performed (all participants have had the opportunity to 
be followed for at least 24 weeks in the randomized double-blind treatment period) and an 
evaluation of the composite endpoint consisting of all-cause mortality or worsening heart 
failure (HF-related hospitalization or HF-related urgent care visits) has been completed (see 
Section 8.2.6), eligible participants may receive open-label treatment with ARRY-371797 
(PF-07265803). The criteria for dose interruptions, reductions, and discontinuations of 
ARRY-371797 (PF-07265803) in the open-label treatment period will be identical to those 
used during the randomized period. 
 
Open-Label Period for Participants Randomized to ARRY-371797 (PF-07265803): 
 
After treatment unblinding, participants randomized to ARRY-371797 (PF-07265803) will 
receive the same dose in the open-label period of the study that they received at the end of 
the double-blinded period (ie, 400 mg BID, 200 mg BID, or 100 mg BID). 
 
Open-Label Period for Participants Randomized to Placebo: 
 
After treatment unblinding, participants randomized to placebo will undergo eligibility 
assessment concurrent with the open-label baseline visit and, if eligible, will receive ARRY- 
371797 (PF-07265803) at a starting dose of 400 mg BID in the open-label period of the 
study. 
 
Number of Participants 
 
Following a planned blinded sample size re-estimation, up to 200 eligible participants with 
symptomatic cardiomyopathy due to LMNA mutations will be randomized, including at least 
160 participants with NYHA functional Class II or III and up to 40 participants with NYHA 
functional Class IV , at approximately 60 to 90 investigational centers, globally. The sample 
size determination is detailed in Section 9.2. 


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Intervention Groups and Duration 
 
The study consists of a maximum of a 35-day screening phase, followed by a randomized, 
double-blind treatment period and then an open-label ARRY-371797 (PF-07265803) 
treatment period and survival follow-up. 
 
Participants may continue to receive study intervention as long as no treatment 
discontinuation criteria are met. 
 
Participants will be randomized (1:1) to the following groups: 
 
• ARRY-371797 (PF-07265803): 400 mg BID (4×100 mg tablets, BID) 
(800 mg total daily dose) 
 
• Matching placebo: 4 tablets BID (8 tablets daily) 
Placebo and active intervention tablets will be identical in appearance during the 
double-blind treatment period to maintain the study blind. 
 
If a participant has safety or tolerability issues at 4 tablets BID (ARRY-371797 (PF- 
07265803) [400 mg BID] or placebo), study intervention may be reduced to 2 tablets BID 
(ARRY-371797 (PF-07265803) [200 mg BID] or placebo) as described in this protocol. If a 
participant has tolerability issues at 2 tablets BID (ARRY-371797 (PF-07265803) [200 mg 
BID] or placebo), study intervention may be further reduced to 1 tablet BID (ARRY-371797 
(PF-07265803) [100 mg BID] or placebo) as described in Section 6.6 of this protocol. 
 
If study intervention is not well tolerated at any dose level, treatment will be permanently 
discontinued for that participant. See Section 7.1 Discontinuation of Study Intervention for 
details. 
 
Data Monitoring Committee or Other Independent Oversight Committee 
 
Data Monitoring Committee: 
 
The DMC will be responsible for reviewing safety and PK data at regular intervals during the 
randomized portion of the study. Additionally, the DMC will review efficacy data at a formal 
interim futility analysis planned after the first 60 Class II/III randomized participants have 
completed the Week 12 assessment or have discontinued from the study prior to Week 12. A 
separate DMC Charter will be established that outlines DMC membership and specifies what 
data will be reviewed, instructions for unblinding of data, along with the timing and 
frequency of the reviews. DMC recommendations will be provided to the sponsor in 
compliance with the DMC Charter. 


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Steering Committee: 
 
The SC will be appointed by the sponsor prior to the initiation of the study. The SC will 
include selected principal investigators from the study, leading experts in HF 
cardiomyopathy, and sponsor representatives. The SC will be involved in the oversight of the 
study and will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. Details on the role of 
the SC and working procedures will be defined in the SC Charter. 
 
Clinical Events Committee: 
 
The CEC will be appointed by the sponsor, or its representative, prior to the initiation of the 
study. The CEC will be responsible for reviewing safety data to aid in adjudicating cause for 
hospitalizations for the composite endpoint of all-cause mortality or worsening heart failure 
(HF-related hospitalizations or HF-related urgent care visits) only. Details on the role of the 
CEC and working procedures will be defined in the CEC Charter. 
 
Statistical Methods 
 
Hierarchical Testing: 
 
The testing strategy controls Type I error across primary and selected secondary endpoints. If 
the van Elteren test of the primary endpoint is found to be statistically significant at 0.05 (2- 
sided) alpha, then a sequential testing plan will be implemented for testing the secondary 
endpoints. 
 
Secondary endpoints will be analyzed in hierarchical order as follows: 
 
• Week 24 change from baseline in KCCQ domains of PL and TSS 
• Composite endpoint consisting of all-cause mortality or worsening heart failure (HF- 
related hospitalization or HF-related urgent care visit) 
• Week 24 change from baseline in NT-proBNP 
 
Efficacy Analyses: 
 
The primary analysis will be performed when all randomized participants in NYHA Class 
II/III have had the opportunity to be followed for at least 24 weeks (or otherwise withdrawn) 
and an evaluation of the composite endpoint consisting of all-cause mortality and worsening 
heart failure (HF-related hospitalization or HF-related urgent care visit) is performed. 
 
Primary Analysis of Change from Baseline in 6MWT at 24 Weeks: 
 
The change from baseline (based on the average of the Day -1 and baseline visit 6MWT 
results) in 6MWT at Week 24 will be analyzed in the NYHA Class II/III participants using a 
rank-based non-parametrical approach. Specifically, the test of superiority will be based on 
the van Elteren test, a stratified extension of the Wilcoxon rank sum test, with deaths 


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assigned the worst rank ordered from shortest to longest survival time and discontinuations 
from study the next lowest rank ordered based on their time to discontinuation, followed by 
changes in 6MWT for all other participants. Participants will be stratified into 4 groups 
according to baseline 6MWT quartile. Missed assessment while a participant remains in the 
trial at or beyond Week 24 will be modelled using the method of MCMC MI assuming a 
multivariate normal distribution over all variables included in the imputation model. This 
imputation will be done by treatment group with number of days on treatment, baseline 
values, and values observed at Weeks 4, 12, 24, and 36 included in the imputation. For 
participants who do not die or discontinue the study prior to Week 24 but have monotone 
missing data and subsequently discontinue the study at a later timepoint, missing data will be 
imputed under missing at random (MAR) for those who discontinue due to issues outside of 
the study (eg, due to COVID-19) and imputed using control-based MI for those who 
discontinue due to post randomization events (eg, AEs or perceived lack of efficacy). 
ARRY-371797 (PF-07265803) will be declared superior to placebo if the null hypothesis of 
no difference between ARRY-371797 (PF-07265803) and placebo is rejected at the 
significance level of 0.05 (2-sided). The p-value will be supplemented with a stratified win 
ratio statistic (and 95% CI) based on the same ranking rules. 
 
Two additional summaries will be provided to interpret the van Elteren test as follows: 
 
• In analyzing the contribution of death and discontinuation components to the primary 
efficacy analysis, the summaries on number of deaths and discontinuations from 
study prior to Week 24, and the reasons for withdrawals from study will be provided. 
It is expected that the death rates will not be negatively affected by the active 
treatment. 
 
• A stratified Hodges-Lehmann (HL) estimator of the treatment difference (with 95% 
CI) will be used to describe the treatment effect on the change from baseline in 
6MWT at Week 24. Missing data at Week 24 due to issues outside of the study (eg, 
COVID-19) will be imputed based on a MAR assumption. Missing data at Week 24 
for discontinuation due to post randomization events (eg, AEs or perceived lack of 
efficacy) will be imputed using control-based multiple imputation. Imputations 
following death will not be utilized as imputed values for participants who died prior 
to the assessment timepoint would not be interpretable. 
 
For participants with observed 6MWT at Week 24, actual values and change from baseline at 
Week 24 will be summarized using descriptive statistics (N, mean, SD, median, Q1, Q3, 
minimum, and maximum) by treatment. An empirical cumulative distribution function 
(eCDF) plot of change from baseline in 6MWT at Week 24 will also be generated for those 
participants with observed 6MWT at Week 24. 
 
Interim Analysis: 
 
An interim futility analysis was performed after the first 60 randomized participants in 
NYHA Class II/III had completed the Week 12 assessment or discontinued from the study 
prior to Week 12. At this analysis, the DMC utilized the futility boundary to consider 


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whether the study should continue to completion or stop early for futility. At the time of the 
planned interim futility analysis, the DMC recommended to continue the study as designed. 
 
Blinded Sample Size Re-estimation: 
 
Following the interim analysis for futility, a planned blinded sample size re-estimation for the 
primary endpoint of change from baseline at Week 24 was conducted using blinded 
cumulative primary efficacy data from the interim data cut . Specifically, a blinded, pooled 
analysis of both treatment groups for estimating variability of change from baseline in 
6MWT at Week 24 and current overall event rates for deaths and study discontinuations prior 
to Week 24 was performed and compared to the assumption used in planning the study. 
Following a planned blinded sample size re-estimation up to 200 eligible participants with 
symptomatic cardiomyopathy due to LMNA will be randomized, including at least 160 
participants with NYHA functional Class II or III and up to 40 participants with NYHA 
functional Class IV. 
 
In addition to the sample size re-estimation for the primary endpoint, the sponsor will 
continually monitor the pooled (blinded) cumulative event counts for the composite safety 
endpoint comprising of all-cause mortality or worsening of heart failure throughout the 
study.. The statistical analysis plan will provide an assessment of the expected number of 
events needed to rule out an upper bound of 1.8 or 2 under various scenarios for given hazard 
ratios. 
 
Safety Analyses: 
 
All AEs will be coded using MedDRA. Incidence tables of participants with AEs will be 
presented for all AEs by maximum severity, SAEs, AEs assessed as related to study 
intervention, and AEs resulting in discontinuation of study intervention. Changes in ECG and 
laboratory measurements will be summarized using descriptive statistics by arm over time. 
The nature and frequency of arrhythmias will be tabulated for analysis by arm over time. 
CCI 
 
 


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1.2. Schema 
 


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1.3. Schedule of Activities 
The SoA tables provide an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct 
evaluations or assessments required to protect the well-being of the participant. 
 
In response to the ongoing global pandemic COVID-19, and the increasing restrictions and concerns on public health, Pfizer has 
provided alternative solutions to accommodate study procedures during this time. Operational alternatives for some tests, procedures, 
and assessments are presented in Appendix 7: Alternative Measures During Public Emergencies. 
 
Schedule of Activities for All Participants in the Randomized Double-Blind Period 
 
Procedure or 
Assessment 
Abbreviations used in this 
table may be found in 
Appendix 10. 
Pre- 
screening 
Screening Period 
Baseline 
Visita 
(Day 1) 
Randomized Double-Blind Period 
Follow-up Period 
Screening 
Visit 
(Day -35 
to 
Day -7) 
Day -1 
Visit 
(Day -1) 
Week 
4i 
Day 29 
(±3 
days) 
Week 
8i 
Day 57 
(±7 
days) 
Week 
12i 
Day 85 
(±7 
days) 
Week 
24i 
Day 169 
(±7 
days) 
Week 
36, 48, 60 
and every 
subsequent 
24 weeks z 
(±7 days) 
Phone 
Contact 
Visit 
every 24 
weeks 
starting at 
Week 72aa 
(±7 days) 
Treatment 
Discon- 
tinuation 
Visit 
Safety 
Follow- 
up Visit 
(30 days 
after last 
dose 
±5 days) 
Survival 
Follow- 
up 
Prescreen Informed 
Consent 
X 
Prescreening IRT 
registration 
X 
LMNA Genetic Analysis 
for Eligibilityb 
X 
Main Informed Consent 
X 
Confirm Eligibility 
Criteria/Medical History 
Xc 
X 
Demography 
X 


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Schedule of Activities for All Participants in the Randomized Double-Blind Period 
 
Procedure or 
Assessment 
Abbreviations used in this 
table may be found in 
Appendix 10. 
Pre- 
screening 
Screening Period 
Baseline 
Visita 
(Day 1) 
Randomized Double-Blind Period 
Follow-up Period 
Screening 
Visit 
(Day -35 
to 
Day -7) 
Day -1 
Visit 
(Day -1) 
Week 
4i 
Day 29 
(±3 
days) 
Week 
8i 
Day 57 
(±7 
days) 
Week 
12i 
Day 85 
(±7 
days) 
Week 
24i 
Day 169 
(±7 
days) 
Week 
36, 48, 60 
and every 
subsequent 
24 weeks z 
(±7 days) 
Phone 
Contact 
Visit 
every 24 
weeks 
starting at 
Week 72aa 
(±7 days) 
Treatment 
Discon- 
tinuation 
Visit 
Safety 
Follow- 
up Visit 
(30 days 
after last 
dose 
±5 days) 
Survival 
Follow- 
up 
Prior/Concomitant 
Medicationsd 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV, TSH, Hepatitis 
B/C 
X 
Serum Pregnancy Teste,f 
X 
Serum FSH Testg 
X 
Complete Physical 
Examh 
X 
Brief Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
PRO (KCCQ, PGI-S, 
PGI-C, EQ-5D-5L)k 
Xl 
X 
X 
X 
X 
6MWT/Borgj,w 
Xm 
X 
Xn 
X 
X 
X 
X 
X 
Activity Monitoring 
X 
 
X 
Vital Sign Measurement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/Chemistry 
Blood Samplesf 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
X 
X 
Urinalysis 
Xo 
Xo 
Xo 
Xo 
Xo 
Xo 
Every 24 
weeks o 
X 
X 
Randomize Participant 
via IRT System 
X 


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Schedule of Activities for All Participants in the Randomized Double-Blind Period 
 
Procedure or 
Assessment 
Abbreviations used in this 
table may be found in 
Appendix 10. 
Pre- 
screening 
Screening Period 
Baseline 
Visita 
(Day 1) 
Randomized Double-Blind Period 
Follow-up Period 
Screening 
Visit 
(Day -35 
to 
Day -7) 
Day -1 
Visit 
(Day -1) 
Week 
4i 
Day 29 
(±3 
days) 
Week 
8i 
Day 57 
(±7 
days) 
Week 
12i 
Day 85 
(±7 
days) 
Week 
24i 
Day 169 
(±7 
days) 
Week 
36, 48, 60 
and every 
subsequent 
24 weeks z 
(±7 days) 
Phone 
Contact 
Visit 
every 24 
weeks 
starting at 
Week 72aa 
(±7 days) 
Treatment 
Discon- 
tinuation 
Visit 
Safety 
Follow- 
up Visit 
(30 days 
after last 
dose 
±5 days) 
Survival 
Follow- 
up 
Urine Pregnancy Teste 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGsj 
Xp 
Xp 
Xp 
X 
Echocardiogramj 
X 
X 
X 
X 
X 
Every 24 
weeks 
X 
Arrhythmia 
Assessmentj,q 
X 
X 
X 
X 
X 
X 
PK Blood Samplef 
Xr 
Xr 
Xr 
Xr 
Xr 
Xs 
PD Blood Samplef 
Xt 
Xt 
Xt 
Xt 
Xt 
Blood Sample for LMNA 
in vitro diagnostic 
developmentx 
X 
Dispense Study 
Intervention 
X 
X 
X 
X 
X 
X 
Review Dosing Diary 
X 
X 
X 
X 
X 
X 
X 
Assess AEsy 
Xu 
Xu 
Xu 
X 
X 
X 
X 
X 
X 
X 
X 
Assess 
Hospitalization/ER/Urge 
nt Care Visits 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xv 
Survival Follow-upv 
X 


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Schedule of Activities for All Participants in the Randomized Double-Blind Period 
 
Procedure or 
Assessment 
Abbreviations used in this 
table may be found in 
Appendix 10. 
Pre- 
screening 
Screening Period 
Baseline 
Visita 
(Day 1) 
Randomized Double-Blind Period 
Follow-up Period 
Screening 
Visit 
(Day -35 
to 
Day -7) 
Day -1 
Visit 
(Day -1) 
Week 
4i 
Day 29 
(±3 
days) 
Week 
8i 
Day 57 
(±7 
days) 
Week 
12i 
Day 85 
(±7 
days) 
Week 
24i 
Day 169 
(±7 
days) 
Week 
36, 48, 60 
and every 
subsequent 
24 weeks z 
(±7 days) 
Phone 
Contact 
Visit 
every 24 
weeks 
starting at 
Week 72aa 
(±7 days) 
Treatment 
Discon- 
tinuation 
Visit 
Safety 
Follow- 
up Visit 
(30 days 
after last 
dose 
±5 days) 
Survival 
Follow- 
up 
a. 
The baseline visit should occur within 3 days of the Day -1 visit. Note: The maximum screening period from the Screening Visit to Day 1 cannot exceed 35 days. 
b. 
The central accredited clinical laboratory will be used to assess LMNA mutation status if the LMNA mutation status is unknown at time of prescreening or if the genetic test was 
not performed by an accredited clinical laboratory. The LMNA mutation test results from the central accredited clinical laboratory must be available and confirmed prior to 
entering the screening period. Participants with identified pathogenic, likely pathogenic or VUS LMNA mutation status documented by results from an accredited clinical 
laboratory can enter in the screening period. 
c. 
Includes history of use of tobacco, alcohol, and drugs of abuse. 
d. 
Includes all prescription and nonprescription drugs, vitamins, and dietary or herbal supplements administered within 35 days prior to Day 1. 
e. 
Required for WOCBP only. Must be completed prior to dosing. Urine pregnancy tests are required every 12 weeks during the randomized double-blind period. Pregnancy tests 
will also be done whenever 1 menstrual cycle is missed (or when potential pregnancy is otherwise suspected). 
f. 
Blood collection to be performed in accordance with the methods described in the Laboratory Manual. 
g. 
Required for postmenopausal females <60 years of age. 
h. 
Includes height (at screening) and weight. 
i. 
Participants who discontinue study treatment prior to Week 24 should continue to have all assessments performed as scheduled through the Week 24 Visit. 
j. 
Screening echocardiogram will be done locally and will be used to determine eligibility. These assessments for Class IV participants are optional; however, if any of these 
procedures are completed during the course of the trial, the results should be captured. Following the week 24 visit, an echocardiogram will be done every 24 weeks thereafter. 
k. 
Perform KCCQ first, followed by PGI-S and PGI-C before other visit assessments. Participants should complete the EQ-5D-5L after the PGI questionnaires. 
l. 
KCCQ and PGI-S collected at baseline, PGI-C not collected at baseline. 
m. Screening visit 6MWT must be completed at least 27 days prior to the baseline 6MWT on Day -1. 
n. 
Complete 6MWT before completing other baseline activities in order to confirm participant eligibility. 
o. 
Collection of hematology/chemistry blood sample and urinalysis sample prior to dosing. Following the week 24 visit, urinalysis will be collected every 24 weeks thereafter. 
p. 
ECGs will be performed predose and 2 hours (± 30 min) postdose through Week 12. Must be performed prior to blood collection or vital sign measurement, where applicable. 
q. 
Detected by ICD/CRT-D applicable device interrogation. 
r. 
Collection of PK blood sample: Baseline: predose, Week 4: predose, Week 8 predose and 2 samples at approximately 1.5 hours (± 1 hour postdose, at least 15 minutes apart) 
and after vital signs measurements, Week 12: predose and 5 hours (± 1 hour), Week 24: predose and 5 hours (± 1 hour), Treatment Discontinuation: Any time during clinic visit. 
s. 
Only collected if participant discontinues treatment prior to the Week 24 Visit. 
t. 
Collection of PD blood sample: predose at all visits and additionally at 1.5 hour (± 1 hour) postdose at Week 8. 
u. 
Any AE that occurs from the signing of the informed consent until first dose of study intervention (or placebo) is to be recorded on the AE eCRF. 
v. 
Participants will be followed for overall survival and HF-related hospitalizations or HF-related urgent care visits approximately every 3 months per phone call until death, lost to 
follow-up, withdrawal of consent or initiation of the open-label treatment period, whichever occurs first. 


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Schedule of Activities for All Participants in the Randomized Double-Blind Period 
 
Procedure or 
Assessment 
Abbreviations used in this 
table may be found in 
Appendix 10. 
Pre- 
screening 
Screening Period 
Baseline 
Visita 
(Day 1) 
Randomized Double-Blind Period 
Follow-up Period 
Screening 
Visit 
(Day -35 
to 
Day -7) 
Day -1 
Visit 
(Day -1) 
Week 
4i 
Day 29 
(±3 
days) 
Week 
8i 
Day 57 
(±7 
days) 
Week 
12i 
Day 85 
(±7 
days) 
Week 
24i 
Day 169 
(±7 
days) 
Week 
36, 48, 60 
and every 
subsequent 
24 weeks z 
(±7 days) 
Phone 
Contact 
Visit 
every 24 
weeks 
starting at 
Week 72aa 
(±7 days) 
Treatment 
Discon- 
tinuation 
Visit 
Safety 
Follow- 
up Visit 
(30 days 
after last 
dose 
±5 days) 
Survival 
Follow- 
up 
w. 6MWT will include the Borg fatigue assessment both before and after the walk assessment. The 6MWT should be done predose on clinic visit days. 
x. 
A 2 mL blood sample will be collected and sent to the central laboratory for participants who did not use central laboratory to confirm eligibility. 
y. 
Only in Japan, adverse events will be assessed by telephone contact at Week 2 [Day 15 (± 3 days)]. Participants will be instructed to visit site if requested by the investigator. 
z. 
Following the Week 60 visit, all subsequent on-site clinic visits will be conducted every 24 weeks while the participant remains on study intervention. 
aa. Starting at Week 72, a phone contact visit must be performed and every subsequent 24 weeks to assess pregnancy (at-home urine pregnancy test for WOCBP), SAE/AEs, HF- 
related hospitalizations, HF-related urgent care visits, assess any changes to concomitant medications and assess status of study intervention and ensure the participant dosing 
diary is completed. 


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Schedule of Activities for Open-Label Period 
 
Procedure or Assessment 
Abbreviations used in this 
table may be found in 
Appendix 10. 
Baseline 
Visit 
(Day 1) 
Open-Label Period 
Follow-up Period 
Week 4 
(±3 days) 
Week 8 
(±7 days) 
Week 12 
(±7 days) 
Week 24 
(±7 days) 
Every subsequent 
24 weeks 
(±7 days) 
Treatment 
Discontinuation 
Visit 
Safety Follow-up Visit 
(30 days after last dose 
±5 days) 
Clinic Visits for Participants 
Randomized to ARRY- 
371797 (PF-07265803) 
X 
X 
X 
Clinic Visits for Participants 
Randomized to Placeboa 
X 
X 
X 
X 
X 
X 
X 
X 
Confirm Eligibility Criteriaa 
X 
PRO (KCCQ, PGI-S, PGI-C, 
EQ-5D-5L)c 
X 
X 
X 
X 
X 
Concomitant Medicationsd 
X 
X 
X 
X 
X 
X 
X 
X 
Brief Physical Exame 
X 
X 
X 
X 
X 
X 
X 
X 
6MWT/Borgb,f,g 
X 
X 
X 
X 
X 
X 
Vital Sign Measurement 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology/Chemistry 
Blood Samplesh 
X 
Xi 
Xi 
Xi 
Xi 
Xi 
X 
X 
Urinalysis 
X 
Xi 
Xi 
Xi 
Xi 
Every 24 weeksi 
X 
X 
Urine Pregnancy Testj 
X 
X 
X 
X 
X 
X 
12-Lead ECGsf,k 
Xk 
Xk 
Xk 
X 
Echocardiogramf 
X 
X 
X 
X 
X 
Every 24 weeks 
X 
Arrhythmia Assessmentf,l 
X 
X 
X 
X 
X 


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Schedule of Activities for Open-Label Period 
 
Procedure or Assessment 
Abbreviations used in this 
table may be found in 
Appendix 10. 
Baseline 
Visit 
(Day 1) 
Open-Label Period 
Follow-up Period 
Week 4 
(±3 days) 
Week 8 
(±7 days) 
Week 12 
(±7 days) 
Week 24 
(±7 days) 
Every subsequent 
24 weeks 
(±7 days) 
Treatment 
Discontinuation 
Visit 
Safety Follow-up Visit 
(30 days after last dose 
±5 days) 
Dispense Study 
Interventionalm 
X 
X 
X 
X 
X 
X 
Review Dosing Diary 
X 
X 
X 
X 
X 
X 
Assess AEs 
X 
X 
X 
X 
X 
X 
X 
X 
a. 
Participants who cross over from placebo to ARRY-371797 (PF-07265803) intervention must meet all inclusion criteria, and none of the exclusion criteria as listed in 
Section 5.1.4, and Section 5.2.3, respectively. 
b. 
6MWT will include the Borg fatigue assessment both before and after the walk assessment. The 6MWT should be done predose on clinic visit days. 
c. 
Perform KCCQ first, followed by PGI-S,PGI-C, and EQ-5D-5L before all other visit assessments. PGI-C is not collected at baseline. 
d. 
Includes all prescription and nonprescription drugs, vitamins, and dietary or herbal supplements. 
e. 
Includes weight. 
f. 
These assessments for Class IV participants are optional. If any of these procedures are completed during the course of the trial, the results should be captured. Following the 
Week 24 visit, an echocardiogram will be performed every 24 weeks thereafter. 
g. 
Complete 6MWT after KCCQ and PGI-S but before completing other baseline activities in order to confirm participant eligibility. 
h. 
Blood collection to be performed in accordance with the methods described in the Laboratory Manual. 
i. 
Collection of hematology/chemistry blood sample and urinalysis sample prior to dosing. Following the Week 24 visit, urinalysis will be collected every 24 weeks thereafter. 
j. 
Required for WOCBP only. Must be completed prior to dosing. Urine pregnancy tests are required every 12 weeks during the open-label period. Pregnancy test will also be 
done whenever a menstrual cycle is missed or when potential pregnancy is otherwise suspected. 
k. 
ECGs will be performed predose and 2 hours (± 30 min) postdose through Week 12. Must be performed prior to blood collection or vital sign measurement, where applicable. 
l. 
Detected by ICD/CRT-D applicable device interrogation. 
m. Participants who received PF-07265803 in the double-blind period will continue to have study intervention dispensed every 24 weeks. 


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2. INTRODUCTION 
ARRY-371797 (PF-07265803) is a potent and selective, oral small molecule inhibitor of the α 
isoform of p38 MAPK. Mutations in the LMNA gene encoding nuclear lamina components 
cause nuclear envelope dysfunction leading to altered nuclear activity, impaired structural 
dynamics and aberrant cell signaling including activation of p38α MAPK signaling pathways. 
Structural alterations in the nuclear envelope and connected cytoskeleton resulting 
from LMNA make cardiomyocytes highly susceptible to damage even by physiological 
mechanical stress, leading to a disease specific maladaptive activation of the p38α MAPK. 
Activation of p38 MAPK has been observed in the hearts of animal models and adult patients 
with LMNA-related DCM compared to wild-type/healthy individuals. Inhibition of p38 MAPK 
in this disease setting may halt aberrant apoptosis and cardiac remodeling resulting in improved 
cardiac function. 
 
2.1. Study Rationale 
In the completed Phase 2 study ARRAY-797-231, treatment with ARRY-371797 (PF- 
07265803) resulted in rapid (<4 weeks), sustained increases in functional capacity in 
participants with LMNA-related DCM (described in Section 2.2.4.3). Improvements on the 
6MWT compared to baseline, the primary endpoint, were mirrored by favorable changes in 
NT-proBNP levels, LVEF, and RV fractional area. ARRY-371797 (PF-07265803) was 
generally well tolerated. The AEs for most participants were mild to moderate, and only 1 
participant discontinued the study because of a treatment-related AE. In the completed long- 
term rollover extension study ARRAY-797-001 (C4411001), ARRY-371797 (PF-07265803) 
was generally well tolerated, with evidence suggesting preserved exercise capacity over an 
extended period of follow-up. Preserved exercise capacity was mirrored by favorable trends 
in NT-proBNP levels. 
 
Based on these clinical data, inhibition of p38 MAPK with the selective p38 inhibitor 
ARRY-371797 (PF-07265803) may provide a novel therapeutic approach and has the 
potential to fill an unmet medical need for the treatment of symptomatic LMNA-related DCM 
and merits further clinical investigation. 
 
2.1.1. Rationale for Selection of the Primary Efficacy Endpoint 
The 6MWT is a measure of participant exercise tolerance as an estimate of functional 
capacity. Improvement in 6MWT is a direct measure of a favorable therapeutic intervention 
and is associated with reduced morbidity and mortality in heart failure patients.1,2,3,4,5 Change 
in 6MWT distance has been the most commonly utilized primary endpoint in clinical studies 
conducted for regulatory approval of therapies in participants with PAH. In studies of 
ambrisentan, bosentan, and riociguat, improvements versus placebo in mean 6MWT distance 
in PAH participants were 32 m (range of 6% to 13% increase), 54 m (range of 8% to 19% 
increase), and 36 m (range of 8% to 11% increase), respectively, across a number of clinical 
studies.6,7,8 In heart failure with reduced ejection fraction, a 30-to-50m increase in 6MWT 
distance was associated with significant improvement in NYHA functional class and health- 
related Qol, and was utilized as an endpoint for de novo medical devices approval intended 
for unmet medical need for life threatening and irreversibly debilitating diseases and 
conditions.9 


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2.1.2. Rationale for Selection of the Secondary Endpoint - Composite Endpoint of All- 
Cause Mortality or Worsening Heart Failure (HF-related hospitalization or HF-related 
urgent care visits) 
An important evaluation in determining the safety of PF-07265803 treatment will include an 
estimate of the effect on overall survival. LMNA-related DCM is a rare condition limiting 
clinical trial sample size, and the mortality rate expected during this study (approximately 
10%) further precludes a statistically rigorous evaluation of the treatment effect on overall 
survival. Thus, an assessment of worsening heart failure (WHF) including HF-related 
hospitalizations or HF-related urgent care visits will be analyzed as part of a composite 
endpoint (see Section 9.4.3.4). 
 
Heart failure is a progressive condition and the need for treatment to manage worsening HF 
signs and symptoms in the outpatient, emergency department, or hospitalization setting, is 
associated with worse prognosis.10 The use of worsening heart failure as part of a composite 
endpoint is supported by large prospective and retrospective studies indicating that 
worsening of heart failure, directly correlate with an increase in mortality risk.11 Overall, 
patients admitted for HF have a high event rate (>50%), with a mortality rate between 10% 
and 15% and a re-hospitalization rate within 6 months after discharge of 30% to 
40%.12,13,14,15,16 In the real-world setting, worsening of heart failure is associated with a 2- 
year mortality rate of 22.5% with more than 50% of patients being rehospitalized within 30 
days of the worsening event.14 
Taken together, these data from multiple large clinical studies indicate that WHF correlate 
strongly with mortality, supporting the use of a composite endpoint that considers both WHF 
and all-cause mortality to assess the potential for increased mortality risk from ARRY- 
371797 (PF-07265803) treatment. To standardize data collection, HF-related hospitalizations 
and HF-related urgent care visits will be adjudicated by an independent Clinical Events 
Committee (see Section 9.4.3.4). 
 
2.2. Background 
2.2.1. LMNA-Related Dilated Cardiomyopathy 
Lamins are critical protein components of the nuclear lamina, which lie between the inner 
nuclear membrane and the chromatin. They provide structural support for the cell nucleus, 
and participate in many different nuclear processes, including chromatin organization, 
connecting the nucleus to the cytoplasm, gene transcription, and mitosis. Mutations in the 
LMNA gene encoding nuclear lamina components cause nuclear envelope 
dysfunction leading to altered nuclear activity, impaired structural dynamics and aberrant cell 
signaling including activation of p38α MAPK signaling pathways. Structural alterations in 
the nuclear envelope and connected cytoskeleton resulting from LMNA mutations make 
cardiomyocytes highly susceptible to damage even by physiological mechanical stress, 
leading to a disease specific maladaptive activation of the p38α MAPK. 
 
Mutations in LMNA cause a variety of human diseases, known collectively as laminopathies. 
DCM, which is also referred to as non-ischemic HFrEF, is one of the more common 
phenotypes associated with LMNA mutations. Mutations in the LMNA gene are the second 


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CCI 
most common cause of idiopathic DCM after those in TTN17 and account for around 6% of 
all cases. LMNA-related DCM can present as a de novo mutation or more frequently as an 
autosomal dominant inheritance, and is usually accompanied by CCD. LMNA-related DCM 
is a rare disease affecting less than 5 persons per 10,000 both in EU18 and in the US19. 
Patients with LMNA-related DCM frequently suffer from atrioventricular conduction defects 
and have a significantly increased risk of sudden death due to ventricular arrhythmias.17 The 
majority of patients with LMNA-related DCM follow a clinical course starting with CCD in 
early to mid-adulthood, with some early mortality due to sudden cardiac arrest from a fatal 
arrhythmia or embolus. Over time, most patients progress to DCM, which can lead to rapidly 
progressive HF. 
 
Although the age of presentation in LMNA-related DCM varies, the age of onset typically 
appears to be in the third and fourth decades.17,19,20,21 Furthermore, LMNA-related DCM 
patients have a more malignant clinical course than other DCM types, due to high rates of 
progressive HF and sudden cardiac death from ventricular tachyarrhythmia, despite 
conventional HF therapies, unless prevented by an ICD.22,23,24 Spontaneous improvement is 
not seen in LMNA-related DCM, and while the response to conventional HF therapies has not 
been fully characterized in this specific form of DCM, the relentless progression of disease 
despite conventional medical therapies suggests that it is poor. 
 
Currently, there is no effective, disease-specific treatment available for LMNA-related DCM. 
To date, treatment is limited to conventional therapies for heart failure with reduced ejection 
fraction(angiotensin-converting-enzyme inhibitors , angiotensin 2 receptor blockers or 
angiotensin receptor-neprilysin inhibitor, beta blockers, sodium-glucose cotransporter-2 
inhibitors, aldosterone antagonists, and diuretics) which do not address the etiology of the 
disease . Progressive deterioration in LV function and refractory HF symptoms are often 
treated with resynchronization therapy (bi-ventricular pacing). Risk of SCD is managed with 
ICD or CRT-D. In patients whose disease continues to progress in spite of aggressive 
cardiovascular management, left ventricular assist device (LVAD) and cardiac 
transplantation may be considered. 
 


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2.2.3. Nonclinical Studies with ARRY-371797 (PF-07265803) 
Detailed information regarding nonclinical studies of ARRY-371797 (PF-07265803) is 
presented in the IB. 
 
2.2.3.1. Nonclinical Pharmacology 
Numerous in vitro and in vivo studies were performed to evaluate and confirm the ability of 
ARRY-371797 (PF-07265803) to interact with its intended target, p38 MAPK. In enzyme 
studies, ARRY-371797 (PF-07265803) inhibits p38α with a half maximal inhibitory 
concentration (IC50) of 8.2 nM. In cellular studies, ARRY-371797 (PF-07265803) is a potent 
inhibitor of p38-mediated downstream phosphorylation of HSP27 in HeLa cells with an IC50 
of 17 nM. This compound has demonstrated little to no activity against over 210 enzymes, 
receptors, channels, and transporters. 
 
Two in vivo murine models of LMNA-related DCM have allowed exploration of 
pathophysiologic mechanisms of disease progression and novel therapies for these 
conditions. In vivo studies have demonstrated that p38 MAPK is activated in murine models 
of LMNA-related DCM and that this activation of p38 MAPK precedes the development of 
cardiac dysfunction. ARRY-371797 (PF-07265803) has been tested in the homozygous 
LMNA H222P model of EDMD with cardiomyopathy (EDMD2, MIM:181350) and in the 
homozygous LMNA N195K model of LMNA-related DCM, one of the original LMNA 
mutations linked to familial DCM with conduction defects (CMD1A, 
OMIM:150330.0006).29,30 These 2 nonclinical models bracket the spectrum of phenotypes 
(EDMD2: cardiac and skeletal muscle disease and DCM: cardiac disease only). Results from 
these studies confirm that treatment with ARRY-371797 (PF-07265803) improves cardiac 
CCI 


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structure and function and reduces myocardial apoptosis. In these mouse studies, the LV 
functional measures of LVEDD/body weight and LVESD/body weight are indices that 
correlate with the human clinical study endpoints of LVEDVI and LVESVI, respectively. 
The measure of LVEF is common to both mouse and human echocardiography. In addition, 
ARRY-371797 (PF-07265803) improves survival in the murine LMNA-related DCM model 
(LMNA N195K). 
 
2.2.3.2. Nonclinical Drug Metabolism 
In vitro experiments indicated that ARRY-371797 (PF-07265803) has moderate membrane 
permeability and may be a substrate for active P-gp efflux. ARRY-371797 (PF-07265803) 
was moderately, but reversibly, bound to plasma proteins in vitro across mouse, monkey, and 
human plasma, as was AR00420643, the principal acid metabolite in vivo. AR00420643(PF- 
07327859), is formed in in vitro incubations with liver microsomes, hepatocytes, plasma, or 
blood. Other, less abundant, metabolites that are found in vitro or in vivo are a result of 
oxidative metabolism. No glucuronide conjugates were detected in hepatocyte incubations. 
No human specific metabolites were detected in liver microsomes or hepatocytes. 
 
Multiple Phase 1 enzymes (CYPs, FMOs, amidases, and esterases) are involved in the 
metabolism of ARRY-371797 (PF-07265803). In vitro CYP-mediated metabolism was 
primarily by CYP3A4 and CYP2D6; however, these enzymes do not generate the principal 
acid metabolite in vivo. Other Phase 1 enzymes (FMOs, amidases, and esterases) convert 
ARRY-371797 (PF-07265803) to the acid metabolite AR00420643 (PF-07327859) in vitro. 
 
ARRY-371797 (PF-07265803) and its metabolites were weak inhibitors of the major CYP 
isoforms in vitro (CYPs 1A2, 2B6, 2C8, CYP2C19, CYP2D6, CYP3A). The principal acid 
metabolite (AR00420643, PF-07327859) and the N-desmethyl acid metabolite 
(AR00486705) are weak inhibitors of CYP2C9. Based on circulating concentrations at the 
clinical dose of 400 mg BID, ARRY-371797 (PF-07265803) and metabolites have a low 
potential to elicit a DDI due to competitive inhibition of CYP enzymes. 
 
ARRY-371797 (PF-07265803) is a time-dependent inhibitor of CYP2D6 and the lactam 
metabolite (AR00428028) is a time-dependent inhibitor of CYP3A4. In in vitro studies in 
human hepatocytes, ARRY-371797 (PF-07265803) and its metabolites are inducers of 
CYP3A mRNA, while only metabolites AR00420643 and AR00428028 induce CYP2B6 
mRNA and enzyme activity. Based on potential for mixed induction/inhibition of CYP3A4, 
the net effect of ARRY-371797 (PF-07265803) interaction with drugs that are identified as 
CYP3A4 substrates cannot be predicted. Based on in vitro results, following 
coadministration of ARRY-371797 (PF-07265803) there is a potential for induction of 
CYP2B6 and potential for time-dependent inhibition of CYP2D6. 
 
ARRY-371797 (PF-07265803) has a low potential to elicit clinically relevant DDIs 
involving UGT enzymes or interactions with transporters BCRP, OAT1/3, OATP1B1/3, or 
OCT1/2, or MATE1/2K . ARRY-371797 (PF-07265803) is a weak inhibitor of MDR1 (P- 
gp), a DDI with substrates of MDR1 cannot be ruled out. 


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2.2.3.3. Nonclinical Toxicity and Safety 
Nonclinical toxicity studies have indicated that ARRY-371797 (PF-07265803) was tolerated 
at repeat oral doses of up to 30 mg/kg BID in rats and monkeys with GI side effects and 
minimal clinical pathology changes. Microscopic changes of skeletal muscle myofiber 
degeneration were reversible in monkeys administered doses of up to 100 mg/kg BID for 28 
days. Microscopic findings of skeletal muscle myofiber degeneration in rats administered 
ARRY-371797 (PF-07265803) for 28 days were partially reversible with respect to severity 
and incidence at 100 mg/kg BID (200 mg/kg/day). In the chronic dosing studies for up to 26 
weeks in rats and 9 months in monkeys at doses up to 30 mg/kg BID, there were no adverse 
microscopic findings. In general, administration of ARRY-371797 (PF-07265803) at doses 
of up to 30 mg/kg BID was tolerated in-life in rats and monkeys in the chronic toxicity 
studies. Administration of ARRY-371797 (PF-07265803) to monkeys for up to 3 months was 
associated with microscopic findings of skeletal muscle fiber changes, with no associated 
clinical chemistry changes. These skeletal muscle changes were reversible after the 1-month 
recovery phase and not observed following 9 months of total dosing or following the 3- 
month, dose-free recovery phase. Evidence of gastric irritation and increased gastric fluid 
secretion was observed in safety pharmacology GI studies in rats after a single oral dose of 
100 mg/kg of ARRY-371797 (PF-07265803). After repeat administration of ARRY-371797 
(PF-07265803) increased incidence of watery stools/feces were observed during the dosing 
phase in monkeys and generally resolved after dosing cessation during the recovery phases. 
 
ARRY-371797 (PF-07265803) had no significant effects on ophthalmologic examinations, 
coagulation parameters, troponins (evaluated only in monkeys), or urinalysis parameters after 
administration of doses of up to 100 mg/kg BID in rats and monkeys for 28 consecutive days 
and up to 30 mg/kg BID in the chronic dosing studies in rats and monkeys. Increases in liver 
enzymes (ALT and AST), total bilirubin, BUN, glucose levels, and decreases in potassium 
levels were observed in rats after administration of ARRY-371797 (PF-07265803) at doses 
of up to 100 mg/kg BID in the 28 day study only. Mild to moderate increases in liver 
enzymes (ALT and/or AST) were observed in monkeys. Reversible increases in 
lymphocytes were observed in rats. These clinical pathology changes did not appear to have 
any functional or pathological consequences. No ECG, heart rate, and blood pressure 
abnormalities related to ARRY-371797 (PF-07265803) administration were observed in 
monkeys. 
 
There was no evidence of genotoxicity in the 2 in vitro assays (bacterial reverse mutation or 
mouse lymphoma) and the in vivo assay (mouse micronucleus). The genotoxicity tests were 
conducted at concentrations of the standard limits for these test systems. There is little to no 
risk of phototoxicity with the administration of ARRY-371797(PF-07265803). The embryo- 
fetal developmental toxicity studies support the exclusion of pregnant women from clinical 
studies of ARRY-371797 (PF-07265803) and the continued requirement that WOCBP use 
appropriate contraception. 


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2.2.4. Clinical Experience with ARRY-371797 (PF-07265803) 
ARRY-371797 (PF-07265803) has been investigated in 10 completed placebo-controlled 
clinical studies involving 485 participants treated for up to 12 weeks, including 5 Phase 1 
studies in healthy participants and 5 studies (1 Phase 1b and 4 Phase 2) in participants with 
painful inflammatory conditions (RA, AS, OA, and postsurgical pain). 
 
ARRY-371797 (PF-07265803) has also been evaluated in a completed Phase 2 study in 
12 participants treated up to 48 weeks (Study ARRAY 797-231) with ARRY-371797 (PF- 
07265803) in participants with LMNA-related DCM, and in a completed open-label long- 
term rollover extension study (ARRAY-797-001) from ARRAY-797-231 in 8 participants 
assessed at Weeks 48, 72, 96, 120, and 144 from Phase 2 study baseline. 
 
Detailed information regarding clinical studies of ARRY-371797 (PF-07265803) is presented 
in the IB. 
 
2.2.4.1. Clinical Pharmacokinetics 
The clinical PK of ARRY-371797 (PF-07265803) and AR00420643 have been evaluated in 
healthy participants following single- and repeat-dose administration. Following single doses 
of ARRY-371797 (PF-07265803), exposure of ARRY-371797 (PF-07265803) increased in a 
dose-proportional manner up to the highest dose evaluated (2000 mg total daily dose). After 
repeat-dose administration, exposure increased in a nearly dose-proportional manner. The 
maximal plasma concentrations (Cmax) were generally observed approximately 1 to 2 hours 
following dose administration with consistent plasma concentration-time profile shapes at all 
doses evaluated. The terminal half-life (t½) was approximately 1.5 to 5 hours and was 
dose-dependent, with longer t½ at higher doses. Less than 2-fold accumulation was observed 
(1.3 to 1.8). In general, low-to-moderate inter-subject variability was observed for 
exposure-related PK parameters. CCI 
 
 
 
 
 
 
The metabolite (AR00420643)-to-parent ratio ranged from approximately 9 to 22, with 
higher exposures to the metabolite, AR00420643, observed relative to the parent, 
ARRY-371797 (PF-07265803). Additional circulating metabolites were analyzed in Study 
ARRAY-797-231, including a lactam (AR00428028) and N-desmethyl product of the acid 
metabolite (AR00486705). Geometric mean metabolite-to-parent ratio at Week 4 was 13.5 
predose (n = 10) and 0.766 at 1 to 2 hours postdose (n = 12) for AR00428028 and 2.65 
predose (n = 10) and 0.327 1-2 hours postdose (n = 12) for AR00486705. 
 
Exposure was also assessed with sparse sampling in the RA, AS, OA, and postsurgical pain 
participant populations. Although formal PK analyses were not performed, evaluation of 
plasma concentration data indicated that exposure to ARRY-371797 (PF-07265803) was 
comparable to that in healthy participants. 


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2.2.4.2. Clinical Pharmacodynamics 
Treatment-related changes in BNP and NT-proBNP have been documented as predictors 
of patient-centered outcomes in chronic heart failure, including improvements in symptoms, 
quality of life and exercise capacity.31 In Clinical Study ARRAY-797-231, decreases from 
baseline in NT-proBNP by original assigned dose ranged from 5.3 to 508.8 pmol/L for the 
100 mg BID group and from 192.0 to 610.6 pmol/L for the 400 mg BID group. The overall 
(dose groups combined) mean decrease in NT-proBNP at Weeks 4, 12, 24, 36, and 48 were 
559.7, 444.9, 340.6, 296.5, and 284.0 pmol/L, respectively. The mean change in NT-proBNP 
for the dose groups combined is shown in Figure 1. 
 
Figure 1. 
Mean NT-proBNP Over Time from Study ARRAY-797-231 
 
2.2.4.3. Clinical Efficacy 
In Study ARRAY-797-231, the efficacy of 48 weeks of treatment with ARRY-371797 (PF- 
07265803) at 2 dose levels (100 mg BID [N = 6] or 400 mg BID [N = 6]) was investigated in 
12 stable participants with symptomatic LMNA-related DCM. The primary efficacy endpoint 
was the change from baseline in 6MWT at Week 12. Both dose groups showed 
improvements in distance at this time point. Participants in this study were allowed to 
continue to receive ARRY-371797 (PF-07265803) on a rollover protocol. Eight participants 
were enrolled and the mean 6MWT improved by >30 m (>10% mean increase) from Phase 2 
study baseline up to Week 120. The change in 6MWT data through Week 144 with both dose 
groups combined is shown in Figure 2. 


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Figure 2. Mean Change in 6MWT Over Time From Studies ARRAY-797-231 and 
ARRAY-797-001 – Combined Dose Groups 
 
 
 
 
 
 
80% CI of the mean 6MWT distance is included for each time point. 
6MWT, 6-minute walk test; LTE, long-term extension. 
 
A total of 4 participants in the 100 mg BID group and 1 participant in the 400 mg BID group 
showed at least 10% improvement in 6MWT at Week 12. The overall mean change at 
Week 12 in 6MWT for the dose groups combined was 69.4 m (22.5% increase from 
baseline). An approximate 10% improvement in 6MWT is considered to be clinically 
meaningful based on discussions with clinical experts and on FDA approvals for PAH drugs 
where 6MWT improvements ranged from 6% to 19%.6,7,8,32 
The secondary efficacy endpoint for the 6MWT was the change from baseline at Weeks 4, 
24, 36, and 48, and 4 weeks after dose escalation. These results were supportive of the 
primary endpoint. Improvements in 6MWT distance ranged from approximately 39.3 to 
86.6 m (12.5% to 28.6% increase) for the 100 mg BID group and 23.7 to 69.3 m (8.0% to 
20.8% increase) for the 400 mg BID group. At Week 28 (or 4 weeks after dose escalation), 
participants who were dose escalated to 400 mg BID showed an improvement in 6MWT of 
77.7 m (24.3% increase from baseline). The overall (dose groups combined) mean changes in 
6MWT at Weeks 4, 24, 36, and 48 were 46.7, 53.8, 63.0, and 55.3 m, respectively. 


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Echocardiographic parameters tended to be variable between visits. In general, measurements 
of LVEF and RV fractional area suggested overall stability of, or a trend for improvements 
in, left or RV function with ARRY-371797 (PF-07265803) treatment. 
 
2.2.4.4. Clinical Safety 
In 5 completed Phase 1 studies of ARRY-371797 (PF-07265803) in healthy participants, 
ARRY-371797 (PF-07265803) demonstrated an acceptable safety profile when administered 
at single doses up to 900 mg QD, up to 400 mg/day for 14 days and up to 2000 mg/day for 
7 days. The most commonly reported AEs in participants receiving ARRY-371797 (PF- 
07265803) were dizziness, headache, diarrhea, nausea, and acne; the incidence of these AEs 
was not clearly related to the ARRY-371797 (PF-07265803) dose, nor to the duration of 
exposure. 
 
No clinically meaningful association has been observed between treatment with 
ARRY-371797 (PF-07265803) and abnormalities in hematology or urinalysis parameters. In 
participants with knee pain due to OA (Study ARRAY-797-223), mild elevations in CK and 
AST, and mild reductions in mean arterial pressure were observed in participants receiving 
ARRY-371797 (PF-07265803). No other association between treatment with ARRY-371797 
(PF-07265803) and changes in vital signs in any of the clinical studies has been observed. 
 
While there is no nonclinical evidence of QT prolongation, in a pooled analysis across 
clinical studies, there is some evidence for dose-related prolongation of QTcF compared with 
placebo in participants receiving ARRY-371797 (PF-07265803). The magnitude of mean 
placebo-adjusted QTcF prolongation at Tmax for the dose of 400 mg BID is approximately 
8 msec. 
 
2.2.4.4.1. Clinical Safety in Participants with LMNA-related Dilated Cardiomyopathy 
In Study ARRAY-797-231, the safety of 48 weeks of treatment with ARRY-371797 (PF- 
07265803) at 2 dose levels (100 mg BID [N = 6] or 400 mg BID [N = 6]) was investigated in 
12 stable participants with symptomatic LMNA-related DCM. All 12 participants were 
evaluated for safety. Table 1 summarizes AEs reported in >1 participant or reported as 
Grade 3/4 severity in Study ARRAY-797-231. 


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Table 1. 
Summary of Adverse Events, Regardless of Causality, Reported in 
>1 Participant or Reported as Grade 3/4 (Study ARRAY-797-231) 
 
Preferred Term 
ARRY-371797 
N = 12 
All Grades 
n (%) 
Grade 3/4 
n (%) 
Stomatitis 
3 (25.0) 
0 
Accidental overdosea 
2 (16.7) 
0 
Acne 
2 (16.7) 
0 
Atrial fibrillation 
2 (16.7) 
1 (8.3) 
Dry eye 
2 (16.7) 
0 
Liver function test abnormal 
2 (16.7) 
1 (8.3) 
Pyrexia 
2 (16.7) 
1 (8.3) 
Rash 
2 (16.7) 
1 (8.3) 
Upper respiratory tract infection 
2 (16.7) 
0 
Cardiac failure 
1 (8.3) 
1 (8.3) 
Congestive cardiomyopathy 
1 (8.3) 
1 (8.3) 
Musculoskeletal pain 
1 (8.3) 
1 (8.3) 
Neck pain 
1 (8.3) 
1 (8.3) 
Ventricular tachycardia 
1 (8.3) 
1 (8.3) 
a. 
Two participants each took 2 additional capsules during the study, one participant at Week 36 and 
1 participant at Week 48. 
Preferred terms are sorted by descending order of frequency in the ARRY-371797 all-grades column. 
AEs were coded using MedDRA v16.1. 
 
 
There were no deaths during the study. SAEs were reported in 3 participants (25%). In the 
400 mg BID group, 1 participant experienced SAEs of Grade 3 atrial fibrillation and Grade 4 
cardiac failure and abnormal liver function tests; the latter was assessed as related to 
concomitant amiodarone treatment. In the 100 mg BID group, 1 participant experienced 
SAEs of ventricular tachycardia and congestive cardiomyopathy and another participant 
experienced SAEs of pyrexia, musculoskeletal pain, neck pain, and subcorneal pustular 
dermatosis (all Grade 3). All SAEs resolved and were assessed by the investigator as not 
related to study intervention. No nonserious Grade 3/4 AEs were reported. 
 
Events resulting in treatment discontinuation were reported in 3 participants (25%). In the 
400 mg BID group, 1 participant experienced Grade 4 cardiac failure assessed as not related 
to study intervention and another participant experienced Grade 2 stomatitis assessed as 
treatment related. In the 100 mg BID group, 1 participant experienced Grade 3 congestive 
cardiomyopathy assessed as not related to study intervention. 
 
In the long-term rollover extension study to the Phase 2 study in patients with LMNA-related 
DCM (Study ARRAY-797-001; N = 8), treatment with ARRY-371797 (PF-07265803) was 
well tolerated. Six participants (75.0%) experienced SAEs, none of which were considered 
related to study intervention. The most frequently reported TEAEs were ventricular 
tachycardia in 5 participants (62.5%) and accidental overdose in 4 participants (50.0%; no 
associated AEs were reported) and cardiac failure congestive, diarrhea, dyspnea, and 
orthostatic hypotension in 2 participants (25.0%) each. Two participants (25.0%) were 


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discontinued from study intervention due to TEAEs of heart transplant and cardiac failure 
congestive, respectively; neither were considered related to study intervention. There were no 
deaths during the study. Additional information regarding the safety of ARRY-371797 (PF- 
07265803) is presented in the IB. 
 
2.3. Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of ARRY-371797 (PF-07265803) may be found in the IB, which is the SRSD 
for this study. 
 
2.3.1. Risk Assessment 
 
Potential Risk of Clinical 
Significance 
Summary of Data/Rationale 
for Risk 
Mitigation Strategy 
Study Intervention ARRY-371797 (PF-07265803) 
An identified risk associated with 
this study intervention is stomatitis. 
It is a common (≥1/100 to <1/10) 
event in the protocol population. 
The potential risks are based on 
adverse events reported in early 
studies of ARRY-371797. 
AEs will be monitored on an 
ongoing basis. Instructions for 
managing potential cases of 
stomatitis are provided (see 
Section 6.6). 
 
2.3.2. Benefit Assessment 
The clinical safety and efficacy profile of ARRY-371797 (PF-07265803) as observed in the 
Phase 2 study (Clinical Study ARRAY-797-231) of participants with LMNA-related DCM 
indicated that ARRY-371797 (PF-07265803) is overall well tolerated and demonstrated some 
trends towards improvement in exercise capacity (6MWT distance) and other measures of 
HF severity. 
 
In this study, the efficacy of 48 weeks of treatment with ARRY-371797 (PF-07265803) at 
2 dose levels (100 mg BID [N = 6] or 400 mg BID [N = 6]) was investigated in 12 stable 
participants with symptomatic LMNA-related DCM. The primary efficacy endpoint was the 
change from Baseline in 6MWT at Week 12 and both dose groups showed improvements in 
distance at this time point. 
 
In the long-term rollover extension study to the Phase 2 study in participants with LMNA- 
related DCM (ARRAY-797-001 [C4411001]; N=8). The clinical safety and efficacy were 
assessed up to at least 96 weeks. The mean duration of exposure from the start of the rollover 
study was 113.1 weeks. ARRY-371797 (PF-07265803) was generally well tolerated, with 
evidence suggesting preserved exercise capacity over an extended period of follow-up. 
Preserved exercise capacity was mirrored by favorable trends in NT-proBNP levels. 
 
2.3.3. Overall Benefit/Risk Conclusion 
The benefit/risk assessment remains favorable for continuing the development of 
ARRY-371797 (PF-07265803) in participants with LMNA-related DCM. 


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3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS 
Study objectives and corresponding endpoints are provided in the Table 3 below. 
 
Per protocol, participants who discontinue study treatment prior to Week 24 will continue to 
have all assessments performed as scheduled through the Week 24 Visit. All data collected 
during the study will be included for the analyses of efficacy regardless of discontinuation of 
study treatment or study drug interruption. 
 
Objectives 
Endpoints 
Primary: 
Primary: 
Evaluate the effect of ARRY-371797 (PF-07265803) on 
functional capacity (as measured by the 6 Minute Walk 
Test [6MWT]) compared to placebo. 
New York Heart Association Class (NYHA) II/III 
participants only: Change from baseline in 6MWT at Week 
24. 
Secondary: 
Secondary: 
Evaluate additional measures of efficacy of ARRY-371797 
(PF-07265803) compared to placebo in the randomized 
period. 
NYHA Class II/III participants only: Change from baseline 
in 6MWT at Weeks 4 and 12. 
NYHA Class II/III participants only: Change from baseline 
in Kansas City Cardiomyopathy Questionnaire (KCCQ) 
Physical Limitation (PL) and Total Symptom Score (TSS) 
domains at Weeks 12 and 24. 
NYHA Class II/III participants only: Change from baseline 
in Patient Global Impression (PGI) scores at Weeks 12 and 
24: 
• 
Patient Global Impression of Severity (PGI-S); 
• 
Patient Global Impression of Change (PGI-C). 
NYHA Class II/III participants only: Change from baseline 
in N-terminal pro-brain natriuretic peptide (NT‑proBNP) at 
Weeks 4, 12, and 24. 
Evaluate the impact of ARRY-371797 (PF-07265803) on 
composite endpoint of all-cause mortality, or worsening 
heart failure (WHF). 
Defined as the time from randomization to the first 
occurrence of any event of death due to any cause, or 
worsening heart failure (HF-related hospitalization or HF- 
related urgent care visit). 
Evaluate the impact of ARRY-371797 (PF-07265803) on 
overall survival (OS). 
OS 
Evaluate the safety of ARRY-371797 (PF-07265803) 
compared to placebo. 
Safety as determined by: 
• 
Incidence and severity of Adverse Events (AEs); 
• 
Changes in clinical safety laboratory tests, vital 
signs, and 12 lead electrocardiography (ECGs); 
• 
Incidence and severity of ventricular or atrial 
arrhythmias detected using existing ICD/cardiac 
resynchronization therapy defibrillator (CRT-D) 
or other applicable device interrogations. 
CCI 
 
 


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Objectives 
Endpoints 
 
 
CCI 
 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI 


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This protocol will use an independent endpoint adjudication Clinical Events Committee 
(CEC) to determine whether certain investigator-reported events meet the definition of 
disease-related efficacy endpoints, using predefined endpoint criteria. 
 
4. STUDY DESIGN 
4.1. Overall Design 
This multinational Phase 3 study will evaluate the efficacy, safety, and PK following 
treatment with ARRY-371797 (PF-07265803) compared with placebo (1:1 randomization) in 
at least 160 participants with LMNA-related DCM in NYHA functional Class II and III . 
Additional LMNA-related DCM NYHA functional Class IV participants (up to 40) may be 
randomized (1:1) and will be assessed for overall safety and time from randomization to HF- 
related hospitalization, HF-related urgent care visits or death due to any cause, in addition to 
PK and efficacy, if feasible. A schematic of the study design is presented in Section 1.2. The 
sample size was increased following a planned blinded sample size re-estimation. Up to 200 
eligible participants with symptomatic cardiomyopathy due to LMNA mutations will be 
randomized at approximately 60 to 90 investigational centers, globally. The sample size 
determination is detailed in Section 9.2. 
 
The study will be conducted in 2 parts: a randomized, double-blind treatment period, 
followed by an ARRY-371797 (PF-07265803) open-label treatment period. During the 
randomized, double-blind period, participants, investigators, site personnel, and sponsor 
personnel directly involved with the conduct of the study will remain blinded to assigned 
treatment. The double-blind period will continue until the primary analysis which includes 
an assessment of the primary efficacy endpoint and completion of an evaluation of a 
composite endpoint consisting of all-cause mortality or worsening heart failure (HF-related 
hospitalization or HF-related urgent care visits). Following the primary analysis, a seamless 
transition to the open-label phase may begin and ongoing treatments will be unblinded and 
participants receiving placebo may initiate treatment with ARRY-371797 (PF-07265803) 
provided eligibility criteria are met. 
CCI 
CCI 
Endpoints 
Objectives 


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The end of the study is reached once the last participant has had the opportunity to be 
followed for at least 24 weeks in the open-label period of the study or has discontinued from 
the study. 
 
The study will have an independent DMC to review safety and PK data at regular intervals 
and efficacy data at a formal interim futility analysis (Section 9.6.1). A study SC will be 
involved in oversight of the study and will ensure transparent management of the study 
according to the protocol (Section 9.6.2). A CEC will be utilized to adjudicate causes for HF- 
related hospitalizations and HF-related urgent care visits (Section 9.6.3). 
 
A central laboratory will be used for analyses of ECGs, ECHO, NT-proBNP, and safety 
laboratory assessments; local laboratories will be used for analyses of ECHO at screening 
only to determine eligibility. 
 
Pre-defined in the protocol, a formal interim futility analysis was performed on the 6MWT 
data at Week 12 after the first 60 randomized NYHA Class II/III participants had completed 
the Week 12 assessment or otherwise discontinued from the study prior to Week 12. 
 
4.1.1. Prescreening and Screening for Randomized Double-Blind Treatment Period 
All participants with DCM who meet the prescreening eligibility criteria for the study will be 
assessed for the presence of eligible LMNA mutation(s) using an assay performed by an 
accredited clinical laboratory. 
 
The central accredited clinical laboratory will be used to assess LMNA mutation status if the 
LMNA mutation status is unknown at time of prescreening or if the genetic test was not 
performed by an accredited clinical laboratory. The LMNA mutation test results from the 
central accredited clinical laboratory must be available and confirmed prior to entering the 
screening period. 
 
Participants with an identified pathogenic (P), likely pathogenic (LP) or VUS LMNA 
mutation status documented by results from an accredited clinical laboratory can enter the 
screening period. Participants who have multiple LMNA variants identified will be enrolled 
on the variant with the highest classification tier and the variant with the highest 
classification will be reported in the eCRF. 
 
All participants will qualify for the study based on cardiac function, symptoms, and other 
eligibility factors during screening. The NYHA Class II/III participants will also qualify for 
the study based on their functional capacity (6MWT). All eligible participants (NYHA Class 
II/III and IV [if feasible]) will return to the clinic for assessment at the Day -1 visit. There 
must be at least 27 days between the 6MWT performed during screening and the 6MWT 
performed at the Day -1 visit. 
 
4.1.2. Randomized Double-Blind Treatment Period 
All eligible participants will return to the clinic for assessment at the baseline visit (Day 1) 
prior to randomization. Randomization will be initially stratified based on NYHA class: 
Class II/III or Class IV. Randomization for NYHA Class II/III participants will be further 


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stratified by the average of the Day -1 and baseline visit (Day 1) 6MWT (<320 m or ≥320 m) 
results, and mutation type (pathogenic/likely pathogenic or VUS). On Day 1, eligible 
participants will be randomized (1:1) to 400 mg BID ARRY-371797 (PF-07265803) or 
placebo. 
 
During the randomized, double-blind period, Class II/III participants will attend clinic visits 
at Weeks 4, 8, 12, 24, 36, 48, 60 and every 24 weeks thereafter during which efficacy and/or 
safety assessments will be performed. Starting at Week 72, a phone contact visit must be 
conducted every subsequent 24 weeks to assess at home urine pregnancy testing (WOCBP 
only), assess SAE/AEs and HF-related hospitalizations/HF-related urgent care visits. In 
addition, assessment of any changes to concomitant medications and assess status of study 
intervention and ensure the participant dosing diary is completed. Class IV participants 
should be encouraged to attend visits in the clinic at Weeks 4, 8, 12, 24, 36, 48, 60 and every 
24 weeks thereafter whenever feasible, based on the participant’s overall condition and 
mobility. If the Class IV participant cannot attend clinic visits, remote assessments after the 
baseline visit (Day 1) may be performed. 
 
Safety assessments include the monitoring of AEs/SAEs, clinical laboratory tests 
(hematology, clinical chemistry, urinalysis, and pregnancy tests), physical examinations, vital 
signs, ECGs, and arrhythmia assessments according to the SoA. All concomitant medications 
and/or therapies will be recorded. Efficacy assessments include the 6MWT, ECHOs, and 
PRO assessments per the SoA. In addition, participants will have pre and postdose blood 
samples collected per the SoA to characterize the plasma PK of ARRY-371797 (PF- 
07265803) and its metabolites in this participant population. Participants will also have blood 
samples collected per the SoA in order to characterize PD markers. For the Class IV 
participants, some assessments are considered optional based on whether the participant is 
ambulatory or not. The following assessments are considered optional for the Class IV 
participants: 6MWT, ECGs, ECHO, arrhythmia assessment, PK assessment, and PD 
assessment. If a Class IV participant enters the study unable to complete any of these 
assessments, but later during the course of the study is able to complete them, these 
assessments should then be completed. 
 
Participants will continue on study treatment as long as the participant has not met predefined 
criteria for treatment discontinuation. All participants should have a treatment 
discontinuation visit as soon as possible after the final dose of study intervention. A safety 
follow-up visit will occur approximately 30 days after the last dose of study intervention. 
Participants who discontinue study treatment prior to Week 24 should continue to have all 
assessments performed as scheduled through the Week 24 visit. Every effort should be made 
to obtain these data. All participants will subsequently be followed for HF-related 
hospitalization or HF-related urgent care visit (see Section 8.2.6) and OS until death or 
initiation of the open-label treatment period, whichever occurs first (see Section 8.12). Every 
effort should be made to obtain these data. 
CCI 
 
 


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CCI 
CCI 
 
 
 
 
 
 
 
 
 
4.2. Scientific Rationale for Study Design 
Refer to Section 2.1 for the Study Rationale. 
 
4.3. Justification for Dose 
In more than 100 healthy participants and relatively healthy participants, 400 mg BID 
ARRY-371797 (PF-07265803) has proven to be a well-tolerated dose. In Study 
CCI 


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ARRAY-797-223, 41 participants with OA of the knee received 400 mg BID for 28 days, 
and this dosing regimen was well tolerated. In PD studies using clinical samples, 400 mg QD 
doses of ARRY-371797 (PF-07265803) provided inhibition of PD markers p38 pathway 
inhibition (cytokines, CRP) of greater than 80% (Study ARRAY-797-101). In a clinical study 
of pain relief (Study ARRAY 797-221), 400 mg QD of ARRY-371797 (PF-07265803) 
provided maximal effect (associated with p38 MAPK inhibition), with 200 mg ARRY- 
371797 (PF-07265803) providing significantly less benefit. 
 
Doses utilized in the nonclinical studies of LMNA-related DCM, where positive effects on 
cardiovascular function and survival were demonstrated, provided exposure consistent with 
clinical exposure observed with 200 to 400 mg BID of ARRY-371797 (PF-07265803). 
 
Study ARRAY-797-231 was a Phase 2, two-arm study designed to investigate the efficacy 
and safety of 48 weeks of treatment with ARRY-371797 (PF-07265803) in 12 stable 
participants with LMNA-related DCM. In this study, participants were alternately assigned to 
receive ARRY-371797 (PF-07265803) at 100 mg BID or 400 mg BID resulting in n = 6 per 
dose group. Participants in the 100 mg BID dose group were allowed to dose escalate to 400 
mg BID after 24 weeks of treatment. Three participants dose escalated to 400 mg BID after 
their Week 24 visits and all 3 remained at the 400 mg BID dose through Week 48. In this 
study ARRY-371797 (PF-07265803) was generally well tolerated; most AEs were mild and 
only 1 participant discontinued due to a study intervention-related AE. The 400 mg BID dose 
of ARRY-371797 (PF-07265803) appeared to be associated with larger favorable changes in 
NT-proBNP levels than the 100 mg BID dose in an analysis of aggregated mean change from 
baseline at all time points. The safety and efficacy data from these clinical studies provide 
justification for the 400 mg BID dose regimen proposed in this study. 
 
4.4. End of Study Definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
End of the study will occur once the last participant has had the opportunity to be followed 
for at least 24 weeks in the open-label period of the study or has discontinued from the study. 
 
See Section 6.7 for information regarding intervention after the end of the study. The sponsor 
will notify all applicable regulatory agencies in accordance with local requirements when the 
study has ended. 
 
5. STUDY POPULATION 
This study can fulfill its objectives only if appropriate participants are enrolled. The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate. All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted. 


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Participants must fulfill all of the following inclusion criteria and none of the exclusion 
criteria to be eligible for randomization into the study. 
 
In order to maintain diversity in the genetic pool enrolled in the study, no more than 10% of 
participants with the same mutation will be enrolled in the study. 
 
Questions regarding participant eligibility should be addressed to the sponsor or delegate 
prior to enrollment. 
 
5.1. Inclusion Criteria 
5.1.1. Prescreening Eligibility Criteria for LMNA Mutation Testing 
The following criteria define eligibility for prescreening: 
 
5.1.1.1. Prescreening for Participants with Pre-Identified P/LP/VUS LMNA Mutation 
by an Accredited Clinical Laboratory 
1. Provide a signed and dated informed consent document prior to initiation of any study- 
related procedures. Participants under guardianship or partial guardianship will be 
eligible unless prohibited by local laws or by local/central ethic committees. 
 
2. Age ≥18 years at time of informed consent. 
 
3. NYHA functional Class II, III, or IV. 
 
4. Participant will have an ICD (implanted at least 4 weeks prior to initiation of study 
intervention) or CRT-D (CRT initiated at least 6 months prior to initiation of study 
intervention, and defibrillation function activated at least 4 weeks prior to initiation of 
study intervention). Devices must include pacing capabilities or a separate pacemaker 
must be present. 
 
5. Participant will have symptomatic DCM with pre-identified P/LP/VUS LMNA mutation. 
The test result must be obtained from an accredited clinical laboratory. 
 
6. Participant will have a history of reduced EF and at least one of the following: 
 
a. Cardiac conduction disease, including sinus node arrest with junctional rhythms 
or atrioventricular conduction block of at least first degree, ie, PR interval 
≥220 msec during sinus rhythm. 
 
b. Family history of early onset HF/arrhythmia consistent with a diagnosis of 
idiopathic DCM. 
 
c. History of paroxysmal or sustained supraventricular arrhythmias, including atrial 
fibrillation, atrial flutter, supraventricular tachycardia, or sick sinus syndrome. 
 
d. History of paroxysmal or sustained ventricular arrhythmias including ventricular 
tachycardia, and ventricular fibrillation. 


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7. No documented history of a clinical illness or condition other than LMNA mutations that 
is associated with HF or, in the judgment of the investigator, would make the participant 
inappropriate for study participation. 
 
5.1.1.2. Prescreening for Participants with Unknown LMNA Mutation Status or with an 
Identified LMNA Mutation Result not Performed by an Accredited Clinical Laboratory 
1. Provide a signed and dated prescreening informed consent document prior to initiation of 
any study-related procedures. Participants under guardianship or partial guardianship will 
be eligible unless prohibited by local laws or by local/central ethic committees. 
 
2. Age ≥18 years at time of informed consent. 
 
3. NYHA functional Class II, III, or IV. 
 
4. Participant will have an ICD (implanted at least 4 weeks prior to initiation of study 
intervention) or CRT-D (CRT initiated at least 6 months prior to initiation of study 
intervention), and defibrillation function activated at least 4 weeks prior to initiation of 
study intervention. Devices must include pacing capabilities or a separate pacemaker 
must be present. 
 
5. Participant will have a history of reduced EF and at least one of the following: 
 
a. Cardiac conduction disease, including sinus node arrest with junctional rhythms 
or atrioventricular conduction block of at least first degree, ie, PR interval 
≥220 msec during sinus rhythm. 
 
b. Family history of early onset HF/arrhythmia consistent with a diagnosis of 
idiopathic DCM. 
 
c. History of paroxysmal or sustained supraventricular arrhythmias, including atrial 
fibrillation, atrial flutter, supraventricular tachycardia, or sick sinus syndrome. 
 
d. History of paroxysmal or sustained ventricular arrhythmias including ventricular 
tachycardia, and ventricular fibrillation. 
 
6. No documented history of a clinical illness or condition that, in the judgment of the 
investigator, would make the participant inappropriate for study participation. 
 
5.1.2. Inclusion Criteria for NYHA Functional Class II and III Participants 
Participants of NYHA functional Class II or III must meet all of the following criteria at 
screening to be eligible for randomization into the study: 
 
1. Provide a signed and dated informed consent document prior to initiation of any study- 
related procedures. Participants under guardianship or partial guardianship will be 
eligible unless prohibited by local laws or by local/central ethic committees. 


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2. Age ≥18 years at time of informed consent. 
 
3. Participants with symptomatic LMNA-related DCM defined as all of the following: 
 
a. Gene positive for a pathogenic, likely pathogenic or VUS mutation in the LMNA 
gene as determined by an accredited clinical laboratory; 
 
b. NYHA functional Class II or III that has been stable for at least 3 months; 
 
c. Evidence of cardiac impairment as determined by LVEF ≤50%. 
 
4. Participant will have an ICD (implanted at least 4 weeks prior to initiation of study 
intervention) or CRT-D (CRT initiated at least 6 months prior to initiation of study 
intervention and defibrillation function activated at least 4 weeks prior to initiation of 
study intervention). Devices must have activated pacing capabilities or a separate 
pacemaker must be present. 
 
5. Objective functional impairment evidenced by a reduction in 6MWT; participants must 
meet all of the following 6MWT criteria: 
 
a. Screening: 6MWT distance >100 m but ≤450 m, AND 
b. Day -1 visit: 6MWT distance >100 m but ≤485 m, AND 
c. Baseline visit (Day 1): 6MWT distance >100 m but ≤485. 
6. In the judgment of the investigator, the participant has impaired function due to 
symptomatic DCM rather than any noncardiac comorbidity that can significantly impair 
function. 
 
7. Stable medical and/or device therapy consistent with regional (eg, AHA/ACC or ESC) 
guidelines at the investigator discretion, without change in HF drug(s) dose in the past 1 
month. 
 
8. Acceptable hematology laboratory values within 35 days prior to Day 1: 
 
a. Hemoglobin >9.5 g/dL; 
b. WBC count >2500/μL; 
c. Platelet count >100,000/μL. 


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9. Acceptable hepatic and renal function laboratory values within 35 days prior to Day 1: 
 
a. AST and/or ALT ≤4.0×ULN; 
 
b. Total bilirubin <2×ULN (except for Gilbert’s syndrome); 
 
c. eGFR >30 mL/min/1.73 m2 (using the sMDRD formula). In the event sMDRD 
cannot be determined due to the lack of collection of appropriate data (eg, race), 
CrCL >30 mL/min (using the Cockroft-Gault formula). 
10. If participant is female and of childbearing potential, she must not be pregnant or 
breastfeeding or plan to become pregnant during the duration of the trial. She must have a 
negative serum β-HCG test within 7 to 35 days prior to Day 1 and consent to ongoing 
urine pregnancy testing during the course of the study. 
 
11. Male participants and female participants of childbearing potential must agree to use a 
highly effective method of contraception as defined in the study protocol (Section 5.3.1). 
 
12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures. 
 
5.1.3. Inclusion Criteria for NYHA Functional Class IV Participants 
Participants of NYHA functional Class IV must meet all of the following criteria at screening 
to be eligible for randomization into the study: 
 
1. Provide a signed and dated informed consent document prior to initiation of any 
study-related procedures. Participants under guardianship or partial guardianship will be 
eligible unless prohibited by local laws or by local/central ethic committees. 
 
2. Age ≥18 years at time of informed consent. 
 
3. Participants with symptomatic LMNA-related DCM defined as all of the following: 
 
a. Gene positive for a pathogenic, likely pathogenic or VUS mutation in the LMNA gene 
as determined by an accredited clinical laboratory; 
 
b. NYHA functional Class IV that has been stable for at least 1 month 
 
c. Evidence of cardiac impairment as determined by EF ≤50%. 
 
4. Participant will have an ICD (implanted at least 4 weeks prior to initiation of study 
intervention) or CRT-D (CRT initiated at least 6 months prior to initiation of study 
intervention and defibrillation function activated at least 4 weeks prior to initiation of 
study intervention). Devices must have activated pacing capabilities or a separate 
pacemaker must be present. 


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5. Stable medical and/or device therapy consistent with regional (eg, AHA/ACC or ESC) 
guidelines at the investigator discretion, without change in HF drug(s) dose in the past 1 
month. 
 
6. Acceptable hematology laboratory values within 35 days prior to Day 1: 
 
a. Hemoglobin >9.0 g/dL; 
b. WBC count >2,500/μL; 
c. Platelet count >100,000/μL. 
7. Acceptable hepatic and renal function laboratory values within 35 days prior to Day 1: 
 
a. AST and/or ALT ≤4.0×ULN; 
 
b. Total bilirubin <2×ULN (except for Gilbert’s syndrome); 
 
c. eGFR >30 mL/min/1.73 m2 (using the sMDRD formula). In the event sMDRD cannot 
be determined due to the lack of collection of appropriate data (ie, race), CrCL 
> 30 mL/min (using the Cockroft-Gault formula). 
8. If participant is female and of childbearing potential, she must not be pregnant or 
breastfeeding or plan to become pregnant during the duration of the trial. She must have a 
negative serum β-HCG test within 7 to 35 days prior to Day 1 and consent to ongoing 
urine pregnancy testing during the course of the study. 
 
9. Male participants and female participants of childbearing potential must agree to use a 
highly effective method of contraception as defined in the study protocol (Section 5.3.1). 
 
10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures. 
 
5.1.4. Inclusion Criteria for Participants Who Cross Over From Placebo to ARRY- 
371797 (PF-07265803) Treatment in the Open-Label Period 
Participants of NYHA functional Class II, III, or IV must meet all of the following criteria at 
the open-label baseline visit to be eligible for initiating treatment in the open-label period of 
the study: 
 
1. Must be currently on this study (on treatment, defined as no longer than 21 days of 
treatment interruption unless approved by medical monitor [Section 6.6.1]). 


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2. Acceptable hematology laboratory values: 
 
a. Hemoglobin > 9.0 g/dL; 
 
b. WBC count > 2,500/μL; 
 
c. Platelet count > 100,000/μL. 
 
3. Acceptable hepatic and renal function laboratory values: 
 
a. AST and/or ALT ≤4.0×ULN; 
 
b. Total bilirubin <2.0×ULN (except for Gilbert’s syndrome); 
 
c. eGFR >30 mL/min/1.73 m2 (using the sMDRD formula). In the event sMDRD 
cannot be determined due to the lack of collection of appropriate data (ie, race), CrCL 
> 30 mL/min (using the Cockroft-Gault formula). 
4. If participant is female and of childbearing potential, she must not be pregnant or 
breastfeeding or plan to become pregnant during the duration of the trial. She must have a 
negative urine pregnancy test at the open-label baseline visit and consent to ongoing 
urine pregnancy testing during the study. 
 
5. Male participants and female participants of childbearing potential must agree to use a 
highly effective method of contraception as defined in the study protocol (Section 5.3.1). 
 
6. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, 
and other study procedures. 
 
5.2. Exclusion Criteria 
5.2.1. Exclusion Criteria for NYHA Functional Class II and III Participants 
Participants of NYHA functional Class II or III meeting any of the following criteria at 
screening are ineligible for randomization into the study: 
 
1. Presence of other form(s) of cardiomyopathy contributing to HF (eg, inflammatory or 
infiltrative cardiomyopathy), clinically significant cardiac anatomic abnormality (eg,LV 
aneurysm), clinically significant coronary artery disease (eg, coronary revascularization, 
exercise -induced angina) or uncorrected, hemodynamically significant (ie, moderate- 
severe) primary structural valvular disease not due to HF, per investigator judgment. 
 
2. Currently receiving intermittent or continuous IV inotrope infusion, or presence of a 
ventricular assist device, or history of prior heart transplantation. Participants listed for 
cardiac transplantation may be enrolled provided transplantation is not likely to occur in 
the next 6 months. 


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3. Any of the following within 3 months prior to screening: myocardial infarction, cardiac 
surgical procedures (other than for pacemaker/ICD/CRT-D implantation or replacement), 
acute coronary syndrome, serious systemic infection with evidence of septicemia, or any 
major surgical procedure requiring general anesthesia. 
 
4. Currently receiving or deemed at high risk of requiring chronic renal replacement therapy 
(eg, hemodialysis or peritoneal dialysis) within 6 months. 
 
5. Initiation of CRT within 6 months prior to screening. 
 
6. Likelihood, in the investigator’s opinion, of undergoing cardiac transplantation, LVAD or 
other device implantation, or other invasive therapeutic cardiac procedure within the next 
6 months; or of requiring continuous IV inotropic treatment, or referral for hospice or 
end-of-life treatment. 
 
7. Treatment with any investigational agent(s) for HF within 35 days prior to Day 1. 
 
8. Malignancy that is active or has been diagnosed within 3 years prior to screening, except 
surgically curatively resected in situ malignancies or surgically cured early breast cancer, 
prostate cancer, skin cancer (basal cell carcinoma, squamous cell carcinoma), thyroid 
cancer, or cervical cancer, or, with prior review by the medical monitor, other early stage 
surgically curatively resected malignancies with less than a 20% expected 2-year 
recurrence rate. 
 
9. Noncardiac condition that limits lifespan to <1 year. 
 
10. Serum positive for hepatitis B surface antigen, viremic hepatitis C, or HIV at screening. 
 
11. Medical, psychiatric, cognitive, or other conditions that compromise the participant’s 
ability to understand the participant information, comply with the study protocol, or 
complete the study. 
 
12. Any severe concurrent disease or condition (eg, active systemic infection) that, in the 
judgment of the investigator, would make the participant inappropriate for study 
participation. 
 
13. Prior exposure to ARRY-371797 (PF-07265803). 
 
14. Prior randomization into this clinical study. 
 
15. Participants with an underlying condition that may impact the ability of the 6MWT to 
reflect changes in cardiovascular function such as: an orthopedic condition that limits 
walking abilities (eg, severe arthritis), significant musculoskeletal pathology, significant 
COPD that limits exercise tolerance, or any other condition that, according to the 
investigator’s assessment, significantly limits a participant’s performance on the 6MWT 
independently from the participant’s cardiomyopathy. 


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16. Documented hypersensitivity/allergy or clinically significant intolerance to any 
component of drug product. 
 
5.2.2. Exclusion Criteria for NYHA Functional Class IV Participants 
Participants of NYHA functional Class IV meeting any of the following criteria at screening 
are ineligible for randomization into the study: 
 
1. Presence of other form(s) of cardiomyopathy contributing to HF (eg, inflammatory or 
infiltrative cardiomyopathy), clinically significant cardiac anatomic abnormality (eg, LV 
aneurysm), clinically significant coronary artery disease (eg, coronary revascularization, 
exercise-induced angina) or uncorrected, hemodynamically significant (ie, moderate- 
severe) primary structural valvular disease not due to HF per investigator judgment. 
 
2. Presence of a ventricular assist device, or history of prior heart transplantation. 
Participants listed for cardiac transplantation may be enrolled. 
 
3. Treatment with any investigational agent(s) for HF within 35 days prior to Day 1. 
 
4. Malignancy that is active or has been diagnosed within 3 years prior to screening, except 
surgically curatively resected in situ malignancies or surgically cured early breast cancer, 
prostate cancer, skin cancer (basal cell carcinoma, squamous cell carcinoma), thyroid 
cancer, or cervical cancer, or, other early stage surgically curatively resected 
malignancies with less than a 20% expected 2-year recurrence rate. 
 
5. Non-cardiac condition that limits lifespan to <1 year. 
6. Serum positive for hepatitis B surface antigen, viremic hepatitis C, or HIV at screening. 
 
7. Medical, psychiatric, cognitive, or other conditions that compromise the participant’s 
ability to understand the participant information, comply with the study protocol, or 
complete the study. 
 
8. Any severe concurrent disease or condition (eg, active systemic infection) that, in the 
judgment of the investigator, would make the participant inappropriate for study 
participation. 
 
9. Prior exposure to ARRY-371797 (PF-07265803). 
 
10. Prior randomization into this clinical study. 
 
11. Documented hypersensitivity/allergy or clinically significant intolerance to any 
component of drug product. 


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5.2.3. Exclusion Criteria for Participants Who Cross Over From Placebo to ARRY- 
371797 (PF-07265803) Treatment in the Open-Label Period 
Participants of NYHA functional Class II, III, or IV meeting any of the following criteria at 
the open-label baseline visit are ineligible for initiating treatment in the open-label period of 
the study. 
 
1. Presence of other form(s) of cardiomyopathy contributing to HF (eg, inflammatory or 
infiltrative cardiomyopathy) or clinically significant cardiac anatomic abnormality 
(eg, LV aneurysm), clinically significant coronary artery disease (eg, coronary 
revascularization, exercise-induced angina) per investigator judgment or uncorrected, 
hemodynamically significant (ie, moderate-severe) primary structural valvular disease 
not due to HF 
 
2. Presence of a ventricular assist device or history of prior heart transplantation. 
Participants listed for cardiac transplantation may be enrolled. 
 
3. Currently receiving or deemed at high risk of requiring chronic renal replacement therapy 
(eg, hemodialysis or peritoneal dialysis) within 6 months. 
 
4. Treatment with any investigational agent(s) for HF at the open-label baseline visit. 
 
5. Malignancy that is active or has been diagnosed within 3 years prior to screening, except 
surgically curatively resected in situ malignancies or surgically cured early breast cancer, 
prostate cancer, skin cancer (basal cell carcinoma, squamous cell carcinoma) thyroid 
cancer, or cervical cancer or, other early stage surgically curatively resected malignancies 
with less than a 20% expected 2-year recurrence rate. 
 
6. Non-cardiac condition that limits lifespan to <1 year. 
7. Medical, psychiatric, cognitive, or other conditions that compromise the participant’s 
ability to understand the participant information, comply with the study protocol, or 
complete the study. 
 
8. Any severe concurrent disease or condition (eg, active systemic infection) that, in the 
judgment of the investigator, would make the participant inappropriate for study 
participation. 
 
9. Documented hypersensitivity/allergy or clinically significant intolerance to any 
component of drug product. 
 
5.3. Lifestyle Considerations 
5.3.1. Contraception 
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 Section 10.4.4) and will confirm that the participant has been instructed in its 


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consistent and correct use. At time points indicated in the SoA, the investigator or designee 
will inform the participant of the need to use highly effective contraception consistently and 
correctly and document the conversation and the participant’s affirmation in the participant’s 
chart (participants need to affirm their consistent and correct use of at least 1 of the selected 
methods of contraception). In addition, the investigator or designee will instruct the 
participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the participant or partner. 
 
5.3.2. Meals and Dietary Restrictions 
Consumption of food will be restricted from 2 hours prior to and 2 hours after study 
intervention administration. Other dietary restrictions should be generally consistent with 
accepted treatment guidelines for participants with HF. 
 
5.3.3. Restrictions on Physical Activity 
Participants should abstain from strenuous exercise (eg, heavy lifting, weight training, and 
aerobic activity) for 48 hours prior to each clinic visit. 
 
5.4. Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the CONSORT publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure details, eligibility 
criteria, and any SAE. 
 
Participants who fail to qualify for study eligibility upon initial screening may be rescreened 
a maximum of 4 additional times. 
 
Prescreening and screening procedures for the randomized double-blind treatment period are 
summarized in Section 4.1.1. 
 
6. STUDY INTERVENTION 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol. 
 
For the purposes of this protocol, study intervention refers to ARRY-371797 (PF-07265803) 
or placebo. 
 
6.1. Study Intervention(s) Administered 
Participants will be randomized (1:1) to receive 4 x 100 mg tablets BID of study intervention 
(either ARRY-371797 (PF-07265803) or placebo) during the double-blind period of the 
study. Both active treatment (ARRY-371797 (PF-07265803)) and placebo will be supplied 


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by the sponsor as brown capsule-shaped film coated tablets in 100 mg dose strength (or 
placebo) for oral administration. 
 
Table 2. 
Dose Levels of Study Intervention 
 
ARRY-371797 (PF-07265803) 
Matching Placebo 
Dose Level 1 
400 mg BID 
(4×100 mg tablets BID) 
4 tablets BID 
Dose Level -1 
200 mg BID 
(2×100 mg tablets BID) 
2 tablets BID 
Dose Level -2 
100 mg BID 
(1×100 mg tablet BID) 
1 tablet BID 
 
Study intervention may be shipped by courier to study participants if permitted by local 
regulations and in accordance with storage and transportation requirements for ARRY- 
371797 (PF-07265803). Pfizer does not permit the shipment of study intervention by mail. 
The tracking record of shipments, including temperature monitoring data, and the chain of 
custody of ARRY-371797 (PF-07265803) must be kept in the participant’s source 
documents/medical records. 
 
6.1.1. Manufacturing and Formulation 
ARRY-371797 (PF-07265803) is supplied by the sponsor as brown capsule-shaped 
film-coated tablets in 100 mg dose strength for oral administration. The ARRY-371797 (PF- 
07265803) film-coated tablets consist of ARRY-371797 (PF-07265803) drug substance, 
microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, croscarmellose 
sodium, colloidal silicon dioxide, glyceryl dibehenate, talc, magnesium stearate, sodium 
hydrogen carbonate, and a commercial film coating (Opadry® 200, Colorcon). 
 
Placebo, identical in appearance to the study intervention, is supplied by the sponsor as 
brown capsule-shaped film-coated tablets for oral administration. The placebo tablets consist 
of lactose monohydrate, microcrystalline cellulose, magnesium stearate, and a commercial 
film coating (Opadry® 200, Colorcon). 
 
6.1.2. Packaging and Labeling 
ARRY-371797 (PF-07265803) 100 mg tablets and placebo tablets will be packaged in HDPE 
bottles with an induction seal and child-resistant closure. Bottles will contain a precounted 
number of tablets required for the appropriate dosage and treatment duration between visits. 
Bottles for the ARRY-371797 (PF-07265803) 100 mg tablets and placebo tablets will be 
labeled, at a minimum, with a unique identifier (medication number), the lot number, 
contents (number of tablets), dosage strength, storage conditions, and the name and address 
of the sponsor. Labels will be in the local language and comply with the legal requirements 
for each country. 


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6.1.3. Administration 
All participants will take their first dose of study intervention in the clinic on the morning of 
the baseline visit (Day 1). Dosing should occur at roughly the same time each day and 
subsequent doses should be taken by the participant approximately every 12 hours. 
 
The dose administered on PK sampling days at the baseline visit and Weeks 4, 8, 12, and 24 
will be administered in the clinic under the supervision of site personnel or under the 
supervision of a physician or home health care nurse (or similarly qualified person) for 
home-based visits to NYHA Class IV participants, if applicable. Study intervention should be 
given after all questionnaires have been completed and predose blood samples for clinical 
laboratory assessments and PK have been collected. The date and exact time of 
administration should be noted by site personnel or a physician or home health care nurse (or 
similarly qualified person) and recorded in the eCRF. 
 
Study intervention is to be taken orally without food. Participants should abstain from all 
food 2 hours prior to and 2 hours after dosing. Participants will swallow the study 
intervention whole with approximately 240 mL (~8 oz) of water and will not chew the 
tablet(s) prior to swallowing. 
 
Participants should not take extra doses of study intervention to compensate for doses missed 
for AEs or any other reason. If a participant vomits at any time after dosing, the dose of study 
intervention should not be readministered. 
 
Participants will receive a diary dispensed at each visit to document self-administered BID 
dosing of study intervention to include the dose taken (number of tablets), the date and time 
of dosing, and if any doses were missed and the reason for the missed dose. Participants will 
be instructed to return any unused study intervention and the participant dosing diary to the 
site at each visit. Corresponding study intervention administration information will be 
reported in the eCRF. 
 
The pharmacist or appropriately trained and designated study personnel or study nurse, or a 
physician or home health care nurse for home visits, will ensure that the appropriate dose is 
dispensed and will provide the participant with at least the appropriate number of tablets for 
the number of doses to be taken prior to the next scheduled visit. The study site personnel 
will train the participant and/or the participant’s caregiver on dosing procedures for the study 
intervention. 
 
6.2. Preparation/Handling/Storage/Accountability 
• The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
 
• Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
interventions must be stored in a secure, environmentally controlled, and monitored 
(manual or automated recording) area in accordance with the labeled storage 


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conditions with access limited to the investigator and authorized site staff. At a 
minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request. Data for nonworking days must 
indicate the minimum and maximum temperatures since previously documented for 
all site storage locations upon return to business. 
 
• Any excursions from the study intervention label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken. The site should 
actively pursue options for returning the study intervention to the storage conditions 
described in the labeling, as soon as possible. Once an excursion is identified, the 
study intervention must be quarantined and not used until Pfizer provides permission 
to use the study intervention. Specific details regarding the definition of an excursion 
and information the site should report for each excursion will be provided to the site 
in the Pharmacy Manual/IP Manual. 
 
• Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the label. 
 
• Study interventions should be stored in their original containers. 
• Site staff will instruct participants on the proper storage requirements for take-home 
study intervention. 
 
• The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records), such as the 
IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record. All study intervention that is 
taken home by the participant, both used and unused, must be returned to the 
investigator by the participant. Returned study intervention must not be redispensed 
to the participants. 
 
• Further guidance and information for the final disposition of unused study 
interventions are provided in the Pharmacy Manual/IP Manual. All destruction must 
be adequately documented. If destruction is authorized to take place at the 
investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer. 
 
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the Pharmacy Manual/IP Manual. 
 
6.2.1. Preparation and Dispensing 
A qualified staff member will dispense the study intervention using the IRT system. A 
second staff member will verify the dispensing. The participant should be instructed to 


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maintain the product in the bottles provided throughout the course of dosing and return the 
bottles to the site at the next study visit. 
 
The site pharmacist will allocate the appropriate bottle(s) of study intervention (ARRY- 
371797 (PF-07265803) or placebo) to each randomized participant, as per the IRT system. 
Site personnel are required to maintain accurate inventory records. 
 
Complete dispensing instructions, dosing instructions, including the timing of study 
intervention administration and instructions for missed doses will be provided in the 
Pharmacy Manual/IP Manual. 
 
6.3. Measures to Minimize Bias: Randomization and Blinding 
Randomization, double-blinding of study intervention and use of multiple study sites are 
elements of the study design that are employed to minimize bias during the study. 
 
To minimize the potential for bias, study participants, all investigational site personnel, and 
all sponsor personnel directly involved with the conduct of the study (ie, with the exception 
of personnel involved in drug supply and safety reporting for fulfillment of regulatory 
requirements) will remain blinded to treatment assignment and aggregate data summaries 
until the primary analysis has been performed and an evaluation of the composite endpoint 
comprised of all-cause mortality and HF-related hospitalization or HF-related urgent care 
visit has been completed. Further exceptions will be made if the blind is broken according to 
the methods described in Section 6.3.2. The outsourced bioanalytical laboratory will be 
permitted to analyze PK samples in an ongoing basis, as sample stability is projected to be 
shorter than the study duration. The sponsor-designated bioanalytical laboratory will analyze 
all samples, both those on the active and control arm, thereby unblinding treatment 
assignment. No randomization data will be shared with the bioanalytical vendor in an ad hoc 
manner. The bioanalytical laboratory is permitted to transfer bioanalytical data to an 
unblinded CRO for generation of tables and figures for the DMC meeting and for the 
purposes of re-assay of PK samples as needed. The sponsor is permitted to review 
bioanalytical data where participant identifiers are omitted or replaced with dummy 
identifiers as part of the open review of the DMC meeting. The randomization schedule will 
be generated and managed by a statistician not assigned to support the study. 
 
6.3.1. Early unblinding of PK data may be exercised to facilitate completion of these 
analyses for regulatory submissions in a timely fashion. See Section 9.4.3.7.1 for 
details.Allocation to Study Intervention 
Blinded treatments will be assigned according to a computerized central randomization list 
using IRT system. The IRT system will assign blinded study intervention to each participant. 
 
For participants entering either the randomized double-blind treatment period or the ARRY- 
371797 (PF-07265803) open-label treatment period, responsible site personnel will identify 
the study intervention bottle(s) to dispense to the participant by using the IRT system which 
will provide the medication number(s) at each dispensing visit. Site personnel will add the 
participant number to the label. 


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6.3.2. Breaking the Blind 
Prior to the initiation of the study, each site will be instructed on the method for breaking the 
blind as described in the Safety Reference Manual. The blind should be broken only in the 
event of a safety emergency for which, in the opinion of the treating physician and/or sponsor 
medical monitor, knowledge of the treatment assignment will influence the appropriate 
medical response. If an emergency occurs that requires unblinding of an individual 
participant, the medical monitor should be contacted prior to unblinding the participant, if 
possible. If not possible, the sponsor medical monitor should be contacted as soon as possible 
after unblinding has occurred. 
 
If the blind is broken for any participant, the site will be required to provide additional 
information, including actions taken, on the eCRF. Complete training regarding the 
designation of persons authorized to request emergency unblinding and the process for 
unblinding a participant will be provided to investigational sites at or before the study 
initiation visit and will be described in the Safety Reference Manual. 
 
6.4. Study Intervention Compliance 
Throughout the study, participants are required to record the time and date of each dose of 
study intervention, if any doses were missed, and the reason for the missed dose in the 
participant dosing diary. Dosing compliance will be reviewed by the site personnel at each 
visit using the participant diary and discussed with the participant at each visit. Any 
clarifications provided by the participant should be recorded in the participant source 
documents. Corresponding study intervention administration information will be reported in 
the eCRF. 
 
6.5. Concomitant Therapy 
Unless specifically prohibited, concomitant medications can be administered at the 
investigator’s discretion to conform to standard practice during the treatment period. 
Ancillary treatments will be administered according to labeled instructions as medically 
indicated for participants. As with any novel therapeutic for which limited clinical 
experience exists, investigators should exercise caution when prescribing concomitant 
medications with ARRY-371797 (PF-07265803). Investigators should contact the sponsor 
when they are unsure whether a drug should be prescribed to a participant in this study. 
 
All concomitant medications are to be recorded on the eCRF using generic drug names when 
possible. 
 
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4). 
 
6.5.1. Prohibited Therapies/Treatment 
The following therapies are prohibited for the NYHA Class II/III participants after signing 
informed consent and will lead to early withdrawal: 
 
• Continuous or intermittent IV inotrope infusion 


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• Chronic renal replacement therapy (eg, hemodialysis or peritoneal dialysis) 
• Cardiac transplantation, LVAD or other device implantation, other cardiac surgery, or 
any invasive therapeutic cardiovascular-related procedure after initiation of study 
intervention. 
 
• Use of other investigational drugs for HF 
• Use of investigational devices 
• For the NYHA Class IV participants, the use of other investigational drugs for HF and 
the use of devices are prohibited after signing informed consent and will lead to early 
withdrawal. 
 
6.5.2. Cautionary Use of Concomitant Medications while on Study Intervention 
Particular caution should be exercised when: 
 
• Considering treatment with a drug known to prolong QT interval and have a known 
risk of causing torsades de pointes (see Appendix 8). While there is no nonclinical 
evidence of QT prolongation, in a pooled analysis across clinical studies, there is 
some evidence for dose-related prolongation of the QT interval corrected for heart 
rate using Fridericia’s formula (QTcF), compared with placebo in patients receiving 
PF-07265803 (PF-07265803). The magnitude of mean placebo-adjusted QTcF 
prolongation at the time to reach peak plasma exposure (Tmax) for the dose of 400 
mg BID is approximately 8 msec. The investigator will make a benefit-risk 
judgement prior to initiating therapy by considering the participant’s prognosis. 
 
• Considering treatment with drugs that are identified as sensitive clinical substrates of 
CYP3A4, CYP2B6, CYP2D6, or MDR1 (reference: https://www.fda.gov/drugs/drug- 
interactions-labeling/drug-development-and-drug-interactions-table-substrates- 
inhibitors-and-inducers#inhibitors, Table 3-1 and 5-1). The net effect of ARRY- 
371797 (PF-07265803) interaction with these drugs is not known. The investigator 
should make a benefit-risk judgement prior to initiating therapy by considering the 
participant’s prognosis and interpretation of ECG findings. 
 
6.6. Dose Modification 
6.6.1. Dose Interruptions, Reductions, and Discontinuations 
Throughout the study, doses of study intervention (ARRY-371797 (PF-07265803) or 
placebo) may be interrupted, reduced, or stopped as necessary for AEs. 
 
Guidelines for dose modifications due to the common AEs reported in prior ARRY-371797 
(PF-07265803) clinical trials and other AEs considered related to study intervention are 
provided in Table 3. These modifications apply to both the double-blind and open-label 
periods of the study. 


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If an individual participant has safety or tolerability issues at 4 x100 mg tablets BID 
(ARRY-371797 (PF-07265803) or placebo), blinded study intervention may be reduced to 2 
x100 mg tablets BID (ARRY-371797 (PF-07265803) or placebo). In addition, a second dose 
reduction from 2 x 100 mg tablets BID (ARRY-371797 (PF-07265803) or placebo) to 1 x 
100 mg tablet BID (ARRY-371797 (PF-07265803) or placebo), is allowed due to safety or 
tolerability issues. Dose reduction should always be considered as an option before 
permanently discontinuing study intervention. 
 
Once a dose has been reduced, all subsequent doses should remain at that dose level unless 
further reduction, interruption, or discontinuation of study intervention is warranted. 
 
If an AE occurs that is not considered related to study intervention, dosing does not have to 
be reduced or modified, if in the investigator’s opinion the AE is due to the underlying 
disease. Decisions regarding dose interruptions or modifications will be based on the 
investigator’s clinical judgement. 
 
If study intervention is not well tolerated at any dose level by an individual participant 
despite dose reduction, treatment will be permanently discontinued for that participant. 
 
If study intervention has been interrupted for more than 21 days, it cannot be restarted in the 
randomized, double-blind period unless approved by the medical monitor. 
 
Table 3. 
Guidelines for ARRY-371797 (PF-07265803) Dose Modifications for 
Adverse Events 
 
Worst Observed Toxicity Grade 
(Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials) 
(unless noted otherwise) 
Dose Modifications for Study Treatment (Dose 
reduction should always be considered as an option before 
permanently discontinuing study intervention). 
Anemia 
Grade 3 
Hemoglobin 8.0-9.4* g/dL 
(* For Class IV/Open-label participants who 
enroll with hemoglobin between 9 and 9.4, 
interruption should occur if hemoglobin <9.0) 
Interrupt study intervention until resolved to hemoglobin 
≥9.5 g/dL (*or returns to >9.0), then 
If resolved in <21 days, resume study treatment at current 
dose level or consider resume at next lower dose level 
If not resolved in <21 days, resume study treatment at next 
lower dose level 
Grade 4 
Hemoglobin <8.0 g/dL, transfusion indicated 
Potentially life-threatening 
Permanently discontinue study treatment 
Stomatitis 
Inflammation of the mouth and lips, characterized by 
circumscribed, inflammatory and necrotic erosive lesions 
Grade 1 
Combined area of ulcers <1 cm, nonblanchable 
erythema of intact skin with associated warmth 
or edema 
Consider topical therapy, eg, OTC medications or acyclovir 
and reassess within ≤7 days 
Maintain dose level of study treatment and reassess within 
≤7 days 


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Table 3. 
Guidelines for ARRY-371797 (PF-07265803) Dose Modifications for 
Adverse Events 
 
Worst Observed Toxicity Grade 
(Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials) 
(unless noted otherwise) 
Dose Modifications for Study Treatment (Dose 
reduction should always be considered as an option before 
permanently discontinuing study intervention). 
Grade 2 
Combined area of ulcers 1-2 cm, partial 
thickness skin or mucosal loss 
First occurrence: 
Consider topical therapy, eg, OTC medications or 
acyclovir, and reassess within ≤7 days 
If condition resolves ≤7 days, maintain study treatment at 
current dose level 
If condition worsens or does not improve with topical 
therapy, reduce study treatment to next lower dose level 
and reassess within ≤7 days 
If condition resolves, resume study treatment at reduced 
dose level 
If condition worsens or does not improve, interrupt study 
treatment until resolved to Grade ≤1 
Second Occurrence: 
Consider topical therapy, eg, OTC medications or 
acyclovir, and reassess within ≤7 days 
If condition worsens or does not improve with topical 
therapy, interrupt study treatment until resolved to 
Grade ≤1 
If condition resolves, resume study treatment at next lower 
dose level 
Grade 3 
Combined area of ulcers >2 cm, full thickness 
skin or mucosal loss involving damage to or 
necrosis of subcutaneous tissue 
First occurrence: 
Interrupt study intervention, consider systemic therapy, eg, 
valacyclovir and reassess within ≤7 days and then weekly 
If condition resolves in ≤21 days, resume study treatment at 
next lower dose level 
If condition worsens or does not improve, permanently 
discontinue study treatment 
Second occurrence: 
Permanently discontinue study treatment 
Grade 4 
Any size ulcer with extensive destruction, tissue 
necrosis or damage to muscle, bone or 
supporting structures 
Permanently discontinue study treatment 
Skin Rash 
Including acne, dermatitis, erythema, rash, maculo-papular 
rash, seborrheic dermatitis 


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Table 3. 
Guidelines for ARRY-371797 (PF-07265803) Dose Modifications for 
Adverse Events 
 
Worst Observed Toxicity Grade 
(Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials) 
(unless noted otherwise) 
Dose Modifications for Study Treatment (Dose 
reduction should always be considered as an option before 
permanently discontinuing study intervention). 
Grade 2 
Rash covering 10% to 30% BSA with or without 
symptoms (eg, pruritus, burning, tightness), 
limiting instrumental ADL 
First Occurrence: 
Maintain dose level of study treatment and rash should be 
closely monitored 
Initiate specific therapy for rash 
Reassess within ≤14 days 
If rash resolves, continue study treatment at current dose 
level 
If rash worsens or does not improve, interrupt study 
intervention until resolved to Grade ≤1 
Second Occurrence: 
Interrupt study treatment, reassess within ≤14 days 
If rash resolves, resume study treatment at next lower dose 
level 
If rash worsens or does not improve, interrupt study 
intervention until resolved to Grade ≤1. If rash resolves, 
resume study intervention at next lower dose level 
Grade 3 
Rash covering >30% BSA with or without 
symptoms (eg, pruritus, burning, tightness), 
limiting instrumental ADL 
First Occurrence: 
Interrupt study intervention until resolved to Grade ≤1. 
Reassess weekly 
Once resolved to Grade ≤1, resume study treatment at 
current dose level or at next lower dose level 
Consider referral to dermatologist and manage per 
recommendation 
Second Occurrence: 
Interrupt study treatment until resolved to Grade ≤1. 
Reassess weekly 
Resume study treatment at next lower dose level 
Consider referral to dermatologist and manage per 
recommendation 
Grade 4 
Life-threatening consequences, urgent 
intervention indicated 
Permanently discontinue study treatment 


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Table 3. 
Guidelines for ARRY-371797 (PF-07265803) Dose Modifications for 
Adverse Events 
 
Worst Observed Toxicity Grade 
(Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials) 
(unless noted otherwise) 
Dose Modifications for Study Treatment (Dose 
reduction should always be considered as an option before 
permanently discontinuing study intervention). 
CK Elevations 
If AE is not considered related to study intervention, dosing 
does not have to be reduced or modified, if in the 
investigator’s opinion the AE is due to the underlying 
disease. 
Grade 2 
CK >1.6-3.0×ULN 
If asymptomatic: 
Maintain dose level of study intervention and reassess CK 
in 7-21 days 
If not resolved in <21 days, reduce study intervention to 
next lower dose level 
If symptomatic (muscle pains, spasms): 
Reduce study intervention to next lower dose until resolved 
to Grade ≤1, then 
If resolved in <21 days, resume dose level 
If not resolved in <21 days, continue study intervention at 
lower dose level 
Grade 3 
CK 3.1-10.0×ULN 
If asymptomatic: 
Maintain dose level of study intervention and monitor 
closely; measure CK weekly for 3 weeks 
If not resolved in <21 days, reduce study treatment to next 
lower dose level 
If symptomatic (muscle pain, spasms): 
Interrupt study intervention until resolved to Grade ≤1 and 
monitor closely, then 
If resolved in <21 days, reduce study treatment to next 
lower dose level 
If not resolved in <21 days, permanently discontinue study 
treatment 
Grade 4 
CK >10.0×ULN 
If asymptomatic: 
Interrupt study intervention until resolved to Grade ≤1 and 
monitor closely, then 
If resolved in <21 days, reduce study treatment to next 
lower dose level 
If not resolved in <21 days, permanently discontinue study 
treatment 
If symptomatic (muscle pain, spasms, weakness): 
Permanently discontinue study intervention 


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Table 3. 
Guidelines for ARRY-371797 (PF-07265803) Dose Modifications for 
Adverse Events 
 
Worst Observed Toxicity Grade 
(Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials) 
(unless noted otherwise) 
Dose Modifications for Study Treatment (Dose 
reduction should always be considered as an option before 
permanently discontinuing study intervention). 
Liver Function-Related Adverse Events 
Stop study treatment and contact the Medical Monitor if a 
participant meets potential DILI / Hy's law criteria. Refer to 
Appendix 5 (Liver safety: suggested actions and follow up 
assessments) for further details. 
Diarrhea 
Grade 2 
4-5 stools or 400-800 g/24 hours 
If the event is non-persistent Grade 2, maintain dose level 
of study intervention and monitor until stabilization or 
resolution 
First occurrence: 
If the event is a persistent or intolerable Grade 2 AE not 
responsive to a specific therapy, interrupt study treatment 
for ≤21 days until resolved to Grade ≤1 then resume study 
treatment at current dose or at the next lower dose level. 
If resolution within 21 days is not reached, please contact 
the Medical Monitor 
Second occurrence: 
If the event is a persistent or intolerable Grade 2 AE not 
responsive to a specific therapy, interrupt study treatment 
for ≤21 days until resolved to Grade ≤1 then resume study 
treatment at the next lower dose level 
If resolution within 21 days is not reached, please contact 
the Medical Monitor 
Grade 2 
See above but complicated by requirement for 
outpatient IV hydration OR 
Grade 3 
6 or more watery stools or >800 g/24 hours or 
requires outpatient IV hydration 
Interrupt study intervention until resolved to Grade ≤1 
If the event resolves ≤21 days, then study treatment may be 
resumed at next lower dose level 
If resolution within 21 days is not reached, please contact 
the Medical Monitor 
Grade 4 
Life-threatening consequences, urgent 
intervention indicated, eg, ER visit or 
hospitalization 
Permanently discontinue study treatment 


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Table 3. 
Guidelines for ARRY-371797 (PF-07265803) Dose Modifications for 
Adverse Events 
 
Worst Observed Toxicity Grade 
(Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials) 
(unless noted otherwise) 
Dose Modifications for Study Treatment (Dose 
reduction should always be considered as an option before 
permanently discontinuing study intervention). 
Nausea, vomiting 
Grade 2 
>2 episodes (separated by 5 minutes) in 24 hours 
or some interference with activity 
If the event is non-persistent Grade 2, maintain dose level 
of study treatment and monitor until stabilization or 
resolution 
First occurrence: 
If the event is a persistent or intolerable Grade 2 AE not 
responsive to a specific therapy, interrupt study treatment 
for ≤21 days until resolved to Grade ≤1 then resume study 
intervention at current dose or at the next dose level. 
If resolution within 21 days is not reached, please contact 
the Medical Monitor 
Second occurrence: 
If the event is a persistent or intolerable Grade 2 AE not 
responsive to a specific therapy, interrupt study treatment 
for ≤21 days until resolved to Grade ≤1 then resume study 
intervention at the next lower dose level 
If resolution within 21 days is not reached, please contact 
the Medical Monitor 
Grade 3 
Prevents daily activity, requires outpatient IV 
hydration 
Interrupt study intervention until resolved to Grade ≤1. 
If the event resolves ≤21 days, then study treatment may be 
resumed at next lower dose level 
Grade 4 
Life-threatening consequences, urgent 
intervention indicated, eg, ER visit or 
hospitalization for hypotensive shock 
Permanently discontinue study treatment 
Headache 
Grade 2 
Repeated use of non-narcotic pain reliever 
>24 hours or some interference with activity 
If the event is non-persistent Grade 2, maintain dose level 
of study intervention and monitor until stabilization or 
resolution 
If the event is a persistent or intolerable Grade 2 AE not 
responsive to a specific therapy, interrupt study treatment 
for ≤21 days until resolved to Grade ≤1, then study 
treatment may be resumed at the current dose or at the next 
dose level. 
If resolution within 21 days is not reached, please contact 
the Medical Monitor 


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Table 3. 
Guidelines for ARRY-371797 (PF-07265803) Dose Modifications for 
Adverse Events 
 
Worst Observed Toxicity Grade 
(Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials) 
(unless noted otherwise) 
Dose Modifications for Study Treatment (Dose 
reduction should always be considered as an option before 
permanently discontinuing study intervention). 
Headache (cont.) 
Grade 3 
Significant; Any use of narcotic pain reliever or 
prevents daily activity 
Interrupt study intervention until resolved to Grade ≤1. 
First occurrence: 
If the event resolves ≤21 days, then study treatment may be 
resumed at the current dose level or at the next lower dose 
level 
If resolution within 21 days is not reached, please contact 
the Medical Monitor 
Second occurrence: 
If the event resolves ≤21 days, then study treatment may be 
resumed at next lower dose level 
If resolution within 21 days is not reached, please contact 
the Medical Monitor 
Grade 4 
ER visit or hospitalization 
Permanently discontinue study treatment 
Study intervention treatment-related adverse 
events 
Grade 2 
Moderate severity: Some interference with 
activity not requiring medical intervention 
If the event is non-persistent Grade 2, maintain dose level 
of study treatment and monitor until stabilization or 
resolution 
If the event is a persistent or intolerable Grade 2 AE not 
responsive to a specific therapy, interrupt study treatment 
for ≤21 days until resolved to Grade ≤1, then study 
treatment maybe resumed at the current dose or at the next 
lower dose level 
If resolution within 21 days is not reached, please contact 
the Medical Monitor 
Grade 3 
Severe severity: Prevents daily activity; requires 
outpatient medical intervention 
Interrupt study treatment until resolved to Grade ≤1 
First occurrence: 
If the event resolves ≤21 days, then study intervention may 
be resumed at the current dose level or at the next lower 
dose level 
If resolution within 21 days is not reached, please contact 
the Medical Monitor 
Second occurrence: 
If the event resolves ≤21 days, then study treatment may be 
resumed at next lower dose level 
If resolution within 21 days is not reached, please contact 
the Medical Monitor 


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Table 3. 
Guidelines for ARRY-371797 (PF-07265803) Dose Modifications for 
Adverse Events 
 
Worst Observed Toxicity Grade 
(Guidance for Industry: Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials) 
(unless noted otherwise) 
Dose Modifications for Study Treatment (Dose 
reduction should always be considered as an option before 
permanently discontinuing study intervention). 
Grade 4 
Potentially Life-threatening: Life-threatening 
consequences; urgent intervention indicated, eg, 
ER visit or hospitalization 
Permanently discontinue study treatment 
 
6.7. Intervention After the End of the Study 
Availability of ARRY-371797 (PF-07265803) following the study's closure through either a 
separate rollover extension protocol or expanded access/compassionate use, if the 
investigator and participant desire to continue treatment, would be at the discretion of the 
sponsor and subject to local conditions and regulations. 
 
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1. Discontinuation of Study Intervention 
It may be necessary for a participant to permanently discontinue study treatment . Reasons 
for permanent discontinuation of study treatment include the following: 
 
• Withdrawal of consent to treatment; 
• LVAD placement, cardiac transplant; 
• Unacceptable AE(s) or failure to tolerate study intervention; 
• Pregnancy or initiation of breastfeeding; 
• Protocol violation that, in the opinion of the investigator and/or sponsor, renders the 
participant unsuitable for further study intervention; 
 
• Study treatment interruption longer than 21 days, unless approved by medical monitor; 
• Discretion of investigator. 
Note that discontinuation of study treatment does not represent withdrawal from the study. If 
study treatment is permanently discontinued prior to the Week 24 visit, the participant will 
remain in the study to continue to have all assessments performed as scheduled through the 
Week 24 visit. Every effort should be made to obtain these data. All participants will 
subsequently be followed for OS, HF-related hospitalization and HF-related urgent care visits 


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approximately every 3 months via phone call until death, lost to follow-up, withdrawal of 
consent or initiation of the open-label treatment period, whichever occurs first (see 
Section 8.12). See the SoA for data to be collected at the time of discontinuation of study 
treatment and follow-up for any further evaluations that need to be completed. Every effort 
should be made to obtain these data. 
 
In the event of discontinuation of study treatment it must be documented on the appropriate 
CRF/in the medical records whether the participant is discontinuing further receipt of study 
intervention or also from study procedures, posttreatment study follow-up, and/or future 
collection of additional information. 
 
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request. Reasons for 
discontinuation from the study include the following: 
 
• Refused further follow-up; 
• Lost to follow-up; 
• Death; 
• Study terminated by sponsor. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
 
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. 
 
The participant will be permanently discontinued from the study intervention and the study at 
that time. 
 
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly. 
 
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations should be performed and no 
additional data should be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent. 
 
7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study treatment will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 


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exception to this is when a participant specifically withdraws consent for any further contact 
with him or her or persons previously authorized by the participant to provide this 
information. Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible. The withdrawal of consent should be 
explained in detail in the medical records by the investigator, as to whether the withdrawal is 
only from further receipt of study treatment or also from study procedures and/or 
posttreatment study follow-up, and entered on the appropriate CRF page. In the event that 
vital status (whether the participant is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law. 
 
7.2.2. Replacement of Participants 
Participants who discontinue prior to study completion will not be replaced. 
 
7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study; 
 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the participant’s medical record; 
 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
 
8. STUDY ASSESSMENTS AND PROCEDURES 
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated informed consent document before performing any study -specific procedures. 
 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
 
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
treatment. 


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Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
 
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
 
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the informed consent document may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified criteria 
and were performed within the time frame defined in the SoA. 
 
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these deviations from protocol-required tests 
and procedures in a timely manner. 
 
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study. 
 
8.1. Screening Assessments 
All participants must have confirmation of the presence of an eligible LMNA mutation by 
documentation from an accredited clinical laboratory before proceeding to screening. 
 
8.1.1. Participant Demographics and Other Baseline Characteristics 
Demographics, prior medications/therapies/procedures (including all prescription and 
nonprescription drugs, vitamins, and dietary or herbal supplements) that were 
administered/conducted within 35 days prior to Day 1, and current medications will be 
recorded. Past and present medical history considered by the investigator to be significant 
will also be recorded. 
 
8.1.2. Follicle-Stimulating Hormone 
Postmenopausal females under 60 years of age will be required to have a serum FSH 
measurement at the screening visit to assess childbearing potential. If the participant is 
postmenopausal and has high FSH level in the postmenopausal range at the screening visit, 
they are considered nonchildbearing and pregnancy tests will not be required during the 
study. 


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8.1.3. Human Immunodeficiency Virus, Hepatitis B, and Hepatitis C Serology 
All participants are required to have negative screening serology tests per central laboratory 
for HIV, hepatitis B surface antigen, and hepatitis C antibody to participate in the study. 
Participants with a screening serology positive for hepatitis C antibody must have a negative 
nucleic acid test to participate in the study. 
 
8.2. Efficacy Assessments 
For Class II and III participants, the 6MWT should be performed at approximately the same 
time of day at each study visit after the baseline visit and ideally, one of the first assessments 
to be performed. The PRO assessments should be performed before the 6MWT has been 
completed, starting with KCCQ, followed by the PGI assessments and ending with the EQ- 
5D-5L. The ECHO assessment should be performed after the 6MWT has been completed. 
For Class IV participants, the 6MWT is optional based on whether the participant is 
ambulatory or not and should only be completed if the investigator feels that the participant 
can complete the test without undue harm. 
 
Participants who discontinue study treatment prior to Week 24 should continue to have all 
efficacy assessments (PRO, 6MWT, ECHO) performed as scheduled through the Week 24 
visit. 
 
8.2.1. 6-Minute Walk Test 
The 6MWT will be performed at the time points specified in the SoA, including at screening, 
at the Day -1 visit and at the baseline visit (Day 1), using the methods described in the 
6MWT Study Manual based on the ATS Statement: Guidelines for the Six-Minute Walk 
Test.33 If the test is deemed unusable by the CPC Core Laboratory, the 6MWT will need to 
be repeated. The 6MWT is to be performed by all Class II and III participants, and as feasible 
for Class IV participants. The Borg fatigue scale will be administered before and after the 
walk distance assessment as part of the 6MWT. 
 
Sites will designate specific site staff to perform the 6MWT. Designated staff performing the 
6MWT will be required to complete initial 6MWT training prior to conducting any 6MWT 
for the trial. Refresher 6MWT training will be provided as needed. 
 
The 6MWT will be performed 3 times (screening, Day -1, and baseline) to confirm 
participant eligibility and establish the baseline value for the primary endpoint. The screening 
visit 6MWT must be performed at least 27 days prior to the Day -1 visit. The screening visit 
6MWT will ensure proper participant familiarization has occurred prior to the baseline 
assessment. The screening visit 6MWT must have a distance of >100 m but ≤450 m and the 
participant must be symptomatic for DCM per investigator judgment in order to remain 
eligible. The Day -1 and baseline visit (Day 1) 6MWTs must have distances of >100 m but 
≤485 m and the participant must be symptomatic for DCM per investigator judgment in order 
to remain eligible. The tests should be performed 1 day apart when possible and no more 
than 3 days apart. Calculation of change from baseline will be based on the average of the 
Day -1 and baseline visit (Day 1) 6MWT results. 


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8.2.2. Activity Monitoring 
An activity monitor will be placed on the participant’s wrist during the screening period and 
then worn continuously for the duration of the randomized study period in free-living 
conditions only if the participant agrees to wear the device. Wrist monitors are expected to 
be used only on ambulatory participants. 
 
Activity monitoring data will be collected continuously during the randomized study period 
capturing real-life activities and movement patterns. Participants who discontinue study 
treatment prior to Week 24 will continue to wear the activity monitor and will have all 
assessments performed as specified in the SoA through the Week 24 Visit. 
 
8.2.3. N-Terminal Pro-Brain Natriuretic Peptide 
Blood samples for analysis of NT-proBNP will be performed as part of the clinical chemistry 
sample collections at the time points specified in the SoA and will be measured by a central 
laboratory at screening and all subsequent time points. 
 
8.2.4. Echocardiogram 
The 2D ECHO complete with contrast, if available, will be performed by trained personnel at 
the time points specified in the SoA, including during screening. 
 
The screening ECHO will be performed at the local laboratory to determine eligibility and 
will only include assessment of LV: systolic and diastolic function; size, mass, and geometry. 
The results from the local laboratory will be used during screening to determine eligibility for 
the study (these are not submitted to the central laboratory). 
 
All the other assessments will be standard transthoracic 2D ECHOs (with contrast, if 
available, to optimize accuracy and precision of intracardiac measurements) and will include: 
 
• LV: systolic and diastolic function; size, mass, and geometry 
• RV size and function; pulmonary artery size 
• Left atrial dimensions, volumes, and pressures 
• Valvular (aortic, mitral, tricuspid, and pulmonary) stenosis and regurgitation 
(severity); TAPSE 
 
• PASP, IVC caliber 
8.2.5. Patient-Reported Outcomes 
8.2.5.1. Kansas City Cardiomyopathy Questionnaire (KCCQ) 
Participants will complete the KCCQ at the time points specified in the SoA. At each visit, 
the KCCQ should be completed prior to the other visit assessments. 


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The KCCQ measures the effects of symptoms, functional limitations, and psychological 
distress on an individual’s health-related quality of life. The KCCQ has 23 items which 
assess the ability to perform activities of daily living, frequency and severity of symptoms, 
the impact of these symptoms, and health-related quality of life. Response options vary by 
question. Domain scores are transformed to a 0 to 100 range; higher scores indicate better 
health status. 
8.2.5.2. Patient Global Impression 
Participants will rate the severity of their heart failure symptoms and physical activity 
limitations during the past week on the 2 Patient Global Impression-Severity (PGI-S) 
questions. Participants will rate the overall change (if any) in their heart failure symptoms 
and physical activity limitations since they began taking the study medication on the 2 
Patient Global Impression-Change (PGI-C) questions. The PGI-S will be completed first 
followed by the PGI-C after completing the KCCQ. Participants will complete the PGI-S and 
the PGI-C at the time points specified in the SoA. These data will be used to provide an 
anchor to define thresholds for improvements in KCCQ. 
 
8.2.5.3. EuroQoL EQ-5D-5L 
The EQ-5D-5L (5 levels version) is a brief, self-administered generic health status instrument 
that takes approximately 5 minutes to complete.34 The instrument consists of two parts. In the 
first part, respondents are asked to rate their current health state on 5 dimensions (mobility, 
self-care, usual activities, pain or discomfort, and anxiety or depression) with each dimension 
having five levels of function ranging from “No problem” to “Extreme problems.” The 
scores from the five dimensions may be used to calculate a single index value, also known as 
a utility score. On the second part respondents rate their current health state on a Visual 
Analog Scale (EQ-5D VAS) with endpoints labeled “best imaginable health state” (score of 
100) and “worst imaginable health state” (score of 0). 
 
Participants will complete the EQ-5D-5L as specified in the SoA. Participants should 
complete the EQ-5D-5L after the Patient Global Assessment questionnaires. 
 
8.2.6. Assessment of Composite Endpoint of All-Cause Mortality or Worsening Heart 
Failure (HF-Related Hospitalization or HF-Related Urgent Care Visits) 
All HF-related hospitalization and urgent outpatient visits will be collected during the study. 
Inpatient hospitalizations are to be reported as SAEs per Appendix 3 and Section 8.4.1 and 
all outpatient urgent care, and ER visits less than 24 hours must be recorded on the urgent 
outpatient/ER visit eCRF form. 
 
All necessary documentation must be submitted for adjudication (see Section 9.6). 
Supportive documentation requested for adjudication may include the following: hospital 
discharge summary, chest X-ray report, prescription sheets/medication administration 
records, ECHO report, relevant laboratory reports (eg, for peak BNP/NT-proBNP), and 
reports for other investigations undertaken (eg, cardiac MRI, radionuclide ventriculogram 
scan, pulmonary artery catheterization). 


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If study treatment is discontinued prior to the Week 24 visit, the participant will remain in the 
study to continue to have all assessments performed as scheduled through the Week 24 visit. 
Every effort should be made to obtain these data. All participants will subsequently be 
followed for survival status, HF-related hospitalization and HF-related urgent care visits (see 
Section 8.12) approximately every 3 months via phone call until death, lost to follow-up, 
withdrawal of consent, or initiation of the open-label treatment period. Every effort should 
be made to obtain these data. 
 
8.3. Safety Assessments 
Planned time points for all safety assessments are provided in the SoA. Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues. 
 
8.3.1. Medical History 
Significant (at the investigator’s discretion) past and present medical history will be recorded 
at the screening and baseline visits only. Any history of use of tobacco, alcohol, and drugs of 
abuse will be recorded at the screening visit. Any history of muscular dystrophy including 
Limb-girdle MD type 1B (LGMD1B), autosomal dominant Emery-Dreifuss MD/EDMD2, 
congenital muscular dystrophy should be recorded. Any ongoing condition observed prior to 
the initiation of study intervention will be recorded as medical history. Any new condition or 
worsening of a pre-existing condition during study conduct after the start of study 
intervention or at any time after consent, if thought to be related to a study procedure, will be 
recorded as an AE. 
 
8.3.2. Physical Examinations 
Physical examinations (either a complete or brief physical examination) will be performed by 
trained medical personnel at the time points specified in the SoA. 
 
Both the complete and brief physical examinations should carefully evaluate the 
cardiovascular and pulmonary system, including but not limited to peripheral pulses, edema, 
breathing, jugular venous distension, and/or other signs of worsening HF. A complete 
physical examination, including height and body weight measurements, will be performed at 
the screening visit. 
 
• Complete physical examination: General physical well-being will be assessed by 
evaluation of HEENT, neck, back (including renal assessment), cardiovascular 
(including peripheral pulses, edema, breathing, jugular venous distension, and/or 
other signs of worsening HF), lungs, abdomen (including liver, spleen, bowel 
sounds), lymph nodes, musculoskeletal system (including spine, joints, muscles, 
bursae), neurological system (including cranial nerves, reflexes, sensation, strength), 
skin (including nails and hair), and other conditions of note. Signs or symptoms of 
muscular dystrophy should be specifically noted. 


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A brief physical examination, including body weight measurement, will be performed at all 
other visits, but may include further evaluation if any areas of concerns are identified. 
 
• Brief physical examination: General physical well-being will be assessed by brief 
evaluation of the skin, HEENT, cardiovascular (including peripheral pulses, edema, 
breathing, jugular venous distension, and/or other signs of worsening HF), lungs, 
abdomen, extremities, new-onset or worsening of muscular dystrophy and other 
conditions of note. 
 
All physical examinations occurring on dosing days must be performed prior to study 
intervention administration. Any treatment-emergent abnormal findings will be recorded as 
AEs. 
 
8.3.3. Vital Signs 
Vital signs (BP, PR, respiratory rate, and temperature) will be measured by trained medical 
personnel at the time points specified in the SoAs, including the screening visit and the 
baseline visit (Day 1). 
 
Sitting BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after 5 minutes of rest. The participant's back should be 
supported and feet on the floor. The same arm (preferably the dominant arm) will be used 
throughout the study. The same size BP cuff and method (automated or manual), which has 
been properly sized and calibrated, will be used to measure BP throughout the study. The use 
of automated devices for measuring BP and PR is preferred; when done manually, PR will be 
measured in the brachial or radial artery for at least 30 seconds. 
 
8.3.4. Arrhythmia Assessment 
An arrhythmia assessment will be performed at the time points specified in the SoA. 
 
Incidence of new discharge, conduction system disease, supraventricular or ventricular 
arrhythmias will be assessed by an ICD/CRT-D applicable device interrogations. ECG values 
of potential clinical concern are listed in Appendix 6. The assessment of the results will be 
completed by the PI or delegate and the assessment will include any interrogations performed 
in between study visits. In the scenario where patient’s device was interrogated between 
visits, results of the reading should be recorded for the period. Results will be analyzed and 
recorded. 
 
8.3.5. Electrocardiograms 
Standard 12-lead ECGs utilizing limb leads (with a 10 second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the heart rate and measures PR, QT, and QTcF intervals and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) will 
not be used given the potential risk of discrepancies with ECGs acquired using standard limb 
lead placement. All scheduled ECGs should be performed after the participant has rested 
quietly for at least 5 minutes in a supine position. 


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ECG data will be submitted to a central laboratory for measurement. The final ECG report 
from the central laboratory should be maintained in the participant’s source documentation 
and be the final interpretation of the ECG recording. Any clinically significant changes from 
the baseline/Day 1 ECG may potentially be AEs (Appendix 6) and should be evaluated 
further, as clinically warranted. 
 
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read 
QTcF value is prolonged, repeat measurements may not be necessary if a qualified medical 
provider’s interpretation determines that the QTcF values are in the acceptable range. 
 
When ECGs are to be performed at the same visits as study intervention administration, 
blood collection and/or vital sign measurements, ECGs should be performed first. Abnormal 
ECGs may be repeated at the investigator’s discretion. Details regarding ECG procedures 
and transmittals will be provided in an ECG Manual. 
 
ECG values of potential clinical concern are listed in Appendix 6. 
 
8.3.6. Clinical Safety Laboratory Assessments 
A central laboratory will be used to analyze all blood and urine samples collected at 
screening and throughout the study for hematology, clinical chemistry, and urinalysis 
laboratory tests. Information on the collection of blood and urine samples and their shipment 
to the central laboratory will be outlined in the Laboratory Manual. 
 
Local site laboratories may be utilized, in addition to the central laboratory, if more rapid 
results are required for treatment decisions or participant safety. If a local site laboratory 
sample is taken, then part of the blood sample obtained for local site laboratory assessment 
should also be sent to the central laboratory for analysis. Local site laboratory results 
obtained during the study will only be captured in the eCRF if the investigator determines 
they are needed to clarify why a treatment decision was made or an AE was recorded. 
 
All blood and urine laboratory test collections must be performed prior to study intervention 
dosing. 
 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues. Results should be recorded on the Unscheduled Lab 
eCRF. 
 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
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the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition. 
 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or medical monitor. 
 
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified. 
 
See Appendix 5 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury. 
 
8.3.7. Pregnancy Testing 
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL. Pregnancy tests will be performed in WOCBP at the times listed in the SoA. 
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior to the participant’s receiving the study intervention. Pregnancy tests will also be done 
whenever 1 menstrual cycle is missed during the active treatment period (or when potential 
pregnancy is otherwise suspected) and at the end of the study. Pregnancy tests may also be 
repeated if requested by IRBs/ECs or if required by local regulations. 
 
All WOCBP are required to undergo a serum pregnancy assessment at screening and urine 
pregnancy assessments during the study at the time points specified in the SoA. Any positive 
test will result in immediate cessation of study intervention administration. 
 
All urine collections for pregnancy tests must be performed and assessed prior to study 
intervention dosing. A negative result should be confirmed and documented in source 
documents and in EDC. 
 
During the double-blind period, an at-home urine pregnancy testing kit with a sensitivity of 
at least 25 mIU/mL will be used by all WOCBP to perform a urine pregnancy test starting at 
Week 72 and then every subsequent 24 weeks. The pregnancy test outcome is documented 
in the participant’s source documents/medical records. If the pregnancy test is positive, the 
EDP should be reported (Section 8.4.5). Confirm that the participant is adhering to the 
contraception method(s) required in the protocol. 
 
8.4. Adverse Events and Serious Adverse Events 
The definitions of an AE and an SAE can be found in Appendix 3. 
 
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc.). 


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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
 
During the active collection period as described in Section 8.4.1, each participant will be 
questioned about the occurrence of AEs in a nonleading manner. 
 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion. 
 
8.4.1. Time Period and Frequency for Collecting AE and SAE Information 
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving study intervention), through and including a 
minimum of 30 calendar days, after the last administration of the study intervention. 
 
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator. 
 
For participants who are screen failures, the active collection period ends when screen failure 
status is determined. 
 
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn. 
 
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form. 
 
Investigators are not obligated to actively seek AEs or SAEs after the participant has 
concluded study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has completed the study, and he/she considers the event 
to be reasonably related to the study intervention, the investigator must promptly report the 
SAE to Pfizer using the CT SAE Report Form. 
 
All participants will be followed for survival follow-up after a participant discontinues study 
intervention. During the survival follow-up period, survival status, and HF-related 
hospitalizations and HF-related urgent care visits will be assessed approximately every 
3 months via phone call until death, lost to follow-up, or withdrawal of consent. HF-related 
hospitalizations and HF-related urgent care visits reported during the survival follow-up 
period are to be recorded on the HF-related hospitalization CRF. SAEs occurring after the 
active reporting period has ended should be reported to the sponsor promptly if the 


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investigator considers the event to be reasonably related to the study intervention. See 
Section 8.12 for event follow-up during the survival follow-up period. 
 
8.4.1.1. Reporting SAEs to Pfizer Safety 
All SAEs occurring in a participant during the active collection period as described in 
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
 
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF 
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.3.1, will be recorded 
on the AE section of the CRF. 
 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant. 
 
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4. 
 
8.4.2. Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3. 
 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
 
8.4.3. Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3). 
 
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
 
Further information on follow-up procedures is given in Appendix 3. 


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8.4.4. Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met. 
 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators. 
 
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
 
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements. 
 
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure 
Environmental exposure, occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include exposure during pregnancy, exposure during 
breastfeeding, and occupational exposure. 
 
Any such exposure to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness. 
 
8.4.5.1. Exposure During Pregnancy 
An EDP occurs if: 
 
• A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 
 
• A male participant who is receiving or has discontinued study intervention exposes a 
female partner prior to or around the time of conception. 
 
• A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure. Below are examples of 
environmental exposure during pregnancy: 
 
• A female family member or healthcare provider reports that she is pregnant after 
having been exposed to the study intervention by ingestion. 


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• A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then exposes his female 
partner prior to or around the time of conception. 
 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 
 
• If EDP occurs in a participant or a participant’s partner, the investigator must report 
this information to Pfizer Safety on the CT SAE Report Form and an EDP 
Supplemental Form, regardless of whether an SAE has occurred. Details of the 
pregnancy will be collected after the start of study intervention and until 30 days after 
the last dose of study intervention for female participants and until 30 days after last 
dose of study intervention for male participants. 
 
• If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form is maintained in the investigator site file. 
 
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP Supplemental Form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported). 
 
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly [in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death]), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 
 
• Spontaneous abortion including miscarriage and missed abortion; 
• Neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs. In addition, infant deaths after 1 month should be 
reported as SAEs when the investigator assesses the infant death as related or 
possibly related to exposure to the study intervention. 


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Additional information regarding the EDP may be requested by the sponsor. Further follow 
up of birth outcomes will be handled on a case-by-case basis (eg, follow up on preterm 
infants to identify developmental delays). In the case of paternal exposure, the investigator 
will provide the participant with the Pregnant Partner Release of Information Form to deliver 
to his partner. The investigator must document in the source documents that the participant 
was given the Pregnant Partner Release of Information Form to provide to his partner. 
 
8.4.5.2. Exposure During Breastfeeding 
An exposure during breastfeeding occurs if: 
 
• A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention. 
 
• A female is found to be breastfeeding while being exposed or having been exposed to 
study intervention (ie, environmental exposure). An example of environmental 
exposure during breastfeeding is a female family member or healthcare provider who 
reports that she is breastfeeding after having been exposed to the study intervention 
by ingestion, inhalation or skin contact. 
 
The investigator must report exposure during breastfeeding to Pfizer Safety within 24 hours 
of the investigator’s awareness, irrespective of whether an SAE has occurred. The 
information must be reported using the CT SAE Report Form. When exposure during 
breastfeeding occurs in the setting of environmental exposure, the exposure information does 
not pertain to the participant enrolled in the study, so the information is not recorded on a 
CRF. However, a copy of the completed CT SAE Report Form is maintained in the 
investigator site file. 
 
An exposure during breastfeeding report is not created when a Pfizer drug specifically 
approved for use in breastfeeding women (eg, vitamins) is administered in accord with 
authorized use. However, if the infant experiences an SAE associated with such a drug, the 
SAE is reported together with the exposure during breastfeeding. 
 
8.4.5.3. Occupational Exposure 
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the CT SAE Report Form, regardless of whether 
there is an associated SAE. Since the information about the occupational exposure does not 
pertain to a participant enrolled in the study, the information is not recorded on a CRF; 
however, a copy of the completed CT SAE Report Form must be maintained in the 
investigator site file. 
 
 
8.4.6. Cardiovascular and Death Events 
See sections 8.2.6 and 8.3.4. 


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8.4.7. Disease -Related Events and/or Disease -Related Outcomes Not Qualifying as AEs 
or SAEs 
Not applicable. 
 
8.4.8. Adverse Events of Special Interest 
Not applicable. 
 
8.4.8.1. Lack of Efficacy 
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to 
Pfizer Safety only if associated with an SAE. 
 
8.4.9. Medical Device Deficiencies 
Not applicable. 
 
8.4.10. Medication Errors 
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
 
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors. 
 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness 
Medication errors 
All (regardless of whether 
associated with an AE) 
Only if associated with an SAE 
 
Medication errors include: 
 
• Medication errors involving participant exposure to the study intervention; 
• Potential medication errors or uses outside of what is foreseen in the protocol that do or 
do not involve the study participant. 
 
In the event of a medication dosing error, the sponsor should be notified within 24 hours. 
 
If applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of 
the CRF. 
 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE. 


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8.5. Treatment of Overdose 
For this study, any dose of ARRY-371797 (PF-07265803) greater than 800 mg within a 
24-hour time period will be considered an overdose. 
 
The sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the investigator/treating physician should: 
1. Contact the medical monitor within 24 hours. 
 
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities 
for at least 5 half-lives or 28 calendar days after the overdose of ARRY-371797 
(PF-07265803) (whichever is longer). 
 
3. Document the quantity of the excess dose as well as the duration of the overdose 
in the CRF. 
 
4. Overdose is reportable to Pfizer Safety only when associated with an SAE. 
 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant. 
 
8.6. Pharmacokinetics 
Venous blood samples for measurement of plasma concentrations of ARRY-371797 (PF- 
07265803) and metabolites will be drawn at the following times/visits as specified in the 
SoA. 
 
• Baseline: predose 
• Week 4: predose 
• Week 8: predose and 2 samples, approximately 1.5 hours (± 1 hours) postdose and at 
least 15 minutes apart 
 
• Week 12: predose and 5 hours (± 1 hour) postdose 
• Week 24: predose and 5 hours (± 1 hour) postdose 
• Treatment Discontinuation Visit: Any time during clinic visit 
All Class II/III participants will have PK blood samples collected during the randomized, 
double-blind period. Class IV participants will have PK blood samples drawn during the 
baseline and Weeks 4, 8, 12, and 24 visits if the participant is ambulatory and has clinic visits 
on the specified nominal week visits. A PK blood sample will be drawn at any time during 
clinic visit, but after vital sign measurement during the treatment discontinuation visit if 
discontinuation occurs prior to the randomized, double-blind period Week 24 visit (as 


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feasible for Class IV participants). No PK blood samples will be collected during the ARRY- 
371797 (PF-07265803) open -label treatment period or after Week 24 of the randomized, 
double-blind period. 
 
The date and actual time of each PK blood sample, both prior to and after dose, should be 
recorded. In addition to analyses of ARRY-371797 (PF-07265803), AR00420643, 
AR00428028, and AR00486705, 
Results and analytical 
methodologies from this analysis will be described in a separate standalone report, if deemed 
appropriate. 
 
Study visits for PK sampling should be scheduled in the morning so that a proper predose PK 
blood sample can be collected. On these visit days, the morning dose of study intervention 
should be taken at the study site, only after collecting the predose PK sample. Predose 
sampling information should include the date and actual time of the previous evening dose 
(except Day 1), including the dose amount taken. Postdose sampling information should 
include the date and actual time of the morning dose, including the dose amount taken. 
 
For days when PK blood samples are to be drawn, the predose sample (except Day 1) should 
not be collected if the participant has missed 3 or more consecutive doses of ARRY-371797 
(PF-07265803) prior to sample collection and the postdose sample should only be collected if 
the participant takes the intended morning dose on the day of PK sampling. Deviations 
related to this should be recorded in the eCRF. 
 
Complete instructions for sample processing, handling and shipment will be provided in the 
Laboratory Manual. 
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8.8. Genetics 
8.8.1. Lamin A/C Genetic Testing 
Participants will be eligible for the study based on results from an accredited clinical 
laboratory findings of a pathogenic, likely pathogenic, or VUS LMNA gene mutation 
following applicable regional genetic variant interpretation guidelines. The sponsor offers the 
option of using a central clinical laboratory to perform the sample analysis to verify 
eligibility. 
 
At Day 1, a 2 mL blood sample for potential LMNA in vitro diagnostic development will be 
collected for participants who did not use the central laboratory to verify eligibility. 
 
Complete instructions for sample collection, handling, and shipment will be provided in the 
Laboratory Manual. 
8.9. Biomarkers 
Biomarkers other than those listed in Sections 8.2.3 and 8.7 are not evaluated in this study. 
 
8.10. Immunogenicity Assessments 
Immunogenicity assessments are not included in this study. 
 
8.11. Health Economics 
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study. 
 
8.12. Survival Follow-up 
If study treatment is discontinued prior to the Week 24 visit, the participant will remain in the 
study to continue to have all assessments performed as scheduled through the Week 24 visit. 
Every effort should be made to obtain these data. All participants will subsequently be 
followed for survival status, HF-related hospitalizations and HF-related urgent care visits 
approximately every 3 months via phone call until death, lost to follow-up, or withdrawal of 
consent, or initiation of the open-label treatment period. 
 
HF-related hospitalizations and HF-related urgent care visits reported during the survival 
follow-up period are to be recorded on the HF-related hospitalization CRF. SAEs occurring 
after the active reporting period has ended should be reported to the sponsor promptly if the 
investigator considers the event to be reasonably related to the study intervention (see 
Section 8.4.1). 
 
Phone calls are acceptable when clinic visits are not already performed. Vital status may be 
ascertained from family, caregivers, or public records, where appropriate. All CV therapies 
and interventional treatments started during the survival follow-up period must be recorded 
on the post double-blind CV treatment and CV surgical and medical procedure eCRF. 


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9. STATISTICAL CONSIDERATIONS 
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a SAP, which will be maintained by the sponsor. The 
SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions or their analyses will also be reflected in a 
protocol amendment. 
 
9.1. Estimands and Statistical Hypotheses 
For the primary endpoint, the null hypothesis is that the treatment groups for ARRY-371797 
(PF-07265803) and placebo do not differ with respect to functional capacity. The alternative 
hypothesis of interest is that there is a difference in functional capacity in favor of ARRY- 
371797 (PF-07265803). Functional capacity will be measured by change from baseline in 
6MWT at Week 24 with a rank-based test to account for deaths or withdrawals prior to 
Week 24. ARRY-371797 (PF-07265803) will be declared superior to placebo if the null 
hypothesis of no difference between ARRY-371797 (PF-07265803) and placebo is rejected 
at the significance level of 0.05 (2-sided). 
 
The testing strategy controls Type I error across primary and selected secondary endpoints. If 
the van Elteren test of the primary endpoint, is found to be statistically significant at 
0.05 (2sided) alpha, then a pre-specified hierarchical order for testing the secondary 
endpoints of Week 24 changes from baseline in the KCCQ domains of PL score and TSS, the 
composite endpoint consisting of all-cause mortality or worsening heart failure (HF-related 
hospitalization or HF-related urgent care visit), and the Week 24 change from baseline in 
NT-proBNP, each at the 0.05 level, will be used to maintain the overall alpha at 0.05. 
 
9.1.1. Estimands 
The primary objective of the study is to evaluate the effect of ARRY-371797 (PF-07265803) 
on functional capacity as measured by the 6MWT compared to placebo in patients with 
symptomatic LMNA-related DCM. Per protocol, participants who discontinue study 
treatment prior to Week 24 will continue to have all assessments performed as scheduled 
through the Week 24 Visit. All data collected during the study will be included for the 
analyses of efficacy regardless of discontinuation of study treatment or study drug 
interruption. 
 
9.2. Sample Size Determination 
Following a pre-specified blinded sample size re-estimation, at least 160 Class II and III 
participants will be included in the efficacy analysis set (EAS). In addition, up to 40 Class 
IV participants may be enrolled (randomized 1:1 to PF‑07265803 and placebo). CCI 
 
 
 
 
 
Sample size estimation was initially determined based on a change from baseline in 6MWT 
at Week 12. Following a protocol amendment to update the primary endpoint to change from 


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baseline in 6MWT at Week 24, the same assumptions were applied given the protocol 
requirement for participants who discontinue study treatment to continue with follow-up 
through at least Week 24 and the anticipated low mortality rate within the study population. 
Sample size and assumptions prior to the pre-specified blinded sample size re-estimation are 
outlined below. The blinded sample size re-estimation was performed by an internal team 
who are not directly involved with the day-to-day activities of the study. To ensure the 
integrity of the trial the specific assumptions resulting in the increase in sample size will not 
be disclosed until the time of primary reporting. 
 
With 60 participants per treatment arm for the primary evaluation of efficacy the study will 
have approximately 90% power to demonstrate a statistically significant effect for the 
primary endpoint of Week 24 6MWT change from baseline, at a 2 sided α=0.05 if the true 
treatment effect is 35 m, there is a SD of 50 m for the change from baseline and 10% of 
participants do not have data recorded at Week 24. This assessment was made by simulation 
and further assuming that: 
• The correlation between the baseline and Week 24 values for the 6MWT is 0.44 as 
observed in a previous study. 
• Data are analyzed using a stratified Wilcoxon Rank-sum test with participants 
stratified into 4 groups according to baseline quartile of 6MWT. 
• 1.25% of participants die before Week 24 and are given the worst set of ranks ordered 
according to their survival time. 
• The participants who are alive and who do not have data recorded at Week 24 are 
given a tied ranking worse than any participant with data recorded and better than any 
participant who died before Week 24. 
• The probability of dropout is related to outcome so that dropout is half as likely for 
participants with Week 24 6MWT values more than one standard deviation (SD) 
above the mean compared to participants one SD below the mean. 
• An interim futility analysis will be performed after the first 60 randomized NYHA 
Class II/III participants from the EAS population have completed the Week 12 
assessment or have discontinued prior to Week 12. 
 
As noted in Section 9.5, blinded data at the time of the interim analysis were utilized to 
evaluate the rates of deaths and study discontinuation prior to Week 24, and the standard 
deviation for the change from baseline in 6MWT at Week 24 to allow for a reassessment of 
the sample size. Following a planned blinded sample size re-estimation, up to 200 eligible 
participants with symptomatic cardiomyopathy due to LMNA will be randomized, including 
at least 160 participants with NYHA functional Class II or III and up to 40 participants with 
NYHA functional Class IV. 


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9.3. Analysis Sets 
For purposes of analysis, the following analysis sets are defined: 
 
Participant Analysis Set 
Description 
Full Analysis Set (FAS) 
The FAS will consist of all randomized participants. 
Participants in the FAS will be analyzed according to the 
treatment to which they were randomized. 
Efficacy Analysis Set 
(EAS) 
The EAS will include all NYHA functional Class II or III 
randomized participants. Participants will be analyzed 
according to the treatment to which they were randomized. 
CCI 
Safety Analysis Set (SAS) 
The SAS will include all participants who received at least 
one dose of study intervention regardless of NYHA 
functional class. Participants will be analyzed according to 
the initial treatment and dose received. This analysis set will 
be used for the WHF, all-cause mortality, and safety 
endpoints. 
Pharmacokinetic Analysis 
Set 
The PK set will consist of all participants who receive at least 
one dose of PF-07265803 and have at least one quantifiable 
postdose PK blood collection with associated valid 
bioanalytical results. 
 
9.4. Statistical Analyses 
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints. 
 
9.4.1. General Considerations 
Endpoints will be summarized by ARRY-371797 (PF-07265803) and placebo groups. 
Unless otherwise stated, the primary presentation of efficacy analyses will be based on the 
EAS. The primary analysis will be performed when all randomized participants in the 
efficacy population have had the opportunity to be followed for at least 24 weeks and an 
evaluation of the composite endpoint comprised of all-cause mortality and worsening heart 
failure (HF-related hospitalization or HF-related urgent care visit) is performed. 


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9.4.2. Primary Endpoint(s) 
9.4.2.1. Primary Efficacy Analysis of Change From Baseline in 6MWT at Week 24 
The change from baseline (based on the average of the Day -1 and baseline visit 6MWT 
results) in 6MWT at Week 24 will be analyzed in the NYHA Class II/III participants using 
the van Elteren test, a rank-based non-parametric approach. ARRY-371797 (PF-07265803) 
will be declared superior to placebo if the null hypothesis of no difference between ARRY- 
371797 (PF-07265803) and placebo is rejected at the significance level of 0.05 (2-sided). 
The p-value will be supplemented with a stratified win ratio statistic (and 95% CI) based on 
the same ranking rules. 
 
Two additional summaries will be provided to interpret the van Elteren test. 
 
• In analyzing the contribution of death and discontinuation components to the primary 
efficacy analysis, the summaries on number of deaths and discontinuations from 
study prior to Week 24, and the reasons for withdrawals from study will be provided. 
It is expected that the death rates will not be negatively affected by the active 
treatment. 
 
• A stratified Hodges-Lehmann (HL) estimator of the treatment difference (with 95% 
CI) will be used to describe the treatment effect on the change from baseline in 
6MWT at Week 24. Missing data at Week 24 due to issues outside of the study (eg, 
COVID-19) will be imputed based on a MAR assumption. Missing data at Week 24 
for discontinuation due to post randomization events (eg, AEs or perceived lack of 
efficacy) will be imputed using control-based multiple imputation. Imputations 
following death will not be utilized as imputed values for participants who died prior 
to the assessment timepoint would not be interpretable. 
 
For participants with observed 6MWT at Week 24, actual values and change from baseline at 
Week 24 will be summarized using descriptive statistics (N, mean, SD, median, Q1, Q3, 
minimum, and maximum) by treatment. An empirical cumulative distribution function 
(eCDF) plot of change from baseline in 6MWT at Week 24 will also be generated for those 
participants with observed 6MWT at Week 24. 
 
For purposes of determining the p-value from the van Elteren test as well as an estimate of 
the win-ratio and corresponding confidence interval, data will be ranked as follows ordered 
from lowest (worst) to highest rank. 
 
• Participants who die before Week 24 will be given the lowest set of ranks ordered 
from shortest to longest survival time. Note that participants who have discontinued 
from study and then died prior to Week 24 are ranked based on survival time, instead 
of time to study discontinuation. 
 
• Participants who are alive at last contact but discontinued the study prior to Week 24, 
and do not have a Week 24 6MWT completed, will be ranked next, ordered based on 


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their time to discontinuation. These participants are defined as ‘dropouts’ for the 
purpose of describing the analyses. 
 
• Participants who remain in the trial at or beyond Week 24 but who have a missing 
Week 24 6MWT (eg, due to COVID-19) will have missing values imputed for the 
endpoint using the method of MCMC MI assuming a multivariate normal distribution 
over all variables included in the imputation model. This imputation will be done by 
treatment group with number of days on treatment, baseline values, and values 
observed at Weeks 4, 12, 24, and 36 included in the imputation. For participants who 
do not die or discontinue the study prior to Week 24 but have monotone missing data 
and subsequently discontinue the study at a later timepoint, missing data will be 
imputed under MAR for those who discontinue due to issues outside of the study (eg, 
due to COVID-19) and imputed using control-based MI for those who 
discontinuation due to post randomization events (eg, AEs or perceived lack of 
efficacy). 
 
• The imputed values from those with the missing assessment will be used along with 
the observed values from all other participants to rank the remaining participants 
from greatest reduction (change less than 0) in Week 24 6MWT to greatest increase. 
 
In all 6MWT analyses, baseline will be calculated as the average of the non-missing 6MWT 
assessments recorded at assessment Day -1 and baseline (prior to randomization). 
 
The van Elteren test, which is a stratified extension of the Wilcoxon Rank Sum Test and the 
stratified win ratio will be calculated on each imputed dataset. The results from these 
multiple datasets will be pooled for overall inference in a way that account for the variability 
between imputations based on Rubin’s rule. In the van Elteren test, each stratum is weighted 
by 1/(nk + 1), where nk denotes the total number of participants in stratum k. The statistical 
significance of Week 24 6MWT will be based on the asymptotic, continuity corrected p- 
value. 
 
Participants will be placed into one of 4 strata according to the quartiles of baseline 6MWT 
as follows: 
 
Participants will be included in stratum one if their overall rank is ≤0.25*n. Participants will 
be included in stratum two if their overall rank is ≤0.5*n and >0.25*n 
Participants will be included in stratum three if their overall rank is ≤0.75*n and >0.5*n 
Participants will be included in stratum four if their overall rank is >0.75*n 
where n is the total number of participants in the EAS. 
 
The change from baseline in 6MWT at Week 4 and Week 12 will be analyzed descriptively 
using the same methods and ranking algorithm replacing Week 24 with the corresponding 
time point. 


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9.4.2.2. Sensitivity Analyses 
For the primary endpoint, sensitivity analyses will be performed to assess the robustness of 
the primary analysis result under different assumptions. . Full details will be provided in the 
SAP. 
 
9.4.3. Secondary Endpoint(s) 
9.4.3.1. Kansas City Cardiomyopathy Questionnaire Domains of TSS and PL 
The TSS, CSS, PL Score, and OSS of the KCCQ will be summarized at both Weeks 12 and 
24 using the same method as described for the primary endpoint analysis. The HL estimates 
and associated 95% CIs will be presented and constructed in the same way as used for 
6MWT. However, only TSS and the PL score will be included in the formal testing 
hierarchy. 
 
Additionally, participants will be defined as having improved for PL and TSS at Week 24 if 
their score improves (increases) by a predefined threshold versus baseline at Week 24. In 
this analysis, missing data due to death or discontinuation from study will be considered a 
nonresponse by setting the endpoint to nonresponsive. The proportion of participants with an 
improvement will be analyzed using the Cochran-Mantel-Haenzel chisquare test with the 
stratification factors used at randomization. The stratification factor for P/LP or VUS may be 
removed if there is insufficient number of events in the stratum. Percentage of participants 
responding in each arm will be summarized using exact binomial 95% CIs.35 The predefined 
threshold will be defined in the SAP prior to unblinding of the database. 
 
Descriptive statistics of the KCCQ domains over time will also be provided. 
 
The eCDF plots of change from baseline in PL and TSS at Week 24 will be provided for 
participants who completed the KCCQ at Week 24. 
 
9.4.3.2. Patient Global Impression Scores 
After completion of the KCCQ, participants will be asked about their PGI-S and their PGI-C. 
For PGI-S, at each visit the proportion of participants with at least a one category and at least 
a 2 category improvement will be summarized at each visit by treatment arm. For PGI-C, at 
each visit the proportion of participants who describe their change in overall status as 
moderately or very much better and very much better will be summarized by treatment arm. 
 
PGI-S and PGI-C data will also be used to interpret improvement thresholds for TSS and PL 
based on a blinded assessment, performed prior to unblinding of data within this study. The 
thresholds will be defined by correlating changes in TSS and PL with changes in PGI-S and 
PGI-C. 
 
9.4.3.3. Change From Baseline in N-terminal Pro-Brain Natriuretic Peptide at Weeks 4, 
12, and 24 
As part of the hierarchical testing strategy, the change from baseline of Week 4, 12, and 24 
NT-proBNP will be analyzed separately using the same method as described for the analysis 


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of 6MWT handling deaths and dropouts in the same way. Likewise, HL estimates and 
associated 95% CIs will be presented and constructed in the same way as used for 6MWT. 
Only the 24-week endpoint will be alpha controlled. 
 
9.4.3.4. The Composite Endpoint of Time to First Occurrence of All-Cause Mortality or 
Worsening Heart Failure (HF-related hospitalization or HF-related urgent care visit) 
An episode of worsening heart failure is either a hospitalization or an urgent visit for heart 
failure confirmed by the CEC as per the criteria in Appendix 9. 
 
The composite endpoint measures the time from randomization to the first occurrence of 
death from any cause, or worsening heart failure defined as HF-related hospitalization or a 
HF-related urgent care visit and will include all data recorded while the participant is on 
study, including while in follow-up. Participants will be censored at the latest time they are 
known to be alive and have not been treated for a confirmed worsening heart failure 
adjudicated event. The composite endpoint will be summarized using the Kaplan-Meier 
method and compared between treatment groups using a stratified Cox model using the strata 
as assigned at randomization and treatment arm as the covariate. The stratification factor for 
P/LP or VUS may be removed if there is insufficient number of events in the stratum. The 
upper confidence limit of a 2-sided 90% CI for the HR will be compared, using the SAS, to a 
value of 2 to rule out an excess risk. A 95% CI will also be presented. 
 
Additionally, analyses of hospitalization for HF and urgent HF visit will be performed to 
examine the contribution of each component of the composite endpoint. 
 
9.4.3.5. Overall Survival 
Overall survival is defined as time from randomization until death due to any cause. 
Participants who do not have a death date by the data cut-off date will be censored for OS at 
their last contact date. Overall survival will be calculated for all participants and summarized 
by treatment arm using the Kaplan-Meier method and compared between treatment arms 
using a stratified Cox model based on the strata as assigned at randomization and treatment 
arm as the covariate. 
 
The primary analysis of OS will be based on the SAS and supportive analyses will be 
performed using the EAS and the FAS. 
 
9.4.3.6. Safety Analysis 
All participants who receive at least one dose of study intervention will be included in the 
safety analyses. 
 
9.4.3.6.1. Adverse Events 
AEs will be coded using MedDRA. Incidence tables of participants with AEs will be 
presented for all AEs by maximum severity, serious AEs, AEs assessed as related to study 
intervention, and AEs resulting in discontinuation of study intervention. 


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9.4.3.6.2. Other Secondary Safety Endpoints 
The nature and frequency of arrhythmias will be tabulated for analysis. Changes in ECG and 
laboratory measurements will be summarized using descriptive statistics by arm over time. 
 
9.4.3.7. Pharmacokinetic Analysis 
Plasma concentrations of ARRY-371797 (PF-07265803) and its metabolites (AR00420643, 
AR00428028, and AR00486705) will be summarized using descriptive statistics by nominal 
time and visit. Results from the analysis of samples from participants randomized to the 
placebo arm will be used only to qualitatively assess consistency of results with respect to the 
randomization. 
 
9.4.3.7.1. Population Pharmacokinetic/Pharmacodynamic Analyses 
PK parameters for participants in the PK Set may be determined for ARRY-371797 (PF- 
07265803) and metabolites (AR00420643, AR00428028, and AR00486705) using a model- 
based approach to estimate PK parameters (eg, Cmax and AUC) and their respective 
variability. PK data may be pooled with prior data from other studies with intensive sampling 
to estimate population parameters and derive Empirical Bayes Estimates of PK parameters 
for participants in this study. 
 
Details of these analyses will be provided in a specific standalone modeling plan and results 
will be reported separately. 
 
Pharmacokinetic/Pharmacodynamic (PK/PD) modeling of ARRY-371797 (PF-07265803) 
treatment group may be done using efficacy and/or safety endpoints compared to the 
corresponding endpoints in the placebo arm. The basic PK/PD model will consist of 
structural variables for treatment arm and the time points out to 24 months. Additional 
important covariates (such as demographics) may be added to the PK/PD model during the 
model building process. Details of any PK/PD analyses will be provided in a pre-defined 
analysis plan and will be reportedly separately. 
 
Early unblinding for PK modeling purposes is planned when ≥ 90% of participants have 
reached 24 weeks post-randomization (or discontinued prior to the Week 24 visit). 
Unblinding will be limited to the PK data (ie, no efficacy data will be provided to the 
analysts/programmers). PK analysts and programmers will be listed on the early unblinding 
for PK/PD form in accordance with applicable Pfizer standard operating procedures for 
releasing randomization codes, early unblinding and breaking the study blind. These data 
programmers and analysts will not serve on this C4411002 study team after the PK early 
unblinding. 
 
These data analysts and programmers will be unblinded early to build the PK and models for 
study readout. Information, such as drug concentration, that may unblind the study will not 
be reported to investigator sites or other Pfizer personnel, who will all remain blinded. There 
will be no impact on the study conduct, analysis, or reporting based on the early unblinding 
of the PK data. The results of these analyses will be reported in a separate pharmacometrics 
analysis report. 


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9.4.5. Other Analyse(s) 
9.4.5.1. Hierarchical Testing 
The testing strategy controls Type I error across primary and selected secondary endpoints. 
If the van Elteren test of the primary endpoint is found to be statistically significant at 0.05 
(2-sided) alpha, then a sequential testing plan will be implemented for testing the secondary 
endpoints. 
 
Secondary endpoints will be analyzed in hierarchical order as follows: 
 
• Week 24 change from baseline in KCCQ domains of PL and TSS 
• Composite endpoint consisting of all-cause mortality or worsening heart failure (HF- 
related hospitalization or HF-related urgent care visit) 
• Week 24 change from baseline in NT-proBNP 
 
9.5. Interim Analyses 
An interim futility analysis was performed after the first 60 randomized participants in 
NYHA Class II/III had completed the Week 12 assessment or discontinued prior to Week 12. 
Change from baseline in the 6MWT at Week 12 was evaluated for this purpose in these 
analyses. The DMC utilized the futility boundary to consider whether the study should 
continue to completion or stop early for futility. The objective of this interim futility analysis 
was not to terminate the study early for the benefit of efficacy, therefore, there was no 
adjustment of alpha for the review. The details on the interim futility stopping boundary for 
the 6MWT at Week 12 is described in the SAP. 
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At the time of the planned interim futility analysis, the DMC recommended to continue the 
study as designed. 
 
Blinded Sample Size Re-estimation 
 
Following the interim analysis for futility, a planned blinded sample size re-estimation for the 
primary endpoint of change from baseline at Week 24 was conducted using blinded 
cumulative primary efficacy data from the interim data cut. Specifically, a blinded, pooled 
analysis of both treatment groups for estimating variability of change from baseline in 
6MWT at Week 24 and current overall event rates for deaths and study discontinuations prior 
to Week 24 was performed and compared to the assumption used in planning the study. 
 
In addition to the sample size re-estimation for the primary endpoint, the sponsor will 
monitor the pooled (blinded) cumulative event counts for the composite safety endpoint 
comprising of all-cause mortality or worsening of heart failure throughout the study . The 
statistical analysis plan will provide an assessment of the expected number of events needed 
to rule out an upper bound of 1.8 or 2 under various scenarios for given hazard ratios. 
 
The blinded sample size re-estimation was performed by a reporting statistician who is not a 
member of the study team and who will maintain independence from the study team for the 
duration of the trial. A detailed description of interim futility analysis and blinded sample 
size re-estimation is documented in the SAP. 
 
9.6. Data Monitoring Committee or Other Independent Oversight Committee 
This study will use a DMC. The DMC is independent of the study team and includes only 
external members. The DMC charter describes the role of the DMC in more detail. 
 
The DMC will be responsible for ongoing monitoring of the efficacy and safety of 
participants in the study according to the charter. The recommendations made by the DMC to 
alter the conduct of the study will be forwarded to the appropriate Pfizer personnel for final 
decision. Pfizer will forward such decisions, which may include summaries of aggregate 
analyses of endpoint events and of safety data that are not endpoints, to regulatory 
authorities, as appropriate. 
 
9.6.1. Data Monitoring Committee 
The DMC will be responsible for reviewing safety and PK data at regular intervals during the 
randomized portion of the study. Additionally, the DMC will review efficacy data at a formal 
interim futility analysis planned after the first 60 Class II/III randomized participants have 
completed the Week 12 assessment or have discontinued from the study prior to Week 12. A 
separate DMC charter will be established that outlines DMC membership and specifies what 
data will be reviewed, instructions for unblinding of data, along with the timing and 
frequency of the reviews. DMC recommendations will be provided to the sponsor in 
compliance with the DMC charter. 


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9.6.2. Steering Committee 
The SC will be appointed by the sponsor prior to the initiation of the study. The SC will 
include selected principal investigators from the study, leading experts in HF 
cardiomyopathy, and sponsor representatives. The SC will be involved in the oversight of the 
study and will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. Details on the role of 
the SC and working procedures will be defined in the SC charter. 
 
9.6.3. Clinical Events Committee 
The CEC will be appointed by the sponsor, or by it’s representative, prior to the initiation of 
the study. The CEC will be responsible for reviewing safety data to aid in adjudicating cause 
for hospitalizations for the composite endpoint of all-cause mortality or worsening heart 
failure (HF-related hospitalizations or HF-related urgent are visits) only. Details on the role 
of the CEC and working procedures will be defined in the CEC charter. 


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines; 
 
• Applicable ICH GCP guidelines; 
• Applicable laws and regulations, including applicable privacy laws. 
The protocol, protocol amendments, informed consent document, SRSD(s), and other 
relevant documents (eg, advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/EC by the investigator and reviewed and approved by the IRB/EC 
before the study is initiated. 
 
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
 
The investigator will be responsible for the following: 
 
• 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; 
 
• Notifying the IRB/EC of SAEs or other significant safety findings as required by IRB/EC 
procedures; 
 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/EC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations. 
 
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately. 
 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of. 


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10.1.2. Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory 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. 
 
10.1.3. Informed Consent Process 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study. The participant or his/her legally authorized representative should be given sufficient 
time and opportunity to ask questions and to decide whether or not to participate in the trial. 
 
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, HIPAA 
requirements, where applicable, and the IRB/EC or study center. 
 
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities. 
 
The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent for the processing of his or her personal data. 
 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the informed consent 
document. 
 
Participants must be reconsented to the most current version of the informed consent 
document(s) during their participation in the study. 
 
A copy of the informed consent document(s) must be provided to the participant or the 
participant’s legally authorized representative. 


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Participants who are rescreened are required to sign a new informed consent document. 
 
Unless prohibited by local requirements or IRB/EC decision, the informed consent document 
will contain a separate section that addresses the use of samples for optional additional 
research. The optional additional research does not require the collection of any further 
samples. The investigator or authorized designee will explain to each participant the 
objectives of the additional research. Participants 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 signature will be required to document a participant’s agreement to allow 
specimens to be used for additional research. Participants who decline to participate in this 
optional additional research will not provide this separate signature. 
 
10.1.4. Data Protection 
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data. 
 
Participants’ personal data will be stored at the study site in encrypted electronic form and 
will be password protected to ensure that only authorized study staff have access. The study 
site will implement appropriate technical and organizational measures to ensure that the 
personal data can be recovered in the event of disaster. In the event of a potential personal 
data breach, the study site will be responsible for determining whether a personal data breach 
has in fact occurred and, if so, providing breach notifications as required by law. 
 
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to his or her actual identity and medical record identification. In 
case of data transfer, the sponsor will protect the confidentiality of participants’ personal data 
consistent with the clinical study agreement and applicable privacy laws. 
 
10.1.5. Dissemination of Clinical Study Data 
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs. 
 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted. 


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www.clinicaltrials.gov 
 
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law. 
 
EudraCT 
 
Pfizer posts clinical trial results on EudraCT for Pfizer-sponsored interventional studies in 
accordance with the format and timelines set forth by EU requirements. 
 
www.pfizer.com 
 
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the corresponding study results are 
posted to www.clinicaltrials.gov. 
 
Documents within marketing authorization packages/submissions 
 
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the EMA website. Clinical data, under Phase 1 of this policy, includes clinical 
overviews, clinical summaries, CSRs, and appendices containing the protocol and protocol 
amendments, sample CRFs, and statistical methods. Clinical data, under Phase 2 of this 
policy, includes the publishing of individual participant data. Policy 0070 applies to new 
marketing authorization applications submitted via the centralized procedure since 
01 January 2015 and applications for line extensions and for new indications submitted via 
the centralized procedure since 01 July 2015. 
 
Data Sharing 
 
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contributes to the scientific understanding of the 
disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion. Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
redacted. 
 
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes. 
 
10.1.6. Data Quality Assurance 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 


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responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
 
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password protected to prevent access by unauthorized third parties. 
 
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion. It is important that the investigator(s) and 
their relevant personnel are available during the monitoring visits and possible audits or 
inspections and that sufficient time is devoted to the process. 
 
Monitoring details describing strategy (eg, risk--based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk--based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan. 
 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
 
Records and documents, including signed informed consent documents, pertaining to the 
conduct of this study must be retained by the investigator for 15 years after study completion 
unless local regulations or institutional policies require a longer retention period. No records 
may be destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor. The investigator must ensure that the records continue to be stored securely for as 
long as they are maintained. 
 
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems. 
 
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 


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provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings. 
 
10.1.7. Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site. 
 
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available. 
 
Definition of what constitutes source data can be found in the monitoring plan. 
 
Description of the use of computerized system is documented in the Data Validation Manual. 
 
10.1.8. Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
 
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date. 
 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed. 
 
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants. 
 
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to: 
 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor’s procedures, or GCP guidelines; 
 
• Inadequate recruitment of participants by the investigator; 
• Discontinuation of further study intervention development. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 


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requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
 
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights. 
 
10.1.9. Publication Policy 
The conditions regulating dissemination of the information derived from this study are 
described in the Clinical Trial Agreement. 
 
10.1.10. Sponsor’s Qualified Medical Personnel 
The contact information for the sponsor’s appropriately qualified medical personnel for the 
study is documented in the study contact list located in the inspection readiness electronic 
system. 
 
To facilitate access to appropriately qualified medical personnel for study-related medical 
questions or problems, participants are provided with an Emergency Contact Card (ECC) at 
the time of informed consent. The ECC contains, at a minimum, (a) protocol and study 
intervention identifiers, (b) participant’s study identification number, (c) site emergency 
phone number active 24 hours/day, 7 days per week, and (d) Pfizer Call Center number. 
 
The ECC is intended to augment, not replace, the established communication pathways 
between the investigator, site staff, and study team. The ECC is to be used by healthcare 
professionals not involved in the research study only, as a means of reaching the investigator 
or site staff related to the care of a participant. The Pfizer Call Center number should only be 
used when the investigator and site staff cannot be reached. The Pfizer Call Center number is 
not intended for use by the participant directly; if a participant calls that number directly, he 
or she will be directed back to the investigator site. 


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10.2. Appendix 2: Clinical Laboratory Tests 
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues. 
 
Table 4. 
Protocol -Required Safety Laboratory Assessments 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
RBC 
Platelets 
WBC 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Albumin 
Alkaline phosphatase 
AST 
GGT 
ALT 
Bicarbonate (CO2) 
Total bilirubin 
BUN 
Calcium 
Chloride 
CK 
Creatinine 
Glucose 
Magnesium 
Inorganic Phosphate 
Potassium 
Total protein 
Sodium 
Uric acid 
Direct bilirubin (if total 
bilirubin values are 
abnormal) 
NT-proBNP 
Troponins 
C-reactive protein 
Blood 
Glucose 
Ketones 
Leukocytes 
pH 
Protein 
At screening only: 
• 
HIV, Hepatitis B and C 
• 
TSH 
• 
eGFR calculation 
• 
LMNA mutation 
If applicable: 
• 
Serum pregnancy test 
• 
Urine pregnancy test 
• 
FSH 
 
Investigators must document their review of each laboratory safety report. 


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow--up, and Reporting 
10.3.1. Definition of AE 
 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention. 
 
 
Events Meeting the AE Definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE: 
• Is associated with accompanying symptoms. 
• Requires additional diagnostic testing or medical/surgical intervention. 
• Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy. 
• Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 


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Events NOT Meeting the AE Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen. 
 
10.3.2. Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 
 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a.  Results in death 
b. Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe. 
c.  Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 


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Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e.  Is a congenital anomaly/birth defect 
f. Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or nonpathogenic 
The event may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate. 
g. Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 


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10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs During the Active 
Collection Period 
 
AE and SAE Recording/Reporting 
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the CT SAE Report Form to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
nonserious AEs; and (3) exposure to the study intervention under study during pregnancy 
or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF. When the same data are collected, the forms must be 
completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information. 
Safety Event 
Recorded on the CRF 
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness 
SAE 
All 
All 
Nonserious AE 
All 
None 
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding 
All AEs/SAEs associated 
with exposure during 
pregnancy or breastfeeding 
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)* 
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF 
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)** 
Environmental or 
occupational exposure to 
the product under study 
to a nonparticipant (not 
involving EDP or EDB) 
None. Exposure to a study 
nonparticipant is not 
collected on the CRF 
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported*** 


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* 
EDP (with or without an associated AE or SAE): any pregnancy information is reported to Pfizer 
Safety using the CT SAE Report Form and EDP Supplemental Form; if the EDP is associated with 
an SAE, then the SAE is reported to Pfizer Safety using the CT SAE Report Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form, which would also include details 
of any SAE that might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the CT SAE Report Form. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The severity rating of an AE refers to its intensity. The severity of each AE will be 
determined by the Investigator using the Guidance for Industry: Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical Trials 
(US Department of Health and Human Services 2007), or modified grading parameter as 
specified in the dose modification table. For events that are not addressed by these 
guidelines, severity will be categorized according to the following criteria: 
Grade 1 
MILD; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2 
MODERATE; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
Grade 3 
SEVERE; severe or medically significant but not immediately life- 
threatening; hospitalization or prolongation of hospitalization indicated; 
disabling; limiting self-care activities of daily living 


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Grade 4 
LIFE-THREATENING; life-threatening consequences; urgent intervention 
indicated 
Grade 5 
FATAL 
 
 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. The investigator will use clinical judgment 
to determine the relationship. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. 
• The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
• If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form and in accordance 
with the SAE reporting requirements. 


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Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers. 
• New or updated information will be recorded in the originally submitted 
documents. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information. 
10.3.4. Reporting of SAEs 
 
 
 
SAE Reporting to Pfizer Safety via CT SAE Report Form 
• Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety. 
• In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames. 


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10.4. Appendix 4: Contraceptive Guidance 
10.4.1. Male Participant Reproductive Inclusion Criteria 
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 30 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s): 
 
• Refrain from donating sperm. 
PLUS either: 
• Be abstinent from heterosexual intercourse with a female of childbearing potential as 
their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and 
agree to remain abstinent. 
 
OR 
 
• Must agree to use a male condom when engaging in any activity that allows for 
passage of ejaculate to another person. 
 
• In addition to male condom use, a highly effective method of contraception may be 
considered in WOCBP partners of male participants (refer to the list of highly effective 
methods below in Section 10.4.4. 
 
10.4.2. Female Participant Reproductive Inclusion Criteria 
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies: 
 
• Is not a WOCBP (see definitions below in Section 10.4.3). 
OR 
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), preferably with low user dependency, as described below during the 
intervention period and for at least 30 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate any reproductive safety risk of the study 
intervention(s). The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention. 
 
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with high user dependency, as described below during the intervention 
period and for at least 30 days after the last dose of study intervention, which corresponds 
to the time needed to eliminate any reproductive safety risk of the study intervention(s). 
In addition, a second effective method of contraception, as described below, must be 


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used. The investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention. 
 
• A WOCBP agrees not to donate eggs (ova, oocytes) for the purpose of reproduction 
during this period. The investigator should evaluate the effectiveness of the contraceptive 
method in relationship to the first dose of study intervention. 
 
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
 
10.4.3. Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered. 
 
Women in the following categories are not considered WOCBP: 
 
1. Premenopausal female with 1 of the following: 
 
• Documented hysterectomy; 
• Documented bilateral salpingectomy; 
• Documented bilateral oophorectomy. 
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry. 
 
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study. 
 
2. Postmenopausal female: 
 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition, a 
 
• high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT. 


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• female on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
 
10.4.4. Contraception Methods 
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials. 
 
Highly Effective Methods That Have Low User Dependency 
 
5. Implantable progestogen-only hormone contraception associated with inhibition 
of ovulation. 
 
6. Intrauterine device. 
 
7. Intrauterine hormone-releasing system. 
 
8. Bilateral tubal occlusion. 
 
9. Vasectomized partner. 
 
• Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be 
used. The spermatogenesis cycle is approximately 90 days. 
 
Highly Effective Methods That Are User Dependent 
 
10. Combined (estrogen- and progestogen-containing) hormonal contraception 
associated with inhibition of ovulation: 
 
• Oral (it is recommended that participants experiencing vomiting or diarrhea should be 
counseled to use non-oral methods of contraception); 
 
• Intravaginal; 
• Transdermal; 
• Injectable. 


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11. Progestogen-only hormone contraception associated with inhibition of ovulation: 
 
• Oral (it is recommended that participants experiencing vomiting or diarrhea should be 
counseled to use non-oral methods of contraception); 
 
• Injectable. 
12. Sexual abstinence: 
 
• Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. 
 
One of the following effective barrier methods must be used in addition to the highly 
effective methods listed above that are user dependent: 
 
• Male or female condom with or without spermicide; 
• Cervical cap, diaphragm, or sponge with spermicide; 
• A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods). 


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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow--up Assessments 
Potential Cases of Drug-Induced Liver Injury 
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.” In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants who experience a transaminase elevation above 3×ULN should be monitored 
more frequently to determine if they are an “adaptor” or are “susceptible.” 
 
In the majority of DILI cases, elevations in AST and/or ALT precede TBili elevations 
(>2×ULN) by several days or weeks. The increase in TBili typically occurs while AST/ALT 
is/are still elevated above 3×ULN (ie, AST/ALT and TBili values will be elevated within the 
same laboratory sample). In rare instances, by the time TBili elevations are detected, 
AST/ALT values might have decreased. This occurrence is still regarded as a potential DILI. 
Therefore, abnormal elevations in either AST OR ALT in addition to TBili that meet the 
criteria outlined below are considered potential DILI (assessed per Hy’s law criteria) cases 
and should always be considered important medical events, even before all other possible 
causes of liver injury have been excluded. 
 
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions. Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values: 
 
• Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3×ULN AND a TBili value 
>2×ULN with no evidence of hemolysis and an alkaline phosphatase value <2×ULN 
or not available. 
 
• For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline: 
 
• Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3×ULN; or >8×ULN (whichever is 
smaller). 
 
• Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1×ULN or if the value reaches >3×ULN 
(whichever is smaller). 
 
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. 


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The participant should return to the investigator site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results. This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
 
In addition to repeating measurements of AST and ALT and TBili for suspected Hy’s law 
cases, additional laboratory tests should include albumin, CK, direct and indirect bilirubin, 
GGT, PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given 
to drawing a separate tube of clotted blood and an anticoagulated tube of blood for further 
testing, as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such 
as review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected. Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum samples for acetaminophen/paracetamol drug and/or protein adduct levels may be 
warranted. 
 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities. 
 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology. 


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10.6. Appendix 6: ECG Findings of Potential Clinical Concern 
 
ECG Findings That May Qualify as AEs 
• Marked sinus bradycardia (rate <40 bpm) lasting minutes. 
• New PR interval prolongation >280 msec. 
• New prolongation of QTcF to >480 msec (absolute) or by ≥60 msec from 
baseline. 
• New-onset atrial flutter or fibrillation, with controlled ventricular response rate: 
ie, rate <120 bpm. 
• New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration. 
• Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes. 
ECG Findings That May Qualify as SAEs 
• QTcF prolongation >500 msec. 
• New ST-T changes suggestive of myocardial ischemia. 
• New-onset left bundle branch block (QRS >120 msec). 
• New-onset right bundle branch block (QRS >120 msec). 
• Symptomatic bradycardia. 
• Asystole: 
• In awake, symptom-free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 
• In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer; 
• Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm. 
• Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute). 


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• Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (heart 
rate <40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as 
torsades de pointes]). 
• Type II second-degree (Mobitz II) AV block. 
• Complete (third-degree) heart block. 
ECG Findings That Qualify as SAEs 
• Change in pattern suggestive of new myocardial infarction. 
• Sustained ventricular tachyarrhythmias (>30 seconds’ duration). 
• Second- or third-degree AV block requiring pacemaker placement. 
• Asystolic pauses requiring pacemaker placement. 
• Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion. 
• Ventricular fibrillation/flutter. 
• At the discretion of the investigator, any arrhythmia classified as an adverse 
experience. 
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs. 


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10.7. Appendix 7: Alternative Measures During Public Emergencies 
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer. 
 
Use of these alternative study measures is expected to cease upon the return of business as 
usual (including the lifting of any quarantines and travel bans/advisories). 
 
Alternative Facilities for Safety Assessments 
 
In the event that a participant is unable to attend onsite visits, every effort will be made to 
follow up with the participant by phone contact at the time of scheduled visit per the SoA. 
Video contact can be used if permitted by local regulations. The study participants must be 
reminded to promptly communicate to the investigative site staff any change in their health 
status. During the phone (or video) contact, at a minimum, the following information must be 
collected and reviewed: 
 
AE(s) including SAE(s) and concomitant medication(s) since last contact. AEs/SAEs 
reporting process must be followed per Section 8.4. 
 
If at any time, in the investigator’s judgment, the safety of a study participant is at risk due to 
an inability to adequately conduct required safety evaluations, strong consideration should be 
given to discontinuing the study participant from study intervention. Such a determination 
should be made in consultation with the sponsor’s medical monitor. 
 
Laboratory Testing 
 
If a study participant is unable to visit the site for protocol-specified safety laboratory 
evaluations, testing may be conducted at a local laboratory if permitted by local 
regulations. The local laboratory may be a standalone institution or within a hospital. The 
following safety laboratory evaluations may be performed at a local laboratory: 
 
• 
Hematology, Blood Chemistry and Pregnancy testing 
 
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/ 
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible. The local laboratory reports should be filed in the participant’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF. 
 
The investigative site staff must ensure to collect the local laboratory reference ranges and 
certifications/accreditations for filing at the investigational site. In addition, the local 
laboratory will be recorded on the Form 1572. 


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Study Intervention: 
 
If the safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study 
intervention must be considered. 
 
Assessment of the study participant’s overall condition and laboratory test results prior to the 
administration of study intervention remains the responsibility of the investigator or 
medically qualified staff and should be performed in accordance with the protocol, 
irrespective of whether additional study intervention supply is dispensed or shipped. 
 
• Participants should be reminded that dosing diaries must be maintained per protocol and 
reminded to return unused study intervention and completed dosing diaries, as required by 
protocol, when possible. 
 
• Dispensation of extra drug supply to the study participant at a clinic visit (preferred 
option) or direct shipment via courier to a study participant’s home (as allowed by local 
applicable laws and regulations) is permitted provided the investigator site staff assesses and 
determines that it is appropriate to do so, and the study participant verbally consents to this. 
The study participant’s consent should be well documented in the medical record. 
 
• 
If extra dispensation or direct shipment of study intervention to a study participant is 
necessary, please contact the sponsor in advance so that guidance/instructions can be 
provided, and study intervention supply can be tracked as the global COVID-19 pandemic 
situation continues to evolve. 


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10.8. Appendix 8 Cautionary Concomitant Medications while on Study Intervention 
Drugs with known TdP risks. Downloaded from https://crediblemeds.org/new-drug-list/, 
filtered to include only “Known Risk of TdP” drugs. Accessed 07 Jan 2022. 
 
Generic Name 
Brand Names (Partial List) 
Drug Class 
Aclarubicin 
(Only on Non US Market) 
Aclacin, Aclacinomycine, Aclacinon, 
Aclaplastin, Jaclacin 
Anti-cancer 
Amiodarone 
Cordarone, Pacerone, Nexterone 
Antiarrhythmic 
Anagrelide 
Agrylin, Xagrid 
Phosphodiesterase 3 inhibitor 
Arsenic trioxide 
Trisenox 
Anti-cancer 
Astemizole 
(Removed from US Market) 
Hismanal 
Antihistamine 
Azithromycin 
Zithromax, Zmax 
Antibiotic 
Bepridil 
Vascor 
Antianginal 
Cesium Chloride 
Energy Catalyst 
Toxin 
Chloroquine 
Aralen 
Antimalarial 
Chlorpromazine 
Thorazine, Largactil, Megaphen 
Antipsychotic / Antiemetic 
Chlorprothixene 
(Only on Non US Market) 
Truxal 
Antipsychotic 
Cilostazol 
Pletal 
Phosphodiesterase 3 inhibitor 
Ciprofloxacin 
Cipro, Cipro-XR, Neofloxin 
Antibiotic 
Cisapride 
(Removed from US Market) 
Propulsid 
GI stimulant 
Citalopram 
Celexa, Cipramil 
Antidepressant, SSRI 
Clarithromycin 
Biaxin, Prevpac 
Antibiotic 
Cocaine 
Cocaine 
Local anesthetic 
Disopyramide 
Norpace 
Antiarrhythmic 
Dofetilide 
Tikosyn 
Antiarrhythmic 
Domperidone 
(Only on Non US Market) 
Motilium, Motillium, Motinorm 
Costi, Nomit 
Antiemetic 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Donepezil 
Aricept 
Cholinesterase inhibitor 
Dronedarone 
Multaq 
Antiarrhythmic 
Droperidol 
Inapsine, Droleptan, Dridol, Xomolix 
Antipsychotic / Antiemetic 
Erythromycin 
E.E.S., Robimycin, EMycin, Erymax, 
Ery- Tab, Eryc Ranbaxy, Erypar, 
Eryped, Erythrocin Stearate Filmtab, 
Erythrocot, 
E-Base, Erythroped, Ilosone, MY-E, 
Pediamycin, Abboticin, Abboticin- 
ES, Erycin, PCE Dispertab, 
Stiemycine, Acnasol, Tiloryth 
Antibiotic 
Escitalopram 
Cipralex, Lexapro, Nexito, Anxiset- 
E, Exodus, Esto, Seroplex, Elicea, 
Lexamil, Lexam, Entact, Losita, 
Reposil, Animaxen, Esitalo, Lexamil 
Antidepressant, SSRI 
Flecainide 
Tambocor, Almarytm, Apocard, 
Ecrinal, Flécaine 
Antiarrhythmic 
Fluconazole 
Diflucan, Trican 
Antifungal 
Gatifloxacin 
(Removed from US Market) 
Tequin 
Antibiotic 
Grepfloxacin 
(Removed from US Market) 
Raxar 
Antibiotic 
Halofantrine 
(Only on Non US Market) 
Halfan 
Antimalarial 
Haloperidol 
Haldol, Aloperidin, Bioperidolo, 
Brotopon, Dozic, Duraperidol, 
Einalon S, Eukystol, Halosten, 
Keselan, Linton, Peluces, Serenace, 
Serenase, Sigaperidol 
Antipsychotic 
Hydroquinidine 
(Dihydroquinidine) 
(Only on Non US Market) 
Serecor 
Antiarrhythmic 
Hydroxychloroquine 
Plaquenil, Quineprox 
Antimalarial, Anti- 
inflammatory 
Ibogaine 
(Only on Non US Market) 
Psychedelic 
Ibutilide 
Corvert 
Antiarrhythmic 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Levofloxacin 
Levaquin, Tavanic 
Antibiotic 
Levomepromazine 
(Methotrimeprazine) 
(Only on Non US Market) 
Nosinan, Nozinan, Levoprome 
Antipsychotic 
Levomethadyl acetate 
(Removed from US Market) 
Orlaam 
Opioid agonist 
Levosulpiride 
(Only on Non US Market) 
Lesuride, Levazeo, Enliva 
Antipsychotic 
Meglumine antimoniate 
(Only on Non US Market) 
Glucantime 
Antiparasitic 
Mesoridazine 
(Removed from US Market) 
Serentil 
Antipsychotic 
Methadone 
Dolophine, Symoron, Amidone, 
Methadose, Physeptone, Heptadon 
Opioid agonist 
Mobocertinib 
Exkivity 
Tyrosine kinase inhibitor 
Moxifloxacin 
Avelox, Avalox, Avelon 
Antibiotic 
Nifekalant 
(Only on Non US Market) 
Shinbit 
Antiarrhythmic 
Ondansetron 
Zofran, Anset, Ondemet, Zuplenz, 
Emetron, Ondavell, Emeset, 
Ondisolv, Setronax 
Antiemetic 
Oxaliplatin 
Eloxatin 
Anti-cancer 
Papaverine HCl (Intra- coronary) 
Vasodilator, Coronary 
Pentamidine 
Pentam 
Antifungal 
Pimozide 
Orap 
Antipsychotic 
Probucol 
(Removed from US Market) 
Lorelco 
Antilipemic 
Procainamide 
Pronestyl, Procan 
Antiarrhythmic 


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Generic Name 
Brand Names (Partial List) 
Drug Class 
Propofol 
Diprivan, Propoven 
Anesthetic, general 
Quinidine 
Quinaglute, Duraquin, Quinact, 
Quinidex, Cin-Quin, Quinora 
Antiarrhythmic 
Roxithromycin 
(Only on Non US Market) 
Rulide, Xthrocin, Roxl-150, Roxo, 
Surlid, Rulide, Biaxsig, Roxar, 
Roximycinv, Roxomycin, Rulid, 
Tirabicin, Coroxin 
Antibiotic 
Sertindole 
(Only on Non US Market) 
Serdolect, Serlect 
Antipsychotic, atypical 
Sevoflurane 
Ultane, Sojourn 
Anesthetic, general 
Sotalol 
Betapace, Sotalex, Sotacor 
Antiarrhythmic 
Sparfloxacin 
(Removed from US Market) 
Zagam 
Antibiotic 
Sulpiride 
(Only on Non US Market) 
Dogmatil, Dolmatil, Eglonyl, 
Espiride, Modal, Sulpor 
Antipsychotic, atypical 
Sultopride 
(Only on Non US Market) 
Barnetil, Barnotil, Topral 
Antipsychotic, atypical 
Terfenedine 
(Removed from US Market) 
Seldane 
Antihistamine 
Terlipressin 
(Only on Non US Market) 
Teripress, Glypressin, Terlipin, 
Remestyp, Tresil, Teriss 
Vasoconstrictor 
Terodiline 
(Only on Non US Market) 
Micturin, Mictrol 
Muscle relaxant 
Thioridazine 
Mellaril, Novoridazine, Thioril 
Antipsychotic 
Vandetanib 
Caprelsa 
Anti-cancer 


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10.9. Appendix 9: Definitions of Heart Failure Events 
Hospitalization for Heart Failure: Must meet ALL of the following criteria 
The participant is admitted to the hospital with a primary diagnosis of HF. 
1. The participant’s length-of-stay extends for at least 24 hours (or a change in calendar day 
if the admission and discharge times are unavailable). 
 
2. The participant exhibits documented new or worsening symptoms due to HF on 
presentation including at least ONE of the following: 
 
a. Dyspnea (dyspnea with exertion, dyspnea at rest, orthopnea, paroxysmal nocturnal 
dyspnea) 
 
b. Decreased exercise tolerance 
 
c. Fatigue 
 
3. The participant has objective evidence of new or worsening HF, consisting of at least 
TWO physical exam findings OR one physical exam finding and at least ONE laboratory 
criterion, including: 
 
a. Physician examination findings considered to be due to heart failure, including new 
or worsened: 
 
i. 
Peripheral edema 
 
ii. 
Increasing abdominal distension or ascites (in the absence of primary hepatic 
disease) 
 
iii. 
Pulmonary rales/crackles/crepitations 
 
iv. 
Increased jugular venous pressure and/or hepatojugular reflux 
 
v. 
S3 gallop 
 
vi. 
Clinically significant or rapid weight gain thought to be related to fluid retention 
 
b. Laboratory evidence of new or worsening HF, if obtained within 24 hours of 
presenting, including: 
 
i. 
Increased BNP/NT-proBNP concentrates consistent with decompensation of heart 
failure (such as BNP > 500 pg/mL or NT-proBNP > 2,000 p/mL). In participants 
with chronically elevated natriuretic peptides, a significant increase should be 
noted above baseline. 
 
ii. 
Radiological evidence of pulmonary congestion 


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iii. 
Non-invasive diagnostic evidence of clinically significant elevated left-or 
right--sided ventricular filling pressure or low cardiac output. 
 
OR 
 
iv. 
Invasive diagnostic evidence with right heart catheterization showing a 
pulmonary capillary wedge pressure (pulmonary artery occlusion pressure) 
≥18 mmHg, central venous pressure ≥12 mm/Hg, or a cardiac index 
<2.2 L/min/m2 
4. The participant receives initiation or intensification of treatment specifically for HF, 
including at least ONE of the following: 
 
a. Augmentation in oral diuretic therapy 
 
b. Intravenous diuretic or vasoactive agent (eg, inotrope, vasopressor, or vasodilator) 
 
a. Mechanical or surgical intervention, including: 
 
i. 
Mechanical circulatory support (eg, intra-aortic balloon pump, ventricular assist 
device, extracorporeal membrane oxygenation, total artificial heart) 
 
ii. 
Mechanical fluid removal (eg, ultrafiltration, hemofiltration, dialysis) 
 
An Urgent Heart Failure Visit: Is an event that meets all of the following: 
 
1. The participant has an urgent, unscheduled office/practice or emergency department visit 
for a primary diagnosis of HF, but not meeting the criteria for HF hospitalization. 
 
2. All signs and symptoms for HF hospitalization (ie, symptoms, physical examination 
findings/laboratory evidence of new or worsening HF, as indicated above) must be met. 
 
3. The participant receives initiation or intensification of treatment specifically for HF, as 
detailed in the above section with the exception of oral diuretic therapy, which will not be 
sufficient. 
 
Source: Hicks K, Hung H, Mahaffey K, et al. Standardized definitions for cardiovascular and stroke endpoint 
events in clinical trials. Clinical Data Interchange Standards Consortium (Standardized Data Collection for 
Cardiovascular Trials Initiative); August 20, 2014. 2017. 


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10.10. Appendix 10: Country Specific Requirements 
 
 
10.10.1. Japan 
Electrocardiograms 
NOTE: The cardiologist confirms ECG data immediately after measuring ECG, and if ECG 
data meets ECG values of “ECG Findings of Potential Clinical Concern” listed in 
Appendix 6, the investigator’s clinical judgment and the background regarding whether dose 
interruptions, reductions, and discontinuations of study intervention are needed must be 
documented. 
 
Contraception Methods 
 
In accordance with Japanese regulations regarding the use of contraceptive methods, the 
following contraceptive methods should be used in Japan. 
 
Highly Effective Methods That Have Low User Dependency 
 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomized partner 
o Vasectomized partner is a highly effective contraceptive method provided that 
the partner is the sole sexual partner of the WOCBP and the absence of sperm 
has been confirmed. If not, an additional highly effective method of 
contraception should be used. The spermatogenesis cycle is approximately 90 
days. 
 
Highly Effective Methods That Are User Dependent 
 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
 
o Oral (it is recommended that participants experiencing vomiting or diarrhea 
should be counseled to use non-oral methods of contraception) 
 
• Sexual abstinence: 
o Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk 
associated with the study intervention. The reliability of sexual abstinence 


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needs to be evaluated in relation to the duration of the study and the preferred 
and usual lifestyle of the participant. 
 
One of the following effective barrier methods must be used in addition to the highly 
effective methods listed above that are user dependent: 
 
• Male or female condom with or without spermicide; 
• Diaphragm; 
• A combination of male condom with diaphragm (double-barrier methods). 
 
 
10.10.2. France 
Contrat Unique 
 
1. GCP Training 
 
Before enrolling any participants, the investigator and any subinvestigators will 
complete the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP 
Training”) or training deemed equivalent by Pfizer. Any investigators who later join 
the study will do the same before performing study-related duties. For studies of 
applicable duration, the investigator and subinvestigators will complete Pfizer GCP 
Training or equivalent every 3 years during the term of the study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials. 
 
2. Study Intervention 
 
No participants or third-party payers will be charged for study intervention. 
 
3. Urgent Safety Measures 
 
In addition, the investigator will inform Pfizer immediately of any urgent safety 
measures taken by the investigator to protect the study participants against any 
immediate hazard, and of any serious breaches of this protocol or of ICH GCP that 
the investigator becomes aware of. 
 
4. Termination Rights 
 
Pfizer retains the right to discontinue development of ARRY-371797 (PF-07265803) 
at any time. 


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10.11. Appendix 11: Abbreviations 
The following is a list of abbreviations that may be used in the protocol. 
 
Abbreviation 
Term 
2D 
2-dimensional 
6MWT 
6-minute walk test 
ACC 
American College of Cardiology 
ACMG 
American College of Medical Genetics and Genomics 
ADL 
activities of daily living 
AE 
adverse event 
AHA 
American Heart Association 
ALT 
alanine aminotransferase 
AS 
ankylosing spondylitis 
AST 
aspartate aminotransferase 
ATS 
American Thoracic Society 
AUC 
area under the plasma concentration-time curve 
β-HCG 
beta-human chorionic gonadotropin 
BID 
twice daily 
BNP 
brain natriuretic peptide 
BP 
blood pressure 
BSA 
body surface area 
BUN 
blood urea nitrogen 
C 
Celsius 
CCD 
Cardiac conduction disease 
CDISC 
Clinical Data Interchange Standards Consortium 
CEC 
clinical events committee 
CI 
confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
creatine kinase 
Cmax 
maximal plasma concentration 
CO2 
carbon dioxide (bicarbonate) 
COPD 
chronic obstructive pulmonary disease 
COVID-19 
coronavirus disease 2019 
CRA 
clinical research associate 
CrCL 
creatinine clearance 
CRO 
contract research organization 
CRP 
C-reactive protein 
CRT 
cardiac resynchronization therapy 
CRT-D 
cardiac resynchronization therapy defibrillator 
CSR 
Clinical Study Report 
CTFG 
Clinical Trial Facilitation Group 
CRT 
cardiac resynchronization therapy 
CSS 
Clinical Summary Score 
CT 
Clinical Trial 


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Abbreviation 
Term 
CV 
cardiovascular 
CYP 
cytochrome P450 
DCM 
dilated cardiomyopathy 
DDI 
drug-drug interaction 
DILI 
drug-induced liver injury 
DMC 
data monitoring committee 
EAS 
efficacy analysis set 
EC 
ethics committee 
ECC 
Emergency Contact Card 
eCDF 
empirical cumulative distribution function 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EDMD 
Emery-Dreifuss muscular dystrophy 
EDP 
exposure during pregnancy 
eGFR 
estimated glomerular filtration rate 
EF 
ejection fraction 
EMA 
European Medicines Agency 
EQ-5D-5L 
EuroQol-5 Dimensions-5 Levels 
ER 
emergency room 
ERK 
extracellular signal-regulated kinase 
ESC 
European Society of Cardiology 
EU 
European Union 
EudraCT 
European Clinical Trials Database 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FMO 
flavin-containing monooxygenase 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GI 
gastrointestinal 
HDPE 
high-density polyethylene 
HEENT 
head, eyes, ears, nose, throat 
HF 
heart failure 
HFrEF 
heart failure with reduced ejection fraction 
HFS 
hospitalization-free survival 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HL 
Hodges-Lehmann 
HR 
hazard ratio 
HSP27 
heat shock protein 27 
HRT 
hormone replacement therapy 


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Abbreviation 
Term 
HRU 
healthcare resource utilization 
IA 
Interim Analysis 
IB 
investigator’s brochure 
IC50 
half-maximal inhibitory concentration 
ICD 
implantable cardioverter defibrillator 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IL 
interleukin 
IP 
Investigational Product 
IPAL 
Investigational Product Accountability Log 
IRB 
institutional review board 
IRT 
interactive response technology system 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IV 
intravenous 
IVC 
inferior vena cava 
JNK 
c-Jun N-terminal kinase 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LMNA 
gene encoding the lamin A/C protein 
LOCF 
last observation carried forward 
LP 
likely pathogenic 
LTE 
long-term extension 
LV 
left ventricle, left ventricular 
LVAD 
left ventricular assist device 
LVEDD 
left ventricular end diastolic diameter 
LVEDVI 
left ventricular end diastolic volume index 
LVEF 
left ventricular ejection fraction 
LVESD 
left ventricular end systolic diameter 
LVESVI 
left ventricular end systolic volume index 
MAO 
monoamine oxidase 
MAP3K 
mitogen-activated protein kinase kinase kinase 
MAPK 
mitogen-activated protein kinase 
MAPKK 
mitogen-activated protein kinase kinase 
MAR 
missing at random 
MD 
muscular dystrophy 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCMC 
Markov chain Monte Carlo 
MI 
multiple imputation 
MMRM 
mixed models for repeated measurements 
mRNA 
messenger ribonucleic acid 
MRI 
magnetic resonance imaging 
msec 
millisecond 
N 
number of participants 


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Abbreviation 
Term 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
OA 
osteoarthritis 
OTC 
over-the-counter 
OS 
overall survival 
OSS 
Overall Summary Score 
P 
pathogenic 
p-p38 
phospho-p38 
PACL 
Protocol Administrative Change Letter 
PAH 
pulmonary arterial hypertension 
PASP 
pulmonary artery systolic pressure 
PD 
pharmacodynamics(s) 
PGI 
Patient Global Impression 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
P-gp 
permeability glycoprotein 
PK 
pharmacokinetic(s) 
PL 
Physical Limitation 
PPS 
per-protocol set 
PR 
ECG interval from the onset of P wave to the onset of the QRS 
complex 
PRO 
patient-reported outcomes 
QA 
quality assurance 
QD 
once daily 
QoL 
quality of life 
QT 
QT interval: a measurement of the time between the start of the Q 
wave and the end of the T wave in an ECG 
QTc 
corrected QT interval 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RA 
rheumatoid arthritis 
RBC 
red blood cell 
RV 
right ventricular 
RVEDD 
right ventricular end-diastolic diameter 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAR 
serious adverse reaction 
SAS 
safety analysis set 
SC 
steering committee 
SCD 
sudden cardiac death 
SD 
standard deviation 
SEM 
standard error of the mean 
sMDRD 
Simplified Modification of Diet in Renal Disease 
SoA 
schedule of activities 


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Abbreviation 
Term 
SOP 
standard operating procedure 
SRSD 
single reference safety document 
SS 
safety set 
SUSAR 
suspected unexpected serious adverse reaction 
t½ 
terminal half-life 
TAPSE 
tricuspid annular plane systolic excursion 
TEAE 
treatment-emergent adverse event 
TdP 
torsades de pointes 
Tmax 
time to maximum plasma exposure 
TNFα 
tumor necrosis factor-alpha 
TOC 
Table of Contents 
TSH 
thyroid-stimulating hormone 
TSS 
Total Symptom Score 
TTN 
titin 
ULN 
upper limit of normal 
UGT 
uridine 5'-diphospho Glucuronosyltransferase 
US 
United States 
VAS 
Visual Analog Scale 
VUS 
variant of uncertain significance 
WBC 
white blood cell 
WHF 
worsening heart failure 
WOCBP 
woman/women of childbearing potential 


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10.12. Appendix 12: Protocol Amendment History 
The protocol amendment summary of changes table for the current amendment is located 
directly before the TOC. The protocol amendment summary of changes tables for past 
amendment(s) can be found below: 
 
Protocol Amendment Summary of Changes Table 
 
Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
Protocol Version 7 
17Feb2021 
Changed primary endpoint change from baseline 
in 6MWT at 12 weeks to 24 weeks. Rationale: 
Clinical relevance of durability of response up to 
24 weeks as per regulatory feedback. 
Update previous safety hospitalization free 
survival composite endpoint by adding heart 
failure related urgent care visits as a part of 
worsening heart failure. Rationale: clinical 
relevance of including in the statistical analysis 
events already being collected and adjudicated. 
Statistical changes included: 1) clarifications on 
the sample size assumptions and a blinded 
sample size re-estimation after IA futility for the 
primary endpoint, 2) implementation of the 
blinded monitoring of cumulative event counts 
for the composite endpoint of all-cause mortality 
and worsening heart failure throughout the study 
to assess impact on the sample size, 3) additional 
details on the primary analysis and imputation 
method, and 4) updates on the analysis method 
on the composite endpoint for all-cause mortality 
and worsening heart failure, and the hierarchical 
testing. Rationale: To align with the changes in 
the primary endpoint and the composite endpoint 
to assess all-cause mortality and worsening heart 
failure. 
Added cautionary use of CYP3A4 inhibitors and 
inducers. Rationale: Based on emerging data 
suggesting potential for mixed 
induction/inhibition of CYP3A4, the effect of 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
PF-07265803 (ARRY-371797) interaction with 
drugs that are identified as being metabolized by 
CYP3A4 is not known. 
Updated minimum Frequency of Pregnancy 
Testing to every 12 weeks rather than monthly. 
Rationale: Sponsor’s reproductive safety 
guidelines no longer requires every 4 weeks. 
CCI 
In Class II/III participants, added measures of 
efficacy on change from baseline in Borg fatigue 
scale of 6MWT at Weeks 4, 12 and 24, and 
every 12 weeks after. Rationale: To obtain a 
more complete understanding of the change from 
baseline in the Borg fatigue scale of 6MWT. 
CCI 


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Document History 
 
Document/Version Version Date 
Summary and Rationale for Changes 
 
 
CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rationale: To obtain a more complete 
understanding of recurrent HF-related 
hospitalizations, change in daily activity 
measures, and change in health status and 
physical activity. 
 
Allow the use of an accredited clinical 
laboratory rather than limiting genetic testing to 
a central laboratory for determination of LMNA 
variants and to allow participants with LMNA 
variant of uncertain significance (VUS) to be 
enrolled. Rationale: To align with the genetic 
testing requirements in the completed Phase 2 
trial, which did not utilize a single central 
laboratory. Genetic testing has become more 
routine and is now commonly performed in 
many clinical laboratories. LMNA-DCM is a 
diagnosis of exclusion. Genetic test results of 
VUS may change to LP/P as more clinical cases 
are confirmed. 
 
Modified the introduction and background 
section. Rationale: Updated to provide 
clarification and further information based on 
review of the literature. 
 
Updated kinship language to allow for no more 
than 10% of participants enrolled with the same 
mutation rather than 4 individuals from a single 
family. Rationale: Modified to have a holistic 
view of entire population and mutations, and 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
considering family members can have different 
mutations. 
Modified inclusion criteria language to clarify if 
a participant has a CRT-D, defibrillation must be 
activated at least 4 weeks prior to initiation of 
study intervention. Rationale: To ensure proper 
functionality of the defibrillator function prior to 
study intervention. 
Modified inclusion criteria to expand the 
cardiovascular conditions required at 
prescreening. Rationale: To ensure the 
appropriate participants are being prescreened. 
Remove 6MWT % predicted distance (Troosters 
et al 1999) from 6MWT inclusion criteria. 
Rationale: Eligibility to be based on absolute 
distance walked vs % predicted as the perceived 
prognostic value of the % predicted is not 
superior to the absolute distance observed via the 
6MWT 
The screening ECHO can be done locally and is 
not required to be sent to central laboratory. 
Rationale: Streamline the screening process and 
requirements. 
Removed 24-hour Holter monitoring language 
and clarify arrythmia assessment requirements. 
Rationale: All participants are required to have 
an ICD/CRT device at study entry and can be 
monitored continuously. 
Reduced the number of ECGs and no longer 
require triplicate ECG. Rationale: Unnecessary 
burden of ECGs given that participants have an 
ICD/CRT device in place. 
Modified the survival follow-up section to 
include HF-related hospitalizations and HF- 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
related urgent care visits being collected as part 
of the analysis. 
Added an Alternative Measures during Public 
Emergences appendix. Rationale: A COVID-19 
contingency plan was issued in a PACL dated 
20May2020 and the language was updated to 
align with Pfizer’s required protocol template 
language. 
Protocol v6 dated 09Mar2020 was moved into 
the Sponsor’s protocol template. Rationale: To 
align with Pfizer’s standard template language. 
Protocol Version 6 
09 March 2020 
At the time of this protocol amendment, the 
study had been initiated at 66 study centers and 
28 participants had been randomized. Protocol 
version 6 was generated to include the following 
key changes: 
• Update to Exclusion #10 for Class II/III and 
duplicate Exclusion #7 for Class IV based on 
an administrative letter submitted 
09 Apr 2019. 
• Rationale: To modify the list of slow 
growing or curatively resected 
malignancies to allow participants to be 
enrolled. 
• Updated inclusion criteria language to ensure 
that ICD/CRT-D devices also include pacing 
capabilities. 
• Rationale: To be certain that all devices 
have pacing capabilities. 
• Regarding the number of participants 
required at the interim analysis and the 
futility boundary for early stopping. 
• Rationale: To reduce the error rate of 
making an incorrect decision of early 
stopping for futility at the interim 
analysis. 
• To update the power of the primary analysis 
from 80% to approximately 90% for the 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
primary endpoint of change from baseline in 
the 6MWT at Week 12. 
• Rationale: Power increase from 80% to 
approximately 90% is as a result of the 
change in the timing of the interim 
analysis as well as a change in the 
method for determining the futility 
boundary. 
• To update language relating to the sensitivity 
analysis for the primary endpoint. 
• Rationale: To remove detailed 
descriptions of sensitivity analysis and 
provide them in the SAP. 
• Update language around abnormal labs as 
AEs. 
• Rationale: To comply with the requested 
wording from a Health Authority and to 
align with the Global protocol template. 
• Add risk/benefit section (the changes are in 
alignment with the IB). 
• Rationale: To comply with the requested 
wording from a Health Authority and to 
align with the Global protocol template. 
• Updated language around the responsibilities 
of the DMC. 
• Rationale: To clarify that the DMC is 
reviewing safety and PK throughout the 
study but only efficacy data at 
prespecified timepoints. 
• To add the compound designation 
“PF-07265803” to ARRY-371797. 
• Rationale: To reflect a new compound 
designation and align with the IB. 
• Corrected Table 6, Schedule of Events for 
Open-Label Period 
• Rationale: Corrected the footnote in the 
schedule of arrythmia assessments to 
align assessments with Section 8.5.1.2.9. 
Protocol Version 5 
17 January 
2019 
At the time of this protocol amendment, the 
study had been initiated at 46 study centers and 
7 participants had been randomized. Protocol 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
version 5 was generated to include the following 
key changes: 
CCI 
• To clarify that participants will have the 
opportunity to be followed for at least 
24 weeks prior to the primary analysis being 
performed. 
• Rationale: The Week 24 assessment is 
not required for this analysis. 
• To reduce the number of participants needed 
at the interim analysis, to occur after 
• NYHA Class II/III participants have 
completed the Week 12 assessment or have 
discontinued before Week 12, rather than 
after 60 participants have met the same 
criteria. 
• Rationale: To obtain a more rapid 
evaluation of potential efficacy. 
• To update the power of the primary analysis 
from 90% to 80% for the primary endpoint 
of change from baseline in the 6MWT at 
Week 12. 
• Rationale: By including the interim 
analysis with a futility boundary of 
17 meters, the overall study power is 
80%. At the interim analysis, the 
predictive power will be ≥40% to 
continue the study. 
• For the interim analysis, descriptions of 
analysis of the pooled standard deviation of 
change from baseline 6MWT data and the 
blinded assessment of powering assumptions 
at the interim analysis were deleted. Text 
now specifies that the change from baseline 
in 6MWT at Week 12 will be analyzed 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
nonparametrically, as in the primary 
analysis. The futility boundary is updated to 
be based on predictive power. 
• Rationale: To remove detailed 
descriptions of the pooled analysis of 
standard deviation of change from 
baseline 6MWT data, descriptions of the 
blinded assessment of powering 
assumptions and futility boundaries from 
the protocol and provide them only in the 
SAP. 
• To change inclusion criteria that describe the 
timing of testing for acceptable hematology, 
hepatic and renal function, lengthening the 
period for obtaining acceptable values from 
within 3 weeks to within 35 days prior to 
Day 1. 
• Rationale: To align collection of these 
laboratory data with the duration of the 
screening period. 
• To clarify that blood collection for central 
analysis of the LMNA gene mutation for 
participants with known LMNA mutation per 
local lab may be performed during screening. 
• Rationale: To provide a better sequence 
of assessments at sites. 
• To increase the number of times that 
participants can be rescreened. 
• Rationale: To provide more opportunities 
for participants to meet study entry 
criteria. 
Protocol Version 4 
27 August 2018 
At the time of this protocol amendment, the 
study had been initiated at 13 study centers and 
4 participants had been randomized. Protocol 
version 4 was generated to include the following 
key changes: 
• To classify HFS and OS as efficacy 
endpoints rather than safety endpoints, 
therefore adding a new secondary objective. 
• Rationale: To clarify which endpoints are 
safety related. 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
• To clarify that the open-label phase of the 
study will begin seamlessly after the primary 
analysis is completed. 
• Rationale: To clarify the transition 
between the randomized and open-label 
phases of the study. 
• To clarify the description of the end of study 
and update the conditions necessary to 
continue treatment after the end of study in a 
protocol amendment or separate rollover 
protocol, as permitted by local regulations 
and only after Health Authority and EC 
approval. 
• Rationale: To clarify when the study will 
end and under what circumstances 
participants can continue to receive study 
intervention. 
• To allow the use of ECHOs obtained from 
local laboratories in complying with 
screening requirements. 
• Rationale: Locally performed reads of 
ECHOs can document an EF ≤50% 
during screening. The central result is no 
longer needed to assess eligibility. 
• To change the timing of when LMNA 
mutation status must be confirmed by the 
central laboratory. Deleterious LMNA 
mutation status must be confirmed prior to 
randomization. Participants may satisfy 
screening criteria with either local or central 
LMNA results. 
• Rationale: To ensure that all participants 
who receive study intervention have the 
LMNA mutation. 
• To standardize wording describing which 
assessments will be conducted when feasible 
for NYHA Class IV participants and to allow 
flexibility in determining which assessments 
must be conducted in clinic. 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
• Rationale: To provide consistency and 
flexibility for participants who are not 
ambulatory. 
• To increase the duration of the screening 
period from 28 to 35 days prior to Day 1 and 
update the timing of all assessments during 
the screening period throughout the protocol. 
• Rationale: To extend the screening 
window for flexibility of scheduling 
participants around weekends and 
holidays. 
• To permit unblinded bioanalytical data to be 
transferred to an unblinded CRO for reassay 
of PK samples. 
• Rationale: To allow for reanalysis of 
discrepant bioanalytical results from PK 
samples as the study duration is projected 
to be longer than the stability of the 
measured analytes. 
• To modify the inclusion criteria related to 
signing informed consent to add that 
participants under guardianship or partial 
guardianship will be eligible unless 
prohibited by local laws by ECs. 
• Rationale: To clarify that there may be 
differences in the ability of these 
participants to participate in the study, 
depending on the site’s location. 
• To add inclusion criteria to require affiliation 
to a social security system or beneficiary 
status, if applicable. 
• Rationale: To include standard language 
for all possible applicable country 
regulations. 
• To delete the inclusion criteria that required 
that participants have serum NT-proBNP 
>400 pg/mL. 
• Rationale: To allow enrollment of 
participants based on LMNA mutation 
status and clinical criteria. 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
• To modify the exclusion criteria for all 
participants pertaining to pregnancy or 
breastfeeding to also exclude participants 
who plan to become pregnant during the 
duration of the trial. 
• Rationale: Any participant planning to 
become pregnant should be excluded 
from the trial. 
• To add an exclusion criterion for the NYHA 
functional Class II and III participants in 
order to exclude participants with an 
underlying condition that may impact the 
ability of the 6MWT to reflect changes in 
cardiovascular function. 
• Rationale: To ensure that the 6MWT 
reflects changes in cardiovascular 
function. 
• To add exclusion criteria for participants 
who have hypersensitivity or intolerance to 
the drug product and to add information on 
the commercial film coating used in 
manufacturing. 
• Rationale: To reduce the potential risk to 
participants who receive treatment. 
• To prohibit donation of sperm or ova during 
treatment and for 90 days after the last dose 
for sperm and 30 days after the last dose for 
ova. Also, to clarify the description of when 
contraceptives are required. 
• Rationale: To prevent potential damage 
to sperm and ova that are donated or that 
might result in a pregnancy. 
• To clarify and make the timing of laboratory 
tests (ie, PK tests, PD tests, and assessment 
of renal function status) and collection of 
vital signs and ECGs consistent throughout 
the protocol. 
• Rationale: To reduce the potential for site 
error. 
• To require IXRS contact during the 
screening visit. 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
• Rationale: To track participants who are 
in prescreening versus screening. 
• To specify that the EAS will include 
participants with a confirmed LMNA 
deleterious mutation and to remove the 
requirement that there is a maximum of 
5 participants in the EAS who do not have a 
centrally confirmed LMNA mutation. 
• Rationale: This amendment requires that 
all participants who are randomized into 
the study possess a centrally confirmed 
LMNA mutation. 
• To correct a typographic error in the 
description of the statistical analysis of the 
KCCQ domains of TSS and PL. 
• Rationale: To provide clarity regarding 
the planned analysis. 
• To specify that the log of the ratio of Week 
4, 12, and 24 NT-proBNP values will be 
analyzed. 
• Rationale: To provide clarity that the log 
ratio will be analyzed. 
Protocol Version 3 
26 March 2018 
At the time of this protocol amendment, the 
study had not been initiated at any study centers 
and no participants had been treated. Protocol 
version 3 was generated to include the following 
key changes: 
• To require central laboratory evaluations at 
screening instead of local laboratory 
evaluations. 
• Rationale: To maintain consistent 
collection of data throughout the study. 
• To add that the DMC will review PK data. 
• Rationale: To clarify that the DMC will 
review all pertinent data. 
• To add Borg fatigue assessments as part of 
the 6MWT. 
• Rationale: To align with all aspects of the 
6MWT per the ATS Committee on 
Proficiency Standards for Clinical 
Pulmonary Function Laboratories. ATS 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
statement: Guidelines for the Six-minute 
Walk Test. 
• To modify the inclusion criteria pertaining to 
the ICD/CRT-D in order to clarify a time 
frame in which the ICD/CRT-D could be 
implanted/initiated. 
• Rationale: To provide a window of time 
to have these devices implanted/initiated 
to provide flexibility to the participants. 
• To modify Appendix 3 in order to change the 
definition of HF-related hospitalization and 
to provide a definition for HF-related urgent 
visits. 
• Rationale: To align with CDISC 
Guidance “Standardized Definitions for 
Cardiovascular and Stroke Endpoint 
Events in Clinical Trials”. 
• To clarify that survival follow-up will only 
be collected during the randomized period 
and not the open-label period. 
• Rationale: To clarify that data will not be 
collected after the endpoint has been 
reached in the randomized period. 
• To add a rationale for the secondary safety 
endpoint pertaining to HFS. 
• Rationale: To provide justification for 
this secondary endpoint. 
• To modify the statistical methodology used 
for estimation and testing of treatment 
effects. 
• Rationale: To align the use of 
stratification in the estimation approach 
of the primary endpoint with the testing 
approach; to clarify the hierarchical 
testing procedure to align with intended 
labeling claims; to add and remove 
sensitivity analyses to more appropriately 
characterize and assess robustness of the 
treatment effect estimates; and, to update 
the approach to analysis of PROs. 


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Document History 
Document/Version Version Date 
Summary and Rationale for Changes 
Protocol Version 2 
23 October 
2017 
Generated to include US regulatory guidance 
and also included clarifications and corrections. 
Protocol Version 1 
10 March 2017 
Developed to support discussions with the US 
regulatory authorities but was not submitted to 
investigational sites, IRBs/ECs, or regulatory 
authorities outside the US. 


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11. REFERENCES 
 
 
 
1 
Awwad O, El-Zahwy SS, Shawky A, et al. Short term statin treatment in idiopathic 
dilated cardiomyopathy. Egypt Heart J. 2012;64(1):15-20. 
 
2 
Han L, Guo S, Lin X, et al. Torasemide reduces dilated cardiomyopathy, complication 
of arrhythmia, and progression to heart failure. Genet Mol Res. 2014;13(3):7262-74. 
 
3 
Youssif A, Abdelaziz A, Afify MJGH. PW062 Cardiac Resynchronization Therapy 
Optimization Using Trans Esophageal Doppler In Patients With Dilated 
Cardiomyopathy. Med J Cairo Univ. 2014;1(9):e274-e75. 
 
4 
Bittner V, Weiner DH, Yusuf S, et al. Prediction of mortality and morbidity with a 
6-minute walk test in patients with left ventricular dysfunction. JAMA. 
1993;270(14):1702-7. 
 
5 
Guyatt GH, Sullivan MJ, Thompson PJ, et al. The 6-minute walk: a new measure of 
exercise capacity in patients with chronic heart failure. CMAJ. 1985;132(8):919. 
 
6 
Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial 
hypertension. N Engl J Med. 2002;346(12):896-903. 
 
7 
Galiè N, Olschewski H, Oudiz RJ, et al. Ambrisentan in Pulmonary Arterial 
Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy 
Studies (ARIES) Group. Ambrisentan for the treatment of pulmonary arterial 
hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, 
double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2. 
Circulation. 2008;117(23):3010-19. 
 
8 
Ghofrani H-A, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary 
arterial hypertension. N Engl J Med. 2013;369:330-40. 
 
9 
Ferreira JP, Duarte K, Graves TL, et al. Natriuretic peptides, 6-min walk test, and 
quality-of-life questionnaires as clinically meaningful endpoints in HF trials. JACC. 
2016;68(24):2690-707. 
 
10 
Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic burden of 
hospitalizations for heart failure: lessons learned from hospitalized heart failure 
registries. JACC. 2014;63(12):1123-33. 
 
11 
Young JB, Dunlap ME, Pfeffer MA, et al. Candesartan in Heart Failure Assessment of 
Reduction in M, Morbidity I, Committees. Mortality and morbidity reduction with 
Candesartan in patients with chronic heart failure and left ventricular systolic 


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dysfunction: results of the CHARM low-left ventricular ejection fraction trials. 
Circulation. 2004;110(17):2618-26. 
 
12 
Okumura N, Jhund PS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, 
Swedberg K, Zile MR, Solomon SD, Packer M. Importance of clinical worsening of 
heart failure treated in the outpatient setting: evidence from the Prospective Comparison 
of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart 
Failure Trial (PARADIGM-HF). Circulation. 2016;133(23):2254-62. 
 
13 
Skali H, Dwyer EM, Goldstein R, et al. Prognosis and response to therapy of first 
inpatient and outpatient heart failure event in a heart failure clinical trial: MADIT‐ 
CRT. European J Heart Fail. 2014;16(5):560-5. 
14 
Butler J, Yang M, Manzi MA, et al. Clinical course of patients with worsening heart 
failure with reduced ejection fraction. JACC. 2019;73(8):935-44. 
 
15 
Hall MJ, Levant S, DeFrances CJ. Hospitalization for congestive heart failure: United 
States, 2000-2010. US Department of Health and Human Services, Centers for Disease 
Control and Prevention, National Center for Health Statistics; 2012. 
 
16 
Setoguchi S, Stevenson LW. Hospitalizations in patients with heart failure: who and 
why. JACC; 2009. 
 
17 
Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a 
diverse genetic architecture. Nat Rev Cardiol. 2013;10(9):531. 
 
18 
Quiat D, Witkowski L, Zouk H, et al. Retrospective analysis of clinical genetic testing in 
pediatric primary dilated cardiomyopathy: testing outcomes and the effects of variant 
reclassification. J Am Heart Assoc. 2020;9:e016195. 
 
19 
Taylor MR, Fain PR, Sinagra G, et al. Natural history of dilated cardiomyopathy due to 
lamin A/C gene mutations. JACC. 2003;41(5):771-80. 
 
20  Fatkin D, MacRae C, Sasaki T, et al. Missense mutations in the rod domain of the lamin 
A/C gene as causes of dilated cardiomyopathy and conduction-system disease. N Engl J 
Med. 1999;341(23):1715-24. 
 
21 
Kumar S, Baldinger SH, Gandjbakhch E, et al. Long-term arrhythmic and 
nonarrhythmic outcomes of lamin A/C mutation carriers. J Am Coll Cardiol. 
2016;68(21):2299-307. 


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22 
BÉCANE HM, Bonne G, Varnous S, et al. High incidence of sudden death with 
conduction system and myocardial disease due to lamins A and C gene mutation. Pacing 
Clin Electrophysiol. 2000;23(11):1661-6. 
 
23 
Meune C, Van Berlo JH, Anselme F, et al. Primary prevention of sudden death in 
patients with lamin A/C gene mutations. N Engl J Med. 2006;354(2):209-10. 
 
24 
Van Berlo JH, De Voogt WG, Van Der Kooi AJ, et al. Meta-analysis of clinical 
characteristics of 299 carriers of LMNA gene mutations: do lamin A/C mutations 
portend a high risk of sudden death? J Mol Med. 2005;83(1):79-83. 
 
25 
Baldassare JJ, Bi Y, Bellone CJJTJoI. The role of p38 mitogen-activated protein kinase 
in IL-1β transcription. J Immunol. 1999;162(9):5367-73. 
 
26 
Brook M, Sully G, Clark AR, et al. Regulation of tumour necrosis factor α mRNA 
stability by the mitogen‐activated protein kinase p38 signalling cascade. FEBS Lett. 
2000;483(1):57-61. 
27 
Kumar S, Boehm J, Lee JCJNrDd. p38 MAP kinases: key signalling molecules as 
therapeutic targets for inflammatory diseases. Nat Rev Drug Discov. 2003;2(9):717-26. 
 
28 
Arabacilar P, Marber M. The case for inhibiting p38 mitogen-activated protein kinase in 
heart failure. Front Pharmacol. 2015;6:102. 
 
29 
Muchir A, Wu W, Choi JC, et al. Abnormal p38α mitogen-activated protein kinase 
signaling in dilated cardiomyopathy caused by lamin A/C gene mutation. Human Mol 
Genet. 2012;21(19):4325-33. 
 
30 
Saqib A, Tsubouchi T, Koch JM, et al. Inhibition of Site Specific Phosphorylation of 
Retinoblastoma Protein by a p38 Inhibitor Decreases Apoptosis, Improves Survival and 
Prevents Cardiomyopathy Caused by a Mutation in LMNA gene. Circulation. 
2011;124:A15685. 
 
31 
Greene SJ, Mentz RJ, Fiuzat M, et al. Reassessing the Role of Surrogate End Points in 
Drug Development for Heart Failure. Circulation. 2018;138(10):1039-1053. 
 
32 
Simonneau G, Barst RJ, Galie N, et al. Treprostinil Study Group. Continuous 
subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with 
pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. 
Am J Respir Crit Care Med. 2002;165(6):800–4. 


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33 
ATS statement: guidelines for the six-minute walk test. ATS committee on proficiency 
standards for clinical pulmonary function laboratories. Am J Respir Crit Care Med. 
2002;166(1):111-7. 
 
34 
EuroQol Group. EuroQol: A new facility for the measurement of health-related quality 
of life. Health Policy 1990;16:199-208. 
 
35 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case 
of the binomial. Biometrika. 1934;26(4):404-13. 

SAP_001.pdf: 
ARRY-371797 (PF-07265803) Protocol C4411002 (previously ARRAY-797-301) Statistical Analysis Plan 
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Page 1 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol C4411002 
 
 
A PHASE 3, MULTINATIONAL, RANDOMIZED, PLACEBO-CONTROLLED 
STUDY OF ARRY-371797 (PF-07265803) IN PATIENTS WITH SYMPTOMATIC 
DILATED CARDIOMYOPATHY DUE TO A LAMIN A/C GENE MUTATION 
(REALM-DCM) 
 
 
 
 
 
 
Statistical Analysis Plan 
(SAP) 
 
 
 
 
 
 
 
 
Version: 
4.0 
 
Date: 
20Jun2022 


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TABLE OF CONTENTS 
LIST OF TABLES.......................................................................................................................... 4 
LIST OF FIGURES ........................................................................................................................ 4 
APPENDICES ................................................................................................................................ 5 
1. VERSION HISTORY .............................................................................................................. 6 
2. INTRODUCTION ................................................................................................................... 8 
2.1. Study Objectives, Endpoints, and Estimands .............................................................. 9 
2.2. Study Design ............................................................................................................... 12 
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................... 14 
3.1. Primary Endpoint(s) .................................................................................................... 14 
3.2. Secondary Endpoint(s) ................................................................................................ 14 
CCI  
 
3.4. Baseline Variables ....................................................................................................... 17 
3.5. Safety Endpoints.......................................................................................................... 17 
3.5.1. Adverse Events ............................................................................................... 18 
3.5.2. Laboratory Data .............................................................................................. 18 
3.5.3. Other Safety Assessments.............................................................................. 19 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) ................................................... 19 
5. GENERAL METHODOLOGY AND CONVENTIONS .................................................... 20 
5.1. Hypotheses and Decision Rules ................................................................................. 20 
5.2. General Methods ......................................................................................................... 22 
5.2.1. Analyses for Continuous Endpoints.............................................................. 22 
5.2.2. Analyses for Binary Endpoints...................................................................... 26 
5.2.3. Analyses for Categorical Endpoints.............................................................. 26 
5.2.4. Analyses for Time-to-Event Endpoints......................................................... 26 
5.3. Methods to Manage Missing Data .............................................................................. 26 
5.3.1. Continuous Endpoints .................................................................................... 26 
5.3.2. Binary Endpoints............................................................................................ 29 
6. ANALYSES AND SUMMARIES ....................................................................................... 29 
6.1. Primary Endpoint(s) .................................................................................................... 29 
6.1.1. Primary Analysis ............................................................................................ 29 
6.1.2. Sensitivity Analyses ....................................................................................... 30 


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6.1.2.1. Sensitivity Analysis Using a Mixed-Effect Model for 
Repeated Measures (MMRM) ............................................................. 30 
6.1.2.2. Sensitivity Analysis Using Trimmed Mean in 
Combination With MI .......................................................................... 30 
6.1.2.3. Sensitivity Analysis to Assess the Impact of Heart Failure 
Determined Withdrawal ....................................................................... 31 
6.1.2.4. Sensitivity Analysis to Assess the Impact of the 
COVID-19 Pandemic ........................................................................... 32 
6.2. Secondary Endpoint(s) ................................................................................................ 32 
6.2.1. Change From Baseline in 6MWT at Weeks 4 and 12 in NYHA 
Class II/III Participants ........................................................................................ 32 
6.2.2. Change From Baseline in KCCQ Domains at Weeks 12 and 24 in 
NYHA Class II/III Participants........................................................................... 32 
6.2.3. Change From Baseline in PGI Scores at Weeks 12 and 24 in NYHA 
Class II/III Participants ........................................................................................ 33 
6.2.4. Change From Baseline in NT-proBNP at Weeks 4, 12, and 24 in 
NYHA Class II/III Participants........................................................................... 33 
6.2.5. The Composite Time to First Occurrence of All-Cause Mortality or 
Worsening Heart Failure ..................................................................................... 34 
6.2.6. Overall Survival ............................................................................................. 34 
CCI  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CCI  
 
6.4. Subset Analyses ........................................................................................................... 38 
6.5. Baseline and Other Summaries and Analyses............................................................ 39 
6.5.1. Baseline Summaries ....................................................................................... 39 
6.5.2. Study Conduct and Participant Disposition .................................................. 39 
6.5.3. Study Treatment Exposure and Compliance ................................................ 39 
6.5.4. Concomitant Medications and Nondrug Treatments ................................... 40 
6.6. Safety Summaries and Analyses................................................................................. 40 
6.6.1. Adverse Events ............................................................................................... 40 
6.6.2. Laboratory Data .............................................................................................. 41 
6.6.3. Vital Signs ...................................................................................................... 41 
6.6.4. Electrocardiograms and Arrhythmia Assessment ........................................ 41 
6.6.5. Physical Examination..................................................................................... 41 
7. INTERIM ANALYSES......................................................................................................... 41 
7.1. Introduction.................................................................................................................. 41 
7.2. Interim Analyses and Summaries ............................................................................... 44 
7.2.1. Interim Futility Analysis ................................................................................ 44 
8. REFERENCES ....................................................................................................................... 45 
9. APPENDICES ........................................................................................................................ 46 
LIST OF TABLES 
Table 1. 
Summary of Changes ..................................................................................... 6 
Table 2. 
Study Objective and Endpoints ..................................................................... 9 
Table 3. 
Algorithm Defining for Win/Loss/Tie at a Given Time Point .................. 25 
Table 4. 
Expected Number of Events on Death or WHF to Rule Out a Non- 
inferiority HR Margin of 1.8 or 2 with Time to the First Composite 
Event Analysis .............................................................................................. 43 
LIST OF FIGURES 
Figure 1. 
Study Schema ............................................................................................... 13 


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APPENDICES 
Appendix 1. Summary of Primary and Secondary Efficacy Analyses ...................................... 46 
Appendix 2. Programming Specifications ................................................................................... 57 
Appendix 3. Definition and Use of Visit Windows in Reporting ............................................. 59 
Appendix 4. Endpoint Derivations .............................................................................................. 60 
Appendix 4.1. Kansas City Cardiomyopathy Questionnaire (KCCQ) ...................................... 60 
Appendix 4.2. Patient Global Impression Scales ........................................................................ 61 
Appendix 4.3. Borg Fatigue Assessment..................................................................................... 63 
Appendix 5. List of Abbreviations .............................................................................................. 64 


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1. VERSION HISTORY 
This statistical analysis plan (SAP) for Study C4411002 (previously ARRAY-797-301) is 
based on Protocol Amendment 8 dated 09Feb2022. 
 
Table 1. 
Summary of Changes 
 
Version/Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
03Mar2021 
Amendment 7 
17Feb2021 
Not applicable (N/A) 
N/A 
Amendment 1 
Amendment 7 
1.Updated the testing orders of NT- 1. Clarified that the KCCQ PL 
03June2021 
17Feb2021 
proBNP and KCCQ PL and TSS 
domain score is tested prior to the 
Version 2.0 
domains in the hierarchical testing 
TSS in the endpoint hierarchy; 
procedure in Section 5.1 as 
Moved NT-proBNP in the 
requested by FDA. 
hierarchical testing procedure after 
the composite endpoint of time to 
first worsening heart failure or all- 
cause mortality. 
2. Provided additional details on 
2. Added the detailed specifications 
blinded sample size re-estimation in on re-estimating study sample size 
Section 7.1 Interim Analysis. 
based on the interim blinded data. 
3. Added clarification regarding 
3. Clarified that the primary method 
primary method to describe the 
to describe the treatment effect for 
treatment effect and additional 
the primary efficacy endpoint will be 
missing data summary in Section 
a stratified HL median difference in 
6.1.1. 
the change of 6MWT from baseline 
at Week 24, and that the win ratio 
will be used as a supportive analysis; 
added additional descriptive 
summary on missing data reason and 
imputation type. 
4. Editorial changes in Section 
4. Moved the description of stratified 
5.2.1. 
win-ratio method as a supportive 
analysis after the stratified HL 
method. 
5. Clarified the testing order on the 
5. Added a sentence that the KCCQ 
KCCQ PL prior to the KCCQ TSS 
PL will be tested first followed by the 
in Section 6.2.2 to be consistent 
KCCQ TSS. 
with Section 5.1. 
6. Updated Appendix 2 to align 
6. Inserted the SAS statements on 
Programming Specifications with 
imputing monotone missing values 
imputation algorithm in Section 
under MAR; Added the number of 
5.3.1. 
days on treatment as a covariate in 
the imputation model for intermittent 
and monotone missing data. 


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Table 1. 
Summary of Changes 
 
Version/Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
7. Updated Appendix 3 to extend 
analysis visit window to account 
for the potential impact of COVID- 
19 pandemic on follow-ups. 
7. Extended analysis visit window to 
± 3 weeks from ± 2 weeks for 
efficacy variables collected at the 
Week 12 visit or after in the 
randomized period. 
Amendment 2 
22Mar2022 
Version 3.0 
Amendment 8 
09Feb2022 
1.Updated the title page to include 
study name and branding 
implemented after protocol version 
7 approval. 
2.Updated Sections 2.1, 3.2, and 
3.3, 6.3 to remove specified 
timepoints to be consistent with 
protocol amendment. 
3.Updated Section 2.2 to reflect the 
new study sample size based on the 
blinded sample size re-estimation 
(BSSR) for the primary endpoint 
and added clarification on survival 
follow-up. 
4.Modified the definition of the 
Efficacy Analysis Dataset and 
NYHA Class IV Analysis dataset to 
include all randomized participants 
in the respective analyses in 
Section 4. 
5.Updated Sections 5.1 and 7.1 to 
reflect the new study sample size 
based on the completed BSSR for 
the primary endpoint following the 
interim futility analysis. The 
sentences referencing 52 events 
required to assess the composite 
all-cause mortality or worsening 
heart failure (WHF) was removed 
after adding more text to Section 
7.1 clarifying the number of events 
on all-cause mortality or WHF 
needed under various scenarios. 
6.Updated Section 6.1.1 to add a 
responder analysis and cumulative 
distribution plot to characterize the 
treatment effect on the primary 
endpoint. 
1.Added the study name (REALM- 
DCM) to the title page. 
2.Removed specified timepoint in 
secondary and CCI 
endpoints 
given measurements are assessed 
throughout the double-blind period. 
3.Included a change in the number of 
participants randomized into the 
study and added the text regarding 
survival follow-up. 
4.Removed the inclusion criterion 
“with a LMNA gene mutation that is 
pathogenic, likely pathogenic or 
VUS” in the definition of Efficacy 
Analysis Dataset and NYHA Class 
IV Analysis dataset. 
5.Added the text regarding the DMC 
recommendation to continue the 
study as designed based on futility 
analysis and a change in the number 
of participants randomized into the 
study based on the BSSR. Additional 
sample size calculation was added to 
assess the number of events needed 
under various scenarios for blinded 
monitoring of the composite endpoint 
of time to first occurrence of all- 
cause mortality or WHF. The text 
specifying 52 events are required to 
assess the composite endpoint was 
removed. 
6.Added the details on the definition 
of the responder analysis and the 
cumulative distribution plot of 
responses by change from baseline in 
6MWT to Week 24. 


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Table 1. 
Summary of Changes 
 
Version/Date 
Associated 
Protocol 
Amendment 
Rationale 
Specific Changes 
7.Updated Section 6.1.2 to add a 
new sensitivity analysis to the 
primary endpoint using a mixed- 
effect model for repeated measure 
(MMRM). 
7.Included a detailed description of 
the MMRM specification. 
Amendment 3 
20Jun2022 
Version 4.0 
1. Updated Section 4 to add an 
interim analysis set used for interim 
futility assessment on change from 
baseline in 6MWT at Week 24. 
2. Updated Sections 5 and 7 to add 
an additional interim analysis to 
assess futility based on change 
from baseline in 6MWT at Week 
24 given the change in timepoint of 
the primary endpoint from 12 to 24 
weeks and the longer than 
anticipated duration of the 
enrollment period. 
1. Provide the definition of interim 
analysis set corresponding to the 
interim futility analysis on change 
from baseline in 6MWT at Week 24. 
2. Included detailed specifications on 
the interim futility analysis of change 
from baseline in 6MWT at Week 24. 
 
2. INTRODUCTION 
Dilated cardiomyopathy due to lamin A/C gene mutations (LMNA-related DCM) can present 
as a de novo mutation or more frequently as an autosomal dominant inheritance, and is 
usually accompanied by supraventricular and ventricular arrhythmias and/or conduction 
system disease (CSD). The majority of patients with LMNA-related DCM follow a clinical 
course starting with CSD and/or arrhythmias in early to mid-adulthood, with some early 
mortality due to sudden cardiac arrest from a fatal arrhythmia or embolus.  Over time, most 
patients progress to DCM, which can lead to rapidly progressive heart failure (HF). 
Currently, there is no effective, disease-specific treatment available for LMNA-related DCM. 
To date, treatment is limited to conventional therapies for HF with reduced ejection fraction 
(angiotensin-converting-enzyme inhibitors, angiotensin 2 receptor blockers or angiotensin 
receptor-neprilysin inhibitor, beta blockers, aldosterone receptor antagonists, inhibitors of 
sodium-glucose cotransporter 2 and diuretics) which are largely symptomatic and supportive. 
Progressive deterioration in left ventricular (LV) function and refractory HF symptoms are 
often treated with resynchronization therapy (bi-ventricular pacing [CRT]). Risk of sudden 
cardiac death (SCD) is managed with placement of an implantable cardioverter defibrillator 
(ICD) or CRT defibrillator (CRT-D).  In patients whose disease continues to progress in spite 
of aggressive cardiovascular management, left ventricle assist device and cardiac 
transplantation may be considered. 
 
The C4411002 pivotal Phase 3 study will evaluate the clinical efficacy and safety of 
PF-07265803 in participants with symptomatic LMNA-related DCM who meet study 
eligibility criteria. 


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This SAP provides the detailed methodology for summary and statistical analyses of the data 
collected in Study C4411002.  This document may modify the plans outlined in the protocol; 
however, any major modifications of the primary endpoint definition or its analysis will also 
be reflected in a protocol amendment. Any deviations from this analysis plan will be 
described in the clinical study report (CSR). 
 
2.1. Study Objectives, Endpoints, and Estimands 
Study objectives and corresponding endpoints are provided in Table 2 below. Participants 
who discontinue study treatment or have study drug interruption prior to Week 24 will 
continue to have all assessments performed as scheduled through the Week 24 Visit. All data 
collected during the study will be included for the analyses of efficacy regardless of 
discontinuation of study treatment or study drug interruption. 
 
The estimand for the primary and secondary endpoints will employ a combination of a 
treatment policy strategy and a composite strategy.  For the intercurrent event of death (due 
to any cause) and study discontinuation prior to the analysis time point, a composite strategy 
will be used, where death and study discontinuation will be considered unfavorable and 
represented by lowest (worst) set of ranks of a combined outcome variable as described in 
Section 5.2.1.  For premature discontinuation of randomized treatment, a treatment policy 
strategy will be used. 
 
Table 2. 
Study Objective and Endpoints 
 
Objectives 
Endpoints 
Primary: 
Primary: 
Evaluate the effect of ARRY-371797 (PF-07265803) on 
functional capacity (as measured by the 6 Minute Walk 
Test [6MWT]) compared to placebo. 
New York Heart Association (NYHA) Class II/III 
participants only: Change from baseline in 6MWT at 
Week 24. 
Secondary: 
Secondary: 
Evaluate additional measures of efficacy of ARRY-371797 
(PF-07265803) compared to placebo in the randomized 
period. 
NYHA Class II/III patients only: Change from baseline in 
6MWT at Weeks 4 and 12. 
NYHA Class II/III participants only: Change from baseline 
in Kansas City Cardiomyopathy Questionnaire (KCCQ) 
Physical Limitation (PL) and Total Symptom Score (TSS) 
domains at Weeks 12 and 24. 
NYHA Class II/III participants only: Change from baseline 
in Patient Global Impression (PGI) scores at Weeks 12 and 
24: 
• 
Patient Global Impression of Severity (PGI-S); 
• 
Patient Global Impression of Change (PGI-C). 
NYHA Class II/III participants: Change from baseline in 
N-terminal pro-brain natriuretic peptide (NT-proBNP) at 
Weeks 4, 12, and 24. 


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Table 2. 
Study Objective and Endpoints 
 
Objectives 
Endpoints 
Evaluate the impact of ARRY-371797 (PF-07265803) on 
composite endpoint of all-cause mortality, or worsening 
heart failure (WHF). 
Defined as the time from randomization to the first 
occurrence of any event of death due to any cause, or 
worsening heart failure (HF-related hospitalization or 
HF-related urgent care visit). 
Evaluate the impact of ARRY-371797 (PF-07265803) on 
overall survival (OS). 
OS 
Evaluate the safety of ARRY-371797 (PF-07265803) 
compared to placebo. 
Safety as determined by: 
• 
Incidence and severity of Adverse Events (AEs); 
• 
Changes in clinical safety laboratory tests, vital signs, 
and 12 lead electrocardiography (ECGs); 
• 
Incidence and severity of ventricular or atrial 
arrhythmias detected using existing ICD/cardiac 
resynchronization therapy defibrillator (CRT-D) or 
other applicable device interrogations. 
CCI 


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Table 2. 
Study Objective and Endpoints 
 
 
Objectives 
Endpoints 
CCI


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2.2. Study Design 
This multinational Phase 3 study will evaluate the efficacy, safety, and PK following 
treatment with ARRY-371797 (PF-07265803) compared with placebo (1:1 randomization) in 
at least 160 participants with LMNA- related DCM in NYHA functional Class II and III. 
Additional LMNA-related DCM in NYHA functional Class IV participants (up to 40) may be 
randomized (1:1) and will be assessed for overall safety and time from randomization to 
HF-related hospitalization, HF-related urgent care visits or death due to any cause, in 
addition to PK and efficacy, if feasible.  The sample size was increased following completion 
of a planned blinded sample size re-estimation. Up to 200 eligible participants with 
symptomatic cardiomyopathy due to LMNA mutations will be randomized, at approximately 
60 to 90 investigational centers, globally.  The sample size determination is detailed in 
Section 5.1. 
 
The study will be conducted in 2 parts: a randomized, double-blind treatment period, 
followed by an ARRY-371797 (PF-07265803) open-label treatment period.  During the 
randomized, double-blind period, participants, investigators, site personnel, and the sponsor 
personnel directly involved with the conduct of the study will remain blinded to assigned 
treatment. The double-blind period will continue until the primary analysis which includes 
an assessment of the primary efficacy endpoint and completion of an evaluation of a 
composite endpoint consisting of all-cause mortality or worsening heart failure (HF-related 
hospitalization or HF-related urgent care visits).  Following the primary analysis, a seamless 
transition to the open-label phase may begin and ongoing treatments will be unblinded and 
participants receiving placebo may initiate treatment with ARRY-371797 (PF-07265803) 
provided eligibility criteria are met. The end of the study is reached once the last participant 
has had the opportunity to be followed for at least 24 weeks in the open-label period of the 
study or has discontinued from the study. 
 
Participants who discontinue study drug prior to Week 24 should continue to have all 
assessments performed as scheduled through the Week 24 Visit.  Every effort should be 
made to obtain these data.  During the randomized period of the study, all patients enrolled in 
the study will be followed for survival approximately every 3 months until death, lost to 
follow-up, or withdrawal of consent, or initiation of the open-label treatment period, 
whichever occurs first. Phone calls are acceptable when clinic visits are not already 
performed.  Vital status may be ascertained from family, caregivers, or public records, where 
appropriate. 


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Figure 1. Study Schema 
 
 
 
 
 
DCM=dilated cardiomyopathy; LMNA=gene encoding the lamin A/C protein; NYHA=New York Heart 
Association; 6MWT=6 Minute Walk Test. 


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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS 
3.1. Primary Endpoint(s) 
• NYHA Class II/III participants: Change from baseline in 6MWT at Week 24. 
 
3.2. Secondary Endpoint(s) 
• NYHA Class II/III participants: Change from baseline in 6MWT at Weeks 4 and 12. 
 
• NYHA Class II/III participants: Change from baseline in KCCQ PL and TSS domains at 
Weeks 12 and 24. 
 
The KCCQ measures the effects of symptoms, functional limitations, and psychological 
distress on an individual’s health-related quality of life. The KCCQ has 23 items which 
assess the ability to perform activities of daily living, frequency and severity of symptoms, 
the impact of these symptoms, and health-related quality of life (QoL).  Response options 
vary by question.  Summaries on distinct domains derived from the individual questions in 
the KCCQ are provided in Appendix 4.1. Domain scores are transformed to a 0 to 100 
range; higher scores indicate better health status. 
 
• NYHA Class II/III participants: Change from baseline in PGI scores at Weeks 12 and 24: 
 
• PGI-S; 
 
• PGI-C. 
 
Participants will rate the severity of their heart failure symptoms and physical activity 
limitations during the past week on the 2 PGI-S questions (see Appendix 4.2).  Participants 
will rate the overall change (if any) in their heart failure symptoms and physical activity 
limitations since they began taking the study medication on the 2 PGI-C questions (see 
Appendix 4.2).  The PGI-S will be completed first followed by the PGI-C after completing 
the KCCQ.  These data will be used to provide an anchor to define thresholds for 
improvements in KCCQ. 
 
• NYHA Class II/III participants: Change from baseline in NT-proBNP at Weeks 4, 12, 
and 24 
 
• The composite endpoint of all-cause mortality, or WHF: Defined as the time from 
randomization to the first occurrence of any event of death due to any cause, or 
worsening heart failure (HF-related hospitalization or HF-related urgent care visit). 
 
• OS 
 
• Safety as determined by: 
 
• Incidence and severity of AEs; 


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• Changes in clinical safety laboratory tests, vital signs and 12-lead ECGs; 
 
• Incidence and severity of ventricular or atrial arrhythmias detected using existing 
ICD/CRT-D or other applicable device interrogations. 
CCI  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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CCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3.4. Baseline Variables 
Randomization is initially stratified based on NYHA class: Class II/III or Class IV. NYHA 
Class II/III participants will be further stratified by the average of the Day -1 and Baseline 
Visit (Day 1) 6MWT (<320 m or ≥320 m), and LMNA mutation type (pathogenic/likely 
pathogenic [P/LP] or variants of unknown significance [VUS]). 
 
In all 6MWT analyses, baseline will be calculated as the average of the non-missing 6MWT 
assessments recorded at assessment Day -1 and baseline (prior to randomization).  Calculated 
baseline values for the 6MWT will be labeled as “Baseline (Calculated)” in the outputs to 
distinguish them from the Baseline visit values collected on the electronic case report form 
(eCRF).  Baseline (Calculated) 6MWT values will be used in stratified efficacy analyses 
where analyses will be stratified by quartiles of baseline 6MWT. 
 
Baseline for secondary and CCI 
endpoints is defined as the last observation up to and 
including Baseline Visit (Day 1). 
 
3.5. Safety Endpoints 
Safety will be assessed by medical history, physical examinations, vital signs, ECG including 
ICD/CRT-D interrogations, clinical laboratory tests, and the spontaneous reporting of AEs, in 
all participants who received at least 1 dose of study intervention. Unscheduled safety 
assessments may be performed at any time during the study to assess any perceived safety 
concerns. 


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3.5.1. Adverse Events 
Medical Dictionary for Regulatory Activities (MedDRA) will be used to classify all AEs 
with respect to system organ class (SOC) and preferred term (PT). 
 
The treatment emergent safety reporting period is defined as the period from the date of the 
first dose up to 30 days after the last dose of the study drug.  An AE is considered a 
treatment-emergent adverse event (TEAE) if the event started during that reporting period. 
 
Safety endpoints will be assessed by: 
 
• Incidence of TEAEs. 
 
• Incidence of Serious Adverse Events (SAEs). 
 
Hematology 
Chemistry 
Urinalysis 
Other 
Hemoglobin 
Hematocrit 
red blood cells (RBC) 
Platelets 
white blood cells (WBC) 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Albumin 
Alkaline phosphatase 
aspartate 
aminotransferase (AST) 
Gamma- 
glutamyltransferase 
(GGT) 
alanine aminotransferase 
(ALT) 
Bicarbonate (CO2) 
Total bilirubin 
blood urea nitrogen 
(BUN) 
Calcium 
Chloride 
creatine kinase (CK) 
Creatinine 
Glucose 
Magnesium 
Inorganic Phosphate 
Potassium 
Total protein 
Sodium 
Uric acid 
Direct bilirubin (if total 
bilirubin values are 
abnormal) 
NT-proBNP 
Troponins 
C-reactive protein 
Blood 
Glucose 
Ketones 
Leukocytes 
hydrogen ion 
concentration (pH) 
Protein 
At screening only: 
• 
Human 
immunodeficiency 
virus (HIV), Hepatitis 
B and C 
• 
thyroid-stimulating 
hormone (TSH) 
• 
estimated glomerular 
filtration ratio (eGFR) 
calculation 
• 
LMNA mutation 
If applicable: 
• 
Serum pregnancy test 
• 
Urine pregnancy test 
• 
follicle-simulating 
hormone (FSH) 
• Incidence of AEs leading to discontinuation. 
 
3.5.2. Laboratory Data 
Laboratory testing will be performed at screening and throughout the study.  The tests 
detailed in the table below will be performed by the central laboratory. 


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3.5.3. Other Safety Assessments 
• Complete physical examination and brief physical examination. 
 
• Vital Signs: parameters include blood pressure (systolic and diastolic), pulse rate, 
respiratory rate, and temperature. 
 
• Arrhythmia assessment: incidence of new and clinically significant ventricular or atrial 
arrhythmias will be assessed by an ICD/CRT-D applicable device interrogations. 
 
• ECG: A single 12-Lead ECG produces the following parameters: heart rate, PR, QT, 
corrected QT intervals (ie,correcting QT Fridericia method [QTcF]), and QRS complex. 
The ECG will also be interpreted for clinically significant findings. 
 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS) 
For purposes of analysis, the following analysis sets are defined: 
 
Participant Analysis Set 
Description 
Full Analysis Set (FAS) 
The FAS will consist of all randomized participants. 
Participants in the FAS will be analyzed according to the 
treatment to which they were randomized. 
Efficacy Analysis Set 
(EAS) 
The EAS will include all NYHA functional Class II or III 
randomized participants.  Participants will be analyzed 
according to the treatment to which they were randomized. 
CCI 
Interim Analysis Set 1 
(IAS1) 
A subset of the EAS which includes the first 60 randomized 
NYHA Class II or III participants with a LMNA gene 
mutation that is pathogenic, likely pathogenic or VUS.  This 
analysis set will be used for interim futility assessment on 
change from baseline in 6MWT at Week 12 . 
Interim Analysis Set 2 
(IAS2) 
A subset of the EAS which includes the first 68 randomized 
NYHA Class II or III participants with a LMNA gene 
mutation that is pathogenic, likely pathogenic or VUS.  This 
analysis set will be used for interim futility assessment on 
change from baseline in 6MWT at Week 24. 
Safety Analysis Set (SAS) 
The SAS will include all participants who received at least 
1 dose of study intervention regardless of NYHA functional 
class. Participants will be analyzed according to the initial 
treatment received. This analysis set will be used for the 
WHF, all-cause mortality, and safety endpoints. 


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Participant Analysis Set 
Description 
Pharmacokinetic Set (PK) 
The PK set will consist of all participants who receive at least 
1 dose of PF-07265803 and have at least 1 quantifiable 
postdose PK blood collection with associated valid 
bioanalytical results. 
 
5. GENERAL METHODOLOGY AND CONVENTIONS 
5.1. Hypotheses and Decision Rules 
Sample Size Determination 
 
Following a pre-specified blinded sample size re-estimation, at least 160 NYHA Class II and 
III participants will be included in the EAS.  In addition, up to 40 NYHA Class IV 
participants may be enrolled (randomized 1:1 to PF‑07265803 and placebo) CCI 
 
 
 
 
 
Sample size estimation was initially determined based on a change from baseline in 6MWT 
at Week 12.  Following a protocol amendment to update the primary endpoint to change from 
baseline in 6MWT at Week 24, the same assumptions were applied given the protocol 
requirement for participants who discontinue study treatment to continue with follow-up 
through at least Week 24 and the anticipated low mortality rate within the study population. 
Sample size and assumptions prior to the pre-specified blinded sample size re-estimation are 
outlined below. The blinded sample size re-estimation was performed by an internal team 
who are not directly involved with the day-to-day activities of the study. To ensure the 
integrity of the trial the specific assumptions resulting in the increase in sample size will not 
be disclosed until the time of primary reporting. 
 
With 60 participants per treatment arm the study will have approximately 90% power to 
demonstrate a statistically significant effect for the primary endpoint of Week 24 6MWT 
change from baseline, at a 2-sided a=0.05 if the true treatment effect is 35 meters, there is a 
standard deviation (SD) of 50 meters for the change from baseline and 10% of participants 
do not have data recorded at Week 24.  This assessment was made by simulation and further 
assuming that: 
 
• The correlation between the baseline and Week 24 values for the 6MWT is 0.44 as 
observed in the completed Phase 2 study ARRAY-797-231. 
 
• Data are analyzed using a stratified Wilcoxon Rank-sum test with participants stratified 
into 4 groups according to baseline quartile of 6MWT. 
 
• 1.25% of participants die before Week 24 and are given the worst set of ranks ordered 
according to their survival time. 


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• The participants who are alive and who do not have data recorded at Week 24 are given a 
tied ranking worse than any participant with data recorded and better than any participant 
who died before Week 24. 
 
• The probability of dropout is related to outcome so that dropout is half as likely for 
participants with Week 24 6MWT values more than 1 standard deviation (SD) above the 
mean compared to participants 1 SD below the mean. 
 
• An interim futility analysis will be performed after the first 60 randomized NYHA 
Class II/III participants from the EAS population have completed the Week 12 
assessment or have discontinued prior to Week 12. 
 
As noted in Section 7.1, blinded data at the time of the interim futility analysis were utilized 
to evaluate the rates of deaths and study discontinuation prior to Week 24, and the standard 
deviation for the change from baseline in 6MWT at Week 24 to allow for a reassessment of 
the sample size.  Following completion of the planned blinded sample size re-estimation, up 
to 200 eligible participants with symptomatic cardiomyopathy due to LMNA will be 
randomized, including at least 160 participants with NYHA functional Class II or III and up 
to 40 participants with NYHA functional Class IV. 
 
Primary Efficacy Analysis 
 
For the primary endpoint, the null hypothesis is that the treatment groups for PF-07265803 
and placebo do not differ with respect to functional capacity. The alternative hypothesis of 
interest is that there is a difference in functional capacity in favor of PF-07265803. 
Functional capacity will be measured by change from baseline in 6MWT at Week 24 with a 
rank-based test to account for deaths or withdrawals prior to Week 24 (see Section 6.1). 
PF-07265803 will be declared superior to placebo if the null hypothesis of no difference 
between PF-07265803 and placebo is rejected at the significance level of 0.05 (2-sided). 
 
If the primary endpoint of change from baseline in 6MWT at Week 24 is statistically 
significant, inferential testing on secondary endpoints will be performed in the following 
hierarchical order: Week 24 change from baseline in the KCCQ PL score, Week 24 change 
from baseline in the KCCQ TSS, the composite endpoint comprised of all-cause mortality or 
worsening heart failure (HF-related hospitalization or HF-related urgent care visit), and NT- 
proBNP.  To maintain the overall alpha at 0.05, each hypothesis will be tested at the 0.05 
level if the endpoint earlier in the hierarchy is deemed statistically significant. CCI 
 
 
Interim Futility Analysis for Change from Baseline in 6MWT at Week 12 
 
An interim futility analysis of change from baseline in 6MWT at Week 12 was performed 
after the first 60 randomized NYHA Class II/III participants had completed the Week 12 
assessment or discontinued from the study prior to Week 12. The non-binding futility 
boundary was calculated as function of information using Hwang-Shih-DeCani spending 
function with gamma = -1.54. The one-sided p-value boundary for information fraction 
equal to 0.5 was 0.315 at the interim look.  As the objective of this interim futility analysis 


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was not to terminate the study early for the benefit of efficacy, no adjustment of alpha is 
needed as a result of the interim analysis. At the time of the planned interim futility analysis, 
the DMC recommended to continue the study as designed. 
 
Blinded Sample Size Re-Estimation and All-Cause Mortality or WHF Event Monitoring 
 
Following the interim analysis for futility described above, a blinded sample size re- 
estimation for the primary endpoint of change from baseline in 6MWT at Week 24 was 
conducted by an internal BSSR review committee using blinded cumulative primary efficacy 
data from the interim data cut.  Specifically, a blinded, pooled analysis across treatment 
groups was used to estimate variability of change from baseline in 6MWT assessments at 
Week 24 and the overall event rates for deaths and discontinuations prior to Week 24. 
Further details on blinded sample size re-estimation are described in Section 7.1 Interim 
Analysis. 
 
In addition to the sample size re-estimation for the primary endpoint, the sponsor will 
monitor the pooled (blinded) cumulative event counts for the composite safety endpoint 
comprising of all-cause mortality or worsening of heart failure throughout the study.  Further 
details on the blinded assessment of the composite endpoint are provided in Section 7.1. 
 
Interim Futility Analysis for Change from Baseline in 6MWT at Week 24 
 
Given the change in timepoint of the primary endpoint from 12 to 24 weeks and the longer 
than anticipated duration of the enrollment period, an additional interim futility analysis 
based on the primary endpoint of change from baseline in 6MWT at Week 24 will be 
conducted after the first 68 randomized NYHA Class II/III participants have completed the 
Week 24 assessment or discontinued from the study prior to Week 24 (see Section 7). 
 
 
5.2. General Methods 
Analysis results will be presented using descriptive statistics.  For continuous variables, the 
number of participants (n), mean, SD or standard error (SE), median, first quartile (Q1), third 
quartile (Q3), minimum, and maximum will be presented. For binary and categorical 
variables, the number and percentage of subjects in each category will be presented. 
 
All statistical tests will be 2-sided and performed at the 5% significance level unless 
otherwise specified. 
 
5.2.1. Analyses for Continuous Endpoints 
For the analyses of the primary and secondary endpoints (ie, 6MWT, KCCQ, and 
NT-proBNP), a rank-based non-parametric approach will be used that accounts for deaths or 
discontinuations from study prior to the analysis time point. Participants who died will be 
ranked below those who discontinued from study, and those participants, in turn, will be 
ranked below all those who completed the study.  The relative ranks will be determined by 
survival time among those participants who died and by length of time in the study among 
those who discontinued from study.  The p-value from the van Elteren test will be provided 


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to assess the statistical significance of the treatment difference between PF-07265803 and 
placebo. 
 
The following summaries will be provided to describe the treatment effect: 
 
• A summary of the stratified Hodges-Lehmann (HL) median difference between treatment 
groups in the change from baseline to the analysis time point and corresponding 95% CI 
(primary description of the treatment effect). 
 
• A stratified win-ratio and corresponding 95% confidence interval (CI). 
 
• A summary of the number of deaths and discontinuations prior to the analysis time point 
on each treatment arm. 
 
The Van Elteren Test and Algorithm for Ranking 
 
The van Elteren test is an extension of the stratified Wilcoxon Rank-sum test.  In the 
van Elteren test, each stratum is weighted by 1/(nk + 1), where nk denotes the total number of 
participants in stratum k.  Participants will be placed into 1 of 4 strata according to the 
quartiles of baseline value of the 6MWT endpoint as follows: 
 
• Participants will be included in stratum 1 if their overall rank is ≤0.25*n. 
 
• Participants will be included in stratum 2 if their overall rank is and >0.25*n and ≤0.5*n. 
 
• Participants will be included in stratum 3 if their overall rank is >0.5*n and ≤0.75*n. 
 
• Participants will be included in stratum 4 if their overall rank is >0.75*n. 
where n is the total number of participants in the EAS. 
After multiple imputation (see Section 5.3.1) and prior to analysis, the continuous primary 
and secondary endpoints (ie, 6MWT, KCCQ, and NT-proBNP) at each time point of interest 
will be ranked as follows ordered from lowest (worst) to highest rank on each imputed 
dataset. 
 
• Participants who die prior to the analysis time point will be given the lowest set of ranks 
ordered from shortest to longest survival time. Note that participants who have 
discontinued from study and then died prior to the analysis timepoint are ranked based on 
survival time, instead of time to study discontinuation. 
 
• Participants who discontinue from study prior to the analysis time point for any reason 
will be ranked next lowest ordered based on their time to discontinuation. 
 
• Participants who remain in the trial at or beyond the analysis time point but who have a 
missing assessment in the endpoint (eg, due to COVID-19) will have missing values 
imputed for the endpoint using the method of Markov chain Monte Carlo (MCMC) 
multiple imputation (MI) assuming a multivariate normal distribution over all variables 


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k=l
 
 
included in the imputation model. This imputation will be done by treatment group with 
number of days on treatment, baseline values, and values observed at Weeks 4, 12, 24, 
and 36 included in the imputation.  For participants who do not die or discontinue the 
study prior to the analysis time point but have monotone missing data and subsequently 
discontinue the study at a later timepoint, missing data will be imputed under missing at 
random (MAR) for those who discontinue due to issues outside of the study (eg, due to 
COVID-19) and imputed using control-based MI for those who discontinuation due to 
post randomization events (eg, AEs or perceived lack of efficacy). 
 
• The imputed values from those with the missing assessment will be used along with the 
observed values from all other participants to rank the remaining participants from 
greatest reduction (change less than 0) to greatest increase for the endpoint at the analysis 
time point. 
 
The van Elteren test will be performed on each imputed dataset. The statistical significance 
of the analysis will be based on the asymptotic, continuity corrected p-value. The results 
from these multiple datasets will be pooled using the Rubin’s rule (see Section 5.3.1). 
 
Stratified Hodges-Lehmann (HL) Estimator 
 
A stratified HL estimate will be used to describe the treatment effect (magnitude of change) 
for the endpoint at the analysis time point.  Participants will be stratified by baseline 6MWT 
quartiles. Missing data due to issues outside of the study (eg, due to COVID-19 pandemic) 
will be imputed based on a missing at random (MAR) assumption. Missing data for 
discontinuation due to post randomization events (eg, AE or perceived lack of efficacy) will 
be imputed using control-based MI (see Section 5.3.1).  Imputations following death will not 
be utilized as imputed values for participants who died prior to the assessment timepoint 
would not be interpretable. 
 
In each multiply imputed dataset, the within stratum HL estimate will be calculated as the 
median of the n1k*n2k pairwise differences between n1k and n2k participants in the 2 treatment 
arms. The overall stratified HL estimate is then calculated in each multiply imputed dataset 
as a weighted average of the within stratum HL estimates by weighting each stratum HL 
estimate by wk = (nk + 1)/∑(nk + 1). That is ∆೦HL = ∑S 
wk∆೦k, where ∆೦k is the HL estimator 
in the kth stratum and ∑S 
w  = 1, w >0. This linear combination ∆೦HL is asymptotically 
k=l 
k 
k 
median unbiased and normally distributed with standard error given by 
SE =    ∑S 
(Wk SE )2.  Thus, as with van Elteren and win ratio, the overall stratified HL 
k=l 
j 
estimates calculated for each imputation can then be pooled using the Rubin’s rule (see 
Section 5.3.1). 
 
The Win Ratio and Algorithm for Defining Winners/Losers/Ties 
 
A stratified win ratio will be used to aid in the interpretation of the van Elteren test.  It is 
essentially the ratio of the win proportion for the active treatment to the win proportion for 
the control group. The win ratio is connected to the Mann-Whitney U test under the 


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framework of prioritized pairwise comparisons (Dong, 2020).1   The treatment is beneficial 
compared to the control if the win ratio is greater than 1. 
 
The stratified win ratio is based on the principle that each participant in the PF-07265803 
group is compared with every participant in the placebo group within each stratum (ie, 
baseline 6MWT quartile) in a pair-wise manner. Applying the same ranking algorithm used 
in the van Elteren test, the pair-wise comparison proceeds in hierarchical fashion using time 
to death for those who died prior to the analysis time point first, followed by time to 
discontinuation from study for those who discontinued prior to the analysis time point, and 
then changes from baseline in the endpoint at the time point. 
 
The detailed algorithm defining for ‘Win’, ‘Loss’ and ‘Tie’ is provided in Table 3 below. 
For each pair, the active treatment participant (PF-07265803) is labelled as a 'winner' or a 
'loser' based on status at or prior to the analysis time point (eg, Week 24 for the primary 
analysis).  The win ratio is the total number of winners divided by the total numbers of 
losers. 
 
Table 3. 
Algorithm Defining for Win/Loss/Tie at a Given Time Point 
 
Placebo 
Died time XP 
Alive/discontinued 
from study time YP 
Alive/ 
change from baseline 
ZP 
Active 
treatment 
(PF- 
07265803) 
Died time XA 
If XA < XP, then 
Category = ‘Loss’ for 
active treatment 
If XA > XP, then 
Category = ‘Win’ for 
active treatment 
Else category = ‘Tie’ 
Category = ‘Loss’ for 
active treatment 
Category = ‘Loss’ for 
active treatment 
Alive/discontinued 
from study time YA 
Category = ‘Win’ for 
active treatment 
If YA < YP, then 
Category = ‘Loss’ for 
active treatment 
If YA > YP, then 
Category = ‘Win’ for 
active treatment 
Else category = ‘Tie’ 
Category = ‘Loss’ for 
active treatment 
Alive/change from 
baseline ZA 
Category = ‘Win’ for 
active treatment 
Category = ‘Win’ for 
active treatment 
If ZA < ZP, then 
Category = ‘Loss’ for 
active treatment 
If ZA > ZP, then 
Category = ‘Win’ for 
active treatment 
Else Category = ‘Tie’ 
Footnote: if a participant withdrew and then died prior to the analysis timepoint, the participant will be 
counted as death. 


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The stratified win ratio is achieved by counting the wins separately within each stratum 
(ie, stratum-specific wins) and then combining the stratum-specific wins to estimate the 
stratified win ratio. A weighting, defined as the reciprocal of the stratum size, is used in this 
calculation. The variance estimate of the stratified win ratio will be calculated based on 
Equation (8) of Dong, et al (2018).2 
 
This process produces a stratified win ratio for each imputed dataset.  As with the van Elteren 
test, the results from these multiple datasets will be pooled using the Rubin’s rule (see 
Section 5.1). 
 
5.2.2. Analyses for Binary Endpoints 
For analysis of the binary endpoints, observations after death or discontinuation from study, 
or missing values for any reasons will be handled by setting the endpoint to nonresponsive. 
This method of handling missing response is known as missing response as non-response 
(MR-NR). A Cochran-Mantel-Haenszel (CMH) test stratified by stratification factors at 
randomization (see Section 3.4) will be used as a test for proportions of participants (see 
Section 6.2.2).  The stratification factor for P/LP vs VUS will be removed if the number of 
events in the stratum by either treatment group is less than 2. P-value from the CMH test, the 
estimate of proportion, difference in proportion and the corresponding 95% CI of participants 
with response at each visit between PF-07265803 versus placebo will be presented. 
 
5.2.3. Analyses for Categorical Endpoints 
The frequency and percentage for each category will be presented for categorical endpoints. 
 
5.2.4. Analyses for Time-to-Event Endpoints 
Time-to-event endpoints including the composite endpoint of all-cause mortality and 
worsening heart failure and OS will be summarized using the Kaplan-Meier method and 
estimated survival curves will be displayed graphically when appropriate.  Graphs will 
describe the number of participants at risk over time. The median, quartiles, and 
probabilities of an event at points in time will be estimated by the Kaplan-Meier method. 
The number of subjects at risk, number of events and number of censored observations will 
be summarized. 
 
Time-to-event endpoints will also be analyzed using the Cox proportional hazards model 
with treatment and the strata as assigned at randomization (see Section 3.4) as the covariates. 
The stratification factor for P/LP vs VUS will be removed if the number of events in the 
stratum by either treatment group is less than 2. The hazard ratio, its 90% and 95% 2-sided 
CIs will be calculated. 
 
5.3. Methods to Manage Missing Data 
5.3.1. Continuous Endpoints 
MI approach will be used to handle missing data in the analyses of primary and secondary 
endpoints (ie, 6MWT, KCCQ, and NT-proBNP) through the Week 24 visit. The extent and 
pattern of missing data for the primary and secondary endpoints will be summarized 
separately by treatment group. 


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There are 2 sources that contribute to missing data for the efficacy measures which will be 
handled using MI: 
 
1) Premature discontinuation from study. 
 
2) Missed assessments while the participants remain in the trial (eg, due to COVID-19 
pandemic). 
 
Note that the protocol specifies that participants who discontinued study treatment prior to 
Week 24 should continue to have all assessments performed as scheduled through the 
Week 24 Visit. Therefore, such participants are not considered as a source of missing data. 
 
Missing data due to issues outside of the study (eg, due to COVID-19 pandemic) will be 
imputed based on a MAR assumption.  In the van Elteren test, premature discontinuation 
from study are incorporated in the endpoint definition through the ranking rules (see 
Section 5.2.1).  Missing data for discontinuation due to post randomization events (eg, AEs 
or perceived lack of efficacy) will be imputed using a control-based MI (see Section 5.3.1) in 
the stratified HL estimation of treatment effect for the primary and secondary endpoints (see 
Section 6.1.1 and Section 6.2). Additional sensitivity analysis using a control-based MI for 
discontinuations from study due to heart failure prior to analysis time point in the 
PF-07265803 will be performed (see Section 5.3.1 and Section 6.1.2.3). 
 
The MI procedure replaces each missing value with a set of plausible values that represent the 
uncertainty about the right value to impute. This is a 4-step process. 
 
Step 1 (imputing intermittent missing data): The dataset will be converted into monotone 
missing pattern by imputing intermittent missing data as the first step.  Intermittent missing 
values will be imputed using the MCMC method assuming a multivariate normal distribution 
over all variables included in the imputation model. This imputation will be done by 
treatment group with number of days on treatment, baseline 6MWT, and values observed at 
Weeks 4, 12, 24 and 36 included in the imputation.  This procedure will generate 
100 multiply imputed datasets.  The monotone data will then be imputed with monotone 
regression method. 
 
Step 2 (imputing monotone missing data): Monotone missing data due to study withdrawal 
related to COVID-19 pandemic or monotone missing data while participants ongoing at the 
data cutoff will be imputed under MAR.  Imputation will be undertaken within each 
treatment arm with number of days on treatment, mutation type (VUS vs P/LP), baseline and 
previous values as covariates. Monotone missing values for participants with study 
withdrawal for other reasons by the data cutoff date will be imputed using the imputation 
model built from the placebo group, ie, assuming the missing data in the treatment group will 
have a profile that equals the profile of the placebo group (ie, a copy-reference imputation). 
Number of days on treatment, mutation type (VUS vs P/LP), baseline 6MWT, and all prior 
assessments will be included as covariates in the monotone imputation model. The sample 
SAS statement can be found in Appendix 2. 
 
Step 3 (performing analysis using each imputed dataset): These multiple imputed datasets 
will be analyzed using data methods specified in Section 5.2.1. The van Elteren test, the 


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stratified win ratio, and the stratified HL estimates will be calculated on each of the 
100 imputed datasets. 
 
Step 4 (combine results): Resulting treatment effect parameter estimators and standard errors 
from each of 100 multiple imputed datasets from Step 3 will be combined to obtain the 
pooled treatment effect and variance parameter estimators according to Rubin’s rules. Note 
that Rubin's rules for combining multiply imputed estimates are based on asymptotic theory. 
 
For pooling results from the van Elteren tests on the imputed datasets, additional steps 
outlined below need to be undertaken in using the Rubin’s rule. 
 
l 
M 
• Let SMI  = M ∑k=l Sk  represent the mean van Elteren statistics across M imputations, 
where Sk  denotes the van Elteren statistic for each imputation. 
• Let W೦ = l ∑M 
W  represent the average within-imputation variance, where W 
M 
k=l 
k 
k 
denotes the variance estimate of the van Elteren statistics within each imputation. 
 
• Let B೦ = l  ∑M (S  − S )2 be the between-imputation variance of the van Elteren 
M-l 
statistics. 
k=l 
k 
MI 
• Let v೦MI = W೦ + (1 + 
l ) B೦ be the total variance across imputations. 
M 
• 
Let v = (M − 1)  1 + 
w೦
 
(l    ) ೦ 
M 
2    be the degrees of freedom for the t-distribution. 
The test statistic is T = SMI-EO(S) , where E  (S) is expected value of S under the null 
  ೦MI 
0 
hypothesis of no treatment effect.  The E0(S) is subtracted from each SMI  input so the 
procedure’s reported null test comparing SMI to 0 yields the appropriate null test without any 
additional computation. 
 
With regard to pooling results from the win ratio tests on the imputed datasets, since the 
distribution of the log (win ratio) is better approximated by a normal distribution for finite n 
(Dong et al, 2016),3 the logarithm of the stratified win ratios will be applied prior to the 
Rubin’s rules. The combined estimate of the stratified win ratio and CI on logarithmic scale 
can then be back transformed to get the overall pooled estimate for the stratified win ratio 
and its 95% CI. 
With regard to pooling HL estimates from the imputed data sets, since the linear 
combinations ∆೦HL are asymptotically median unbiased and normally distributed with standard 
error given by SE =    ∑S 
(Wk SE )2, these estimates are used to produce the final Hodges- 
Lehmann estimator. 
k=l 
jk 


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5.3.2. Binary Endpoints 
For binary endpoints analyzed at each scheduled visit separately (see Section 6.2.2 and 
Section 6.2.3), participants with missing data at a time point for any reason will be defined as 
MR-NR at that time point. 
 
6. ANALYSES AND SUMMARIES 
The primary analysis will be performed when all randomized participants in NYHA 
Class II/III have had the opportunity to be followed for at least 24 weeks (or otherwise 
withdrawn) and an evaluation of the composite endpoint consisting of all-cause mortality and 
worsening heart failure (HF-related hospitalization or HF-related urgent care visit) can be 
performed.  For analysis purposes, all dated assessments for efficacy will be categorized into 
analysis windows.  Analysis windows for primary, secondary, and CCI 
endpoints are 
provided in Appendix 3. 
 
 
6.1. Primary Endpoint(s) 
6.1.1. Primary Analysis 
The change from baseline (based on the average of the Day-1 and baseline visit 6MWT 
results) in 6MWT at Week 24 will be analyzed in the NYHA Class II/III participants using 
the van Elteren test, a rank-based non-parametrical approach (see Section 5.2.1).  PF- 
07265803 will be declared superior to placebo if the null hypothesis of no difference between 
PF-07265803 and placebo is rejected at the significance level of 0.05 (2-sided). 
 
The primary method to describe the treatment effect for change from baseline in 6MWT at 
Week 24 will be a stratified HL median difference (with 95% CI) (see Section 5.2.1). The 
stratified HL median difference of Week 24 change from baseline in 6MWT between 
PF-07265803 and placebo will be estimated for participants surviving 24 weeks.  Imputations 
for missing data are described in Section 5.2.1. Number of missing measurements at Week 
24, reasons for missingness, and the type of imputation used (MAR, copy-reference, etc.) 
will be summarized. 
 
As supportive analysis, a stratified win ratio statistic (and 95% CI) as described in 
Section 5.2.1 will be reported using the same ranking used in the hypothesis testing to aid in 
the interpretation of the van Elteren test. 
 
In analyzing the contribution of death and discontinuation components to the primary 
efficacy analysis, descriptive summaries on number of deaths and discontinuations from 
study prior to Week 24, and the reasons for withdrawals from study will be provided. 
 
For participants with observed 6MWT at Week 24, actual values and change from baseline at 
Week 24 will be summarized using descriptive statistics (N, mean, SD, median, Q1, Q3, 
minimum, and maximum) by treatment. 
CCI 


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Improvement in 6MWT will be categorized into the following: ≥15m, ≥30m, ≥45m, ≥60m, 
≥75m.  Percent of participants in each category of 6MWT based on observed change from 
baseline to Week 24 will be tabulated by treatment arm. A cumulative distribution of 
responses for PF-07265803 vs Placebo will also be generated, with observed change from 
baseline to Week 24 on the X-axis and the percentage of participants experiencing a change 
value of X points or above on the Y axis. 
 
6.1.2. Sensitivity Analyses 
6.1.2.1. Sensitivity Analysis Using a Mixed-Effect Model for Repeated Measures 
(MMRM) 
A MMRM model will be used for treatment comparison of change from baseline for 
participants who survive to Week 24. The MMRM will include treatment arm, visit, 
interaction of treatment arm and visit as fixed effects and baseline 6MWT as a covariate and 
all data up to Week 24.  The unstructured covariance matrix will be used to model the within- 
subject variance-covariance errors.  If the algorithm does not converge, the Toeplitz, first- 
order autoregressive or compound symmetric covariance structure will be considered in the 
order listed until convergence is obtained.  The MMRM analysis assumes MAR without 
explicitly imputing missing data. Rubin's method will be used to pool the MMRM estimates, 
standard errors and 95% confidence interval across the 100 multiply imputed datasets.  Least 
square mean difference, its 95% CI and p-value will be tabulated for treatment comparison. 
 
6.1.2.2. Sensitivity Analysis Using Trimmed Mean in Combination With MI 
To assess the sensitivity to the missing rates due to death and study discontinuation, a 
trimmed means analysis combining with multiple imputation will be performed on the EAS 
by treating death and study discontinuation prior to Week 24 as worst outcomes and 
trimming an equal fraction of these unfavorable outcomes from each treatment group to 
examine the robustness of primary efficacy results.  Missing data at Week 24 due to issues 
out of study (eg, due to COVID-19 pandemic) will be imputed under MAR using MI. The 
combination of MI and the trimmed means approach can improve estimates when the 
assumptions of each hold (Ocampo, et al 2019).5 
 
The trimmed mean method assumes that all subjects meeting trimming criteria (ie, death and 
study discontinuations) have equally bad non-numerical outcomes and will be ranked the 
worst. In the trimmed mean approach combining with MI, the missing data from participants 
who missed the 6MWT assessment while remaining in the study during the assessment 
window, will be imputed based on the distribution of the observed outcomes from 
participants who completed the week 24 visit given the MAR assumption. Imputation will 
be undertaken within treatment group with number of days on treatment, baseline and 
previous values as covariates. The imputed values from those with the missing assessment 
and the observed values from those who completed the assessment will be used to rank the 
remaining participants from greatest reduction (change less than 0) to greatest increase. An 
equal fraction of the worst outcomes will then be trimmed from each treatment group based 
on the ranked data. The fraction trimmed is pre-specified at a fixed percentage (ie, 30%) to 
ensure all patients who have died or discontinued from study prior to Week 24 are trimmed. 


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MI relies on the asymptotically normal distribution which applies to the trimmed mean. The 
trimmed mean analysis estimates the difference between the means of the included upper 
proportion of the outcome distribution for each treatment arm. Imputed data are utilized to 
calculate trimmed means estimates on each imputed dataset. The least squares mean 
difference in change from baseline to Week 24 for PF-07265803 minus Placebo and its 
standard error will be calculated using an analysis of covariance (ANCOVA) with treatment 
and baseline as covariates. Rubin’s rules will be used to summarize the results of the 
trimmed means applied to each partially imputed dataset. 
 
The 95% CI of the difference in trimmed means for treatment groups and p-value for testing 
the null hypothesis of no difference in the trimmed means will be calculated by 
1,000 permutation tests using random shuffling the treatment assignments within the 
datasets. 
 
6.1.2.3. Sensitivity Analysis to Assess the Impact of Heart Failure Determined 
Withdrawal 
In this sensitivity analysis, missing value for participants with study withdrawal related to 
adjudication-confirmed HF-related events in the PF-07265803 arm will be imputed based on 
the distribution of the values in the placebo arm, while the missing data for any other reasons 
will be imputed under MAR (see Section 5.3.1).  Note that imputations for participants who 
have died prior to Week 24 are not performed. 
 
The imputed data sets can be used for the van Elteren test, stratified win ratio, and for the 
stratified HL estimation, with deaths excluded from the HL estimation. Rubin’s rule will be 
applied to pool multiply imputed estimates for overall inference (see Section 5.2.1 and 
Section 5.3.1). The ranking for the van Elteren test is as follows: 
 
• Participants who die before Week 24 will be given the lowest set of ranks according to 
their survival time (as in the primary analysis). Note if a patient withdrew and then died 
prior to the analysis timepoint, the patient will be counted as death. 
 
• Participants who discontinue from study prior to Week 24 due to heart failure will have 
Week 24 values imputed based on the distribution of the Week 24 values in the placebo 
arm (see Section 5.3.1). 
 
• Participants who discontinued prior to Week 24 for reason other than heart failure will 
have 6MWT values imputed under MAR using MI (see Section 5.3.1). 
 
• Participants who remain in the trial at or beyond Week 24 but who have a missing 
Week 24 6MWT assessment (eg, due to COVID-19) will have 6MWT values imputed 
under MAR using MI (as in the primary analysis). 
 
• The imputed values will be used along with the observed values from all other 
participants to rank the remaining participants from greatest reduction (change less than 
0) in Week 24 6MWT to greatest increase (as in the primary analysis). 


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6.1.2.4. Sensitivity Analysis to Assess the Impact of the COVID-19 Pandemic 
The COVID-19 pandemic has impacted study conduct leading to participants missing visits 
and for some participants the 6MWT course changed after the baseline visit due to 
COVID-19 restrictions having impacted the original course. Additional sensitivity analyses 
may be performed to address the potential impact of COVID-19-related changes to study 
conduct on the primary efficacy analysis: 
 
• Exclude data from participants who had a change in the 6MWT course after baseline 
visit. 
 
• Exclude data from participants at a given site who would have had endpoint assessment 
during disruptions period, regardless of post-randomization outcomes (see FDA, 2020 
guidance).4   In this approach, all potentially impacted participants will be identified 
through the site location and randomization dates that are associated with endpoint 
ascertainment. The impacted period for each region and/or site will be defined prior to 
unblinding. 
 
For the sensitivity analyses related to the impact of COVID-19 as described above, data will 
be ranked and analyzed in the same way as described for the primary efficacy analysis (see 
Section 6.1.1).  P-value from the van Elteren test, stratified win ratio and HL estimate of 
treatment difference in 6MWT will be provided along with summaries on deaths and 
withdrawals by treatment group (see Section 5.2.1). 
 
6.2. Secondary Endpoint(s) 
 
6.2.1. Change From Baseline in 6MWT at Weeks 4 and 12 in NYHA Class II/III 
Participants 
 
The change from baseline in 6MWT at Weeks 4 and 12 will be summarized using the same 
method as described for the primary endpoint analysis (see Section 5.2.1 and Section 6.1.1). 
However, the nominal p-value produced based on van Elteren test will be for exploratory 
purpose only. 
 
In addition, a plot for the mean observed change from baseline (SE) of 6MWT at each 
timepoint (ie, Weeks 4, 12, and 24, and every 12 weeks) will be provided by treatment to 
support the durability of efficacy on 6MWT. 
 
6.2.2. Change From Baseline in KCCQ Domains at Weeks 12 and 24 in NYHA 
Class II/III Participants 
The TSS, Clinical Summary Score (CSS), PL score and Overall Summary Score (OSS) of the 
KCCQ will be analyzed at both Weeks 12 and 24 using the same method as described for the 
primary endpoint analysis (see Section 5.2.1 and Section 6.1.1). Missing data will be 
handled in the same fashion as the analysis of 6MWT at Week 24 (see Section 5.3.1). 
Likewise, the HL estimates and associated 95% CIs will be presented and constructed in the 
same way as used for 6MWT (see Section 5.2.1).  Only PL and TSS will be included in the 
formal testing hierarchy comparing the difference between treatment arms (PL will be tested 
first followed by TSS). 


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Additionally, participants will be defined as having improved for PL and TSS at Week 24 if 
their score improves (increases) by a pre-defined threshold vs baseline at Week 24.  In this 
analysis, participants with missing data at a time point for any reason will be defined as 
MR-NR at that time point (see Section 5.2.2). The proportion of participants with an 
improvement will be analyzed using the CMH test as described in Section 5.2.2. The 
pre-defined threshold will be defined prior to unblinding of the database. The analyses to 
establish the pre-defined threshold will be described in a supplemental analysis plan. The 
threshold analysis results will be reported separately from the CSR. 
 
Descriptive statistics of the KCCQ domains at each visit will also be provided. 
 
6.2.3. Change From Baseline in PGI Scores at Weeks 12 and 24 in NYHA Class II/III 
Participants 
For each question on the PGI-S, the number and proportion of participants with at least a 
1-category and at least a 2-category improvement from baseline will be summarized at each 
visit by treatment arm. Participants with missing data at a time point for any reason will be 
defined as MR-NR at that time point.  Any participant who has a baseline assessment of none 
or mild will be excluded from the denominator in calculating the proportion. 
 
For each question on the PGI-C, the number and proportion of participants who describe 
their change in overall status as “Moderately better” or “Very much better” will be 
summarized at each visit by treatment arm. Participants with missing data at a time point for 
any reason will be defined as MR-NR at that time point. 
 
PGI-S and PGI-C data will also be used to interpret improvement thresholds for the PL and 
TSS based on a blinded assessment, which will be performed prior to unblinding of the data. 
The thresholds will be defined by evaluating the relationship between changes on the PL and 
TSS and changes in the corresponding PGI-S and PGI-C questions.  The details about the 
analyses to establish the pre-defined threshold will be described in a supplemental PRO SAP. 
 
6.2.4. Change From Baseline in NT-proBNP at Weeks 4, 12, and 24 in NYHA 
Class II/III Participants 
As part of the hierarchical testing strategy described in Section 6.2, the change of Week 24 
NT-proBNP from baseline will be analyzed using the same method as described for the 
primary analysis (see Section 5.2.1 and Section 6.1.1). Missing data will be handled in the 
same fashion as the analysis of 6MWT at Week 12 (see Section 5.3.1).  Likewise, the HL 
estimates and associated 95% CIs will be presented and constructed in the same way as used 
for 6MWT (see Section 5.2.1). 
 
The change of Week 4 and Week 12 NT-proBNP from baseline will also be analyzed. Only 
the 24-week endpoint will be alpha controlled for the hierarchical testing. The p-value from 
the van Elteren test on Week 4 and Week 12 NT-proBNP will be for exploratory purpose 
only. 


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6.2.5. The Composite Time to First Occurrence of All-Cause Mortality or Worsening 
Heart Failure 
An episode of worsening heart failure is either a hospitalization or an urgent visit for heart 
failure confirmed by the clinical event committee (CEC) as per the criteria in Protocol 
Appendix 9.  Only adjudicated and confirmed events will be included in the analyses. 
 
The composite endpoint measures the time from randomization to the first occurrence of 
death from any cause, or worsening heart failure defined as HF-related hospitalization or a 
HF-related urgent care visit and will include all data recorded while the participant is on 
study, including while in follow-up.  Participants will be censored at the latest time they are 
known to be alive and have not experienced any HF-related hospitalization or a HF-related 
urgent care visits. 
 
The composite endpoint will be summarized using the Kaplan-Meier method and compared 
between treatment groups using a stratified Cox model using the strata as assigned at 
randomization (see Section 3.4) and treatment arm as a fixed effect. The stratification factor 
for P/LP vs VUS will be removed if the number of events in the stratum by either treatment 
group is less than 2. The upper confidence limit of a 2-sided 90% CI for the HR will be 
compared, using the SAS, to a value of 2 to rule out an excess risk.  A 95% CI will also be 
presented. As a supportive analysis, the composite endpoint will be analyzed using the EAS. 
 
Additionally, analyses of time to HF-related hospitalization and time to urgent care visit will 
be performed to examine the contribution of each component of the composite endpoint, with 
date of death from any cause as an additional point of censoring. 
 
6.2.6. Overall Survival 
Overall Survival (OS) is defined as time from randomization until death due to any cause and 
will include all data recorded while the participant is on study, including while in follow-up. 
For a participant who did not complete the study, ie, who was lost to follow-up or withdrew 
consent, if the vital status for the participant can be retrieved from public information, the 
vital status (dead or alive) at the end of the study collected from public sources will be 
included in the analysis of death from any cause.  Participants who do not have a death date 
will be censored for OS at their last contact date.  OS will be calculated for all participants 
and summarized by treatment arm using the Kaplan-Meier method and compared between 
treatment arms using a stratified Cox model as described in Section 5.2.4. 
 
The primary analysis of OS will be based on the SAS and supportive analyses will be 
performed using the EAS. 
CCI  
 
 
 


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CCI 
CCI 


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CCI 


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CCI 


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CCI  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.4. Subset Analyses 
Subgroup analyses for the primary endpoint and for alpha-controlled secondary endpoints 
will be performed if the sample size is sufficient within each individual subgroup.CCI   
The objective of the subgroup 
analyses is to investigate the consistency of treatment effect across subgroups of clinical 
importance. The study is not powered for statistical significance within the subgroups. The 
subgroups of interest include: 
 
• Mutation type (P/LP vs VUS); 
 
• NYHA Class (II vs III); 
 
• Baseline 6MWT stratum (<320 meters vs ≥320 meters); 
CCI 


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• Race (Caucasian vs non-Caucasian); 
 
• Region (North America vs Rest of the World); 
 
• Age (≥18 to <35 years; ≥35 to <50 years; ≥50 to 65 years; and ≥65 years); 
 
• Gender (male vs female). 
 
Key safety analyses will be provided by demographic subgroup (age, gender, race).  These 
analyses include AEs by PT (related and all-cause); SAEs by PT (related and all-cause); AEs 
leading to study drug discontinuation and deaths. 
 
6.5. Baseline and Other Summaries and Analyses 
6.5.1. Baseline Summaries 
Demographics and baseline characteristics listed in Section 3.4 will be summarized. 
 
6.5.2. Study Conduct and Participant Disposition 
The below participant populations/sets will be summarized for PF-07265803 and placebo: 
 
• Enrolled; 
 
• Randomly assigned to investigational product; 
 
• Treated; 
 
• Each analysis dataset (FAS, EAS, NYHA Class IV, SAS, PK). 
 
Participant disposition (eg, discontinuation from treatment, discontinuation from study, 
reason for discontinuation, completed study, and ongoing) will be summarized for 
PF-07265803 and placebo. 
Medication errors will be listed. 
6.5.3. Study Treatment Exposure and Compliance 
Duration of exposure to study drug, and average daily dose will be summarized by treatment 
arm. 
 
• Duration of exposure (weeks) = (last dose date – first dose date + 1)/7; 
 
• Average daily dose (mg/day) = cumulative dose (mg) / number of actual dosing days. 
 
where cumulative dose (mg) is calculated as total dose given during the study treatment 
exposure, and number of actual dosing days is calculated as [duration of exposure 
(days) – number of days of interruption]. 


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Duration of exposure will also be categorized by time intervals (ie, <4 weeks, ≥4 – <8 weeks, 
≥8 – <12 weeks, ≥12 – <24 weeks, ≥24 – <52 weeks, ≥52 – <104 weeks, ≥104 – <156 weeks, 
≥156 weeks) for which frequency counts and percentages of participants will be provided. 
Frequency counts and percentages of participants who have dose reductions or interruptions, 
and the corresponding reasons, will be summarized. 
 
The percentage of study drug compliance for the overall treatment period will be derived for each 
participant as the number of actual dosing days (excluding days of interruption) relative to the 
duration of exposure (day). A participant will be considered compliant with the dosing 
regimen if he or she receives 80% to 120% of the expected number of doses, in accordance 
with the protocol. The number and percentage of participants who are compliant with the 
dosing regimen will be summarized. 
 
6.5.4. Concomitant Medications and Nondrug Treatments 
The World Health Organization (WHO)-Drug coding dictionary will be used to classify 
concomitant medications. 
 
The number and percent of participants who took each concomitant medication will be 
provided for PF-07265803 and placebo. 
 
6.6. Safety Summaries and Analyses 
Safety data will be summarized descriptively, where appropriate. Categorical outcomes (eg,  
AEs) will be summarized by participant counts and percentage.  Continuous outcome (eg, 
pulse rate, etc) will be summarized using n, mean, median, standard deviation. Change from 
baseline in vital signs will also be summarized.  Participant listings will be produced for 
these safety endpoints accordingly. 
 
It should be recognized that most studies are not designed to reliably demonstrate a causal 
relationship between the use of a pharmaceutical product and an AE or a group of AEs. 
Except for select events in unique situations, studies do not employ formal adjudication 
procedures for the purpose of event classification. As such, safety analysis is generally 
considered as descriptive analyses. 
 
6.6.1. Adverse Events 
AEs for participants who discontinue from the study due to AEs will be listed and 
summarized by SOC and PT for PF-07265803 and placebo. 
 
Incidence of TEAEs (all causalities and treatment-related) will be summarized by SOC and 
incidence and severity of TEAEs (all causalities and treatment related) will be summarized 
by SOC and PT for PF-07265803 and placebo. 
 
Deaths and SAEs will be listed and incidence of SAEs (all causalities) will be summarized 
by SOC and PT for PF-07265803 and placebo. 


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6.6.2. Laboratory Data 
Incidence of laboratory test abnormalities will be summarized for PF-07265803 and placebo 
without regard to baseline abnormality, for normal baseline, and for abnormal baseline. 
Additionally, changes from baseline to last observation in laboratory test parameters will be 
summarized descriptively for PF-07265803 and placebo. 
 
6.6.3. Vital Signs 
Observed values and changes from baseline in vital sign parameters will be summarized 
descriptively for PF-07265803 and placebo by visit. 
 
6.6.4. Electrocardiograms and Arrhythmia Assessment 
Changes from baseline in ECG parameters will be summarized descriptively for 
PF-07265803 and placebo by visit.  The nature and frequency of arrhythmias will be 
tabulated by PF-07265803 and placebo. 
 
6.6.5. Physical Examination 
Physical examination data will be listed. 
 
7. INTERIM ANALYSES 
7.1. Introduction 
Interim Futility Analysis for Change from Baseline in 6MWT at Week 12 
 
A formal, non-binding, interim futility analysis of change from baseline in 6MWT at Week 
12 was performed after the first 60 randomized participants in the EAS had the opportunity 
to be assessed at the Week 12 visit (ie, participants who completed the Week 12 visit, or 
discontinued the study prior to Week 12). As the objective of this interim futility analysis 
was not to terminate the study early for the benefit of efficacy, no adjustment of alpha is 
needed as a result of this interim analysis. 
 
The data cut-off date for the interim futility analysis was made when the 60th randomized 
participants with NYHA Class II/III reached 12 weeks, or discontinued the study prior to 
Week 12. The interim futility analysis at Week 12 was comprised of all those 
60 participants.  The interim analysis of change of 6MWT from baseline to Week 12 was 
summarized using the same methodology as described for the primary analysis in 
Section 5.2.1 and Section 6.1.1. The p-value from the van Elteren test was reported, and the 
stratified HL estimate on treatment effect was included. 
 
The non-binding futility boundary was calculated as function of information using Hwang- 
Shih-DeCani spending function with gamma = -1.54.  With 50% information at the interim 
analysis (ie, 60 out of 120 randomized participants in the EAS who had the opportunity to 
complete the Week 12 assessment, including those who discontinued prior to Week 12), the 
futility boundary would be crossed if the one-sided p-value from the primary analysis of 
change from baseline in 6MWT at Week 12 is ≥0.315. The exact futility boundary was to be 
updated based on the actual number of participants and information fraction included at the 


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interim; however no changes were required as the 50% fraction was achieved at the time of 
the interim analysis. 
 
The analysis of changes from baseline in 6MWT at 24 weeks was performed at the interim 
based on a subset of the 60 randomized participants who completed a Week 24 visit, and all 
participants with a time difference of at least 24 weeks between the date of randomization 
and the targeted clinical cut-off. Note deaths or study discontinuations among participants 
who were randomized 24 or more weeks prior to the targeted clinical cut-off date were 
included. 
 
Week 4 6MWT change from baseline was summarized descriptively.  The number and 
percentage of deaths and discontinuations prior to Weeks 4, 12, and 24, and the reasons for 
discontinuations were provided. 
 
The interim futility analysis was performed by an independent team of statistician(s) and 
programmer(s) and the results were unblinded only to the external data monitoring 
committee (DMC). The DMC evaluated the primary endpoint of the study and utilized the 
futility boundary to consider whether the study should continue to completion or stop early 
for futility.  The futility boundary was a guideline for the DMC and was not a binding rule; 
interpretation of the efficacy data relative to the boundary was made by the DMC in the 
context of the entire study results, and recommendations made to the Sponsor accordingly. 
 
At the time of the first planned interim futility analysis, the DMC recommended to continue 
the study as designed. 
 
Blinded Sample Size Re-Estimation and All-Cause Mortality or WHF Event Monitoring 
 
Following the interim analysis for futility, a planned blinded sample size re-estimation for the 
primary endpoint of change from baseline in 6MWT at Week 24 was conducted by an 
internal BSSR review committee using blinded cumulative primary efficacy data from the 
interim data cut.  The BSSR committee did not have access to the unblinded data. 
 
A similar simulation model utilized to determine the initial sample size (see Section 5.1) was 
utilized for sample size re-estimation using the pooled estimate for the baseline 6MWT 
assessment, the variance for the change from baseline in 6MWT at Week 24, the pooled 
event rates for death and the pooled event rates for study discontinuation (excluding deaths) 
prior to Week 24 estimated from the interim analysis data cut. Modifications to the 
simulation utilized at the time of the initial sample size calculation are detailed in a separate 
document and were mainly a result of pooled estimates at the time of sample size re- 
estimation where the initial sample size considered estimated values on the placebo arm. 
 
This blinded sample size re-estimation procedure was conducted by an independent blinded 
statistician who was not a member of the DMC or the study team. The final decision on 
sample size and power for this study was determined by the internal BSSR committee, 
independent of the study team. Following completion of the planned blinded sample size re- 
estimation, up to 200 eligible participants with symptomatic cardiomyopathy due to LMNA 
will be randomized, including at least 160 participants with NYHA functional Class II or III 


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and up to 40 participants with NYHA functional Class IV. The rationale for the increase in 
sample size have been documented but will not be disclosed until the time of primary 
reporting. 
 
Blinded sample size reassessment based on updating a nuisance parameter such as pooled 
common variance or event rate does not inflate the type I error.  Therefore, there will be no 
adjustment to alpha due to this blinded sample size re-estimation procedure. 
 
Details on the role of the internal BSSR committee and working procedures are defined in a 
separate BSSR Charter. 
 
In addition to the sample size re-estimation for the primary endpoint, the study team will 
monitor the pooled (blinded) cumulative event counts for the composite safety endpoint of 
all-cause mortality or WHF throughout the study.  The expected number of events on death 
or WHF needed to rule out an upper bound of 2-sided CI for a non-inferiority margin of 1.8 
or 2 with time to the first composite event analysis under various scenarios for given HR is 
provided in Table 4. 
 
Table 4. 
Expected Number of Events on Death or WHF to Rule Out a Non- 
inferiority HR Margin of 1.8 or 2 with Time to the First Composite Event 
Analysis 
 
Statistical Power 
Expected 
Effect size (HR) 
Non-inferiority 
Margin=2 
Non-inferiority 
Margin=1.8 
90% CI 
95% CI 
90% CI 
95% CI 
80% 
0.9 
39 
50 
52 
66 
0.95 
45 
57 
61 
77 
1 
52 
66 
72 
91 
90% 
0.9 
54 
66 
72 
88 
0.95 
62 
76 
84 
103 
1 
72 
88 
100 
122 
 
 
Interim Futility Analysis for Change from Baseline in 6MWT at Week 24 
 
Given the change in timepoint of the primary endpoint from 12 to 24 weeks following 
protocol amendment #7 and the longer than anticipated duration of the enrollment period, an 
additional interim futility analysis of change from baseline in 6MWT at Week 24 will be 
conducted after the first 68 randomized NYHA Class II/III participants having completed the 
Week 24 assessment or discontinued from the study prior to Week 24 (ie, 42.5% information 
following the sample size re-estimation).  The assessment of futility will be based on change 
from baseline in 6MWT at Week 24 using a Hwang-Shih-DeCani spending function with 
gamma =6.7. With 42.5% information at the interim analysis (ie, 68 out of 160 randomized 
participants completed the Week 24 visit or otherwise having died or withdrawn from the 
study prior to Week 24), the futility boundary will be crossed if the one-sided p-value based 
on the van Elteren test is > 0.05. 


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The interim futility analysis of change of 6MWT from baseline to Week 24 will be 
summarized using the same methodology as described for the primary analysis in Section 
5.2.1 and Section 6.1.1. The p-value from the van Elteren test will be reported, and the 
stratified HL estimate on treatment effect will be included.  An independent team of 
statistician(s) and programmer(s) will be responsible for performing the interim analyses for 
the DMC.  Detailed implementation of the interim analysis is described in the DMC Charter 
(separate documentation). 
 
7.2. Interim Analyses and Summaries 
7.2.1. Interim Futility Analysis 
The following summaries were provided for the interim futility analysis on change from 
baseline in 6MWT at Week 12: 
 
• Summary of Deaths and Discontinuations Prior to the Analysis Timepoint (Weeks 4, 12, 
and 24) 
 
• Summary of Observed Values of 6MWT and Change from Baseline at Week 4, 12, and 
24 
 
• Van Elteren Test Results and Stratified Hodges-Lehmann Estimator of 6MWT Change 
from Baseline at Week 12 
 
• Van Elteren Test Results and Stratified Hodges-Lehmann Estimator of 6MWT Change 
from Baseline at Week 24 
 
• Line Graph of Mean Observed Change from Baseline in 6MWT at Weeks 4, 12, and 24 
for PF-07265803 and placebo 
 
• Van Elteren Test Results and Stratified Hodges-Lehmann Estimator of 6MWT Change 
from Baseline at Week 12: Sensitivity Analysis to Assess the Impact of Heart Failure 
Determined Withdrawal at Week 12 
 
• Van Elteren Test Results and Stratified Hodges-Lehmann Estimator of 6MWT Change 
from Baseline at Week 24: Sensitivity Analysis to Assess the Impact of Heart Failure 
Determined Withdrawal at Week 24 
 
The following summaries are planned for the interim futility analysis on change from 
baseline in 6MWT at Week 24: 
 
• Summary of Deaths and Discontinuations Prior to Week 24 
 
• Summary of Observed Values of 6MWT and Change from Baseline at Week 24 
 
• Van Elteren Test Results and Stratified Hodges-Lehmann Estimator of 6MWT Change 
from Baseline at Week 24 


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8. REFERENCES 
1. 
Dong G, Hoaglin DC, Qui J, et al. The win ratio on interpretation and handling of ties. 
Stat Biopharm Res. 2020;12(1):99-106. 
 
2. 
Dong G, Qiu J, Wang D, et al. The stratified win ratio. J Biopharm Stat. 
2018;28(4):778-96. 
 
3. 
Dong G, Li D, Ballerstedt S, et al. A generalized analytic solution to the win ratio to 
analyze a composite endpoint considering the clinical importance order among 
components. Pharm Stat. 2016;15(5):430-7. 
 
4. 
Food and Drug Administration. Guidance for Industry: statistical considerations for 
clinical trials during the COVID-19 public health emergency. Available from: 
https://www.fda.gov/media/139145/download. Published: Jun 2020. Accessed: 30 Jul 
2020. 
 
5. 
Ocampo A, Schmidli H, Quarg P, et al. Identifying treatment effects using trimmed 
means when data are missing not at random, https://arxiv.org/pdf/1908.01044.pdf. 
 
6. 
Liu L, Wolfe RA, Huang X. Shared frailty models for recurrent events and a terminal 
event. Biometrics, 2004;60(3);747-56. 
 
7. 
Rogers JK, Yaroshinsky A, Pocock SJ, et al. Analysis of recurrent events with an 
associated informative dropout time: application of the joint frailty model. Stat Med. 
2016;35(13):2195-205. 


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9. APPENDICES 
Appendix 1. Summary of Primary and Secondary Efficacy Analyses 
 
Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for Handling Intercurrent Events 
and Missing Data 
Analysis Model 
Change from Baseline in 6MWT at Weeks 4, 12, and 24 
Change from baseline in 
6MWT at Week 24 
Primary 
analysis 
EAS 
Hypothesis testing: Deaths prior to week 24 will be assigned the 
worst rank and discontinuations from study prior to week 24 the 
next lowest rank, followed by changes in 6MWT for all other 
participants. All data collected regardless of discontinuation of 
randomized treatment will be included. Intermittent missing data 
will be imputed with MCMC. For participants who do not die or 
discontinue the study prior to Week 24 but have monotone 
missing Week 24 and subsequently discontinue the study at a 
later timepoint, missing data will be imputed under MAR for 
those who discontinue due to issues outside of the study (eg, 
COVID-19) and imputed using control-based MI for those who 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy). 
Estimation of treatment effect (magnitude of change in 
6MWT): Missing data due to issues outside of the study (eg, 
COVID-19) will be imputed under MAR. Missing data for 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy) will be imputed using control-based 
MI. Imputations following death will not be utilized as imputed 
values for participants who died prior to the assessment 
timepoint would not be interpretable. Intermittent missing data 
will be imputed with MCMC. 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 
Stratified Hodges- 
Lehmann estimator by 
baseline 6MWT 
quartile 
Change from baseline in 
6MWT at Week 24 
Summary 
EAS 
Observed 6MWT and change from baseline 
Number of deaths and discontinuations prior to the analysis time 
point 
N/A 


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Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for Handling Intercurrent Events 
and Missing Data 
Analysis Model 
Change from baseline in 
6MWT at Week 24 
Sensitivity 
EAS 
Death and study discontinuation prior to analysis time point will 
be treated as worst outcomes with an equal fraction trimmed 
from each treatment group. Missing data due to issues out of 
study (eg, due to COVID-19 pandemic) will be imputed under 
MAR using MI. 
Trimmed Mean in 
combination with MI 
Change from baseline in 
6MWT at Week 24 
Sensitivity 
EAS 
Missing value for participants with study withdrawal related to 
adjudication-confirmed HF-related events in the PF-07265803 
arm will be imputed based on the distribution of the values in the 
placebo arm. Intermittent missing data will be imputed with 
MCMC and all other monotone missing data will be imputed 
under MAR. 
All else the same as the primary analysis. 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 
Stratified Hodges- 
Lehmann estimator by 
baseline 6MWT 
quartile 
Change from baseline in 
6MWT at Week 24 
Sensitivity 
EAS 
Data from participants with a change in the 6MWT course from 
baseline visit will be excluded. 
All else the same as the primary analysis. 
van Elteren and win 
ratio (95% CI) stratified 
by baseline 6MWT 
quartile 
Stratified Hodges- 
Lehmann estimator by 
baseline 6MWT 
quartile 
Change from baseline in 
6MWT at Week 24 
Sensitivity 
EAS 
Data from participants at a given site impacted by COVID-19 
disruptions period regardless of post-randomization outcomes 
will be excluded. 
All else the same as the primary analysis. 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 
Stratified Hodges- 
Lehmann estimator by 
baseline 6MWT 
quartile 


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Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for Handling Intercurrent Events 
and Missing Data 
Analysis Model 
Change from baseline in 
6MWT at Week 12 
Main analysis 
EAS 
Hypothesis testing: Deaths prior to week 12 will be assigned the 
worst rank and discontinuations from study prior to week 12 the 
next lowest rank, followed by changes in 6MWT for all other 
participants. All data collected regardless of discontinuation of 
randomized treatment will be included. Intermittent missing data 
will be imputed with MCMC. For participants who do not die or 
discontinue the study prior to Week 12 but have monotone 
missing Week 12 and subsequently discontinue the study at a 
later timepoint, missing data will be imputed under MAR for 
those who discontinue due to issues outside of the study (eg, 
COVID-19) and imputed using control-based MI for those who 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy). 
Estimation of treatment effect (magnitude of change in 
6MWT): Missing data due to issues outside of the study (eg, 
COVID-19) will be imputed under MAR. Missing data for 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy) will be imputed using control-based 
MI. Imputations following death will not be utilized as imputed 
values for participants who died prior to the assessment 
timepoint would not be interpretable. Intermittent missing data 
will be imputed with MCMC. 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 
Stratified Hodges- 
Lehmann estimator by 
baseline 6MWT 
quartile 
Change from baseline in 
6MWT at Week 12 
Summary 
EAS 
Observed 6MWT and change from baseline 
Number of deaths and discontinuations prior to the analysis time 
point 
N/A 
Change from baseline in 
6MWT at Week 12 
Sensitivity 
EAS 
Missing value due to discontinuation from study due to heart 
failure in the PF-07265803 arm will be imputed based on the 
distribution of the values in the placebo arm. Intermittent missing 
data will be imputed with MCMC and all other monotone 
missing data will be imputed under MAR. 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 
Stratified Hodges- 
Lehmann estimator by 


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Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for Handling Intercurrent Events 
and Missing Data 
Analysis Model 
All else the same as the primary analysis. 
baseline 6MWT 
quartile 
Change from baseline in 
6MWT at Week 4 
Main analysis 
EAS 
Hypothesis testing: Deaths prior to Week 4 will be assigned the 
worst rank and discontinuations from study prior to Week 4 the 
next lowest rank, followed by changes in 6MWT for all other 
participants. All data collected regardless of discontinuation of 
randomized treatment will be included. Intermittent missing data 
will be imputed with MCMC. For participants who do not die or 
discontinue the study prior to Week 4 but have monotone 
missing Week 4 and subsequently discontinue the study at a later 
timepoint, missing data will be imputed under MAR for those 
who discontinue due to issues outside of the study (eg, COVID- 
19) and imputed using control-based MI for those who 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy). 
Estimation of treatment effect (magnitude of change in 
6MWT): Missing data due to issues outside of the study (eg, 
COVID-19) will be imputed under MAR. Missing data for 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy) will be imputed using control-based 
MI. Imputations following death will not be utilized as imputed 
values for participants who died prior to the assessment 
timepoint would not be interpretable. Intermittent missing data 
will be imputed with MCMC. 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 
Stratified Hodges- 
Lehmann estimator by 
baseline 6MWT 
quartile 
Change from baseline in 
6MWT at Week 4 
Summary 
EAS 
Observed 6MWT and change from baseline 
Number of deaths and discontinuations prior to the analysis time 
point 
N/A 


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Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for Handling Intercurrent Events 
and Missing Data 
Analysis Model 
Change from Baseline in KCCQ PL and TSS at Weeks 12 and 24 
Change from baseline in 
KCCQ PL at Week 12 
Main analysis 
EAS 
Hypothesis testing: Deaths prior to Week 12 will be assigned 
the worst rank and discontinuations from study prior to Week 12 
the next lowest rank, followed by changes in KCCQ PL for all 
other participants. All data collected regardless of 
discontinuation of randomized treatment will be included. 
Intermittent missing data will be imputed with MCMC. For 
participants who do not die or discontinue the study prior to 
Week 12 but have monotone missing Week 12 and subsequently 
discontinue the study at a later timepoint, missing data will be 
imputed under MAR for those who discontinue due to issues 
outside of the study (eg, COVID-19) and imputed using control- 
based MI for those who discontinuation due to post 
randomization events (eg, AEs or perceived lack of efficacy). 
Estimation of treatment effect (magnitude of change in 
KCCQ PL): Missing data due to issues outside of the study (eg, 
COVID-19) will be imputed under MAR. Missing data for 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy) will be imputed using control-based 
MI. Imputations following death will not be utilized as imputed 
values for participants who died prior to the assessment 
timepoint would not be interpretable. Intermittent missing data 
will be imputed with MCMC. 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 
Stratified Hodges- 
Lehmann estimator by 
baseline 6MWT 
quartile 
Change from baseline in 
KCCQ PL at Week 12 
Summary 
EAS 
Observed KCCQ PL and change from baseline 
N/A 
Change from baseline in 
KCCQ PL at Week 24 
Main analysis 
EAS 
Hypothesis testing: Deaths prior to Week 24 will be assigned 
the worst rank and discontinuations from study prior to Week 24 
the next lowest rank, followed by changes in KCCQ PL for all 
other participants. All data collected regardless of 
discontinuation of randomized treatment will be included. 
Intermittent missing data will be imputed with MCMC. For 
participants who do not die or discontinue the study prior to 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 


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Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for Handling Intercurrent Events 
and Missing Data 
Analysis Model 
Week 24 but have monotone missing Week 24 and subsequently 
discontinue the study at a later timepoint, missing data will be 
imputed under MAR for those who discontinue due to issues 
outside of the study (eg, COVID) and imputed using control- 
based MI for those who discontinuation due to post 
randomization events (eg, AEs or perceived lack of efficacy). 
Estimation of treatment effect (magnitude of change in 
KCCQ PL): Missing data due to issues outside of the study (eg, 
COVID-19) will be imputed under MAR. Missing data for 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy) will be imputed using control-based 
MI. Imputations following death will not be utilized as imputed 
values for participants who died prior to the assessment 
timepoint would not be interpretable. Intermittent missing data 
will be imputed with MCMC. 
Stratified Hodges- 
Lehmann estimator by 
baseline 6MWT 
quartile 
Change from baseline in 
KCCQ PL at Week 24 
Summary 
EAS 
Observed KCCQ PL and change from baseline 
N/A 
Responder analysis of change 
from baseline in KCCQ PL at 
Week 24 
Summary 
EAS 
All data collected will be included regardless of intercurrent 
events. 
A participant with a missing data for any reason will be 
considered a non-responder for the visit of interest. 
Cochran-Mantel-Haens 
zel test stratified by 
stratification factors at 
randomization 
Change from baseline in 
KCCQ TSS at Week 12 
Main analysis 
EAS 
Hypothesis testing: Deaths prior to Week 12 will be assigned 
the worst rank and discontinuations from study prior to Week 12 
the next lowest rank, followed by changes in KCCQ TSS for all 
other participants. All data collected regardless of 
discontinuation of randomized treatment will be included. 
Intermittent missing data will be imputed with MCMC. For 
participants who do not die or discontinue the study prior to 
Week 12 but have monotone missing Week 12 and subsequently 
discontinue the study at a later timepoint, missing data will be 
imputed under MAR for those who discontinue due to issues 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 


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Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for Handling Intercurrent Events 
and Missing Data 
Analysis Model 
outside of the study (eg, COVID) and imputed using control- 
based MI for those who discontinuation due to post 
randomization events (eg, AEs or perceived lack of efficacy). 
Estimation of treatment effect (magnitude of change in 
KCCQ TSS): Missing data due to issues outside of the study 
(eg, COVID-19) will be imputed under MAR. Missing data for 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy) will be imputed using control-based 
MI. Imputations following death will not be utilized as imputed 
values for participants who died prior to the assessment 
timepoint would not be interpretable. Intermittent missing data 
will be imputed with MCMC. 
Stratified Hodges- 
Lehmann estimator by 
baseline 6MWT 
quartile 
Change from baseline in 
KCCQ TSS at Week 12 
Summary 
EAS 
Observed KCCQ TSS and change from baseline 
N/A 
Change from baseline in 
KCCQ TSS at Week 24 
Main analysis 
EAS 
Hypothesis testing: Deaths prior to Week 24 will be assigned 
the worst rank and discontinuations from study prior to Week 24 
the next lowest rank, followed by changes in KCCQ TSS for all 
other participants. All data collected regardless of 
discontinuation of randomized treatment will be included. 
Intermittent missing data will be imputed with MCMC. For 
participants who do not die or discontinue the study prior to 
Week 24 but have monotone missing Week 24 and subsequently 
discontinue the study at a later timepoint, missing data will be 
imputed under MAR for those who discontinue due to issues 
outside of the study (eg, COVID) and imputed using control- 
based MI for those who discontinuation due to post 
randomization events (eg, AEs or perceived lack of efficacy). 
Estimation of treatment effect (magnitude of change in 
KCCQ TSS): Missing data due to issues outside of the study 
(eg, COVID-19) will be imputed under MAR. Missing data for 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy) will be imputed using control-based 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 
Stratified Hodges- 
Lehmann estimator by 


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Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for Handling Intercurrent Events 
and Missing Data 
Analysis Model 
MI. Imputations following death will not be utilized as imputed 
values for participants who died prior to the assessment 
timepoint would not be interpretable. Intermittent missing data 
will be imputed with MCMC. 
baseline 6MWT 
quartile 
Change from baseline in 
KCCQ TSS at Week 24 
Summary 
EAS 
Observed KCCQ TSS and change from baseline 
N/A 
Responder analysis of change 
from baseline in KCCQ TSS 
at Week 24 
Summary 
EAS 
All data collected will be included regardless of intercurrent 
events. 
A participant with a missing data for any reason will be 
considered a non-responder for the visit of interest. 
Cochran-Mantel-Haens 
zel test stratified by 
stratification factors at 
randomization 
Change from Baseline in PGI Scores at Weeks 12 and 24 
Change from Baseline in PGI 
Scores at Weeks 12 
Summary 
EAS 
All data collected will be included regardless of intercurrent 
events. 
A participant with a missing data for any reason will be 
considered a non-responder for the visit of interest. 
NA 
Change from Baseline in PGI 
Scores at Weeks 24 
Summary 
EAS 
All data collected will be included regardless of intercurrent 
events. 
A participant with a missing data for any reason will be 
considered a non-responder for the visit of interest. 
NA 
Change from Baseline in NT-proBNP at Weeks 4, 12, and 24 
Change from baseline in 
NT-proBNP at Week 4 
Main analysis 
EAS 
Hypothesis testing: Deaths prior to Week 4 will be assigned the 
worst rank and discontinuations from study prior to Week 24 the 
next lowest rank, followed by changes in NT-proBNP for all 
other participants. All data collected regardless of 
discontinuation of randomized treatment will be included. 
Intermittent missing data will be imputed with MCMC. For 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 


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Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for Handling Intercurrent Events 
and Missing Data 
Analysis Model 
participants who do not die or discontinue the study prior to 
Week 4 but have monotone missing Week 4 and subsequently 
discontinue the study at a later timepoint, missing data will be 
imputed under MAR for those who discontinue due to issues 
outside of the study (eg, COVID) and imputed using control- 
based MI for those who discontinuation due to post 
randomization events (eg, AEs or perceived lack of efficacy). 
Estimation of treatment effect (magnitude of change in 
NT-proBNP): Missing data due to issues outside of the study 
(eg, COVID-19) will be imputed under MAR. Missing data for 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy) will be imputed using control-based 
MI. Imputations following death will not be utilized as imputed 
values for participants who died prior to the assessment 
timepoint would not be interpretable. Intermittent missing data 
will be imputed with MCMC. 
Stratified Hodges- 
Lehmann estimator by 
baseline 6MWT 
quartile 
Change from baseline in 
NT-proBNP at Week 4 
Summary 
EAS 
Observed NT-proBNP and change from baseline 
N/A 
Change from baseline in 
NT-proBNP at Week 12 
Main analysis 
EAS 
Hypothesis testing: Deaths prior to Week 12 will be assigned 
the worst rank and discontinuations from study prior to Week 12 
the next lowest rank, followed by changes in NT-proBNP for all 
other participants. All data collected regardless of 
discontinuation of randomized treatment will be included. 
Intermittent missing data will be imputed with MCMC. For 
participants who do not die or discontinue the study prior to 
Week 12 but have monotone missing Week 12 and subsequently 
discontinue the study at a later timepoint, missing data will be 
imputed under MAR for those who discontinue due to issues 
outside of the study (eg, COVID) and imputed using control- 
based MI for those who discontinuation due to post 
randomization events (eg, AEs or perceived lack of efficacy). 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 


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Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for Handling Intercurrent Events 
and Missing Data 
Analysis Model 
Estimation of treatment effect (magnitude of change in 
NT-proBNP): Missing data due to issues outside of the study 
(eg, COVID-19) will be imputed under MAR. Missing data for 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy) will be imputed using control-based 
MI. Imputations following death will not be utilized as imputed 
values for participants who died prior to the assessment 
timepoint would not be interpretable. Intermittent missing data 
will be imputed with MCMC. 
Stratified Hodges- 
Lehmann estimator by 
baseline 6MWT 
quartile 
Change from baseline in 
NT-proBNP at Week 12 
Summary 
EAS 
Observed NT-proBNP and change from baseline 
N/A 
Change from baseline in 
NT-proBNP at Week 24 
Main analysis 
EAS 
Hypothesis testing: Deaths prior to Week 24 will be assigned 
the worst rank and discontinuations from study prior to Week 24 
the next lowest rank, followed by changes in NT-proBNP for all 
other participants. All data collected regardless of 
discontinuation of randomized treatment will be included. 
Intermittent missing data will be imputed with MCMC. For 
participants who do not die or discontinue the study prior to 
Week 24 but have monotone missing Week 24 and subsequently 
discontinue the study at a later timepoint, missing data will be 
imputed under MAR for those who discontinue due to issues 
outside of the study (eg, COVID) and imputed using control- 
based MI for those who discontinuation due to post 
randomization events (eg, AEs or perceived lack of efficacy). 
Estimation of treatment effect (magnitude of change in 
NT-proBNP): Missing data due to issues outside of the study 
(eg, COVID-19) will be imputed under MAR. Missing data for 
discontinuation due to post randomization events (eg, AEs or 
perceived lack of efficacy) will be imputed using control-based 
MI. Imputations following death will not be utilized as imputed 
values for participants who died prior to the assessment 
van Elteren and win 
ratio stratified by 
baseline 6MWT 
quartile 
Stratified Hodges- 
Lehmann estimator by 
baseline 6MWT 
quartile 


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Endpoint 
Analysis Type 
Population 
Data Inclusion and Rules for Handling Intercurrent Events 
and Missing Data 
Analysis Model 
timepoint would not be interpretable. Intermittent missing data 
will be imputed with MCMC. 
Change from baseline in 
NT-proBNP at Week 24 
Summary 
EAS 
Observed NT-proBNP and change from baseline. 
N/A 
The Composite Endpoint of All-Cause Mortality or Worsening Heart Failure 
Time to first occurrence of 
all-cause mortality or 
worsening heart failure 
Main analysis 
SAS/EAS 
All available data will be included. 
Missing data will not be imputed. 
Kaplan-Meier method 
and stratified Cox 
regression by strata at 
randomization, where 
appropriate 
Component analysis of time to 
HF-related hospitalization and 
time to urgent care visit 
Supportive 
analysis 
SAS 
All available data will be included. 
Missing data will not be imputed. 
Kaplan-Meier method 
and stratified Cox 
regression by strata at 
randomization, where 
appropriate 
Overall Survival 
Time to All-Cause Mortality 
Main analysis 
SAS/EAS 
All available data will be included. 
Missing data will not be imputed 
Kaplan-Meier method 
and stratified Cox 
regression by strata at 
randomization, where 
appropriate 


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Appendix 2. Programming Specifications 
 
The following sample SAS statement provides the framework for the MI method specified in 
Section 5.3.1. 
 
/* Convert dataset into monotone missing data pattern (impute intermittent missing data) */ 
 
PROC MI data=<dataset> nimpute=1000 seed=349782 out=<dataset1>; 
EM MAXITER = 1000 ; 
VAR tmtrt baseline week4-week36; 
MCMC chain=multiple nbiter=500 niter=500 impute=monotone initial=em 
(maxiter=1000); 
BY treatment; 
RUN; 
/* Impute monotone missing value under MAR*/ 
PROC MI data=<dataset1> seed=229856 nimpute=1 out=<dataset2>; 
CLASS mutation; 
MONOTONE reg(/details); 
VAR mutation tmtrt baseline week4 week12 week24; 
BY _imputation_ treatment _; 
RUN; 
/* Impute monotone missing value under MNAR*/ 
PROC MI data=<dataset1>  seed=287561 nimpute=1 out=<dataset2>; 
CLASS treatment mutation; 
MONOTONE reg(/details); 
MNAR model(week4-week12/ modelobs=(trt='0'));  /* trt='0' represents placebo */ 
VAR mutation tmtrt baseline week4 week12 week24; 
BY _imputation_; 
RUN; 
 
/* Combine results*/ 
 
PROC MIANALYZE data=<dataset3>; 
MODELEFFECTS estimate; 
STDERR; 
RUN; 
 
Sample SAS code for the van Elteren analysis specified in Section 5.2.1 is given below. 
 
PROC NPAR1WAY data=<dataset4> (refclass= '0'); 
CLASS treatment; 
VAR value; 
STRATA bstrata/ranks=stratum weights=stratum Wilcoxon ; 
ODS output WilcoxonStrataTest=<dataset3>; 
RUN; 
Sample SAS code for the stratified HL analysis specified in Section 5.2.1 is given below. 


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/* Step 1: output the within-stratum HL estimate, and the standard error of the HL estimate 
with the HL option in SAS PROC NPAR1WAY */ 
 
PROC NPAR1WAY data=<dataset5> HL (refclass=’0’); /*refclass='0' represents placebo*/ 
CLASS treatment; 
VAR value; 
OUTPUT out=HLdata; 
BY bstrata; 
RUN; 
 
/* Step 2: calculate stratified HL estimate as weighted averages of the within-stratum HL 
estimates where the weights are proportional to the strata sizes wk = (nk +1)/∑(nk + 1) */ 
 
PROC DATA= HLdata; 
wj=(nstrata+1)/wtot; 
asy_HL=_HL_*wj; 
asy_var=(E_HL*wj)*(E_HL*wj); 
RUN; 


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Appendix 3. Definition and Use of Visit Windows in Reporting 
 
The below analysis windows will be used for the efficacy variables in the randomized period. 
If two or more visits fall into the same window, keep the one closest to the Target Day. If 
two visits are equaled distant from the Target Day in absolute value, the later visit should be 
used. 
 
An analysis visit window ± 3 weeks will be applied for efficacy variables collected at the 
protocol-defined visits (ie, the Week 12 visit or after) with the exception of the Week 4 visit. 
For the Week 4 visit, an analysis visit window ± 2 weeks will be used. 
 
Visit Label 
Target Day 
Definition [Day window] 
Screening 
Days -35 to -1 
Baseline 
Day 1, Baseline 
Day 1 
Week 4 
29 
Days 15 to 43 
Week 12 
85 
Days 64 to 106 
Week 24 
169 
Days 148 to 190 
Similarly for every subsequent 
12 weeks* 
*An analysis visit window ± 3 weeks will be applied 
 
If a participant dies within a visit window but has a 6MWT assessment within the window 
the 6MWT value will be used, even if the death date is closer to the intended visit study day 
than the 6MWT date. For example, if a participant has a 6MWT on study day 80, but dies on 
study Day 84, the 6MWT from study Day 80 will be used. 
 
Safety endpoints (eg, vital signs) will be summarized by study visits if required. 


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Appendix 4. Endpoint Derivations 
 
Appendix 4.1. Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item self-administered 
questionnaire developed to independently measure the participant’s perception of their health 
status, which includes heart failure symptoms, impact on physical and social function, and 
how their heart failure impacts their quality of life (QOL) within a 2-week recall period. 
Summaries on distinct domains that are derived from the individual questions in the KCCQ 
are provided below.  The column “Evaluable Criteria” indicates that the domain score will 
not be evaluable unless the required number of questions have been completed. 
 
Domain 
Questionnaire 
Number 
Evaluable Criteria 
Physical Limitation 
1 
At least 3 items from the 6-part question completed 
Symptom 
Symptom Frequency 
3, 5, 7, 9 
At least 2 questions completed 
Symptom Burden 
4, 6, 8 
At least 1 question completed 
Self-efficacy 
11, 12 
Not analyzed 
Quality of Life 
12, 13, 14 
At least 1 question completed 
Social Limitation 
15 
At least 2 items from the 4-part question completed 
 
In addition, the following summary scores are derived based on individual domain scores: 
 
• Total Symptom Score (TSS) includes symptom frequency scores and symptom 
burden scores. 
 
• Clinical Summary Score (CSS) includes total symptom and physical limitation 
scores to correspond with NYHA Classification. 
 
• Overall Summary Score (OSS) includes the total symptom, physical limitation, 
social limitations and quality of life scores. 
 
For each domain score, the response to each question is converted to a percentage between 
0 and 100 by subtracting one from the individual score and dividing by the number of 
possible responses minus one with the worst outcome assigned a value of 1 and the best 
outcome a value corresponding to the number of possible responses.  Therefore, a higher 
score reflects better health status. For example, for questions 5 and 7, where there are 
7 possible responses, if a participant completed ‘several times a day’ their percentage score 
would be 100*(2-1)/6 = 17%.  For questions 1 and 15, the responses of ‘Limited for other 
reasons or did not do’ and ‘Does not apply or did not do for other reasons’ are not scored and 
treated as missing. 


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Appendix 4.2. Patient Global Impression Scales 
 
PATIENT GLOBAL IMPRESSION OF SEVERITY (PGI-S) SCALE 
 
Question 1: 
 
Over the past week, how would you describe the severity of your heart failure symptoms 
(eg, fatigue, edema, palpitations, etc)? 
 
Choose ONE. 
 
_None 
 
_Mild 
 
_Moderate 
 
_Severe 
 
_Very severe 
 
Question 2: 
 
Over the past week, how would you describe the severity of your physical activity limitations 
(eg, dressing, walking, climbing stairs, etc)? 
 
Choose ONE. 
 
_None 
 
_Mild 
 
_Moderate 
 
_Severe 
 
_Very severe 
 
 
Patient’s Signature: 
 
 


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PATIENT GLOBAL IMPRESSION OF CHANGE (PGI-C) SCALE 
 
Question 1: 
 
Since you began taking medication on this clinical study, how would you describe the overall 
change (if any) in your heart failure symptoms (eg, fatigue, edema, palpitations, etc)? 
 
Choose ONE. 
 
_Very much Better 
 
_Moderately Better 
 
_A little Better 
 
_No Change 
 
_A little Worse 
 
_Moderately Worse 
 
_Very much Worse 
 
Question 2: 
 
Since you began taking medication on this clinical study, how would you describe the overall 
change (if any) in your physical activity limitations (eg, dressing, walking, climbing stairs, 
etc)? 
 
Choose ONE. 
 
_Very much Better 
 
_Moderately Better 
 
_A little Better 
 
_No Change 
 
_A little Worse 
 
_Moderately Worse 
 
_Very much Worse 
 
Patient’s Signature: 
 
 


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CCI  
 
 
 
 
 
CCI 


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Appendix 5. List of Abbreviations 
 
Abbreviation 
Term 
6MWT 
6 Minute Walk Test 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BSSR 
blinded sample size re-estimation 
BUN 
blood urea nitrogen 
CEC 
clinical event committee 
CK 
creatine kinase 
CI 
confidence interval 
CO2 
carbon dioxide (bicarbonate) 
Cmax 
maximum observed concentration 
CMH 
Cochran-Mantel-Haenszel 
CRT 
cardiac resynchronization therapy 
CRT-D 
cardiac resynchronization therapy defibrillator 
CSD 
conduction system disease 
CSR 
clinical study report 
CSS 
clinical summary score 
DCM 
dilated cardiomyopathy 
DMC 
data monitoring committee 
EAS 
efficacy analysis set 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ECG 
electrocardiogram 
eGFR 
estimated glomerular filtration ratio 
EQ-5D-5L 
EuroQol 5 Dimension 5 Level 
FAS 
full analysis set 
FSH 
follicle-simulating hormone 
GGT 
Gamma-glutamyltransferase 
HF 
heart failure 
HIV 
human immunodeficiency virus 
HL 
Hodges-Lehmann 
HR 
hazard ratio 
IAS 
interim analysis set 
ICD 
implantable cardioverter defibrillator 
IVC 
inferior vena cava 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LMNA 
gene encoding the lamin A/C protein 
LV 
left ventricular 
LVEF 
left ventricular ejection fraction 
LVEDVI 
left ventricular end diastolic volume indices 


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Abbreviation 
Term 
LVESVI 
left ventricular end systolic volume indices 
MAPK 
mitogen-activated protein kinase 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCMC 
Markov chain Monte Carlo 
MI 
multiple imputation 
MR-NR 
missing response as non-response 
MVPA 
moderate to vigorous physical activity 
N/A 
not applicable 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 
NYHA 
New York Heart Association 
OS 
overall survival 
OSS 
overall summary score 
P/LP 
pathogenic/likely pathogenic 
PA 
physical activity 
PASP 
pulmonary artery systolic pressure 
PD 
pharmacodynamic(s) 
PGI 
Patient Global Impression 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
pH 
hydrogen ion concentration 
PK 
pharmacokinetic(s) 
PK/PD 
pharmacokinetic/pharmacodynamic 
PL 
physical limitation 
PR 
ECG interval from the onset of P wave to the onset of the QRS 
complex 
PRO 
patient-reported outcome 
PT 
preferred term 
Q1 
first quartile 
Q3 
third quartile 
QOL 
quality of life 
QT 
QT interval: a measurement of the time between the start of the Q 
wave and the end of the T wave in an ECG 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RBC 
red blood cells 
RV 
right ventricular 
RVEDD 
right ventricular end-diastolic diameter 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SCD 
sudden cardiac death 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 


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Abbreviation 
Term 
TAPSE 
tricuspid annular plane systolic excursion 
TEAE 
treatment emergent adverse events 
TSH 
thyroid-stimulating hormone 
TSS 
total symptom score 
VAS 
visual analog scale 
VUS 
variant of unknown significance 
WBC 
white blood cells 
WHF 
worsening heart failure 
WHO 
World Health Organization