Clinical trial NCT03044353
Conditions: Amyloidosis
Keywords: echocardiography (ECHO) skin biopsy monoclonal anti-serum amyloid p component antibody (anti-SAP mAb) Amyloidosis cardiac magnetic resonance imaging (CMR) biomarkers cardiac functional measures left ventricular mass
Sponsor: GlaxoSmithKline
Start date: 2017-07-10; Completion date: 2019-01-03
Enrollment: 7 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is intended to evaluate whether monthly repeated courses of administration of GSK2315698 followed by GSK2398852 is associated with a reduction in cardiac amyloid load in patients with cardiac amyloidosis, monitored by cardiac magnetic resonance imaging (CMR) and echocardiography (ECHO), and whether this is associated with an improvement in cardiac function. Cohort 1 is transthyretin cardiomyopathy (ATTR-CM) , cohort 2 is patients with immunoglobulin light chain (AL) systemic amyloidosis at greater than 6 months post chemotherapy, cohort 3 newly diagnosed AL systemic amyloidosis undergoing chemotherapy. Primary objectives for the study are assessment of reduction in cardiac amyloid load after repeated administrations of Anti-SAP treatment as evaluated by CMR in all study groups and assessment of safety \& tolerability of repeated administration of Anti-SAP treatment, including compatibility with chemotherapy treatment in patients with AL systemic amyloidosis. This is an open label, non-randomised, three-group, monthly repeat Anti-SAP treatment study in systemic amyloidosis patients with cardiac dysfunction caused by cardiac amyloidosis. Subjects will receive up to 6 courses of Anti-SAP treatment. Maximum total duration for a subject in the study is approximately 18 months.

Detailed description:

Arms: arm 1: Cardiac transthyretin (TTR) amyloidosis (transthyretin amyloid cardiomyopathy \[ATTR-CM\]) participants with mutant genotypes primarily associated with familial amyloidotic cardiomyopathy (FAC) and wild-type TTR will be included. Participants will receive 6 anti-SAP treatments, consisting of carboxy pyrrolidine hexanoyl pyrrolidine carboxylate (CPHPC) followed by anti-SAP monoclonal antibody (mAb) at monthly intervals. During each anti-SAP treatment, participants will receive CPHPC intravenous (IV) infusion once daily for up to 72 hours. After 72 hours of CPHPC administration, participants will be administered intravenous infusion of anti-SAP mAb over 6-8 hours each on Days 1 and 3. The starting dose level of anti-SAP mAb will be 600 milligrams (mg) (divided into 2 infusions of 300 mg). In each treatment session, CPHPC will be administered as subcutaneous (SC) injection for 11 days from the day of first dose of anti-SAP mAb. arm 2: Immunoglobin light chain amyloidosis (AL) participants who attain either a very good partial response (VGPR), or complete response (CR), to systemic chemotherapy (including autologous stem cell transplantation) will be included. Participants will receive 6 anti-SAP treatments, consisting of CPHPC followed by anti-SAP mAb at monthly intervals. During each anti-SAP treatment, participants will receive CPHPC IV infusion once daily for up to 72 hours. After 72 hours of CPHPC administration, participants will be administered IV infusion of anti-SAP mAb over 6-8 hours each on Days 1 and 3. The starting dose level of anti-SAP mAb will be 600 mg (divided into 2 infusions of 300 mg). In each treatment session, CPHPC will be administered by as SC injection for 11 days from the day of first dose of anti-SAP mAb. arm 3: Newly diagnosed Mayo stage II/IIIa AL participants who attain a free light chain CR during the first 3 cycles of first-line chemotherapy where the first cycle was cyclophosphamide, bortezomib, dexamethasone (CyBorD) will be included. Participants will receive 6 anti-SAP treatments, consisting of CPHPC followed by anti-SAP mAb at monthly intervals. During each anti-SAP treatment, participants will receive CPHPC IV infusion once daily for up to 72 hours. After 72 hours of CPHPC administration, participants will be administered IV infusion of anti-SAP mAb over 6-8 hours each on Days 1 and 3. The starting dose level of anti-SAP mAb will be 600 mg (divided into 2 infusions of 300 mg). In each treatment session, CPHPC will be administered as SC injection for 11 days from the day of first dose of anti-SAP mAb.
Interventions: intervention 1: GSK2315698 (CPHPC) intervention 2: GSK2398852 (anti-SAP mAb)
Intervention descriptions: intervention 1: 20mg/hour, IV (in the vein) for up to 72hours followed by 60mg three times daily subcutaneous injection for 11 days. Number of cycles: up to 6. Dose level and frequency adjusted according to renal function intervention 2: Up to 1200mg, IV divided over days 1 and 3. Number of cycles: up to 6. Dose level adjusted based on tolerability.

Protocol documents:
Prot_000.pdf: 
2015N249732_02
CONFIDENTIAL
The GlaxoSmithKline group of companies
201464
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A multiple treatment session, open label phase 2 clinical study of 
GSK2398852 administered following and together with 
GSK2315698 in cohorts of patients with cardiac amyloidosis
Compound Number:
GSK2315698+GSK2398852
Development Phase:
II
Effective Date:
[05-MAR-2018]
Protocol Amendment Number:  02
Author (s):
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2015N249732_00
2016-MAY-09
Original
2015N249732_01
2017-APR-20
Amendment No. 1
Changes made to reflect regulatory input from the FDA. Other changes made to correct 
minor errors included in the original version.
2015N249732_02
2018-MAR-05
Amendment No. 2
Regulatory input from the FDA on clarifying requirements for recruitment.
Define plasma SAP depletion target level of <3 mg/L.
Inclusion criterion for LVmass updated for Groups 2 and 3 to reflect the AL patient 
population.
Reflect regulatory safety update information for Gadolinium contrast agents.
Dermatology review timings adjusted for grade 3 rash incidences.
Other changes made for clarity and to correct minor typographical errors.
Copyright 2018 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


PPD
PPD


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MEDICAL MONITOR/SPONSOR INFORMATION PAGE
Medical Monitor/SAE Contact Information: 
Role
Name
Day Time Phone Number 
and email address
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
Site Address
Primary 
Medical 
Monitor 
GlaxoSmithKline
Medicines
Research &
Development,
Gunnels Wood
Road, Stevenage
SG1 2NY United
Kingdom
Secondary 
Medical 
Monitor
SAE 
contact  
information 
Medical
monitor 
as above
Sponsor Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). If applicable, the details of the alternative Sponsor and contact 
person in the territory will be provided to the relevant regulatory authority as part of the 
clinical trial application.   
Regulatory Agency Identifying Number(s): EudraCT: 2016-000276-23, IND: 129568
PPD


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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number: 201464
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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5
TABLE OF CONTENTS
PAGE
1.
PROTOCOL SYNOPSIS FOR STUDY 201464........................................................9
2.
INTRODUCTION....................................................................................................15
2.1.
Study Rationale ..........................................................................................15
2.2.
Brief Background ........................................................................................15
2.3.
Summary of First In Human (FIH) Findings.................................................16
2.4.
Purpose of phase 2 Study...........................................................................17
2.4.1.
Multimodality cardiac imaging......................................................18
3.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................19
4.
STUDY DESIGN ....................................................................................................22
4.1.
Overall Design ............................................................................................22
4.2.
Treatment Groups and Duration .................................................................25
4.3.
Number of Subjects ....................................................................................26
4.4.
Justification of the study design ..................................................................26
4.4.1.
Combining Anti-SAP Treatment with Chemotherapy....................27
4.4.1.1.
Scheduling of Anti-SAP Treatment with 
Chemotherapy............................................................28
4.5.
Justification of Dosing Regimen..................................................................29
4.5.1.
GSK2315698 (CPHPC - Plasma SAP Depleter) ..........................29
4.5.2.
GSK2398852 (anti-SAP mAb)......................................................30
4.5.3.
Dosing schedule for GSK2315698 (CPHPC) + 
GSK2398852 (anti-SAP mAb)......................................................32
4.6.
Benefit:Risk Assessment ............................................................................32
4.6.1.
Risk Assessment .........................................................................33
4.6.1.1.
Potential for Cardiotoxicity..........................................33
4.6.1.2.
Summary of rashes ....................................................33
4.6.1.3.
Potential for Circulating Immune Complex 
Formation...................................................................34
4.6.1.4.
Surveillance for Long-Term Toxicities.........................34
4.6.2.
Risk Assessment Table ...............................................................35
4.6.3.
Benefit Assessment.....................................................................42
4.6.4.
Overall Benefit:Risk Conclusion...................................................42
5.
SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA .............43
5.1.
Inclusion Criteria.........................................................................................43
5.2.
Exclusion Criteria........................................................................................47
5.3.
Screening/Baseline/Run-in Failures............................................................50
5.4.
Withdrawal/Stopping Criteria.......................................................................50
5.4.1.
Liver Chemistry Stopping Criteria ................................................51
5.4.1.1.
Study Treatment Restart or Rechallenge....................51
5.4.2.
Renal Function Stopping Criteria .................................................51
5.4.3.
Platelet Stopping Criteria .............................................................52
5.4.4.
Neutrophil Stopping Criteria.........................................................52
5.4.5.
Cardiovascular Safety Stopping Criteria ......................................52
5.4.5.1.
Individual subject cardiovascular stopping 
criteria ........................................................................52


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5.4.6.
QTc Stopping Criteria ..................................................................53
5.4.6.1.
Individual Subject QTcF Stopping Criteria ..................53
5.4.7.
Dermatological Toxicity Stopping Criteria.....................................53
5.4.7.1.
Individual subject dermatological stopping 
criteria ........................................................................53
5.4.8.
Haematological Stopping Criteria (Groups 2 & 3).........................53
5.4.8.1.
Individual subject haematological stopping 
criteria ........................................................................53
5.4.9.
Study Safety Stopping Criteria.....................................................54
5.5.
Subject Withdrawal Procedures..................................................................54
5.6.
Replacement of Withdrawn Subjects ..........................................................54
5.7.
Subject and Study Completion....................................................................54
6.
STUDY TREATMENT ............................................................................................55
6.1.
Investigational Product and Other Study Treatment....................................55
6.1.1.
Anti-SAP treatment......................................................................55
6.2.
Planned Dose Adjustments- Subject Specific Dose Adjustment 
Criteria........................................................................................................56
6.2.1.
CPHPC dosing regimen according to renal function ....................56
6.2.2.
Dose-Level Reduction Schedule for anti-SAP mAb Due to 
Adverse Events............................................................................56
6.2.3.
Dose-Interval Extension between Anti-SAP Treatment 
Sessions......................................................................................57
6.2.4.
Dose Modifications for Skin Rashes.............................................57
6.3.
Blinding.......................................................................................................58
6.4.
Packaging and Labelling.............................................................................58
6.5.
Preparation/Handling/Storage/Accountability..............................................58
6.6.
Compliance with Study Treatment Administration.......................................59
6.7.
Treatment of Study Treatment Overdose....................................................59
6.8.
Treatment after the End of the Study ..........................................................59
6.9.
Lifestyle and/or Dietary Restrictions............................................................59
6.9.1.
Alcohol, and Tobacco ..................................................................59
6.9.2.
Activity .........................................................................................60
6.10.
Concomitant Medications and Non-Drug Therapies....................................60
6.10.1.
Permitted Medications and Non-Drug Therapies..........................60
6.10.2.
Prohibited Medications and Non-Drug Therapies.........................61
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................62
7.1.
Time and Events Table...............................................................................63
7.2.
Screening and Critical Baseline Assessments ............................................70
7.2.1.
Demographic/Medical History Assessments ................................70
7.3.
Efficacy.......................................................................................................70
7.4.
Safety .........................................................................................................70
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)..........70
7.4.1.1.
Time period and Frequency for collecting AE 
and SAE information...................................................70
7.4.1.2.
Method of Detecting AEs and SAEs ...........................71
7.4.1.3.
Follow-up of AEs and SAEs........................................71
7.4.1.4.
Regulatory Reporting Requirements for SAEs............71
7.4.2.
Pregnancy ...................................................................................72
7.4.3.
Physical Exams ...........................................................................72
7.4.4.
Vital Signs....................................................................................72


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7.4.5.
Electrocardiogram (ECG).............................................................72
7.4.6.
Echocardiography (ECHO) ..........................................................73
7.4.7.
Cardiac Electrical Monitoring & Implantable Devices. ..................73
7.4.7.1.
Lead II Telemetry .......................................................73
7.4.7.2.
Cardiac Recording......................................................73
7.4.7.3.
Insertion of a PPM or ICD for Prophylactic 
Reasons.....................................................................73
7.4.8.
Clinical Safety Laboratory Assessments ......................................74
7.5.
Pharmacokinetics .......................................................................................76
7.5.1.
Blood Sample Collection..............................................................76
7.5.2.
Sample Analysis ..........................................................................76
7.6.
Biomarker(s) / Pharmacodynamic Markers (PD).........................................77
7.6.1.
Pharmacodynamic markers in blood............................................77
7.6.2.
Imaging........................................................................................77
7.6.2.1.
Cardiac Magnetic Resonance (CMR) Imaging............77
7.6.2.2.
SAP scan (Groups 2 and 3 and where 
available)....................................................................78
7.6.2.3.
99mTc-DPD or 99mTc-PYP Radioscintigraphy ...............78
7.6.3.
Exploratory Biomarkers................................................................78
7.6.3.1.
Blood biomarkers .......................................................79
7.6.3.2.
RNA Transcriptome Research....................................79
7.6.3.3.
RNA Expression Research of a Subset of RNA 
Species ......................................................................80
7.6.3.4.
Access to other biopsy tissue .....................................80
7.7.
Immunogenicity...........................................................................................80
7.7.1.
Anti-GSK2398852 antibodies (ADA) ............................................80
7.7.2.
Immune complexes......................................................................80
7.7.3.
Auto-antibodies............................................................................81
7.8.
Efficacy.......................................................................................................81
7.8.1.
Six Minute Walk Test ...................................................................81
7.8.2.
Safety/exploratory Biomarkers.....................................................81
7.9.
Health Outcomes........................................................................................81
7.9.1.
MOS 36-item short-form health survey (MOS SF-36)...................81
7.9.2.
Kansas City Cardiomyopathy Questionnaire (KCCQ) ..................81
7.9.3.
European Organisation for Research and Treatment of 
Cancer (EORTC) .........................................................................81
7.9.4.
Dermatology Quality of Life Index (DLQI).....................................82
7.9.5.
Questionnaire Administration.......................................................82
7.10.
Exit Interview ..............................................................................................82
7.11.
Genetics .....................................................................................................83
8.
DATA MANAGEMENT ...........................................................................................84
9.
STATISTICAL CONSIDERATIONS AND DATA ANALYSES .................................85
9.1.
Hypotheses.................................................................................................85
9.2.
Sample Size Considerations.......................................................................85
9.2.1.
Sample Size Assumptions ...........................................................85
9.2.2.
Sample Size Sensitivity................................................................86
9.2.3.
Sample Size Re-estimation or Adjustment...................................87
9.3.
Data Analysis Considerations .....................................................................87
9.3.1.
Analysis Populations....................................................................87
9.3.2.
Interim Analysis ...........................................................................87


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9.4.
Key Elements of Analysis Plan ...................................................................88
9.4.1.
Primary Analyses.........................................................................88
9.4.2.
Secondary Analyses ....................................................................89
10. STUDY GOVERNANCE CONSIDERATIONS........................................................90
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............90
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................90
10.3.
Quality Control (Study Monitoring) ..............................................................91
10.4.
Quality Assurance.......................................................................................91
10.5.
Study and Site Closure ...............................................................................91
10.6.
Records Retention......................................................................................92
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publically Available Clinical Trials Registers and Publication .................92
10.8.
Periodic Meeting with Investigators.............................................................93
10.8.1.
Individual Subject Review............................................................93
10.8.2.
Periodic Study Review.................................................................94
11. REFERENCES.......................................................................................................95
12. APPENDICES........................................................................................................97
12.1.
Appendix 1 – Abbreviations and Trademarks..............................................97
12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments ............................................................................................100
12.3.
Appendix 3: Guidance on the Clinical Management of Rash 
Associated with Anti-SAP mAb .................................................................102
12.3.1.
Background ...............................................................................102
12.3.2.
Investigation of rash...................................................................103
12.3.3.
Management of Rash.................................................................104
12.3.3.1.
Modification of anti-SAP mAb dose based on 
rash..........................................................................105
12.3.4.
Emergency management of rash with systemic /mucosal 
involvement ...............................................................................106
12.3.5.
Post-Inflammatory Hyperpigmentation (PIH)..............................106
12.4.
Appendix 4: Genetic Research .................................................................107
12.5.
Appendix 5: Definition of and Procedures for Recording, Evaluating, 
Follow-Up and Reporting of Adverse Events.............................................110
12.5.1.
Definition of Adverse Events......................................................110
12.5.2.
Definition of Serious Adverse Events.........................................111
12.5.3.
Definition of Cardiovascular Events ...........................................112
12.5.4.
Recording of AEs and SAEs ......................................................113
12.5.5.
Evaluating AEs and SAEs..........................................................114
12.5.6.
Reporting of SAEs to GSK.........................................................115
12.6.
Appendix 6: Collection of Pregnancy Information......................................116
12.6.1.
Modified List of Highly Effective Methods for Avoiding 
Pregnancy in Females of Reproductive Potential (FRP) ............116
12.6.2.
Collection of Pregnancy Information ..........................................117
12.6.3.
Pregnancy in female partner of a male study subject.................118
12.7.
Appendix 7: Reference tables...................................................................119
12.8.
Appendix 8: Protocol Amendments...........................................................121


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1.
PROTOCOL SYNOPSIS FOR STUDY 201464
Rationale
The study is intended to evaluate whether repeated courses of administration of 
GSK2315698 (carboxy pyrrolidine hexanoyl pyrrolidine carboxylate [CPHPC]) followed 
by GSK2398852 (monoclonal anti-serum amyloid p component antibody [anti-SAP 
mAb]) is associated with a reduction in cardiac amyloid load in patients with 
transthyretin cardiomyopathy (ATTR-CM) and immunoglobulin light chain (AL) 
systemic amyloidosis, monitored by cardiac magnetic resonance imaging (CMR) and 
echocardiography (ECHO), and whether this is associated with an improvement in 
cardiac function.
In this document GSK2315698 is referred to as CPHPC and GSK2398852 is referred to 
as anti-SAP mAb.  The administration of CPHPC and anti-SAP mAb is referred to in 
this document as Anti-SAP treatment.
The study will also evaluate the systemic and cardiac safety of repeated administrations 
of CPHPC followed by anti-SAP monoclonal antibody (mAb), as well as the 
pharmacodynamic compatibility of CPHPC and anti-SAP mAb with chemotherapy 
regimens in patients with newly diagnosed AL amyloidosis.
Objective(s)/Endpoint(s)
Objectives
Endpoints
Primary (all groups)
Assessment of reduction in cardiac amyloid 
load after repeated administrations of Anti-
SAP treatment as evaluated by CMR in all 
study groups
Change in left ventricular (LV) mass over 
time from baseline to 8-week follow-up
Assessment of safety & tolerability of 
repeated administration of Anti-SAP
treatment, including compatibility with 
chemotherapy treatment in Group 3
Clinical safety data from adverse events 
(AEs), clinical laboratory tests, vital signs, 
12-lead electrocardiogram (ECG), cardiac 
monitoring and ECHO to 8-week follow-
up
Incidence and grading of skin rashes 
classified using the Common Terminology 
Criteria for Adverse Events (CTCAE)
Secondary
Investigation of rash associated with Anti-
SAP treatment
Histopathological & immunohistochemical 
examination of skin biopsies + blood 
biomarkers (as data permit)
Characterisation of the pharmacokinetics of 
anti-SAP mAb
Descriptive pharmacokinetic (PK)
parameters including the maximum 
concentration (Cmax), the time associated 
with Cmax (Tmax), and the area under the 


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Objectives
Endpoints
concentration-time profile (AUC).
Assessment of changes in circulating 
markers associated with pharmacodynamic 
effect during repeated administrations 
Circulating biomarkers including but not 
limited to classical complement pathway 
components, acute phase proteins (e.g. c 
reactive protein [CRP], SAA) and 
cytokines (e.g. IL6, IL8, IL10, TNF).
Evaluation of changes in imaging markers 
of cardiac dysfunction monitored by serial 
CMR and / or ECHO.
Change in cardiac functional measures, 
including, but not limited to strain (e.g. 
global longitudinal strain [GLS]), LV twist, 
stroke volume (SV), ejection fraction (EF), 
end diastolic volume (EDV) & E/E’ ratio 
over time from baseline to 8 week follow-
up
Exploratory
To assess the reduction in cardiac amyloid 
load after repeated administrations of 
Anti-SAP treatment as evaluated by CMR 
in all study groups
Change in cardiac extracellular volume 
(ECV) over time from baseline to 8-week 
follow-up
Assessment of effects of Anti-SAP 
treatment on individual patient quality of 
life
Change in individual patient quality of life 
as measured by the MOS SF-36,  KCCQ, 
DLQI and EORTC QLQ 30 questionnaires 
over time from baseline to 8-week follow-
up
Assessment of clinical cardiac functional 
improvement
Change in 6 minute walk test (6MWT)
distance (Groups 1 and 2) from baseline to 
8-week follow-up.
Change in NT-proBNP from baseline to 
8-week follow-up
Assessment of reduction in cardiac uptake 
of radioisotope bone tracers (Group 1 only)
Change in 99mTc-DPD or 99mTc-PYP 
uptake from baseline to 8-week follow-up 
Assessment of change in amyloid load on 
SAP scan (Groups 2 & 3 only and where 
SAP scan available)
Change in overall body load and in affected 
organs (excluding cardiac load) on SAP 
scan assessment from baseline to 8-week 
follow-up 
Assess the correlation between circulating 
biomarkers and structural and functional 
CMR measures
Circulating biomarkers (e.g. cardiac - NT-
proBNP and Troponin T, cytokines) over 
time 
Structural, Functional, and Tissue 
Characterization CMR measures over time, 
as data permit


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Objectives
Endpoints
Evaluate changes in imaging markers of 
cardiac structure as monitored by serial 
CMR and / or ECHO imaging
Change in cardiac structural measures, 
including, but not limited to structure LV
wall thickness (CMR and/or ECHO), and 
LV mass (ECHO) over time from baseline 
to 8-week follow-up
Evaluate changes in imaging markers of 
cardiac tissue characterization as monitored 
by serial CMR
Change in cardiac tissue characterization 
measures, including, but not limited to late-
Gadolinum enhancement (LGE), native T1 
and ECV, over time from baseline to 8-
week follow-up
Assess the correlation between myocardial 
perfusion using CMR and cardiac 
structural, functional, and tissue 
characterization as measured by CMR 
and/or ECHO
Dynamic contrast enhanced (DCE)-CMR 
measuring myocardial vascular perfusion 
and structural, functional, and tissue 
characterization measures (CMR and/or 
ECHO), as data permit
Assessment of the immunogenicity of 
anti-SAP mAb when co-administered with 
CPHPC.
Measurement of anti-drug antibodies 
before and after treatment with anti-SAP 
mAb (baseline and 8-week follow-up)
To characterise the subject experience of 
Anti-SAP Treatment regimen
Subject Exit Interviews completed over the 
telephone after the 8 week follow-up or 
Early Withdrawal Visit
Long term follow-up
Assessment of long term safety at 6 and 12 
months post last anti-SAP mAb dose
Clinical safety data from adverse events 
(AEs), clinical laboratory tests, vital signs, 
12-lead ECG, cardiac monitoring and 
ECHO
Assessment of AntiSAP treatment 
outcomes at 6 and 12 months post last 
anti-SAP mAb dose
Long term changes in LV mass over time 
up to 12-month follow-up
Long term changes in imaging markers 
from CMR and / or ECHO over time up to 
12-month follow-up (as per 8-week follow-
up)
Long term changes in NT-proBNP over 
time up to 12-month follow-up
Long term changes in 6MWT distance over 
time up to 12-month follow-up (Groups 1 
and 2).
Measurement of anti-drug antibodies at 6 
and 12 month follow-up


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Overall Design
This is an open label, non-randomised, three-group, monthly repeat Anti-SAP treatment 
study in systemic amyloidosis patients with cardiac dysfunction caused by cardiac 
amyloidosis. Subjects will be required to participate in up to six Anti-SAP treatment 
sessions receiving anti-SAP mAb at monthly intervals. Anti-SAP treatment consists of 
CPHPC followed by anti-SAP mAb.
Within a given treatment session, anti-SAP mAb will be given as two 6-8 hour infusions, 
on Day 1 and Day 3.  CPHPC administration will consist of intravenous (IV) infusion for 
48 to 72 hours prior to anti-SAP mAb administration, followed by CPHPC sub-cutaneous 
(SC) injections for 11 days after the start of anti-SAP mAb administration.  Subjects will 
attend a follow-up visit 8 weeks after final dose of anti-SAP mAb.
Subjects will attend 2 further follow-up sessions at 6 and 12 months after last Anti-SAP 
treatment session. Maximum total duration for a subject in the study is approximately 18 
months.
Treatment Groups and Duration
Three patient Groups will be studied:
Group 1: Cardiac TTR patients (mutant genotypes primarily associated with 
familial amyloidotic cardiomyopathy (FAC) & wild-type TTR) with clinical cardiac 
dysfunction measurable by CMR. Subjects will be evaluated for the cardiac / systemic 
safety, and overall magnitude of cardiac amyloid load reduction, with repeated 
administrations of Anti-SAP treatment on a monthly schedule for up to 6 courses.
Group 2: Post-Chemotherapy AL amyloidosis patients whom have attained either a 
very good partial response (VGPR), or complete response (CR), to systemic 
chemotherapy (including autologous stem cell transplantation), and have residual clinical 
cardiac dysfunction that is measurable by CMR. Subjects will be evaluated for cardiac / 
systemic safety, and overall magnitude of cardiac amyloid load reduction, with repeated 
administrations of Anti-SAP treatment on a monthly schedule for up to 6 courses.
Group 3: Newly diagnosed Mayo stage II or IIIa AL amyloidosis patients, and with 
plasma NT-proBNP levels 8500 ng/L, who have attained a free light chain CR 
following first-line chemotherapy cycles 1, 2 or 3 where at least the first cycle of 
chemotherapy has been cyclophosphamide, bortezomib, dexamethasone (CyBorD). 
Subjects in Group 3 will be evaluated for cardiac / systemic safety, and overall magnitude 
of cardiac amyloid reduction, with repeated administrations of Anti-SAP treatment on a 
monthly schedule for a total of up to 6 courses. 
AntiSAP treatment will commence during the last week of the next scheduled cycle of 
chemotherapy immediately after the preceding cycle in which a free light chain CR status 
was attained, and in those patients where there is no intent to immediately proceed to an 
autologous stem cell transplant.
The Study is a three-group study. Group 1 and Group 2 will begin recruitment in parallel. 


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Recruitment into Group 3 will only be initiated after data has been reviewed and an 
acceptable cardiac and systemic safety profile for Anti-SAP treatment has been 
demonstrated and following review by regulatory agencies.
Type and Number of Subjects
A minimum of 30 subjects will be recruited initially, comprising 10 subjects per group. 
Additional subjects may be enrolled in each of the three groups to assist in interpretation 
of safety and / or pharmacodynamic (PD) data based on emerging data. 
Analysis
Hypotheses
No formal statistical hypothesis tests are planned in this study. 
Interim analyses
Data will be reviewed on an ongoing basis throughout the study, including, but not 
limited to, safety, imaging, PK, PD, clinical and biomarker data.
Study specific decisions will be supported by the periodic review of study data.  The first 
review will take place once 5 subjects have completed at least 3 courses of Anti-SAP 
treatment.  Outcomes from the periodic data reviews may include:

Regulatory interactions and initiation of recruitment in to Group 3 

Triggering of phase 3 planning and related regulatory interactions 

Sample size re-estimation/adjustment 

Adjustment of the schedule and timing of assessments

Confirmed continuation of the study
An interim analysis on a clean data cut will be conducted once at least 10 subjects per 
group have completed their 8-week follow-up visit. Further details will be provided in the 
Reporting and Analysis Plan (RAP) regarding key deliverables for this interim.
The final analyses will be conducted once all subjects have completed their 12-month 
follow-up visit.
Primary analyses - LV mass 
Analyses detailed below will be performed on data from each study group separately. 
Individual subject profiles over time for LV mass will be plotted using historical pre-trial 
standard of care subject data, where available, and within-study data on the same subject,
pre and post Anti-SAP treatment. Absolute values and changes from baseline in LV mass 
will also be summarized over time. 


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The longitudinal profile of LV mass post Anti-SAP treatment will be analyzed using a 
Bayesian linear mixed model (LMM). The intention is to also include two sources of 
historical MRI data in the model from one participating site that will be informative of 
the standard of care LV mass profile over time: 
1. Pre-trial MRI data for patients enrolling in the study, collected as part of their 
medical history, where available 
2. Repeat historical MRI data for patients not enrolled in the study (2 to 3 scans 
per patient) 
For subjects who prematurely discontinue treatment, follow-up MRI scans at 8 weeks, 6 
months and12 months post last dose will be performed where possible. All retrieved LV
mass data post treatment-discontinuation will be incorporated directly within the model. 
This will be achieved in two ways: (i) fitting a LMM following a Pattern Mixture Model 
(PMM) framework, uniquely identifying patterns of treatment discontinuation; and (ii) 
fitting a LMM to all data ignoring whether subjects prematurely discontinued Anti-SAP 
treatment. 
Any missing data will be imputed assuming a Missing Not at Random mechanism with 
the historical MRI data acting as reference. 
Posterior distributions at time points of interest post Anti-SAP treatment (e.g. after 3 
doses, at 8-week follow-up) will be presented graphically. Probability statements around 
the magnitude of LV mass and/or the reduction in LV mass post Anti-SAP treatment at 
selected time points will also be presented. Similarly, posterior distributions and 
probability statements will be presented for standard of care. 
Further details will be provided in the RAP. 
Primary analyses – Safety
Safety data (e.g. AEs, vital signs, haematology, biochemistry, urinalysis, ECGs, holter, 
rash) will be summarized by study group in tabular and/or graphical format. Posterior 
probabilities of a true adverse event rate being > 10%, > 30% and >50% will be presented 
for specific AEs (e.g. rash, anti-SAP mAb infusion-related reactions, cardiac AEs), 
derived within a Bayesian framework with a neutral non-informative conjugate 
Beta(1/3,1/3) prior distribution.
Further details will be provided in the RAP.


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2.
INTRODUCTION
Carboxy pyrrolidine hexanoyl pyrrolidine carboxylate (CPHPC) + anti- serum amyloid p 
component (SAP) monoclonal antibody (mAb) is a novel combination therapy, in fact an 
obligate therapeutic partnership, which promotes clearance of amyloid deposits from the 
tissues and is being developed in order to treat patients with systemic amyloidosis and 
alleviate the cardiac and other organ dysfunction caused by amyloid.
The heart is probably the most commonly clinically affected organ in systemic 
amyloidosis. Myocardial deposition of amyloid in transthyretin (ATTR-CM) and 
immunoglobulin light chain (AL) amyloidosis causes restrictive cardiomyopathy and 
arrhythmias. Cardiac dysfunction is a major cause of morbidity and the main determinant 
of disease-related survival. Removal of amyloid deposits from the myocardium could 
thus improve cardiac function, reduce symptoms and prolong survival in patients with 
ATTR and AL amyloidosis.
2.1.
Study Rationale
The principal aim of this phase 2 study is to investigate the extent of cardiac amyloid 
removal, the associated improvement in cardiac function, and the cardiac / systemic 
safety profile of Anti-SAP treatment (GSK2315698 + GSK2398852), given monthly for 
up to 6 sessions.
2.2.
Brief Background
In systemic amyloidosis normally soluble plasma proteins misfold and then aggregate as 
abnormal insoluble fibrils in the extracellular space, disrupting the architecture and 
function of affected tissues and organs, causing disease which is usually fatal [Pepys,
2006].  About 30 different proteins are known to form amyloid fibrils in different types of 
amyloidosis.  The most common types are AL amyloidosis, caused by monoclonal 
immunoglobulin light chains, and ATTR amyloidosis, caused by wild type or variant
(mutant) transthyretin (TTR).  Involvement of the heart is the most important determinant 
of outcome in both these forms of amyloidosis, leading to restrictive cardiomyopathy 
with predominantly diastolic dysfunction and heart failure with normal ejection fraction.  
Amyloid is deposited early in the subendocardium, causing a high incidence of 
arrhythmias, and deposition then proceeds asymmetrically, usually predominantly 
affecting the interventricular septum and left ventricular wall.
Existing treatment for systemic amyloidosis comprises maintenance and/or replacement 
of the function of amyloidotic organs and also, if possible, reduction of the production of 
the protein precursors of the amyloid fibrils.  However, even when these approaches are 
successful, regression of amyloid deposits is very variable and is always very slow.  No 
approved treatments exist which impact cardiac amyloid deposits.  A new approach, 
directly targeting amyloid deposits for clearance from the tissues, would have the 
potential to deliver substantial clinical benefit. The approach here is based on targeting of 
human serum amyloid P component (SAP).


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SAP is a normal, circulating, constitutive plasma glycoprotein which is always present as 
a minor component of all human amyloid deposits of all types.  SAP is a member of the 
pentraxin protein family which is characterized by calcium dependent binding to various 
ligands.  SAP avidly binds specifically but reversibly to all amyloid fibrils and in patients 
with systemic amyloidosis there is a dynamic equilibrium between SAP bound to the 
amyloid deposits and about 50-150 mg of SAP free in the plasma and extracellular fluid.  
SAP is produced only by hepatocytes and its plasma concentration is rather tightly 
maintained regardless of the presence, absence and extent of amyloid deposition.  In 
contrast the amyloid bound SAP pool reflects the mass of the amyloid fibrils present and 
can comprise grams of SAP.
The drug (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-
carboxylic acid (CPHPC) efficiently and highly specifically depletes circulating SAP 
from the plasma for as long as the drug is administered [Pepys, 2002; Sahota, 2015].  
This treatment also removes some SAP from the amyloid deposits but it does not remove 
it all.  After depletion of plasma SAP by CPHPC, anti-SAP antibodies can be given 
without being consumed by interaction with circulating SAP and without causing 
formation of large amounts of immune complexes in the circulation.  The antibodies can 
then reach and bind to residual SAP in the amyloid deposits and trigger the normal 
opsonophagocytic processes for removal of abnormal debris from the extracellular space.
In Amyloid A (AA) amyloidotic mice engineered or treated to have human SAP in their 
amyloid deposits, administration of a single dose of polyclonal or monoclonal antibodies 
to human SAP produced almost complete clearance of massive amyloid deposits from the 
liver and spleen [Bodin, 2010].  Cardiac amyloid deposits were significantly reduced 
after two doses of anti-SAP antibody [Simons, 2013].  The amyloid clearance was 
dependent on binding of the antibody to the amyloid deposits, activation of the classical 
complement pathway, complement deposition on the amyloid, and availability of 
macrophages.  Destruction of amyloid was mediated by macrophage derived 
multinucleated giant cells (MGCs) which surrounded, engulfed and degraded the amyloid 
fibrils [Milde, 2015].  The whole process was completed within about 16 days from 
antibody dosing and was well tolerated without evidence of additional organ dysfunction.  
Normal histology was restored with amyloid absent and no residual infiltrating or 
inflammatory cells. A major reason for using SAP as the target in this approach is its 
universality in all amyloid deposits in all forms of amyloidosis, so that the same 
therapeutic mechanism should operate in all types and tissues.
GSK is developing this approach comprising an obligate therapeutic partnership, 
involving prior administration of CPHPC to deplete SAP from the plasma so that a fully 
humanized IgG1 monoclonal anti-SAP antibody (GSK2398852) can then be given to 
target systemic amyloid deposits for clearance from the tissues. 
2.3.
Summary of First In Human (FIH) Findings
A GSK-sponsored phase 1 study is complete.  The study demonstrated proof-of-
pharmacology for the obligate therapeutic partnership of CPHPC + anti-SAP mAb in 
patients with AL amyloidosis, AA amyloidosis and patients with different types of 
hereditary systemic amyloidoses, all with predominantly abdominal organ involvement


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GlaxoSmithKline Document Number 2012N141587, GSK2398852 + GSK2315698 
Investigator's Brochure].

Overall Anti-SAP treatment was associated with an acceptable systemic safety 
profile in patients whose amyloid predominantly involved the abdominal viscera.

The following risks were identified:
o
Administration of anti-SAP mAb was associated with an infusion reaction. 
This was substantially mitigated by premedication with hydrocortisone 
and antihistamine.
o
Rashes were commonly reported following anti-SAP mAb infusion (refer 
to Section 12.3 Appendix 3 Rash and investigator’s brochure (IB
GlaxoSmithKline Document Number 2012N141587, GSK2398852 + 
GSK2315698 Investigator's Brochure])for more information and 
mitigation plans).
o
Transient pain and erythema at sites of injection and infusion of CPHPC 
were common but not treatment limiting.

Preliminary results in a small number of AL and ATTR patients with cardiac 
amyloidosis showed Anti-SAP treatment at doses of mAb up to 1200mg were 
generally well-tolerated with a similar safety profile to those subjects without 
evidence of cardiac amyloid.

Patients showing reduction of amyloid load following Anti-SAP treatment in the 
FIH study generally also had substantial reduction in total plasma C3 
concentration, consistent with the mechanism of action characterized in the 
preclinical model.

Plasma cytokine assays in subjects in the first in human (FIH) study showed 
increases in circulating IL-10, IL-8, TNF, and IL-6 values typically within the 
first 6 hours of anti-SAP mAb administration.  Subjects showing reduction of 
amyloid load following treatment in the FIH study also typically had acute phase 
responses of C-reactive protein (CRP) and serum amyloid A protein (SAA).

There were no preliminary clinical safety signals in the FIH study suggesting any 
direct visceral organ toxicity after one or more courses of anti-SAP mAb treatment 
in patients with systemic AL, ATTR, apolipoprotein A-I amyloidosis (AApoAI), 
fibrinogen A alpha chain amyloidosis (AFib), ATTR or AA amyloidosis, although 
one subject who developed hypotension during the immediate infusion reaction to 
anti-SAP mAb had a transient increase in plasma creatinine.  
2.4.
Purpose of phase 2 Study
The principal aim of this study is to investigate the benefit-risk profile of Anti-SAP 
treatment administered monthly for up to 6 treatments.  Prognosis in AL and ATTR 
amyloidosis mostly depends on cardiac involvement and removal of cardiac amyloid will 


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be quantitatively monitored by comprehensive imaging evaluation coupled with detailed 
assessment of cardiac function and cardiac safety.  The main adverse events observed in 
the FIH study (Study SAP115570), specifically at anti-SAP mAb doses ≥ 600mg, were 
skin rashes and these will therefore be closely monitored and thoroughly investigated.
2.4.1.
Multimodality cardiac imaging
This will consist of serial cardiac magnetic resonance imaging (CMR) and 
echocardiography (ECHO). 
CMR methods precisely and specifically quantify the left ventricle (LV) mass and the 
cardiac extracellular volume (ECV), both of which are increased by the presence and 
extent of cardiac amyloid deposition.  Raised ECV values have been shown to be 
associated with a worse clinical prognosis in AL amyloidosis [Banypersad, 2015].  
Neither LV mass nor ECV measurements have previously been shown to be markers of 
clinically beneficial regression of cardiac amyloid, both because these CMR parameters 
have only recently become available and because there are no existing therapies that 
reliably promote significant clearance of cardiac amyloid.  However, knowledge of the 
pathogenic mechanisms by which amyloid deposits cause dysfunction in the heart and 
other organs, coupled with the favourable evidence on liver function from Study 
SAP115570 strongly suggest that reduction in cardiac amyloid load detected by sufficient 
reduction towards normal of LV mass and cardiac ECV is likely to be accompanied by 
improved cardiac function and symptomatic improvement, and will be assessed in this 
study in an exploratory manner.
In addition, bone tracer scintigraphy using either 99mTc-3,3-diphosphono-1,2-
propanodicarboxylic acid (99mTc-DPD) or 99mTc-pyrophosphate (99mTc-PYP) will also be 
performed in Group 1 only (patients with ATTR-CM). It has been shown that 99mTc-DPD 
and 99mTc PYP in routine use for many years as bone scan agents in the United Kingdom 
and United States of America respectively, can also be used to image cardiac amyloid in 
patients with ATTR [Rapezzi, 2011]. 


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3.
OBJECTIVE(S) AND ENDPOINT(S)
Objectives
Endpoints
Primary (all groups)
Assessment of reduction in cardiac 
amyloid load after repeated administrations 
of Anti-SAP treatment as evaluated by 
CMR in all study groups
Change in LV mass over time from 
baseline to 8-week follow-up
Assessment of safety & tolerability of 
repeated administration of Anti-SAP
treatment, including compatibility with 
chemotherapy treatment in Group 3. 
Clinical safety data from adverse events 
(AEs), clinical laboratory tests, vital signs, 
12-lead electrocardiogram (ECG), cardiac 
monitoring and ECHO to 8-week follow-up
Incidence and grading of skin rashes 
classified using the Common Terminology 
Criteria for Adverse Events (CTCAE)
Secondary
Investigation of rash associated with Anti-
SAP treatment
Histopathological & immunohistochemical 
examination of skin biopsies + blood 
biomarkers (as data permit)
Characterisation of the pharmacokinetics 
of anti-SAP mAb
Descriptive pharmacokinetic (PK)
parameters including the maximum 
concentration (Cmax), the time associated 
with Cmax (tmax), and the area under the 
concentration-time profile (AUC).
Assessment of changes in circulating 
markers associated with pharmacodynamic 
effect during repeated administrations 
Circulating biomarkers including but not 
limited to complement pathway 
components, acute phase proteins (e.g. 
CRP, SAA) and cytokines (e.g. IL6, IL8, 
IL10, TNF).
Evaluation of changes in imaging markers 
of cardiac dysfunction monitored by serial 
CMR and / or ECHO.
Change in cardiac functional measures, 
including, but not limited to strain (e.g. 
global longitudinal strain [GLS]), LV twist, 
stroke volume (SV), ejection fraction (EF), 
end diastolic volume (EDV) & E/e’ ratio 
over time from baseline to 8 week follow-
up
Exploratory
To assess the reduction in cardiac amyloid 
load after repeated administrations of 
Anti-SAP treatment as evaluated by CMR 
in all study groups
Change in cardiac ECV over time from 
baseline to 8-week follow-up


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Objectives
Endpoints
Assessment of effects of Anti-SAP 
treatment on individual patient quality of 
life
Change in individual patient quality of life 
as measured by the MOS SF-36, KCCQ, 
DLQI and EORTC QLQ 30 questionnaires 
over time from baseline to 8-week follow-
up
Assessment of clinical cardiac functional 
improvement
Change in 6 minute walk test (6MWT)
distance (Groups 1 and 2) from baseline to 
8-week follow-up 
Change in N-terminal pro b-type 
Natriuretic Peptide (NT-proBNP) from 
baseline to 8-week follow-up
Assessment of reduction in cardiac uptake 
of radioisotope bone tracers (Group 1 only)
Change in 99mTc-DPD or 99mTc-PYP uptake 
from baseline to 8-week follow-up. 
Assessment of change in amyloid load on 
SAP scan (Groups 2 & 3 only and where 
SAP scan available)
Change in overall body load and in affected 
organs (excluding cardiac load) on SAP 
scan assessment  from baseline to 8-week 
follow-up
Assess the correlation between circulating 
biomarkers and structural and functional 
CMR measures
Circulating biomarkers (e.g. cardiac - NT 
proBNP and Troponin-T, cytokines) over 
time 
Structural, Functional, and Tissue 
Characterization CMR measures over time, 
as data permit
Evaluate changes in imaging markers of
cardiac structure as monitored by serial 
CMR and / or ECHO imaging
Change in cardiac structural measures, 
including, but not limited to structure LV 
wall thickness (CMR and/or, ECHO), and 
LV mass (ECHO) over time from baseline 
to 8-week follow-up
Evaluate changes in imaging markers of 
cardiac tissue characterization as 
monitored by serial CMR
Change in cardiac tissue characterization 
measures, including, but not limited to late 
gadolinium enhancement (LGE), native T1 
and ECV, over time from baseline to 8-
week follow-up
Assess the correlation between myocardial 
perfusion using CMR and cardiac 
structural, functional, and tissue 
characterization as measured by CMR 
and/or ECHO
Dynamic contrast enhanced (DCE)-CMR 
measuring myocardial vascular perfusion 
and structural, functional, and tissue 
characterization measures (CMR and/or 
ECHO), as data permit
Assessment of the immunogenicity of 
anti-SAP mAb when co-administered with 
CPHPC.
Measurement of anti-drug antibodies before 
and after treatment with anti-SAP mAb
(baseline and 8-week follow-up)


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Objectives
Endpoints
To characterise the subject experience of 
Anti-SAP Treatment regimen
Subject Exit Interviews completed over the 
telephone after the 8 week follow-up or 
Early Withdrawal Visit
Long term follow-up
Assessment of long term safety at 6 and 12 
months post last anti-SAP mAb dose
Clinical safety data from adverse events 
(AEs), clinical laboratory tests, vital signs, 
12-lead ECG, cardiac monitoring and 
ECHO
Assessment of Anti-SAP Treatment 
outcomes at 6 and 12 months post last 
anti-SAP mAb dose
Long term changes in LV mass over time 
up to 12-month follow-up
Long term changes in imaging markers 
from CMR and / or ECHO over time up to 
12-month follow-up (as per 8-week follow-
up)
Long term changes in NT-proBNP over 
time up to 12 month follow-up
Long term changes in 6MWT distance over 
time up to 12-month follow-up (Groups 1 
and 2).
Measurement of anti-drug antibodies (6 and 
12 month follow-up)


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4.
STUDY DESIGN
4.1.
Overall Design
This is an open label, non-randomised, three-group, monthly repeat Anti-SAP treatment 
study in systemic amyloidosis patients with cardiac dysfunction caused by cardiac 
amyloidosis. Subjects will be required to participate in up to six Anti-SAP treatment 
sessions receiving anti-SAP mAb at monthly intervals. Anti-SAP treatment consists of 
CPHPC followed by anti-SAP mAb.
Figure 1
Schematic of study groups
Group 1
Wild-type and 
variant ATTR-CM
N=10
Monthly Anti-SAP treatment 
- up to 6 treatment sessions
Group2
AL amyloidosis with 
cardiac dysfunction
6 months post 
chemotherapy or 
autologous stem 
cell  (CR/VGPR)
N=10
Group 3 will be initiated following a review 
of safety in cohorts 1 and 2 (See Section 
10.8)
Group 3
Mayo II/IIIa. AL 
amyloidosis with 
cardiac dysfunction
Free light chain CR 
during first three 
cycles of 
chemotherapy 
where at least the 
first cycle was 
CyBorD 
Monthly CPHPC + 
anti-SAP mAb up to 
6 treatment 
sessions
Initial dose of 
anti-SAP mAb 
defined by review 
of cohorts 1 and 2
N=10
N = number of subjects
A screening visit and baseline assessments will be conducted prior to the first Anti-SAP 
treatment session. Cardiac pharmacodynamic assessments will consist of CMR imaging 
and ECHO. Contrast-enhanced CMR imaging to assess changes in cardiac amyloid 
(including ECV) and cardiac safety will be performed at baseline, following the third 


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anti-SAP mAb treatment, and at the 8-week follow-up visit approximately 8 weeks after 
final dose of anti-SAP mAb (see Section 7.6.2 & Cardiac Imaging Manual).  Non 
contrast-enhanced CMR imaging will be scheduled to be performed following the 
second, fourth and fifth anti-SAP mAb treatment to assess changes in cardiac amyloid 
and safety. ECHO will be performed in all subjects prior to the first treatment session 
(baseline), at monthly intervals up to the final treatment session, and at the 8 week 
follow-up visit (see Section 7.4.6 & Cardiac Imaging Protocol). 99mTc-DPD or 
99mTc-PYP scintigraphy will be performed at baseline and at 8 week follow-up in Group 
1 (Figure 2). SAP scan to assess total and individual organ amyloid load will be 
performed at baseline and at 8 week follow-up in Groups 2 and 3 (UK sites only) 
There will be a minimum of 1 month between the start of anti-SAP mAb treatments. If a 
subject shows, on CMR, a reduction in amyloid load consistent with clearance of amyloid 
then Anti-SAP treatment will cease and they will proceed to 8-week follow-up.
Subjects will return to clinic for long term follow-up of safety and functional status 
(including CMR and ECHO), 6 and 12 months post last anti-SAP mAb treatment.
No more than two subjects will be in treatment session 1 (up to Day 24) at each study site 
at any given time.  


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Figure 2
Schedule of Anti-SAP Treatment sessions and cardiac imaging
Screening
Baseline
Session 
1
Session 
2
Session 
3
Session 
4
Session 
5
Session 
6
Follow up
Long term follow up
42 days
Monthly intervals 
8 Weeks post
final mAb 
dose
6 month 
post final 
mAb dose
12 month 
post final 
mAb dose
MRI with 
contrast
MRI with 
contrast
+ECHO
MRI with 
contrast
+ ECHO
MRI with 
contrast
+ ECHO 
MRI with 
contrast
+ ECHO
ECHO
ECHO
MRI+ 
ECHO
MRI+ 
ECHO
MRI+ 
ECHO
ECHO
Bone
tracer 
scinti-
graphy 
(Group 1 
only)
Bone tracer 
scintigraphy 
(Group 1 
only)


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Table 1
Anti-SAP treatment session
Treatment session
Day
Day
-2 & -1
Day
1/2/3
Day
4-11
Day
17
Day
24 1d
Setting
Inpatient
Outpatient
Outpatient
Activity
Plasma SAP 
depletion 
Administration 
of CPHPC 
48 to 72 hours 
IV
Blood SAP 
concentration 
checked before 
anti-SAP mAb 
infusion.
Administration 
of anti-SAP 
mAb
Each infusion of 
anti-SAP mAb 
over 6 to 8 
hours
Dose will be 
split over 2 days 
[day 1 + day 3]
CPHPC 
continues SC
Subjects closely 
monitored.
Inpatient 
safety follow 
up
Administration 
of CPHPC SC 
continues until 
Day 11
Safety follow 
up
Including 
cardiac 
monitoring
Safety follow 
up
Including 
cardiac 
monitoring
PD 
assessments
SC = sub-cutaneous
IV = intravenous
4.2.
Treatment Groups and Duration
Group 1: Cardiac TTR amyloidosis (ATTR-CM) patients, ((mutant genotypes
primarily associated with familial amyloidotic cardiomyopathy (FAC) & wild-type 
TTR)) with clinical cardiac dysfunction measurable by CMR. Subjects will be evaluated 
for cardiac / systemic safety and extent of cardiac amyloid load reduction in response to 
repeated monthly administration of up to 6 Anti-SAP treatments.
Subjects with clinically significant polyneuropathy will not be enrolled.
Group 2: Post-chemotherapy AL amyloidosis patients who have clinical cardiac 
dysfunction measurable by CMR after having had either a complete response (CR) or a 
very good partial response (VGPR) to chemotherapy or autologous stem cell 
transplantation will be evaluated for cardiac/systemic safety and extent of cardiac 
amyloid load reduction in response to repeated monthly administration of up to 6 Anti-
SAP treatments.
Group 3: Newly diagnosed Mayo stage II or IIIa AL amyloidosis patients (plasma 
NT-proBNP levels 8500 ng/L) who have attained a free light chain CR during the first 
three cycles of first-line chemotherapy where the first cycle was cyclophosphamide, 
bortezomib, dexamethasone (CyBorD) will be evaluated for cardiac/systemic safety and 
extent of cardiac amyloid load reduction in response to repeated monthly administration 
of up to 6 Anti-SAP treatments. Anti-SAP treatment will commence during the next 
scheduled cycle of chemotherapy after the cycle in which a free light chain CR was 
attained (see Section 4.4.1 & Figure 3).


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Group 1 and Group 2 will begin recruitment first. Recruitment into Group 3 will start 
only after data has been reviewed and regulatory interaction sought as detailed in Section 
10.8.2. 
4.3.
Number of Subjects
Group 1: Sufficient subjects will be recruited to ensure that at least 10 subjects receive at 
least 3 sessions of Anti-SAP treatment.
Cohort 2: Sufficient subjects will be recruited to ensure that at least 10 subjects receive 
at least 3 sessions of Anti-SAP treatment.
Cohort 3: Sufficient subjects will be recruited to ensure that at least 10 subjects receive 
at least 3 sessions of Anti-SAP treatment.
If subjects prematurely discontinue the study, additional replacement subjects may be 
recruited at the discretion of the Sponsor in consultation with the Investigator (see 
Section 5.5).
4.4.
Justification of the study design
It is not feasible to include a control group in the study for reasons as outlined below. 
Placebo control
In a severe and life-threatening disease such as systemic amyloidosis, the administration 
of a blinded placebo treatment of this complexity and invasiveness is considered 
inappropriate and would not maintain study blind for the following reasons.  Both 
elements are given parenterally, require dose individualization, and in the case of anti 
SAP mAb may require individual dose adaption as treatment progresses.  Furthermore, it 
is recommended that subjects receive premedication with a modest dose of 
hydrocortisone (100 mg) and an antihistamine to mitigate the infusion response related to 
the mechanism of action of anti SAP mAb.  Administration of premedication or placebo 
premedication to a control group is also considered inappropriate. 
Anti-SAP mAb treatment is associated with characteristic adverse effects: specifically an 
infusion reaction (substantially mitigated by premedication) and common appearance of 
rash, thus attempts at blinding would likely be compromised.  These features lead us to 
conclude that use of a blinded control arm is impractical.  
No treatment concurrent control
The intensity of study assessments required for evaluation of safety, pharmacokinetics, 
and pharmacodynamics including the need for prolonged inpatient assessment are such 
that a ‘no treatment’ arm would be inappropriate.


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Dose-response concurrent control
In order to safeguard patient safety it is important to have the ability to adapt the dose 
administered at each dosing session.  If two dose groups were included, this would lead 
to convergence of the doses administered in the two groups and thus frustrate the analysis 
of the two groups. Evaluation of a larger cohort following a single dose adaption regimen 
is expected to provide a more complete assessment of dose response.
Active control
There are no approved treatments which lead to active removal of amyloid or the 
treatment of systemic amyloidosis and therefore an appropriate active control is not
available.
No disease modifying interventions are approved for cardiac ATTR amyloidosis.  
Although there may be periods of relative clinical stability, cardiac ATTR amyloidosis 
progresses inexorably with clinical deterioration.  In cardiac AL amyloidosis, cardiac 
function sometimes stabilises and may even improve after induction of CR by 
chemotherapy but the process is very slow, taking at least 18 months or more.  Recent 
unpublished CMR work from the UK National Amyloidosis Centre (personal 
correspondence with 
 et al; 2016) has for the first time documented regression 
of cardiac AL amyloid deposits in some such patients.  In contrast, the encouraging 
results of the FIH study indicate that, if the present intervention is efficacious in clearing 
cardiac amyloid, clear differences in cardiac function from both the natural history of 
ATTR and the post-chemotherapy course of AL cardiac amyloidosis is likely to be
apparent within the 6 month treatment duration of this study.
4.4.1.
Combining Anti-SAP Treatment with Chemotherapy
Subjects in Group 3 will have attained a free light chain complete response (CR) during 
the first three cycles of chemotherapy where at least the first cycle was CyBorD. 
Subjects will not receive Anti-SAP treatment until a CR has been achieved to mitigate 
against any impact of an interaction between chemotherapy and Anti-SAP treatment.
The total number of chemotherapy cycles which shall be administered, and the specific 
dosages of each individual chemotherapy constituent, for each subject will be at the 
discretion of the Investigator.
The preferred timing for the first Anti-SAP treatment session is during the last week of 
the next scheduled chemotherapy cycle after the cycle in which a free light chain CR was 
confirmed.
Administration of the first Anti-SAP treatment session can be delayed at Investigator 
discretion based upon an individual subject’s chemotherapy-related toxicity profile and 
clinical cardiac status. The first Anti-SAP should be at the earliest possible opportunity 
during any week of chemotherapy between cycles 2 - 4.
PPD


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A subject will be withdrawn from the study if the first Anti-SAP treatment session cannot 
be started by the end of the last week of cycle 4 chemotherapy.
Changes to the chemotherapy regimen may be made by the treating haematologist based 
on emerging data but these will be discussed with the Medical Monitor. If the change 
calls for the use of a prohibited medication (Section 6.10.2) the subject will be 
withdrawn.
4.4.1.1.
Scheduling of Anti-SAP Treatment with Chemotherapy 
Two specific Anti-SAP treatment scheduling conditions will apply in Group 3 to reduce 
the potential for development of overlapping toxicities between the individual 
constituents of Anti-SAP treatment and chemotherapy:
1. IV CPHPC - IV CPHPC infusion must not be on the same day(s) as 
chemotherapy is administered. Maintenance subcutaneous (SC) CPHPC 
administration is permitted.
2. Anti-SAP mAb - There must be at least a 2 day interval between the:
a). Last administered sub-cycle of chemotherapy and the first split dose of 
anti-SAP mAb;
b). Second split anti-SAP mAb dose and the next scheduled sub-cycle of 
chemotherapy.
As outlined as an example in Figure 3, the inter-cycle (and / or intra-cycle) scheduling of
chemotherapy can be modified at the discretion of the Investigator to facilitate the 
delivery of Anti-SAP treatment following the above two conditions.


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Figure 3
Scheduling of Chemotherapy - example for CyBorD
Illustrative example in which the first Anti-SAP treatment is administered during the last 
week of Cycle 3 CyBorD in a subject who has attained a free light chain CR by 
completion of cycle 2 - Note the 2 day interval on either side of Anti-SAP treatment 
constituents and CyBorD chemotherapy
Anti-SAP treatment will be given on a monthly basis for up to five further treatment 
sessions. When chemotherapy has been completed (i.e. maximal haematological response 
has been attained) or discontinued (e.g. chemotherapy related toxicities), Anti-SAP 
treatment may continue to be administered as planned on a monthly schedule until 
completion of up to six treatment sessions.
The Investigator may delay administration of the next scheduled Anti-SAP treatment 
session by a maximum of 1 month thereby extending the interval between Anti-SAP 
treatment sessions up to a maximum of 8 weeks to facilitate sufficient resolution of 
chemotherapy-related toxicities (see Section 6.2.3 & Figure 4).
4.5.
Justification of Dosing Regimen
4.5.1.
GSK2315698 (CPHPC - Plasma SAP Depleter)
In the FIH study (SAP115570), the standard dosing regimen of CPHPC consisted of an 
IV infusion of 20 mg/hour for 72 hours prior to anti-SAP mAb administration. This 
regimen was reliably effective in depleting circulating SAP to <2 mg/L (using a Hycult 
ELISA assay). The current study is using a MSD assay and due to difference in SAP 
concentration scale between the assay types, a SAP concentration of <3 mg/L will be the 
target plasma SAP depletion level in this study. Since there is no precedent for the 


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present treatment, this empirical target SAP concentration was adopted on the basis of 
evaluation of the potential for formation of harmful circulating immune complexes and 
safety evaluation in the FIH study did not identify signals suggestive of adverse effects 
from residual SAP. 
CPHPC is predominantly cleared from the plasma by the kidneys and excreted in the 
urine.  CPHPC doses will therefore be adjusted (see Section 6.2.1, Table 2) based on
individual renal function as measured by glomerular filtration rate (eGFR) using the 
existing pharmacokinetics/pharmacodynamics (PK/PD) model of CPHPC [Sahota, 2015]. 
Subjects in the FIH study achieved the target plasma SAP by 48 hours CPHPC IV 
treatment and therefore the duration of the initial CPHPC infusion prior to administration 
of anti-SAP mAb has been shortened in this study. On retrospective analysis most, but 
not all, subjects in the FIH study had achieved the target plasma SAP depletion by 24 
hours CPHPC (IV) with further depletion to 48 hours. Blood SAP concentration will be 
checked after 24 hours of administration of CPHPC to confirm administration of anti-
SAP mAb on the next day. If at the 24 hour timepoint the target SAP level is not 
achieved, a check at 48 hours will be performed and, if target achieved, subjects will 
receive anti-SAP mAb on the following day (i.e. after ~72 hours of CPHPC IV).
A retrospective analysis of PK shows that 9 days post mAb infusion is sufficient for anti-
SAP mAb to fall to a low level at the dose levels proposed in this phase 2 study. 
Therefore in each treatment session, from the day of first IV infusion of anti-SAP mAb, 
CPHPC will be administered by SC injection for 11 days in order to maintain the 
depletion of circulating SAP while anti-SAP antibody remains in the plasma.  Thereafter, 
as observed in the FIH study, only minimal traces of anti-SAP mAb are detectable, with 
almost no binding activity for SAP.  Return of the normal circulating SAP concentration 
after stopping CPHPC therefore poses a low risk of formation of potentially harmful 
immune complexes.
4.5.2.
GSK2398852 (anti-SAP mAb)
The proposed starting dose level of anti-SAP mAb dose in this study is 600mg given as a 
divided dose of two infusions of 300 mg over 6-8 hours each on Days 1 and 3. This dose 
level and regimen is expected to be well tolerated based on previous experience and to be 
pharmacologically active in a proportion of patients (estimated to be 30% based on 
previous experience).
Dose escalation on subsequent sessions will be considered on a case by case basis based 
on tolerability and evidence of pharmacodynamic effect. It is proposed that the dose in 
subsequent treatment sessions will be maximally 1200 mg, given as two infusions over 6-
8 hours each, on Days 1 and 3.  The dose and regimen is based on the results of the FIH 
study (SAP115570), and has been selected to promote rapid elimination of amyloid 
deposits whilst minimising adverse effects.
Efficacy considerations. The therapeutic mechanism by which anti-SAP antibody 
mediates amyloid clearance has been characterized in the pre-clinical model and is 
dependent on classical complement pathway activation triggered by binding of the 
antibody to SAP coating the amyloid fibrils.  Initiation of the classical pathway requires 
formation of hexameric assemblies of IgG antibody molecules bound to their cognate 


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antigen in order to fix C1q.  In the FIH clinical study, just as in the pre-clinical model, the 
therapeutic anti-SAP mAb was very swiftly cleared from the circulation. The rate of 
decline in plasma concentration was related to the whole body amyloid load and was 
most rapid in subjects with substantial hepatic amyloidosis who had by far the greatest 
total amyloid burden.  The dose of anti-SAP antibody was progressively increased in 
consecutive subjects in the FIH study, amyloid removal first being seen at 246 mg with 
reduction in hepatic amyloid load.  Incrementally increased single doses in subsequent 
individual subjects up to a maximum of 2000 mg were generally well tolerated.  In 
subjects in whom amyloid clearance was subsequently observed, anti-SAP mAb 
administration was generally associated with an initial pro-inflammatory cytokine spike 
followed by an acute phase response of CRP and SAA, accompanied by a decrease in 
plasma C3 concentration.
Consistent with the pre-clinical mechanism and the established molecular stoichiometry 
of classical pathway complement activation, the FIH study showed a close relationship 
between the estimated whole body load of amyloid-associated SAP and the dose of anti-
SAP mAb required to trigger the systemic inflammatory response, plasma complement 
consumption and amyloid clearance.  The available evidence is consistent with the 
antibody most easily and rapidly accessing amyloid deposits in the liver and spleen which 
have sinusoidal capillary endothelium specialised for maximal filtration of the blood 
through the parenchyma. By contrast cardiac capillaries have tight endothelial junctions 
in cardiac capillaries which is likely to restrict access to the myocardial extracellular 
space.  Nevertheless pre-clinical work showed reduction in myocardial amyloid deposits 
with repeat anti-SAP dosing [Simons, 2013], and preliminary observations in the FIH 
study showed some evidence of engagement of target mechanism in the heart.
Although doses up to 2000 mg were well tolerated in those with a large (hepatic) amyloid 
load, much of the target patient population for this phase 2 study will have a small to 
moderate amyloid load. The dose response information from the FIH study in those with 
renal amyloidosis (also a small/moderate load population) show that a dose level of 600 
mg is effective in about one third of the subjects treated but at a dose level of 1200 mg 
the response rate is substantially higher (>80%).  It is recognized that while the dose of 
1200 mg is associated with a high rate of amyloid clearance, it is also associated with 
rash which has been severe in one case. At this time the most likely causes of the rash are 
related to the peak concentration of the anti-SAP mAb. For this reason the anti-SAP mAb 
dose in this study will be split: administered as two infusions (duration of 6-8hr) on Days 
1 and 3. This will have the effect of blunting the maximum concentration while
maintaining a moderate concentration in the plasma for longer. This approach may also 
enhance delivery of anti-SAP mAb to the heart. 
Safety considerations.  Most subjects receiving more than 200 mg of anti SAP antibody 
in the FIH study experienced reactions varying in incidence and severity, which included 
headache; flushing; hot or cold feelings; chest discomfort; chills; facial, orbital and 
peripheral oedema; nausea; vomiting; diarrhoea; fatigue; tachycardia; pre-syncope.  
These symptoms were reduced by slowing or temporarily interrupting the infusion and 
were further mitigated by pre medication with a modest dose of hydrocortisone and
chlorphenamine.  However, over the next few days many recipients of anti-SAP antibody 
doses of 600 mg or more developed mild or moderate urticarial and/or macular rashes of 


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variable and sometimes extensive distribution.  Urticaria responded well to antihistamine.  
Macular lesions were more persistent but resolved spontaneously without sequelae.
The risk of skin rashes will be mitigated by giving the anti-SAP mAb dose in two slowly 
infused portions on Days 1 and 3, with availability of a reduced dose schedule according 
to the safety assessment algorithm in Section 6.2. Emerging results will be reviewed 
regularly to enable dose reduction if necessary and to select the appropriate starting dose 
for Group 3.
4.5.3.
Dosing schedule for GSK2315698 (CPHPC) + GSK2398852 
(anti-SAP mAb)
There is an urgent need for rapid reduction in cardiac amyloid load in both AL and ATTR 
amyloidosis.  The FIH study showed the anti-SAP intervention can remove systemic 
amyloid deposits from the abdominal viscera.  The rate of amyloid clearance was 
apparently also similar in the patients as had been documented in the mouse model, with 
improvement towards normal hepatic stiffness indicating that the effect on liver amyloid 
of a single antibody dose is apparent by 2 weeks.  The mechanistic basis for amyloid 
removal by Anti-SAP treatment is the same in the heart as in other tissues but there are 
no readily tractable experimental animal models of cardiac amyloidosis.  Nevertheless in 
a transgenic mouse SAA model in which some cardiac amyloid is present, the deposits 
were reduced one month after two doses of anti-SAP administered a month apart 
[Simons, 2013].  Six patients with abundant cardiac amyloid were treated in the FIH 
study with up to 3 doses of anti-SAP mAb but the shortest interval between doses was 2 
months. One subject showed a reduction in LV mass; others showed biomarker evidence 
of engagement of the PD mechanism and some evidence of this in the heart (transient rise 
in NT-proBNP).  In order to achieve optimal efficacy as quickly as possible, Anti-SAP 
treatment will be administered monthly for up to six cycles in the present study.  More 
frequent antibody dosing is not possible because it would require uninterrupted depletion 
of plasma SAP by continuous CPHPC dosing.  This would risk excessive depletion of the 
amyloid-associated SAP target for the antibody, a sufficient density of binding to which 
is essential for triggering the crucial complement activation which attracts macrophages 
to form the MGCs and remove the amyloid.
Emerging results will be reviewed regularly to enable appropriate adjustment of initial 
and ongoing doses (Section 6.2.2)
4.6.
Benefit:Risk Assessment
The purpose of the phase 2 study is to evaluate the benefit:risk profile of Anti-SAP 
treatment in ATTR and AL systemic amyloidosis patients with cardiac involvement. 
Summaries of the pre-clinical and clinical studies conducted with CPHPC alone and with 
CPHPC + anti-SAP mAb are presented in the IB [GlaxoSmithKline Document Number 
2012N141587, GSK2398852 + GSK2315698 Investigator's Brochure].


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4.6.1.
Risk Assessment
The main identified risk for the phase 2 study is rash associated with administration of 
the anti-SAP mAb. The engagement of the antibody, complement and macrophage 
mechanisms of amyloid clearance within the myocardium carries a potential risk of 
cardiotoxicity. 
4.6.1.1.
Potential for Cardiotoxicity
The intended and desired PD mechanism by which anti-SAP mAb treatment mediates 
clearance of amyloid deposits from the extracellular space is absolutely dependent on 
antibody binding to amyloid deposits in the heart, activation of complement and 
attraction of macrophage infiltration and fusogenic activation to form MGCs.  The 
clinical experience to date has been reassuring that these processes or the consequent 
removal of amyloid do not have adverse effects on tissues or organs, including the heart.  
However it could be speculated that cardiac function could be impaired through 
disturbance of electrophysiology and/or myocardial contractility or perfusion.
The present study design therefore includes comprehensive assessment and monitoring 
designed specifically to detect and characterize these and any other adverse cardiac 
effects which may arise.  Baseline will include leadless non-implantable ECG analysis, 
for example using BodyGuardian, to provide the individual’s own control profile for any 
changes following treatment.  Monitoring during the study will comprise in-patient
telemetry, out-patient leadless ECG analysis (e.g. BodyGuardian) between treatment
sessions, monthly ECHO & CMR imaging, and serial monitoring of cardiac blood 
biomarkers.  Any adverse effects on cardiac function will thus be detected promptly, 
enabling swift and appropriate intervention and management.
4.6.1.2.
Summary of rashes
Many subjects who received 600 mg or more of anti-SAP mAb in the FIH study 
(SAP115570) developed variably, polymorphic urticarial and/or macular skin rashes with 
a range of different anatomical distribution, severity and persistence; though all but one 
were self-limiting.  Skin biopsy in one affected subject shows leukocytoclastic vasculitis 
but importantly with no evidence of either fibrinoid changes or necrosis. There was also 
no demonstrable deposition of immunoglobulins, complement or immune complexes in 
the tissues.  One AL amyloidosis patient who was concomitantly receiving an 
immunomodulatory drug (IMiD) (i.e. lenolidamide), had an erythema multiforme-like 
rash which rapidly responded to a short course of treatment with 60 mg oral 
prednisolone.
The pathogenic mechanism responsible for these rashes is not known but, importantly, it 
was not associated with any systemic symptoms, signs or organ dysfunction, and in 
particular, there was no evidence of arthritis or systemic vasculitis in the eye, kidneys or 
elsewhere.
In the present study subjects will be carefully monitored by the Investigator for 
development of any rash during or between treatment cycles, with additional timely 
review by a dermatologist if clinically indicated.  Management of the rash specified in 


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Section 12.3 Appendix 3 may be modified during the study in light of emerging new 
immunological and pathological information.
4.6.1.3.
Potential for Circulating Immune Complex Formation
Depletion of plasma SAP by CPHPC is never complete because the liver continues to 
produce about 100 mg of SAP daily.  Infusion of anti-SAP mAb must therefore 
inevitably lead to formation of SAP-anti-SAP mAb immune complexes in the circulation.  
Initially these complexes must be in antibody excess and both experimental and clinical 
studies of immune complex disease indicate this antigen:antibody ratio is least likely to 
be pro-inflammatory.  However as the anti-SAP antibody is rapidly cleared from the 
plasma due to its binding to the SAP target in amyloid deposits, formation of potentially 
inflammatory immune complexes could contribute to the infusion reactions and skin 
rashes caused by anti-SAP mAb treatment.
In order to mitigate this potential risk, blood samples for determination of SAP/anti-SAP 
mAb immune complexes will be taken from all subjects in this study as a safety 
measurement at the time-points specified in the Time & Events tables (Section 7.1) and 
in the event of a rash. Timing of the assessments may be adjusted based on emerging 
data.
4.6.1.4.
Surveillance for Long-Term Toxicities
All subjects will be asked to return for follow up assessments including cardiac imaging 
at 6 and 12 months post last anti-SAP mAb dose.   


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4.6.2.
Risk Assessment Table
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Investigational Product (IP) [GSK2398852; anti-SAP mAb]
Acute onset rash within 
first 7 days of infusing anti-
SAP mAb
Many patients who received 600 mg or more of anti-SAP 
mAb in the FIH study (SAP115570) developed variable 
polymorphic urticarial and/or macular skin rashes with a 
range of different anatomical distributions, severity, and 
persistence, with all but one case being self-resolving and 
self-limiting.
Skin biopsy in one AL amyloidosis patient who had a 
diffuse maculopapular rash after being administered 
600mg anti-SAP mAb on the first treatment session was 
reported as a leukocytoclastic vasculitis (LCV). In this 
biopsy sample there was no demonstrable deposition of 
immunoglobulins, complement or immune complexes in 
the tissues. 
A second AL amyloidosis patient with improving liver load 
(after 1st treatment session) had a diffuse rash after 
receiving 1G anti-SAP mAb on their 2nd treatment session. 
The morphological changes on skin biopsy would be 
consistent with a lymphocytic vasculitis/LCV although no 
definitive conclusion was reached by the reporting 
pathologist.
Dermatological monitoring 
Prompt clinical dermatology review and skin biopsy after
onset of any skin rash (i.e. grade 1)
Use of topical or systemic anti-inflammatory medications 
including corticosteroids and anti-histamines
Reduction of anti-SAP mAb dose and/or frequency if the 
mitigation strategies are not sufficient (see Section 6.2.2 & 
Section 6.2.3)
Discontinuation of anti-SAP mAb if rash persists or worsens 
despite mAb dose reduction and the subject is severely 
affected
Immunosuppressive effects of dexamethasone and 
cyclophosphamide in the CyBorD chemotherapy regimen 
may suppress the rash


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Post-inflammatory 
hyperpigmentation (PIH) 
Some FIH study patients who experienced repeated 
rashes with repeat anti-SAP mAb dosing developed 
variable PIH.
PIH is benign but may only resolve fully after weeks or 
months especially in darker skinned individuals.  Subjects 
with hereditary cardiac amyloidosis caused by the V122I
TTR variant, which is very largely confined to ethnicities 
originating in Africa, will thus be at greater risk.
All subjects who develop PIH will be monitored clinically for 
cumulative progression of PIH after each successive session 
of Anti-SAP treatment
Dermatology review for all PIH occurrences
DLQI questionnaire will be used for both acute rashes and 
PIH
Infusion Reactions
Most subjects receiving more than 200 mg of anti SAP 
antibody in the FIH study experienced reactions varying in 
incidence and severity, which included headache; flushing; 
hot or cold feelings; chest discomfort; chills; facial, orbital 
and peripheral oedema; nausea; vomiting; diarrhoea; 
fatigue; tachycardia; pre-syncope.  These symptoms were 
reduced by slowing or temporarily interrupting the infusion 
and were further mitigated by pre-medication with a 
modest dose of hydrocortisone and chlorphenamine.
Total anti-SAP mAb dose given slowly over 6-8 hours, 2 days 
apart.
Interrupting the infusion and/or reducing the rate of 
administration of each mAb infusion
Hydrocortisone premedication with a single 100 mg IV bolus
Antihistamine premedication 
Careful monitoring of blood pressure, fluid balance and urine 
output with immediate access to IV fluids, especially in 
subjects with any impairment of renal function and or 
development of hypotension and/or vomiting and/or 
arrhythmias.
Use of anti-emetics for nausea & vomiting
Myocarditis
Cardiac remodelling 
associated with removal of 
amyloid
The intended and desired PD mechanism by which anti-
SAP mAb treatment mediates clearance of amyloid 
deposits from the extracellular space is absolutely 
dependent on antibody binding to amyloid deposits in the 
heart, activation of complement and attraction of 
Comprehensive inpatient and outpatient cardiac monitoring 
comprising:
Serial heart rate and blood pressure measurement
Continuous inpatient telemetry during and after each infusion 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
macrophage infiltration and fusogenic activation to form 
MGCs. The clinical experience to date has been 
reassuring that these processes or the consequent 
removal of amyloid do not have adverse effects on tissues 
or organs, including the heart. However it could be 
speculated that cardiac function could be impaired through
disturbance of electrophysiology and/or myocardial 
contractility or perfusion.
of anti-SAP mAb 
Serial 12-lead ECG recording
Serial assay of plasma cardiac troponin T and NT-proBNP 
concentration 
Serial ECHO 
Serial CMR imaging
CMR & ECHO imaging at  6 & 12 months after the final anti-
SAP mAb treatment
Non-implantable, ECG recording devices (e.g. 
BodyGuardian) will be used to detect abnormalities in cardiac 
electrophysiology on discharge from in-patient stay and at 8-
week and 6-month follow-up
Investigational Product (IP) [GSK2315698 - CPHPC]
Epistaxis 
Small volume nose bleeds have been noted in a few 
subjects in previous studies. These events have been self-
limiting and not associated with any evidence of 
thrombocytopenia or coagulopathy. The relationship to 
Anti-SAP treatment is not apparent.
Group 3 patients will receive GSK2315698 at the same 
time as CyBorD chemotherapy which is known to cause 
thrombocytopenia and anaemia, potentially increasing the 
severity of epistaxis.
Serial blood haematology and baseline and session 1 post 
dose coagulation assessment. 
Serial coagulation if epistaxis or other bleeding abnormalities
occur. If abnormalities are observed in coagulation tests, 
additional investigations including platelet function tests may 
be performed.
Serial heart rate and blood pressure measurement


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Chemotherapy
Overlapping of acute 
toxicity between anti-SAP 
mAb and bortezomib-
containing chemotherapy
Cyclophosphamide, bortezomib & dexamethasone 
(CyBorD) and other cytotoxic chemotherapy regimens 
used in AL amyloidosis have systemic adverse effects 
including nausea, vomiting, hypotension and diarrhoea, 
which are also symptoms of the infusion reactions caused 
by anti-SAP mAb 
Anti-SAP mAb will be administered at least 48 hours before 
the start of a chemotherapy cycle to minimise overlap of 
acute toxicity. 
Attenuation of PD efficacy 
of anti-SAP antibody by 
chemotherapy agents
Amyloid clearance mediated by anti-SAP antibody 
depends absolutely on attraction of macrophages to the 
amyloid deposits, their fusion into MGCs and the efficient 
functioning of these cells.  The effects on these processes 
of high dose dexamethasone and of the cytotoxic 
chemotherapy agents within the drug combinations used in 
AL amyloidosis are not known.
Anti-SAP mAb will be administered at least 48 hours before 
the start of a chemotherapy cycle to minimise risk of 
attenuation of the efficacy of anti-SAP mAb by the anti-
inflammatory and cytotoxic actions of the chemotherapy 
drugs.
Myelosuppression, 
thrombocytopenia, 
neutropenia and sepsis
Cyclophosphamide, bortezomib & dexamethasone 
(CyBorD) and other cytotoxic chemotherapy regimens 
used in AL amyloidosis have inevitable myelosuppressive 
effects, often leading to symptomatic anemia and other 
cytopenias and their complications, including sepsis
Serial haematology
Platelet and red blood cell replacement / transfusion, and / or 
use of granulocyte colony stimulating factor for severe 
neutropenia, as directed by the treating haematologist
Serial monitoring of body temperature, CRP, heart rate and 
blood pressure
Sepsis management according to standard local procedures 
for neutropenic patients.


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Bortezomib-induced rashes
There are limited data on bortezomib-induced rashes in AL 
amyloidosis chemotherapy. However, in patients with 
recurrent, treatment refractory, multiple myeloma, 
bortezomib when incorporated into similar chemotherapy 
regimens has been reported to cause rashes in 
approximately 20% of recipients, predominantly CTC 
grades 1 -2 with severe CTC grades 3 – 4 in < 1% 
[Richardson, 2003].  The rashes are polymorphic in clinical 
characteristic with different histological appearances 
including leukocytoclastic vasculitis [Agterof , 2005], and 
lymphocytic vasculitis [Pour, 2005].
The intermediate dose CyBorD schedule which will be used 
in Group 3 subjects. - weekly administration of bortezomib 
during a 5-week cycle, this provides a high clonal response 
rate [Kropff, 2007] and is known to cause fewer rashes than 
CyBorD regimens that involve biweekly administration of 
bortezomib [Case, 2012]
CMR Contrast Agent - gadolinium (Gd) 
Delayed excretion and 
tissue accumulation of 
gadolinium contrast agent 
after repeated contrast 
CMR scans
Gadolinium is mostly excreted in the urine and this is 
impaired in subjects with reduced renal function. Patients 
with systemic AL amyloidosis very often have renal 
amyloid and impaired renal function while cardiac ATTR 
patients are all elderly and therefore may also have non-
amyloid chronic kidney disease.  All these individuals are 
therefore at increased risk of Gd accumulation.
FDA and MHRA have issued an alert for tissue 
accumulation of Gd in organs including the brain following 
its repeated use, including some patients with normal renal 
function, although no new neurological complications have 
been reported to date
Exclusion of patients with GFR < 40 mLs/min 
GFR will be checked prior to each Gd contrast CMR and if 
GFR is <40mL/min then CMR without Gd contrast will be 
performed
Gd contrast CMR will be performed at five scheduled visits 
over the 18 month study period
Other CMR scans will be without Gd contrast
Gd contrast agents for this study are gadoteric acid, 
gadoteridol, and gadobutrol.


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Nephrogenic systemic 
fibrosis (NSF) / 
dermatopathy (NSD)
A very rare cause of cutaneous and, even more rarely, 
systemic fibrosis, including in the heart, caused by Gd 
contrast agents, with typical rash and characteristic 
histopathology. Possibly related to impaired renal function.
Exclusion of patients with GFR < 40 mL/min (see exclusion 
criteria)
Serial monitoring of serum creatinine 
Dermatological inspection for rashes.
Skin biopsy if clinically indicated.
Allergic reactions to Gd 
contrast 
Gd contrast agents can cause allergic reactions especially 
with IV bolus administration
History before infusion regarding any reactions to previous 
imaging contrast agents.
Slow IV infusion of Gd contrast with ability to stop 
immediately if subject develops symptoms.
Procedural risks 
Skin biopsy
Skin biopsy is a minimally invasive procedure but has been 
associated with scarring, bleeding and infection.
Skin biopsies will be taken from non-sensitive areas only. 
Biopsies will not be taken from the head, neck, hands, feet or 
genitalia.
To minimise the risk of bleeding the biopsy site will be
sutured or 'steri-strip' applied as per site policy
All skin biopsies should be undertaken by trained individuals 
under aseptic conditions according to site policy
Cumulative radioactivity 
from scans
Ionising radiation exposure from SAP scan (UK Groups 
2&3 only) comes from the administered radioligand and CT 
examination. The total radiation burden per subject is 
calculated as 8 mSv per SAP scan; total 16 mSv for two 
scans and this corresponds to a lifetime risk of a fatal 
malignancy of about 1 in 1250 [ICRP, 2007].
Group 1 subjects will undergo a 99m-Tc-DPD or 99m-Tc-PYP 
Subjects will undergo baseline and post treatment scan thus 
will remain below the 20mSv exposure limit recommendation.
The scans are medically justified and provide proven 
evidence of changes in amyloid load. 


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
bone scan and will be exposed to 6.7mSv per scan, total 
13.4 mSv for two scans and this corresponds to a lifetime 
risk of a fatal malignancy of about 1 in 1500 [ICRP, 2007] 
Subjects will receive either an SAP scan or a DPD scan, 
not both.
The International Commission on Radiological Protection
(ICRP) 2007 has recommended a maximum occupational 
adult effective dose limit of 20 mSv per year, averaged 
over a defined period of 5 years (not exceeding 50 mSv in 
a single year) [ICRP, 2007]


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4.6.3.
Benefit Assessment
Extracellular deposition of amyloid fibrils is the major and overwhelmingly most 
important cause of organ damage and disease in systemic amyloidosis.  Study 
SAP115570 confirmed that clearance of amyloid from the tissues (liver) improved 
function towards normal.  The major causes of cardiac dysfunction in cardiac 
amyloidosis are restrictive cardiomyopathy, which is directly related to the myocardial 
stiffness produced by infiltration of the heart with stiff inelastic amyloid, and 
arrhythmias.  Thus a reduction in cardiac amyloid load by Anti-SAP treatment has the 
potential to improve diastolic filling, increase stroke volume and restore cardiac output 
towards normal.  Similarly normalisation of myocardial architecture with reduction of the 
ECV, which is substantially expanded and distorted by amyloid, has the potential to 
reduce the electrophysiological instability responsible for arrhythmias.
4.6.4.
Overall Benefit:Risk Conclusion
Cardiac involvement in AL and ATTR-CM amyloidosis is the major cause of morbidity 
and mortality.  If Anti-SAP treatment reduces the cardiac amyloid load sufficiently to 
improve cardiac function, alleviate heart failure and prevent ventricular arrhythmias, it 
has the potential to have a substantial impact on quality and duration of life in these 
conditions whilst also reducing hospital admissions and other medical treatment.  The 
infusion reactions and skin rashes experienced so far are considered manageable and 
mitigation plans are in place.  The hypothetical cardiac risks are important but 
preliminary safety in six patients with cardiac amyloidosis is encouraging. 
On the basis that this treatment has potential for substantial benefit that cannot be 
obtained from existing treatments, the potential and identified risks are considered 
manageable and thus acceptable.


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5.
SELECTION OF STUDY POPULATION AND 
WITHDRAWAL CRITERIA
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational product or other study 
treatment that may impact subject eligibility is provided in the Investigators Brochure [IB
GlaxoSmithKline Document Number 2012N141587].
Deviations from inclusion and exclusion criteria are not allowed because they can 
potentially jeopardize the scientific integrity of the study, regulatory acceptability or 
subject safety. Therefore, adherence to the criteria as specified in the protocol is essential.
5.1.
Inclusion Criteria
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
AGE
1. Between 18 and 80 years of age inclusive, at the time of signing the informed 
consent. 
SEX
2. Gender: Male and female.
Males: 
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
for a cycle of spermatogenesis following five terminal half-lives after the last dose of 
study medication.
a. Vasectomy with documentation of azoospermia.
b. Male condom plus partner use of one of the contraceptive options below:

Contraceptive subdermal implant 

Intrauterine device or intrauterine system 

Combined Oral Contraceptive [Hatcher, 2007] or Injectable progestogen 
[Hatcher, 2007]

Contraceptive vaginal ring [Hatcher, 2007]

Percutaneous contraceptive patches [Hatcher, 2007]
This is an all-inclusive list of those methods that meet the following GSK definition of 
highly effective: having a failure rate of less than 1% per year when used consistently and 
correctly and, when applicable, in accordance with the product label. For non-product 
methods (e.g., male sterility), the investigator determines what is consistent and correct 
use. The GSK definition is based on the definition provided by the ICH [ICH, M3 (R2)


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2009].
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception.
Females
A female subject is eligible to participate if she is not pregnant (as confirmed by a 
negative Urine human chorionic gonadotrophin (hCG) test), not lactating, and at least one 
of the following conditions applies:
a.
Non-reproductive potential defined as:
Pre-menopausal females with one of the following:
Documented tubal ligation
Documented hysteroscopic tubal occlusion procedure with follow-up 
confirmation of bilateral tubal occlusion 
Hysterectomy
Documented Bilateral Oophorectomy
Postmenopausal defined as:
60 years old
Twelve(12) months of spontaneous amenorrhea with an appropriate clinical profile, 
e.g. age appropriate, > 45 years, in the absence of hormone replacement therapy 
(HRT) or medical suppression of the menstrual cycle (e.g. leuprolide treatment) in 
questionable cases a blood sample with simultaneous follicle stimulating hormone 
(FSH) and oestradiol levels consistent with menopause (refer to laboratory reference 
ranges for confirmatory levels).  Females on HRT and whose menopausal status is in 
doubt will be required to use one of the highly effective contraception methods if 
they wish to continue their HRT during the study.  Otherwise, they must discontinue 
HRT to allow confirmation of post-menopausal status prior to study enrolment.
b.
Reproductive potential and agrees to follow one of the options listed in the Modified 
List of Highly Effective Methods for Avoiding Pregnancy in Females of 
Reproductive Potential (FRP) (see Appendix 6) from 30 days prior to the first dose of 
study medication and until 3 months after the last dose of study medication.
The investigator is responsible for ensuring that subjects understand how to properly use 
these methods of contraception
INFORMED CONSENT
3. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form
OTHER
4. Late-Gadolinum enhancement (LGE) on CMR indicative of cardiac amyloidosis


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Inclusion Criteria for Group 1
[1] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
5. ATTR cardiomyopathy (ATTR-CM)
a) Subjects with a diagnosis of hereditary ATTR amyloidosis  should have a known 
amyloidogenic TTR mutation demonstrated by genotyping AND is recognised to 
be primarily associated with cardiomyopathy AND one of the following:
Definite histochemical identification of amyloid by Congo red staining and green 
birefringence in crossed polarised light in cardiac or other tissue biopsy and 
identification of TTR as the amyloid fibril protein either by 
immunohistochemistry or proteomic analysis.
Note: Subjects with a confirmed mutation but who have not been biopsied may be 
eligible if they have an affected close blood relative whose amyloid has been 
confirmed histochemically.  Such cases should be discussed with the Medical 
Monitor.
OR
Scintigraphy:  99mTc-DPD with Grade 2 cardiac uptake or 99mTc-PYP with either 
Grade 2 or 3 cardiac uptake. 
b) Subjects with a diagnosis of wild type ATTR-CM must be negative by genotyping 
AND have one of the following:
Definite histochemical identification of amyloid by Congo red staining and green 
birefringence in crossed polarised light in cardiac or other tissue biopsy and
identification of TTR as the amyloid fibril protein either by 
immunohistochemistry or proteomic analysis
OR
Scintigraphy 99mTc-DPD with Grade 2 cardiac uptake or 99mTc-PYP with Grade 2 
or 3 cardiac uptake.
6. LVmass on CMR > 200g
7. Clinically stable in New York heart association (NYHA) class 2 or 3 for the 3 months 
preceding screening 


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Inclusion Criteria for Group 2
[1] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
8. Subject medically diagnosed with AL amyloidosis that has required chemotherapy or 
an autologous stem cell transplant based upon:
AL amyloidosis confirmed by biopsy with immunohistochemical staining or proteomic 
identification of AL amyloid fibril type, in subjects with definite monoclonal 
gammopathy in whom causative mutations of amyloidogenic genes have been excluded
9. Clinically stable in NYHA class 2 or 3 for the 3 months preceding screening 
10. 6 months after completing any line of chemotherapy, or after autologous stem cell 
transplantation, and having attained either a very good partial response (VGPR) or a 
complete response (CR), and without the need for haematological maintenance 
therapies
11. LV mass on CMR > 150g
Inclusion Criteria for Group 3
[1] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
12. Newly diagnosed AL amyloidosis based upon:
AL amyloidosis confirmed by biopsy with immunohistochemical staining or proteomic 
identification of AL amyloid fibril type in subjects with definite monoclonal 
gammopathy in whom causative mutations of amyloidogenic genes have been excluded
13. Mayo stage II or IIIa 
14. Confirmed free light chain complete response (CR) during the first three cycles of 
first-line chemotherapy where at least the first cycle has been with CyBorD
15. LV mass on CMR > 150g


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5.2.
Exclusion Criteria
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
1. Cardiomyopathy primarily caused by non-amyloid diseases (e.g. ischemic heart 
disease; valvular heart disease)
2. Interval from the Q wave on the ECG to point T using Fredericia's formula
(QTcF) > 500 msec
3. Sustained / symptomatic monomorphic ventricular tachycardia (VT), or rapid 
polymorphic VT, at screening
4. Unstable heart failure defined as emergency hospitalization for worsening, or 
decompensated heart failure, or syncopal episode within 1 month of screening.
5. Implantable cardiac defibrillator (ICD) or permanent pacemaker (PPM) at 
screening
6. NT-proBNP >8500ng/L
7. Glomerular filtration rate (GFR) at Screening < 40 mL/min
8. Any active and persistent dermatological condition
9. Existing diagnosis of any type of dementia
10. History of allogeneic stem cell transplantation, prior solid organ transplant, or 
anticipated to undergo solid organ transplantation, or left ventricular assist device
(LVAD) implantation, during the course of the study.
11. Malignancy within last 5 years, except for basal or squamous cell carcinoma of 
the skin, or carcinoma in situ of the cervix that has been successfully treated.
Note: Subjects with a history of other malignancies that have been curatively 
treated may be eligible, but must be discussed with and approved by the Medical 
Monitor. Previous or current diagnosis of symptomatic multiple myeloma
12. Acute coronary syndrome, or any form of coronary revascularization procedure 
(including coronary artery bypass grafting [CABG]), within 6 months of 
screening. 
13. Stroke within 6 months of screening, or transient ischaemic attack (TIA) within 3 
months of screening
14. Symptomatic, clinically significant autonomic neuropathy which the Principal 
Investigator (PI) feels will preclude administration of study treatment
15. Hypoalbuminaemia (serum albumin < 30 g/L) 
16. Uncontrolled hypertension during screening
17. Alanine transaminase ALT >3x upper limit of normal (ULN) AND bilirubin 
>1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated 
and direct bilirubin <35%)


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CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
18. Peripheral oedema at Screening that in the opinion of the PI or designee might 
prevent adequate absorption of subcutaneously administered CPHPC
19. Urine dipstick positive (>1+) for blood during screening with investigation 
indicating glomerular haematuria. If other causes are identified, subjects may be 
enrolled on resolution of the abnormality
20. Presence of any co-morbid or an uncontrolled medical condition (e.g. diabetes 
mellitus), which in the opinion of the investigator would increase the potential risk 
to the subject. Investigator should liaise with the Medical Monitor where there is 
uncertainty as to the eligibility of a patient
21. Positive test for hepatitis B hepatitis C, and / or human immunodeficiency virus 
(HIV) during screening, or within 3 months prior to first dose of study treatment
22. Unwillingness or inability to follow the procedures outlined in the protocol
CONCOMITANT MEDICATIONS
23. Use of GSK2315698 (CPHPC), or participation in a separate clinical trial 
involving CPHPC within 3 months of screening
24. Any prohibited concomitant medication as per Section 6.10.2 within 28 days of 
screening
DIAGNOSTIC ASSESSMENTS AND OTHER CRITERIA
25. Donation of blood or blood products in excess of 500 mL within 84 days of 
screening
26. Lactating females 
27. Poor or unsuitable venous access
OTHER
28. Treatment with another investigational drug, biological agent, or device within 
6 months of screening, or 5 half-lives of the study agent, whichever is longer.
CONTRAINDICATIONS 
29. History of sensitivity to any of the study medications, or metabolite thereof or a 
history of drug or other allergy that, in the opinion of the investigator or Medical 
Monitor, contraindicates their participation


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CARDIAC MAGNETIC RESONANCE (CMR) SCANNING
30. Orthopnoea of sufficient severity to preclude supine scanning as determined at 
screening
31. Contraindication to MRI contrast agents
32. Inability to fit inside scanner due to body size (girth) 
33. Contraindication for MRI scanning (as assessed by local MRI safety 
questionnaire), which includes but is not limited to:
a. Intracranial aneurysm clips (except Sugita) or other metallic objects
b. Intra- orbital metal fragments that have not been removed
c. Pacemakers or other implanted cardiac rhythm management/monitoring devices 
and non-MR conditional heart valves
d. Inner ear implants
e. History of claustrophobia
99mTC-PYP OR 99mTC-DPD BONE TRACER RADIOSCINTOGRAPHY 
34. Orthopnoea of sufficient severity to preclude supine scanning as determined at 
Screening 
35. Previous allergic reaction to radioisotope bone tracers
36. Previous inclusion in a research protocol involving nuclear medicine, positron 
emission tomography (PET) or radiological investigations with significant 
radiation burden (a significant radiation burden being defined as 10 mSv in 
addition to natural background radiation, in the previous 3 years).
Exclusion Criteria for Group 1
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
37. Has any of the following:
a. Fulfilment of diagnostic criteria for AL amyloidosis 
b. TTR polyneuropathy  and / or intracranial TTR involvement including 
ophthalmological disease
38. Non-amyloidosis related chronic liver disease (with the exception of Gilbert’s 
syndrome or clinically asymptomatic gallstones)
Note: Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric 
varices, or persistent jaundice
39. Platelet count < 125x109 / L 


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Exclusion criteria for Group 2
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
40. Chronic liver disease or current active liver or biliary disease not attributable to 
amyloidosis (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
Note: Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric 
varices, or persistent jaundice
Exclusion criteria for Group 3
CONCURRENT CONDITIONS/MEDICAL HISTORY (INCLUDES LIVER 
FUNCTION AND QTc INTERVAL) 
41. Chronic liver disease or current active liver or biliary disease not attributable to 
amyloidosis (with the exception of Gilbert’s syndrome or asymptomatic gallstones).
Note: Stable chronic liver disease should generally be defined by the absence of 
ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric 
varices, or persistent jaundice
42. Platelet count < 75x109 /L
5.3.
Screening/Baseline/Run-in Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently enrolled. In order to ensure transparent reporting of screen failure 
subjects, meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, and respond to queries from Regulatory Authorities, a minimal set of 
screen failure information is required including Demography, Screen Failure details, 
Eligibility Criteria, and Serious Adverse Events (see Section 7.4.1.4).
5.4.
Withdrawal/Stopping Criteria
The following actions must be taken in relation to a subject who fails to attend the clinic 
for a required study visit:

The site must attempt to contact the subject and re-schedule the missed visit as 
soon as possible. 

The site must counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the subject wishes to and/or should 
continue in the study. 

In cases where the subject is deemed ‘lost to follow up’, the investigator or 
designee must make every effort to regain contact with the subject (where 
possible, 3 telephone calls and if necessary a certified letter to the subject’s last 


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known mailing address or local equivalent methods). These contact attempts 
should be documented in the subject’s medical record. 

Should the subject continue to be unreachable, only then will he/she be considered 
to have withdrawn from the study with a primary reason of “Lost to Follow-up”. 
A subject may withdraw from study treatment at any time at his/her own request, or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioural or 
administrative reasons. If a subject withdraws from the study, he/she may request 
destruction of any samples taken, and the investigator must document this in the site 
study records. 
Individual subjects may be withdrawn at the Investigator’s discretion at any time during 
the Study, provided there is a valid and confirmable clinical reason. The presence of 
severe AEs predefined as stopping criteria below in Section 5.4, or severe adverse events 
(SAE) as defined in Section 12.5, Appendix 5, will lead to the withdrawal of an 
individual subject. Withdrawn subjects will be replaced by new subjects as per the 
guidance in Section 5.5
Whenever possible subjects must complete CPHPC maintenance following anti-SAP 
mAb dose for safety reasons (Section 4.5).
5.4.1.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event aetiology (in alignment with the food & 
drug administration [FDA] premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Liver Safety Required Actions and Follow-up Assessments Section can be found in 
Section 12.2, Appendix 2.
5.4.1.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject participating in this study is not allowed.
5.4.2.
Renal Function Stopping Criteria
Dosing of a subject with study treatment will be stopped permanently if 24-hour 
creatinine clearance is confirmed as < 30mL/min.
If a subject’s estimated glomerular filtration rate (eGFR) by Modification of Diet in 
Renal Disease (MDRD) is <40 mL/min/1.73m2 or if the eGFR by MDRD decreases from 
baseline by >50%, this will trigger a further investigation.
Subjects who have eGFR 30 – 40 mL/min/1.73m2 (or 24-hour creatinine clearance [CrCl]
of 30 – 40 mL/min) will continue treatment at the discretion of the Investigator in 
consultation with the Medical Monitor. If the GFR or CrCl remains below 40 


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mL/min/1.73m2 or mL/min respectively at the time of the next scheduled contrast 
enhanced CMR then a non-enhanced CMR will be performed. If the CrCl recovers to 
40 mL/min then a contrast enhanced CMR should be performed at the next scheduled 
CMR).
Whenever possible subjects must complete CPHPC maintenance following anti-SAP 
mAb dose for safety reasons (dose adjustment of CPHPC may be necessary - see Table 
2).
5.4.3.
Platelet Stopping Criteria
In the event of a platelet count <30x109/L no further AntiSAP treatment will be 
administered until the platelet count returns to 30 x 109/L. 
5.4.4.
Neutrophil Stopping Criteria
In the event of a neutrophil count 0.5x109 / L no further AntiSAP treatment will be 
administered until the neutrophil count returns to > 0.5x109 / L.
Subjects who experience a septic episode during the study, febrile neutropenia or 
otherwise, should be treated with antibiotics according to local study site protocols, and 
must not receive any further AntiSAP treatment until sufficient clinical resolution from 
the septic episode has occurred as determined by the Investigator.
5.4.5.
Cardiovascular Safety Stopping Criteria
5.4.5.1.
Individual subject cardiovascular stopping criteria
A subject who meets any criterion below will be withdrawn from the study.
1.
Acute coronary syndrome or myocardial infarction
2.
Decompensated heart failure, or worsening heart failure that is refractory to 
medical management
3.
New & symptomatic bradyarrhythmia 
4.
New sustained monomorphic VT, or development of new rapid polymorphic VT, 
or new VF
5.
Symptomatic myocarditis
6. Requirement for LVAD implantation, or consideration of urgent cardiac 
transplantation during the Study
7. Development of any rhythm disorder during the study which requires treatment 
with a permanent cardiac pacemaker, or ICD. Subjects who require insertion of a 
permanent cardiac pacemaker or an ICD for prophylactic reasons may continue–
see Section 7.4.7.3


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5.4.6.
QTc Stopping Criteria

The QTc should be based on single or averaged QTc values of triplicate 
electrocardiograms obtained over a brief (e.g., 5-10 minute) recording period. 
5.4.6.1.
Individual Subject QTcF Stopping Criteria
A subject who meets either criterion below will be withdrawn from the study treatment. 
QTcF correction formula should be used throughout, including at screening and for 
discontinuation of any individual subject at any time during the study.
QTcF ≥ 530msec, irrespective of bundle branch block status
or,
Change from baseline: QTcF > 60 msec
5.4.7.
Dermatological Toxicity Stopping Criteria
5.4.7.1.
Individual subject dermatological stopping criteria
A subject who meets any criterion below will be withdrawn from further treatment in the 
study. 

Grade 4 Common Terminology Criteria (CTC) skin rash

Peripheral oedema which is deemed by the Investigator to be affecting the 
systemic absorption of SC CPHPC (CPHPC administration should continue by 
intravenous (IV) infusion to Day 11)

Skin toxicity of any CTC grade which is refractory to dermatological treatment

Clinical evidence of skin necrosis, irrespective of CTC rash grade, at any time 
during the study

Symptoms of a systemic vasculitis, including but not restricted to, development 
of new arthritis or iritis, vasculitic purpura or other lesions of skin and/or mucous 
membranes and/or retina, and / or clinical evidence of organ dysfunction (e.g. 
nephritis)
5.4.8.
Haematological Stopping Criteria (Groups 2 & 3)
5.4.8.1.
Individual subject haematological stopping criteria
A subject who meets any criterion below will be withdrawn from the study. 

Confirmed haematological clonal relapse requiring immediate chemotherapy


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5.4.9.
Study Safety Stopping Criteria
If any of the following are recorded and considered potentially related to Anti-SAP 
treatment this will trigger a full safety review and no new recruitment into the study will 
occur:
Cardiac: Development of symptomatic myocarditis 
Dermatological: Development of CTC Grade 4 rash
Immunological: Clinical evidence of a systemic vasculitis affecting any visceral organ 
In the event that recruitment is temporarily halted, this will be reported to relevant 
regulatory and ethics authorities. Resumption of recruitment will only take place with the 
permission of the relevant authorities.
5.5.
Subject Withdrawal Procedures
Subjects withdrawn following one or more administrations of anti SAP mAb should 
follow the procedures at the 8 week follow-up visit shown in the Time and Events Table.
Subjects withdrawn following administration of CPHPC but no administration of anti 
SAP mAb should follow the procedures at the 8 week follow-up visit shown in the Time 
and Events Table, with the exception of: Blood sampling for anti-SAP mAb, Cardiac 
MRI, ECHO, 99mTc-DPD / PYP scans (Group 1 only), SAP Scan (Groups 2 & 3, UK 
only) or out-patient cardiac monitoring.
5.6.
Replacement of Withdrawn Subjects
For each group, subjects withdrawn from study treatment prior to completion of three 
Anti-SAP treatment sessions will be replaced. Subjects requiring insertion of a PPM or 
ICD prior to completion of three Anti-SAP treatment sessions will also be replaced.
5.7.
Subject and Study Completion
A completed subject is one who has completed at least three courses of AntiSAP 
treatment and including the 8 week follow-up visit.
The end of the study is defined as the last subject’s last visit.


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6.
STUDY TREATMENT
6.1.
Investigational Product and Other Study Treatment
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments
6.1.1.
Anti-SAP treatment
Study Treatment
Product name:
GSK2315698 (CPHPC)
GSK2398852 (anti-SAP mAb)
Dosage form:
GSK2315698 Solution for 
Subcutaneous Injection or 
Intravenous Infusion, 200 mg/mL
GSK2398852 Concentrate for Solution 
for Infusion, 100 mg/mL
Unit dose 
strength(s)/Dosag
e level(s):
Unit dose strength: 200mg/mL 
provided as 2mL solution per vial
Dosage levels: variable dependent 
on renal function
Unit dose strength: 100 mg/mL provided 
as 1 mL solution per vial. 
Dosage levels variable (1200mg, 900mg, 
600mg or 300mg) 
Route/
Administration/
Duration:
Intravenous infusion usually for 48 
hours and up to 72 hours
Subcutaneous injection up to 3x 
daily for 11 days from initial mAb 
dose per treatment session
Intravenous infusion to be administered 
over 2 days (Day 1 and Day 3) with 6-8h 
infusion/day.
Dosing 
instructions:
Study medication will be diluted in 
0.9% w/v sodium chloride and
administered by intravenous 
infusion by study personnel 
following specified regimens and by 
subcutaneous injection by study 
personnel in in-patient setting and 
by subject in out-patient setting
Study medication will be diluted in 0.9% 
w/v sodium chloride and administered by 
intravenous infusion by study personnel 
following specified regimens
Manufacturer/
source of 
procurement:
Manufactured and supplied by GSK
[0.9% w/v sodium chloride for 
dilution sourced locally by site]
Manufactured and supplied by GSK
[0.9% w/v sodium chloride for dilution 
sourced locally by site]


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6.2.
Planned Dose Adjustments- Subject Specific Dose 
Adjustment Criteria
6.2.1.
CPHPC dosing regimen according to renal function
Table 2
CPHPC dosing regimen according to renal function
Renal Function
IV dose 
level
SC dose 
regimen
Time points of SC administration
eGFRa
(mL/min/1.73m2)
Day 1b
1st mAb dose 
per treatment 
session
Subsequent days
(Days 2-10)
Subsequent day
(Day 11)
64
20mg/hour
60 mg t.i.d 
14:00, 22:00
08:00, 14:00, 22:00
08:00
46 and < 64
10mg/hour
60 mg t.i.d 
14:00, 22:00
08:00, 14:00, 22:00
08:00
39 and < 46
10mg/hour
60 mg b.i.d 
21:00
09:00, 21:00
09:00
33 and < 39
5mg/hour
60 mg b.i.d
21:00
09:00, 21:00
09:00
27 and < 33
5mg/hour
60 mg o.d
-
09:00
09:00
a.
eGFR determined by MDRD must be used to define CPHPC dose based on renal function. The most recent 
eGFR value available at the time of the pharmacy prescription being prepared will be used to determine the 
CPHPC dosing requirement for the treatment session. Should subsequent eGFR results within that treatment 
session show a change in eGFR, the CPHPC dosing requirement will not be altered as a result. Changes to 
eGFR which the Investigator considers to be a safety concern should be discussed with the Medical Monitor.   
b.
IV CPHPC on Day 1 stops at ~09:00
t.i.d. = three times daily; b.i.d. = two times daily; o.d. = once daily
6.2.2.
Dose-Level Reduction Schedule for anti-SAP mAb Due to 
Adverse Events
When it is deemed clinically appropriate, the Investigator is advised to maintain the 
dose-intensity of anti-SAP mAb throughout the study. 
Reductions in dose level are at the discretion of the Investigator in consultation with the 
GSK study team during the dose confirmation meeting, and can be triggered based upon 
the intensity of the adverse event (AE) which is observed during any treatment session 
and is reasonably attributable to anti-SAP mAb. (See Figure 4). The recommended dose 
reduction scheme is provided in Figure 4 although greater than 300 mg reductions would 
be allowed based on clinical tolerability.
a) First dose reduction will be to 900 mg (300mg on D1, 600mg on D3)
b) Second dose reduction to 600mg (300mg on D1, 300mg on D3)
c) Third dose reduction to 300mg (150mg on D1, 150mg on D3)
No further dose modifications will be permitted below the 300mg dose level.
Note: If a dose reduction is required following Session 1, then the Session 2 mAb dose 
level will be 300mg (‘c’ in the above list).
If tolerability is unacceptable at the 300mg dose level, the Investigator must withdraw the 
subject from further study treatment, and inform the Medical Monitor at the earliest 
possible opportunity.


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Figure 4
Dose-Reduction Schedule for anti-SAP mAb
6.2.3.
Dose-Interval Extension between Anti-SAP Treatment Sessions
At the Investigator's discretion and in consultation with the GSK study team during the 
dose confirmation meeting an Anti-SAP treatment session may be delayed up to a 
maximum of 1 month (i.e. maximum anti-SAP mAb treatment interval of 8 weeks) to 
allow for clinical stabilisation and / or recovery of incompletely resolved adverse events 
caused by any constituent of Anti-SAP treatment, or chemotherapy in Group 3 patients.
The Investigator must review the affected subject's status on at least a weekly basis 
(or more frequently based on the AE) until the AE(s) has completely resolved. 
Administration of the next Anti-SAP treatment should be scheduled at the earliest 
possible opportunity after the Investigator has deemed the subject to have recovered 
sufficiently to continue treatment. 
Subjects must be withdrawn from further study treatment if the persistent AE(s) is still 
deemed by the Investigator to be insufficiently resolved to allow further treatment 8 
weeks after administration anti-SAP mAb.
Please refer to Appendix 3 for detailed management of anti-SAP mAb skin rashes
6.2.4.
Dose Modifications for Skin Rashes
Refer to Section 12.3 Appendix 3


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Dose reduction of anti-SAP mAb will be based upon the clinical grade (intensity) of the 
rash and its duration (persistence) until complete resolution of active lesions during each 
monthly Anti-SAP treatment session.
The available clinical, immunological and pathological findings from each rash affected 
subject (see Section 12.3, Appendix 3) will be discussed at the Individual Subject Review 
meeting (see Section 10.8.1) before administration of the next scheduled Anti-SAP 
treatment session.
6.3.
Blinding
This is a non-randomised open-label study. All Investigators and GSK Study Team 
members, except those involved in central imaging core laboratory review, have direct 
access to the subject’s individual study treatment and dosing schedules for each 
constituent drug.
All CMR & ECHO cardiac imaging investigations, but not the 99mTc-DPD or 99mTc-PYP 
scintigraphy, will be centrally reviewed at designated central core laboratories. 
CMR & ECHO after each Anti-SAP treatment session will be assessed at the study site as 
part of safety evaluation.
6.4.
Packaging and Labelling
The contents of the label will be in accordance with all applicable regulatory 
requirements.
6.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK2398852 and 
GSK2315698 will be detailed in a Study Specific Technical Agreement/Memo (TTS) or 
Pharmacy Manual which will be accompanied by a Quality Agreement.

Only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment.  All study 
treatments must be stored in a secure environmentally controlled and monitored 
(manual or automated) area in accordance with the labelled storage conditions 
with access limited to the investigator and authorized site staff. 

The investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (i.e. receipt, reconciliation and final disposition records).  

Further guidance and information for final disposition of unused study treatment 
are provided in the study reference manual (SRM). 

Under normal conditions of handling and administration, study treatment is not 
expected to pose significant safety risks to site staff. Take adequate precautions to 
avoid direct eye or skin contact and the generation of aerosols or mists. In the case 


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of unintentional occupational exposure notify the monitor, Medical Monitor 
and/or GSK study contact.

Material Safety Data Sheets (MSDS)/equivalent document describing 
occupational hazards and recommended handling precautions either will be 
provided to the investigator, where this is required by local laws, or is available 
upon request from GSK.
6.6.
Compliance with Study Treatment Administration
When the individual dose for a subject is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second member of the study site staff. 
Subjects will be dosed at the site, and will receive study treatment directly from the 
Investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
CPHPC (prior to anti-SAP mAb administration) and anti-SAP mAb will be intravenously 
administered to subjects at the site.  Administration will be documented in the source 
documents and reported in the CRF.
6.7.
Treatment of Study Treatment Overdose
For this study, any dose of CPHPC or anti-SAP mAb greater than the intended dose 
within the scheduled dosing period will be considered an overdose.
GSK does not recommend specific treatment for an overdose.
6.8.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given to the post-
study care of the subject’s medical condition, whether or not GSK is providing specific 
post-study treatment.
Given the lack of information about the safety and efficacy of Anti-SAP treatment in AL 
and ATTR-CM, treatment will not be provided after the end of the study. This may be 
reviewed once more information is available. 
6.9.
Lifestyle and/or Dietary Restrictions
The following restrictions apply from recruitment into the study and until the 8 week 
follow-up visit
6.9.1.
Alcohol, and Tobacco
During each resident dosing session, subjects will abstain from alcohol and tobacco for 
12 hours prior to admission and until discharge.


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6.9.2.
Activity
Subjects will abstain from strenuous exercise for at least 48 hours prior to each blood 
collection for clinical laboratory tests.  Subjects may participate in light recreational 
activities during in-patient part of the study (e.g., watch television, read).
6.10.
Concomitant Medications and Non-Drug Therapies
6.10.1.
Permitted Medications and Non-Drug Therapies
Subjects usual medication can be continued during this study with the exception of those 
listed in Section 6.10.2.
Paracetamol can be administered if clinically indicated at the discretion of the 
Investigator up to and including the recommended maximum total daily dose.
New chronic concomitant medication should be discussed with the GSK Medical 
Monitor.
Pre-medication prior to anti-SAP mAb
A non-selective antihistamine (e.g. Chlorphenamine 10-20 mg) and hydrocortisone 100 
mg (or equivalent) should be given prior to each infusion of anti-SAP mAb. Additional 
administrations of either or both medications are permitted at discretion of Investigator or 
designee if symptoms require this.
Prophylactic treatments for rash
If a rash and associated symptoms (e.g. pruritus) are experienced by a subject at a 
treatment session, during subsequent treatment sessions prophylactic treatment (any first 
and / or second generation H1 antihistamine) are permitted at discretion of Investigator or 
designee.


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6.10.2.
Prohibited Medications and Non-Drug Therapies
The following restrictions apply from pre-screening up to the 8 week follow-up visit.
Medication
Pre-screen restriction
Tafamidis, diflunisal, doxycyline, tauroursodeoxycholic acid (TUDCA)
28 days
Green tea extract
28 days
Immunomodulatory drug (e.g. IMiD)
12 weeks
Disease-modifying drug for any type of autoimmune disease (e.g. rheumatoid 
arthritis), including but not restricted to, methotrexate, cyclophosphamide, or 
anti-cytokine antibodies
12 weeks
Antibody therapy for amyloidosis treatment 
At any time
Conditioning chemotherapy for stem cell harvesting)
6 weeks
Where these are deemed to be clinically necessary by the treating physician the 
individual subject will be withdrawn from the study.


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7.
STUDY ASSESSMENTS AND PROCEDURES
This section lists the parameters of each planned study assessment. The exact timing of 
each assessment is listed in the Time and Events Table (Section 7.1). Detailed procedures 
for obtaining each assessment are provided in the SPM. Whenever vital signs, 12-lead 
ECGs and blood sampling are scheduled for the same nominal time, the assessments 
should occur in the following order: 12-lead ECG, vital signs, blood draws.  The timing 
of the assessments should allow the blood draw to occur at the exact nominal time when 
applicable.
The timing and number of planned study assessments, including safety, pharmacokinetic, 
pharmacodynamic/biomarker may be altered during the course of the study based on 
newly available data (e.g. to obtain data closer to the time of peak plasma concentrations) 
to ensure appropriate monitoring. The change in timing or addition of time points for any 
planned study assessments must be approved and documented by GSK, but this will not 
constitute a protocol amendment. The Institutional Review Board/Institutional Ethics 
Committee (IRB/IEC) will be informed of any safety issues that require alteration of the 
safety monitoring scheme. No more than 500 mL of blood will be taken for each Anti-
SAP treatment.


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7.1.
Time and Events Table
Table 3
Overview All Groups (for details of inpatient stay see Table 4)
Session 1
Session 2
Session 3
Session 4
Session 5
Session 6
Follow-up
Screening1
Baseline2
Day -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
8week  F/U3
6 months3
12 months3
Inpatient stay at unit4, 14
X
X
X
X
X
X
Outpatient visit at unit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Informed consent
X
Medical history/risk 
factors/demographics
X
Inclusion/exclusion criteria
X
Safety Assessments
Physical examination5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MOS SF-36, KCCQ, 
EORTC6 questionnaires
X
X
DLQI questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
12 lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lead II telemetry
X
X
X
X
X
X
Cardiac monitor7
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Laboratory Assessments
FSH/E2 - see Table 6
X
Urine βhCG8
X
X
X
X
X
X
X
X
X
Haem/clin chem/urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
24h Urine collection for 
protein and creatinine9
X
X
X
X
X
X
X
X
X
HepB/Hep C/HIV
X


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Session 1
Session 2
Session 3
Session 4
Session 5
Session 6
Follow-up
Screening1
Baseline2
Day -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
8week  F/U3
6 months3
12 months3
Blood biomarkers
Complement and 
Inflammatory markers
X
X
X
X
X
X
X
Troponin T/NT-ProBNP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Anti-Drug Antibody (anti-
SAP mAb)
X
X
X
X
Auto-antibodies
X
mAb/SAP immune complex
X
X
Pharmacokinetics/SAP10
Blood sampling for SAP
X
X
X
X
X
X
X
X
X
X
X
Blood sampling for CPHPC
X
X
X
X
X
X
Blood sampling for anti-
SAP mAb
X
X
X
X
X
X
X
X
X
X
X
X
X
Imaging Procedures
Cardiac MRI with contrast13
X1
X
X
X
X
Cardiac MRI without 
contrast
X
X
X
ECHO
X
X
X
X
X
X
X
X
X
X
SAP scan -  Groups 2/3 UK 
only
X
X
Bone scan (DPD/ PYP) –
Group 1 only
X
X
Other
Skin biopsy / blood sample 
/ urinalysis / EOSI11
(X)
(X)
(X)
(X)
(X)
(X)
6MWT - Groups 1 & 2
X
X
X
X
X
Genetic sample12(optional)
X
Exit Interview
X


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Session 1
Session 2
Session 3
Session 4
Session 5
Session 6
Follow-up
Screening1
Baseline2
Day -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
8week  F/U3
6 months3
12 months3
Ongoing Subject Review
Concomitant therapy
X
Adverse event review
X
Footnotes:
1.
Screening to take place within 42 days of start of treatment. CMR at screening will be performed after a subject has passed all other screening assessments
2.
Baseline will be anytime after eligibility confirmed from screening and before anti-SAP treatment start 
3.
Follow-up at timepoint from last anti-SAP mAb dose
4.
Refer to Table 4 for details of monthly inpatient visit
5.
Complete examination at screening only, brief examination at all other time-points. Weight will be recorded at Baseline, D17 and D24. Abdominal girth will be recorded at Baseline.
6.
EORTC Groups 2 and 3 only
7.
Out-patient cardiac recording using suitable device see Section 7.4.7.2. Recording at baseline, 8wk follow-up and 6 month follow-up for approximately 2 weeks
8.
Pregnancy test before commencement of CPHPC infusion
9.
24hr collection - 3.5ml serum biochemistry sample to be taken for creatinine measurements at time points where there are no corresponding clinical chemistry samples. Day 
indicated in Table represents the end of the 24hr collection period.
10. Sampling time points in Table 4 and Table 5
11. In the event of rash, assessments to be performed (see Table 8). The Investigator/Sub-Investigator must perform a twice daily review 
12. Informed consent for optional genetics sub-study must be obtained before collecting a sample
13. For subjects with a GFR <40ml/min/1.73m2, MRI will be performed at the scheduled times but without contrast
14. Subjects are allowed to be admitted on Day -3 to allow for pre-dose assessments to be performed


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Table 4
Inpatient stay
Study procedures
Day -213
pre-CPHPC dose
Day -2 
Day -1
Day 1-3
anti-SAP mAb dose1
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Safety Assessments
Brief physical examination (including skin)14
X
X
X
X
X
X
X
X
X
X
X
X
12 lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
Lead II telemetry
-------------------------------------------------------------------------------------------
Cardiac monitoring2
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Administration
Administration of CPHPC (2 days IV infusion)
X
X3
Administration of CPHPC (SC )
X
X
X
X
X
X
X
X
X12
Administration of anti-SAP mAb (6h IV infusion on days 1 and 3)
X
Clinical Laboratory Assessments
Haem/clin chem/urinalysis
X
X
X
X
X
X
24h Urine collection for protein and creatinine4
X
X
X
Urine microscopy5
X
X
X
X
Blood biomarkers
Complement and Inflammatory Markers
X
X
X
Cytokines
X
X
X
X
Troponin T/NT-ProBNP
X
X
X
X
X
X
X
X
X
X
Blood sampling for mAb/SAP immune complex 6
X
X
Pharmacokinetics/SAP
Blood sampling for SAP 
X
X7
X
X
X


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Study procedures
Day -213
pre-CPHPC dose
Day -2 
Day -1
Day 1-3
anti-SAP mAb dose1
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Blood sampling for CPHPC8
X8
Blood sampling for anti-SAP mAb
X
X
X
X
Ongoing Subject Review
Skin biopsy9/blood sample/urinalysis/EOSI10
X11
(X)
Concomitant therapy
X
Adverse event review
X
Footnotes: all timings relative to first anti-SAP mAb dose of session
1.
See Table 5 for expanded details of days 1 to 3
2.
At PI discretion appropriate alternate telemetry device may be used.during days 5-10. Cardiac monitoring continues to Day 19 and to be performed with suitable device see 
Section 7.4.7.2
3.
If SAP levels are not below target then the CPHPC will be dosed for a further day and anti-SAP mAb dose deferred 1 day
4.
24h collection - 3.5mL serum biochemistry sample to be taken for creatinine measurements at time points where there are no corresponding clinical chemistry samples. Day 
6 represents the start of the collection period, Day 11 represents the end of the collection period. See Table 5 for details of Day 1-3.
5.
Renal examination of urine i.e. not just dipstick and culture 
6.
Session 1 only
7.
Rapid  turnaround to ensure SAP depleted to target prior to dosing anti-SAP mAb
8.
Group 3 only
9.
Biopsies only on any rash development (i.e. ≥ Grade 1) and will be decided by clinical judgement of the Investigator dermatologist (see Table 8 for full assessments)
10. In the event of a rash the Investigator/Sub-Investigator must perform a twice daily review
11. On confirmation from medical monitor see Table 8
12. Morning dose only to be administered (see Table 2)
13. Subjects are allowed to be admitted on Day -3 to allow for pre-dose assessments to be performed
14. Weight should be recorded on D-2, D5, D8 and D11. Abdominal girth should be recorded on D-2 and D11


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Table 5
Detailed Events - Days 1 to 3 (anti-SAP mAb dosing)
Study procedure
Day 1
Day 2
Day 3
Pre-dose
0h
1h
2h
3h
4h
6h
8h
12h
16h
24h
28h
32h
36h
40h
Pre-dose
0h
1h
2h
3h
4h
6h
8h
12h
16h
Safety assessments
12 lead ECG
X
X
X
X
X
X
X
X
X
X
X
Lead II telemetry
-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug administration
Administration of 
CPHPC (SC)- see Table 
2
X
X
X
Administration of anti-
SAP mAb
X
n/a
X
Clinical lab assessments
Haem/clin 
chem/urinalysis
X
X8,9
X
24h Urine collection for 
protein and creatinine1
X
X
Urine microscopy
X
X
X
X
X
X
Blood sample mAb/SAP 
immune complex2
X
X3
X3
Blood biomarkers
Complement & 
Inflammatory markers
X
X
X
X
X9
X
X
X
X
Cytokines
X
X
X
X
X9
X
X
X
X
Troponin T/NT-proBNP
X
X9
X
Pharmacokinetics
Blood sampling - SAP
X
X
X5
X
X
Blood sampling-
CPHPC4
X
X5
X


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Study procedure
Day 1
Day 2
Day 3
Pre-dose
0h
1h
2h
3h
4h
6h
8h
12h
16h
24h
28h
32h
36h
40h
Pre-dose
0h
1h
2h
3h
4h
6h
8h
12h
16h
Blood sampling - anti-
SAP mAb
X
X6
X
X
X5
X
X6
Ongoing subject review
Skin biopsy/blood 
sample/urinalysis/EOSI7
(X)
(X)
(X)
Concomitant therapy 
review
X
X
X
Adverse event review
X
X
X
Footnotes: all timings relative to first anti-SAP mAb dose of session
1.
24h collection - 3.5mL serum biochemistry sample to be taken for creatinine measurements at time points where there are no corresponding clinical chemistry samples. Day 
indicated in the Table represents the start (pre-dose) of the 24hr collection period.
2.
Session 1 only
3.
At end of anti-SAP mAb infusion
4.
CPHPC sampling is for Group 3 only
5.
Blood sample to be taken immediately prior to first CPHPC SC injection and 2h post CPHPC SC injection of that day
6.
Blood Sampling to coincide with the end of infusion of the anti-SAP mAb
7.
Biopsies on any rash development will be decided by clinical judgement of the Investigator and dermatologist (see Table 8 for full assessments) Skin biopsies & paired blood 
sample / urinalysis should only be performed for each new and / or clinically progressive rash
8.
To include clotting tests for Session 1 only (see Table 6)
9.
Time shown to indicate early in the day only – not a specific time. The collection of these should be timed with other pre-dose sample collection in order to minimise 
inconvenience and needle-sticks for the subjects.


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7.2.
Screening and Critical Baseline Assessments
7.2.1.
Demographic/Medical History Assessments
The following demographic parameters will be captured:  year of birth, gender, race and 
ethnicity.
Medical/medication history will be assessed as related to the eligibility criteria listed in 
Section 5. 
Cardiovascular medical history/risk factors (as detailed in the case report form [CRF]) 
will be assessed at screening.
Medical/medication/family history will be assessed as related to the inclusion/exclusion 
criteria listed in Section 5.
Procedures conducted as part of the subject’s routine clinical management and obtained 
prior to signing of informed consent may be utilized for Screening or baseline purposes 
provided the procedure meets the protocol-defined criteria and has been performed in the 
timeframe of the study. Whenever available pre-trial magnetic resonance imaging (MRI)
data related to the assessments in this study will be obtained from medical history.
7.3.
Efficacy
The study is not designed to measure efficacy however the cardiac function assessments 
i.e. NT-proBNP, Six Minute Walk Test, and Health Outcome Questionnaires may 
provide some insight into efficacy.
7.4.
Safety
Planned time points for all safety assessments are listed in the Time and Events Tables 
(Section 7.1).  Additional time points for safety tests (such as vital signs, physical exams 
and laboratory safety tests) may be added during the course of the study based on newly 
available data to ensure appropriate safety monitoring.
7.4.1.
Adverse Events (AE) and Serious Adverse Events (SAEs)
The definitions of an AE or SAE can be found in Section 12.5, Appendix 5
The investigator and their designees are responsible for detecting, documenting and 
reporting events that meet the definition of an AE or SAE. 
7.4.1.1.
Time period and Frequency for collecting AE and SAE information

Any SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy) or related to a GSK 
product will be recorded from the time a subject consents to participate in the 
study up to and including any follow-up contact. 


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
AEs will be collected from the start of Study Treatment until the 8 week follow-
up contact (see Section 7.4.1.3), at the time points specified in the Time and 
Events Tables (Section 7.1).

Medical occurrences that begin prior to the start of study treatment but after 
obtaining informed consent may be recorded on the Medical History/Current 
Medical Conditions section of the CRF.

All SAEs will be recorded and reported to GSK within 24 hours, as indicated in 
Section 12.5.6.

Investigators are not obligated to actively seek AEs or SAEs in former study 
subjects. However, if the investigator learns of any SAE, including a death, at any 
time after a subject has been discharged from the study, and he/she considers the 
event reasonably related to the study treatment or study participation, the 
investigator must promptly notify GSK.
NOTE: The method of recording, evaluating and assessing causality of AEs and SAEs 
plus procedures for completing and transmitting SAE reports to GSK are provided in 
Section 12.5.4.
7.4.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, since 
your last visit/contact?”
7.4.1.3.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
subject at subsequent visits/contacts.  All SAEs, and non-serious AEs of special interest 
(as defined in Section 4.6.2) will be followed until resolution, until the condition 
stabilizes, until the event is otherwise explained, or until the subject is lost to follow-up 
(as defined in Section 5.4). Further information on follow-up procedures is given in 
Section 12.5.
7.4.1.4.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to GSK of SAEs related to study treatment (even 
for non- interventional post-marketing studies) is essential so that legal obligations and 
ethical responsibilities towards the safety of subjects and the safety of a product under 
clinical investigation are met. 
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 


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comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority IRB/IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.4.2.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after the start of dosing and until final study follow-up.

If a pregnancy is reported then the investigator should inform GSK within 2 
weeks of learning of the pregnancy and should follow the procedures outlined in
Appendix 6
7.4.3.
Physical Exams

A complete physical examination will include, at a minimum, assessment of the 
Cardiovascular, Respiratory, Skin, Gastrointestinal and Neurological systems. 
Height and weight (and girth) will also be measured and recorded. 

A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). Weight and 
abdominal girth measurements will also be included at times stated in the Time 
and Events Table.

Investigators should pay special attention to clinical signs related to previous 
serious illnesses
7.4.4.
Vital Signs

Vital signs will be measured in semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure and pulse rate. 
7.4.5.
Electrocardiogram (ECG)

Single 12-lead ECGs will be obtained at each time point during the study using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, 
QT, and QTcF intervals.  Refer to Section 5.4.6 for QTc withdrawal criteria and 
additional QTc readings that may be necessary.

In-patient Lead II continuous telemetry will be used during in-patient AntiSAP 
treatment sessions. Full disclosures will be reviewed in detail and the review 
maintained as part of the subject’s source documents.


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7.4.6.
Echocardiography (ECHO)
ECHO methodology will be detailed in a separate Image Acquisition Manual.
Echocardiography (ECHO) will be performed by a qualified echocardiographer or 
cardiologist at the timepoints detailed in Section 7.1 Time and Events Tables. At the 
discretion of the Investigator, an ECHO may be requested at any time during the study 
for safety reasons e.g. increase in NT-ProBNP levels, investigation of suspected 
myocarditis, or to confirm worsening of cardiac function caused by any study treatment 
(e.g. bortezomib) or disease.
7.4.7.
Cardiac Electrical Monitoring & Implantable Devices.
7.4.7.1.
Lead II Telemetry
Lead II telemetry will be used for electrical cardiac monitoring during in-patient AntiSAP 
treatment session as detailed in Section 7.1 Time and Events Tables. A baseline reading 
will be obtained before administration of anti-SAP mAb with telemetry commencing the 
day prior to start of anti-SAP mAb infusion (i.e. Day -1 to Day 1 pre anti-SAP mAb 
infusion). 
7.4.7.2.
Cardiac Recording
Cardiac recording devices will be used for electrical cardiac monitoring at the times as 
detailed in Section 7.1 Time and Events Tables.
The type of device will be at the discretion of the Study site and might include, but is not 
restricted to, use of a BodyGuardian or Cardio-Net device.
The recording will be analysed prior to the next anti-SAP treatment and the analysis 
reviewed by the Investigator.
Following confirmation of eligibility, a baseline assessment for up to two weeks will be 
performed to provide baseline data. Whenever feasible the same device as that used at 
baseline will be used for subsequent measures.
7.4.7.3.
Insertion of a PPM or ICD for Prophylactic Reasons
Subjects who require insertion of a PPM or ICD for prophylactic reasons during the study 
can continue to receive Anti-SAP treatment, at the discretion of the Investigator in 
consultation with the Medical Monitor 
A contrast-enhanced CMR should be performed whenever possible before PPM or ICD 
insertion during study treatment (this will represent the final CMR imaging in these 
subjects).


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For all subjects who have a PPM or ICD inserted it is recommended that they have an 
implantable device check:
i). On Day 4 
ii). In the event of a rise in plasma NT-proBNP 2-fold above baseline 
iii). 24 hours before in-patient discharge
Subjects who have a PPM or ICD implanted during Anti-SAP treatment will have no 
further CMR and will continue to be imaged with ECHO only (bone tracer scintigraphy 
in Group 1 subjects where technically feasible).
There must not be more than an 8 week interval between the last Anti-SAP treatment 
session and the subsequent one after PPM or ICD insertion, or otherwise, the subject will 
be withdrawn from further study treatment.
7.4.8.
Clinical Safety Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 6 must be conducted in 
accordance with the Laboratory Manual, and Protocol Time and Events Schedule.
Laboratory requisition forms must be completed and samples must be clearly labelled 
with the subject number, protocol number, site/centre number, and visit date. Details for 
the preparation and shipment of samples will be provided by the laboratory and are 
detailed in the SRM and/or the laboratory manual. Reference ranges for all safety 
parameters will be provided to the site by the laboratory responsible for the assessments.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in subject management or are 
considered clinically significant by the investigator (e.g., SAE or AE or dose 
modification) the results must be recorded in the CRF.
Refer to the SRM for appropriate processing and handling of samples to avoid duplicate 
and/or additional blood draws.
Study-required clinical safety laboratory assessments will be performed by a local
laboratory. All other laboratory assessments will be performed by a central laboratory. 
The results of each test must be entered into the CRF.
Local laboratory results are required in the event that the central laboratory results are not 
available in time for either a treatment and/or response evaluation to be performed. In 
this case if a local sample is required it is important that the sample for central analysis is 
obtained at the same time. Additionally if the local laboratory results are used to make 
either a treatment or response evaluation, the results must be entered into the CRF.
Haematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed in Table 6.


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Table 6
Protocol Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Haematology
Platelet Count
RBC Indices:
WBC count with Differential:
RBC Count
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
MCHC
Monocytes
WBC count (absolute)
Eosinophils
Reticulocyte count
Basophils
Clinical 
Chemistry 1
BUN
Potassium
AST (SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT (SGPT)
Total Protein
Glucose 
Calcium
Alkaline phosphatise
Albumin
Chloride
Total CO2
LDH
CK
Uric acid
Other safety

Troponin-T (including High Sensitivity)

NT-proBNP
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood and ketones by dipstick

Microscopic examination

Urine creatinine, albumin and protein from 24h collection
Pregnancy 
testing 
Serum or urine hCG Pregnancy test (as needed for women of child 
bearing potential)
Other 
Screening 
Tests

HIV

Hepatitis B (HBsAg)

Hepatitis C (Hep C antibody)

FSH and estradiol (as needed in women of non-child bearing 
potential only)

Alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Serum or urine hCG Pregnancy test (as needed for women of child 
bearing potential) 2

Clotting tests – PT and APTT
Further Tests 
(Session 1, 
Day 2 only)

Clotting tests – PT and APTT


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Laboratory 
Assessments
Parameters
Investigation 
of adverse 
bleeding event

Clotting tests – PT and APTT

Platelet function tests (at discretion of Investigator or designee)
NOTES :
1.
Details of Liver Chemistry Stopping Criteria and Required Actions and Follow-Up 
Assessments after liver stopping or monitoring event are given in Section 5.4.1 and  
Appendix 2
2.
Local urine testing will be standard for the protocol unless serum testing is required 
by local regulation or ethics committee.
All laboratory tests with values that are considered clinically significantly abnormal for 
this patient population during participation in the study or within 7 days after the last 
dose of study treatment should be repeated until the values return to normal or baseline.  
If such values do not return to normal within a period judged reasonable by the 
investigator, the aetiology should be identified and the sponsor notified.
7.5.
Pharmacokinetics
7.5.1.
Blood Sample Collection
Blood samples for pharmacokinetic (PK) analysis of GSK2315698 and GSK2398852 will 
be collected at the time points indicated in Section 7.1, Time and Events Tables. The 
actual date and time of each blood sample collection will be recorded. The timing of PK 
samples may be altered and/or PK samples may be obtained at additional time points to 
ensure thorough PK monitoring.  
2mL of blood will be collected into ethylenediaminetetraacetic acid (EDTA) tubes.
Processing, storage and shipping procedures are provided in the Study Reference Manual 
(SRM). 
7.5.2.
Sample Analysis
Plasma analysis will be performed under the management of Bioanalysis, 
Immunogenicity & Biomarkers (BIB), In Vitro In Vivo Translation (IVIVT), PTS,
GlaxoSmithKline.  Concentrations of CPHPC (GSK2315698) and anti-SAP mAb 
(GSK2398852) will be determined in plasma samples using the currently approved 
analytical methodology.  Raw data will be stored in the good laboratory practice (GLP)
Archives, GlaxoSmithKline.


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7.6.
Biomarker(s) / Pharmacodynamic Markers (PD)
The following biomarkers and PD markers will be collected at the time points indicated 
in Section 7.1, Time and Events Tables.
The timing of assessments may be altered as information is obtained. Details of PD 
assessments and blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the SRM.
Companion Diagnostic Assay Development: 
Aliquots of serum/plasma taken for PD analysis in this study will be stored and may be 
used in the development and validation of a companion diagnostic assay to measure SAP 
levels.
7.6.1.
Pharmacodynamic markers in blood
Blood samples for pharmacodynamic analysis of the following parameters will be 
collected at the time points indicated in Section 7.1, Time and Events Tables. The actual 
date and time of each blood sample collection will be recorded.
The timing of PD samples may be altered as information is obtained. Details of PD blood 
sample collection (including volume to be collected), processing, storage and shipping 
procedures are provided in the SRM.

SAP concentration

A 4mL blood sample will be collected at the time points as per Section 7.1, 
Time and Events Tables
Samples collected  Day -1 will be analysed immediately to confirm sufficient 
SAP depleted to target prior to dosing anti-SAP mAb 

Renal Function and Liver function tests (also collected as safety measures)
7.6.2.
Imaging
7.6.2.1.
Cardiac Magnetic Resonance (CMR) Imaging 
Subjects will be asked to refrain from alcohol, caffeine, and nicotine on the days of CMR 
exams. Each CMR imaging session will take approximately 45-60 minutes, with a 
maximum scan time inside of the scanner of 90 minutes. If a scanning failure occurs at 
any visit, if feasible a rescan is allowed within 7 days of the failed scan after consultation 
and agreement with the GSK medical monitor. For scans involving contrast, there will be 
a minimum of 24 hours prior to rescan.
Contrast enhanced MRI scans using an intravenous injection of a gadolinium based 
contrast agent (GBCA) will be performed at the time points specified in Time & Events 
tables (Section 7.1). A GBCA dose less than or equal to 0.1 mmol/kg will be used at each 
contrast enhanced scanning session. Acceptable GBCA agents for this study are gadoteric 
acid, gadoteridol, and gadobutrol. Non-contrast enhanced MRI scans will also be 
performed as indicated in the Time & Events table (Section 7.1).


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Whenever possible, the contrast enhanced MRI scan at screening will be performed 
after a subject has passed other eligibility requirements. This scan will serve as the 
baseline examination.
For each subject, follow-up CMR examinations will be performed on the same scanner as 
the baseline examination. Where this is not possible (e.g. due to scanner failure), the use 
of an alternative scanner may be approved by the study team in consultation with the 
central imaging core lab.
Further details of site training and qualification procedures, and scanning protocols are 
provided in a dedicated Image Acquisition Manual to ensure consistency across study 
sites. Additional exploratory CMR endpoints, as detailed in the Imaging Acquisition 
Guidelines, may also be acquired for exploratory purposes.
All CMR scans will be reviewed at the site for clinical abnormalities. Image analysis for 
the CMR endpoints will be performed by a central core lab.
7.6.2.2.
SAP scan (Groups 2 and 3 and where available)
Amyloid load in liver, spleen, kidney, bone marrow, other involved organs, except the 
heart, and total body, will be assessed by SAP scintigraphy at baseline and at 8 week 
follow-up.
SAP scintigraphy is the most comprehensive method for estimating total body amyloid 
load [Hawkins, 1988], but it is only available for the UK subjects in this phase 2 study.  
SAP scintigraphy (SAP scan) will be performed in UK for Groups 2and 3 only.
Methodology will be detailed in a separate Image Acquisition Manual.
7.6.2.3.
99mTc-DPD or 99mTc-PYP Radioscintigraphy 
Radioscintigraphy with 99mTc-DPD or 99mTc-PYP will be used to quantify cardiac 
amyloid load in Group 1 subjects at the time points specified in Time & Events tables 
(Section 7.1).
Methodology will be detailed in a separate Image Acquisition Manual.
7.6.3.
Exploratory Biomarkers
With the subject’s consent, serum, urine and possibly tissue samples (e.g. skin biopsy) 
will be collected during this study and may be used for the purposes of measuring novel 
biomarkers to identify factors that may influence amyloidosis and/or medically related 
conditions, as well as the biological and clinical responses to Anti-SAP treatment, as well 
as drug-induced toxicities. If relevant, this approach will be extended to include the 
identification of biomarkers associated with adverse events. Novel candidate biomarkers
of the biological response associated with skin rashes and/or the action of GSK2398852 
may be identified by application of:

RNA transcriptome analysis of blood and skin samples.


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
Measurement of the levels of a subset of RNA species on blood and skin samples.
Samples will be collected at the time points indicated in Time & Events tables (Section 
7.1). The timing of the collections may be adjusted on the basis of emerging data from 
this study or other new information in order to ensure optimal evaluation of the PD 
endpoints. Analysis of these samples may not take place if other information from the 
study would indicate that they will not provide useful additional information. 
For further instructions on the collection and handling of samples refer to the Study 
Reference Manual. 
7.6.3.1.
Blood biomarkers
Plasma Cytokines
5mL blood sample for serum will be collected for the purposes of measuring biomarkers 
of immune function. These may include but are not limited to TNFα, IL-10, IL-8, IL-6, 
IL-13, IL-2, IL-4, IL-12 (p70), IL1& IFN.
Cardiac biomarkers
3.5mL blood samples for serum will be collected to measure exploratory measures of 
cardiac efficacy including but not limited to: NT-proBNP. 
Inflammatory markers and Fluid phase Complement Markers.
5mL blood samples for serum will be collected to measure:

complement markers including but not limited to: C3, C4, CH50 and those listed 
in Table 8

inflammatory biomarkers including but not limited to: CRP, high-sensitivity C-
reactive protein (hsCRP), SAA
7.6.3.2.
RNA Transcriptome Research
Transcriptome studies may be conducted using microarray, and/or alternative equivalent 
technologies, which facilitates the simultaneous measurement of the relative abundances 
of thousands of RNA species resulting in a transcriptome profile for each biopsy sample.  
This will enable the evaluation of changes in transcriptome profiles that may correlate 
with biological response relating to skin rash, amyloid related diseases or the action of 
GSK2398852.
A 2.5mL blood sample will be collected and the same samples may also be used to 
confirm findings by application of alternative technologies.


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7.6.3.3.
RNA Expression Research of a Subset of RNA Species
RNA expression studies may be conducted using quantitative RT-PCR, and/or alternative 
equivalent technologies, which can facilitate the simultaneous measurement of the 
relative abundances of hundreds of RNA species resulting in a RNA expression profile 
for each skin sample.  The RNAs assayed may be those involved with the pathogenesis of 
disease, the absorption, distribution, metabolism, or excretion of study treatment, or in 
the subject’s response to study treatment. In addition, continuing research may identify 
other proteins or regulatory RNAs that may be involved in response to GSK2398852 or 
the pathogenesis of disease. The RNAs that code for these proteins and/or regulatory 
RNAs may also be studied. This will enable the evaluation of changes in RNA expression 
profiles that may correlate with biological response relating to skin rash and disease and 
medically related conditions or the action of study treatment.
7.6.3.4.
Access to other biopsy tissue
Where a subject requires biopsy, as part of any clinical investigative procedures as 
directed by the treating physician, a sample of the tissue will be sent to GSK where 
possible. Routine and special histopathological investigations, including histochemical 
and/or immunohistochemical stains will be performed to assess for amyloid deposits, 
inflammatory cellular infiltrates including multinucleated giant cells and macrophages as 
well as for markers of any parenchymal tissue disruption.
7.7.
Immunogenicity
7.7.1.
Anti-GSK2398852 antibodies (ADA)
Blood samples for determination of anti-GSK2398852 antibodies will be taken from all 
subjects in this study as a safety measurement at the time-points specified in the Time 
and Events Tables (Section 7.1). Timing of the assessments may be adjusted based on 
emerging data.
Samples will be analysed for the presence of anti-GSK2398852 antibodies using an 
analytically validated screening assay. If sera contain anti-GSK2398852 antibodies in the 
screening assay, they will be further analysed for specificity and titres of antibodies.
Samples will be retained for further characterisation of neutralising activity if required 
and reported separately. The immunogenicity assessment report will include the 
incidence and titres of anti-GSK2398852 binding antibodies.
7.7.2.
Immune complexes
4mL blood samples for determination of SAP/anti-SAP mAb immune complexes will be 
taken as a safety measurement at the time-points specified in the Time & Events tables 
(Section 7.1) and Table 8. Timing of the assessments may be adjusted based on emerging 
data.


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7.7.3.
Auto-antibodies
3mL blood samples for determination of antinuclear antibodies (ANA), anti-neutrophil
cytoplasmic antibodies (ANCA), anti-double strand-DNA antibody (refer to Table 8)
7.8.
Efficacy
7.8.1.
Six Minute Walk Test
The 6-Minute Walk Test (6MWT) assessment will be conducted according to the 
American Thoracic Society guidelines (in accordance with local standard operating 
procedures).
7.8.2.
Safety/exploratory Biomarkers
Some of the samples taken primarily for assessment of safety, such as proteinuria, and 
some safety/ exploratory biomarkers, such as NT-proBNP, may also provide evidence of 
efficacy.
7.9.
Health Outcomes
7.9.1.
MOS 36-item short-form health survey (MOS SF-36)
The MOS SF-36 has 36 questions. All questions are scored using normative based 
scoring.  Software is available that assists in the scoring of the MOS SF-36 
(QualityMetric Health Outcomes Scoring Software 2.0, Saris-Baglama, 2007), and details 
on scoring can be found in the SF-36v2 user manual.
7.9.2.
Kansas City Cardiomyopathy Questionnaire (KCCQ)
The Kansas City Cardiomyopathy Questionnaire is a 23-item, self-administered 
instrument that quantifies physical function, symptoms (frequency, severity and recent 
change), social function, self-efficacy and knowledge, and quality of life.
7.9.3.
European Organisation for Research and Treatment of Cancer 
(EORTC)
The European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 (EORTC QLQ C30) is a questionnaire developed to assess the quality 
of life of cancer patients and consists of 30 questions. Subjects in Groups 2 and 3 only 
will complete this questionnaire.


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7.9.4.
Dermatology Quality of Life Index (DLQI)
The dermatology quality of life index is a simple 10 item validated questionnaire that has 
been used to assess the impact of skin diseases on patient quality of life. It will be 
administered to subjects in the study who develop dermatological toxicity.
7.9.5.
Questionnaire Administration
Subjects will complete the questionnaires at the time-points specified in the Time and 
Events Tables,
The Investigator or designee will ask the subject to complete the questionnaire during the 
clinical visit separately from the medical history and the standard AE and concomitant 
medication questions.
Questionnaires should be completed in a quiet place (preferably the same place each 
time, if possible) and at as consistent a time during the study visits as possible.  To avoid 
biasing responses, subjects should not be told the results of diagnostic tests prior to 
completing the questionnaire.  Regardless of when the questionnaire is completed, the 
subject should be given adequate time to complete all items.  No stated or implied time 
limit for completing the questionnaire items will be given.
The subject should be asked to complete the questionnaire completely and accurately.  If 
the subject requests help or clarification of any question, he should be asked to read the 
instructions again and to give the best answer possible to each question.  Subjects should 
be encouraged to report their own experiences and opinions.  The investigator will not 
provide the subject with an answer to any question nor interpret any portion of the 
question.
7.10.
Exit Interview
Exit interviews will be conducted after the 8 week follow-up or Early Withdrawal Visit 
and over the telephone, in a subset of subjects only, to explore subjects’ experience with 
study treatment. Exit interviews are qualitative interviews conducted with study subjects 
to capture subject experiences in drug development on completion of participation in a 
clinical study. Interview questions are designed to fully assess a subject’s experience 
with a study medication and study requirements and are administered in a semi-structured 
format over the telephone by a trained interviewer independent of study sites and 
sponsor. Subject feedback will be captured in a data collection sheet as well as being 
audio-taped for subsequent transcription and qualitative analysis and reported separately. 
The Exit interview technique and questions will be described in the SRM.


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7.11.
Genetics
If the patient provides additional informed consent, genetic research aimed at 
understanding variability in patients’ response to GSK2398852 & GSK2315698 (or other 
therapies that subjects may receive while participating in the clinical study) with regard 
to safety, pharmacokinetics, and efficacy may be undertaken on a genetic sample 
collected at Baseline. Information regarding the genetic research is included in Section 
12.4. Participation in the genetic research is voluntary and refusal to participate will not 
affect the subject’s eligibility to participate in the main study.
The IEC and, where required, the applicable Regulatory Authority must approve the 
genetic assessments before these can be conducted. The approval(s) must be in writing 
and will clearly specify approval of the genetic assessments (i.e., approval of Section 
12.4). In some cases, approval of the genetic assessments can occur after approval is 
obtained for the rest of the study. If so, the written approval will clearly indicate that 
approval of the genetic assessments is being deferred and in most cases, the study, except 
for genetic assessments, can be initiated. When genetic assessments will not be approved, 
then the approval for the rest of the study will clearly indicate this and therefore, the 
genetic assessments will not be conducted.
Information regarding genetic research is included in Appendix 4 Section 12.4.


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8.
DATA MANAGEMENT

For this study subject data will be entered into GSK defined CRFs, transmitted 
electronically to GSK or designee and combined with data provided from other 
sources in a validated data system

Management of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, 
e.g., removing errors and inconsistencies in the data

Adverse events and concomitant medications terms will be coded using MedDRA 
(Medical Dictionary for Regulatory Activities) and an internal validated 
medication dictionary, GSKDrug

Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0 will be used

CRFs (including queries and audit trails) will be retained by GSK, and copies will 
be sent to the investigator to maintain as the investigator copy.  Subject initials 
will not be collected or transmitted to GSK according to GSK policy


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9.
STATISTICAL CONSIDERATIONS AND DATA 
ANALYSES
9.1.
Hypotheses
No formal statistical tests are planned in this study. 
9.2.
Sample Size Considerations
9.2.1.
Sample Size Assumptions
The planned sample size is based on feasibility and the level of precision the study would 
provide around the estimated change in structural cardiac MRI measure LV mass, used to 
assess cardiac amyloid load and estimated adverse event rates. 
Assuming a standard deviation of 20g for the change in LV mass, the half width for the 
95% confidence interval (CI) around the estimated change in LV mass at 8-week
follow-up based on the observed data would be 14g. For example, the 95% CI around 
an observed change in LV mass of 70g at final follow-up would be (56, 84), i.e. a lower 
limit of more than 50g.
Based on a sample size of 10 per study group and various observed adverse event rates, 
Table 7 below presents the following:
i)
95% credible intervals for the adverse event rate
ii) probability of a true adverse event rate > 10%, 30% or 50%,
derived within a Bayesian framework with a non-informative conjugate prior 
distribution, Beta(1/3,1/3)


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Table 7
95% credible intervals for adverse event rates and probabilities of 
adverse event rates > x%
N
Observed 
number of 
subjects 
experiencing 
AE
Observed 
rate
Lower 
95% 
Credible 
Interval 
Limit
Upper 
95% 
Credible 
Interval 
Limit
Prob. of true AE rate > x%, 
given observed data
> 10%
> 30%
> 50%
10
0/10
0.00
0.00
0.18
0.09
0.00
0.00
10
1/10
0.10
0.01
0.37
0.51
0.06
0.00
10
2/10
0.20
0.04
0.50
0.83
0.24
0.02
10
3/10
0.30
0.09
0.60
0.96
0.50
0.10
10
4/10
0.40
0.15
0.70
0.99
0.75
0.26
10
5/10
0.50
0.22
0.78
1.00
0.91
0.50
10
6/10
0.60
0.30
0.85
1.00
0.98
0.74
10
7/10
0.70
0.40
0.91
1.00
1.00
0.90
10
8/10
0.80
0.50
0.96
1.00
1.00
0.98
10
9/10
0.90
0.63
0.99
1.00
1.00
1.00
10
10/10
1.00
0.82
1.00
1.00
1.00
1.00
9.2.2.
Sample Size Sensitivity
Figure 5 provides an assessment of the sensitivity of the sample size to differing 
assumptions around the standard deviation for the change in LV mass. 
Figure 5
Sensitivity of the Sample Size - LVmass
Note: ‘Mean to limit distance’ = 95% Confidence Interval half width


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9.2.3.
Sample Size Re-estimation or Adjustment
The sample size will be re-assessed based on the emerging data. The sample size in one 
or more groups may be adjusted if, for example, the observed variability is larger than 
that assumed at the study design stage for changes in LV mass. 
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The ‘Safety Population’ is defined as subjects who receive at least one dose of study 
medication. This population will be used for the summary and analysis of all data 
including safety, efficacy, pharmacodynamic and pharmacokinetic data.
9.3.2.
Interim Analysis
Data will be reviewed on an ongoing basis throughout the study, including but not limited 
to, safety, imaging, PK, PD, clinical and biomarker data.  
Study specific decisions will be supported by the periodic review of study data, as 
described in Section 10.8.2. The first review will take place once 5 subjects have 
completed at least 3 courses of Anti-SAP treatment.  Outcomes from the periodic data 
reviews may include:

Regulatory interactions and initiation of recruitment in to Group 3 

Triggering of phase III planning and related regulatory interactions 

Sample size re-estimation/adjustment (see Section 9.2.3)

Adjustment of the schedule and timing of assessments

Confirmed continuation of the study.
A further interim analysis will be conducted once at least 10 subjects per group have 
completed their 8-week follow-up visit. Further details will be provided in the Reporting 
and Analysis Plan regarding key deliverables for this interim.
The final analyses will be conducted once all subjects have completed their 12-month 
follow-up visit.


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9.4.
Key Elements of Analysis Plan
9.4.1.
Primary Analyses
LV mass 
Analyses detailed below will be performed on data from each study group separately. 
Individual subject profiles over time for LV mass will be plotted using historical pre-trial 
standard of care subject data, where available, and within-study data from the same 
subject pre and post Anti-SAP treatment. Absolute values and changes from baseline in 
LV mass will also be summarized over time. 
The longitudinal profile of LV mass post Anti-SAP treatment will be analyzed using a 
Bayesian linear mixed model (LMM). The intention is to also include two sources of 
historical MRI data in the model from one participating site that will be informative of 
the standard of care LV mass profile over time: 
1. Pre-trial MRI data for subjects enrolling in the study, collected as part of their 
medical history, where available 
2. Repeat historical MRI data for subjects not enrolled in the study (2 to 3 scans 
per subject).
For subjects who prematurely discontinue treatment, follow-up MRI scans at 8 weeks, 6 
months and12 months post last dose will be performed where possible. All retrieved LV 
mass data post treatment-discontinuation will be incorporated directly within the model. 
This will be achieved in two ways: (i) fitting a LMM following a Pattern Mixture Model 
(PMM) framework, uniquely identifying patterns of treatment discontinuation; and (ii) 
fitting a LMM to all data ignoring whether subjects prematurely discontinued Anti-SAP 
treatment. 
Any missing data will be imputed assuming a Missing Not at Random mechanism with 
the historical MRI data acting as reference. 
Posterior distributions at time points of interest post Anti-SAP treatment (e.g. after 3 
doses, at 8-week follow-up) will be presented graphically. Probability statements around 
the magnitude of LV mass and/or the reduction in LV mass post Anti-SAP treatment at 
selected time points will also be presented. Similarly, posterior distributions and 
probability statements will be presented for standard of care. 
Further details will be provided in the reporting and analysis plan. 
Safety
Safety data (e.g. AEs, vital signs, haematology, biochemistry, urinalysis, ECGs, Holter, 
rash) will be summarized by study group in tabular and/or graphical format.  Posterior 
probabilities of a true adverse event rate being > 10%, > 30% and >50% will be presented 
for specific AEs (e.g. rash, anti-SAP mAb infusion-related reactions, cardiac AEs), 


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derived within a Bayesian framework with a neutral non-informative conjugate 
Beta(1/3,1/3) prior distribution.
Further details will be provided in the Reporting and Analysis Plan.
9.4.2.
Secondary Analyses
For both compounds (GSK2315698 and GSK2398852), plasma concentration-time data 
will be listed and summarised, and pharmacokinetic parameters of GSK2398852 will be 
calculated using non-compartmental methods with WinNonlin, version 6 or higher.
Individual profiles over time and summary tables will be presented for circulating PD 
markers of interest, e.g. IL6, IL8, IL10, CRP, SAA, C3, C4 and CH50.
Functional CMR and ECHO measures (eg stroke volume, left ventricular ejection 
fraction, end diastolic volume etc) will be analysed as described for LV mass, as data 
permit.
Further details of the secondary, exploratory and long term follow-up analyses will be 
specified in the reporting and analysis plan.


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10.
STUDY GOVERNANCE CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements, 
and with GSK policy.
The study will also be conducted in accordance with ICH Good Clinical Practice (GCP), 
all applicable subject privacy requirements, and the guiding principles of the current 
version of the Declaration of Helsinki.  This includes, but is not limited to, the following:

IRB/IEC review and favourable opinion/approval of the study protocol and 
amendments as applicable

Obtaining signed informed consent

Investigator reporting requirements (e.g. reporting of AEs/SAEs/protocol 
deviations to IRB/IEC)

GSK will provide full details of the above procedures, either verbally, in writing, 
or both.

Signed informed consent must be obtained for each subject prior to participation 
in the study

The IEC/IRB, and where applicable the regulatory authority, approve the clinical 
protocol and all optional assessments, including genetic research.  

Optional assessments (including those in a separate protocol and/or under separate 
informed consent) and the clinical protocol should be concurrently submitted for 
approval unless regulation requires separate submission.  

Approval of the optional assessments may occur after approval is granted for the 
clinical protocol where required by regulatory authorities.  In this situation, 
written approval of the clinical protocol should state that approval of optional 
assessments is being deferred and the study, with the exception of the optional 
assessments, can be initiated.


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10.3.
Quality Control (Study Monitoring)

In accordance with applicable regulations including GCP, and GSK procedures, 
GSK monitors will contact the site prior to the start of the study to review with the 
site staff the protocol, study requirements, and their responsibilities to satisfy 
regulatory, ethical, and GSK requirements.  

When reviewing data collection procedures, the discussion will also include 
identification, agreement and documentation of data items for which the CRF will 
serve as the source document.
GSK will monitor the study and site activity to verify that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any 
other study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents
10.4.
Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK 
may conduct a quality assurance assessment and/or audit of the site records, and 
the regulatory agencies may conduct a regulatory inspection at any time during or 
after completion of the study. 

In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all 
relevant documents and to allocate their time and the time of their staff to discuss 
the conduct of the study, any findings/relevant issues and to implement any 
corrective and/or preventative actions to address any findings/issues identified.
10.5.
Study and Site Closure

Upon completion or premature discontinuation of the study, the GSK monitor will 
conduct site closure activities with the investigator or site staff, as appropriate, in 
accordance with applicable regulations including GCP, and GSK Standard 
Operating Procedures.

GSK reserves the right to temporarily suspend or prematurely discontinue this 
study at any time for reasons including, but not limited to, safety or ethical issues 
or severe non-compliance. For multicenter studies, this can occur at one or more 
or at all sites.  

If GSK determines such action is needed, GSK will discuss the reasons for taking 
such action with the investigator or the head of the medical institution (where 
applicable).  When feasible, GSK will provide advance notification to the 
investigator or the head of the medical institution, where applicable, of the 
impending action.


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
If the study is suspended or prematurely discontinued for safety reasons, GSK will 
promptly inform all investigators, heads of the medical institutions (where 
applicable) and/or institution(s) conducting the study. GSK will also promptly 
inform the relevant regulatory authorities of the suspension or premature 
discontinuation of the study and the reason(s) for the action.  

If required by applicable regulations, the investigator or the head of the medical 
institution (where applicable) must inform the IRB/IEC promptly and provide the
reason for the suspension or premature discontinuation.
10.6.
Records Retention

Following closure of the study, the investigator or the head of the medical 
institution (where applicable) must maintain all site study records (except for 
those required by local regulations to be maintained elsewhere), in a safe and 
secure location.  

The records must be maintained to allow easy and timely retrieval, when needed 
(e.g., for a GSK audit or regulatory inspection) and must be available for review 
in conjunction with assessment of the facility, supporting systems, and relevant 
site staff.  

Where permitted by local laws/regulations or institutional policy, some or all of 
these records can be maintained in a format other than hard copy (e.g., microfiche, 
scanned, electronic); however, caution needs to be exercised before such action is 
taken.  

The investigator must ensure that all reproductions are legible and are a true and 
accurate copy of the original and meet accessibility and retrieval standards, 
including re-generating a hard copy, if required.  Furthermore, the investigator 
must ensure there is an acceptable back-up of these reproductions and that an 
acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to 
comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to that site for the study, as dictated by 
any institutional requirements or local laws or regulations, GSK 
standards/procedures, and/or institutional requirements.  

The investigator must notify GSK of any changes in the archival arrangements, 
including, but not limited to, archival at an off-site facility or transfer of 
ownership of the records in the event the investigator is no longer associated with 
the site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publically Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 


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opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The procedures and timing for public disclosure of the results summary and for 
development of a manuscript for publication will be in accordance with GSK Policy.
10.8.
Periodic Meeting with Investigators
10.8.1.
Individual Subject Review 
Prior to administration of the next Anti-SAP treatment in each subject, there will be a 
review of the available data by:
1. the Principal Investigator (or appropriate designee) having consulted with local 
haematologist, cardiologist, radiologist (CMR / ECHO analyst), and / or 
dermatologist regarding any findings or concerns, additional attendees will be 
invited as required
2. GSK team including Medical Monitor, GSK Study Team Leader, additional 
attendees will be invited as required
The purpose of this review is to consider:

whether it is appropriate to continue with Anti-SAP treatment in that subject 
based on a benefit / risk assessment, and

the dose level for anti-SAP mAb
The review will be a holistic review of the case, but the following will be considered 
specifically:

Adverse events

Whether the subject has experienced a rash

Cardiac safety including outpatient ECG recording and ECHO/CMR 

Biochemistry, haematology, and urinalysis


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10.8.2.
Periodic Study Review
Patients with systemic amyloidosis are complex and their treatment highly 
individualized. In a rare disease the precise characteristics of the patient must be taken 
into account when assessing safety. In addition to meetings of the GSK Safety Review 
team, meetings will be held with Investigators to conduct periodic holistic evaluation of 
the safety profile. 
These meetings will include the following individuals:

Investigator from each study site

Relevant functional experts (e.g. cardiologist, haematologist, dermatologist)

GSK medical monitor, statistician, study team leader, clinical safety 
representative
External experts may also be invited.
These meetings will make recommendations on the following based on the review:

Whether the schedule and timing of assessments are appropriate based on the 
observed safety profile

Whether sufficient information is available to start recruitment of Group 3
The Sponsor will be responsible for the final decision on the schedule of assessments 
and identifying the trigger point for recruitment into Group 3. Recruitment into Group 
3 will not start until a review of available safety information has been conducted by 
regulatory agency.
Scheduled review meetings will be held:
1. After 5 subjects have completed at least 3 treatment sessions
2. After 5 subjects have completed 6 treatment sessions (or 8-week follow-up)
Additional review meetings will be scheduled based on on-going data.


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11.
REFERENCES
Agterof MJ, Biesma DH. Bortezomib-Induced Skin Lesions. N Engl J Med.
2005;352:2534
Banypersad SM, Fontana M, Maestrini V, Sado DM et al,. T1 mapping and survival in 
systemic light-chain amyloidosis. Eur Heart J. 2015.36(4):244-51
Bodin K, Ellmerich S, Kahan MC et al. Antibodies to human serum amyloid P 
component eliminate visceral amyloid deposits. Nature. 2010;468:93-97.
Case EC, Wu S, Gerecitano JF, Lacouture ME. Risk of skin rash with the proteasome 
inhibitor bortezomib: Updated systematic review and meta-analysis, J Clin Oncol 2012 
ASCO Annual Meeting Abstracts; 30 (No 15_suppl;abstr 9092)
Comenzo RL, Reece D, Palladini G et al. Consensus guidelines for the conduct and 
reporting of clinical trials in systemic light-chain amyloidosis. Leukemia. 
2012;26(11):2317-25
Fontana M, Pica S, Reant P et al. Prognostic Value of Late Gadolinium Enhancement 
Cardiovascular Magnetic Resonance in Cardiac Amyloidosis. Circulation. 2015:132(16): 
1570-9
GlaxoSmithKline Document Number 2012N141587. GSK2398852 + GSK2315698 
Investigator's Brochure (IB) Effective 05 JAN 2016.
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, editors. 
Contraceptive Technology. 19th edition. New York: Ardent Media, 2007: 24. Table 3-2.
Hawkins PN, Myers MJ, Epenetos AA, Caspi D, Pepys MB. Specific localization and 
imaging of amyloid deposits in vivo using 123I-labeled serum amyloid P component. J. 
Exp. Med. 1988;167:903-913.
ICH, M3 (R2), 2009]
ICRP, 2007. The 2007 Recommendations of the International Commission on 
Radiological Protection. ICRP Publication 103. Ann. ICRP 37 (2-4).
Kropff M, Bisping G, Schuck E. Bortezomib  et al in combination with intermediate-dose 
dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple 
myeloma. Br J Haematol. 2007;138(3):330-337
Milde, R., J. Ritter, G. A. Tennent, A. Loesch, F. Martinez, S. Gordon, M. B. Pepys, A. 
Verschoor and L. Helming. Multinucleated giant cells are specialized for complement-
mediated phagocytosis and large target destruction. Cell Rep. 2015;13:1937-48
Palladini G, Sachchithanantham S, Milani P, Gillmore J, Foli A, Lachmann H, Basset M, 
Hawkins P, Merlini G, Wechalekar AD.A European collaborative study of 


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cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL 
amyloidosis. Blood. 2015 30;126(5):612-5.
Pepys MB, Herbert J, Hutchinson WL et al. Targeted pharmacological depletion of 
serum amyloid P component for treatment of human amyloidosis. Nature. 
2002;417(6886):254-9.
Pepys MB. Amyloidosis. Annu. Rev. Med. 2006;57:223-241.
Pour L, Hajek L, Zdenek A, Krejci M, Krivanova A, Vorlicek J. Skin lesions induced by 
bortezomib. Haematologica 2005;90(12):118)
Rapezzi C, Quarta CC, Guidalotti PL et al. Role of (99m)Tc-DPD scintigraphy in 
diagnosis and prognosis of hereditary transthyretin-related cardiac amyloidosis. JACC 
Cardiovasc Imaging. 2011;4(6):659-70
Richards DB, Cookson LM, Berges AC et al. Therapeutic Clearance of Amyloid by 
Antibodies to Serum Amyloid P Component. N Engl J Med. 2015 17;373(12):1106-14
Richardson PG, Barlogie B, Berenson J et al. N Engl J Med. 2003;348:2609-2617
Sahota T, Berges A, Barton S, Cookson L, Zamuner S and Richards D. Target Mediated 
Drug Disposition Model of CPHPC in Patients with Systemic Amyloidosis. CPT: 
Pharmacometrics & Systems Pharmacology; 2015; 4(2):116–126.
Saris-Baglama. User’s Manual for the SF-36v2 Health Survey, Second Edition, 2007, 
Chapter 7, pages 81-84.
Simons JP, Al-Shawi R, Ellmerich S et al. Pathogenetic mechanisms of amyloid A 
amyloidosis. Proc Natl Acad Sci U S A. 2013;110(40):16115-20.


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12.
APPENDICES
12.1.
Appendix 1 – Abbreviations and Trademarks
Abbreviations
6MWT
6 minute walk test
AA
Amyloid A 
ANA
antinuclear antibodies
ANCA
anti-neutrophil cytoplasmic antibodies
AE
Adverse Event 
AFib
fibrinogen A alpha chain  amyloidosis
AL
immunoglobin light chain amyloidosis
ALT
alanine transaminase
AApoAI
apolipoprotien A-I amyloidosis
ATTR-CM
transthyretin amyloid cardiomyopathy
AUC
area under the concentration-time profile
BIB
Bioanalysis, Immunogenicity & Biomarkers
BSA
Body surface area
CABG
coronary artery bypass grafting
CI
confidence interval
Cmax
maximum concentration
CMR
cardiac MRI
CPHPC
carboxy pyrrolidine hexanoyl pyrrolidine carboxylate
CONSORT
Consolidated Standards of Reporting Trials
CR
Complete response
CrCl
creatinine clearance
CRF
case report form
CRP
c reactive protein
cTnT
cardiac troponin T
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CV
cardiovascular
CyBorD
cyclophosphamide, bortezomib, dexamethasone
DCE
dynamic contrast enhanced
DLQI
Dermatology Quality of Life Index
DPD/99mTc-DPD
99mTechnetium-dicarboxypropane diphosphonate 
ECG
electrocardiogram
ECHO
echocardiography
ECV
extracellular volume 
EDTA
Ethylenediaminetetraacetic acid
EDV
end diastolic volume
EF
ejection fraction
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay


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EORTC QLQ C30
The European Organisation for Research and Treatment of 
Cancer Quality of Life Questionnaire C30
EOSI
event of specialist interest
FAC
familial amyloid cardiomyopathy
FDA
food & drug administration
FIH
first in human
FRP
female of reproductive potential (FRP)
FLC
free light-chain
FSH
follicle stimulating hormone
GBCA
gadolinium based contrast agent
Gd
gadolinium
GFR
Glomerular filtration rate
GLP
good laboratory practice
GLS
Global longitudinal strain
GSK
GlaxoSmithKline
hCG
human chorionic gonadotrophin
HPLC-MS
hplc-mass spectrometry
HRT
hormone replacement therapy
hsCRP
high-sensitivity C-reactive protein
IB
investigator’s brochure
ICD
implantable cardiac defibrillator
IMiD
immunomodulatory drug
IND
investigational new drug 
IRB/IEC
Institutional Review Board/Institutional Ethics Committee
IV
intravenous
IVIVT
In Vitro In Vivo Translation
L
litre
LCV
leucocytoclastic vasculitis
LGE
late gadolinium enhancement
LMM
linear mixed model
LVAD
left ventricular assist device
LV
left ventricular
mAb
monoclonal antibody
MDRD
Modification of Diet in Renal Disease (equation)
mg
milligram
MGC
multinucleated giant cells
MHRA
Medicines and Healthcare products Regulatory Agency
mL
millilitre
MRI
magnetic resonance imaging
MSDS
Material Safety Data Sheets 
ms
millisecond
NT pro-BNP
N-terminal pro b-type Natriuretic Peptide
NYHA class
New York heart association class
od
once daily
PD
pharmacodynamic
PET
Positron emission tomography


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PI
Principal Investigator
PIH
Post-inflammatory hyperpigmentation
PK
pharmacokinetic
PK/PD
pharmacokinetics/pharmacodynamics
PMM
Pattern Mixture Model
PPM
permanent pacemaker
PYP/99m-Tc-PYP
99mTc-pyrophosphate
QTc
interval from the Q wave on the ECG to point T
QTcF
QTc using Fredericia's formula
RAP
Reporting and Analysis Plan
SAA
serum amyloid A protein
SAE
severe adverse events
SAP
serum amyloid p component
SC
subcutaneous
SRM
study reference manual
SV
stroke volume
TIA
transient ischemic attack
tmax
the time associated with Cmax
TTR
transthyretin
TTS
Study Specific Technical Agreement/Memo
ULN
upper limit of normal
Vd
volume of distribution
VGPR
very good partial response
VT
Ventricular tachycardia
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
BodyGuardian
Cardio-Net
Chiron RIBA
SAS
WinNonlin


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12.2.
Appendix 2: Liver Safety Required Actions and Follow up 
Assessments
Liver chemistry stopping criteria have been designed to assure subject safety and to 
evaluate liver event aetiology (in alignment with the FDA premarketing clinical liver 
safety guidance).
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Liver chemistry stopping criteria and required follow-up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT≥3xULN
If ALT≥3xULN AND bilirubin1,2 2xULN (>35% direct bilirubin)
Or, 
INR >1.5 without warfarin anti-coagulation 
= Report as an SAE
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments following Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue  study treatment 

Report the event to GSK within 24 hours

Complete the liver event CRF, and complete an 
SAE data collection tool if the event also meets 
the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries resolve, 
stabilise, or return to within baseline (see 
MONITORING below)

Do not restart / re-challenge subject with study 
treatment unless allowed per protocol  and GSK 
Medical Governance approval is granted 

If restart/rechallenge not allowed per protocol 
or not granted, permanently discontinue study 
treatment and may continue subject in the study 
for any protocol specified follow up assessments 

Viral hepatitis serology3

Blood sample for pharmacokinetic 
(PK) analysis, obtained within 5 days 
after last dose (mAb or CPHPC)of last 
dose4

Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total 
bilirubin2xULN

Obtain complete blood count with 
differential to assess eosinophilia

Record the appearance or worsening 
of clinical symptoms of liver injury, or 
hypersensitivity, on the AE report form

Record use of concomitant 
medications on the concomitant 
medications report formincluding 
acetaminophen, herbal remedies, 


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MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
event follow up assessments within  24 hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilise or return to within 
baseline

A specialist or hepatology consultation is 
recommended
If ALT3xULN AND bilirubin < 2xULN and INR 
1.5:

Repeat liver chemistries (include ALT, AST, 
alkaline phosphatase, bilirubin)  and perform liver 
event follow up assessments within  24-72 hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake case report form
If ALT≥3xULN AND bilirubin 2xULN 
or INR >1.5:

Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG or gamma globulins).

Serum acetaminophen adduct HPLC 
assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James, 2009]). 

Liver imaging (ultrasound, magnetic 
resonance, or computerised 
tomography) and / or liver biopsy to 
evaluate liver disease; complete Liver 
Imaging and / or Liver Biopsy CRF 
forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally ,if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured, which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants
3.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis 
CRNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing);  Hepatitis E IgM antibody 
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator treatments. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the CRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.3.
Appendix 3: Guidance on the Clinical Management of Rash 
Associated with Anti-SAP mAb
12.3.1.
Background 
In the FIH study, anti-SAP mAb administration, at doses ≥ 600mg were commonly 
associated with the onset of a rash within the first 3 days of completion of anti-SAP mAb 
dosing. The pathogenesis of the rash is not fully understood but the available evidence 
indicates that it is related to the peak plasma concentration of anti-SAP mAb. 
The clinical presentation of rashes showed significant variability with respect to the body 
surface area (BSA) affected and the clinical characteristics of the skin lesions. 
In the FIH study, the clinical appearances of the skin rashes have included, but are not 
restricted to, maculopapular exanthema, urticarial and targetoid lesions. 
No patients in the FIH study had any clinical evidence of either mucosal or systemic / 
organ involvement.
Paraffin embedded H&E staining of two separate skin biopsies from two different AL 
amyloidosis subjects in the FIH study have been obtained. The first subject received a 
total dose of anti-SAP mAb of 600mg on their first treatment. Their skin biopsy showed 
an active leucocytoclastic vasculitis (LCV) with migration of circulating neutrophils into 
the dermal small vessel wall and extravascular tissues with morphological evidence of 
apoptosis. There was no evidence of fibrinoid change or necrosis and there was also very 
little red cell extravasation with very few eosinophils present. The second subject 
received a total dose of anti-SAP mAb of 1000mg on their second treatment session. This 
biopsy showed basket-weave keratosis with epidermal thinning, mild diffuse spongiosis 
with focal vacuolar-interface change, and a mild to moderately dense superficial and mid 
perivascular predominantly lymphocytic inflammatory cell infiltrate with neutrophils and 
neutrophilic debris. No definitive conclusion was reached by the reporting dermato-
pathologist for this skin biopsy sample, but the described morphological changes could 
be consistant with a lymphocytic vasculitis/LCV.
While not definitive these changes are consistent with anti-SAP mAb mediated activation 
of the complement pathway leading to neutrophilic inflammation. Such a 
pathophysiological process is consistent with the observed onset of the rash at the peak 
concentration of anti-SAP mAb and that the most severe case was associated with the 
highest measured concentrations of mAb. 
Alternative explanations have also been considered. 
SAP is also present in microfibrillar mantle of elastic fibres throughout the body and also 
in the lamina rara interna of the glomerulus basement membrane (GBM).  Binding of 
anti-SAP mAb to SAP in these locations could lead to local inflammation. It is possible 
this process could be confined to the skin, but widespread organ toxicity would also be 
expected and this has not been observed to date.


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Amyloid deposits are also present in the skin and the rash could represent the therapeutic 
removal of cutaneous amyloid deposits. Removal of amyloid in other organs has not been 
associated with persistent inflammation and the limited biopsy evidence is also not 
consistent with this process.
12.3.2.
Investigation of rash
Rash is an event of special interest (EOSI) and will undergo comprehensive assessment 
as outlined in Table 8. The assessments performed may be refined as data emerges.
Table 8
Investigation of rash
Investigation
Timing/Procedure
Proposed tests
EOSI form
Rash onset and at least 
every 12 hours until 
resolution or study 
investigator satisfied that 
clinically stable
Formal questionnaire to record rash 
progression/resolution including patient 
assessment of symptoms
Includes assessment of systemic involvement
Photographs
Rash onset and during 
evolution
Photographs from all sites will be reviewed
centrally. 
Skin biopsy
(3-4mm punch)
Biopsy at rash onset may 
also include an unaffected 
area for comparison. To be 
taken as soon as possible 
after rash onset
Consider repeat biopsy if 
rash worsens 
Follow-up biopsy from a rash 
affected region when active 
lesions fully clinically 
resolved 
Up to 10 subjects (5 ATTR 
patients, 5 AL patients) who 
consent to this procedure, 
will be invited to have a 
baseline (pre treatment) 
biopsy to provide a 
comparison
In the event of recurrent 
clinically similar rash in the 
same subject repeat biopsy 
may be omitted
Biopsies will be processed as detailed in the 
SRM
Biopsies will be examined for:
Light microscopy
Congo Red staining and examination under 
polarised light for amyloid
SAP
Immunohistochemistry for cell activation and 
differentiation markers
Immunoglobulins and complement factors
This list is not exhaustive and may be 
modified based on observations


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Investigation
Timing/Procedure
Proposed tests
Blood samples
Paired with each skin biopsy
Multiplex ELISA for blood cytokines, CRP, 
SAA, detection of circulating mAb-SAP 
immune complexes using C1q assays
Fluid phase complement markers: e.g. C3dg / 
total C3 ratio, C3a, C5a, C4a & C5b-C9 (TCC)
ANA; ANCA; anti-DS-DNA antibody
RNA transcriptomic research
Blood renal and liver function tests (if not 
already assessed per routine schedule)
This list is not exhaustive and may be 
modified based on observations
Urinalysis
Rash onset and evolution
Assessment of urine sediment for evidence of 
glomerulonephritis
Protein excretion
12.3.3.
Management of Rash
Rash will be graded using the following criteria based on symptoms and the body surface 
area (BSA) affected [Table 9].
Table 9
Grading criteria for rash 
Rash Grade
Distribution/Symptoms
Action
1
<10% BSA AND 
asymptomatic
Dermatology reviewc before patient 
discharge if rash persists 7 days post-
mAb dose
2
10-30% BSA and/or mild 
symptomsa
Dermatology reviewc before patient 
discharge if rash persists 7 days post-
mAb dose
3
>30% BSA and/or 
moderate/severe symptomsa
Local dermatology reviewc to be performed 
as soon as possible after rash onset, but 
must be performed within 72 hours
4
Any rash with mucosal or 
systemic involvementb
Immediate dermatology review 
Withdraw from study treatment. 
See specific advice Section 12.3.4
a.
Symptoms include: pain, itch and burning
b.
E.g. evidence of renal involvement
c.
In addition, at the discretion of the Investigator or designee a telemedicine review of rash photos and general rash 
management advice from remote dermatologist may be requested


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Dermatological review should also be sought if a persistent rash worsens.
Symptomatic management of mild/moderate rash should be under the direction of the 
Investigator with expert dermatological advice as appropriate. Initial management of 
rashes could include, but is not restricted to, use of emollients, topical corticosteroids and 
antihistamines.
12.3.3.1.
Modification of anti-SAP mAb dose based on rash
In the event that rash appears following the first day’s infusion of anti-SAP mAb the 
following algorithm should be followed [Figure 6]. 
Figure 6
Intra-dosing Management Plan for Rash
Day 1
Day 2
Day 3 (prior to 
dosing)
Day 3
Administer first 
portion of anti-
SAP mAb dose
e.g. 600 mg
Assess for Rash
No rash 
attributable to 
anti-SAP mAb
Proceed with 
dosing second 
portion of anti-
SAP mAb dose 
(e.g. 600 mg)
Rash attributable 
to anti-SAP mAb
Do NOT 
administer anti-
SAP mAb
The decision whether to proceed with further Anti-SAP treatments and the dose level for 
anti-SAP mAb will be based on the severity and persistence of any rash observed.  


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Figure 7
Dosing algorithm for Anti-SAP mAb according to severity of rash
Maximum grade of rash
1
2
3
4
All subjects to be reviewed prior to each Anti-SAP treatment. 
If rash persistent then 
review weekly for 
resolution of rash.
Next Anti-SAP treatment 
can be administered once 
rash resolved.
Anti-SAP mAb dose level 
same as previously 
administered
If rash not resolved by 8 
weeks post last mAb dose 
withdraw from study
If rash persistent then review weekly for resolution of 
rash.
Next Anti-SAP treatment can be administered once rash 
resolved but at reduced dose
If rash not resolved by 8 weeks post last mAb dose 
withdraw from study treatment
Reduce dose by 300 mg from previous dose.  Dose 
levels = 900 mg, 600 mg, 300 mg 
Note: If a dose reduction is required following Session 1, 
then the Session 2 mAb dose level will be 300mg.
If grade 2 or 3 rash observed at 300 mg dose level 
withdraw from study treatment
Follow emergency 
management plan
Withdraw from study
When a dose reduction is warranted the dose of anti-SAP mAb to be administered on 
subsequent treatment session should be modified as outlined in Section 6.2
12.3.4.
Emergency management of rash with systemic /mucosal 
involvement
Severe (Grade 4) rash, with systemic or mucosal involvement is a medical emergency.
An immediate consultation for consideration of transfer of care to high dependency or 
intensive care unit should also be undertaken.
Immediate expert dermatology review should be undertaken.
The subject should be withdrawn from the study and not receive any further anti-SAP 
mAb treatment however CPHPC should continue to be administered to Day 11 whenever 
feasible. 
The GSK medical monitor should be contacted as soon as possible.
The management is largely supportive and should be directed by local expert advice.
At this time there is insufficient information to recommend specific treatment but 
corticosteroids are commonly administered for severe rash with systemic/ mucosal 
involvement.
12.3.5.
Post-Inflammatory Hyperpigmentation (PIH) 
PIH is a recognised chronic complication of acute skin inflammation, and can take weeks 
to months to completely resolve dependent upon the skin layer which is principally 
involved.PIH will be reported separately from rash 


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12.4.
Appendix 4: Genetic Research
Genetics – Background
Naturally occurring genetic variation may contribute to inter-individual variability in 
response to medicines, as well as an individual's risk of developing specific diseases. 
Genetic factors associated with disease characteristics may also be associated with 
response to therapy, and could help to explain some clinical study outcomes. For 
example, genetic variants associated with age-related macular degeneration (AMD) are 
reported to account for much of the risk for the condition [Gorin, 2012] with certain 
variants reported to influence treatment response [Chen, 2012]. Thus, knowledge of the 
genetic aetiology of disease may better inform understanding of disease and the 
development of medicines. Additionally, genetic variability may impact the 
pharmacokinetics (absorption, distribution, metabolism, and elimination), or 
pharmacodynamics (relationship between concentration and pharmacologic effects or the 
time course of pharmacologic effects) of a specific medicine and/or clinical outcomes 
(efficacy and/or safety) observed in a clinical study.
Genetic Research Objectives and Analyses

The objectives of the genetic research are to investigate the relationship between 
genetic variants and: Response to anti-SAP treatment, including any regimens 
under investigation in this study or any concomitant medicines. Response includes 
pharmacokinetics, efficacy and safety/tolerability (e.g. skin rash)

Susceptibility, severity and progression of cardiac amyloidosis and related 
conditions
Genetic data may be generated while the study is underway or following completion of 
the study.  Genetic evaluations may include focused candidate gene approaches and/or 
examination of a large number of genetic variants throughout the genome (e.g. whole 
genome analyses). Genetic analyses will utilize data collected in the study and will be 
limited to understanding the objectives highlighted above. Analyses may be performed 
using data from multiple clinical studies to investigate these research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the study can participate in genetic research. 
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 


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identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.  

A 6 mL blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
A blood sample is collected at the baseline visit and provided informed consent 
for genetic research. Instructions for collection and shipping of the genetic sample 
are described in the laboratory manual. The DNA from the blood sample may 
undergo quality control analyses to confirm the integrity of the sample. If there 
are concerns regarding the quality of the sample, then the sample may be 
destroyed. The blood sample is taken on a single occasion unless a duplicate 
sample is required due to an inability to utilize the original sample.  
The genetic sample is labelled (or “coded”) with the same study specific number used to 
label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study, or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
study.  Genetic informed consent must be obtained prior to any blood being taken.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA 
sample is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 


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Genotype data may be generated during the study or after completion of the study and 
may be analyzed during the study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not been 
analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the study, then the investigator should 
instruct the subject that their genetic sample will be destroyed. No forms are required to 
complete this process as it will be completed as part of the consent and sample 
reconciliation process.  In this instance a sample destruction form will not be available to 
include in the site files.
Provision of Study Results and Confidentiality of Subject’s Genetic Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.
References
Chen H, Yu KD, Xu GZ. Association between Variant Y402H in Age-Related Macular 
Degeneration (AMD) Susceptibility Gene CFH and Treatment Response of AMD: A 
Meta-Analysis. PloS ONE 2012; 7: e42464
Gorin MB. Genetic insights into age-related macular degeneration: Controversies 
addressing risk, causality, and therapeutics. Mol. Asp. Med. 2012; 33:467-486.


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12.5.
Appendix 5: Definition of and Procedures for Recording, 
Evaluating, Follow-Up and Reporting of Adverse Events
12.5.1.
Definition of Adverse Events
Adverse Event Definition:

An AE is any untoward medical occurrence in a patient or clinical investigation 
subject, temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.

NOTE: An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.
Events meeting AE definition include:

Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements), including those that worsen from baseline, and felt to be clinically 
significant in the medical and scientific judgement of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-
harming intent.  This should be reported regardless of sequelae).

Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE.  However, the signs and symptoms and/or clinical 
sequelae resulting from lack of efficacy will be reported if they fulfil the definition 
of an AE or SAE.
Events NOT meeting definition of an AE include:

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 subject’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 subject’s 


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Events NOT meeting definition of an AE include:
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
12.5.2.
Definition of Serious Adverse Events
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease, etc).
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, 
at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
subject was at risk of death at the time of the event.  It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:

In general, hospitalization signifies that the subject 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 out-patient setting.  Complications that occur during hospitalization are 
AEs.  If a complication prolongs hospitalization or fulfils 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.

Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity
NOTE:

The term disability means a substantial disruption of a person’s ability to conduct 


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normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhoea, influenza, 
and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday 
life functions but do not constitute a substantial disruption
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether 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 subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.  These should also be considered 
serious.

Examples of such events are 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
g.
Is associated with liver injury and impaired liver function defined as:

ALT 3xULN and total bilirubin* 2xULN (>35% direct), or

ALT 3xULN and INR** > 1.5.
* Serum bilirubin fractionation should be performed if testing is available; if unavailable, 
measure urinary bilirubin via dipstick.  If fractionation is unavailable and ALT 3xULN 
and total bilirubin 2xULN, then the event is still to be reported as an SAE.
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants.  If INR measurement is obtained, the value is to be 
recorded on the SAE form.
h.
Grade 4 rash

Refer to Appendix 2 for the required liver chemistry follow-up instructions
12.5.3.
Definition of Cardiovascular Events
Cardiovascular Events (CV) Definition:
Investigators will be required to fill out the specific CV event page of the CRF for the 
following AEs and SAEs:

Myocardial infarction/unstable angina

Congestive heart failure


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Cardiovascular Events (CV) Definition:

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
12.5.4.
Recording of AEs and SAEs
AEs and SAE Recording:

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) 
relative to the event.

The investigator will then record all relevant information regarding an AE/SAE in 
the CRF

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GSK in lieu of completion of the GSK, AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by GSK.  In this instance, all subject identifiers, with the exception of the 
subject number, will be blinded on the copies of the medical records prior to 
submission of to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms.

Subject-completed Value Evidence and Outcomes questionnaires and the collection 
of AE data are independent components of the study.

Responses to each question in the Value Evidence and Outcomes questionnaire will 
be treated in accordance with standard scoring and statistical procedures detailed by 
the scale’s developer.

The use of a single question from a multidimensional health survey to designate a 
cause-effect relationship to an AE is inappropriate.


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12.5.5.
Evaluating AEs and SAEs
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and will assign it to one of the following categories:

Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities.

Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities

Severe:  An event that prevents normal everyday activities. - an AE that is assessed 
as severe will not be confused with an SAE. Severity is a category utilized for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least one of the pre-defined 
outcomes as described in the definition of an SAE.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
the occurrence of each AE/SAE.

A "reasonable possibility" is meant to convey that there are facts/evidence or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled 
out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as natural history of the underlying diseases, concomitant 
therapy, other risk factors, and the temporal relationship of the event to the study 
treatment will be considered and investigated.

The investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in the determination of 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 when an SAE has occurred and the investigator has minimal 
information to include in the initial report to GSK.  However, it is very important 
that the investigator always make an assessment of causality for every event 
prior to the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information, amending the SAE data collection tool accordingly.

The causality assessment is one of the criteria used when determining regulatory 
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 may be indicated or as requested by GSK to 
elucidate as fully as possible the nature and/or causality of the AE or SAE.

The investigator is obligated to assist.  This may include additional laboratory tests 
or investigations, histopathological examinations or consultation with other health 
care professionals.

If a subject dies during participation in the study or during a recognized follow-up 
period, the investigator will provide GSK with a copy of any post-mortem findings, 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to GSK within the designated 
reporting time frames.
12.5.6.
Reporting of SAEs to GSK
SAE reporting to GSK via electronic data collection tool

Primary mechanism for reporting SAEs to GSK will be the electronic data collection 
tool

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and e-mail in portable document format (PDF) to 
both the primary and secondary medical monitors (details on the medical monitor / 
sponsor contact information page of this protocol), and also to GSK’s case 
management group mailbox 
 

Site will enter the serious adverse event data into the electronic system as soon as it 
becomes available.

The investigator will be required to confirm review of the SAE causality by ticking 
the ‘reviewed’ box at the bottom of the eCRF page within 72 hours of submission of 
the SAE.

After the study is completed at a given site, the electronic data collection tool (e.g., 
InForm system) will be taken off-line to prevent the entry of new data or changes to 
existing data

If a site receives a report of a new SAE from a study subject or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, the site can report this information on a paper SAE form or to the medical 
monitor by telephone.

Contacts for SAE receipt can be found at the beginning of this protocol on the 
Sponsor/Medical Monitor Contact Information page.
PPD


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12.6.
Appendix 6: Collection of Pregnancy Information
12.6.1.
Modified List of Highly Effective Methods for Avoiding Pregnancy 
in Females of Reproductive Potential (FRP)
The list does not apply to FRP with same sex partners or for subjects who are and will 
continue to be abstinent from penile-vaginal intercourse on a long term and persistent 
basis, when this is their preferred and usual lifestyle. Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.
1.
Contraceptive subdermal implant
2.
Intrauterine device or intrauterine system
3.
Combined estrogen and progestogen oral contraceptive [Hatcher, 2011]
4.
Injectable progestogen [Hatcher, 2011]
5.
Contraceptive vaginal ring [Hatcher, 2011]
6.
Percutaneous contraceptive patches [Hatcher, 2011]
7.
Male partner sterilization with documentation of azoospermia prior to the female 
subject's entry into the study, and this male is the sole partner for that subject 
[Hatcher, 2011]. The documentation on male sterility can come from the site 
personnel’s: review of subject’s medical records, medical examination and/or semen 
analysis, or medical history interview provided by her or her partner.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
Contraceptive requirements for male subjects with female partners of reproductive 
potential (when applicable).
Male subjects with female partners of child bearing potential must comply with the 
following contraception requirements from the time of first dose of study medication 
until [at least five half-lives of study medication OR for a cycle of spermatogenesis 
following five terminal half-lives] after the last dose of study medication.
1.
Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s: review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview.
2.
Male condom plus partner use of one of the contraceptive options below that meets 
the SOP effectiveness criteria including a <1% rate of failure per year, as stated in 
the product label:

Contraceptive subdermal implant

Intrauterine device or intrauterine system

Combined estrogen and progestogen oral contraceptive [Hatcher, 2011] 


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
Injectable progestogen [Hatcher, 2011]

Contraceptive vaginal ring [Hatcher, 2011]

Percutaneous contraceptive patches [Hatcher, 2011]
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring that subjects understand how to properly use these methods of contraception.
12.6.2.
Collection of Pregnancy Information

Investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study

Information will be recorded on the appropriate form and submitted to GSK within 2 
weeks of learning of a subject's pregnancy.

Subject will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow up information on mother and infant, which will be 
forwarded to GSK.  Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. 

Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy will be reported as an AE or 
SAE.

A spontaneous abortion is always considered to be an SAE and will be reported as 
such.

Any SAE occurring as a result of a post-study pregnancy which is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK 
as described in Appendix 5. While the investigator is not obligated to actively seek 
this information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating 

will be withdrawn from the study treatment study


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12.6.3.
Pregnancy in female partner of a male study subject

Investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study.  

After obtaining the necessary signed informed consent from the female partner 
directly, the investigator will record pregnancy information on the appropriate form 
and submit it to GSK within 2 weeks of learning of the partner’s pregnancy

Partner will also be followed to determine the outcome of the pregnancy.  
Information on the status of the mother and child will be forwarded to GSK. 

Generally, follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date.  Any termination of the pregnancy will be reported regardless of foetal 
status (presence or absence of anomalies) or indication for procedure.
References
Hatcher RA, Trussell J, Nelson AL, Cates W Jr, Stewart F, Kowal D, Policar MS, 
editors. Contraceptive Technology. 20th edition. Atlanta, Georgia: Ardent Media, Inc., 
2011: 50. Table 3-2.


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12.7.
Appendix 7: Reference tables
Table 10
Haematologic Response to Chemotherapy
Criteria
Response
Complete Response - CR
Normalization of the free light chain levels and ratio, negative 
serum and urine immunofixation
Very Good partial Response  - VGPR
Reduction in the dFLC to o40 mg/L
Partial Response - PR
A greater than 50% reduction in the dFLC
No Response
Less than PR
[Comenzo, 2012]
Table 11
Mayo stage and prognosis in AL amyloidosis
Stage 
I 
II 
IIIa 
IIIb
Both markers 
below 
threshold 
Either greater than 
threshold 
Both greater than 
threshold
BNP≤ 8500 ng/L
Both greater than 
threshold
BNP> 8500 ng/L
Survival @24 
months
Approx 100% 
60%
60%
30%
Proportion of 
patients
18%
33%
29%
20%
Thresholds for cTnT and NT-proBNP are < 0.035 µg/L and < 332 ng/L, respectively [Palladini,
2015]
Equation 1
4-variable MDRD formulafor estimated glomerular filtration rate 
(eGFR)
If serum creatinine (SCr) in μmol/L
eGFR= 186.3 x (SCr/88.4)-1.154 x (age, y)-0.203 x (0.742 if female) x (1.21 if black)
If SCr in mg/dL:
eGFR = 186.3 x (SCr)-1.154 x (age, y)-0.203 x 1.212 (if black) x 0.742 (if female).  
Note: ethnic group only has adjustment for African/African American; age is in years


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Classification- for groups
Table 12
New York Heart Association (NYHA) Classification
Patient Symptoms
I
No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, 
palpitation, dyspnea (shortness of breath).
II
Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in 
fatigue, palpitation, dyspnea (shortness of breath).
III
Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity 
causes fatigue, palpitation, or dyspnea.
IV
Unable to carry on any physical activity without discomfort. Symptoms of heart failure at 
rest. If any physical activity is undertaken, discomfort increases.
References
Comenzo RL, Reece D, Palladini et al. Consensus guidelines for the conduct and 
reporting of clinical trials in systemic light-chain amyloidosis. Leukemia. 
2012;26(11):2317-25
Palladini G, Sachchithanantham S, Milani P et al.A European collaborative study of 
cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL 
amyloidosis. Blood. 2015 30;126(5):612-5


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12.8.
Appendix 8: Protocol Amendments
Amendment 1
Where the Amendment Applies
Throughout the protocol
Summary of Amendment Changes 
Changes made to reflect regulatory input from the FDA. Other changes made to correct 
minor errors included in the original version.
List of Specific Changes
Medical Monitor / Sponsor Information Page
RATIONALE FOR CHANGE
Update to Primary Medical Monitor contact details and a change in Secondary Medical 
Monitor.
PREVIOUS TEXT
Primary Medical 
Monitor 
GlaxoSmithKline
Medicines
Research &
Development,
Gunnels Wood
Road, 
Stevenage
SG1 2NY United
Kingdom
Secondary Medical 
Monitor
GlaxoSmithKline
Clinical Unit
Cambridge
Addenbrooke’s
Hospital
Box 128, Hills
Rd,
Cambridge CB2
2GG
United Kingdom
REVISED TEXT
PPD


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Primary 
Medical 
Monitor 
GlaxoSmithKline
Medicines
Research &
Development,
Gunnels Wood
Road, 
Stevenage
SG1 2NY United
Kingdom
Secondary 
Medical 
Monitor
GlaxoSmithKline
Clinical Unit
Cambridge
Addenbrooke’s
Hospital
Box 128, Hills
Rd,
Cambridge CB2
2GG
United Kingdom
Protocol Synopsis, Objectives and Endpoints
RATIONALE FOR CHANGE
Inclusion of objective and endpoint to investigate subject experience of study treatment.
REVISED TEXT
To characterise the subject experience of 
Anti-SAP Treatment regimen
Subject Exit Interviews completed over 
the telephone after the 8 week follow-up 
or Early Withdrawal Visit
Protocol Synopsis, Treatment Groups and Duration
RATIONALE FOR CHANGE
Correction of unit.
PREVIOUS TEXT
PPD


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Group 3: Newly diagnosed Mayo stage II or IIIa AL amyloidosis patients, and with 
plasma NT-proBNP levels 8500 ng/mL 
REVISED TEXT
Group 3: Newly diagnosed Mayo stage II or IIIa AL amyloidosis patients, and with 
plasma NT-proBNP levels 8500 ng/mL
Protocol Synopsis, Treatment Groups and Duration
RATIONALE FOR CHANGE
Clarification that the regulatory agencies will be involved in the decision to start 
recruitment into Group 3.
PREVIOUS TEXT
Recruitment into Group 3 will only be initiated after data has been reviewed and an 
acceptable cardiac and systemic safety profile for Anti-SAP treatment has been 
demonstrated. 
REVISED TEXT
Recruitment into Group 3 will only be initiated after data has been reviewed and an 
acceptable cardiac and systemic safety profile for Anti-SAP treatment has been 
demonstrated and following review by regulatory agencies.
Protocol Synopsis, Analysis
RATIONALE FOR CHANGE
Clarification that regulatory agency interactions may follow a data review.
PREVIOUS TEXT
Study specific decisions will be supported by the periodic review of study data.  The first 
review will take place once 5 subjects have completed at least 3 courses of Anti-SAP 
treatment.  Outcomes from the periodic data reviews may include:

Initiation of recruitment in to Group 3 
REVISED TEXT


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Study specific decisions will be supported by the periodic review of study data.  The first 
review will take place once 5 subjects have completed at least 3 courses of Anti-SAP 
treatment.  Outcomes from the periodic data reviews may include:

Regulatory interactions and initiation of recruitment in to Group 3 
3.Objectives and Endpoints
RATIONALE FOR CHANGE
Inclusion of objective and endpoint to investigate subject experience of study treatment.
PREVIOUS TEXT
None
REVISED TEXT
To characterise the subject experience of 
Anti-SAP Treatment regimen
Subject Exit Interviews completed over 
the telephone after the 8 week follow-up 
or Early Withdrawal Visit
4.1 Overall Design
RATIONALE FOR CHANGE
Inclusion of statement to restrict the number of subjects on active treatment at each site at 
any given time.
PREVIOUS TEXT
Subjects will return to clinic for long term follow-up of safety and functional status 
(including CMR and ECHO), 6 and 12 months post last anti-SAP mAb treatment.
REVISED TEXT
Subjects will return to clinic for long term follow-up of safety and functional status 
(including CMR and ECHO), 6 and 12 months post last anti-SAP mAb treatment.
No more than two subjects will be in active treatment (dosing) at each study site at 
any given time.  


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4.1 Overall Design, Figure 2
RATIONALE FOR CHANGE
Increase in the duration of the combined screening and baseline period due to 
requirement of 2 week cardiac assessment at baseline.
PREVIOUS TEXT
28 days
REVISED TEXT
28 42 days
4.1 Overall Design, Table 1 (Day 4-11)
RATIONALE FOR CHANGE
Removal of allowance to self-administer CPHPC.
PREVIOUS TEXT
Inpatient safety follow up
Administration of CPHPC SC continues until Day 11
[Subjects may be allowed to self administer SC CPHPC as outpatients at investigators’ 
discretion]
REVISED TEXT
Inpatient safety follow up
Administration of CPHPC SC continues until Day 11
[Subjects may be allowed to self administer SC CPHPC as outpatients at investigators’ 
discretion]
Protocol Synopsis, Objectives and Endpoints, Table 1 (Day 17)
RATIONALE FOR CHANGE
Removal of 1 day window around visit.
PREVIOUS TEXT
17 1d


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REVISED TEXT
17 1d
4.2  Treatment Groups and Duration
RATIONALE FOR CHANGE
Correction of unit.
PREVIOUS TEXT
Group 3: Newly diagnosed Mayo stage II or IIIa AL amyloidosis patients (plasma 
NT-proBNP levels 8500 ng/mL) 
-----------------------------------------------------------------------------------------------------------
Group 1 and Group 2 will begin recruitment first. Recruitment into Group 3 will start 
only after data has been reviewed as detailed in Section 10.8.2. 
REVISED TEXT
Group 3: Newly diagnosed Mayo stage II or IIIa AL amyloidosis patients (plasma 
NT-proBNP levels 8500 ng/mL)
-----------------------------------------------------------------------------------------------------------
Group 1 and Group 2 will begin recruitment first. Recruitment into Group 3 will start 
only after data has been reviewed and regulatory interaction sought as detailed in 
Section 10.8.2. 
4.5.1  GSK2315698 (CPHPC - Plasma SAP Depleter)
RATIONALE FOR CHANGE
To clarify that the circulating SAP level of 2mg/L from the FIH (SAP115570) study was 
determined using a Hycult ELISA assay.
PREVIOUS TEXT
In the FIH study (SAP115570), the standard dosing regimen of CPHPC consisted of an 
IV infusion of 20 mg/hour for 72 hours prior to anti-SAP mAb administration. This 
regimen was reliably effective in depleting circulating SAP to <2 mg/L. Since there is no 
precedent for the present treatment, this empirical target SAP concentration was adopted 
on the basis of evaluation of the potential for formation of harmful circulating immune 


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complexes and safety evaluation in the FIH study did not identify signals suggestive of 
adverse effects from residual SAP. 
REVISED TEXT
In the FIH study (SAP115570), the standard dosing regimen of CPHPC consisted of an 
IV infusion of 20 mg/hour for 72 hours prior to anti-SAP mAb administration. This 
regimen was reliably effective in depleting circulating SAP to <2 mg/L (using Hycult 
ELISA assay). Since there is no precedent for the present treatment, this empirical target 
SAP concentration was adopted on the basis of evaluation of the potential for formation 
of harmful circulating immune complexes and safety evaluation in the FIH study did not 
identify signals suggestive of adverse effects from residual SAP. 
4.5.2 GSK2398852 (anti-SAP mAb)
RATIONALE FOR CHANGE
To reduce the dose given in Session 1 to 600mg. The dose planned for the other sessions 
(1200mg) remains unchanged. 
PREVIOUS TEXT
The anti-SAP mAb dose in this study is 1200 mg in each monthly cycle, given as two 
infusions over 6-8 hour each, on Days 1 and 3.  The dose and regimen is based on the 
results of the FIH study (SAP115570), and has been selected to promote rapid 
elimination of amyloid deposits whilst minimising adverse effects.
------------------------------------------------------------------------------------------------------
Although doses up to 2000 mg were well tolerated in those with a large (hepatic) amyloid 
load, much of the target patient population for this phase 2 study will have a small to 
moderate amyloid load. The dose response information from the FIH study in those with 
renal amyloidosis (also a small/moderate load population) show that a dose level of 600 
mg is effective in about one third of the subjects treated but at a dose level of 1200 mg 
the response rate is substantially higher (>80%).  It is recognized that while the dose of 
1200 mg is associated with a high rate of amyloid clearance, it is also associated with 
rash which has been severe in one case. At this time the most likely causes of the rash are 
related to the peak concentration of the anti-SAP mAb. For this reason the anti-SAP mAb 
dose in this study will be split: administered as two infusions (duration of 6-8hr) of 600 
mg on Days 1 and 3. This will have the effect of blunting the maximum concentration
while maintaining a moderate concentration in the plasma for longer. This approach may
also enhance delivery of anti-SAP mAb to the heart. 
The risk of skin rashes will be mitigated by giving the anti-SAP mAb dose in two slowly 
infused 600 mg portions on days 1 and 3, with availability of a reduced dose schedule 
according to the safety assessment algorithm in Section 6.2. Emerging results will be 
reviewed regularly to enable dose reduction if necessary and to select the appropriate 
starting dose for Group 3.


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REVISED TEXT
The proposed starting dose level of anti-SAP mAb dose in this study is 600mg given as 
a divided dose of two infusions of 300 mg over 6-8 hours each on Days 1 and 3. This 
dose level and regimen is expected to be well tolerated based on previous experience 
and to be pharmacologically active in a proportion of patients (estimated to be 30% 
based on previous experience).
Dose escalation on subsequent sessions will be considered on a case by case basis 
based on tolerability and evidence of pharmacodynamic effect. It is proposed that 
the dose in subsequent treatment sessions will be maximally 1200 mg in each monthly
cycle, given as two infusions over 6-8 hours each, on Days 1 and 3.  The dose and 
regimen is based on the results of the FIH study (SAP115570), and has been selected to 
promote rapid elimination of amyloid deposits whilst minimising adverse effects.
Although doses up to 2000 mg were well tolerated in those with a large (hepatic) amyloid 
load, much of the target patient population for this phase 2 study will have a small to 
moderate amyloid load. The dose response information from the FIH study in those with 
renal amyloidosis (also a small/moderate load population) show that a dose level of 600 
mg is effective in about one third of the subjects treated but at a dose level of 1200 mg 
the response rate is substantially higher (>80%).  It is recognized that while the dose of 
1200 mg is associated with a high rate of amyloid clearance, it is also associated with 
rash which has been severe in one case. At this time the most likely causes of the rash are 
related to the peak concentration of the anti-SAP mAb. For this reason the anti-SAP mAb 
dose in this study will be split: administered as two infusions (duration of 6-8hr) of 600 
mg on Days 1 and 3. This will have the effect of blunting the maximum concentration 
while maintaining a moderate concentration in the plasma for longer. This approach may
also enhance delivery of anti-SAP mAb to the heart. 
The risk of skin rashes will be mitigated by giving the anti-SAP mAb dose in two slowly 
infused 600 mg portions on dDays 1 and 3, with availability of a reduced dose schedule 
according to the safety assessment algorithm in Section 6.2. Emerging results will be 
reviewed regularly to enable dose reduction if necessary and to select the appropriate 
starting dose for Group 3.
4.6.1.1 Potential For Cardiotoxicity
RATIONALE FOR CHANGE
Clarification that Baseline and Outpatient ECG analysis will be performed using
BodyGuardian.
PREVIOUS TEXT
The present study design therefore includes comprehensive assessment and monitoring 
designed specifically to detect and characterize these and any other adverse cardiac 
effects which may arise.  Baseline will include leadless non-implantable ECG analysis, 


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for example using ZioPatch, to provide the individual’s own control profile for any 
changes following treatment.  Monitoring during the study will comprise in-patient 
telemetry, out-patient leadless ECG analysis (e.g. ZioPatch) between treatment sessions, 
monthly ECHO & CMR imaging, and serial monitoring of cardiac blood biomarkers.  
Any adverse effects on cardiac function will thus be detected promptly, enabling swift 
and appropriate intervention and management.
REVISED TEXT
The present study design therefore includes comprehensive assessment and monitoring 
designed specifically to detect and characterize these and any other adverse cardiac 
effects which may arise.  Baseline will include leadless non-implantable ECG analysis, 
for example using ZioPatch BodyGuardian, to provide the individual’s own control 
profile for any changes following treatment.  Monitoring during the study will comprise 
in-patient telemetry, out-patient leadless ECG analysis (e.g. ZioPatch BodyGuardian) 
between treatment sessions, monthly ECHO & CMR imaging, and serial monitoring of 
cardiac blood biomarkers.  Any adverse effects on cardiac function will thus be detected 
promptly, enabling swift and appropriate intervention and management.
4.6.1.3 Potential for Circulating Immune Complex Formation
RATIONALE FOR CHANGE
To include that anti-SAP immune complex assessments will be performed in the event of 
a rash.
PREVIOUS TEXT
In order to mitigate this potential risk, blood samples for determination of SAP/anti-SAP 
mAb immune complexes will be taken from all subjects in this study as a safety 
measurement at the time-points specified in the Time & Events tables (Section 7.1). 
Timing of the assessments may be adjusted based on emerging data.
REVISED TEXT
In order to mitigate this potential risk, blood samples for determination of SAP/anti-SAP 
mAb immune complexes will be taken from all subjects in this study as a safety 
measurement at the time-points specified in the Time & Events tables (Section 7.1) and 
in the event of a rash. Timing of the assessments may be adjusted based on emerging 
data.


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4.6.2 Risk Assessment Table, Myocarditis / Cardiac remodelling associated with 
removal of amyloid
RATIONALE FOR CHANGE
Clarification that Baseline and Outpatient ECG analysis will be performed using Body 
Guardian and correction of assessment timepoints.
PREVIOUS TEXT
Non-implantable, ECG recording devices (e.g. ZioPatch) will be used to detect 
abnormalities in cardiac electrophysiology on discharge from in-patient stay and at 8-
week and 6 and 12 month follow-up
REVISED TEXT
Non-implantable, ECG recording devices (e.g. ZioPatch BodyGuardian) will be used to 
detect abnormalities in cardiac electrophysiology on discharge from in-patient stay and at 
8-week and 6- and 12 month follow-up
4.6.2 Risk Assessment Table, Epistaxis
RATIONALE FOR CHANGE
Clarification of the clinical mitigation strategy should epistaxis occur.
PREVIOUS TEXT
Baseline coagulation and serial blood haematology
Serial coagulation if epistaxis occurs.
REVISED TEXT
Serial blood haematology and bBaseline and session 1 post dose coagulation 
assessment. and serial blood haematology
Serial coagulation if epistaxis or other bleeding abnormalities occurs. If abnormalities 
are observed in coagulation tests, additional investigations including platelet 
function tests may be performed.


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4.6.2 Risk Assessment Table, Cytopenia
RATIONALE FOR CHANGE
Removal of Cytopenia risk from the risk assessment table as in vitro data demonstrates 
that GSK2315698 does not inhibit either Pgp or BCRP up to 300µM.
PREVIOUS TEXT
Although no observations in the preclinical and 
clinical use of GSK2315698, have shown any 
evidence of it mediating DDI effects, in silico 
modelling suggests that it could potentially 
inhibit PGP-1 & BRCP drug efflux transporters, 
thereby augmenting the cytopenic effects of 
cyclophosphamide within the CyBorD 
chemotherapy regimen
Serial blood haematology
REVISED TEXT
Although no observations in the preclinical and 
clinical use of GSK2315698, have shown any 
evidence of it mediating DDI effects, in silico 
modelling suggests that it could potentially 
inhibit PGP-1 & BRCP drug efflux transporters, 
thereby augmenting the cytopenic effects of 
cyclophosphamide within the CyBorD 
chemotherapy regimen
Serial blood haematology
5.1 Inclusion Criteria, Inclusion Criteria for Group 2 and Inclusion Criteria for 
Group 3 (same wording applies to inclusion criteria for both groups)
RATIONALE FOR CHANGE
To provide clarification regarding presence of any mutations in amyloidgenic genes will 
establish the eligibility criteria for this group. Once there is a positive identification of a 
mutation in an amyloidogenic gene then patients are not tested for all known mutations.
PREVIOUS TEXT
AL amyloidosis confirmed by biopsy with immunohistochemical staining or proteomic 
identification of AL amyloid fibril type, in subjects with definite monoclonal 
gammopathy in whom causative mutations of all known relevant amyloidogenic genes 
have been excluded


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REVISED TEXT
AL amyloidosis confirmed by biopsy with immunohistochemical staining or proteomic 
identification of AL amyloid fibril type, in subjects with definite monoclonal 
gammopathy in whom causative mutations of all known relevant amyloidogenic genes 
have been excluded
6.2.1 CPHPC dosing regimen according to renal function
RATIONALE FOR CHANGE
In SAP115570 (FIH) pharmacokinetic data from blood samples collected on the ninth 
day after antiSAP mAb administration the PK levels of antiSAP mAb were below the 
target and therefore dose of CPHPC is not required following the morning dose on Day 
11 (ninth day after antiSAP mAb administration). Additional column showing the dose 
regimen on Day 11 is added to indicate only the morning dose on Day 11 is required.
PREVIOUS TEXT
Renal Function
IV dose level
SC dose regimen
Time points of SC administration
eGFRa
(mL/min/1.73m2)
Day 1b
1st mAb dose per 
treatment session
Subsequent days
(Days 2-11)
64
20mg/hour
60 mg t.i.d 
14:00, 22:00
08:00, 14:00, 22:00
46 and < 64
10mg/hour
60 mg t.i.d 
14:00, 22:00
08:00, 14:00, 22:00
39 and < 46
10mg/hour
60 mg b.i.d 
21:00
09:00, 21:00
33 and < 39
5mg/hour
60 mg b.i.d
21:00
09:00, 21:00
27 and < 33
5mg/hour
60 mg o.d
-
09:00
REVISED TEXT
Renal Function
IV dose 
level
SC dose 
regimen
Time points of SC administration
eGFRa
(mL/min/1.73m2)
Day 1b
1st mAb dose 
per treatment 
session
Subsequent days
(Days 2-110)
Subsequent day
(Day 11)
64
20mg/hour
60 mg t.i.d 
14:00, 22:00
08:00, 14:00, 22:00
08:00
46 and < 64
10mg/hour
60 mg t.i.d 
14:00, 22:00
08:00, 14:00, 22:00
08:00
39 and < 46
10mg/hour
60 mg b.i.d 
21:00
09:00, 21:00
09:00
33 and < 39
5mg/hour
60 mg b.i.d
21:00
09:00, 21:00
09:00
27 and < 33
5mg/hour
60 mg o.d
-
09:00
09:00


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6.2.2 Dose-Level reduction Schedule for anti-SAP mAb due to Adverse Events
RATIONALE FOR CHANGE
To provide clarification of the composition of doses of antiSAP mAb  in any dose 
reduction and information on dose level reduction with the introduction of Session 1 total 
dose of 600mg.
PREVIOUS TEXT
Reductions in dose level are at the discretion of the Investigator in consultation with the 
GSK study team during the dose confirmation meeting, and can be triggered based upon 
the intensity of the adverse event (AE) which is observed during any treatment session 
and is reasonably attributable to anti-SAP mAb. (See Figure 4)
a) First dose reduction will be to 900 mg 
b) Second dose reduction to 600mg 
c) Third dose reduction to 300mg 
No further dose modifications will be permitted below the 300mg dose level.
REVISED TEXT
Reductions in dose level are at the discretion of the Investigator in consultation with the 
GSK study team during the dose confirmation meeting, and can be triggered based upon 
the intensity of the adverse event (AE) which is observed during any treatment session 
and is reasonably attributable to anti-SAP mAb. (See Figure 4). The recommended dose 
reduction scheme is provided in Figure 4 although greater than 300 mg reductions 
would be allowed based on clinical tolerability.
1. First dose reduction will be to 900 mg (300mg on D1, 600mg on D3)
2. Second dose reduction to 600mg (300mg on D1, 300mg on D3)
3. Third dose reduction to 300mg (150mg on D1, 150mg on D3)
No further dose modifications will be permitted below the 300mg dose level.
Note: If a dose reduction is required following Session 1, then the Session 2 mAb 
dose level will be 300mg (‘c’ in the above list).
Study Treatment, Preparation/Handling/Storage/Accountability
RATIONALE FOR CHANGE
Removal of text discussing subjects' self-administration of CPHPC as this option is no 
longer applicable.


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REVISED TEXT

If required the subjects may self-administer treatment by sub-cutaneous injection 
of CPHPC if discharged from clinical unit prior to completion of administration. 
Subjects will receive training on sub-cutaneous injection prior to discharge and 
will only be discharged if the PI considers they are competent to administer.
6.6 Compliance with Study Treatment Administration
RATIONALE FOR CHANGE
Removal of text discussing subjects' self-administration of CPHPC as this option is no 
longer applicable.
PREVIOUS TEXT
When subjects are dosed at the site, they will receive study treatment directly from the 
Investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
When subjects self-administer study treatment(s) at home, compliance with CPHPC will 
be assessed through querying the subject during the site visits and documented in the 
source documents and CRF.  A record of the number of vials/syringes dispensed to and 
taken by each subject must be maintained and reconciled with study treatment and 
compliance records.  Treatment start and stop dates, including dates for treatment delays 
and/or dose reductions will also be recorded in the CRF.
REVISED TEXT
When sSubjects will be dosed at the site, they and will receive study treatment directly 
from the Investigator or designee, under medical supervision.  The date and time of each 
dose administered in the clinic will be recorded in the source documents.  The dose of 
study treatment and study subject identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study 
treatment.  
When subjects self-administer study treatment(s) at home, compliance with CPHPC will 
be assessed through querying the subject during the site visits and documented in the 
source documents and CRF.  A record of the number of vials/syringes dispensed to and 
taken by each subject must be maintained and reconciled with study treatment and 
compliance records.  Treatment start and stop dates, including dates for treatment delays 
and/or dose reductions will also be recorded in the CRF.


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7.1 Time and Events Table, Table 3
RATIONALE FOR CHANGE
To include timepoints / clarification not included in the previous version of the protocol, 
and to include edits made as part of the current amendment
REVISED TEXT

Outpatient visit added at Session 1, ‘Day 24’

Haematology/Clinical Chemistry/Urinalysis added at all Sessions ‘Day-2 to 11’

24hr Urine collection for protein and creatinine added at 6 month Follow-up visit

Inclusion of an Exit interview at 8 week Follow-up visit

Edit to Footnote ‘1’ to state screening to take place within 42 days of start of 
treatment

Edit to Footnote ‘7’ to include that out-patient cardiac recording will be for 
approximately 2 weeks at both the 8 week and 6 month follow-up timepoints in 
addition to baseline

Addition of Footnote ‘13’ (For subjects with a GFR <40ml/min/1.73m2,  MRI will 
be performed at the scheduled times but without contrast)

Addition of Footnote ‘14’ (Subjects are allowed to be admitted on Day -3 to allow 
for pre-dose assessments to be performed)

Addition of lines for ‘Concomitant therapy’ and Adverse event review’
7.1 Time and Events Table, Table 4
RATIONALE FOR CHANGE
To include timepoints / clarification not included in the previous version of the protocol, 
and to include edits made as part of the current amendment
REVISED TEXT

Edit to Footnote 3 to replace SAP levels being ‘below 2mg/L’ with being ‘below 
target’

Addition of Footnote ‘12’ to state that ‘Morning dose only to be administered (see 
Table 2)’ on Day 11

Addition of Footnote ‘13’ (Subjects are allowed to be admitted on Day -3 to allow 
for pre-dose assessments to be performed)
7.1 Time and Events Table, Table 5
RATIONALE FOR CHANGE
To include timepoints / clarification not included in the previous version of the protocol, 
and to include edits made as part of the current amendment


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REVISED TEXT

Addition of ‘of that day’ to Footnote ‘5’ to clarify reference of blood sampling 
times

Addition of Footnote ‘8’ (To include clotting tests for Session 1 only – see Table 
6)
7.4.7.2 Cardiac Recording
RATIONALE FOR CHANGE
Ziopatch device will not be used in this study. Text is amended to provide the example of 
'BodyGuardian' may be used as a cardiac recording device, and that baseline assessment 
of cardiac recording will be up to 2 weeks.
PREVIOUS TEXT
The type of device will be at the discretion of the Study site and might include, but is not 
restricted to, use of a ZioPatch or Cardio-Net device.
The recording will be analysed prior to the next anti-SAP treatment and the analysis 
reviewed by the Investigator.
Following confirmation of eligibility, a baseline assessment for two weeks will be 
performed to provide baseline data. Whenever feasible the same device as that used at 
baseline will be used for subsequent measures.
REVISED TEXT
The type of device will be at the discretion of the Study site and might include, but is not 
restricted to, use of a ZioPatch BodyGuardian or Cardio-Net device.
The recording will be analysed prior to the next anti-SAP treatment and the analysis 
reviewed by the Investigator.
Following confirmation of eligibility, a baseline assessment for up to two weeks will be 
performed to provide baseline data. Whenever feasible the same device as that used at 
baseline will be used for subsequent measures.
7.4.8 Clinical Safety Laboratory Assessments
RATIONALE FOR CHANGE
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PREVIOUS TEXT
Study-required laboratory assessments will be performed by a central laboratory. Where 
applicable some laboratory assessments will be performed by a local laboratory. 
The results of each test must be entered into the CRF.
REVISED TEXT
Study-required clinical safety laboratory assessments will be performed by a central
local laboratory. All other Where applicable some laboratory assessments will be 
performed by a local central laboratory. The results of each test must be entered into the 
CRF.
7.4.8 Protocol Required Safety Laboratory Assessments (Table 6)
RATIONALE FOR CHANGE
To include PT and APTT on Session 1, Day 2 in order to assess clotting function. To 
include clotting tests and, if required platelet function tests as investigation of adverse 
bleeding events.
REVISED TEXT
Further Tests 
(Session 1, 
Day 2 only)

Clotting tests – PT and APTT
Investigation 
of adverse 
bleeding 
event

Clotting tests – PT and APTT

Platelet function tests (at discretion of Investigator or designee)
7.5.1 Blood Sample Collection
RATIONALE FOR CHANGE
Correction of individual blood sample collection volumes. Total maximum blood volume 
collected per session remains unchanged. 
PREVIOUS TEXT
3mL of blood will be collected into ethylenediaminetetraacetic acid (EDTA) tubes.
REVISED TEXT
3mL 2ml of blood will be collected into ethylenediaminetetraacetic acid (EDTA) tubes.


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7.6.1 Pharmacodynamic markers in blood
RATIONALE FOR CHANGE
Correction of individual blood sample collection volumes. Total maximum blood volume 
collected per session remains unchanged. 
PREVIOUS TEXT
A 3mL blood sample will be collected at the time points as per Section 7.1, Time and 
Events Tables 
REVISED TEXT
A 3mL 4mL blood sample will be collected at the time points as per Section 7.1, Time 
and Events Tables
7.6.3.2 RNA Transcriptome Research
RATIONALE FOR CHANGE
Correction of individual blood sample collection volumes. Total maximum blood volume 
collected per session remains unchanged. 
PREVIOUS TEXT
A 0.5mL blood sample will be collected and the same samples may also be used to 
confirm findings by application of alternative technologies
REVISED TEXT
A 0.5mL 2.5mL blood sample will be collected and the same samples may also be used 
to confirm findings by application of alternative technologies
7.7.2 Immune complexes
RATIONALE FOR CHANGE
Correction of individual blood sample collection volumes. Total maximum blood volume 
collected per session remains unchanged. 
PREVIOUS TEXT
0.5mL blood samples for determination of SAP/anti-SAP mAb immune complexes will 
be taken as a safety measurement at the time-points specified in the Time & Events tables 


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(Section 7.1) and Table 8. Timing of the assessments may be adjusted based on emerging 
data.
REVISED TEXT
0.5 4mL blood samples for determination of SAP/anti-SAP mAb immune complexes will 
be taken as a safety measurement at the time-points specified in the Time & Events tables 
(Section 7.1) and Table 8. Timing of the assessments may be adjusted based on emerging 
data.
7.10 Exit Interview
RATIONALE FOR CHANGE
Exit Interviews are added to better understand the patient perspective of systemic 
amyloidosis, to characterize patient experience and treatment benefit with Anti-SAP
treatment, and to better understand patient involvement in the clinical trial. The output of 
this research will be used to understand the impact of the treatment as well as inform the 
design and endpoints for future clinical studies from the patient perspective.
REVISED TEXT
7.10 Exit Interview 
Exit interviews will be conducted after the 8 week follow-up or Early Withdrawal 
Visit and over the telephone, in a subset of subjects only, to explore subjects’ 
experience with study treatment. Exit interviews are qualitative interviews 
conducted with study subjects to capture subject experiences in drug development 
on completion of participation in a clinical study. Interview questions are designed
to fully assess a subject’s experience with a study medication and study 
requirements and are administered in a semi-structured format over the telephone 
by a trained interviewer independent of study sites and sponsor. Subject feedback 
will be captured in a data collection sheet as well as being audio-taped for 
subsequent transcription and qualitative analysis and reported separately. The Exit 
interview technique and questions will be described in the SRM.
9.3.2 Interim Analysis
RATIONALE FOR CHANGE
Clarification that regulatory agency interactions may follow a data review.
PREVIOUS TEXT

Initiation of recruitment in to Group 3 


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REVISED TEXT

Regulatory interactions and initiation of recruitment in to Group 3 
10.8.1 Individual Subject Review
RATIONALE FOR CHANGE
To state that a benefit / risk assessment will make up part of the individual subject review
PREVIOUS TEXT
The purpose of this review is to consider:

whether it is appropriate to continue with Anti-SAP treatment in that subject, and

the dose level for anti-SAP mAb
REVISED TEXT
The purpose of this review is to consider:

whether it is appropriate to continue with Anti-SAP treatment in that subject 
based on a benefit / risk assessment, and

the dose level for anti-SAP mAb
10.8.2 Periodic Study Review
RATIONALE FOR CHANGE
To include a statement that regulatory agency review of safety information will be 
conducted prior to commencement of recruitment into Group 3 
PREVIOUS TEXT

Whether the schedule and timing of assessments are appropriate based on the 
observed safety profile

Whether sufficient information is available to start recruitment of Group 3

The Sponsor will be responsible for the final decision on the schedule of 
assessments and trigger point for recruitment into Group 3


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REVISED TEXT

Whether the schedule and timing of assessments are appropriate based on the 
observed safety profile

Whether sufficient information is available to start recruitment of Group 3
The Sponsor will be responsible for the final decision on the schedule of 
assessments and identifying the trigger point for recruitment into Group 3. 
Recruitment into Group 3 will not start until a review of available safety 
information has been conducted by regulatory agency. The Sponsor will be 
responsible for the final decision on the schedule of assessments and trigger point for 
recruitment into Group 3
Trademark Information
RATIONALE FOR CHANGE
To update the trademark part of the protocol to accurately reflect changes made in the 
current amendment.
PREVIOUS TEXT
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Cardio-Net
Chiron RIBA
SAS
WinNonlin
ZioPatch
REVISED TEXT
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Cardio-Net
Chiron RIBA
SAS
WinNonlin
ZioPatch BodyGuardian


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Appendix 3, Investigation of Rash, Table 3 (skin biopsies)
RATIONALE FOR CHANGE
To provide clarification that from the 10 subjects who provide a baseline biopsy, 5 of 
these will be ATTR patients and the other 5 will be AL patients
PREVIOUS TEXT
Up to 10 subjects will be invited to have a baseline (pre treatment) biopsy to provide a 
comparison
REVISED TEXT
Up to 10 subjects (5 ATTR patients, 5 AL patients) who consent to this procedure, 
will be invited to have a baseline (pre treatment) biopsy to provide a comparison
Appendix 3, Investigation of Rash, Table 3 (Blood samples)
RATIONALE FOR CHANGE
Correction of typographical error and inclusion of test not listed in previous version of 
protocol
PREVIOUS TEXT
Paired with each skin biopsy
Multiplex ELISA for blood cytokines, CRP, 
SAA, detection of circulating mAb-SAP 
immune complexes using C1q assays
Fluid phase complement markers: C3dg / total 
C3 ratio, C3a, C5a, C4a & C5b-C9 (TCC)
ANA; ANCA; anti-DS-DNA antibody
Blood renal and liver function tests (if not 
already assessed per routine schedule)
This list is not exhaustive and may be 
modified based on observations


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REVISED TEXT
Paired with each 
skin biopsy
Multiplex ELISA for blood cytokines, CRP, SAA, detection of circulating mAb-
SAP immune complexes using C1q assays
Fluid phase complement markers: e.g. C3dg / total C3 ratio, C3a, C5a, C4a 
& C5b-C9 (TCC)
ANA; ANCA; anti-DS-DNA antibody
RNA transcriptomic research
Blood renal and liver function tests (if not already assessed per routine 
schedule)
This list is not exhaustive and may be modified based on observations
Appendix 3, Figure 7
RATIONALE FOR CHANGE
Inclusion of text regarding dose reduction following Session 1
PREVIOUS TEXT
Maximum grade of rash
1
2
3
4
All subjects to be reviewed prior to each Anti-SAP treatment. 
If rash persistent then 
review weekly for 
resolution of rash.
Next Anti-SAP treatment 
can be administered once 
rash resolved.
Anti-SAP mAb dose level 
same as previously 
administered
If rash not resolved by 8 
weeks post last mAb dose 
withdraw from study
If rash persistent then review weekly for resolution of 
rash.
Next Anti-SAP treatment can be administered once rash 
resolved but at reduced dose
If rash not resolved by 8 weeks post last mAb dose 
withdraw from study treatment
Reduce dose by 300 mg from previous dose.  Dose 
levels = 900 mg, 600 mg, 300 mg 
If grade 2 or 3 rash observed at 300 mg dose level 
withdraw from study treatment
Follow emergency 
management plan
Withdraw from study
REVISED TEXT
Maximum grade of rash
1
2
3
4
All subjects to be reviewed prior to each Anti-SAP treatment. 
If rash persistent then 
review weekly for 
resolution of rash.
Next Anti-SAP treatment 
If rash persistent then review weekly for resolution of 
rash.
Next Anti-SAP treatment can be administered once rash 
Follow emergency 
management plan
Withdraw from study


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can be administered once 
rash resolved.
Anti-SAP mAb dose level 
same as previously 
administered
If rash not resolved by 8 
weeks post last mAb dose 
withdraw from study
resolved but at reduced dose
If rash not resolved by 8 weeks post last mAb dose 
withdraw from study treatment
Reduce dose by 300 mg from previous dose.  Dose 
levels = 900 mg, 600 mg, 300 mg 
Note: If a dose reduction is required following 
Session 1, then the Session 2 mAb dose level will be 
300mg.
If grade 2 or 3 rash observed at 300 mg dose level 
withdraw from study treatment
Appendix 5, Reporting of SAEs to GSK
RATIONALE FOR CHANGE
Clarification of the process by which sites should inform GSK of SAE should the 
electronic data collection tool be unavailable
PREVIOUS TEXT

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the medical monitor
REVISED TEXT

If the electronic system is unavailable for greater than 24 hours, the site will use the 
paper SAE data collection tool and fax it to the medical monitor e-mail in portable 
document format (PDF) to both the primary and secondary medical monitors 
(details on the medical monitor / sponsor contact information page of this 
protocol), and also to GSK’s case management group mailbox 
Section 11, References
RATIONALE FOR CHANGE
Inclusion of Reference
REVISED TEXT
Saris-Baglama. User’s Manual for the SF-36v2 Health Survey, Second Edition, 2007, 
Chapter 7, pages 81-84.
PPD


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Amendment 2
Where the Amendment Applies
Global
Summary of Amendment Changes 
Regulatory input from the FDA on clarifying requirements for recruitment. 
Define plasma SAP depletion target level of <3 mg/L.
Inclusion criterion for LVmass updated for Groups 2 and 3 to reflect the AL patient 
population 
Reflect regulatory safety update information for Gadolinium contrast agents.
Dermatology review timings adjusted for grade 3 rash incidence.
Other changes made for clarity and to correct minor typographical errors.
List of Specific Changes
4.1 Overall Design
RATIONALE FOR CHANGE
FDA feedback has clarified the intention is to limit enrolment to 2 subjects at each site 
per month.
PREVIOUS TEXT
No more than two subjects will be in active treatment (dosing) at each study site at any 
given time.  
REVISED TEXT
No more than two subjects will be in active treatment session 1 (up to Day 24) (dosing)
at each study site at any given time.  
4.5.1 GSK2315698 (CPHPC - Plasma SAP Depleter)
RATIONALE FOR CHANGE
The antiSAP mAb interferes with the Hycult SAP ELISA assay that was used in previous 
clinical studies at GSK and so that assay cannot be used in this study once the antiSAP 
mAb has been administered. An alternative Meso Scale Discovery (MSD) immunoassay 
for the measurement of SAP has been developed by GSK. The target concentration of 
SAP measured by the Hycult assay was <2 mg/L before administration of anti-SAP mAb. 
Based on the re-calibration the equivalent target using the MSD assay is <3 mg/L. This is 


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considered to provide clinical comparability with the target applied in a previous study 
[SAP115570] which was well tolerated in human subjects in that study
also
Correction of typographical error.
PREVIOUS TEXT
This regimen was reliably effective in depleting circulating SAP to <2 mg/L (using 
Hycult ELISA assay).
also
Blood SAP concentration will be checked after 24 hours of administration of CPHPC to 
confirm administration of anti-SAP mAb on the next day to.
REVISED TEXT
This regimen was reliably effective in depleting circulating SAP to <2 mg/L (using a
Hycult ELISA assay). The current study is using a MSD assay and due to difference 
in SAP concentration scale between the assay types, a SAP concentration of <3 mg/L 
will be the target plasma SAP depletion level in this study).
also
Blood SAP concentration will be checked after 24 hours of administration of CPHPC to 
confirm administration of anti-SAP mAb on the next day to.
4.6.2
Risk Assessment Table (CMR Contrast Agent - gadolinium)
RATIONALE FOR CHANGE
MHRA have issued restrictions on gadolinium-containing contrast agents due to the 
association of higher retention of gadolinium in the brain with linear 
gadolinium-containing contrast agents. Section 7.6.2.1. details that the macrocyclic 
agents gadoteric acid, gadoteridol, and gadobutrol are to be used in this study, these 
accepted agents are added to the mitigation strategy for risk in the table in Section 4.6.2.
for clarity.


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PREVIOUS TEXT
Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
CMR Contrast Agent - gadolinium (Gd) 
Delayed excretion and 
tissue accumulation of 
gadolinium contrast agent 
after repeated contrast 
CMR scans
Gadolinium is mostly excreted in the urine and this is 
impaired in subjects with reduced renal function. Patients 
with systemic AL amyloidosis very often have renal 
amyloid and impaired renal function while cardiac ATTR 
patients are all elderly and therefore may also have non-
amyloid chronic kidney disease.  All these individuals are 
therefore at increased risk of Gd accumulation.
FDA have issued an alert for tissue accumulation of Gd in 
organs including the brain following its repeated use, 
including some patients with normal renal function, 
although no new neurological complications have been 
reported to date
Exclusion of patients with GFR < 40 mLs/min 
GFR will be checked prior to each Gd contrast CMR and if 
GFR is <40mL/min then CMR without Gd contrast will be 
performed
Gd contrast CMR will be performed at five scheduled visits 
over the 18 month study period
Other CMR scans will be without Gd contrast
REVISED TEXT


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
CMR Contrast Agent - gadolinium (Gd) 
Delayed excretion and 
tissue accumulation of 
gadolinium contrast agent 
after repeated contrast 
CMR scans
Gadolinium is mostly excreted in the urine and this is 
impaired in subjects with reduced renal function. Patients 
with systemic AL amyloidosis very often have renal 
amyloid and impaired renal function while cardiac ATTR 
patients are all elderly and therefore may also have non-
amyloid chronic kidney disease.  All these individuals are 
therefore at increased risk of Gd accumulation.
FDA and MHRA have issued an alert for tissue 
accumulation of Gd in organs including the brain following 
its repeated use, including some patients with normal renal 
function, although no new neurological complications have 
been reported to date
Exclusion of patients with GFR < 40 mLs/min 
GFR will be checked prior to each Gd contrast CMR and if 
GFR is <40mL/min then CMR without Gd contrast will be 
performed
Gd contrast CMR will be performed at five scheduled visits 
over the 18 month study period
Other CMR scans will be without Gd contrast
Gd contrast agents for this study are gadoteric acid, 
gadoteridol, and gadobutrol


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5.1 Inclusion Criteria
RATIONALE FOR CHANGE
In contrast to ATTR patients, an LVmass measure on CMR of >200g is markedly less 
common in cardiac AL patients and would therefore impede recruitment. Review of 
historical data indicates that the LVmass for these patients is generally lower than that for 
ATTR patients. The new LVmass inclusion criterion for AL patients in Groups 2 and 3 
considers the published literature [Fontana; 2015], and does not impact the sample size 
assumptions made in Section 9.2.1.
PREVIOUS TEXT
OTHER
4. Late-Gadolinum enhancement (LGE) on CMR indicative of cardiac amyloidosis
5. LVmass on CMR > 200 g 
REVISED TEXT
OTHER
4. Late-Gadolinum enhancement (LGE) on CMR indicative of cardiac amyloidosis
5. LVmass on CMR > 200 g 
and subsequent re-numbering of list
Inclusion Criteria for Group 1
[1] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
6. LVmass on CMR > 200 g
and subsequent re-numbering of list
Inclusion Criteria for Group 2
[1] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
11. LV mass on CMR > 150 g
and subsequent re-numbering of list


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Inclusion Criteria for Group 3
[1] TYPE OF SUBJECT AND DIAGNOSIS INCLUDING DISEASE SEVERITY 
15. LV mass on CMR > 150 g 
and subsequent re-numbering of list
5.5 
Subject Withdrawal Procedures
RATIONALE FOR CHANGE
Inclusion of section to detail procedures to follow should a subject be withdrawn from the 
study after enrolment
REVISED TEXT
Subjects withdrawn following one or more administrations of mAb should follow 
the procedures at the 8 week follow-up visit shown in the Time and Events Table.
Subjects withdrawn following administration of CPHPC but no administration of 
anti SAP mAb should follow the procedures at the 8 week follow-up visit shown in 
the Time and Events Table, with the exception of: Blood sampling for anti-SAP 
mAb, Cardiac MRI, ECHO, 99mTC-DPD / PYP scans (Group 1 only), SAP Scan 
(Groups 2 & 3, UK only) or out-patient cardiac monitoring.
6.2 
Table 2 CPHPC dosing regimen according to renal function
RATIONALE FOR CHANGE
Additional text in Footnote to clarify CPHPC dosing requirements should a change in 
eGFR occur during a treatment session.
PREVIOUS TEXT
eGFR determined by MDRD must be used to define CPHPC dose based on renal 
function.
REVISED TEXT
eGFR determined by MDRD must be used to define CPHPC dose based on renal 
function. The most recent eGFR value available at the time of the pharmacy 
prescription being prepared will be used to determine the CPHPC dosing 
requirement for the treatment session. Should subsequent eGFR results within that 
treatment session show a change in eGFR, the CPHPC dosing requirement will not 
be altered as a result. Changes to eGFR which the Investigator considers to be a 
safety concern should be discussed with the Medical Monitor.


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6.8 
Treatment after the End of the Study
RATIONALE FOR CHANGE
Correction of typographical error
PREVIOUS TEXT
Given the lack information about the safety and efficacy of Anti-SAP treatment in AL 
and ATTR-CM, treatment will not be provided after the end of the study. This may be 
reviewed once more information is available
REVISED TEXT
Given the lack of information about the safety and efficacy of Anti-SAP treatment in AL 
and ATTR-CM, treatment will not be provided after the end of the study. This may be 
reviewed once more information is available.
6.10.1 
Permitted Medications and Non-Drug Therapies 
RATIONALE FOR CHANGE
Addition of text to allow for administration of prophylactic treatments.
REVISED TEXT
Prophylactic treatments for rash
If a rash and associated symptoms (e.g. pruritus) are experienced by a subject at a 
treatment session, during subsequent treatment sessions prophylactic treatment 
(any first and / or second generation H1 antihistamine) are permitted at discretion of 
Investigator or designee.
7.1 
Time and Events Table, Table 3 Overview of all groups
RATIONALE FOR CHANGE
Addition in clarification in footnote regarding physical examinations
also
Addition of clarification in footnote regarding 24hr urine collection timepoints.
PREVIOUS TEXT
Full examination at screening only, brief examination at all other time-points.


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also
24hr collection - 3.5ml serum biochemistry sample to be taken for creatinine 
measurements at time points where there are no corresponding clinical chemistry 
samples.
REVISED TEXT
Complete Full examination at screening only, brief examination at all other time-points.
Weight will be recorded at Baseline, D17 and D24. Abdominal girth will be recorded 
at Baseline.
also
24hr collection - 3.5ml serum biochemistry sample to be taken for creatinine 
measurements at time points where there are no corresponding clinical chemistry
samples.  Day indicated in Table represents the end of the 24hr collection period.
7.1 
Time and Events Table, Table 4
RATIONALE FOR CHANGE
Alteration to how Lead II telemetry is displayed in the table 
also
Extension of D-1 biopsy to include D-2
also
Addition of footnote relating to Brief Physical Examination to include weight and girth 
measurements during in patient stay.
also
Addition of Footnote 14 regarding physical examinations
PREVIOUS TEXT
24h collection - 3.5mL serum biochemistry sample to be taken for creatinine 
measurements at time points where there are no corresponding clinical chemistry 
samples.
REVISED TEXT
24h collection - 3.5mL serum biochemistry sample to be taken for creatinine 
measurements at time points where there are no corresponding clinical chemistry 


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samples. Day 6 represents the start of the collection period, Day 11 represents the 
end of the collection period. See Table 5 for details of Day 1-3.
also
Weight should be recorded on D-2, D5, D8 and D11. Abdominal girth should be 
recorded on D-2 and D11.
7.1 
Time and Events Table, Table 5 
RATIONALE FOR CHANGE
Alteration to how D2 times are represented in the table 
also
Alteration to how Lead II telemetry is displayed in the table 
also
Changes to footnote to clarify 24hr urine collection periods
also
Addition of footnote to clarify early assessment timings 
PREVIOUS TEXT
24h collection - 3.5mL serum biochemistry sample to be taken for creatinine 
measurements at time points where there are no corresponding clinical chemistry 
samples. 
REVISED TEXT
24h collection - 3.5mL serum biochemistry sample to be taken for creatinine 
measurements at time points where there are no corresponding clinical chemistry 
samples. Day indicated in the Table represents the start (pre-dose) of the 24hr 
collection period.
also
Time shown to indicate early in the day only – not a specific time. The collection of 
these should be timed with other pre-dose sample collection in order to minimise 
inconvenience and needle-sticks for the subjects.


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7.4.3 Physical Exams
RATIONALE FOR CHANGE
Additional assessments included during brief physical examination
PREVIOUS TEXT

A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).
REVISED TEXT

A brief physical examination will include, at a minimum assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). Weight and girth 
measurements will also be included at times stated in the Time and Events 
Table.
7.4.8 Clinical Safety Laboratory Assessments
RATIONALE FOR CHANGE
Clarification that Troponin measurements include those for High Sensitivity 
PREVIOUS TEXT

Troponin-T
REVISED TEXT

Troponin-T (including High Sensitivity)
11 
References
Addition of Fontana, M (2015) reference to support LV mass historical data
12.3.3 Management of Rash (Table 9, Rash Grade 3)
RATIONALE FOR CHANGE
Skin rashes to date have been reported as mild adverse events where the highest reported 
grade has been a grade 2 rash in one Group 1 subject; this was promptly resolved with the 
administration of oral steroids.
This prompt steroid sensitivity of the rash in the Group 1 subject is clinically typical for 
any urticarial vasculitis rash caused by an early leucocytoclastic mechanism, and is
consistent with the prompt rash resolution seen with the administration of oral steroids in 


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a cardiac AL amyloidosis subject treated with GSK2398852 in the first-in-human study 
(GSK study 115570).
On the emerging phase 2 study rash background, an advisory therapeutic algorithm for 
the management of skin rashes – which includes the use of steroids (either as ointments / 
creams / oral) and anti-histamines - has been developed. Detailed in the study reference 
manual (SRM).
Given the consistent pathological results of an early leucocytoclastic vasculitis on all skin 
biopsies, and the known steroid responsiveness of this type of skin vasculitis), relaxation 
of the timeframe for dermatologist 'face to face' review for grade 3 rash from 'within 24 
hours of rash onset' to 'within 72 hours' is considered to be acceptable from a safety 
perspective. The availability of telemedicine review of rash photographs and general rash 
management advice from external, remote dermatologist is added for sites to use at the 
discretion of the Investigator or designee.
PREVIOUS TEXT
Table 9 
Grading criteria for rash
Rash 
Grade Distribution/Symptoms
Action
1
<10% BSA AND 
asymptomatic
Dermatology review 
before patient discharge if 
rash persists 7 days 
post-mAb dose
2
10-30% BSA and/or mild 
symptomsa
Dermatology review 
before patient discharge if 
rash persists 7 days 
post-mAb dose
3
>30% BSA and/or 
moderate/severe 
symptomsa
Dermatology review within 
24 hours
4
Any rash with mucosal 
or systemic 
involvementb
Immediate dermatology
review 
Withdraw from study
treatment. 
See specific advice 
Section 12.3.4
a.
b.
Symptoms include: pain, itch and burning
c.
E.g. evidence of renal involvement
REVISED TEXT


2015N249732_02
CONFIDENTIAL
201464
156
Table 9 
Grading criteria for rash
Rash Grade
Distribution/Symptoms
Action
1
<10% BSA AND 
asymptomatic
Dermatology reviewc before patient 
discharge if rash persists 7 days post-
mAb dose
2
10-30% BSA and/or mild 
symptomsa
Dermatology reviewc before patient 
discharge if rash persists 7 days post-
mAb dose
3
>30% BSA and/or 
moderate/severe symptomsa
Local dermatology reviewc to be 
performed as soon as possible after 
rash onset, but must be performed
within 72 hours
4
Any rash with mucosal or 
systemic involvementb
Immediate dermatology review 
Withdraw from study treatment. 
See specific advice Section 12.3.4
a.
Symptoms include: pain, itch and burning
b.
E.g. evidence of renal involvement
c.
In addition, at the discretion of the Investigator or designee a telemedicine review of rash photos and 
general rash management advice from remote dermatologist may be requested

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
201464
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and analysis plan for a multiple treatment session, 
open label phase 2 clinical study of GSK2398852 
administered following and together with GSK2315698 in 
cohorts of patients with cardiac amyloidosis
Compound Number 
:
GSK2398852+GSK2315698
Effective Date 
:
01-MAY-2018
Description:

The purpose of this RAP is to describe the planned analyses and outputs to be 
included in the Clinical Study Report for Protocol 201464.

This RAP is intended to describe the efficacy, safety, pharmacokinetic, 
pharmacodynamic and biomarker analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Interim and Final Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval Method
20-APR-2018
Pharma TMF
Principal Statistician (Clinical Statistics)
20-APR-2018
Pharma TMF
Principal Statistician (Clinical Statistics)
Senior Director (Clinical Pharmacology 
Modelling and Simulation)
20-APR-2018
Pharma TMF
Director (Clinical Pharmacology Modelling and 
Simulation)
23-APR-2018
Pharma TMF
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
201464
2
RAP Team Approvals:
Approver
Date
Approval Method
01-MAY-2018
Pharma TMF
Physician Project Lead (Future Pipelines 
Discovery)
27-APR-2018
Pharma TMF
Clinical Investigation Lead (Future Pipelines 
Discovery)
20-APR-2018
Pharma TMF
Programming Manager (Clinical Programming)
24-APR-2018
Pharma TMF
Clinical Program Lead (CPSSO)
01-MAY-2018
Pharma TMF
Manager (CPSSO Data Management)
20-APR-2018
Pharma TMF
Physician Project Lead (Future Pipelines 
Discovery)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
23-APR-2018
Pharma TMF
Director (Clinical Statistics)
20-APR-2018
Pharma TMF
Programming Manager (Clinical Programming)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
201464
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................7
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses.................................................................................11
3.
PLANNED ANALYSES ..........................................................................................11
3.1.
Interim Analyses .........................................................................................11
3.2.
Final Analyses ............................................................................................14
4.
ANALYSIS POPULATIONS ...................................................................................14
4.1.
Protocol Deviations.....................................................................................15
4.2.
Standard of Care Population and Database................................................15
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................16
6.
STUDY POPULATION ANALYSES .......................................................................16
6.1.
Overview of Planned Analyses ...................................................................16
7.
PRIMARY STATISTICAL ANALYSES....................................................................17
7.1.
Pharmacodynamic Analyses (LV Mass Measured by CMR) .......................17
7.1.1.
Overview of Planned Pharmacodynamic Analyses (LV 
Mass Measured by CMR) ............................................................17
7.1.2.
Planned Pharmacodynamic Statistical Analyses (LV Mass 
Measured by CMR)......................................................................18
7.2.
Safety Analyses..........................................................................................25
7.2.1.
Overview of Planned Adverse Events Analyses...........................25
7.2.2.
Overview of Planned Clinical Laboratory Analyses ......................26
7.2.3.
Overview of Planned Other Safety Analyses................................27
8.
SECONDARY STATISTICAL ANALYSES .............................................................28
8.1.
Pharmacodynamic and biomarker analyses................................................28
8.1.1.
Overview of Planned Pharmacodynamic and Biomarker 
Analyses......................................................................................28
8.1.2.
Planned Pharmacodynamic and Biomarker Statistical 
Analyses......................................................................................30
8.2.
Immunogenicity Analyses ...........................................................................34
8.2.1.
Overview of Planned Immunogenicity Analyses...........................34
8.3.
Pharmacokinetic Analyses..........................................................................35
8.3.1.
Overview of Planned Pharmacokinetic Analyses .........................35
8.3.2.
Drug Concentration Measures .....................................................35
8.3.2.1.
Plasma concentration of GSK2315698.......................35
8.3.2.2.
Plasma concentration of GSK2398852.......................35
8.3.3.
Population Pharmacokinetic (PopPK) Analyses...........................36
8.3.3.1.
GSK2315698..............................................................36
8.3.3.2.
GSK2398852..............................................................36


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201464
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8.4.
Pharmacokinetic / Pharmacodynamic Analyses..........................................36
8.5.
Efficacy Analyses........................................................................................36
8.5.1.
Overview of Planned Efficacy Analyses .......................................36
8.6.
Quality of Life Analyses ..............................................................................37
8.6.1.
Overview of Planned Quality of Life Analyses..............................37
8.6.2.
MOS SF-36 Questionnaire...........................................................38
8.6.3.
KCCQ Questionnaire ...................................................................38
8.6.4.
EORTC QLQ C30 Questionnaire .................................................39
8.6.5.
DLQI questionnaire......................................................................40
8.7.
Exit Interviews ............................................................................................40
9.
REFERENCES.......................................................................................................41
10. APPENDICES........................................................................................................42
10.1.
Appendix 1: Time & Events.........................................................................43
10.1.1.
Protocol Defined Time & Events ..................................................43
10.2.
Appendix 2: Treatment States and Phases.................................................50
10.2.1.
Treatment Phases .......................................................................50
10.2.2.
Treatment Sessions.....................................................................50
10.2.3.
AE Onset Time and Duration .......................................................51
10.3.
Appendix 3: Data Display Standards & Handling Conventions....................52
10.3.1.
Study Treatment & Sub-group Display Descriptors......................52
10.3.2.
Baseline Definition & Derivations .................................................52
10.3.2.1.
Baseline Definitions....................................................52
10.3.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................52
10.3.3.
Derivation of MOS SF-36 Scores.................................................52
10.3.3.1.
Recoding of MOS SF-36 ............................................52
10.3.3.2.
Handling Missing MOS SF-36 Items...........................55
10.3.3.3.
Domain Scale Scores.................................................55
10.3.3.4.
Standardized Z Scores...............................................56
10.3.3.5.
Norm-based Domain Scores (NBS)............................56
10.3.3.6.
Physical and Mental Component Summaries 
(PCS and MCS)..........................................................56
10.3.4.
Derivation of KCCQ Scores .........................................................57
10.3.5.
Derivation of EORTC QLQ-C30 Scores.......................................61
10.3.5.1.
Scale definition and score derivation ..........................61
10.3.5.2.
Handling of missing items...........................................62
10.3.5.3.
SAS code examples ...................................................62
10.3.6.
Derivation of DLQI Scores ...........................................................63
10.3.6.1.
Scale definition and score derivation ..........................63
10.3.6.2.
Handling of missing items...........................................63
10.3.7.
Derivation of LGE variable ...........................................................64
10.3.8.
Derivation of DCE-CMR Global Measure of Myocardial 
Perfusion .....................................................................................64
10.3.9.
Reporting Process & Standards...................................................64
10.4.
Appendix 4: Derived and Transformed Data ...............................................66
10.4.1.
General........................................................................................66
10.4.2.
Study Population..........................................................................66
10.4.3.
Safety ..........................................................................................67
10.5.
Appendix 5: Premature Withdrawals & Handling of Missing Data ...............68
10.5.1.
Premature Withdrawals................................................................68


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201464
5
10.5.2.
Handling of Missing Data.............................................................68
10.5.2.1.
Handling of Missing/Partial Dates...............................68
10.5.2.2.
Handling of Missing Data for Statistical 
Analysis......................................................................69
10.6.
Appendix 6: Values of Potential Clinical Importance ...................................70
10.6.1.
Haematology Values of Potential Clinical Importance ..................70
10.6.1.1.
Study Group 1 ............................................................70
10.6.1.2.
Study Group 2 ............................................................70
10.6.1.3.
Study Group 3 ............................................................70
10.6.2.
Chemistry Values of Potential Clinical Importance.......................71
10.6.3.
Liver Function Test Values of Potential Clinical Importance.........71
10.6.4.
ECG Values and QTc Change of Potential Clinical 
Importance...................................................................................71
10.6.5.
Vital Sign Values and Changes of Potential Clinical 
Importance...................................................................................72
10.7.
Appendix 7: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................73
10.7.1.
Statistical Analysis Assumptions..................................................73
10.8.
Appendix 8: Population Pharmacokinetic Analyses.....................................74
10.8.1.
Systems.......................................................................................74
10.8.2.
Data Assembly.............................................................................74
10.8.3.
Population Pharmacokinetic Analysis for GSK2315698 ...............74
10.8.4.
Population Pharmacokinetic Analysis for GSK2398852 ...............74
10.8.5.
Reporting.....................................................................................75
10.8.6.
Specifications for NONMEM-specific Dataset (PK 
GSK2315698)..............................................................................75
10.8.7.
Specifications for NONMEM-specific Dataset (PK 
GSK2398852)..............................................................................77
10.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses ......................80
10.9.1.
Systems.......................................................................................80
10.9.2.
Data Assembly.............................................................................80
10.9.3.
Pharmacokinetic/Pharmacodynamic Analysis for plasma 
SAP Concentration ......................................................................80
10.9.4.
Reporting.....................................................................................80
10.9.5.
Specifications for NONMEM-specific Dataset (SAP)....................81
10.10. Appendix 10 – Abbreviations & Trade Marks ..............................................83
10.10.1. Abbreviations...............................................................................83
10.10.2. Trademarks .................................................................................85
10.11. Appendix 11: List of Data Displays..............................................................86
10.11.1. Data Display Numbering..............................................................86
10.11.2. Mock Example Shell Referencing ................................................86
10.11.3. Deliverable [Priority].....................................................................87
10.11.4. Study Population Tables..............................................................88
10.11.5. Pharmacodynamic and Biomarker Tables....................................90
10.11.6. Pharmacodynamic and Biomarker Figures ................................101
10.11.7. Safety Tables.............................................................................111
10.11.8. Safety Figures ...........................................................................114
10.11.9. Pharmacokinetic Tables.............................................................115
10.11.10.Pharmacokinetic Figures ...........................................................115
10.11.11.Efficacy Tables ..........................................................................117
10.11.12.Efficacy Figures .........................................................................117
10.11.13.Quality of Life Tables .................................................................118


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10.11.14.ICH Listings ...............................................................................118
10.11.15.Non-ICH Listings........................................................................122
10.12. Appendix 12: Example Mock Shells for Data Displays ..............................124


CONFIDENTIAL
201464
7
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol:
Revision Chronology:
2015N249732_00
09-MAY-2016
Original
2015N249732_01
20-APR-2017
Changes made to reflect regulatory input from the FDA. Other 
changes made to correct minor errors included in the original 
version.
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
Pharmacokinetic (PK) parameters for GSK2398852 will be derived based on a population 
PK model rather than descriptively summarized. The sparse sampling schedule is 
unlikely to allow reliable estimation of the parameters by descriptive summary.
There are no other changes or deviations to the originally planned statistical analysis 
specified in study protocol amendment 1 (Dated: 20-APR-2016).
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints
Assessment of reduction in cardiac 
amyloid load after repeated 
administrations of Anti-SAP 
treatment as evaluated by CMR in 
all study groups
Change in left ventricular (LV) mass over time 
from baseline to 8-week post-treatment follow-up
Assessment of safety & tolerability 
of repeated administration of Anti-
SAP treatment, including 
compatibility with chemotherapy 
treatment in Group 3
Clinical safety data from adverse events (AEs), 
clinical laboratory tests, vital signs, 12-lead 
electrocardiogram (ECG), cardiac monitoring and 
ECHO to 8-week post-treatment follow-up
Incidence and grading of skin rashes classified 
using the Common Terminology Criteria for 
Adverse Events (CTCAE)


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201464
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Objectives
Endpoints
Secondary Objectives
Secondary Endpoints
Investigation of rash associated 
with Anti-SAP treatment
Histopathological & immunohistochemical 
examination of skin biopsies + blood biomarkers 
(as data permit)
Characterisation of the 
pharmacokinetics of anti-SAP mAb
PK parameters including the maximum 
concentration (Cmax), the time associated with 
Cmax (tmax), and the area under the concentration-
time profile (AUC).
Assessment of changes in 
circulating markers associated with 
pharmacodynamic effect during 
repeated administrations
Circulating biomarkers including but not limited to 
complement pathway components, acute phase 
proteins (e.g. CRP, SAA) and cytokines (e.g. IL6, 
IL8, IL10, TNF).
Evaluation of changes in imaging 
markers of cardiac dysfunction 
monitored by serial CMR and / or 
ECHO.
Change in cardiac functional measures, including, 
but not limited to strain (e.g. global longitudinal 
strain [GLS]), LV twist, stroke volume (SV), 
ejection fraction (EF), end diastolic volume (EDV) 
& E/e’ ratio over time from baseline to 8 week 
post-treatment follow-up
Exploratory Objectives
Exploratory Endpoints
To assess the reduction in cardiac 
amyloid load after repeated 
administrations of Anti-SAP 
treatment as evaluated by CMR in 
all study groups
Change in cardiac ECV over time from baseline to 
8-week post-treatment follow-up
Assessment of effects of Anti-SAP
treatment on individual subject
quality of life
Change in individual subject quality of life as 
measured by the MOS SF-36, KCCQ, DLQI and 
EORTC QLQ 30 questionnaires over time from 
baseline to 8-week post-treatment follow-up
Assessment of clinical cardiac 
functional improvement
Change in 6 minute walk test (6MWT) distance 
(Groups 1 and 2) from baseline to 8-week post-
treatment follow-up
Change in N-terminal pro b-type Natriuretic 
Peptide (NT-proBNP) from baseline to 8-week
post-treatment follow-up
Assessment of reduction in cardiac 
uptake of radioisotope bone tracers 
(Group 1 only)
Change in 99mTc-DPD or 99mTc-PYP uptake
from baseline to 8-week post-treatment follow-up.


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201464
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Objectives
Endpoints
Assessment of change in amyloid 
load on SAP scan (Groups 2 & 3 
only and where SAP scan 
available)
Change in overall body load and in affected organs 
(excluding cardiac load) on SAP scan assessment 
from baseline to 8-week post-treatment follow-up
Assess the correlation between 
circulating biomarkers and 
structural and functional CMR 
measures
Circulating biomarkers (e.g. cardiac – NT proBNP 
and high-sensitivity (hs) Troponin-T, cytokines) 
over time
Structural, Functional, and Tissue Characterization 
CMR measures over time, as data permit
Evaluate changes in imaging 
markers of cardiac structure as 
monitored by serial CMR and / or 
ECHO imaging
Change in cardiac structural measures, including, 
but not limited to LV wall thickness (CMR and/or, 
ECHO), and LV mass (ECHO) over time from 
baseline to 8-week post-treatment follow-up
Evaluate changes in imaging 
markers of cardiac tissue 
characterization as monitored by 
serial CMR
Change in cardiac tissue characterization measures, 
including, but not limited to late gadolinium 
enhancement (LGE), native T1 and ECV, over time 
from baseline to 8-week post-treatment follow-up
Assess the correlation between 
myocardial perfusion using CMR 
and cardiac structural, functional, 
and tissue characterization as 
measured by CMR and/or ECHO
Dynamic contrast enhanced (DCE)-CMR
measuring myocardial vascular perfusion and 
structural, functional, and tissue characterization 
measures (CMR and/or ECHO), as data permit
Assessment of the immunogenicity 
of anti-SAP mAb when co-
administered with CPHPC.
Measurement of anti-drug antibodies before and 
after treatment with anti-SAP mAb (baseline and 8-
week post-treatment follow-up)
To characterise the subject 
experience of Anti-SAP Treatment 
regimen
Subject Exit Interviews completed over the 
telephone after the 8 week follow-up or Early 
Withdrawal Visit


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201464
10
Objectives
Endpoints
Long term follow-up Objectives
Long term follow-up Endpoints
Assessment of long term safety at 6 
and 12 months post last anti-SAP 
mAb dose
Clinical safety data from adverse events (AEs), 
clinical laboratory tests, vital signs,12-lead ECG, 
cardiac monitoring and ECHO
Assessment of Anti-SAP 
Treatment outcomes at 6 and 12 
months post last anti-SAP mAb 
dose
Long term changes in LV mass over time up to 12-
month post-treatment follow-up
Long term changes in imaging markers from CMR 
and / or ECHO over time up to 12-month post-
treatment follow-up (as per 8-week follow-up)
Long term changes in NT-proBNP over time up to 
12 month post-treatment follow-up
Long term changes in 6MWT distance over time up 
to 12-month post-treatment follow-up (Groups 1 
and 2).
Measurement of anti-drug antibodies (6 and 12 
month post-treatment follow-up)
2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

Open label, non-randomised, three-group, monthly repeat Anti-SAP 
treatment study in systemic amyloidosis subjects with cardiac dysfunction 
caused by cardiac amyloidosis.

The three groups are:
o
Group 1: Cardiac TTR subjects
o
Group 2: Post-chemotherapy AL amyloidosis subjects
o
Group 3: Newly diagnosed Mayo stage II or IIIa AL amyloidosis 
subjects with cardiac dysfunction

Group 1 and Group 2 will begin recruitment in parallel. Recruitment into 
Group 3 will only be initiated after data has been reviewed and an 
acceptable cardiac and systemic safety profile for Anti-SAP treatment has 
been demonstrated and following review by regulatory agencies.

A minimum of 10 subjects per group will be recruited initially. Additional 
subjects may be enrolled in each of the 3 groups based on emerging data. 

Subjects will be required to participate in up to six Anti-SAP treatment 
sessions receiving anti-SAP mAb at monthly intervals. Anti-SAP treatment 
consists of CPHPC followed by anti-SAP mAb.


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201464
11
Overview of Study Design and Key Features

Within a given treatment session, anti-SAP mAb will be given as two 6-8 
hour infusions, on Day 1 and Day 3. CPHPC administration will consist of 
intravenous (IV) infusion for 48 to 72 hours prior to anti-SAP mAb 
administration, followed by CPHPC sub-cutaneous (SC) injections for 11 
days after the start of anti-SAP mAb administration.
Dosing

Details of dosing regimens and considerations for dosing adjustments are 
described in Section 4.5 of the protocol.
Treatment 
Assignment

Repeated administrations of Anti SAP treatment on a monthly schedule for 
up to 6 courses for subjects in all 3 groups. 
Interim 
Analysis

Interim analyses will take place according to the triggering rules described in 
Table 1 and their content will follow the analysis selections given in Table 2.

Further details can be found in Section 3.1
2.4.
Statistical Hypotheses
No formal hypothesis will be tested.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
Data will be reviewed on an ongoing basis throughout the study, including but not limited 
to, safety, imaging, PK, PD, clinical, biomarker data.
Study specific decisions will be supported by the periodic review of study data, as 
described in Section 10.8.2 of the protocol. 
Interim analyses will take place as described in Table 1. In the event that an interim 
analysis is not required anymore, this will be documented by the study team prior to the 
interim analysis. 
A selection of RAP analyses will be provided at each interim analysis, depending on the 
number of subjects available and the number of cohorts concerned, as per Table 2. Study 
data included as part of the interim selection will be cleaned prior to analysis.


CONFIDENTIAL
201464
12
Table 1
Interim Analysis Trigger and Analysis Selection
Interim Analysis Trigger
Interim Analysis 
Selection [1]
Group 1, 5 subjects with at least 3 courses of Anti-SAP treatment
Selection #1 for Group 1
Group 1, 10 subjects with at least 3 courses of Anti-SAP treatment
Selection #1 for Group 1
Group 1, 10 subjects completing 8-week post-treatment follow-up visit
Selection #2 for Group 1
Group 2, 3 subjects with at least 3 courses of Anti-SAP treatment
Selection #1 for Group 2 
Group 2, 5-7 subjects with at least 3 courses of Anti-SAP treatment
Selection #1 for Group 2
Group 2, 10 subjects with at least 3 courses of Anti-SAP treatment
Selection #1 for Group 2
Group 2, 10 subjects completing 8-week post-treatment follow-up visit
Selection #2 for Group 2
Group 3, 5-7 subjects with at least 3 courses of Anti-SAP treatment
Selection #1 for Group 3
Group 3, 10 subjects with at least 3 courses of Anti-SAP treatment
Selection #1 for Group 3
Group 3, 10 subjects completing 8-week post-treatment follow-up visit
Full RAP deliverables for 
All 3 Groups
[1] Selection details in Table 2
Table 2
Details of Interim Analysis Selection
Analysis
Interim Analysis 
Selection #1
Interim Analysis 
Selection #2
Primary pharmacodynamic endpoint (LV mass by CMR)

Tabulated descriptive statistics, Plots of 
individual profiles
Y
Y

Statistical Inference Summaries and Figures[1],  
Listings
Y
Imaging markers monitored by serial CMR and / or ECHO[2]: GLS (CMR & ECHO), LV twist
(CMR), SV (CMR & ECHO), EF (CMR & ECHO), EDV (CMR & ECHO) E/e’ ratio (ECHO), E/A ratio 
(ECHO), E-wave deceleration time on the mitral flow (ECHO), LA volume index (ECHO), RV FAC 
(ECHO), global and segmental T1 (CMR), global and segmental ECV (CMR), other global and 
segmental strain measurements (CMR), global and segmental myocardial perfusion (CMR)

Tabulated descriptive statistics, Plots of 
individual profiles
Y
Y

Statistical Inference Summaries and Figures[1] , 
Listings
Y
Exploratory assessment of clinical cardiac functional improvement (6MWT, Groups 1 and 2 
only)

Tabulated descriptive statistics, Plots of 
individual profiles
Y
Y

Listings
Y
Exploratory assessment of reduction in cardiac uptake of radioisotope bone tracers (99mTc-
DPD or 99mTc-PYP, Group 1 only)

Listings
Y
Y
Exploratory assessment of amyloid load on SAP scan (Groups 2 & 3 where SAP scan 
available)

Listings
Y
Y


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201464
13
Analysis
Interim Analysis 
Selection #1
Interim Analysis 
Selection #2
Safety and Tolerability

AE listings

AE posterior probabilities [3]

Skin rash listing 

Laboratory individual profile plots for NT pro 
BNP, hs-Troponin T, serum Creatinine, eGFR
and C3

Profile plots for blood pressure and heart rate

Listings of ECG abnormalities

Listing of clinical chemistry, hematology and 
urinalysis

Cardiac monitoring investigator narratives (not 
available from clinical database)
Y
Y

Other laboratory individual profile plots and 
listings (incl. circulating markers associated with 
PD effect and safety lab parameters)
Y
Pharmacokinetics (mAb and CPHPC)

Individual plasma CPHPC plots vs sample 
occasion (by group and treatment cycle) 

Individual plasma mAb plots vs sample occasion 
(by group and treatment cycle) 
Y
Y
Pharmacodynamics

Plasma SAP plot vs sample occasion (stratified
by group and treatment cycle) 
Y
Y
NOTES:
Y = Yes: Analysis selected at interim.
[1] Statistical inferential analyses (see Section 8.1 for details) may be triggered earlier than for Selection #2 based on 
initial results and phase III planning requirements. Analyses involving multiple imputation of missing data will not be 
performed at the interim.
[2] The CMR / ECHO parameters of interest will be selected prior to analysis, possibly revised for each interim as 
necessary and captured as a note to file.
[3] AE posterior probabilities may be provided after 10 subjects complete at least 3 courses of Anti-SAP treatment in a 
given cohort
Please refer to Appendix 11: List of Data Displays which details the interim and/or final 
analysis selection for each display being generated.
The population of interest for selected interim analyses will be the Safety population. 
Analyses on the Standard of Care population will be performed, at the earliest, when all 
subjects from a given study group complete their 12-month post-treatment follow-up 
visit. 
Outcomes from the periodic data reviews may include:

Regulatory interactions and initiation of recruitment into Group 3

Triggering of Phase III planning and related regulatory interactions

Sample size re-estimation/adjustment


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
Adjustment of the schedule and timing of the assessments

Confirmed continuation of the study.
3.2.
Final Analyses
The final planned analyses (including full RAP deliverables for all 3 groups) will be 
performed after the completion of the following sequential steps:
1.
All subjects have completed their 12-month post-treatment follow-up visit.
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
3.
All criteria for releasing the randomisation codes have been met. 
4.
Randomisation codes have been distributed according to RandAll NG procedures.
Even though this is an open-label non-randomised study, randomisation codes will be 
produced per GSK processes and assigned to all subjects who pass screening.
The final analyses may also be performed after all subjects from a single study group 
have completed their 12-month post-treatment follow-up visit. The same sequential steps 
would apply, as for the completion of all 3 study groups.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Screened

Comprises of subjects who sign the Informed 
Consent

Screen Failures
Enrolled

Comprises of subjects who ultimately pass 
screening, even if rescreened.

The following subjects are included in the 
Enrolled population: Subjects who have been 
assigned a randomisation code.

Screen failures are excluded from the 
enrolled population.

Study Population
(Selected Outputs)
Safety

Comprises of all subjects who receive at least 
one dose of study treatment (any dose of 
GSK2315698 or GSK2398852) 

Study Population

Safety

Efficacy

PD/Biomarkers

PK
Standard of Care

Comprises of subjects providing standard of 
care data from the observational database, as 
described in Section 4.2

Study Population

PD
NOTES : 

Please refer to Appendix 11: List of Data Displays which details the population to be used for each display being 
generated.


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4.1.
Protocol Deviations

Important protocol deviations (including deviations related to study 
inclusion/exclusion criteria, conduct of the trial, subject management or subject
assessment) will be summarised and listed.

Protocol deviations will be tracked by the study team throughout the conduct of the 
study in accordance with the Protocol Deviation Management Plan.
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations are captured and categorised on the protocol deviations dataset. 
o
This dataset will be the basis for the listings of protocol deviations.

A separate listing of all inclusion/exclusion criteria deviations will also be provided. 
This listing will be based on data as recorded on the inclusion/exclusion page of the 
eCRF.
4.2.
Standard of Care Population and Database
The Standard of Care population will consist of a selection of subjects followed at the 
National Amyloidosis Centre (NAC) and part of an observational database providing 
demographic and pharmacodynamic (imaging) data.
This selection will consist of subjects with available imaging assessment of cardiac 
parameters by serial CMR and / or ECHO. AL subjects will be further restricted to those
meeting key inclusion/exclusion criteria for this study. Subjects enrolled in this study will 
be excluded from the Standard of Care data in order to ensure independent data sets. The 
final Standard of Care subject selection will be documented prior to database freeze.
The Standard of Care data will be transmitted electronically from the NAC or from the 
Central Imaging Core Laboratory. It will be stored with the study data in a validated data 
system (HARP study reporting area).


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 3 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 3
Overview of Appendices
Section
Component
Section 10.1
Appendix 1: Time & Events
Section 10.2
Appendix 2: Treatment States and Phases
Section 10.3
Appendix 3: Data Display Standards & Handling Conventions
Section 10.4
Appendix 4: Derived and Transformed Data
Section 10.5
Appendix 5: Premature Withdrawals & Handling of Missing Data
Section 10.6
Appendix 6: Values of Potential Clinical Importance
Section 10.7
Appendix 7: Model Checking and Diagnostics for Statistical Analyses
Section 10.8
Appendix 8: Population Pharmacokinetic Analyses
Section 10.9
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the “Safety” population, unless otherwise 
specified. Screen failures will be summarised or listed based on the “Screened”
population.
Analyses detailed in this section will be performed on data from each study group 
separately. Data displays will be paginated by study groups.
Table 4 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 11: List of Data Displays.


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Table 4
Overview of Planned Study Population Analyses
Display Type
Data Displays Generated
Table
Listing
Subject Disposition
Subject Disposition
Y
Reasons for Screening Failures
Y
Y
Reasons for Withdrawals
Y
Subjects Enrolled by Country and Site ID
Y
Planned and Actual Treatments
Y
Treatment Status and Reason for Discontinuation of Study 
Treatment
Y
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Inclusion and Exclusion Criteria Deviations
Y
Populations Analysed
Study Populations
Y
Subjects Excluded from Analysis Populations
Y
Demography[1]
Demography Characteristics
Y
Y
Age Ranges
Y
Race and Racial Combinations
Y
Y
Concomitant Medications
Concomitant Medication
Y
Y
Medical Conditions
Y
Y
Exposure
Exposure to CPHPC Treatment
Y
Y
Exposure to mAb Treatment
Y
Y
NOTES :

Y = Yes display generated.

[1] If data allows, tables and listings for demography will be provided for the Standard of Care Population (in 
addition to the Safety Population)
7.
PRIMARY STATISTICAL ANALYSES
7.1.
Pharmacodynamic Analyses (LV Mass Measured by CMR)
7.1.1.
Overview of Planned Pharmacodynamic Analyses (LV Mass 
Measured by CMR)
The primary pharmacodynamic analyses (summary statistics and statistical analysis) will 
be based on the “Safety” population unless otherwise specified. 
Analyses detailed in this section will be performed on data from each study group 
separately. Data displays will be paginated by study groups.
Table 5 provides an overview of the planned primary pharmacodynamic analyses, with 
full details of data displays being presented in Appendix 11: List of Data Displays.


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Table 5
Overview of Planned Pharmacodynamic Analyses
Endpoint 
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
L
Primary endpoint (key efficacy endpoint)
Change from baseline 
in LV mass
Y 
Y
LV mass (absolute 
values) [1]
Y
Y
Y
Y
Y [2]
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents Tables related to any summaries (i.e. descriptive statistics) of the observed 
raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

[1] Statistical analyses will be performed on the absolute values, but mean changes from first dose of 
anti-SAP mAb will be estimated from the model.

[2] Individual figures of absolute values are profile plots by subject identifiers
7.1.2.
Planned Pharmacodynamic Statistical Analyses (LV Mass 
Measured by CMR)
Primary Statistical Analyses
Endpoint 
The primary endpoint is change from baseline in LV mass (g) measured by CMR at 8-week post-
treatment follow-up.
Descriptive summaries, listings and plots will be provided for LV mass (g) measured by CMR.
The primary inferential analysis will model absolute values of LV mass and mean changes from 
first dose of anti-SAP mAb will be estimated from the statistical model over time at each protocol 
planned timepoint, i.e. at 2, 3, 4, 5, 8, 11 and 17 months. Note that the 8, 11 and 17-month 
timepoints correspond to the planned 8-week, 6-month and 12-month follow-up visits for a subject 
completing all 6 treatment sessions. Please refer to Appendix 11: List of Data Displays which 
details the population to be used for each display being generated.
Planned MRI scans are scheduled at screening, throughout treatment, with additional follow-up 
scans planned once a subject completes treatment or discontinues. Historical MRI scans (prior to 
trial start) will also be retrieved for some subjects. Measurements will therefore be available pre-
treatment (i.e. pre-trial and screening), on-treatment and post-treatment.
Model Specification
Model 1
The primary analysis models LV mass values over time using two linear components (i.e. two 
slopes) corresponding to the on-treatment and post-treatment parts of the data. As such it makes 
use of all available study data (i.e. both on- and post-treatment data). It allows for the derivation of 


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changes from first dose of anti-SAP mAb at planned timepoints with posterior probabilities of 
interest. The primary analysis is performed without any missing data imputation. Multiple 
imputation of missing data will also be considered as sensitivity analyses, as described in the  
“Handling of Missing Data for Analysis” Section.
A Bayesian two-piece linear mixed model (LMM) will be fitted to all study data collected after 
informed consent, i.e. pre-treatment (screening), on-treatment, and post-treatment visits. The 
primary analysis model will exclude pre-trial data from the observational database. This Bayesian 
two-piece LMM will incorporate information regarding when treatment was stopped by including an 
intercept and two different slope parameters for (i) on-treatment and (ii) post-treatment data, as 
described in Leuchs et al (2014).
The change in slope from on-treatment to post-treatment will be assumed to take place 56 days (8 
weeks) after last dose of anti-SAP mAb, which is the planned visit day of the 8-week follow-up MRI
scan.  
LV mass is the dependent variable. Time will be defined as a number of days with respect to first 
dose of anti-SAP mAb, and derived as the assessment date – date of first dose of anti-SAP mAb. 
For screening scans, time will be set to 0. 
All LV mass measurements will be included as absolute values in the model. The mean change 
from first dose of anti-SAP mAb at any given time point will be estimated as the resulting 
population average over all subjects’ posterior draws.
The likelihood is given by 
ij
Y ~
)
,
(
2
e
ij
N


, with  
ij
i
ij
i
i
ij
X
X
2
2
1
1
0







Where, for the ith subject and jth observation, 
ij
Y is the LV mass, and X1ij and X2ij are 
transformations of the number of days relative to first dose of anti-SAP mAb, Xij, such that:







i
i
i
ij
ij
ij
t
t
t
X
X
X
ij
1
X
  when 
          
when 
          
      with ti 56 days after last dose of anti-SAP mAb








i
i
ij
i
ij
ij
t
t
X
t
X
X
ij
2
X
 when 
when 
          
0
          with ti 56 days after last dose of anti-SAP mAb
Terms fitted in the model include:

Continuous Covariates: Number of days relative to first dose of anti-SAP mAb (denoted by 
Xij with transformed X1ij and X2ij in the way described above)
Non-informative prior distributions are defined for all parameters of the Bayesian model, with:
i
0

~
)
,
(
0
0 

N
i1

~
)
,
(
1
1 

N
i
2

~
)
,
(
2
2 

N
e

~
)
01
.
0,
01
.
0
(
InvGam


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0

~
)
01
.
0,
01
.
0
(
InvGam
1

~
)
01
.
0,
01
.
0
(
InvGam
2

~
)
01
.
0,
01
.
0
(
InvGam
with hyperparameters:
0~
)
10000
,0
(
N
1~
)
10000
,0
(
N
2~
)
10000
,0
(
N
Example of primary SAS code: 
proc mcmc data = ADDATA outpost=OUTPOST nmc=50000 thin=5 NBI=1000
seed=7893;
  PARMS beta0 beta1 beta2 sigmae sigma0 sigma1 sigma2;
  PRIOR sigma: ~ IGAMMA(0.01, SCALE=0.01);
  PRIOR beta: ~ NORMAL(0, var=10000);
  RANDOM alpha0 ~ NORMAL(beta0, var=sigma0) SUBJECT=SUBJID;
  RANDOM alpha1 ~ NORMAL(beta1, var=sigma1) SUBJECT=SUBJID;
  RANDOM alpha2 ~ NORMAL(beta2, var=sigma2) SUBJECT=SUBJID;
  mu = alpha0 + alpha1 * X1 + alpha2 * X2;
  MODEL Y ~ NORMAL(mu, var=sigmae);
run;
Correlation between regression parameters:
If data and model convergence allow, the correlation between regression parameters may be taken 
into account by use of a multivariate normal (MN) distribution. The joint prior distribution for 
intercept and slope parameters will be as follows:
where 
, i.e. the covariance matrix 
follows an Inverse Wishart 
distribution with k degrees of freedom and inverse-scale matrix . The least informative Inverse 
Wishart distribution will be chosen by setting k to 3, and 
to some prior guess at the value of the 
covariance matrix multiplied by k (Lunn et al, 2012).with hyperparameters:
Example of SAS code with correlation between regression parameters:
proc mcmc data = ADDATA outpost=OUTPOST nmc=50000 thin=5 NBI=1000
seed=7893;
  ARRAY alpha[3];
  ARRAY beta[3];
  ARRAY siga[3,3];
  ARRAY omega[3,3] (1000 0 0 0 1 0 0 0 1);
  ARRAY mub[3] (0 0 0);


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  ARRAY sigb[3,3] (10000 0 0 0 10000 0 0 0 10000);
  PARMS beta sigma ve;
  PRIOR beta ~ MVN(mub, sigb);
  PRIOR siga ~ IWISH(3, omega);
  PRIOR sige ~ IGAMMA(0.01, SCALE=0.01);
  RANDOM alpha ~ MVN(beta, siga) SUBJECT=SUBJID;
  mu = alpha[1] + alpha[2] * ADY1 + alpha[3] * ADY2;
  MODEL AVAL ~ NORMAL(mu, var=sige);
run;
Model 2
A Bayesian LMM will be fitted ignoring the change in slope from on-treatment to post-treatment 
data, i.e. including only one slope parameter from first dose of anti-SAP mAb. Other model 
assumptions will remain the same. 
Model 3
If the observational database provides sufficient pre-trial data, a Bayesian three-piece LMM will be 
fitted. This Bayesian three-piece LMM will incorporate information regarding when treatment was 
started/stopped by including an intercept and three different slope parameters for (i) pre-treatment, 
(ii) on-treatment and (iii) post-treatment data. The slope parameter will be assumed to change after 
the first dose of anti-SAP mAb, and 56-days after the last dose of anti-SAP mAb.
In this model, screening scans will be assigned to the actual day of scan measurement (unlike 
Model 1 and Model 2 where screening scans are assigned to Day 0).
Standard of Care Data Analysis
In order to support study data interpretation and missing data imputation for Model 1 (see 
“Handling of Missing Data for Analysis”, Option 3), a Bayesian LMM will be fitted to reference 
standard of care data. The LMM will include a subject effect, an intercept and a continuous linear 
effect of time (slope).
All available post-diagnosis data from subjects in the Standard of Care population will be used for 
this Bayesian LMM analysis of Standard of Care data.
Further details on Standard of Care data are provided in Section 4.2.


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Handling of Missing Data for Analysis
Model 1 will be repeated with several options for the handling of missing post-treatment data, 
corresponding to different assumptions.
Option 1 “No imputation”
Model 1 will first be performed without any missing data imputation. The Bayesian two piece LMM 
makes use of post-treatment information through the inclusion of on- and post-treatment slopes. As 
a consequence, post- discontinuation data contribute to the estimation of population mean changes 
over time. Without data imputation, missing post-treatment values are assumed to follow the same 
pattern as observed post-treatment values (i.e. ‘Missing at Random’ [MAR] assumption).
As such, subjects who drop out and only have partial or absolutely no on-treatment or post-
treatment data will still contribute to the analysis model estimates using their available on-treatment 
and/or post-treatment data. Unobserved on-/post-treatment data will be assumed to follow a similar 
pattern as on-/post-treatment data observed in other subjects.
Option 2 “Internal study data as reference”
Missing 8-week, 6-month and 12-month follow-up visit values may however follow a separate 
pattern from respectively observed 8-week, 6-month and 12-month follow-up visit values, in which 
case there could be a ‘Missing Not at Random’ (MNAR) mechanism.
A Pattern Mixture Model (PMM) framework makes it possible to impute follow-up visit values under 
the MNAR assumption. The imputation process will be performed for missing follow-up visits, i.e. 
for 8-week, 6-month and 12-month follow-up visits. Treatment session missing LV mass 
measurements will be assumed to be MAR, and will therefore not follow any imputation process. 
Two patterns of subjects are considered at each follow-up visit:

Pattern of subjects with an observed assessment at follow-up visits

Pattern of subjects with a missing assessment at follow-up visits
The MNAR assumption with Option 2 is that missing values only depend on prior visit values, i.e. 
they do not depend on any future measurements (for any subjects). Therefore, missing follow visit
values will be imputed using the available data with a non-future dependence restriction. The 
imputation will be as follows:
1.
Identify study subjects with a missing follow-up visit (either 8-week, 6-month or 12-month 
follow-up). These are the values to impute.
2.
Fit a linear regression model to the observed study follow-up visit data (follow-up visit i), 
regressing upon each of the i – 1 preceding follow-up visits as well as the last treatment 
session assessment (included as continuous effects in the model). This is the imputation 
model.
3.
Impute missing values identified in Step 1 m times using the model described in Step 2:
a.
Draw m values for the effect parameters for the imputation model from the posterior 
distribution given the observed study data
b.
Under each of the m models, and for each missing visit, impute the corresponding 


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predicted value, thus generating m imputed datasets.
Imputed values will be assigned to the planned follow-up study day, i.e. 8 weeks (56 days), 6 
months (183 days) or 12 months (365 days) after the subject last mAb dose.
Option 3 “Standard of care data as reference”
Option 3 will follow the same PMM approach as Option 2, with a different reference method for the 
imputation of missing follow-up visit values. Missing follow-up visit values will be assumed to follow 
the same pattern as the Standard of Care reference data. The imputation will be as follows: 
1.
Identify study subjects with a missing follow-up visit (either 8-week, 6-month or 12-month
follow-up). These are the values to impute.
2.
Fit a linear mixed model to the reference standard of care data as defined in the “Model 
Specifications” section. This is the imputation model.
3.
Impute missing values identified in Step 1 m times using the model described in Step 2:
a.
Draw m values for the effect parameters for the imputation model from the posterior 
distribution given the standard of care data
b.
Under each of the m models, and for each missing follow-up visit, impute the 
corresponding predicted value, thus generating m imputed datasets. Missing follow-
up visit LV mass measurements will be imputed assuming LV mass follows the 
standard of care predicted slope from the last non-missing LV mass assessment 
date. 
Imputed values will be assigned to the planned follow-up study day, i.e. 8 weeks (56 days), 6 
months (183 days) or 12 months (365 days) after the subject last mAb dose.
Irrespective of the reference base used, once the multiple imputed datasets have been generated, 
the analysis model is fitted to each imputed dataset. Draws from the posterior distributions of each 
imputed dataset will then be mixed to summarize the posterior distribution, as described by Zhou
and Reiter (2010).
Prior distributions for all parameters in the model will be similar to those specified for the primary 
analysis, i.e. non-informative normal distributions (
)
10000
,0
(
N
) for regression parameters and 
non-informative inverse gamma distributions (
)
01
.
0,
01
.
0
(
InvGam
) for variance parameters. 
Posterior distributions will follow the primary analysis presentation.
Model Checking & Diagnostics

Refer to Appendix 7: Model Checking and Diagnostics for Statistical Analyses. 
Results Presentation

Study subjects

Summaries of the posterior distribution, including the mean, median, SD and 95% credible 
interval (CrInt) will be tabulated for the following parameters:
o
Intercept, on-treatment slope and post-treatment slope

Summaries of the posterior distribution, including the mean, median, SD and 95% CrInt will 
be produced for the change from first dose of anti-SAP mAb at each planned protocol time


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point, i.e. at 2, 3, 4, 5, 8, 11 and 17 months.

The posterior probability of a reduction in LV mass from first dose of anti-SAP mAb of >0g, 
>50g, 70g will be provided for each of the above contrasts. Reduction thresholds of 
interest may be revised based on emerging data.

Posterior distribution plots will be produced for slope parameters and changes from first 
dose of anti-SAP mAb to 2, 3, 4, 5, 8, 11 and 17 months

The posterior mean change from baseline will be plotted over time together with 95% 
credible intervals

Absolute values and changes from baseline will also be descriptively summarized over 
time.

Individual subject profile plots of LV mass over time will be produced

Standard of care subjects

Summaries of the posterior distribution, including the mean, median, SD and 95% CrInt will 
be tabulated for the following parameters:
o
Intercept, slope

Summaries of the posterior distribution, including the mean, median, SD and 95% CrInt will 
be produced for the change from first scan at the same time points as for study subjects, 
i.e. at 2, 3, 4, 5, 8, 11 and 17 months.

Posterior distribution plots will be produced for the slope parameter and changes from first 
scan to 2, 3, 4, 5, 8, 11 and 17 months

Absolute values and changes from first scan will also be descriptively summarized over 
time.

Individual subject profile plots of LV mass over time will be performed
Sensitivity and Supportive Statistical Analyses
The models described above all assume that the relationship between time and LV mass is linear.
This assumption will be investigated within the same two-piece Bayesian Linear Mixed Model by 
exploring other functions of time including:

Restricted Cubic Splines

Polynomial

Negative exponential 
There will be no missing data imputation for these sensitivity analyses.
Prior distributions for all parameters in the model will be similar to those specified for the primary 
analysis, i.e. non-informative normal distributions (
)
10000
,0
(
N
) for regression parameters and 
non-informative inverse gamma distributions (
)
01
.
0,
01
.
0
(
InvGam
) for variance parameters. 
Posterior distributions will follow the primary analysis presentation.


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7.2.
Safety Analyses
7.2.1.
Overview of Planned Adverse Events Analyses
The safety analyses will be based on the “Safety” population.
Analyses detailed in this section will be performed on data from each study group 
separately. Data displays will be paginated by study groups.
Unless stated otherwise, summaries will only include AEs assigned to the on-treatment 
phase. The only exceptions will be the summaries of pre-treatment and post-treatment 
AEs by System Organ Class (SOC) and Preferred Term (PT).
Unless stated otherwise, summaries of on-treatment AEs will display AE frequencies 
over the full duration of the on-treatment phase. Two summaries will display AE 
frequencies by individual treatment session instead: All AEs by SOC, PT and Treatment 
Session; Rashes by SOC, PT, Maximum CTCAE Grade and Treatment Session. See 
Appendix 2: Treatment States and Phases for more details on AE assignment to treatment 
phases and treatment sessions.
Table 6 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 11: List of Data Displays.
Table 6
Overview of Planned Adverse Events Analyses
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
L
Adverse Events (AEs)
All AEs by SOC and PT
Y
Y
Pre-Treatment AEs by SOC and PT
Y
Post-Treatment AEs by SOC and PT
Y
All AEs by SOC, PT and Treatment Session
Y
Most Frequent [1] Adverse Events by Overall Frequency
Y
Drug-Related AEs by SOC and PT 
Y
Subject Numbers for Individual AEs
Y
Relationship Between AE SOCs, PT and Verbatim Text
Y
Posterior Probabilities for Specific AEs 
Y
Summary of Common (≥5%) Non-Serious Adverse Events 
Y
Serious and Other Significant AEs
Fatal Serious AEs
Y
Y
Drug-Related Fatal Serious AEs
Y
Non-Fatal Serious AEs
Y
Y
Serious AEs  
Y
Reasons for Considering as a Serious AE
Y
Drug-Related Non-Fatal Serious AEs
Y
Serious AEs by SOC and PT (Subjects & No. of Occurrences)
Y
AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study 
Y
Y


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Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
L
Treatment by SOC and PT
Anti-SAP mAb infusion related reactions[2]
Y
AEs related to treatments other than study drug
Y
Rashes
Rashes by SOC, PT and Maximum CTCAE Grade
Y
Y
Rashes by SOC, PT, Maximum CTCAE Grade and Treatment Session
Y
Rash Details
Y
NOTES:

T = Table, L = Listings, Y = Yes display generated, SOC = System Organ Class, PT = Preferred Term.

Summary = Represents Tables related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents Listings related to any displays of individual subject observed raw data.

[1] AEs occurring in more than one subject in a given cohort

[2] AEs selected based on the following list of PTs: “Headache”, “Flushing”, “Feeling hot”, “Feeling cold”, “Chest 
discomfort”, “Chills”, “Face oedema”, “Oedema peripheral”, “Orbital oedema”, “Nausea”, “Vomiting”, “Diarrhoea”, 
“Fatigue”, “Tachycardia”, “Presyncope”, “Infusion related reaction”. This list will be reviewed and finalised prior to 
database freeze.
Posterior distributions of the true proportion of subjects with AEs will be derived within a 
Bayesian framework for a selection of specific drug-related AEs. This selection of AEs 
will be periodically reviewed during the study interims triggered by at least 10 subjects 
completing at least 3 courses of anti-SAP treatment in a given cohort. A final list will be 
agreed and documented prior to database freeze.
Posterior 95% CrInt for the true proportion of subjects with a specified AE will be 
provided together with the posterior probabilities that the true proportion of subjects with 
that AE is >10%, >30% and >50%.
Prior distributions will be neutral non-informative conjugate Beta(1/3,1/3) prior 
distributions.
7.2.2.
Overview of Planned Clinical Laboratory Analyses
The safety analyses will be based on the “Safety” population, unless otherwise specified.
Table 7 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 11: List of Data Displays.


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Table 7
Overview of Planned Clinical Laboratory Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
T
F
L
T
Chemistry
Clinical Chemistry 
Y[1]
Y
Y
Hematology
Hematology 
Y[2]
Y
Y
Clinically-Relevant Changes in Haemoglobin
Y
Y
Urinalysis
Urinalysis
Y
Y
Hepatobiliary (Liver)
Liver Monitoring/Stopping Event Reporting
Y
Hepatobiliary Laboratory Abnormalities
Y
Medical Conditions for Subjects with Liver Stopping 
Events
Y
Substance Use for Subjects with Liver Stopping Events
Y
Scatter Plot of Maximum vs. Baseline for ALT
Y
Scatter Plot of Maximum ALT vs Maximum Total Bilirubin
Y
All Laboratory
All Laboratory Data for Subjects with any Value of PCI
Y
Laboratory Values of PCI
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents Tables related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

[1] Liver Function and Renal function parameters. Individual figures of absolute values are profile plots by subject 
identifiers. 

[2] Haemoglobin only. Individual figures of absolute values are profile plots by subject identifiers.
The number and percentage of subjects with clinically-relevant changes in haemoglobin 
between Day -2 and timepoints up to Day 24 will be summarised for each study group
and by treatment session. Two thresholds of clinical relevance will be defined as 
reductions from Day -2 of at least 10g/L and 20 g/L. 
7.2.3.
Overview of Planned Other Safety Analyses
The safety analyses will be based on the “Safety” population, unless otherwise specified.
Table 8 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 11: List of Data Displays.


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Table 8
Overview of Planned Other Safety Analyses
Endpoint / Parameter/ Display Type
Absolute
Change from BL
Summary
Individual
Summary
T
F[1]
L
T
ECG
ECG Findings 
Y
Y
Maximum Emergent QTc Values by Category
Y
ECG Values
Y
Y
Maximum Change from Baseline in QTc Values by 
Category
Y
All ECG Values for Subjects with any Value of PCI
Y
ECG Values of PCI
Y
Abnormal ECG Findings
Y
Echocardiogram and Cardiac Monitoring 
Cardiac monitoring [2]
Y
All echocardiogram results for subjects requiring 
unscheduled assessment [3]
Y
Vital Signs
Vital Signs
Y
Y
Y
All Vital Signs for Subjects with any Value of PCI
Y
Vital Signs of PCI
Y
NOTES:

T = Table, F = Figures, L = Listings, Y = Yes display generated, PCI = Potential Clinical Importance

Summary = Represents Tables related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

[1] Individual figures of absolute values are profile plots by subject identifiers. 

[2] Cardiac monitoring comments will be listed from the clinical database. Individual subject narratives will be 
provided separately by investigator.

[3] Subset of echocardiogram results for subjects with any unscheduled echocardiogram triggered for safety 
reasons. All echocardiogram data to be included for these subjects by treatment session.
8.
SECONDARY STATISTICAL ANALYSES
8.1.
Pharmacodynamic and biomarker analyses
8.1.1.
Overview of Planned Pharmacodynamic and Biomarker Analyses
The secondary and exploratory pharmacodynamic and biomarker analyses (summary 
statistics and statistical analysis) will be based on the “Safety” population unless 
otherwise specified. 
Analyses detailed in this section will be performed on data from each study group 
separately. Data displays will be paginated by study groups.


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Table 9 provides an overview of the planned secondary and exploratory 
pharmacodynamic and biomarker analyses, with full details of data displays being 
presented in Appendix 11: List of Data Displays.
Table 9
Overview of Planned Secondary Pharmacodynamic and Biomarker 
Analyses
Endpoint
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Summary
T
F
L
T
F[2]
L
T
Secondary Pharmacodynamic and Biomarker Endpoints
Imaging markers of cardiac dysfunction monitored by serial CMR and / or ECHO
GLS, LV twist, SV, EF, 
EDV measured by 
CMR and E/e’ ratio
measured by ECHO
Y[1]
Y[1]
Y[1]
Y
Y
Y
Y
GLS, SV, EF, EDV 
measured by ECHO
Y
Y
Y
Y
Circulating markers associated with pharmacodynamic effect during repeated administrations 
Fluid Phase 
complement markers : 
C3, C4, CH50
Y
Y
Y
Y
Inflammatory 
biomarkers : hsCRP, 
SAA
Y
Y
Y
Y
Plasma Cytokines: 
TNFα, IL-8, IL-6, IL-10, 
IL-13, IL-2, IL-4, IL-
12p70, IL 1β, IFNγ
Y
Y
Y
Y
Exploratory Pharmacodynamic and Biomarker Endpoints
Cardiac amyloid load as evaluated by CMR 
Cardiac ECV 
Y[1]
Y[1]
Y[1]
Y
Y
Y
Y
Cardiac biomarkers
hs-Troponin T, NT-
Pro-BNP
Y
Y
Y
Y
Cardiac uptake of radioisotope bone tracers (Group 1 only)
99mTc-DPD, 99mTc-PYP 
uptake
Y
Y
Amyloid load on SAP scan (Groups 2 & 3 only and where SAP scan available)
Overall body load and 
in affected organs 
(excluding cardiac 
load)
Y
Y
Y
Y
Imaging markers of cardiac structure as monitored by serial CMR and / or ECHO imaging
LV mass (ECHO)
Y[1]
Y[1]
Y[1]
Y
Y
Y
Y
LV wall thickness 
(CMR and/or ECHO)
Y
Y
Y
Y
Evaluate changes in imaging markers of cardiac tissue characterization as monitored by serial CMR
Native T1 and ECV
Y[1]
Y[1]
Y[1]
Y
Y
Y
Y
Native T2, LGE
Y
Y
Y
Y


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Endpoint
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Summary
T
F
L
T
F[2]
L
T
Other imaging markers of cardiac dysfunction monitored by serial CMR and / or ECHO
Longitudinal, Radial 
and Circumferential 
Strain (CMR and/or 
ECHO)
Y
Y
Y
Y
E/A ratio, E-wave 
deceleration time, LA 
volume index, RV FAC 
(ECHO)
Y
Y
Y
Y
Myocardial perfusion
DCE-CMR measure of 
myocardial perfusion
Y
Y
Y
Y
Plasma SAP concentration
SAP concentration
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

[1] Statistical analyses will be performed on the absolute values, but mean changes from first dose of anti-SAP 
mAb will be estimated from the model..

[2] Individual figures of absolute values are profile plots by subject identifier

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents Tables related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data
8.1.2.
Planned Pharmacodynamic and Biomarker Statistical Analyses
Secondary Statistical Analyses for Imaging Markers of Cardiac Dysfunction
Endpoints
Imaging markers of cardiac dysfunction monitored by serial CMR and / or ECHO include:

Global Longitudinal Strain (GLS) measured by CMR and ECHO. GLS includes 3 separate 
measurements: feature tracking and tagging (CMR) and speckle tracking (ECHO)

LV twist measured by CMR 

Stroke Volume (SV) measured by CMR and ECHO

Ejection Fraction (EF) measured by CMR and ECHO

End Diastolic Volume (EDV) measured by CMR and ECHO

E/e’ ratio measured by ECHO, with 2 separate measurements: lateral, septal
The following endpoints are listed as exploratory endpoints in the protocol, however analyses will 
follow those of secondary endpoints markers:

LV Mass measured by ECHO 

ECV (Global) measured by serial CMR

Native T1 (Global) measured by serial CMR
Descriptive summaries, listings and plots will be provided for each of these.
Statistical analyses will be performed for a selection of imaging markers. This selection of markers 
will include all markers measured by serial CMR as well as LV Mass and E/e’ ratio measured by 


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Secondary Statistical Analyses for Imaging Markers of Cardiac Dysfunction
ECHO. Other markers measured by ECHO will be summarised using descriptive statistics only.
Inferential analyses will model absolute values, and mean changes from first dose of anti-SAP mAb 
will be estimated from the statistical model over time at the planned protocol time points:
at 2, 3, 4, 5, 8, 11 and 17-month time points for CMR endpoints
at 1, 2, 3, 4, 5, 6, 8, 11, 17 month time points for ECHO endpoints
Note that the 8, 11 and 17-month timepoints correspond to the planned 8-week, 6-month and 12-
month follow-up visits for a subject completing all 6 treatment sessions.
Planned MRI and/or ECHO scans are scheduled at screening or baseline, throughout treatment, 
with additional follow-up scans planned once a subject completes treatment or discontinues. 
Historical MRI and/or ECHO scans (prior to trial start) will also be retrieved for some subjects. 
Measurements will therefore be available pre-treatment (i.e. pre-trial and screening), on-treatment 
and post-treatment.
Model Specification
Model 1 described for the primary endpoint of LV mass in Section 7.1.2 will be performed for the 
selection of secondary imaging markers of cardiac dysfunction for which statistical analyses are 
planned (all markers measured by serial CMR, and LV Mass and E/e’ ratio measured by ECHO).
Model 1 goodness-of-fit will be assessed by visual investigation of residual plots. If the two-piece 
LMM is found to be an inappropriate fit for the data, models 2, 3 and other sensitivity analyses 
exploring different functions of time may also be performed as described for the primary endpoint 
of LV mass in Section 7.1.2. There will be no missing data imputation for these sensitivity analyses. 
If data permits, the standard of care data analysis described for the primary endpoint of LV mass in 
Section 7.1.2 will also be performed for secondary imaging markers of cardiac dysfunction.
Handling of Missing Data for Analysis
The handling of missing post-treatment data will be handled with Option 1 described in Section 
7.1.2 (i.e. no imputation). Options 2 and 3 may be additionally considered after an initial review of 
analysis results.
Model Checking & Diagnostics

Refer to Appendix 7: Model Checking and Diagnostics for Statistical Analyses. 


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Secondary Statistical Analyses for Imaging Markers of Cardiac Dysfunction
Results Presentation

Study subjects

Model results and descriptive summaries will follow the same presentation as described for 
the primary endpoint of LV mass in Section 7.1.2

As for the primary endpoint, posterior probabilities for changes from first dose of anti-SAP 
mAb above or below specific thresholds may be considered. Thresholds of interest will be 
defined based on emerging data.

Standard of care subjects

Model results and descriptive summaries will follow the same presentation as described for 
the primary endpoint of LV mass in Section 7.1.2. Some endpoints may not be available for 
Standard of Care subjects, and outputs will be produced where applicable.
Secondary Analyses for Circulating markers
Endpoints 
Circulating markers associated with pharmacodynamic effect during repeated administrations:

Complement markers : C3, C4, CH50

Inflammatory biomarkers : hsCRP, SAA

Plasma cytokines : TNFα, IL-8, IL-6, IL-10, IL-13, IL-2, IL-4, IL-12p70, IL 1β, IFNγ
Model Specification
These continuous endpoints will be summarized using descriptive statistics only. Refer to Section 
10.3.9 for reporting standards.
Handling of Missing Data for Analysis
Missing data will not be imputed for these descriptive analyses.
Results Presentation

Absolute values and changes from baseline will be descriptively summarized over time by 
visit across all treatment sessions and follow-up periods where applicable.

Individual subject profiles over time will be plotted.
Exploratory Pharmacodynamic and Biomarker Analyses
Endpoint(s)
Exploratory Pharmacodynamic and Biomarker endpoints are as follows:

Cardiac amyloid load as evaluated by CMR
o
Cardiac ECV (Global, Segmental)

Cardiac biomarkers


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Exploratory Pharmacodynamic and Biomarker Analyses
o
hs-Troponin T, NT-Pro-BNP

Cardiac uptake of radioisotope bone tracers
o
99mTc-DPD
o
99mTc-PYP

Amyloid load on SAP scan
o
Overall body load in affected organs (excluding cardiac load)

Imaging markers of cardiac structure as monitored by serial CMR and / or ECHO imaging
o
LV wall thickness (CMR and ECHO)
o
LV mass (ECHO)

Other imaging markers of cardiac dysfunction as monitored by serial CMR and /or ECHO:
o
E/A ratio (ECHO)
o
E-wave deceleration time on the mitral inflow (ECHO)
o
Left Atrial (LA) volume index (ECHO)
o
Right Ventricle Fractional Area Change (FAC) (ECHO)
o
Longitudinal, Radial and Circumferential Strain (Global and Segmental values by 
CMR and/or ECHO)

Evaluate changes in imaging markers of cardiac tissue characterization as monitored by 
serial CMR
o
LGE
o
Native T1 (Global, Segmental)
o
Native T2 (Global, Segmental)

DCE-CMR measure of myocardial perfusion (Global, Segmental)

Plasma SAP concentrations
The derivation of LGE is described in Section 10.3.7. The derivation of the DCE-CMR global 
measure of myocardial perfusion is described in Section 10.3.8.
Model Specification
These endpoints, whether continuous or categorical, will be summarized using descriptive 
statistics. Segmental values (where applicable) will not be tabulated. Refer to Section 10.3.9 for
reporting standards.
In addition, inferential analyses will be performed for LV mass (ECHO), ECV (Global) and Native 
T1. These analyses are already described as part of the secondary statistical analyses for imaging 
markers of cardiac dysfunction.
The association between cardiac MRI markers (structural: LV Mass and ECV; tissue 
characterization: native T1 and LGE; functional: LV twist, GLS, SV and EF) and a selection of 
endpoints (biomakers: NT proBNP, hs-Troponin T; PD: DCE-CMR global measure of perfusion;
efficacy: 6MWT; QoL: MOS SF-36 Physical and Mental component summary scores and KCCQ 
overall summary score) will be studied using Spearman correlation coefficients.
These correlations will be calculated at the following time points: baseline, treatment session 3 Day 
24 visit, 8-week follow-up visit, 6-month follow-up visit and 12-month follow-up visit.


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Exploratory Pharmacodynamic and Biomarker Analyses
Handling of Missing Data for Analysis
Missing data will not be imputed for these descriptive analyses.
Results Presentation
For each exploratory pharmacodynamic and biomarker endpoint:

Absolute values and changes from baseline will be descriptively summarized over time by 
visit across all treatment sessions and follow-up periods where applicable.

Individual subject profiles over time will be plotted. Imaging marker segmental values will 
be displayed on the same plot, i.e. plots will include as many curves as segments. The 
legend will identify all segment categories.
For analyses of association between endpoints:

Spearman correlation coefficients will be tabulated by timepoint for all pairs of endpoints to 
be studied, together with 95% confidence intervals

Scatter plots will be produced to visualize the association for all pairs of endpoints to be 
studied, by timepoint and across all timepoints
8.2.
Immunogenicity Analyses
8.2.1.
Overview of Planned Immunogenicity Analyses
The immunogenicity analyses will be based on the “Safety” population, unless otherwise 
specified. 
Analyses detailed in this section will be performed on data from each study group 
separately. Data displays will be paginated by study groups.
Table 10 provides an overview of the planned immunogenicity analyses, with full details 
of data displays being presented in Appendix 11: List of Data Displays.
Table 10
Overview of Planned Immunogenicity Analyses
Endpoints
Absolute
Summary
Individual
T
L
Anti-drug antibodies
Y
Y
Immune complexes
Y
Y
Auto-antibodies
Y
Y
NOTES :

T = Summary Tables, L =  Individual subject Listings, Y = Yes display generated.

Summary = Represents Tables related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents Listings related to any displays of individual subject observed raw data


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8.3.
Pharmacokinetic Analyses
8.3.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the “Safety” population, unless 
otherwise specified.
Table 11 provides an overview of the planned statistical summary of drug concentrations,
with full details being presented in Appendix 11: List of Data Displays and Appendix 8: 
Population Pharmacokinetic Analyses. 
Table 11
Overview of Planned Pharmacokinetic Analyses
Endpoints
Summary
Individual
T
F
F
L
GSK2315698 concentration[1]
Y
Y
Y[2]
Y
GSK2398852 concentration
Y
Y
Y[2]
Y
NOTES :

T = Table, F = Figure, L = Listings, Y = Display generated.

Summary = Represents TF related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.

[1] Group 3 only  

[2] Linear and Semi-Log plots will be created on the same display
8.3.2.
Drug Concentration Measures
Refer to Appendix 3: Data Display Standards & Handling Conventions (Section 10.3.9:
Reporting Process & Standards).
8.3.2.1.
Plasma concentration of GSK2315698

The data will be listed by subject group, ID, treatment session and sampling occasion.

The pattern of the data will be explored by plots of concentration vs time. Data will 
be connected for each subject while stratified by subject group, by treatment session
and by both.

Summary statistics will be generated by sampling occasion, while stratified by subject
group, by treatment session, and by both.
8.3.2.2.
Plasma concentration of GSK2398852

The data will be listed by subject group, ID, treatment session and sampling occasion.

The pattern of the data will be explored by plots of concentration vs time. Data will 
be connected for each subject while stratified by subject group, by treatment session 
and by both.

Summary statistics will be generated by sampling occasion, while stratified by subject
group, by treatment session, and by both.


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8.3.3.
Population Pharmacokinetic (PopPK) Analyses
8.3.3.1.
GSK2315698
Concordance in CPHPC pharmacokinetics between this study and previous studies will 
be assessed by visual predictive check of the concentration data from this study against a 
model that was developed with data from studies CPH113776 and CPH114527. This
assessment will be reported by Clinical Pharmacology Modelling and Simulation 
(CPMS) and will be included as an appendix to the Clinical Study Report (CSR). Refer to 
Appendix 8: Population Pharmacokinetic Analyses (Section 10.8.1)
8.3.3.2.
GSK2398852
The primary goal of this analysis is to characterize the population pharmacokinetics of
GSK2398852 administered intravenously in subjects with cardiac amyloidosis. A 
summary of the planned population pharmacokinetic analyses is outlined below:

Drug plasma concentration-time data will be subjected to nonlinear mixed effects 
modelling using the program NONMEM to develop a population PK model.  

The influence of subject demographics, baseline characteristics, including disease 
activity, and co-medication on the pharmacokinetics of GSK2398852 in this 
population will be investigated.

The individual subject PK parameters will be estimated and summarised.

To support this analysis a NONMEM file will be generated.  

The details for the analysis including dataset specifications are provided in Appendix 
8: Population Pharmacokinetic Analyses with detailed methodology for the analysis.
8.4.
Pharmacokinetic / Pharmacodynamic Analyses
Blood concentration of SAP prior to mAb administration will be assessed with and 
without stratification of subject groups and treatment course, by visual predictive check 
using a previously established PKPD model, taking into account for assay difference if 
applicable. This assessment will be reported by CPMS and will be included as an 
appendix to the CSR. See Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses 
for details.
8.5.
Efficacy Analyses
8.5.1.
Overview of Planned Efficacy Analyses
The efficacy analyses will be based on the “Safety” population, unless otherwise 
specified. 
Analyses detailed in this section will be performed on data from each study group 
separately. Data displays will be paginated by study groups.


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Table 12 provides an overview of the planned efficacy analyses, which will consist of 
6MWT analyses for Study Groups 1 and 2 only. This analysis of 6MWT corresponds to 
the protocol objective of cardiac functional assessment. Full details of data displays are 
presented in Appendix 11: List of Data Displays.
Table 12
Overview of Planned Efficacy Analyses
Endpoints
Absolute
Change from Baseline
Summary
Individual
Summary
T
L
F
T
6MWT (Groups 1 and 2 only)
Y
Y
Y
Y
NOTES :

T = Summary Tables, F = Figure, L = Individual subject Listings, Y = Yes display generated.

Summary = Represents Tables related to any summaries (descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data
8.6.
Quality of Life Analyses
8.6.1.
Overview of Planned Quality of Life Analyses
The quality of life analyses will be based on the “Safety” population, unless otherwise 
specified. 
Analyses detailed in this section will be performed on data from each study group 
separately. Data displays will be paginated by study groups.
Table 13 provides an overview of the planned quality of life analyses, with full details of 
data displays being presented in Appendix 11: List of Data Displays.
Table 13
Overview of Planned Quality of Life Analyses
Endpoints
Absolute
Change from Baseline[1]
Summary
Individual
Summary
T
L
T
MOS SF-36 domain and overall 
scores
Y
Y
Y
KCCQ scores
Y
Y
Y
EORTC QLQ-C30 scores
Y
Y
Y
DLQI overall and section scores
Y
Y
Y
NOTES :

T = Summary Tables, L =  Individual subject Listings, Y = Yes display generated.

Summary = Represents Tables related to any summaries (descriptive statistics) of the observed raw 
data.

Individual = Represents Listings related to any displays of individual subject observed raw data

[1] Quality of life endpoints are collected at Baseline and 8-week follow-up, therefore changes from 
baseline will only be derived for the 8-week follow-up timepoint


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8.6.2.
MOS SF-36 Questionnaire
The Medical Outcomes Survey Short Form 36 (MOS SF-36) has 36 questions evaluating 
the subjects’ quality of life over a 1 week period.  Appendix 3: Data Display Standards & 
Handling Conventions (Section 10.3.3) gives details of the derivation steps which will be 
applied to the MOS SF-36: 

Recoding of MOS SF-36

Handling Missing MOS SF-36 Items

Domain Scale Scores

Standardized Z Scores

Norm-based Domain Scores (NBS)

Physical and Mental Component Summaries (PCS and MCS)
All questions are scored using normative-based scoring.  
The norm-based scores (NBS) at baseline and 8-week follow-up and changes from 
baseline at 8-week follow-up for each domain and the overall physical and mental 
component summaries will be summarized and listed:

Physical functioning (PF)

Role-physical (RP)

Bodily pain (BP)

General health (GH)

Vitality (VT)

Social functioning (SF)

Role-emotional (RE)

Mental health (MH)

Physical component summary (PCS)

Mental component summary (MCS).
SF-36 items and scales are scored so that a higher score indicates a better health state.
The NBS scales would be expected to be distributed around 50 with a standard deviation 
of 10 for healthy individuals.
8.6.3.
KCCQ Questionnaire
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item, self-administered 
questionnaire. There are 10 summary scores derived from the KCCQ items:

Physical limitation

Symptom stability

Symptom frequency

Symptom burden

Total symptom Score

Self efficacy

Quality of life


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
Social limitation

Overall summary score

Clinical summary score
Scores are transformed to a range of 0-100, in which higher scores reflect better health 
status. Appendix 3: Data Display Standards & Handling Conventions (Section 10.3.4) 
provides details of the derivation for each of these scores, including instructions as how 
to handle missing data.
8.6.4.
EORTC QLQ C30 Questionnaire
The European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire C30 (EORTC QLQ C30) consists of 30 questions. Subjects from groups 2 
and 3 only will complete this questionnaire.
The EORTC QLQ-C30 is composed of both multi-item scales and single-item measures. 
These include:

Global heal status / QoL scale

Functional scales:
o
Physical functioning
o
Role functioning
o
Emotional functioning
o
Cognitive functioning
o
Social functioning

Symptom scales /items
o
Fatigue
o
Nausea and vomiting
o
Pain 
o
Dyspnoea
o
Insomnia
o
Appetite loss
o
Constipation
o
Diarrhoea
o
Financial difficulties
Scores are transformed to a range of 0-100, in which higher scores reflect higher response 
levels. Therefore:

A high score for a functional scale represents a high / healthy level of functioning

A high score for the global health status / QoL represents a high QoL

However, a high score for a symptom scale represents a high level of 
symptomatology / problems
Appendix 3: Data Display Standards & Handling Conventions (Section 10.3.5) provides 
details of the derivation for each of these scores, including instructions as how to handle 
missing data.


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8.6.5.
DLQI questionnaire
The dermatology quality of life index (DLQI) is a 10-item validated questionnaire that 
has been used to assess the impact of skin disease on subject quality of life. It will be 
administered to subjects in the study who develop dermatological toxicity.
The DLQI is composed of an overall score, as well as of 6 section scores, as follows:

Symptoms and feelings

Daily activities

Leisure

Work and school

Personal relationships

Treatment
The higher the score, the more quality of life is impaired.
Derivation of the overall score and of the 6 section scores is provided in Appendix 3: 
Data Display Standards & Handling Conventions (Section 10.3.6). Handling of missing 
answers is also described.
8.7.
Exit Interviews
Exit interviews will be conducted over telephone after the 8-week follow-up (or 
following the last study visit if a subject withdraws from the study without attending the 
8-week follow-up visit) in a subset of subjects only, to explore subjects’ experience with 
study treatment.  A qualitative research report will be prepared and provided separately 
by an external service supplier (Adelphi). As a consequence, there is no corresponding 
plan for data displays. 


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9.
REFERENCES
GSK Document Number 2012N146440_00, CPH113776, CPH114527, Technical 
Pharmacokinetic/Pharmacodynamic report for GSK2315698 in healthy volunteers and in 
patients with systemic amyloidosis, 13-JUN-2014
GSK Document Number 2015N249732_00, 201464, A multiple treatment session, open 
label phase 2 clinical study of GSK2398852 administered following and together with 
GSK2315698 in cohorts of patients with cardiac amyloidosis, 09-MAY-2016
Leuchs, A. K., Zinserling, J., Schlosser-Weber, G., Berres, M., Neuhäuser, M., & Benda, 
N. (2014). Estimation of the treatment effect in the presence of non-compliance and 
missing data. Statistics in medicine, 33(2), 193-208.
Lunn D, Jackson C, Best N, Thomas A, Spiegelhalter D (2012). The BUGS Book: A 
Practical Introduction to Bayesian Analysis. CRC Press
Zhou, Xiang, and Jerome P. Reiter. "A note on Bayesian inference after multiple 
imputation." The American Statistician 64.2 (2010): 159-163.


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10.
APPENDICES
Section
Appendix
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 10.1
Appendix 1: Time and Events
Section 10.2
Appendix 2: Treatment States & Phases
Section 10.3
Appendix 3: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 10.4
Appendix 4: Derived and Transformed Data

General, Study Population & Safety

Efficacy

Pharmacokinetic

Pharmacodynamic and or Biomarkers
Section 10.5
Appendix 5: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 10.6
Appendix 6: Values of Potential Clinical Importance
Section 10.7
Appendix 7: Model Checking and Diagnostics for Statistical Analyses
Section 10.8
Appendix 8: Population Pharmacokinetic Analyses
Section 10.9
Appendix 9: Pharmacokinetic / Pharmacodynamic (or Biomarker) Analyses
Other RAP Appendices
Section 10.10
Appendix 10: Abbreviations & Trade Marks
Section 10.11
Appendix 11: List of Data Displays
Section 10.12
Appendix 12: Example Mock Shells for Data Displays


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10.1.
Appendix 1: Time & Events
10.1.1.
Protocol Defined Time & Events
Table 14
Overview All Groups (for details of inpatient stay see Table 15)
Session 1
Session 2
Session 3
Session 4
Session 5
Session 6
Follow-up
Screening1
Baseline2
Day -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
8week  F/U3
6 months3
12 months3
Inpatient stay at unit4, 14
X
X
X
X
X
X
Outpatient visit at unit
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Informed consent
X
Medical history/risk 
factors/demographics
X
Inclusion/exclusion criteria
X
Safety Assessments
Physical examination5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
MOS SF-36, KCCQ, EORTC6
questionnaires
X
X
DLQI questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
12 lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lead II telemetry
X
X
X
X
X
X
Cardiac monitor7
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical Laboratory Assessments
FSH/E2 - see Table 6
X
Urine βhCG8
X
X
X
X
X
X
X
X
X
Haem/clin chem/urinalysis
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
24h Urine collection for protein and 
creatinine9
X
X
X
X
X
X
X
X
X


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Session 1
Session 2
Session 3
Session 4
Session 5
Session 6
Follow-up
Screening1
Baseline2
Day -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
Days -2 to 11
Day 17
Day 24 1 day
8week  F/U3
6 months3
12 months3
HepB/Hep C/HIV
X
Blood biomarkers
Complement and Inflammatory 
markers
X
X
X
X
X
X
X
hs-Troponin T/NT-ProBNP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Anti-Drug Antibody (anti-SAP mAb)
X
X
X
X
Auto-antibodies
X
mAb/SAP immune complex
X
X
Pharmacokinetics/SAP10
Blood sampling for SAP
X
X
X
X
X
X
X
X
X
X
X
Blood sampling for CPHPC
X
X
X
X
X
X
Blood sampling for anti-SAP mAb
X
X
X
X
X
X
X
X
X
X
X
X
X
Imaging Procedures
Cardiac MRI with contrast13
X1
X
X
X
X
Cardiac MRI without contrast
X
X
X
ECHO
X
X
X
X
X
X
X
X
X
X
SAP scan -  Groups 2/3 UK only
X
X
Bone scan (DPD/ PYP) – Group 1 
only
X
X
Other
Skin biopsy / blood sample / 
urinalysis / EOSI11
(X)
(X)
(X)
(X)
(X)
(X)
6MWT - Groups 1 & 2
X
X
X
X
X
Genetic sample12(optional)
X
Exit Interview
X
Ongoing Subject Review
Concomitant therapy
X
Adverse event review
X


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Footnotes:
1.
Screening to take place within 42 days of start of treatment. CMR at screening will be performed after a subject has passed all other screening assessments
2.
Baseline will be anytime after eligibility confirmed from screening and before anti-SAP treatment start 
3.
Follow-up at timepoint from last anti-SAP mAb dose
4.
Refer to Table 15 for details of monthly inpatient visit
5.
Full examination at screening only, brief examination at all other time-points
6.
EORTC Groups 2 and 3 only
7.
Out-patient cardiac recording using suitable device see Protocol Section 7.4.7.2. Recording at baseline, 8wk follow-up and 6 month follow-up for approximately 2 weeks
8.
Pregnancy test before commencement of CPHPC infusion
9.
24h collection - 3.5ml serum biochemistry sample to be taken for creatinine measurements at time points where there are no corresponding clinical chemistry samples
10. Sampling time points in Table 15 and Table 16
11. In the event of rash, assessments to be performed (see Protocol Table 8). The Investigator/Sub-Investigator must perform a twice daily review 
12. Informed consent for optional genetics sub-study must be obtained before collecting a sample
13. For subjects with a GFR <40ml/min/1.73m2,  MRI will be performed at the scheduled times but without contrast
14. Subjects are allowed to be admitted on Day -3 to allow for pre-dose assessments to be performed


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Table 15
Inpatient stay
Study procedures
Day -213
pre-CPHPC dose
Day -2 
Day -1
Day 1-3
anti-SAP mAb dose1
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Safety Assessments
Brief physical examination (including skin)
X
X
X
X
X
X
X
X
X
X
X
X
12 lead ECG
X
X
X
X
X
X
X
X
X
X
X
X
Lead II telemetry
X
X
X
X
X
X
X
X
Cardiac monitoring2
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
Study Drug Administration
Administration of CPHPC (2 days IV infusion)
X
X3
Administration of CPHPC (SC )
X
X
X
X
X
X
X
X
X12
Administration of anti-SAP mAb (6h IV infusion on days 1 and 3)
X
Clinical Laboratory Assessments
Haem/clin chem/urinalysis
X
X
X
X
X
X
24h Urine collection for protein and creatinine4
X
X
X
Urine microscopy5
X
X
X
X
Blood biomarkers
Complement and Inflammatory Markers
X
X
X
Cytokines
X
X
X
X
hs-Troponin T/NT-ProBNP
X
X
X
X
X
X
X
X
X
X
Blood sampling for mAb/SAP immune complex 6
X
X
Pharmacokinetics/SAP
Blood sampling for SAP 
X
X7
X
X
X
Blood sampling for CPHPC8
X8
Blood sampling for anti-SAP mAb
X
X
X
X


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Study procedures
Day -213
pre-CPHPC dose
Day -2 
Day -1
Day 1-3
anti-SAP mAb dose1
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Ongoing Subject Review
Skin biopsy9/blood sample/urinalysis/EOSI10
X11
(X)
Concomitant therapy
X
Adverse event review
X
Footnotes: all timings relative to first anti-SAP mAb dose of session
1.
See Table 16 for expanded details of days 1 to 3
2.
At PI discretion appropriate alternate telemetry device may be used.during days 5-10. Cardiac monitoring continues to Day 19 and to be performed with suitable device see 
Protocol Section 7.4.7.2 
3.
If SAP levels are not below target then the CPHPC will be dosed for a further day and anti-SAP mAb dose deferred 1 day
4.
24h collection - 3.5mL serum biochemistry sample to be taken for creatinine measurements at time points where there are no corresponding clinical chemistry samples
5.
Renal examination of urine i.e. not just dipstick and culture 
6.
Session 1 only
7.
Rapid  turnaround to ensure SAP depleted to target prior to dosing anti-SAP mAb
8.
Group 3 only
9.
Biopsies only on any rash development (i.e. ≥ Grade 1) and will be decided by clinical judgement of the Investigator dermatologist (see Protocol Table 8 for full 
assessments)
10. In the event of a rash the Investigator/Sub-Investigator must perform a twice daily review
11. On confirmation from medical monitor see Protocol Table 8
12. Morning dose only to be administered (see Protocol Table 2)
13. Subjects are allowed to be admitted on Day -3 to allow for pre-dose assessments to be performed


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Table 16
Detailed Events - Days 1 to 3 (anti-SAP mAb dosing)
Study procedure
Day 1
Day 2
Day 3
Pre-dose
0h
1h
2h
3h
4h
6h
8h
12h
16h
0h
4h
8h
12h
16h
Pre-dose
0h
1h
2h
3h
4h
6h
8h
12h
16h
Safety assessments
12 lead ECG
X
X
X
X
X
X
X
X
X
X
X
Lead II telemetry
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Study drug administration
Administration of CPHPC
(SC)- see Table 2
X
X
X
Administration of anti-
SAP mAb
X
n/a
X
Clinical lab assessments
Haem/clin 
chem/urinalysis
X
X8
X
24h Urine collection for 
protein and creatinine1
X
X
Urine microscopy
X
X
X
X
X
X
Blood sample mAb/SAP 
immune complex2
X
X3
X3
Blood biomarkers
Complement & 
Inflammatory markers
X
X
X
X
X
X
X
X
X
Cytokines
X
X
X
X
X
X
X
X
X
hs-Troponin T/NT-
proBNP
X
X
X


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Study procedure
Day 1
Day 2
Day 3
Pre-dose
0h
1h
2h
3h
4h
6h
8h
12h
16h
0h
4h
8h
12h
16h
Pre-dose
0h
1h
2h
3h
4h
6h
8h
12h
16h
Pharmacokinetics
Blood sampling - SAP
X
X
X5
X
X
Blood sampling- CPHPC4
X
X5
X
Blood sampling - anti-
SAP mAb
X
X6
X
X
X5
X
X6
Ongoing subject review
Skin biopsy/blood 
sample/urinalysis/EOSI7
(X)
(X)
(X)
Concomitant therapy 
review
X
X
X
Adverse event review
X
X
X
Footnotes: all timings relative to first anti-SAP mAb dose of session
1.
24h collection - 3.5mL serum biochemistry sample to be taken for creatinine measurements at time points where there are no corresponding clinical chemistry samples
2.
Session 1 only
3.
At end of anti-SAP mAb infusion
4.
CPHPC sampling is for Group 3 only
5.
Blood sample to be taken immediately prior to first CPHPC SC injection and 2h post CPHPC SC injection of that day 
6.
Blood Sampling to coincide with the end of infusion of the anti-SAP mAb
7.
Biopsies on any rash development will be decided by clinical judgement of the Investigator and dermatologist (see Protocol Table 8 for full assessments) Skin biopsies & 
paired blood sample / urinalysis should only be performed for each new and / or clinically progressive rash
8.
To include clotting tests for Session 1 only (see Protocol Table 6)


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10.2.
Appendix 2: Treatment States and Phases
The handling of missing or partial AE dates and times and their impact on the assigned 
treatment phase/session and the calculation of onset time and duration is described in 
Section 10.5.2.1.
10.2.1.
Treatment Phases
Treatment phases are defined for the purpose of AE summaries and listings.
AEs will be assigned to on-treatment, pre-treatment and post-treatment phases according 
to the time of occurrence relative to Dates/Times of First and Last Doses of Study Drug.
Treatment Phase
Definition
Pre-Treatment 
Date/Time < First Dose Date/Time of Study Drug1
On-Treatment
First Dose Date/Time of Study Drug1≤ Date/Time ≤Last Dose Date/Time of Study 
Drug2 + 56 Days
Post-Treatment
Date/Time > Last Dose Date/Time of Study Drug2 + 56 Days
1Earliest dose of GSK2315698 or GSK2398852 in the study
2Latest dose of GSK2315698 or GSK2398852 in the study
Unless stated otherwise, AE summaries will only include AEs assigned to the on-
treatment phase. The only exceptions will be the summaries of pre-treatment and post-
treatment AEs by SOC and PT. All AE listings will include treatment phase assignment.
10.2.2.
Treatment Sessions
Treatment sessions are defined for the purpose of specific AE or PK summaries by 
treatment session. Only two AE summaries will display AE frequencies by treatment 
session: All AEs by SOC, PT and Treatment Session; Rashes by SOC, PT, Maximum 
CTCAE Grade and Treatment Session. All AE listings will include treatment session 
assignment.
AEs and PK samples will be assigned to treatment sessions according to the time of 
occurrence relative to Dates/Times of First and Last Doses of Study Drug for each 
treatment session.


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Treatment Sessions
Definition
Treatment Session 1
Session 1 First Dose Date/Time of Study Drug1 ≤ Date/Time < Session 2 First 
Dose Date/Time of Study Drug1 or Session 1 Last Dose Date/Time of Study 
Drug2 + 56 Days (if Session 2 is not applicable). 
Treatment Session 2
Session 2 First Dose Date/Time of Study Drug1 ≤ Date/Time < Session 3 First 
Dose Date/Time of Study Drug1 or Session 2 Last Dose Date/Time of Study 
Drug2 + 56 Days (if Session 3 is not applicable).
Treatment Session 3
Session 3 First Dose Date/Time of Study Drug1 ≤ Date/Time < Session 4 First 
Dose Date/Time of Study Drug1 or Session 3 Last Dose Date/Time of Study 
Drug2 + 56 Days (if Session 4 is not applicable).
Treatment Session 4
Session 4 First Dose Date/Time of Study Drug1 ≤ Date/Time < Session 5 First 
Dose Date/Time of Study Drug1 or Session 4 Last Dose Date/Time of Study 
Drug2 + 56 Days (if Session 5 is not applicable).
Treatment Session 5
Session 5 First Dose Date/Time of Study Drug1 ≤ Date/Time < Session 6 First 
Dose Date/Time of Study Drug1 or Session 5 Last Dose Date/Time of Study 
Drug2 + 56 Days (if Session 6 is not applicable).
Treatment Session 6
Session 6 First Dose Date/Time of Study Drug1 ≤ Date/Time < Session 6 Last 
Dose Date/Time of Study Drug2 + 56 Days 
1Earliest treatment session dose of GSK2315698 or GSK2398852
2Latest treatment session dose of GSK2315698 or GSK2398852
10.2.3.
AE Onset Time and Duration
The following AE onset times and duration will be included in all AE listings.
Definition
Onset Day Since 
First Dose of 
Study Drug1
(Days)
If First Dose Date/Time of study drug1 ˃AE Onset Date/Time, Onset Day = AE Onset 
Date - First Dose Date
If First Dose Date/Time of study drug1 ≤ AE Onset Date/Time, Onset Day = AE Onset 
Date - First Dose Date +1 Day
Missing if subjects is not exposed to any study drug
Onset Day Since 
Treatment 
Session First 
Dose of CPHPC 
(Days)
If Session CPHPC First Dose Date/Time of study drug ˃  AE Onset Date/Time, Onset 
Day = AE Onset Date – Session CPHPC First Dose Date
If Session CPHPC First Dose Date/Time of study drug ≤ AE Onset Date/Time, Onset 
Day = AE Onset Date – Session CPHPC First Dose Date +1 Day
Missing if AE not assigned to treatment session
Onset Day Since 
Treatment 
Session First 
Dose of mAb 
(Days)
If Session mAb First Dose Date/Time of study drug ˃  AE Onset Date/Time, Onset Day 
= AE Onset Date – Session mAb First Dose Date
If Session mAb First Dose Date/Time of study drug ≤ AE Onset Date/Time, Onset Day 
= AE Onset Date – Session mAb First Dose Date +1 Day
Missing if AE not assigned to treatment session
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on Inform/CRF OR value is missing.
1Earliest dose of GSK2315698 or GSK2398852 in the study


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10.3.
Appendix 3: Data Display Standards & Handling 
Conventions
10.3.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
A
GSK2315698 + GSK2398852
Anti-SAP
10.3.2.
Baseline Definition & Derivations
10.3.2.1.
Baseline Definitions
For all endpoints, the baseline value used for descriptive summaries and listings will be 
the latest assessment prior to first administration of anti-SAP treatment.
The first administration of anti-SAP treatment will be defined as the first administration 
of either study drug, i.e. CPHPC or anti-SAP mAb. 
10.3.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
Maximum Change from Baseline
= Calculate the change from baseline at each given timepoint 
after baseline (over treatment sessions and follow up period)
and determine the maximum change
NOTES :

Unless otherwise specified, the baseline definitions specified in Section 10.3.2.1 Baseline Definitions will be used 
for derivations for endpoints / parameters and indicated on summaries and listings.

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all change from baseline displays.
10.3.3.
Derivation of MOS SF-36 Scores
10.3.3.1.
Recoding of MOS SF-36 
Some of the items in the SF-36 will be re-coded as follows such that higher values 
represent better functioning:


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Physical Functioning (PF): Items 3a-3j:
No Recoding Required
Response choices
Pre-coded value
Final value
Yes, limited a lot
1
1
Yes, limited a little
2
2
No, not limited at all
3
3
Role Physical (RP): Items 4a-4d:
No Recoding Required
Response choices
Pre-coded value
Final value
All of the time
1
1
Most of the time
2
2
Some of the time
3
3
A little of the time
4
4
None of the time
5
5
Bodily Pain (BP): Item 7:
Response choices
Pre-coded value
Final value
None
1
6.0
Very mild
2
5.4
Mild
3
4.2
Moderate
4
3.1
Severe
5
2.2
Very severe
6
1.0
Bodily Pain (BP): Item 8 
Scoring for item 8--if both items 7 and 8 are answered:
Response
choices
If item 8
Pre-coded value
and
Item 7
Pre-coded value
then
Item 8
final item value
Not at all
1
1
6
Not at all
1
2 through 6
5
A little bit
2
1 through 6
4
Moderately
3
1 through 6
3
Quite a bit
4
1 through 6
2
Extremely
5
1 through 6
1
Bodily Pain (BP): Item 8 
Scoring for item 8--if item 7 is not answered:
Response choices
Pre-coded value
Final value
Not at all
1
6.0
A little bit
2
4.75
Moderately
3
3.5
Quite a bit
4
2.25
Extremely
5
1.0
General Health (GH): Items 1 and 11a-11d:
Item 1
Response choices
Pre-coded value
Final value
Excellent
1
5.0
Very good
2
4.4
Good
3
3.4
Fair
4
2.0
Poor
5
1.0
Item 11a & 11c
Response choices
Pre-coded value
No Recoding Required 
Final value
Definitely true
1
1


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Mostly true
2
2
Don’t know
3
3
Mostly false
4
4
Definitely false
5
5
Item 11b & 11d
Response choices
Pre-coded value
Final value
Definitely true
1
5
Mostly true
2
4
Don’t know
3
3
Mostly false
4
2
Definitely false
5
1
Vitality (VT): Items 9a, 9e, 9g, & 9i:
Item 9a & 9e
Response choices
Pre-coded value
Final value
All of the time
1
5
Most of the time
2
4
Some of the time
3
3
A little of the time
4
2
None of the time
5
1
Item 9g & 9i
Response choices
Pre-coded value
No Recoding Required 
Final value
All of the time
1
1
Most of the time
2
2
Some of the time
3
3
A little of the time
4
4
None of the time
5
5
Social Functioning (SF): Items 6 & 10:
Item 6
Response choices
Pre-coded value
Final value
Not at all
1
5
Slightly
2
4
Moderately
3
3
Quite a bit
4
2
Extremely
5
1
Item 10
Response choices
Pre-coded value
No Recoding Required 
Final value
All of the time
1
1
Most of the time
2
2
Some of the time
3
3
A little of the time
4
4
None of the time
5
5
Role Emotional (RE): Items 5a - 5c:
Response choices
Pre-coded value
No Recoding Required 
Final value
All of the time
1
1
Most of the time
2
2
Some of the time
3
3
A little of the time
4
4
None of the time
5
5


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Mental Health (MH): Items 9b, 9c, 9d, 9f, & 9h:
Items 9b,9c, & 9f 
Response choices
Pre-coded value
No Recoding Required 
Final value
All of the time
1
1
Most of the time
2
2
Some of the time
3
3
A little of the time
4
4
None of the time
5
5
Item 9d & 9h
Response choices
Pre-coded value
Final value
All of the time
1
5
Most of the time
2
4
Some of the time
3
3
A little of the time
4
2
None of the time
5
1
10.3.3.2.
Handling Missing MOS SF-36 Items
For each of the eight domain scales (PF, RP, BP, GH, VT, SF, RE and MH), the Half-
Scale Rule will be applied for missing data.  If any items within a domain scale are 
missing (but at least half of the items in the domain scale have responses), then the final 
value for the missing items should be substituted with the average of the final values 
within the domain (i.e. after recoding if necessary) for the same subject.  If any items 
within a domain scale are missing (but fewer than half of the items in the domain scale 
have responses), then the domain scale will be set to missing. Each domain score will be 
considered missing if more than half of the items within the scale have missing values.
10.3.3.3.
Domain Scale Scores
After item recoding and imputing of missing values, a raw score will be computed for 
each domain scale.  This score is the simple algebraic sum of responses for all items in 
that scale as shown in the table below:
Domain
Actual raw score
(sum final values
after re-coding)
Lowest and 
highest possible 
raw scores
Possible raw
score range
Physical functioning (PF)
3a+3b+3c+3d+3e+3f+
3g+3h+3i+3j
10, 30
20
Role-physical (RP)
4a+4b+4c+4d
4, 20
16
Bodily pain (BP)
7+8
2, 12
10
General health (GH)
1+11a+11b+11c+11d
5, 25
20
Vitality (VT)
9a+9e+9g+9i
4,20
16
Social functioning (SF)
6+10
2, 10
8
Role-emotional (RE)
5a+5b+5c
3, 15
12
Mental health (MH)
9b+9c+9d+9f+9h
5, 25
20
After item re-coding, a raw score is computed for each scale and transformed to a 0 to 
100 scale as shown below:  


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Example: A Physical Functioning raw score of 21 would be transformed as follows:
where the lowest possible score=10 and the possible raw score range=20.
10.3.3.4.
Standardized Z Scores
Each transformed domain scale score is standardised using a z-score transformation, 
subtracting a population mean and dividing the resultant value by a population standard 
deviation.  The population means and standard deviations of the transformed domain 
scores are based on the 1998 US general population.  The formulas for z-score 
standardization of domain scales are thus:
PF_Z = (Transformed PF – 83.29094) / 23.75883
RP_Z = (Transformed RP – 82.50964) / 25.52028
BP_Z = (Transformed BP – 71.325227) / 23.66224
GH_Z = (Transformed GH – 70.84570) / 20.97821
VT_Z = (Transformed VT – 58.31411) / 20.01923
SF_Z = (Transformed SF – 84.30250) / 22.91921
RE_Z = (Transformed RE – 87.39733) / 21.43778
MH_Z = (Transformed MH – 74.98685) / 17.75604.
10.3.3.5.
Norm-based Domain Scores (NBS)
Norm-based scoring (NBS) makes it possible to compare and interpret the SF-36 domain 
scale scores.  The norm-based scores (NBS) for the 8 domains are derived by multiplying 
each z-score by 10 and adding 50 to the result.  
10.3.3.6.
Physical and Mental Component Summaries (PCS and MCS)
The Physical Component Summary (PCS) and Mental Component Summary (MCS) 
scores are derived in two steps.  First, aggregate scores are derived using a weighted 
mean of the z-scores calculated (see Section 10.3.3.4) using the formulae shown below:
AGG_PHYS = 
(PF_Z * 0.42402) + (RP_Z * 0.35119) + (BP_Z * 0.31754) + 
(GH_Z *0.24954) + (VT_Z * 0.02877) + (SF_Z * -0.00753) + 
(RE_Z* -0.19206) + (MH_Z * -0.22069)
AGG_MENT = (PF_Z * -0.22999) + (RP_Z * -0.12329) + (BP_Z * -0.09731) 
+(GH_Z * -0.01571) + (VT_Z * 0.23534) + (SF_Z * 0.26876) 
+(RE_Z* 0.43407) + (MH_Z * 0.48581).


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Secondly, the aggregate physical and mental summary scores are transformed to PCS and 
MCS score by multiplying each value by 10 and adding 50 to the result.  This NBS 
standardisation of the PCS and MCS means that results for one summary score can be 
compared to the other, and their scores have a direct interpretation in relation to the 
distribution of scores in the general US population.
10.3.4.
Derivation of KCCQ Scores
There are 10 summary scores within the KCCQ, which are calculated as follows:
1. Physical Limitation

Code responses to each of Questions 1a-f as follows:
o
Extremely limited = 1
o
Quite a bit limited = 2
o
Moderately limited = 3
o
Slightly limited = 4
o
Not at all limited = 5
o
Limited for other reasons or did not do = <missing value>

If at least three of Questions 1a-f are not missing, then compute
Physical Limitation Score = 
100*[(mean of Questions 1a-f actually answered) – 1]/4
2. Symptom Stability

Code the response to Question 2 as follows:
o
Much worse = 1
o
Slightly worse = 2
o
Not changed = 3
o
Slightly better = 4
o
Much better = 5
o
I’ve had no symptoms over the last 2 weeks = 3

If Question 2 is not missing, then compute
Symptom Stability Score = 100*[(Question 2) – 1]/4
3. Symptom Frequency

Code responses to Questions 3, 5, 7 and 9 as follows:
o
Question 3
•
Every morning = 1
•
3 or more times a week but not every day = 2
•
1-2 times a week = 3
•
Less than once a week = 4


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•
Never over the past 2 weeks = 5
o
Questions 5 and 7
•
All of the time = 1
•
Several times a day = 2
•
At least once a day = 3
•
3 or more times a week but not every day = 4
•
1-2 times a week = 5
•
Less than once a week = 6
•
Never over the past 2 weeks = 7
o
Question 9
•
Every night = 1
•
3 or more times a week but not every day = 2
•
1-2 times a week = 3
•
Less than once a week = 4
•
Never over the past 2 weeks = 5

If at least two of Questions 3, 5, 7 and 9 are not missing, then compute:
S3 = [(Question 3) – 1]/4
S5 = [(Question 5) – 1]/6
S7 = [(Question 7) – 1]/6
S9 = [(Question 9) – 1]/4
Symptom Frequency Score = 100*(mean of S3, S5, S7 and S9)
4. Symptom Burden

Code responses to each of Questions 4, 6 and 8 as follows:
o
Extremely bothersome = 1
o
Quite a bit bothersome = 2
o
Moderately bothersome = 3
o
Slightly bothersome = 4
o
Not at all bothersome = 5
o
I’ve had no swelling/fatigue/shortness of breath = 5

If at least one of Questions 4, 6 and 8 is not missing, then compute
Symptom Burden Score = 
100*[(mean of Questions 4, 6 and 8 actually answered) – 1]/4
5. Total Symptom Score
= mean of the following available summary scores:
o
Symptom Frequency Score
o
Symptom Burden Score


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6.  Self-Efficacy

Code responses to Questions 10 and 11 as follows:
o
Question 10
•
Not at all sure = 1
•
Not very sure = 2
•
Somewhat sure = 3
•
Mostly sure = 4
•
Completely sure = 5
o
Question 11
•
Do not understand at all = 1
•
Do not understand very well = 2
•
Somewhat understand = 3
•
Mostly understand = 4
•
Completely understand = 5

If at least one of Questions 10 and 11 is not missing, then compute
Self-Efficacy Score = 
100*[(mean of Questions 10 and 11 actually answered) – 1]/4
7. Quality of Life

Code responses to Questions 12, 13 and 14 as follows:
o
Question 12
•
It has extremely limited my enjoyment of life = 1
•
It has limited my enjoyment of life quite a bit = 2
•
It has moderately limited my enjoyment of life = 3
•
It has slightly limited my enjoyment of life = 4
•
It has not limited my enjoyment of life at all = 5
o
Question 13
•
Not at all satisfied = 1
•
Mostly dissatisfied = 2
•
Somewhat satisfied = 3
•
Mostly satisfied = 4
•
Completely satisfied = 5
o
Question 14
•
I felt that way all of the time = 1
•
I felt that way most of the time = 2
•
I occasionally felt that way = 3
•
I rarely felt that way = 4
•
I never felt that way = 5


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
If at least one of Questions 12, 13 and 14 is not missing, then compute
Quality of Life Score = 
100*[(mean of Questions 12, 13 and 14 actually answered) – 1]/4
8. Social Limitation

Code responses to each of Questions 15a-d as follows:
o
Severely limited = 1
o
Limited quite a bit = 2
o
Moderately limited = 3
o
Slightly limited = 4
o
Did not limit at all = 5
o
Does not apply or did not do for other reasons = <missing value>

If at least two of Questions 15a-d are not missing, then compute
Social Limitation Score = 
100*[(mean of Questions 15a-d actually answered) – 1]/4
9. Overall Summary Score
= mean of the following available summary scores:
o
Physical Limitation Score
o
Total Symptom Score
o
Quality of Life Score
o
Social Limitation Score
10. Clinical Summary Score
= mean of the following available summary scores:
o
Physical Limitation Score
o
Total Symptom Score
“Means of questions actually answered” imply the following:

If there are n questions in a scale, and the subject must answer m to score the 
scale, but the subject answers only n-i, where n-i >= m, the mean should be 
calculated as
(sum of the responses to those n-i questions) / (n-i)
not
(sum of the responses to those n-i questions) / n


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10.3.5.
Derivation of EORTC QLQ-C30 Scores
10.3.5.1.
Scale definition and score derivation
The EORTC QLQ-C30 is composed of both multi-item scales and single-item measures. 
These include 5 functional scales, 3 symptom scales, 1 global health status / QoL scale, 
and 6 single items.
The item (question) numbers included in each scale, as well as the item ranges are 
summarised in Table 14.
Table 17
Scoring the EORTC QLQ-C30 (version 3.0)
Scale
Number 
of items
Item 
range*
Item 
numbers
Function 
scales
Global Health Status / QoL
Global Health Status / QoL
(revised)a
QL2
2
6
29, 30
Functional Scales
Physical functioning (revised)a
Role functioning (revised)a
Emotional functioning
Cognitive functioning
Social functioning
PF2
RF2
EF
CF
SF
5
2
4
2
2
3
3
3
3
3
1 to 5
6, 7
21 to 24
20, 25
26, 27
F
F
F
F
F
Symptom scales / items
Fatigue
Nausea and vomiting
Pain
Dyspnoea
Insomnia
Appetite loss
Constipation
Diarrhoea
Financial difficulties
FA
NV
PA
DY
SL
AP
CO
DI
FI
3
2
2
1
1
1
1
1
1
3
3
3
3
3
3
3
3
3
10, 12, 18
14, 15
9, 19
8
11
13
16
17
28
* Item range is the difference between the possible maximum and the minimum response to individual 
items; most items take values from 1 to 4, giving range = 3.
a(revised) scales are those that have been changed since EORTC QLQ-C30 version 1.0, and their short 
names are indicated by a suffix “2” – for example, PF2.
For all scales, the Raw Score (RS) is the mean of the component items:
Then for Function scales:


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And for Symptom scales /items and Global health status / QoL:
10.3.5.2.
Handling of missing items
For multi-item scales:

If at least half of the items from a given scale have been answered, then missing 
items can be ignored and the calculations should be made using available (non-
missing) items only. The denominator in the derivation of RS (‘n’) becomes the 
number of non-missing items. 

If less than half of the items have been answered, then set the score to missing
For single-item scales, a missing measurement will result in a missing score.
10.3.5.3.
SAS code examples
SAS code examples are provided in the EORTC QLQ C-30 scoring manual for emotional 
functioning and dyspnoea scales.
“SAS statements (SAS for Windows, release 6.08) to calculate the score for the EF scale 
could be written as follows; XNUM is used to count the number of non-missing items, 
which should be at least half the total NITEMS items in the scale. Thus this code 
calculates the average of the nonmissing values, and transforms this average to range 
from 0 to 100 provided that the subject has completed at least half the necessary items.
For emotional functioning (EF) there are 4 items, each with a range of 3:
NITEMS = 4;
XNUM = N(OF Q21,Q22,Q23,Q24);
XMEAN = MEAN(OF Q21,Q22,Q23,Q24);
IF XNUM GE NITEMS / 2 THEN
EF = (1 - (XMEAN-1)/3 ) * 100;
For dyspnoea (DY), a symptom comprising a single item with a range of 3:
DY = ((Q8-1)/3) * 100;”


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10.3.6.
Derivation of DLQI Scores
10.3.6.1.
Scale definition and score derivation
The scoring of each DLQI question is as follows: 
Answer
Score
Very much
3
A lot
2
A little
1
Not at all
0
Not relevant
0
Question unanswered
0
Question 7 “prevented work or studying”
3
The DLQI is calculated by summing the score of each question resulting in a maximum 
of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. 
Meaning of DLQI Scores:
Score
Meaning
0-1
No effect at all on patient’s life
2-5
Small effect on patient’s life
6-10
Moderate effect on patient’s life
11-20
Very large effect on patient’s life
21-30
Extremely large effect on patient’s life
Detailed analysis of the DLQI:
The DLQI can be analysed under six headings as follows:
Symptoms and feelings
Questions 1 and 2
Score maximum 6
Daily activities
Questions 3 and 4
Score maximum 6
Leisure
Questions 5 and 6
Score maximum 6
Work and School
Question 7
Score maximum 3
Personal relationships
Questions 8 and 9
Score maximum 6
Treatment
Question 10
Score maximum 3
10.3.6.2.
Handling of missing items

If one question is left unanswered this is scored 0 and the scores are summed and 
expressed as usual out of a maximum of 30.

If two or more questions are left unanswered the questionnaire is not scored.

If question 7 is answered 'yes' this is scored 3. If question 7 is answered 'no' or 
'not relevant' but then either 'a lot' or 'a little' is ticked this is then scored 2 or 1. If 
it is answered 'no', but the second half is left incomplete, the score will remain 0.

If two or more response options are ticked, the response option with the highest
score should be recorded.


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
If there is a response between two tick boxes, the lower of the two score options 
should be recorded.

The DLQI can be analysed by calculating the score for each of its six sub-scales 
(see above). When using sub-scales, if the answer to one question in a sub-scale is 
missing, that sub-scale should not be scored.
10.3.7.
Derivation of LGE variable
The LGE variable will be defined as follows:

If Transmural value is ‘Yes’, then LGE will be set to ‘Transmural’

Else of Endocardial value is ‘Yes’, then LGE will be set to ‘Endocardial’

Else LGE will be set to ‘No’
10.3.8.
Derivation of DCE-CMR Global Measure of Myocardial Perfusion
The DCE-CMR global measure of myocardial perfusion will be derived as the mean of 
myocardial blood flow in each segment, weighted by each segment size.
The formula will be as follows: 
, where n is the number of segments, wi the 
segment size and xi the absolute myocardial blood flow for segment i.
10.3.9.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: UK1SALX00175
HARP Area
: \ARPROD\gsk2398852\mid201464
QC Spreadsheet
: \ARPROD\gsk2398852\mid201464\Final_02\Documents
QC spreadsheets will also be produced and saved for each interim under:
: \ARPROD\gsk2398852\mid201464\internal_XX\Documents
Analysis Datasets 

Analysis datasets will be created according to CDISC standards (ADaM).
Generation of RTF Files

RTF files will be generated.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.24: General Principles
o
5.01 to 5.08: Principles Related to Data Listings


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Reporting Standards
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for 
reporting of data based on the raw data collected.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but 
may be adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses :

Nominal visits will be used for the purpose of descriptive summary tables

Actual times relative to the first study dose of anti-SAP mAb will be used in individual 
subject plots, and for statistical analyses unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled 
visit days on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing (first dose of either GSK2315698 or 
GSK2398852) will be shown in listings (Refer to IDSL Statistical Principle 5.05.1).
Unscheduled Visits

Unscheduled visits will be used for baseline derivations in summary tables (see Section 
10.3.2.1). Post-baseline unscheduled visits will not be included in summary tables, with the 
exception of the following summaries: summary of subjects meeting emergent 
hepatobiliary laboratory abnormality criteria, summary of ECG findings, summary of 
maximum emergent QTc Values by category, summary of maximum change from baseline 
in QTc values by category

All unscheduled visits will be included in individual subject plots.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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10.4.
Appendix 4: Derived and Transformed Data
10.4.1.
General
Multiple Measurements at One Time Point

Mean of the measurements will be calculated and used in any derivation of summary 
statistics but if listed, all data will be presented.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day = Day post-first study dose of aSAP mAb

Calculated as the number of days from the first study dose of aSAP mAb:

Ref Date = Missing                          → Study Day = Missing 

Ref Date < aSAP mAb Dose Date   → Study Day = Ref Date – aSAP mAb First Study 
Dose Date    

Ref Data ≥ aSAP mAb Dose Date   → Study Day = Ref Date – (aSAP mAb First Study 
Dose Date) + 1    
Derivation of Time in Months

Time in months will be used to derive change at 3, 5, 8, 12 and 18 months, and slope 
parameters (units per month) for primary and secondary statistical analyses. It will also be 
used for the horizontal axis of Figures PD_F1 and PD_F4 (see Appendix 12: Example Mock 
Shells for Data Displays)

Time in months will be derived as Time in days / 30.4375, with Time in days defined as the 
assessment date – date of first dose of anti-SAP mAb. 
10.4.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2]
Extent of Exposure

Number of days of exposure to CPHPC will be calculated based on the following formula in 
each Treatment Session:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

The cumulative dose of CPHPC will be calculated from the sum of the individual doses 


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Extent of Exposure
administered in each dosing session and over the study as a whole.

Number of days of exposure to anti-SAP mAb will be calculated as the number of doses 
administered.  

The cumulative dose of aSAP mAb will be calculated from the sum of the individual doses 
administered (over all dosing sessions).
10.4.3.
Safety
ECG Parameters
RR Interval

IF RR interval (msec) is not provided directly, then RR can be derived as :
[1] If QTcB is machine read & QTcF is not provided, then :
[2] If QTcF is machine read and QTcB is not provided, then: 
Corrected QT Intervals

IF RR interval (msec) is provided then missing QTcB and/or QTcF will be derived as :
Adverse Events
AE’S OF Special Interest
A selection of AEs of interest for which posterior probabilities will be derived will be 
periodically reviewed and its finalization will be documented prior to database freeze (see 
Section 7.2.1).
Non-Quantifiable Laboratory an Biomarker Values
o
For laboratory values < lower limit of quantification:
o
the character value (‘<x’) will be listed;
o
the numeric value will be imputed as half the limit of quantification (x/2) for figures 
and tables. 
o
For laboratory values > upper limit of quantification:
o
the character value (‘>x’) will be listed;
o
the numeric value will be imputed as the limit of quantification (x) for figures and 
tables.


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10.5.
Appendix 5: Premature Withdrawals & Handling of Missing 
Data
10.5.1.
Premature Withdrawals
Element
Reporting Detail
General

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
10.5.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing 
displays. Unless all data for a specific visit are missing in which case the 
data is excluded from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
10.5.2.1.
Handling of Missing/Partial Dates
Element
Reporting Detail
General
Missing or partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to 
be recorded for AE start and end dates; that is, the day of the month may be 
missing. In such a case, the following conventions will be applied for calculating 
the time to onset and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the 
date of study drug first dose (earliest dose of GSK2315698 or 
GSK2398852); in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 2: Treatment 
States and Phases.
o
Missing Start Time: 00:00 will be used unless the (possibly imputed) date is 
the date of study drug first dose for any treatment session; in this case the 
study treatment start time will be used and hence the event is considered 
On-treatment as per Appendix 2: Treatment States and Phases.
o
Missing Stop Day: The last day of the month will be used (i.e. a '28’, ‘29’, 
‘30’ or ‘31' will be used for the day dependent on the month and year) or day 
of last follow-up assessment if earlier.
o
Missing Stop Time: There will be no imputation of missing stop times.

Completely missing start or end dates/times will remain missing, with no 


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Element
Reporting Detail
imputation applied. Consequently, time to onset and duration of such events will 
be missing. However, AEs will completely missing start dates/times will be 
assigned to the On-treatment phase and to the subject first treatment session, 
unless an on-treatment start can be ruled out from the end date/time (i.e. if the 
AE ended prior to study treatment start date/time)
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be 
imputed using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' 
will be used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day 
(dependent on the month and year) and 'Dec' will be used for the 
month.

The recorded partial date will be displayed in listings.
10.5.2.2.
Handling of Missing Data for Statistical Analysis
Element
Reporting Detail
Primary 
statistical 
model
Several approaches were considered for the handling of missing data in the primary 
statistical analysis model. Two of them involved the use of multiple imputation of 
missing post-treatment visits. More details can be found in Section 7.1.2.


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10.6.
Appendix 6: Values of Potential Clinical Importance
10.6.1.
Haematology Values of Potential Clinical Importance 
The criteria for values of potential clinical importance will depend on the study group.
10.6.1.1.
Study Group 1
Haematology Analyte
Effect
Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
White Blood Cell Count 
0.60
2.2
Neutrophil Count
0.60
2.2
Haemoglobin
Male
0.70
1.2
Female
0.75
1.2
Platelet Count
0.70
2.50
Lymphocytes
0.60
10.6.1.2.
Study Group 2
Haematology Analyte
Effect
Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
White Blood Cell Count 
0.30
2.2
Neutrophil Count
0.30
2.2
Haemoglobin
Male
0.65
1.2
Female
0.7
1.2
Platelet Count
0.25
2.50
Lymphocytes
0.30
2.2
10.6.1.3.
Study Group 3
Haematology Analyte
Effect
Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
White Blood Cell Count 
0.30
No limit
Neutrophil Count
0.30
No limit
Haemoglobin
Male
0.6
1.2
Female
0.7
1.2
Platelet Count
0.25
2.50
Lymphocytes
0.30


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10.6.2.
Chemistry Values of Potential Clinical Importance 
Chemistry Analyte
Relative – Low
(Multipliers of LLN)
Relative – High
(Multipliers of ULN)
Albumin (mmol/L)
0.75
Calcium (mmol/L)
0.80
1.20
Glucose (mmol/L)
0.60
2.00
Potassium (mmol/L)
0.77
1.17
Sodium (mmol/L)
0.92
1.07
Creatinine (mmol/L)
1.6
10.6.3.
Liver Function Test Values of Potential Clinical Importance
Liver Function Test Analyte
Effect
Potential Clinical Importance (PCI) Range
Unit
ALT/SGPT
High
>3x ULN
U/L
AST/SGOT
High
>3x ULN
U/L
AlkPhos
High
>3x ULN
U/L
T. Bilirubin
High
>2x ULN
mol/L
T. Bilirubin + ALT
High
> 1.5x ULN T.Billirubin
+
> 3x ULN ALT 
mol/L
U/L
10.6.4.
ECG Values and QTc Change of Potential Clinical Importance
ECG Parameter
Potential Clinical Importance Range (PCI)
Unit
Absolute QTc Interval
>500
msec
Increase from Baseline QTc
>60
msec
PR Interval
<110 and >220
msec
QRS Interval
<75 and >110
msec


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10.6.5.
Vital Sign Values and Changes of Potential Clinical Importance 
VS Parameter
Potential Clinical Importance Range (PCI)
Unit
Systolic Blood Pressure 
<90 and > 180 
mmHg
Diastolic Blood Pressure 
<30 and > 110 
mmHg
Heart Rate 
<35 and > 140 
Bpm
Systolic Blood Pressure 
(Change from Baseline)
Increase >50 
mmHg
Decrease < 50 
mmHg
Diastolic Blood Pressure 
(Change from Baseline)
Increase > 30 
mmHg
Decrease < 30 
mmHg
Heart Rate (Change from 
Baseline)
Increase > 50 
bpm
Decrease < 50 
bpm


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10.7.
Appendix 7: Model Checking and Diagnostics for Statistical 
Analyses
10.7.1.
Statistical Analysis Assumptions
Endpoint(s)

LV Mass

Secondary imaging markers of cardiac dysfunction monitored by serial CMR and / or 
ECHO
Analysis

Bayesian LMM

The Bayesian LMM convergence diagnostics available from SAS MCMC procedure will be 
reviewed, such as the Geweke test, sample autocorrelations, effective sample sizes, and 
Monte Carlo errors. 

In case of convergence issues, initial values, burn-in and thinning rate parameters may be 
adapted, or alternative prior distributions considered as appropriate.

Distributional assumptions underlying the model used for analysis will be examined by 
obtaining a normal probability plot of the residuals and a plot of the residuals versus the fitted 
values (i.e. checking the normality assumption and constant variance assumption of the model 
respectively) to gain confidence that the model assumptions are reasonable. 

If there are any departures from the distributional assumptions, alternative models will be 
explored using appropriate transformed data.


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10.8.
Appendix 8: Population Pharmacokinetic Analyses
10.8.1.
Systems
All non-linear mixed effects modelling will be performed using NONMEM (ICON 
Solutions), PsN (Perl Speaks NONMEM) and Pirana (Pirana Software & Consulting BV 
2016).
R (The R Foundation for Statistical Computing) will be used for exploratory graphical 
analysis, graphical model diagnostics and, if needed, modifications of the dataset.
The analysis will be performed by, or under the direct auspices of, Clinical Pharmacology 
Modelling and Simulation (CPMS), GlaxoSmithKline in the GSK modelling environment 
MAP (Model-based Analyses Platform) using the currently supported versions of all 
software packages.
10.8.2.
Data Assembly
The merge of PK, regimen and CRF data together with the creation of the NONMEM-
specific dataset will be performed by, or under the direct auspices of, Clinical Statistics 
(Programmer), GlaxoSmithKline.
This dataset programming will be conducted in the GSK Harmonisation for Analysis and 
Reporting Program (HARP) environment using the currently supported version of SAS. 
The dataset will be consistent with the specifications summarised in Section 10.8.6 and 
Section 10.8.7.
10.8.3.
Population Pharmacokinetic Analysis for GSK2315698
A population PK model has been developed for GSK2315698 in both healthy volunteers 
and subjects with systemic amyloidosis (GSK Document Number 2012N146440_00). 
Using this model, visual predictive checks (VPCs) will be conducted to assess 
graphically whether simulations from the developed model are able to reproduce both the 
central trend and variability in the observed data from the current study as a function of 
time.
The VPC will be based on 1000 simulations with the model and the design structure of 
the observed data (i.e. dose level and time, time of PK sampling and individual values of 
model covariates). The median and the 5th and 95th (or 10th and 90th, dependent on the 
size of the final dataset) will be compared to the observed data. Applicable stratification, 
such as dose level of GSK2315698, treatment cycle, subject group and relevant 
covariates will be used.
10.8.4.
Population Pharmacokinetic Analysis for GSK2398852
Subsequent model development will be data driven. The initial model of choice may be a 
hybrid PBPK model with target mediated drug disposition incorporated. Several tissues 


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may be grouped together in this model, in particular tissues without amyloid deposition. 
If a hybrid PBPK model cannot describe the data, a compartmental model will be tested.
The influence of the following covariates on the PK of GSK2398852 may be 
investigated:

Subject demographics: age, gender and weight or BMI

Disease state at (treatment cycle) baseline: overall amyloid load 
(none/small/moderate/large)

Organ involvement at (treatment cycle) baseline (e.g. liver)
Other covariates such as subject group may be explored as appropriate.
Model acceptability will be judged by convergence, covariance estimation and standard 
goodness-of-fit plots that may include, but are not limited to:

Population and individual predictions versus observations

Conditional weighted residuals versus population predictions and time
For the final PK models visual predictive checks (VPCs) will be conducted in the same 
way as described in Section 10.8.3.
10.8.5.
Reporting
A PK/PD report, describing the population PK analysis of GSK2315698 and 
GSK2398852, as well as the PK/PD analysis of the effect of GSK2315698 on plasma 
SAP (see Section 10.9) will be produced by CPMS, and will be included as an appendix 
to the CSR.
10.8.6.
Specifications for NONMEM-specific Dataset (PK GSK2315698)
The concentration dataset will be a comma separated values (csv) file, named 
“NM_GSK2315698_SAP201464_PK_v1.csv”. The version number will be updated each 
time a new version of the dataset is created.
This file will include events of dosing or concentration as rows, with the variables in the 
table below as columns. Rows will be in increasing order of unique subject identification 
number; and all events in the same subject must be consecutive and in chronological 
order, ending with the last concentration event (i.e. dosing events that occur after the last 
quantifiable concentration in a subject will not be included in the data file).
Non-numerical concentration values (such as missing samples, not assayed samples, non-
quantifiable samples or non-reportable samples) will not be included. Subjects with no 
quantifiable concentration values will not be included.


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Name
Implicit 
Unit
Description 
Programming 
Notes
Format
ID
-
Unique subject identification number
numeric
IDTC
-
Combination of unique subject identification number and 
treatment cycle number:
e.g.
for subj
and treatment cycle 1
e.g.
for subj
and treatment cycle 2
etc
numeric
TRFD
h
Event time from start of first dose of GSK2315698 within a 
treatment cycle
numeric
DV
ng/mL
For concentration events: plasma concentration of 
GSK2315698
For dosing events: 0
numeric
AMT
mg
For dosing events: dose of GSK2315698. Note that for the 
IV dose this should be the total dose given in one IV 
infusion (i.e. over several days). Interruptions due to 
changing of syringes are relatively short, and therefore the 
infusion will be assumed to be continuous.
For concentration events: 0
numeric
RATE
mg/hr
For dosing events of SC dosing: 0
For dosing events of IV dosing: rate of dosing (i.e. dose of 
GSK2315698 in mg divided by infusion duration)
For concentration events: 0
numeric
MDV
-
For concentration events: 0
For dosing events: 1
Numeric
CMT
-
Compartment:
For dosing events of SC dosing: 1
For dosing events of IV dosing: 2
For concentration events: 2
Numeric
NOMT
h
Planned PK sample time
For dosing events: 0
For pre-dose concentration events: 0
Numeric
TRLD
h
Event time from most recent dose of GSK2315698
For dosing events: 0
Numeric
PERD
-
Study period (treatment cycle)
Numeric
DOSEIV
mg/hr
IV dose of GSK2315698 in mg/hr (for all events)
Numeric
DOSESC
mg
SC dose of GSK2315698 in mg (for all events)
Numeric
STUD
-
Numeric part of study identifier (i.e. 201464)
Numeric
AGE
Years
Age at study baseline
Numeric
WT
Kg
Weight at event date, or nearest available previous value 
in same subject
Numeric
BMI
kg/m^2
Body mass index at event date, or nearest available 
previous value in same subject
Numeric
SEX
-
Subject gender:
Male=0
Female=1
Numeric
CRCL
mL/min
Creatinine clearance at session baseline (from MDRD 
measurement at screening visit)
Numeric
PPD
PPD


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Name
Implicit 
Unit
Description 
Programming 
Notes
Format
PATGRP
-
Patient group number:
Group 1 = 1
Group 2 = 2
Group 3 = 3
numeric
AMLOAD
-
Overall amyloid load at treatment cycle baseline:
None=0
Small=1
Moderate=2
Large=3
Numeric
AMLOADBL
-
Overall amyloid load at study baseline:
None=0
Small=1
Moderate=2
Large=3
Numeric
AMLOC
-
Liver involvement at treatment cycle baseline:
Liver involvement=1
No liver involvement =0
Numeric
AMLOCBL
-
Liver involvement at study baseline
Liver involvement=1
No liver involvement =0
Numeric
10.8.7.
Specifications for NONMEM-specific Dataset (PK GSK2398852)
The concentration dataset will be a comma delimited text file, named 
“NM_GSK2398852_SAP201464_PK_v1.csv”. The version number will be updated each 
time a new version of the dataset is created.
This file will include events of dosing or concentration as rows, with the variables in the 
table below as columns. Rows will be in increasing order of unique subject identification 
number; and all events in the same subject must be consecutive and in chronological 
order, ending with the last concentration event (i.e. dosing events that occur after the last 
quantifiable concentration in a subject will not be included in the data file).
Non-numerical concentration values (such as missing samples, not assayed samples, non-
quantifiable samples or non-reportable samples) will not be included. Subjects with no 
quantifiable concentration values will not be included.


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Name
Implicit 
Unit
Description 
Programming 
Notes
Format
ID
-
Unique subject identification number
numeric
IDTC
-
Combination of unique subject identification number and 
treatment cycle:
e.g.
for subj
and treatment cycle 1
e.g.
for subj
nd treatment cycle 2
etc
numeric
TRFD
h
Event time from start of first dose of GSK2398852 within a 
treatment cycle
numeric
DV
ng/mL
For concentration events: plasma concentration of 
GSK2398852
For dosing events: 0
numeric
AMT
mg
For dosing events: dose of GSK2398852. Note that this should 
be the total dose per IV infusion.
For concentration events: 0
numeric
RATE
mg/hr
For dosing events: rate of dosing (i.e. dose of GSK2398852 in 
mg divided by infusion duration)
For concentration events: 0
numeric
MDV
-
For concentration events: 0
For dosing events: 1
Numeric
CMT
-
Compartment:
For dosing events of IV dosing: 1
For concentration events: 1
Numeric
NOMT
h
Planned PK sample time
For dosing events: 0
For pre-dose concentration events: 0
Numeric
TRLD
h
Event time from most recent dose of GSK2398852
For dosing events: 0
Numeric
PERD
-
Study period (treatment cycle)
Numeric
DOSE
mg
Dose of GSK2398852 in mg (for all events)
Numeric
STUD
-
Numeric part of study identifier (i.e. 201464)
Numeric
AGE
Years
Age at study baseline
Numeric
WT
Kg
Weight at event date, or nearest available previous value in 
same subject
Numeric
BMI
kg/m^2
Body mass index at event date, or nearest available previous 
value in same subject
Numeric
SEX
-
Subject gender:
Male=0
Female=1
Numeric
CRCL
mL/min
Creatinine clearance at session baseline (from MDRD 
measurement at screening visit)
Numeric
PATGRP
-
Patient group number:
Group 1 = 1
Group 2 = 2
Group 3 = 3
numeric
AMLOAD
-
Overall amyloid load at treatment cycle baseline:
None=0
Small=1
Moderate=2
Large=3
Numeric
PPD
PPD


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Name
Implicit 
Unit
Description 
Programming 
Notes
Format
AMLOADBL
-
Overall amyloid load at study baseline:
None=0
Small=1
Moderate=2
Large=3
Numeric
AMLOC
-
Liver involvement at treatment cycle baseline:
Liver involvement=1
No liver involvement =0
Numeric
AMLOCBL
-
Liver involvement at study baseline
Liver involvement=1
No liver involvement =0
Numeric


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10.9.
Appendix 9: Pharmacokinetic / Pharmacodynamic Analyses
10.9.1.
Systems
All non-linear mixed effects modelling will be performed using NONMEM (ICON 
Solutions), PsN (Perl Speaks NONMEM) and Pirana (Pirana Software & Consulting BV 
2016).
R (The R Foundation for Statistical Computing) will be used for exploratory graphical 
analysis, graphical model diagnostics and, if needed, modifications of the dataset.
The analysis will be performed by, or under the direct auspices of, Clinical Pharmacology 
Modelling and Simulation (CPMS), GlaxoSmithKline in the GSK modelling environment 
MAP (Model-based Analyses Platform) using the currently supported versions of all 
software packages.
10.9.2.
Data Assembly
The merge of plasma SAP, regimen and CRF data together with the creation of the 
NONMEM-specific dataset will be performed by, or under the direct auspices of, Clinical 
Statistics (Programmer), GlaxoSmithKline.
This dataset programming will be conducted in the GSK Harmonisation for Analysis and 
Reporting Program (HARP) environment using the currently supported version of SAS. 
The dataset will be consistent with the specifications summarised in Section 10.9.5.
10.9.3.
Pharmacokinetic/Pharmacodynamic Analysis for plasma SAP 
Concentration
A population PK/PD model has been developed for the effect of GSK2315698 on SAP in 
plasma in both healthy volunteers and subjects with systemic amyloidosis (GSK 
Document Number 2012N146440_00). Using this model, adjusted for the difference in 
assay, visual predictive checks (VPCs) will be conducted to assess graphically whether 
simulations from the developed model are able to reproduce both the central trend and 
variability in the observed data from the current study as a function of time.
The VPC will be based on 1000 simulations with the model and the design structure of 
the observed data (i.e. dose level and time, time of SAP sampling and individual values 
of model covariates). The median and the 5th and 95th (or 10th and 90th, dependent on the 
size of the final dataset) will be compared to the observed data.  Applicable stratification, 
such as dose level of GSK2315698, treatment cycle, subject group and relevant 
covariates, will be used.
10.9.4.
Reporting
A PK/PD report, describing the population PK analysis of GSK2315698 and 
GSK2398852 (see Section 10.8), as well as the PK/PD analysis of the effect of 


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GSK2315698 on plasma SAP will be produced by CPMS, and will be included as an 
appendix to the CSR.
10.9.5.
Specifications for NONMEM-specific Dataset (SAP)
The concentration dataset will be a comma delimited text file, named 
“NM_GSK2315698_SAP201464_PD_v1.csv”. The version number will be updated each 
time a new version of the dataset is created.
This file will include events of dosing or SAP concentration as rows, with the variables in 
the table below as columns. Rows will be in increasing order of unique subject 
identification number; and all events in the same subject must be consecutive and in 
chronological order, ending with the last SAP concentration event (i.e. dosing events that 
occur after the last quantifiable concentration in a subject will not be included in the data 
file).
Non-numerical concentration values (such as missing samples, not assayed samples, non-
quantifiable samples or non-reportable samples) will not be included. Subjects with no 
quantifiable concentration values will not be included.
Name
Implicit 
Unit
Description 
Programming 
Notes
Format
ID
-
Unique subject identification number
numeric
IDTC
-
Combination of unique subject identification number and 
treatment cycle:
e.g.
for subj
and treatment cycle 1
e.g.
for subj
and treatment cycle 2
etc
numeric
TRFD
h
Event time from start of first dose of GSK2315698 within a 
treatment cycle
numeric
DV
mg/L
For concentration events: plasma concentration of SAP
For dosing events: 0
numeric
AMT
mg
For dosing events: dose of GSK2315698. Note that for the IV 
dose this should be the total dose given in one IV infusion (i.e. 
over several days). Interruptions due to changing of syringes are 
relatively short, and therefore the infusion will be assumed to be 
continuous.
For concentration events: 0
numeric
RATE
mg/hr
For dosing events of SC dosing: 0
For dosing events of IV dosing: rate of dosing (i.e. dose of 
GSK2315698 in mg divided by infusion duration)
For concentration events: 0
numeric
MDV
-
For concentration events: 0
For dosing events: 1
Numeric
CMT
-
Compartment:
For dosing events of SC dosing: 1
For dosing events of IV dosing: 2
For concentration events: 2
Numeric
NOMT
h
Planned sample time for SAP
For dosing events: 0
For pre-dose concentration events: 0
Numeric
TRLD
h
Event time from most recent dose of GSK2315698
For dosing events: 0
Numeric
PPD
PPD


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Name
Implicit 
Unit
Description 
Programming 
Notes
Format
PERD
-
Study period (treatment cycle)
Numeric
DOSEIV
mg/hr
IV dose of GSK2315698 in mg/hr (for all events)
Numeric
DOSESC
mg
SC dose of GSK2315698 in mg (for all events)
Numeric
STUD
-
Numeric part of study identifier (i.e. 201464)
Numeric
AGE
Years
Age at study baseline
Numeric
WT
Kg
Weight at event date, or nearest available previous value in same 
subject
Numeric
BMI
kg/m^2
Body mass index at event date, or nearest available previous 
value in same subject
Numeric
SEX
-
Subject gender:
Male=0
Female=1
Numeric
CRCL
mL/min
Creatinine clearance at session baseline (from MDRD 
measurement at screening visit)
Numeric
PATGRP
-
Patient group number:
Group 1 = 1
Group 2 = 2
Group 3 = 3
numeric
AMLOAD
-
Overall amyloid load at treatment cycle baseline:
None=0
Small=1
Moderate=2
Large=3
Numeric
AMLOADBL
-
Overall amyloid load at study baseline:
None=0
Small=1
Moderate=2
Large=3
Numeric
AMLOC
-
Liver involvement at treatment cycle baseline:
Liver involvement=1
No liver involvement =0
Numeric
AMLOCBL
-
Liver involvement at study baseline
Liver involvement=1
No liver involvement =0
Numeric


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10.10.
Appendix 10 – Abbreviations & Trade Marks
10.10.1.
Abbreviations
Abbreviation
Description
6MWT
6 Minute Walk Test
ADaM
Analysis Data Model
AE
Adverse Event
AL
Immunoglobin Light Chain Amyloidosis
ALT
Alanine Transaminase
AUC
Area Under the Concentration-Time Profile
BMI
Body Mass Index
CDISC
Clinical Data Interchange Standards Consortium
Cmax
Maximum Concentration
CMR
Cardiac MRI
CPHPC
Carboxy Pyrrolidine Hexanoyl Pyrrolidine Carboxylate
CPMS
Clinical Pharmacology Modelling & Simulation
CRF
Case Report Form
CrInt
Credible Interval
CRP
C Reactive Protein
CSR
Clinical Study Report
CTC
Common Terminology Criteria
CTCAE 
Common Terminology Criteria for Adverse Events
DCE
Dynamic Contrast Enhanced
DLQI
Dermatology Quality of Life Index
DP
Decimal Places
DPD/99mTc-
DPD
99mTechnetium-dicarboxypropane diphosphonate
ECG
Electrocardiogram
ECHO
Echocardiography
eCRF
Electronic Case Record Form
ECV
Extracellular Volume
EDV
End Diastolic Volume
EF
Ejection Fraction
eGFR
Estimated Glomerular Filtration Rate
EORTC QLQ 
C30
The European Organisation for Research and Treatment of Cancer 
Quality of Life Questionnaire C30
FAC
Fractional Area Change
FDA
Food and Drug Administration
GLS
Global Longitudinal Strain
GSK
GlaxoSmithKline
hs
High-sensitivity
hsCRP
High-sensitivity C-reactive Protein
ICH
International Conference on Harmonisation
IDSL
Integrated Data Standards Library
HARP
GSK Harmonisation for Analysis and Reporting Program


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Abbreviation
Description
KCCQ
Kansas City Cardiomyopathy Questionnaire
LA
Left Atrial
LGE
Late Gadolinium Enhancement
LLN
Lower Limit of Normal
LMM
Linear Mixed Model
LV
Left Ventricular
mAb
Monoclonal Antibody
MAP
Model-based Analyses Platform
MAR
Missing At Random
MCS
Mental Component Summary
MNAR
Missing Not At Random
MOS SF-36
Medical Outcome Study Short Form (36)
MRI
Magnetic Resonance Imaging
NAC
UK National Amyloidosis Centre
NBS
Norm-Based Domain Scores
NQ
Non-Quantifiable
NT pro-BNP
N-terminal pro b-type Natriuretic Peptide
PCI
Potential Clinical Importance 
PCS
Physical Component Summary
PD
Pharmacodynamic
PK
Pharmacokinetic
PMM
Pattern Mixture Model
PopPK
Population PK
PT
Preferred Term
PYP/99mTc-
PYP
99mTc-Pyrophosphate
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RV
Right Ventricular
SAA
Serum Amyloid A Protein
SAC
Statistical Analysis Complete
SAP
Serum Amyloid P Component
SD
Standard Deviation
SOC
System Organ Class
SV
Stroke Volume
TFL
Tables, Figures & Listings 
tmax
The Time Associated with Cmax
TTR
Transthyretin
ULN
Upper Limit of Normal
VPC
Visual Predictive Check


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10.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
NONE
NONMEM
R
SAS


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10.11.
Appendix 11: List of Data Displays
Unless otherwise specified, data displays will be paginated by study groups. Study groups 
will be displayed by ascending order.
Note that initial interims may only include one study group based on the interim 
triggering rules defined in Section 3.1.  
10.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.n
1.1 to 1.n
Pharmacodynamic and / or Biomarker
2.1 to 2.n
2.1 to 2.n
Safety
3.1 to 3.n
3.1 to 3.n
Pharmacokinetic
4.1 to 4.n
4.1 to 4.n
Efficacy
5.1 to 5.n
5.1 to 5.n
Quality of Life
6.1 to 6.n
6.1 to 6.n
Section
Listings
ICH Listings
1 to x
Other Listings
y to z
10.11.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up display provided in Appendix 12: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’


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10.11.3.
Deliverable [Priority]
For a description of interim analysis trigger and corresponding analysis selection, refer to 
Section 3.1.
Delivery [Priority] [1]
Description
IA1 [X]
Interim Analysis Selection #1 
IA2 [X]
Interim Analysis Selection #2 
SAC [X]
Full RAP Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated.


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10.11.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Disposition
1.1.
Safety
ES1
Summary of Subject Disposition
SAC [3]
1.2.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failures
SAC [3]
1.3.
Enrolled
NS1
Summary of Number of Subjects by Country and Centre ID
SAC [3]
1.4.
Safety
SD1
Summary of Treatment Status and Reason for Discontinuation 
of Study Treatment
SAC [3]
Protocol Deviations
1.5.
Safety
DV1
Summary of Important Protocol Deviations
SAC [3]
Populations Analysed
1.6.
Screened
SP1
Summary of Study Populations
SAC [3]
Demography
1.7.
Safety
DM1
Summary of Demographic Characteristics
SAC [3]
1.8.
Enrolled
DM11
Summary of Age Ranges
SAC [3]
1.9.
Safety
DM6
Summary of Race and Racial Combination Details
SAC [3]
1.10.
Standard of 
Care
DM1
Summary of Demographic Characteristics
SAC [3]
1.11.
Standard of 
Care
DM11
Summary of Age Ranges
SAC [3]
1.12.
Standard of 
Care
DM6
Summary of Race and Racial Combination Details
SAC [3]


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Study Population Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Concomitant Medications 
1.13.
Safety
CM1
Summary of Concomitant Medications
SAC [3]
Medical Conditions
1.14.
Safety
MH1
Summary of Current Medical Conditions
SAC [3]
1.15.
Safety
MH1
Summary of Past Medical Conditions
SAC [3]
Exposure
1.16.
Safety
EX1
Summary of Exposure to CPHPC
Display overall and by treatment 
session
SAC [3]
1.17.
Safety
EX1
Summary of Exposure to anti-SAP mAb
Display overall and by treatment 
session
SAC [3]


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10.11.5.
Pharmacodynamic and Biomarker Tables
Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Pharmacodynamic/Biomarker Endpoint
2.1.
Safety
Non-standard 
PD_T1
Summary of LV mass (g) Measured by CMR Over Time
Includes absolute values and changes 
from baseline 
IA1 [1], IA2[1], 
SAC [1]
2.2.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV mass (g) Measured by CMR, Model: Three-Piece 
Linear Model (Model 1), Missing Data Imputation: None
Include all Bayesian model parameters.
IA2[1], SAC [1]
2.3.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
LV Mass (g) Measured by CMR with Posterior Probabilities of 
Interest, Model: Three-Piece Linear Model (Model 1), Missing 
Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
IA2[1], SAC [1]
2.4.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV mass (g) Measured by CMR, Model: Three-Piece 
Linear Model (Model 1), Missing Data Imputation: Non-Future 
Dependency
Include all Bayesian model parameters.
SAC [1]
2.5.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
LV Mass (g) Measured by CMR with Posterior Probabilities of 
Interest, Model: Three-Piece Linear Model (Model 1), Missing 
Data Imputation: Non-Future Dependency
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
SAC [1]
2.6.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV mass (g) Measured by CMR, Model: Three-Piece 
Linear Model (Model 1), Missing Data Imputation: Based on 
Standard of Care Data
Include all Bayesian model parameters.
SAC [1]


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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.7.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
LV Mass (g) Measured by CMR with Posterior Probabilities of 
Interest, Model: Three-Piece Linear Model (Model 1), Missing 
Data Imputation: Based on Standard of Care Data
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
SAC [1]
2.8.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV mass (g) Measured by CMR, Model: Two-Piece 
Linear Model (Model 2), Missing Data Imputation: None
Include all Bayesian model parameters.
IA2[1], SAC [1]
2.9.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
LV Mass (g) Measured by CMR with Posterior Probabilities of 
Interest, Model: Two-Piece Linear Model (Model 2), Missing 
Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
IA2[1], SAC [1]
2.10.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV mass (g) Measured by CMR, Model: Including 
Restricted Cubic Splines (Sensitivity Model 1), Missing Data 
Imputation: None
Include all Bayesian model parameters.
IA2[1], SAC [1]
2.11.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
LV Mass (g) Measured by CMR with Posterior Probabilities of 
Interest, Model: Including Restricted Cubic Splines (Sensitivity 
Model 1), Missing Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
IA2[1], SAC [1]
2.12.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV mass (g) Measured by CMR, Model: Including 
Polynomial Terms (Sensitivity Model 2), Missing Data 
Imputation: None
Include all Bayesian model parameters.
IA2[1], SAC [1]
2.13.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
LV Mass (g) Measured by CMR with Posterior Probabilities of 
Interest, Model: Model: Including Polynomial Terms (Sensitivity 
Model 2), Missing Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
IA2[1], SAC [1]


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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.14.
Standard of 
Care
Non-standard 
PD_T1
Summary of LV mass (g) Measured by CMR Over Time
Includes absolute values and changes 
from first scan
SAC [1]
2.15.
Standard of 
Care
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV mass (g) Measured by CMR, Model: Linear 
Model, Missing Data Imputation: None
Include all Bayesian model parameters 
(Intercept and Slope).
SAC [1]
2.16.
Standard of 
Care
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
LV Mass (g) Measured by CMR with Posterior Probabilities of 
Interest, Model: Linear Model, Missing Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
SAC [1]
Secondary Imaging Markers of Cardiac Dysfunction
2.17.
Safety
Non-standard 
PD_T1
Summary of Imaging Markers of Cardiac Dysfunctions Over 
Time
Several endpoints: GLS by CMR & 
ECHO (tagging, feature tracking, 
speckle tracking), LV Twist by CMR, SV 
by CMR & ECHO, EF by CMR & 
ECHO, EDV by CMR & ECHO, E/e’ 
ratio by ECHO (lateral and septal)
Includes absolute values and changes 
from baseline.
IA1 [2], IA2[2], 
SAC [2]
2.18.
Standard of 
Care
Non-standard 
PD_T1
Summary of Imaging Markers of Cardiac Dysfunctions Over 
Time
Several endpoints, where available for 
the Standard of Care population: GLS 
by CMR & ECHO (tagging, feature 
tracking, speckle tracking), LV Twist by 
CMR, SV by CMR & ECHO, EF by 
CMR & ECHO, EDV by CMR & ECHO, 
E/e’ ratio by ECHO (lateral and septal)
Includes absolute values and changes 
from first scan.
SAC [2]


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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.19.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of Global Longitudinal Strain (<unit>) Measured by 
CMR, Model: Three-Piece Linear Model (Model 1), Missing Data 
Imputation: None
Include all Bayesian model parameters.
Paginate by GLS type of measurement:
tagging, feature tracking (CMR), 
speckle tracking (ECHO)
IA2[2], SAC [2]
2.20.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
Global Longitudinal Strain (<unit>) Measured by CMR with 
Posterior Probabilities of Interest, Model: Three-Piece Linear 
Model (Model 1), Missing Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
Paginate by GLS type of measurement: 
tagging, feature tracking (CMR), 
speckle tracking (ECHO)
IA2[2], SAC [2]
2.21.
Standard of 
Care
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of Global Longitudinal Strain (<unit>) Measured by 
CMR, Model: Linear Model, Missing Data Imputation: None
Include all Bayesian model parameters 
(Intercept and Slope).
Paginate by GLS type of measurement: 
tagging, feature tracking (CMR), 
speckle tracking (ECHO)
SAC [2]
2.22.
Standard of 
Care
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
Global Longitudinal Strain (<unit>) Measured by CMR with 
Posterior Probabilities of Interest, Model: Linear Model, Missing 
Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
Paginate by GLS type of measurement: 
tagging, feature tracking (CMR), 
speckle tracking (ECHO)
SAC [2]
2.23.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of Left Ventricular Twist (<unit>) Measured by CMR, 
Model: Three-Piece Linear Model (Model 1), Missing Data 
Imputation: None
Include all Bayesian model parameters.
IA2[2], SAC [2]
2.24.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
Left Ventricular Twist (<unit>) Measured by CMR with Posterior 
Probabilities of Interest, Model: Three-Piece Linear Model 
(Model 1), Missing Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
IA2[2], SAC [2]


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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.25.
Standard of 
Care
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of Left Ventricular Twist (<unit>) Measured by CMR, 
Model: Linear Model, Missing Data Imputation: None
Include all Bayesian model parameters 
(Intercept and Slope).
SAC [2]
2.26.
Standard of 
Care
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
Left Ventricular Twist (<unit>) Measured by CMR with Posterior 
Probabilities of Interest, Model: Linear Model, Missing Data 
Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
SAC [2]
2.27.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of Stroke Volume (mL) Measured by CMR, Model: 
Three-Piece Linear Model (Model 1), Missing Data Imputation: 
None
Include all Bayesian model parameters.
IA2[2], SAC [2]
2.28.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
Stroke Volume (mL) Measured by CMR with Posterior 
Probabilities of Interest, Model: Three-Piece Linear Model 
(Model 1), Missing Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
IA2[2], SAC [2]
2.29.
Standard of 
Care
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of Stroke Volume (mL) Measured by CMR, Model: 
Linear Model, Missing Data Imputation: None
Include all Bayesian model parameters 
(Intercept and Slope).
SAC [2]
2.30.
Standard of 
Care
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
Stroke Volume (mL) Measured by CMR with Posterior 
Probabilities of Interest, Model: Linear Model, Missing Data 
Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
SAC [2]
2.31.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of Ejection Fraction (%) Measured by CMR, Model: 
Three-Piece Linear Model (Model 1), Missing Data Imputation: 
None
Include all Bayesian model parameters.
IA2[2], SAC [2]


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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.32.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
Ejection Fraction (%) Measured by CMR with Posterior 
Probabilities of Interest, Model: Three-Piece Linear Model 
(Model 1), Missing Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
IA2[2], SAC [2]
2.33.
Standard of 
Care
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of Ejection Fraction (%) Measured by CMR, Model: 
Linear Model, Missing Data Imputation: None
Include all Bayesian model parameters 
(Intercept and Slope).
SAC [2]
2.34.
Standard of 
Care
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
Ejection Fraction (%) Measured by CMR with Posterior 
Probabilities of Interest, Model: Linear Model, Missing Data 
Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
SAC [2]
2.35.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of End Diastolic Volume (mL) Measured by CMR, 
Model: Three-Piece Linear Model (Model 1), Missing Data 
Imputation: None
Include all Bayesian model parameters.
IA2[2], SAC [2]
2.36.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
End Diastolic Volume (mL) Measured by CMR with Posterior 
Probabilities of Interest, Model: Three-Piece Linear Model 
(Model 1), Missing Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
IA2[2], SAC [2]
2.37.
Standard of 
Care
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of End Diastolic Volume (mL) Measured by CMR, 
Model: Linear Model, Missing Data Imputation: None
Include all Bayesian model parameters 
(Intercept and Slope).
SAC [2]
2.38.
Standard of 
Care
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
End Diastolic Volume (mL) Measured by CMR with Posterior 
Probabilities of Interest, Model: Linear Model, Missing Data 
Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
SAC [2]


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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.39.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of E/e’ Ratio Measured by ECHO, Model: Three-Piece 
Linear Model (Model 1), Missing Data Imputation: None
Include all Bayesian model parameters.
Paginate by type of measurement: 
lateral, septal
IA2[2], SAC [2]
2.40.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
E/e’ Ratio Measured by ECHO with Posterior Probabilities of 
Interest, Model: Three-Piece Linear Model (Model 1), Missing 
Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
Paginate by type of measurement: 
lateral, septal
IA2[2], SAC [2]
2.41.
Standard of 
Care
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of E/e’ Ratio Measured by ECHO, Model: Linear Model, 
Missing Data Imputation: None
Include all Bayesian model parameters 
(Intercept and Slope).
Paginate by type of measurement: 
lateral, septal
SAC [2]
2.42.
Standard of 
Care
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
E/e’ Ratio Measured by ECHO with Posterior Probabilities of 
Interest, Model: Linear Model, Missing Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
Paginate by type of measurement: 
lateral, septal
SAC [2]
2.43.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV Mass (g) Measured by ECHO, Model: Three-
Piece Linear Model (Model 1), Missing Data Imputation: None
Include all Bayesian model parameters.
IA2[2], SAC [2]
2.44.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
LV Mass (g) Measured by ECHO with Posterior Probabilities of 
Interest, Model: Three-Piece Linear Model (Model 1), Missing 
Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
IA2[2], SAC [2]
2.45.
Standard of 
Care
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV Mass (g) Measured by ECHO, Model: Linear 
Model, Missing Data Imputation: None
If data are available for the Standard of 
Care population
Include all Bayesian model parameters 
(Intercept and Slope).
SAC [2]


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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.46.
Standard of 
Care
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
LV Mass (g) Measured by ECHO with Posterior Probabilities of 
Interest, Model: Linear Model, Missing Data Imputation: None
If data are available for the Standard of 
Care population
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
SAC [2]
2.47.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of ECV (Global) (<unit>) Measured by CMR, Model: 
Three-Piece Linear Model (Model 1), Missing Data Imputation: 
None
Include all Bayesian model parameters.
IA2[2], SAC [2]
2.48.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
ECV (Global) (<unit>) Measured by CMR with Posterior 
Probabilities of Interest, Model: Three-Piece Linear Model 
(Model 1), Missing Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
IA2[2], SAC [2]
2.49.
Standard of 
Care
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of ECV (Global) (<unit>) Measured by CMR, Model: 
Linear Model, Missing Data Imputation: None
Include all Bayesian model parameters 
(Intercept and Slope).
SAC [2]
2.50.
Standard of 
Care
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
ECV (Global) (<unit>) Measured by CMR with Posterior 
Probabilities of Interest, Model: Linear Model, Missing Data 
Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
SAC [2]
2.51.
Safety
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of Native T1 (Global) Measured by CMR, Model: Three-
Piece Linear Model (Model 1), Missing Data Imputation: None
Include all Bayesian model parameters.
IA2[2], SAC [2]
2.52.
Safety
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
Native T1 (Global) Measured by CMR with Posterior 
Probabilities of Interest, Model: Three-Piece Linear Model 
(Model 1), Missing Data Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
IA2[2], SAC [2]


CONFIDENTIAL
201464
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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.53.
Standard of 
Care
Non-standard 
PD_T2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of Native T1 (Global) Measured by CMR, Model: Linear 
Model, Missing Data Imputation: None
Include all Bayesian model parameters 
(Intercept and Slope).
SAC [2]
2.54.
Standard of 
Care
Non-standard 
PD_T3
Posterior Distribution of Mean Change from First Dose of mAb in 
Native T1 (Global) Measured by CMR with Posterior 
Probabilities of Interest, Model: Linear Model, Missing Data 
Imputation: None
Probability thresholds to be confirmed 
by clinical team before analysis 
performed.
SAC [2]
Secondary Circulating Markers
2.55.
Safety
Non-standard 
PD_T1
Summary of Fluid Phase Complement Markers Over Time
Several endpoints: C3, C4, CH50
Includes absolute values and changes 
from baseline.
SAC [2]
2.56.
Safety
Non-standard 
PD_T1
Summary of Inflammatory Biomarkers Over Time
Several endpoints: hsCRP, SAA
Includes absolute values and changes 
from baseline.
SAC [2]
2.57.
Safety
Non-standard 
PD_T1
Summary of Plasma Cytokines Over Time
Several endpoints: TNFα, IL-8, IL-6, IL-
10, IL-13, IL-2, IL-4, IL-12p70, IL 1β, 
IFNγ
Includes absolute values and changes 
from baseline.
SAC [2]
Exploratory Pharmacodynamic and Biomarker Endpoints
2.58.
Safety
Non-standard 
PD_T1
Summary of Cardiac ECV (Global) by CMR Over Time
Includes absolute values and changes 
from baseline.
IA1 [3], IA2 [3], 
SAC [3]
2.59.
Safety
Non-standard 
PD_T1
Summary of Cardiac Biomarkers Over Time
Several endpoints: hs-Troponin T, NT-
Pro-BNP
Includes absolute values and changes 
from baseline.
SAC [3]


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201464
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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.60.
Safety
Non-standard 
PD_T5
Summary of Cardiac Uptake of Radioisotope Bone Tracers at 
Baseline and 8-week Follow Up
Several categorical endpoints: 99mTc-
DPD, 99mTc-PYP uptake
Group 1 Only. “No data to display” for 
Groups 2 and 3.
SAC [3]
2.61.
Safety
Non-standard 
PD_T1
Summary of Overall Body Load and in Affected Organs 
(Excluding Cardiac Load) on SAP Scan Over Time
Several endpoints: Overall Load and 
Organ Loads where available
Includes absolute values and changes 
from baseline.
Group 2 & 3 Only. “No data to display” 
for Group 1.
SAC [3]
2.62.
Safety
Non-standard 
PD_T1
Summary of Imaging Markers of Cardiac Structure as Monitored 
by CMR and / or ECHO imaging Over Time
Includes LV wall thickness and LV 
Mass (ECHO)
Includes absolute values and changes 
from baseline.
SAC [3]
2.63.
Safety
Non-standard 
PD_T1
Summary of Other Imaging Markers of Cardiac Dysfunction as 
Monitored by CMR and / or ECHO imaging Over Time
Includes several endpoints: 
Longitudinal, Radial and 
Circumferential Strain (Global values, 
CMR and/or ECHO), E/A ratio (ECHO), 
E-wave deceleration time on the mitral 
inflow (ECHO), LA volume index
(ECHO), RV FAC (ECHO)
Includes absolute values and changes 
from baseline.
IA1 [3], IA2 [3], 
SAC [3]
2.64.
Safety
Non-standard 
PD_T1
Summary of Imaging Markers of Cardiac Tissue 
Characterization as Monitored by CMR Over Time
Includes Native T1 and T2 (Global) 
Includes absolute values and changes 
from baseline.
For interims: include T1 only
IA1 [3], IA2 [3], 
SAC [3]
2.65.
Safety
Non-standard 
PD_T5
Summary of LGE Over Time
SAC [3]


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201464
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Pharmacodynamic and Biomarker: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.66.
Safety
Non-standard 
PD_T1
Summary of DCE-CMR Global Measure of Myocardial Perfusion 
Over Time
Includes absolute values and changes 
from baseline.
IA1 [3], IA2 [3], 
SAC [3]
2.67.
Safety
PK01
Summary of Plasma SAP Concentration-Time Data 
By treatment cycle and sampling 
occasion
SAC [1]
2.68.
Safety
Non-standard 
PD_T4
Summary of Association Between Biomarkers and CMR 
Measures by Timepoint
Association between a selection of 
markers (NT proBNP, hs-Troponin-T 
and cytokines: TNF-α, IL-6 and IL-8) 
and CMR measures (LV Mass, GLS 
and ECV respectively)
SAC [3]
2.69.
Safety
Non-standard 
PD_T4
Summary of Association Between DCE-CME Global Measure of 
Myocardial Perfusion and CMR Measures by Timepoint
Association between DCE-CME 
measure of myocardial perfusion and 
CMR measures (LV Mass, GLS and 
ECV respectively)
SAC [3]
Immunogenicity Endpoints
2.70.
Safety
Non-standard 
PD_T5
Summary of Antidrug Antibodies 
SAC [3]
2.71.
Safety
Non-standard 
PD_T1
Summary of Immune Complexes 
Includes absolute values only (no post-
baseline value).
SAC [3]
2.72.
Safety
Non-standard 
PD_T5
Summary of Auto-antibodies
SAC [3]


CONFIDENTIAL
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10.11.6.
Pharmacodynamic and Biomarker Figures
Pharmacodynamic and Biomarker : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Primary Pharmacodynamic/Biomarker Endpoint
2.1.
Safety
Non-standard 
PD_F1
Profile Plot of LV Mass (g) Measured by CMR Over Time by 
Subject
Includes only one endpoint: LV mass
IA1 [1], IA2 [1], 
SAC [1]
2.2.
Safety
Non-standard 
PD_F2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV Mass (g) Measured by CMR, Model: Three-Piece 
Linear Model (Model 1), Missing Data Imputation: None
Include all Bayesian model parameters.
IA2 [1], SAC [1]
2.3.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in LV Mass (g) Measured by CMR at Timepoints of 
Interest, Model: Three-Piece Linear Model (Model 1), Missing 
Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
IA2 [1], SAC [1]
2.4.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in LV 
Mass Measured by CMR Over Time, Model: Three-Piece Linear 
Model (Model 1), Missing Data Imputation: None
IA2 [1], SAC [1]
2.5.
Safety
Non-standard 
PD_F2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV Mass (g) Measured by CMR, Model: Three-Piece 
Linear Model (Model 1), Missing Data Imputation: Non-Future 
Dependency
Include all Bayesian model parameters.
SAC [1]
2.6.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in LV Mass (g) Measured by CMR at Timepoints of 
Interest, Model: Three-Piece Linear Model (Model 1), Missing 
Data Imputation: Non-Future Dependency
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
SAC [1]
2.7.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in LV 
Mass Measured by CMR Over Time, Model: Three-Piece Linear 
Model (Model 1), Missing Data Imputation: Non-Future 
Dependency
SAC [1]


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Pharmacodynamic and Biomarker : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.8.
Safety
Non-standard 
PD_F2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV Mass (g) Measured by CMR, Model: Three-Piece 
Linear Model (Model 1), Missing Data Imputation: Based on 
Standard of Care Data
Include all Bayesian model parameters.
SAC [1]
2.9.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in LV Mass (g) Measured by CMR at Timepoints of 
Interest, Model: Three-Piece Linear Model (Model 1), Missing 
Data Imputation: Based on Standard of Care Data
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
SAC [1]
2.10.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in LV 
Mass Measured by CMR Over Time, Model: Three-Piece Linear 
Model (Model 1), Missing Data Imputation: Based on Standard 
of Care Data
SAC [1]
2.11.
Safety
Non-standard 
PD_F2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV Mass (g) Measured by CMR, Model: Two-Piece 
Linear Model (Model 2), Missing Data Imputation: None
Include all Bayesian model parameters.
IA2 [1], SAC [1]
2.12.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in LV Mass (g) Measured by CMR at Timepoints of 
Interest, Model: Two-Piece Linear Model (Model 2), Missing 
Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
IA2 [1], SAC [1]
2.13.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in LV 
Mass Measured by CMR Over Time, Model: Two-Piece Linear 
Model (Model 2), Missing Data Imputation: None
IA2 [1], SAC [1]
2.14.
Safety
Non-standard 
PD_F2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV Mass (g) Measured by CMR, Model: Including 
Restricted Cubic Splines (Sensitivity Model 1), Missing Data 
Imputation: None
Include all Bayesian model parameters.
IA2 [1], SAC [1]


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Pharmacodynamic and Biomarker : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.15.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in LV Mass (g) Measured by CMR at Timepoints of 
Interest, Model: Including Restricted Cubic Splines (Sensitivity 
Model 1), Missing Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
IA2 [1], SAC [1]
2.16.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in LV 
Mass Measured by CMR Over Time, Model: Including Restricted 
Cubic Splines (Sensitivity Model 1), Missing Data Imputation: 
None
IA2 [1], SAC [1]
2.17.
Safety
Non-standard 
PD_F2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV Mass (g) Measured by CMR, Model: Including 
Polynomial Terms (Sensitivity Model 2), Missing Data 
Imputation: None
Include all Bayesian model parameters.
IA2 [1], SAC [1]
2.18.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in LV Mass (g) Measured by CMR at Timepoints of 
Interest, Model: Including Polynomial Terms (Sensitivity Model 
2), Missing Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
IA2 [1], SAC [1]
2.19.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in LV 
Mass Measured by CMR Over Time, Model: Including 
Polynomial Terms (Sensitivity Model 2), Missing Data 
Imputation: None
IA2 [1], SAC [1]
2.20.
Standard of 
Care
Non-standard 
PD_F1
Profile Plot of LV Mass Measured by CMR Over Time by Subject
Includes only one endpoint: LV mass
SAC [1]
2.21.
Standard of 
Care
Non-standard 
PD_F2
Posterior Distribution of Bayesian Model Parameters for the 
Analysis of LV Mass (g) Measured by CMR, Model: Linear 
Model, Missing Data Imputation: None
Include all Bayesian model parameters 
(Intercept and Slope)
SAC [1]


CONFIDENTIAL
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Pharmacodynamic and Biomarker : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.22.
Standard of 
Care
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in LV Mass (g) Measured by CMR at Timepoints of 
Interest, Model: Linear Model, Missing Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
SAC [1]
Secondary Imaging Markers of Cardiac Dysfunction
2.23.
Safety
Non-standard 
PD_F1
Profile Plot of Imaging Markers of Cardiac Dysfunction Over 
Time by Subject
Several endpoints: GLS by CMR & 
ECHO (tagging, feature tracking, 
speckle tracking), LV Twist by CMR, SV 
by CMR & ECHO, EF by CMR & 
ECHO, EDV by CMR & ECHO, E/e’ 
ratio by ECHO (lateral, septal)
IA1 [2], IA2 [2], 
SAC [2]
2.24.
Standard of 
Care
Non-standard 
PD_F1
Profile Plot of Imaging Markers of Cardiac Dysfunction Over 
Time by Subject
Several endpoints where available for 
the Standard of Care population: GLS 
by CMR & ECHO (tagging, feature 
tracking, speckle tracking), LV Twist by 
CMR, SV by CMR & ECHO, EF by 
CMR & ECHO, EDV by CMR & ECHO, 
E/e’ ratio by ECHO (lateral, septal)
SAC [2]
2.25.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in Global Longitudinal Strain (<unit>) Measured by 
CMR at Timepoints of Interest, Model: Three-Piece Linear Model 
(Model 1), Missing Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
Paginate by type of measurement: 
tagging, feature tracking (CMR), 
speckle tracking (ECHO)
IA2 [2], SAC [2]
2.26.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in 
Global Longitudinal Strain (<unit>) Measured by CMR Over 
Time, Model: Three-Piece Linear Model (Model 1), Missing Data 
Imputation: None
Paginate by type of measurement: 
tagging, feature tracking (CMR), 
speckle tracking (ECHO)
IA2 [2], SAC [2]


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Pharmacodynamic and Biomarker : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.27.
Standard of 
Care
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in Global Longitudinal Strain (<unit>) Measured by 
CMR at Timepoints of Interest, Model: Linear Model, Missing 
Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
Paginate by type of measurement: 
tagging, feature tracking (CMR), 
speckle tracking (ECHO)
SAC [2]
2.28.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in Left Ventricular Twist (<unit>) Measured by CMR at 
Timepoints of Interest, Model: Three-Piece Linear Model (Model 
1), Missing Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
IA2 [2], SAC [2]
2.29.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in Left 
Ventricular Twist (<unit>) Measured by CMR Over Time, Model: 
Three-Piece Linear Model (Model 1), Missing Data Imputation: 
None
IA2 [2], SAC [2]
2.30.
Standard of 
Care
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in Left Ventricular Twist (<unit>) Measured by CMR at 
Timepoints of Interest, Model: Linear Model, Missing Data 
Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
SAC [2]
2.31.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in Stroke Volume (mL) Measured by CMR at 
Timepoints of Interest, Model: Three-Piece Linear Model (Model 
1), Missing Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
IA2 [2], SAC [2]
2.32.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in 
Stroke Volume (mL) Measured by CMR Over Time, Model: 
Three-Piece Linear Model (Model 1), Missing Data Imputation: 
None
IA2 [2], SAC [2]


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Pharmacodynamic and Biomarker : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.33.
Standard of 
Care
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in Stroke Volume (mL) Measured by CMR at 
Timepoints of Interest, Model: Linear Model, Missing Data 
Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
SAC [2]
2.34.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in Ejection Fraction (%) Measured by CMR at 
Timepoints of Interest, Model: Three-Piece Linear Model (Model 
1), Missing Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
IA2 [2], SAC [2]
2.35.
Safety
Non-standard
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in 
Ejection Fraction (%) Measured by CMR Over Time, Model: 
Three-Piece Linear Model (Model 1), Missing Data Imputation: 
None
IA2 [2], SAC [2]
2.36.
Standard of 
Care
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in Ejection Fraction (%) Measured by CMR at 
Timepoints of Interest, Model: Linear Model, Missing Data 
Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
SAC [2]
2.37.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in End Diastolic Volume (mL) Measured by CMR at 
Timepoints of Interest, Model: Three-Piece Linear Model (Model 
1), Missing Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
IA2 [2], SAC [2]
2.38.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in End 
Diastolic Volume (mL) Measured by CMR Over Time, Model: 
Three-Piece Linear Model (Model 1), Missing Data Imputation: 
None
IA2 [2], SAC [2]


CONFIDENTIAL
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Pharmacodynamic and Biomarker : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.39.
Standard of 
Care
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in End Diastolic Volume (mL) Measured by CMR at 
Timepoints of Interest, Model: Linear Model, Missing Data 
Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
SAC [2]
2.40.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in E/e ratio’ Measured by ECHO at Timepoints of 
Interest, Model: Three-Piece Linear Model (Model 1), Missing 
Data Imputation: None
Include all timepoints of interest (1, 2, 3, 
4, 5, 6, 8, 11 and 17 months)
Paginate by type of measurement: 
lateral, septal
IA2 [2], SAC [2]
2.41.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in E/e 
ratio’ Measured by ECHO Over Time, Model: Three-Piece 
Linear Model (Model 1), Missing Data Imputation: None
Paginate by type of measurement: 
lateral, septal
IA2 [2], SAC [2]
2.42.
Standard of 
Care
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in E/e ratio’ Measured by ECHO at Timepoints of 
Interest, Model: Linear Model, Missing Data Imputation: None
Include all timepoints of interest (1, 2, 3, 
4, 5, 6, 8, 11 and 17 months)
Paginate by type of measurement: 
lateral, septal
SAC [2]
2.43.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in LV mass (g) Measured by ECHO at Timepoints of 
Interest, Model: Three-Piece Linear Model (Model 1), Missing 
Data Imputation: None
Include all timepoints of interest (1, 2, 3, 
4, 5, 6, 8, 11 and 17 months)
IA2 [2], SAC [2]
2.44.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in LV 
Mass (g) Measured by ECHO Over Time, Model: Three-Piece 
Linear Model (Model 1), Missing Data Imputation: None
IA2 [2], SAC [2]
2.45.
Standard of 
Care
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in LV Mass (g) Measured by ECHO at Timepoints of 
Interest, Model: Linear Model, Missing Data Imputation: None
If data are available for the Standard of 
Care population.
Include all timepoints of interest (1, 2, 3, 
4, 5, 6, 8, 11 and 17 months)
SAC [2]


CONFIDENTIAL
201464
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Pharmacodynamic and Biomarker : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.46.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in ECV (Global) (<unit>) Measured by CMR at 
Timepoints of Interest, Model: Three-Piece Linear Model (Model 
1), Missing Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
IA2 [2], SAC [2]
2.47.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in 
ECV (Global) (<unit>) Measured by CMR Over Time, Model: 
Three-Piece Linear Model (Model 1), Missing Data Imputation: 
None
IA2 [2], SAC [2]
2.48.
Standard of 
Care
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in ECV (Global) (<unit>) Measured by CMR at 
Timepoints of Interest, Model: Linear Model, Missing Data 
Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
SAC [2]
2.49.
Safety
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in Native T1 (Global) (<unit>) Measured by CMR at 
Timepoints of Interest, Model: Three-Piece Linear Model (Model 
1), Missing Data Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
IA2 [2], SAC [2]
2.50.
Safety
Non-standard 
PD_F4
Posterior Mean Change from First Dose of Anti-SAP mAb in 
Native T1 (Global) (<unit>) Measured by CMR Over Time, 
Model: Three-Piece Linear Model (Model 1), Missing Data 
Imputation: None
IA2 [2], SAC [2]
2.51.
Standard of 
Care
Non-standard 
PD_F3
Posterior Distribution of Mean Change from First Dose of Anti-
SAP mAb in Native T1 (Global) (<unit>) Measured by CMR at 
Timepoints of Interest, Model: Linear Model, Missing Data 
Imputation: None
Include all timepoints of interest (2, 3, 4, 
5, 8, 11 and 17 months)
SAC [2]
Secondary Circulating Markers
2.52.
Safety
Non-standard 
PD_F1
Profile Plot of Fluid Phase Complement Markers Over Time by 
Subject
Includes several endpoints: C3, C4, 
CH50. At interims C3 only
IA1 [2], IA2 [2], 
SAC [2]


CONFIDENTIAL
201464
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Pharmacodynamic and Biomarker : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.53.
Safety
Non-standard 
PD_F1
Profile Plot of Inflammatory Biomarkers Over Time by Subject
Includes several endpoints: hsCRP, 
SAA
IA2 [2], SAC [2]
2.54.
Safety
Non-standard 
PD_F1
Profile Plot of Plasma Cytokines Over Time by Subject
Includes several endpoints: TNFα, IL-8, 
IL-6, IL-10, IL-13, IL-2, IL-4, IL-12p70, 
IL 1β, IFNγ
IA2 [2], SAC [2]
Exploratory Pharmacodynamic and Biomarker Endpoints
2.55.
Safety
Non-standard 
PD_F1
Profile Plot of Cardiac Extracellular Volume (Global and 
Segmental) by CMR Over Time by Subject
Includes Global and Segmental values.
For segmental data: All segment curves 
should be displayed on the same plot, 
with segment identifiers as legend.
IA1 [3], IA2 [3], 
SAC [3]
2.56.
Safety
Non-standard 
PD_F1
Profile Plot of Cardiac Biomarkers Over Time by Subject
Includes several endpoints: hs-
Troponin T, NT Pro-BNP
IA1 [3], IA2 [3], 
SAC [3]
2.57.
Safety
Non-standard 
PD_F1
Profile Plot of Amyloid Load on SAP Scan Over Time by Subject
Includes several endpoints: Overall 
Body Load and in Affected Organs 
(Excluding Cardiac Load), where 
available
Group 2&3 Only. “No data to display” 
for Group 1.
SAC [3]
2.58.
Safety
Non-standard 
PD_F1
Profile Plot of Imaging Markers of Cardiac Structure by Serial 
CMR and/or ECHO Imaging Over Time by Subject
LV wall thickness (CMR and ECHO), 
LV mass (ECHO)
SAC [3]


CONFIDENTIAL
201464
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Pharmacodynamic and Biomarker : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.59.
Safety
Non-standard 
PD_F1
Profile Plot of Other Imaging Markers of Cardiac Dysfunction by 
Serial CMR and/or ECHO Over Time by Subject
Includes several endpoints: 
Longitudinal, Radial and 
Circumferential Strain (Global, 
Segmental by CMR and/or ECHO), E/A 
ratio (ECHO), E-wave deceleration time 
on the mitral inflow (ECHO), LA volume 
index (ECHO), RV FAC (ECHO)
Do not include GLS as already reported 
as secondary endpoint.
For endpoints with segmental values:  
All segment curves should be displayed 
on the same plot, with segment 
identifiers as legend.
IA1 [3], IA2 [3], 
SAC [3]
2.60.
Safety
Non-standard 
PD_F1
Profile Plot of Imaging Markers of Cardiac Tissue 
Characterization as Monitored by CMR Over Time by Subject
LGE, native T1 (Global, Segmental), 
native T2 (Global, Segmental)
For endpoints with segmental values:  
All segment curves should be displayed 
on the same plot, with segment 
identifiers as legend.
For interims: Include T1 only
IA1 [3], IA2 [3], 
SAC [3]
2.61.
Safety
Non-standard 
PD_F1
Profile Plot of DCE-CMR Global and Segmental Measures of 
Myocardial Perfusion Over Time by Subject
For endpoints with segmental values:  
All segment curves should be displayed 
on the same plot, with segment 
identifiers as legend.
IA1 [3], IA2 [3], 
SAC [3]
2.62.
Safety
Non-standard 
PK_F1
Individual Plasma SAP Concentration-Time Plot (Linear and 
Semi-Log) by Treatment Cycle with Subject Identifiers
IA1 [1], IA2 [1], 
SAC [1]


CONFIDENTIAL
201464
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Pharmacodynamic and Biomarker : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.63.
Safety
Non-standard 
PD_F5
Scatter Plots of Biomarkers versus CMR Measures by Timepoint 
with Subject Identifiers
Scatter plots between a selection of 
markers (NT ProBNP, hs-Troponin-T 
and cytokines: TNF-α, IL-6 and IL-8) 
and CMR measures (LV Mass, GLS 
and ECV)/
SAC [3]
2.64.
Safety
Non-standard 
PD_F5
Scatter Plots of DCE-CME Global Measure of Myocardial 
Perfusion versus CMR/ECHO Measures by Timepoint with 
Subject Identifiers
Scatter plots between DCE-CMR 
measure of myocardial perfusion and 
following CMR measures; LV Mass, 
GLS and ECV.
SAC [3]
10.11.7.
Safety Tables
Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
3.1.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term
SAC [1]
3.2.
Safety
AE3
Summary of Most Frequent Adverse Events by Overall 
Frequency
SAC [1]
3.3.
Safety
AE1
Summary of Drug Related Adverse Events by System Organ 
Class and Preferred Term
SAC [1]
3.4.
Safety
Non-Standard
AE_T1
Summary of Posterior Probabilities for Specific Adverse Events
AE posterior probabilities may be 
provided after 10 subjects complete at 
least 3 courses of Anti-SAP treatment 
in a given cohort (not at first interim)
IA2 [1], SAC [1]


CONFIDENTIAL
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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
3.5.
Safety
AE15
Summary of Common (≥5%) Non-Serious Adverse Events by 
System Organ Class and Preferred Term (Number of Subjects 
and Occurences)
SAC [1]
Serious and Other Significant AEs
3.6.
Safety
AE1
Summary of Fatal Serious Adverse Events by System Organ 
Class and Preferred Term
SAC [1]
3.7.
Safety
AE1
Summary of Drug-Related Fatal Serious Adverse Events by 
System Organ Class and Preferred Term
SAC [1]
3.8.
Safety
AE1
Summary of Non-Fatal Serious Adverse Events by System 
Organ Class and Preferred Term
SAC [1]
3.9.
Safety
AE1
Summary of Drug-Related Non-Fatal Serious Adverse Events by 
System Organ Class and Preferred Term
SAC [1]
3.10.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Subjects and Occurrences)
SAC [1]
3.11.
Safety
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term
SAC [1]
Rashes
3.12.
Safety
AE5B
Summary of Rashes by System Organ Class and Preferred 
Term and Maximum CTCAE Grade
SAC [1]
Chemistry
3.13.
Safety
LB1
Summary of Chemistry Change from Baseline
SAC[1]


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Safety : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Hematology
3.14.
Safety
LB1
Summary of Hematology Change from Baseline
SAC [1]
3.15.
Safety
LB1
Summary of Haemoglobin Change from Baseline Relative to 
Clinical Importance Ranges
SAC [1]
Urinalysis
3.16.
Safety
LB1
Summary of Urinalysis Change from Baseline
Quantitative results only. Other results 
to be listed.
SAC [1]
Hepatobiliary (Liver)
3.17.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
SAC [1]
3.18.
Safety
LIVER10
Summary of Subjects Meeting Emergent Hepatobiliary 
Laboratory Abnormality Criteria
SAC [1]
ECG
3.19.
Safety
EG1
Summary of ECG Findings
SAC [1]
3.20.
Safety
CP_EG11
Summary of Maximum Emergent QTc Values by Category
3.21.
Safety
EG2
Summary of Change from Baseline in ECG Values
SAC [1]
3.22.
Safety
CP_EG12
Summary of Maximum Change from Baseline in QTc Values by
Category
SAC [1]
Vital Signs
3.23.
Safety
VS1
Summary of Change From Baseline in Vital Signs
SAC [1]


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10.11.8.
Safety Figures
Safety : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory
3.1.
Safety
Non-standard 
PD_F1
Profile Plot of Liver Function Parameters Over Time by Subject
IA2 [1], SAC [1]
3.2.
Safety
Non-standard 
PD_F1
Profile Plot of Renal Function Parameters Over Time by Subject
Serum creatinine and eGFR only for 
interim IA1
IA1 [1], IA2 [1], 
SAC [1]
3.3.
Safety
Non-standard 
PD_F1
Profile Plot of Haemoglobin Over Time by Subject
IA2 [1], SAC [1]
3.4.
Safety
Non-standard 
PD_F1
Profile Plot of Vital Signs Parameters Over Time by Subject
Blood pressure and heart rate only for 
interims
IA1 [1], IA2 [1], 
SAC [1]
3.5.
Safety
Non-standard 
PD_F6
Scatter Plot of Maximum vs. Baseline for ALT
SAC [1]
3.6.
Safety
Non-standard 
PD_F6
Scatter Plot of Maximum ALT vs Maximum Total Bilirubin
SAC [1]


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10.11.9.
Pharmacokinetic Tables
Pharmacokinetic : Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK concentration data
4.1.
Safety
PK01
Summary of Plasma GSK2398852 Pharmacokinetic 
Concentration-Time Data 
By treatment cycle and sampling 
occasion
SAC [1]
4.2.
Safety
PK01
Summary of Plasma GSK2315698 Pharmacokinetic 
Concentration-Time Data
By treatment cycle and sampling 
occasion
Group 3 Only
SAC [1]
10.11.10. Pharmacokinetic Figures
Pharmacokinetic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
PK concentration data
4.1.
Safety
Non-standard 
PK_F1
Individual Plasma GSK2398852 Concentration-Time Plot 
(Linear and Semi-Log) by Treatment Cycle with Subject 
Identifiers
For each of the 3 groups, a landscape 
grid plot of 2 rows by 3 columns for the 
6 treatment cycles. Plot drug 
concentrations versus time. Connect 
individual data with lines. Symbol code 
by dose. Colour code by ID. Do this 
separately on log and linear scales. 
IA1 [1], IA2 [1], 
SAC [1]


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Pharmacokinetic : Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.2.
Safety
Non-standard 
PK_F2
Median Plasma GSK2398852 Concentration-Time Plot 
(Linear and Semi-Log) by Treatment Cycle with Group 
Identifier
A landscape grid plot of 2 rows by 3 
columns for the 6 treatment cycles. Plot 
group median of drug concentrations 
versus time. Connect group data with 
lines. Colour code by group. Do this 
separately on log and linear scales.
IA1 [1], IA2 [1], 
SAC [1]
4.3.
Safety
Non-standard 
PK_F1
Individual Plasma GSK2315698 Concentration-Time Plot 
(Linear and Semi-Log) by Treatment Cycle with Subject 
Identifiers
A landscape grid plot of 2 rows by 3 
columns for the 6 treatment cycles. Plot 
drug concentrations versus sampling 
occasion Day/Hour (1/0, 2/0, 2/2, 3/0). 
Connect individual data with lines. 
Symbol code by dose. Colour code by 
ID. Do this separately on log and linear 
scales. 
Group 3 Only
IA1 [1], IA2 [1], 
SAC [1]
4.4.
Safety
Non-standard 
PK_F2
Median Plasma GSK2315698 Concentration-Time Plot 
(Linear and Semi-Log) by Treatment Cycle
A single plot of cycle median of drug 
concentrations versus sampling 
occasion Day/Hour (1/0, 2/0, 2/2, 3/0). 
Connect cycle data with lines. Colour 
code by treatment cycle. Do this 
separately on log and linear scales.
Group 3 only
IA1 [1], IA2 [1], 
SAC [1]


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10.11.11. Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exploratory Efficacy
5.1.
Safety
Group 1&2
Only
Non-standard 
PD_T1
Summary of 6 Minute Walking Test (6MWT) Over Time
Includes absolute values and changes 
from baseline.
IA1 [3], IA2 [3], 
SAC [3]
10.11.12. Efficacy Figures
Efficacy: Figures
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exploratory Efficacy
5.1.
Safety
Group 1&2
Only
Non-standard 
PD_F1
Profile Plot of 6 Minute Walking Test (6MWT) Over Time by 
Subject
Includes only one endpoint:6WMT
IA1 [3], IA2 [3], 
SAC [3]


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10.11.13. Quality of Life Tables
Efficacy: Tables
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Exploratory Efficacy
6.1.
Safety
Non-standard 
PD_T1
Summary of SF-36 Domain and Overall Scores at Baseline and 
8-week Follow Up
Includes absolute values and changes 
from baseline.
SAC [3]
6.2.
Safety
Non-standard 
PD_T1
Summary of KCCQ Scores at Baseline and 8-week Follow Up
Includes absolute values and changes 
from baseline.
SAC [3]
6.3.
Safety
Non-standard 
PD_T1
Summary of EORTC QLQ-C30 Scores at Baseline and 8-week 
Follow Up
Includes absolute values and changes 
from baseline.
SAC [3]
6.4.
Safety
Non-standard 
PD_T1
Summary of DLQI Overall and Section Scores at Baseline and 
8-week Follow Up
Includes absolute values and changes 
from baseline.
SAC [3]
10.11.14. ICH Listings
ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen failures
SAC [3]
2.
Safety
ES2
Listing of Reasons for Study Withdrawal
SAC [3]
3.
Safety
SD2
Listing of Reasons for Study Treatment Discontinuation
SAC [3]
Protocol Deviations
4.
Safety
DV2
Listing of Important Protocol Deviations
SAC [3]
5.
Safety
IE3
Listing of Subjects with Inclusion/ Exclusion Criteria Deviations
SAC [3]


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Populations Analysed
6.
Safety
SP3
Listing of Subjects Excluded from Safety Population
SAC [3]
Demography
7.
Safety
DM2
Listing of Demographic Characteristics
SAC [3]
8.
Safety
DM9
Listing of Race
SAC [3]
Concomitant Medications
9.
Safety
CP_CM3
Listing of Concomitant Medications
SAC [3]
Medical Conditions
10.
Safety
MH2
Listing of Medical Conditions
SAC [3]
Exposure
11.
Safety
EX3
Listing of Exposure to CPHPC
SAC [3]
12.
Safety
EX3
Listing of Exposure to anti-SAP mAb
SAC [3]
Adverse Events
13.
Safety
AE8CP
Listing of All Adverse Events
IA1 [1], IA2 [1], 
SAC [1]
14.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
SAC [1]
15.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
SAC [1]
Serious and Other Significant Adverse Events
16.
Safety
AE8CP
Listing of Fatal Serious Adverse Events
SAC [1]
17.
Safety
AE8CP
Listing of Non-Fatal Serious Adverse Events
SAC [1]
18.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
SAC [1]


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
19.
Safety
AE8CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
SAC [1]
20.
Safety
AE8CP
Listing of Anti-SAP mAb Infusion Related Reactions
Filtering on PTs identified by clinical 
team as infusion-related reactions.
SAC [1]
21.
Safety
AE8CP
Listing of Adverse Events Related to Treatments other than 
Study Drug
SAC [1]
Rashes
22.
Safety
AE8CP
Listing of Adverse Events of Rashes 
SAC [1]
23.
Safety
Non-Standard 
AE_L1
Listing of Rash Details
IA1 [1], IA2 [1], 
SAC [1]
Chemistry
24.
Safety
LB5
Listing of Clinical Chemistry Values
IA1 [1], IA2 [1], 
SAC [1]
Hematology
25.
Safety
LB5
Listing of Hematology Values
IA1 [1], IA2 [1], 
SAC [1]
26.
Safety
LB5
Listing of Haemoglobin Change from Baseline Values
IA2 [1], SAC [1]
Urinalysis
27.
Safety
UR2A
Listing of Urinalysis Data
IA1 [1], IA2 [1], 
SAC [1]
Hepatobilary (Liver)
28.
Safety
MH2
Listing of Medical Conditions for Subjects with Liver Stopping 
Events
SAC [1]


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ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
29.
Safety
SU2
Listing of Substance Use for Subjects with Liver Stopping 
Events
SAC [1]
All Laboratory
30.
Safety
LB5
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Concern/Potential Clinical Importance
IA2 [1], SAC [1]
31.
Safety
LB5
Listing of Laboratory Values of Potential Clinical Importance
IA2 [1], SAC [1]
ECG
32.
Safety
EG3
Listing of All ECG Data for Subjects with Any Value of Potential 
Clinical Importance
IA1 [1], IA2 [1], 
SAC [1]
33.
Safety
EG3
Listing of ECG Values of Potential Clinical Importance
IA1 [1], IA2 [1], 
SAC [1]
34.
Safety
EG5
Listing of Abnormal ECG Findings
IA1 [1], IA2 [1], 
SAC [1]
Echocardiogram and Cardiac Monitoring
35.
Safety
Non-standard
PD_L1
Listing of Cardiac Monitoring Values
SAC [1]
36.
Safety
Non-standard
PD_L1
Listing of All Echocardiogram Results for Subjects Requiring 
Unscheduled Assessments
IA1 [1], IA2 [1], 
SAC [1]
Vital Signs
37.
Safety
VS4
Listing of Vital Signs Values
SAC [1]
38.
Safety
CP_VS4
Listing of Vital Signs of Potential Clinical Importance
SAC [1]
39.
Safety
CP_VS4
Listing of All Vital Signs Data for Subjects with Any Value of 
Potential Clinical Importance
SAC [1]


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10.11.15. Non-ICH Listings
Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacodynamic and Biomarkers
40.
Safety
PD_L1
Listing of Cardiac MRI Data
IA2 [1], SAC [1]
41.
Safety
PD_L1
Listing of ECHO Data
IA2 [2], SAC [2]
42.
Safety
PD_L1
Listing of SAP Scan Data
IA1 [3], IA2 [3], 
SAC [3]
43.
Safety
PD_L1
Listing of Bone Scan Data
IA1 [3], IA2 [3], 
SAC [3]
44.
Safety
PD_L1
Listing of Complement and Inflammatory Biomarkers
IA1 [2], IA2 [2], 
SAC [2]
45.
Safety
PD_L1
Listing of hs-Troponin T and NT-ProBNP
IA1 [3], IA2 [3], 
SAC [3]
46.
Safety
PD_L1
Listing of Anti-Drug Antibody (anti-SAP mAb)
SAC [3]
47.
Safety
PD_L1
Listing of Auto-Antibodies
SAC [3]
48.
Safety
PD_L1
Listing of mAb/SAP Immune Complex
SAC [3]
Quality of Life
49.
Safety
PD_L1
Listing of MOS SF-36 data
SAC [3]
50.
Safety
PD_L1
Listing of KCCQ data
SAC [3]
51.
Safety
PD_L1
Listing of EORTC data
SAC [3]
52.
Safety
PD_L1
Listing of DLQI questionnaire
SAC [3]


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Non-ICH : Listings
No.
Population
IDSL / TST ID / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Efficacy
53.
Safety
PD_L1
Listing of 6MWT data
IA2 [3], SAC [3]
Pharmacokinetics
54.
Safety
PK07
Listing of PK plasma concentrations (GSK2315698 & 
GSK2398852)
SAC [1]


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10.12.
Appendix 12: Example Mock Shells for Data Displays
Example 
: PD_T1 
Page 1 of n
Protocol
: 201464
Population
: Safety
Table x.x
Summary of <Endpoint (unit) or Endpoint Type> Over Time
Cohort: <Study Group X>
    Parameter: <Endpoint (unit)>
         Derivation: <Absolute value> / <Change from Baseline > 
Planned Period
Planned Visit
n
Mean
SD
Median
Min.
Max.
Screening
Screening
x
x.xx
x.xxx
x.xx
x.x
x.x
Baseline
Baseline
x
x.xx
x.xxx
x.xx
x.x
x.x
Treatment Session 1
Session Day X
x
x.xx
x.xxx
x.xx
x.x
x.x
Session Day X
x
x.xx
x.xxx
x.xx
x.x
x.x
Etc.
x
x.xx
x.xxx
x.xx
x.x
x.x
Treatment Session 2
Session Day X
x
x.xx
x.xxx
x.xx
x.x
x.x
Session Day X
x
x.xx
x.xxx
x.xx
x.x
x.x
Etc.
Etc.
x
x.xx
x.xxx
x.xx
x.x
x.x
Follow up
8-week follow up
x
x.xx
x.xxx
x.xx
x.x
x.x
Etc.
x
x.xx
x.xxx
x.xx
x.x
x.x


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Programming notes: Absolute value and Change from baseline to be subsequently presented for a given endpoint. Some tables may display results for 
several endpoints (table repeated for each endpoint). Planned time may need to be displayed within planned timepoint for endpoints with multiple 
assessments within the same day, as necessary.


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Example 
: PD_T2
Page 1 of n
Protocol
: 201464
Population
: Safety
Table x.x
Posterior Distribution of Bayesian Model Parameters for the Analysis of <Endpoint (unit)>
Model: <Three-Piece Linear Model / Three-Piece Model with Restricted Cubic Spline Parameters / Other Model as Appropriate>
Missing Data Imputation: <None / Non-Future Dependence Multiple Imputation / Multiple Imputation Based on Standard of Care Data>
Cohort: <Study Group X>
95% Credible Interval
Parameter
Mean
SD
Median
Lower
Upper
Intercept
xxx.xx
xx.xxx
xxx.xx
xxx.xx
xxx.xx
<Pre-treatment slope (unit/month) >
x.xx
x.xxx
x.xx
x.xx
x.xx
<On-treatment slope (unit/month)>
x.xx
x.xxx
x.xx
x.xx
x.xx
<Post-treatment slope (unit/month)>
x.xx
x.xxx
x.xx
x.xx
x.xx
Programming note: include all Bayesian model parameters as appropriate


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Example 
: PD_T3
Page 1 of n
Protocol
: 201464
Population
: Safety
Table x.x
Posterior Distribution of Mean Change from First Dose of mAb in <Endpoint (unit)> with Posterior Probabilities of Interest
Model: <Three-Piece Linear Model / Three-Piece Model with Restricted Cubic Spline Parameters / Other Model as Appropriate>
Missing Data Imputation: <None / Non-Future Dependence Multiple Imputation / Multiple Imputation Based on Standard of Care Data>
Cohort: <Study Group X>
95% Credible Interval
Parameter 
Mean
SD
Median
Lower
Upper
Prob.
<Chg<0g>
(%)
Prob.
<Chg<-50g>
(%)
Prob.
<Chg<-70g>
(%)
Change from first mAb dose at 2 months
xxx.xx
xx.xxx
xxx.xx
xxx.xx
xxx.xx
xx.x
xx.x
xx.x
Change from first mAb dose at 3 months
xxx.xx
xx.xxx
xxx.xx
xxx.xx
xxx.xx
xx.x
xx.x
xx.x
Change from first mAb dose at 4 months
xxx.xx
xx.xxx
xxx.xx
xxx.xx
xxx.xx
xx.x
xx.x
xx.x
Change from first mAb dose at 5 months
xxx.xx
xx.xxx
xxx.xx
xxx.xx
xxx.xx
xx.x
xx.x
xx.x
Change from first mAb dose at 8 months
xxx.xx
xx.xxx
xxx.xx
xxx.xx
xxx.xx
xx.x
xx.x
xx.x
Change from first mAb dose at 11 months
xxx.xx
xx.xxx
xxx.xx
xxx.xx
xxx.xx
xx.x
xx.x
xx.x
Change from first mAb dose at 17 months
xxx.xx
xx.xxx
xxx.xx
xxx.xx
xxx.xx
xx.x
xx.x
xx.x
Programming note: probability thresholds to be adapted or removed as required


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Example 
: PD_T4 
Page 1 of n
Protocol
: 201464
Population
: Safety
Table x.x
Summary of Association between <Endpoint Type 1/ Endpoint 1 (unit)> and <Endpoint Type 2 / Endpoint 2 (unit)> by Timepoint
Cohort: <Study Group X>
    Endpoints: <Endpoint 1 (unit)> vs <Endpoint 2 (unit)>
Planned Period
Planned Visit
n
Corr.
95% CI
Screening
Screening
x
x.xx
x.xx, x.xx
Baseline
Baseline
x
x.xx
x.xx, x.xx
Treatment Session 1
Session Day X
x
x.xx
x.xx, x.xx
Session Day X
x
x.xx
x.xx, x.xx
Etc.
x
x.xx
x.xx, x.xx
Treatment Session 2
Session Day X
x
x.xx
x.xx, x.xx
Session Day X
x
x.xx
x.xx, x.xx
Etc.
Etc.
x
x.xx
x.xx, x.xx
Follow up
8-week follow up
x
x.xx
x.xx, x.xx
Etc.
x
x.xx
x.xx, x.xx
Note: Spearman correlation coefficients and corresponding 95% confidence intervals derived based on available pairs of endpoint measurements.
Programming note: Planned time may need to be displayed within planned timepoint for endpoints with multiple assessments within the same day, as 
necessary.


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Example 
: PD_T5 
Page 1 of n
Protocol
: 201464
Population
: Safety
Table x.x
Summary of <Categorical Endpoint or Categorical Endpoint Type> Over Time
Cohort: <Study Group X>
    Parameter: <Categorical Endpoint>
Planned Period
Planned Visit
N
Category
n (%)
Baseline
Baseline
x
<Category 1>
xx ( xx.x%)
<Category 2>
xx ( xx.x%)
<Category 3>
xx ( xx.x%)
Treatment Session X
Session Day X
x
<Category 1>
xx ( xx.x%)
<Category 2>
xx ( xx.x%)
<Category 3>
xx ( xx.x%)
Follow up
8-week follow up
x
<Category 1>
xx ( xx.x%)
<Category 2>
xx ( xx.x%)
<Category 3>
xx ( xx.x%)
Etc.
Programming note: Some tables may display results for several endpoints (table repeated for each endpoint).


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Example 
: PD_F1 
Page 1 of n
Protocol
: 201464
Population
: Safety
Figure x.x
Profile Plot of <Endpoint (unit) or Endpoint Type> Over Time by Subject
Cohort: <Study Group X>, Subject: XXX
Note: Black triangles are treatment session first dose of anti-SAP mAb. Vertical Line is first dose of anti-SAP mAb of the first treatment session.
Programming notes: Include as many panels as endpoints. If more than 4 panel rows introduce a second column. If more than 4 rows x 2 columns 
consider moving panels to second page. For imaging markers with segmental values, include as many curves as segments on the same plot (with 
segments identified in legend).


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Example 
: PD_F2
Page 1 of n
Protocol
: 201464
Population
: Safety
Figure x.x
Posterior Distribution of Bayesian Model Parameters for the Analysis of <Endpoint (unit)>
Model: <Three-Piece Linear Model / Three-Piece Model with Restricted Cubic Spline Parameters / Other Model as Appropriate>
Imputation: <None / Non-Future Dependence Multiple Imputation / Multiple Imputation Based on Standard of Care Data>
Cohort: <Study Group X>
     Model Parameter: <Intercept / Pre-treatment Slope / On-treatment Slope / Post-treatment Slope / On/post-treatment RCS parameters...>
<Intercept / Pre-treatment Slope / On-treatment Slope / Post-treatment Slope / On/post-treatment RCS parameters...>
Programming note: include all Bayesian model parameters as appropriate, one by page (as many pages as parameters)


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Example 
: PD_F3
Page 1 of n
Protocol
: 201464
Population
: Safety
Figure x.x
Posterior Distribution of Mean Change from First Dose of Anti-SAP mAb in <Endpoint (unit)> at Timepoints of Interest
Model: <Three-Piece Linear Model / Three-Piece Model with Restricted Cubic Spline Parameters / Other Model as Appropriate>
Imputation: <None / Non-Future Dependence Multiple Imputation / Multiple Imputation Based on Standard of Care Data>
Cohort: <Study Group X>
     Timepoint: <2/3/4/5/8/11/17> Months
Change from first dose of anti-SAP mAb at <3/6/8/12/18> Months
<Note: Vertical lines are thresholds of changes from first dose of anti-SAP mAb for values <-70, -50, 0>>
Programming note: include all timepoints as appropriate (2,3,4,5,8,11,17 months), one by page (as many pages as timepoints)


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Example 
: PD_F4
Page 1 of n
Protocol
: 201464
Population
: Safety
Figure x.x
Posterior Mean Change from First Dose of Anti-SAP mAb in <Endpoint (unit)> Over Time
Model: <Three-Piece Linear Model / Three-Piece Model with Restricted Cubic Spline Parameters / Other Model as Appropriate>
Imputation: <None / Non-Future Dependence Multiple Imputation / Multiple Imputation Based on Historical Data>
Cohort: <Study Group X>
Time since first dose of anti-SAP mAb (months)
Note: Vertical Line is First Dose of Anti-SAP mAb.


CONFIDENTIAL
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134
Example 
: PD_F5
Page 1 of n
Protocol
: 201464
Population
: Safety
Figure x.x
Scatter Plot of <Endpoint Type / Endpoint 1 (unit)> versus <Endpoint Type / Endpoint 2 (unit)> by Timepoint with Subject Identifiers
Cohort: <Study Group X>
      Endpoints: <Endpoint 1 (unit)> vs <Endpoint 2 (unit)>
PPD


CONFIDENTIAL
201464
135
Example 
: PD_F6
Page 1 of n
Protocol
: 201464
Population
: Safety
Figure x.x
Scatter Plot of < Endpoint 1 (unit)> versus <Endpoint 2 (unit)> 
Cohort: <Study Group X>
     Endpoints: <Endpoint 1 (unit)> vs <Endpoint 2 (unit)>
PPD


CONFIDENTIAL
201464
136
Example 
: AE_T1 
Page 1 of n
Protocol
: 201464
Population
: Safety
Table x.x
Summary of Posterior Probabilities for Specific Adverse Events
Cohort: <Study Group X>
95% Credible Interval
Prob. of true subject rate > x%
given observed data
Preferred Term
n / N 
Observed 
subject rate
Lower
Limit
Upper 
Limit
>10%
>30%
>50%
PreferredTerm1
xx / xx
0.xx
0.xx
0.xx
0.xx
0.xx
0.xx
PreferredTerm2
xx / xx
0.xx
0.xx
0.xx
0.xx
0.xx
0.xx
PreferredTerm3
xx / xx
0.xx
0.xx
0.xx
0.xx
0.xx
0.xx
PreferredTerm4
xx / xx
0.xx
0.xx
0.xx
0.xx
0.xx
0.xx
PreferredTerm5
xx / xx
0.xx
0.xx
0.xx
0.xx
0.xx
0.xx
PreferredTerm6
xx / xx
0.xx
0.xx
0.xx
0.xx
0.xx
0.xx
...
xx / xx
0.xx
0.xx
0.xx
0.xx
0.xx
0.xx
Note: Probabilities derived within a Bayesian framework with a non-informative conjugate prior distribution, Beta (1/3,1/3)


CONFIDENTIAL
201464
137
Example 
: PK_F1 
Page 1 of n
Protocol
: 201464
Population
: Safety
Figure x.x
Individual Plasma <GSKXXXXXX> Concentration-Time Plot (Linear and Semi-Log) by Treatment Session with Subject Identifiers
Y axis scale: <Linear / Semi-Log> (Repeat on two pages)
Cohort: <Study Group X>
PPD


CONFIDENTIAL
201464
138
Example 
: PK_F2
Page 1 of n
Protocol
: 201464
Population
: Safety
Figure x.x
Median Plasma <GSKXXXXXX> Concentration-Time Plot (Linear and Semi-Log) by Treatment Session with Group Identifier
Y axis scale: <Linear / Semi-Log> (Repeat on two pages)


CONFIDENTIAL
201464
139
Example 
: PD_L1 
Page 1 of n
Protocol
: 201464
Population
: Safety
Listing x.x
Listing of <Endpoint or Endpoint Type>
Cohort: <Study Group X>
<Variable 1 (unit)>
<Variable 2 (unit)>
<Variable 3 (unit)>
Etc.
Site Id./
Unique 
Subject Id.
Planned 
Period/
Planned Visit
Date/
Study Day
<Planned 
Time / 
Time>
Value
Change 
from 
baseline
Value
Change 
from 
baseline
Value
Change 
from 
baseline
Baseline/
Day – 2
DDMMMYY/
-2
xx:xx/
xx:xx
xxx
xxx
xxx
xxx
xxx
Trt Session 1/
Day X
DDMMMYY/
X
xx:xx/
xx:xx
xxx
xxx
xxx
xxx
xxx
xxx
Etc.
DDMMMYY/
X
xx:xx/
xx:xx
xxx
xxx
xxx
xxx
xxx
xxx
Programming notes: Time column to be removed if not applicable. 
PPD


CONFIDENTIAL
201464
140
Example 
: AE_L1 
Page 1 of n
Protocol
: 201464
Population
: Safety
Listing x.x
Listing of Rash Details
Cohort: <Study Group X>
Site Id./
Unique Subject Id.
Assessment Date/
Time
Rash Form Item
Value
DDMMMYY/
xx:xx
Type or Rash
Maculopapular, Urticarial
Most Severe
Maculopapular
Appearance of lesions
Yes
Percentage of total body surface covered in rash
17%
Rash Location
Head, Trunk
Etc.
Etc.
Programming notes: Time column to be removed if not applicable. 
PPD