Clinical trial NCT03417830
Conditions: Amyloidosis
Keywords: miridesap GSK2315698 89Zirconium labelled Positron Emission Tomography Transthyretin cardiomyopathy GSK2398852 dezamizumab
Sponsor: GlaxoSmithKline
Start date: 2018-04-06; Completion date: 2018-07-20
Enrollment: 2 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The principal aim of this study is to investigate the cardiac uptake of 89Zr-GSK2398852 in subjects with transthyretin cardiomyopathy amyloidosis (ATTR-CM), and its biodistribution to other organs. Low doses of GSK2398852 will be co-administered at levels not high enough for therapeutic benefit. This study will be conducted in two parts: Part A and Part B. Subjects in Part A will participate in up to two dosing sessions and subjects in Part B will participate in one dosing session. Subjects will undergo up to 3 PET scans at varying intervals after 89Zr-GSK2398852 administration. The total duration of study will be approximately 3 to 4 months for subjects in Part A and approximately 2 months for subjects in Part B. Part B of the study will be triggered based on data obtained in Part A and other emerging data.

Detailed description:

Arms: arm 1: Approximately 3 subjects with either wild type or inherited ATTR-CM will be included. Subjects in Part A will participate in two anti-SAP dosing sessions approximately 26 days in duration. The first two subjects in Part A will have up to three 89Zr PET scans, while the remaining subject will undergo up to two 89Zr PET scans. arm 2: Approximately 3 subjects with either wild type or inherited ATTR-CM will be included. Subjects in Part B will participate in one anti-SAP dosing session. Subjects will undergo up to two 89Zr PET scans.
Interventions: intervention 1: GSK2315698 (CPHPC) intervention 2: GSK2398852 (unlabeled anti-SAP mAb) intervention 3: 89Zr-GSK2398852 (89Zr-labeled anti-SAP mAb)
Intervention descriptions: intervention 1: GSK2315698 will be administered as 20 milligrams per hour (20 mg/hour) IV infusion (in the vein) for up to 72 hours followed by 60 milligrams (mg) three times daily as SC injection for 8 days. Dose level and frequency will be adjusted according to renal function. intervention 2: Subjects will be administered up to 490 mg of GSK2398852, IV. Dose level will be adjusted based on emerging imaging data. intervention 3: 89Zr-GSK2398852 will be available as solution containing 10 mg 89Zr-GSK2398852 for Infusion. Subjects will be administered 37 (Megabecquerel) MBq radioactive dose of 89Zr-GSK2398852 by the IV route at each dosing session.

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Protocol Title: An Adaptive, Open-Label Study to Evaluate the Biodistribution of 
89Zirconium-labelled GSK2398852 in the Heart and Other Organs of Patients with
Transthyretin Cardiomyopathy (ATTR-CM) using Positron Emission Tomography (PET) 
Imaging
Protocol Number: 204512
Short Title: Biodistribution of 89Zirconium-labelled GSK2398852 using PET Imaging
Compound 
Numbers:
GSK2315698 + GSK2398852+ Radiolabelled 89Zr-
GSK2398852
Sponsor Name and Legal Registered Address: 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Medical Monitor Name and Contact Information can be found in the Study Reference 
Manual
Regulatory Agency Identifying Number(s): EudraCT 2017-002665-22
Approval Date: 04-OCT-2017
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
SYNOPSIS...............................................................................................................7
2.
SCHEDULE OF ACTIVITIES (SOA).......................................................................11
3.
INTRODUCTION....................................................................................................15
3.1.
Study Rationale ..........................................................................................15
3.2.
Background ................................................................................................16
3.2.1.
Preliminary Evidence of Anti SAP Therapeutic Effect & 
Safety in Cardiac Amyloidosis......................................................17
3.2.2.
Radiolabelled Anti-SAP mAb: 89Zr-GSK2398852........................17
3.3.
Cardiac Amyloidosis Imaging......................................................................18
3.3.1.
89Zr-GSK2398852 PET Imaging...................................................18
3.3.2.
Additional PET Imaging Procedures ............................................19
3.3.2.1.
PiB PET Imaging: Cardiac Amyloid Burden ................19
3.3.2.2.
15O-labelled Water PET Imaging: Myocardial 
Blood Flow .................................................................19
3.3.3.
Cardiac Magnetic Resonance (CMR) Imaging .............................20
3.4.
Benefit/Risk Assessment ............................................................................20
3.4.1.
Risk Assessment for Anti-SAP mAb.............................................20
3.4.1.1.
Rashes.......................................................................20
3.4.1.2.
Potential for mAb Infusion-Related Reactions 
(IRR) ..........................................................................21
3.4.1.3.
Potential for Cardiotoxicity..........................................21
3.4.2.
Radiation exposure......................................................................21
3.4.3.
Risk Assessment .........................................................................23
3.4.4.
Benefit Assessment.....................................................................28
3.4.5.
Overall Benefit:Risk Conclusion...................................................28
4.
OBJECTIVES AND ENDPOINTS...........................................................................28
5.
STUDY DESIGN ....................................................................................................29
5.1.
Overall Design ............................................................................................29
5.2.
Part A and Part B........................................................................................30
5.3.
Study Schematic.........................................................................................31
5.3.1.
Timing of 89Zr-GSK2398852 PET scans.......................................32
5.4.
Administration of CPHPC............................................................................32
5.5.
Plasma SAP Target ....................................................................................33
5.6.
Administration of 89Zr-GSK2398852 in relation to administration of 
unlabelled anti-SAP mAb............................................................................34
5.7.
Number of Subjects ....................................................................................35
5.8.
Treatment Groups and Duration .................................................................35
5.9.
Length of Time Between Dosing Sessions..................................................36
5.10.
Periodic Meeting with Investigators.............................................................36
5.10.1.
Individual Subject Safety Review.................................................36
5.11.
Subject and Study Completion....................................................................36
5.12.
Scientific Rationale for Study Design ..........................................................37
5.12.1.
Justification for the administration of CPHPC & unlabelled 
anti-SAP mAb..............................................................................37


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5.12.1.1.
CPHPC.......................................................................37
5.12.1.2.
Unlabelled Anti-SAP mAb...........................................37
5.13.
Study Overview of Anti-SAP Treatment and 89Zr-GSK2398852 ..................38
5.13.1.
Unlabelled anti-SAP mAb Dose Selection....................................38
5.13.2.
Justification of serial PET scanning per Anti-SAP session ...........40
6.
STUDY POPULATION...........................................................................................40
6.1.
Inclusion Criteria.........................................................................................40
6.2.
Exclusion Criteria........................................................................................42
6.3.
Lifestyle Restrictions...................................................................................44
6.3.1.
Caffeine, Alcohol, and Tobacco ...................................................44
6.3.2.
Activity .........................................................................................45
6.3.3.
In-person Social Interaction .........................................................45
6.4.
Screen Failures...........................................................................................45
7.
TREATMENTS.......................................................................................................45
7.1.
Treatments Administered............................................................................45
7.2.
Dose Modification .......................................................................................47
7.2.1.
CPHPC dosing regimen according to renal function ....................47
7.2.2.
CPHPC Route of Administration Change.....................................47
7.3.
Method of Treatment Assignment ...............................................................47
7.4.
Blinding.......................................................................................................48
7.5.
Preparation/Handling/Storage/Accountability..............................................48
7.6.
Treatment Compliance................................................................................48
7.7.
Concomitant Therapy..................................................................................49
7.7.1.
Pre-medication prior to unlabelled anti-SAP mAb ........................49
7.7.2.
Prohibited Medications and Non-Drug Therapies.........................49
7.8.
Treatment after the End of the Study ..........................................................50
8.
DISCONTINUATION CRITERIA.............................................................................50
8.1.
Discontinuation of Study Treatment ............................................................50
8.1.1.
Discontinuation for failure to deplete plasma SAP levels 
with IV CPHPC ............................................................................50
8.1.2.
Adverse Event Discontinuation Criteria........................................50
8.1.3.
Renal Function Discontinuation Criteria .......................................51
8.1.4.
Cardiovascular Safety Discontinuation Criteria ............................51
8.1.4.1.
Individual subject cardiovascular stopping 
criteria ........................................................................51
8.1.5.
Liver Chemistry Stopping Criteria ................................................51
8.1.6.
QTc Stopping Criteria ..................................................................52
8.1.7.
Dermatological Toxicity Stopping Criteria.....................................53
8.1.7.1.
Individual subject dermatological stopping 
criteria ........................................................................53
8.1.8.
Study Safety Stopping Criteria.....................................................53
8.1.9.
Rechallenge.................................................................................54
8.1.9.1.
Study Treatment Restart or Rechallenge....................54
8.2.
Withdrawal from the Study..........................................................................54
8.3.
Lost to Follow Up........................................................................................54
9.
STUDY ASSESSMENTS AND PROCEDURES .....................................................55
9.1.
Adverse Events...........................................................................................55


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9.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information...................................................................................55
9.1.2.
Method of Detecting AEs and SAEs.............................................56
9.1.3.
Follow-up of AEs and SAEs.........................................................56
9.1.4.
Regulatory Reporting Requirements for SAEs .............................56
9.1.5.
Cardiovascular and Death Events................................................56
9.1.6.
Pregnancy ...................................................................................57
9.2.
Treatment of Overdose...............................................................................57
9.3.
Safety Assessments ...................................................................................57
9.3.1.
Physical Examinations.................................................................58
9.3.2.
Vital Signs....................................................................................58
9.3.3.
Electrocardiograms......................................................................58
9.3.4.
Cardiac Safety Monitoring............................................................58
9.3.4.1.
Electrophysiology .......................................................58
9.3.4.2.
High Sensitivity Cardiac Troponin (hs-cTn) 
Monitoring after a Cardiac Arrhythmia Event ..............60
9.3.4.3.
Imaging for Investigation of Cardiac Adverse 
Events ........................................................................60
9.3.4.4.
Insertion of a PPM or ICD for Prophylactic 
Reasons.....................................................................61
9.3.5.
Clinical Safety Laboratory Assessments ......................................61
9.3.6.
Additional Outpatient Safety Assessments (“Virtual Visit”) ...........61
9.4.
Pharmacokinetics .......................................................................................62
9.4.1.
GSK2398852...............................................................................62
9.4.2.
Plasma radioactivity.....................................................................62
9.5.
Pharmacodynamics ....................................................................................62
9.5.1.
SAP Concentration ......................................................................62
9.6.
Imaging.......................................................................................................62
9.6.1.
89Zr-GSK2398852 PET ................................................................62
9.6.2.
Cardiac Magnetic Resonance (CMR) Imaging .............................63
9.6.3.
Access to Historical Patient ATTR-CM Cardiac Imaging..............64
9.7.
Additional Assessments..............................................................................64
9.7.1.
Access to Diagnostic Patient Cardiac Biopsy Tissue ...................64
9.8.
Efficacy.......................................................................................................64
9.8.1.
Safety/exploratory Biomarkers.....................................................64
10. STATISTICAL CONSIDERATIONS........................................................................64
10.1.
Hypothesis..................................................................................................64
10.2.
Sample Size Considerations.......................................................................65
10.2.1.
Sample Size Re-estimation or Adjustment...................................65
10.3.
Data analysis considerations ......................................................................65
10.3.1.
Populations for Analyses .............................................................65
10.3.2.
Interim Analyses ..........................................................................65
10.3.3.
Inter-Subject Reproducibility of 89Zr-GSK2398852 
Myocardial Uptake.......................................................................66
10.3.4.
Intra-subject confirmation of 89Zr-GSK2398852 Myocardial 
SAP Binding ................................................................................66
10.3.5.
Key Elements of Analysis Plan ....................................................67
10.3.6.
Pharmacokinetics ........................................................................68
10.3.7.
Evaluation of PET images............................................................68
10.3.7.1.
Analysis of PET data ..................................................70


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10.3.7.2.
Storage and potential further analyses of 
images........................................................................70
10.3.8.
Safety ..........................................................................................71
11. REFERENCES.......................................................................................................72
12. APPENDICES........................................................................................................75
12.1.
Appendix 1 Abbreviations and Trademarks.................................................75
12.2.
Appendix 2 Clinical Laboratory Tests..........................................................78
12.3.
Appendix 3 Study Governance Considerations...........................................80
12.4.
Appendix 4 Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .......................................84
12.5.
Appendix 5 Contraceptive Guidance and Collection of Pregnancy 
Information..................................................................................................90
12.6.
Appendix 6 Liver Safety: Required Actions and Follow-up 
Assessments ..............................................................................................95
12.7.
Appendix 7 Guidance on the Clinical Management of Rash 
Associated with Anti-SAP mAb ...................................................................97
12.7.1.
Background .................................................................................97
12.7.2.
Management of Rash...................................................................98
12.7.3.
Emergency management of rash with systemic /mucosal 
involvement .................................................................................98
12.7.4.
Post-Inflammatory Hyperpigmentation (PIH)................................99
12.8.
Appendix 8 Equations and Diagnostic Criteria ..........................................100
12.9.
Appendix 9 Radiation Dose ......................................................................102
12.10. Appendix 10 Schedule of Activities: Flow Diagram ...................................103


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1.
SYNOPSIS
Protocol Title: An Adaptive, Open-Label Study to Evaluate the Biodistribution of 
89Zirconium-labelled GSK2398852 in the Heart and Other Organs of Patients with 
Transthyretin Cardiomyopathy (ATTR-CM) using Positron Emission Tomography (PET) 
Imaging
Short Title: Biodistribution of 89Zirconium-labelled GSK2398852 using PET Imaging
Rationale:
The principal aim of this PET imaging study is to investigate the cardiac uptake of 89Zr-
GSK2398852 in patients with transthyretin amyloidosis restrictive cardiomyopathy 
(ATTR-CM), and its biodistribution to other organs. This study constitutes an adjunct 
study to the Phase 2 trial to evaluate the therapeutic efficacy of anti-serum amyloid P 
component (anti-SAP) treatment (GSK Study Number 201464). This PET study will 
enhance the development of Anti-SAP treatment by providing direct in vivo evaluation of 
anti-SAP monoclonal antibody (mAb) myocardial tissue uptake. 
This adaptive, dose-ranging study of the distribution of 89Zr-GSK2398852 in both cardiac 
and non-cardiac organs/tissues will strengthen the understanding of the therapeutic mAb
biodistribution and provide further insight to optimize this investigational Anti-SAP
therapeutic approach.
NOMENCLATURE:
In this document:

GSK2315698 is referred to as CPHPC (carboxy pyrrolidine hexanoyl pyrrolidine 
carboxylate).

GSK2398852 is referred to as unlabelled anti-SAP mAb.  

89Zirconium-desferrioxamine (Df) labelled anti-SAP mAb is referred to as 89Zr-
GSK2398852.

The administration of CPHPC and anti-SAP mAb is referred to as Anti-SAP 
treatment.

Total Mass Dose (TMD) of anti-SAP mAb = unlabelled anti-SAP mAb + 89Zr-
GSK2398852.


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Primary and Secondary Objectives and Endpoints:
Objective
Endpoint
Primary
Assessment of 89Zr-GSK2398852 cardiac 
uptake as evaluated by PET imaging at different 
mass doses
Standardized Uptake Values (SUV) [i.e. 
Radioactivity concentrations] in focal anatomical 
locations within the heart, as well as SUV of the 
whole heart at different time points after 89Zr-
GSK2398852 administration and at different
anti-SAP mAb TMDs.
Secondary
Assessment of 89Zr-GSK2398852 biodistribution 
in non-cardiac tissues and organs 
Focal and total radioactivity uptake (including, 
but not limited to SUV) in different tissues 
(including potentially at those peripheral tissue 
sites where TTR amyloid deposition can be 
clinically occult) at different time points and after 
different TMDs.
Characterisation of the plasma 
pharmacokinetics of total mAb (unlabelled 
GSK2398852 and 89Zr-GSK2398852)
Descriptive pharmacokinetic (PK) parameters, 
including the maximum concentration in plasma 
(Cmax), the time associated with Cmax (Tmax), 
clearance, terminal half-life (T½) and the area 
under the concentration-time profile (AUC).
Characterisation of the plasma 
pharmacokinetics of radioactivity (89Zr-
GSK2398852 radio-PK)
Descriptive PK parameters including Cmax, 
Tmax, clearance, T½ and AUC based on 
scintillation counter.
Safety & tolerability of Anti-SAP treatment 
including administration of 89Zr-GSK2398852 
All adverse events (AEs) including the incidence 
and grading of skin rashes, cardiac adverse 
events and infusion-related reactions, as well as 
other AEs utilizing standard pharmacovigilance 
practices.
Absolute changes in safety lab parameters, 
including cardiac troponin and N-terminal
prohormone of brain natriuretic peptide (NT-
proBNP). Other safety information, including 
electrocardiogram (ECG), inpatient and 
outpatient cardiac telemetry, vital signs, and 
physical exam data.


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Overall Design:
This is an open-label non-randomised 89Zr-GSK2398852 PET imaging study in clinically 
stable patients with either wild type or inherited ATTR-CM. Subjects will participate in 
up to two dosing sessions.
Each dosing session will include:
Administration of anti-SAP treatment consisting of:
o CPHPC administered via intravenous (IV) infusion for at least 48 hours, 
followed by
o Unlabelled anti-SAP mAb together with 89Zr-GSK2398852 via two 
separate intravenous infusions, and
o CPHPC administered via subcutaneous (SC) injections for at least 9 days.
Up to three PET scans at varying intervals after 89Zr-GSK2398852 administration.
An inpatient stay of up to 11 days, followed by an additional week of outpatient 
cardiac monitoring.
At a single suitable time point, depending on technical and logistic aspects, the subject 
will undergo one additional PET scan with the administration of Carbon-11 Pittsburgh 
Compound B (PiB), a tracer known to bind to amyloid, for the characterization of the 
regional amyloid burden in the heart, and up to two further PET scans with the 
administration of Oxygen-15 labelled water (WAT) for the characterization of the 
regional blood flow in the heart. 
This study has an adaptive study design in order to identify the conditions and dose of 
anti-SAP mAb which provide optimal assessment of cardiac update. As the name 
suggests, systemic amyloidosis is associated with amyloid deposits in multiple organs. 
The delivery of monoclonal antibodies to individual organs depends on the blood flow 
and nature of the endothelium. Because the amount of tracer 89Zr-GSK2398852 is small 
relative to total amyloid load, if given alone it would distribute to the best-perfused 
organs with discontinuous endothelia. For this reason, the radiolabelled tracer will be co-
administered with unlabelled anti-SAP mAb so that distribution will better reflect the 
situation when therapeutic doses are administered. 
During each dosing session, subjects will receive a TMD of anti-SAP mAb ≤500 mg. The 
dose will vary between subjects and dosing sessions, and will be contingent on both the 
PET imaging and 89Zr-GSK2398852 PK findings from the 1st dosing session, or the 
findings from previous subjects.
Number of Subjects:
Sufficient subjects will be screened such that up to six subjects complete the study.


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Treatment Groups and Duration:
This study will be divided into two parts: Part A and an optional Part B.
All subjects will participate in a screening period of up to 35 days. Part A subjects (N=3) 
will participate in up to two dosing sessions approximately 26 days in duration (each). 
Part B subjects (N=3) will participate in one dosing session of approximately 26 days in 
duration. Total duration of the study will be approximately 3-4 months for Part A 
subjects, and approximately 2 months for Part B subjects. 
All subjects will receive IV CPHPC prior to anti-SAP mAb and SC CPHPC post anti-
SAP mAb. Unlabelled anti-SAP mAb will be administered at varying doses throughout 
the study. The radioactivity dose of 89Zr-GSK2398852 will be the same in each dosing 
session for all subjects throughout the study.
The TMD of anti-SAP mAb administered per subject per dosing session in this study is 
determined by the mass dose of unlabelled anti-SAP mAb plus 10 mg associated with 
89Zr-GSK2398852.
The GSK study team including the Medical Monitor will confirm the unlabelled anti-SAP 
mAb dose for each subject prior to administration.


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2.
SCHEDULE OF ACTIVITIES (SOA)
Table 1
Part A and Part B Overview
Dosing Session 1
Dosing Session 2
Part A
X
X
Part B
X
Table 2
Overview All Groups 
Dosing Sessions 1 and 2
Screening1
Baseline2
Day 1: pre- dose
Day 1
Day 2
Day 3: pre-dose mAb
Day 3: anti-SAP mAb dosing 
Day 3: end of mAb infusion18
Day 3: 4 hours post end mAb infusion18
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 11-18
Day 2018
Day 2616, 18
Inpatient stay at unit
-------------------------------------------------------- X -----------------
----------------
Discharge from inpatient
X
Outpatient visit
X
X
X
Remote Contact for Safety 
Assessment
X
Informed consent
X
Medical history/risk 
factors/demographics
X
Inclusion/exclusion criteria
X
Safety Assessments
Physical examination3
X
X
X
X
X
X
X
Adverse event (AE)/ serious 
adverse event (SAE)
Assessment
------------------------------------------------------- X -----------------------------------------------
--------
Concomitant Medications
------------------------------------------------- X -----------------------------------------------
--------
12-lead electrocardiogram 
(ECG)
X
1
3
X
1
3
X
X
X
X
X
X
X
X
X
X
X
X
2
1
X
Continuous Lead II Telemetry20
-------------------------------------------------------- X -----------------------
-------------


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Dosing Sessions 1 and 2
Screening1
Baseline2
Day 1: pre- dose
Day 1
Day 2
Day 3: pre-dose mAb
Day 3: anti-SAP mAb dosing 
Day 3: end of mAb infusion18
Day 3: 4 hours post end mAb infusion18
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 11-18
Day 2018
Day 2616, 18
Remote Continuous Cardiac 
Monitoring4
X
X
X
Vital signs
X
1
3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
2
1
X
Screening Laboratory 
Assessments5
X
Haem/clin chem/ urinalysis
X
X
X
X
X
X
X
Troponin T/ N-terminal 
prohormone of brain natriuretic 
peptide (NT-ProBNP)
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
X
1
5
X
1
5
Investigational medicinal product (IMP) Administration
Carboxy pyrrolidine hexanoyl 
pyrrolidine carboxylate 
(CPHPC) IV
---  X10  --
-
CPHPC SC12
X
1
1
X
X
X
X
X
X
X
X
Premedication 
(hydrocortisone/anti-histamine)
X
Unlabelled anti-SAP mAb
X
7
89Zr-GSK2398852
X
7
Pharmacokinetics (PK)/SAP9
Blood sampling for plasma 
SAP
X
X
6
Anti-SAP mAb PK17
X
X
X
X
X
X
X
89Zr-GSK2398852 radio-PK 
(for scintillation)14
X
X
X
X
X
X
Imaging Procedures
Cardiac Magnetic Resonance 
Imaging (MRI) with contrast
X


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Dosing Sessions 1 and 2
Screening1
Baseline2
Day 1: pre- dose
Day 1
Day 2
Day 3: pre-dose mAb
Day 3: anti-SAP mAb dosing 
Day 3: end of mAb infusion18
Day 3: 4 hours post end mAb infusion18
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 11-18
Day 2018
Day 2616, 18
Echocardiogram (ECHO)
X
Pittsburgh Compound B (PIB) 
Positron Emission Tomography
(PET)
X
15-Oxygen labelled water 
(WAT PET)
X
X
8
89Zr-GSK2398852 PET / 
Computerised Tomography 
(CT)
X
9
X
9 
X
9, 
1
9
Note: If anti-SAP mAb dosing is delayed by one day, then Day 2 assessments should be repeated, 
and all subsequent assessments should be delayed by one day.
Footnotes:
1.
Screening to take place within 35 days of start of Anti-SAP treatment.
2.
Baseline will be any time after eligibility confirmed and before Anti-SAP treatment starts. Procedures may be 
done on different days.
3.
Full examination at screening only, brief examination at all other time-points.
4.
Out-patient cardiac recording (see Section 3.4.1.3): Baseline for approximately 1 week, and from Day 11 for 
approximately 1 week after discharge.
5.
See Other Screening Tests in Appendix 2
6.
Requires rapid turnaround. See Section 5.5 Plasma SAP Target
7.
See Section 5.6 for timing of administration of unlabelled anti-SAP mAb and 89Zr-GSK2398852.
8.
Dosing Session 2 only, if logistically feasible. Can be done any day/time prior to anti-SAP mAb.
9.
Exact timing in relation to end of 89Zr-GSK2398852 infusion will change based on emerging data. See 
Section 5.3.1.
10. CPHPC IV infusion for a minimum of approximately 48 hours. To be stopped prior to mAb infusion.
11. First SC dose to be administered approximately 5 hours after end of IV CPHPC infusion.
12. Administered three times daily. See Section 7.1 and Section 7.2
13. In triplicate.
14. See Table 5
15. Female Subjects Only.
16. The last visit of the final study session will be considered the final follow-up visit. This may be conducted in-
person, or by “virtual visit”.
17. See Table 4 for sampling times and windows.
18. See Table 3 for allowable time/visit windows.
19. Third 89Zr PET-CT to be done in first two subjects who complete Part A, only. Subsequent subjects to 
undergo only two 89Zr PET-CT scans.
20. From Day 6 onward, at investigator discretion, inpatient cardiac monitoring can be performed via remote 
cardiac telemetry device (e.g. BodyGuardian device)
21. If logistically possible.


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Table 3
Allowable Assessment/Visit Windows 
Day 3: End mAb 
Infusion
Day 3: 4 hours post 
end-mAb infusion
Day 20
Day 26
Window
+10 minutes
±10 minutes
±1 day
±2 days
Table 4
Unlabelled anti-SAP mAb PK Sampling (Dosing Sessions 1 and 2)
Pre anti-
SAP mAb 
infusion
Halfway 
through 
infusion 
End of 
unlabelled 
anti-SAP 
mAb 
infusion 
7 hours 
post end 
of anti-
SAP mAb 
infusion
24 hours 
after end 
of 
infusion 
(Day 4)
48 hours
after end 
of 
infusion 
(Day 5)
72 hours
after end 
of 
infusion 
(Day 6)
96 hours
after end 
of 
infusion 
(Day 7)
Anti-SAP 
mAb PK
X
X
X
X
X
X
X
X
Time 
window
±10 
minutes
+10 
minutes
±30 
minutes
±1 hour
±2 hours
±2 hours
±2 hours
Note: Up to three additional samples may be collected and sampling times may be modified based on emerging data.
Table 5
89Zr-GSK2398852 Radio-PK Sampling (Dosing Sessions 1 and 2)
Time after 89Zr-GSK2398852 infusion end
10 minutes
60 
minutes
4 hours
7 hours
24 hours
(Day 4)
48 hours
(Day 5)
72 hours
(Day 6)
89Zr-GSK2398852 
radio-PK (for 
scintillation)
X
X
X
X
X
X
X
Time Window
± 5 
minutes
± 10 
minutes
± 1 hour
± 2 hours
± 4 hours
± 4 hours
± 4 hours
Note: Up to three additional samples may be collected and sampling times may be modified based on emerging data.
Time windows are for guidance; non-adherence to these times will not constitute a protocol deviation.


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3.
INTRODUCTION
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].
Serum amyloid P component (SAP) is a normal, circulating, constitutive plasma 
glycoprotein which is invariably present in human amyloid deposits of all types. 
Anti-SAP treatment is in development for systemic amyloidosis. Anti-SAP treatment 
consists of an obligate combination of Carboxy pyrrolidine hexanoyl pyrrolidine 
carboxylate (CPHPC, miridesap) a small molecule depletor of plasma SAP and an anti-
SAP humanized immunoglobulin G1 (IgG1) mAb (dezamizumab). Depletion of 
circulating SAP by CPHPC [Pepys 2002] enables the administration of anti-SAP 
antibodies which bind to SAP on amyloid deposits, opsonizing them for macrophage 
giant cell mediated clearance. 
Myocardial amyloid deposition in transthyretin amyloidosis (ATTR) causes restrictive 
cardiomyopathy (ATTR-CM) leading to heart failure 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 improve cardiac 
function, reduce symptoms and prolong survival in patients with ATTR amyloidosis, as 
well as in other types of systemic amyloidosis (e.g. amyloid Light-chain [AL]
amyloidosis) where the heart is also frequently involved.
NOMENCLATURE:
In this document: 

GSK2315698 (miridesap) is referred to as CPHPC.

GSK2398852 (dezamizumab) is referred to as unlabelled anti-SAP mAb.  

89Zirconium-desferrioxamine (Df) labelled anti-SAP mAb is referred to as 89Zr-
GSK2398852.

The administration of CPHPC and anti-SAP mAb is referred to as Anti-SAP 
treatment.

Total Mass Dose (TMD) of anti-SAP mAb = unlabelled anti-SAP mAb + 89Zr-
GSK2398852.
3.1.
Study Rationale
The principal aim of this study is to investigate the cardiac uptake of 89Zr-GSK2398852 
in patients with ATTR-CM, and its biodistribution to other organs. 


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The cardiac endothelium is continuous and although the heart is well perfused, regional 
variations occur especially in cardiac amyloidosis. The anti-SAP mAb is expected to 
reach cardiac amyloid but the pharmacokinetics and proportion reaching the heart relative 
to other organs is unknown. This study will augment the interpretation of the ongoing 
phase 2 therapeutic trial by providing important information on the relative uptake of a 
radiolabelled tracer dose of 89Zr-GSK2398852.
The uptake 89Zr-GSK2398852 data will be contextualised by Carbon-11 PiB, a tracer 
known to bind to amyloid, for the characterization of the regional amyloid burden in the 
heart, and up to two further PET scans with the administration of WAT for the 
characterization of the regional blood flow in the heart. 
As the name suggests, systemic amyloidosis is associated with amyloid deposits in 
multiple organs. The delivery of monoclonal antibodies to individual organs depends on 
the blood flow and nature of the endothelium. Because the amount of tracer 89Zr-
GSK2398852 is small relative to total amyloid load, if given alone it would distribute to 
the best perfused organs with discontinuous endothelia. For this reason, the radiolabelled 
tracer will be co-administered with unlabelled anti-SAP mAb so that distribution will 
better reflect the situation when therapeutic doses are administered.
3.2.
Background
Involvement of the heart is the most important determinant of patient survival in the two 
commonest types of systemic amyloidosis: ATTR amyloidosis and AL amyloidosis.
Deposition of both TTR and AL amyloid in the heart leads to restrictive cardiomyopathy
which predominantly causes heart failure with preserved ejection fraction (HFpEF). The 
natural history of amyloid deposition within the heart involves early deposition in the 
subendocardium (causing a high incidence of arrhythmias) followed by asymmetrical
deposition of amyloid within the myocardium mainly affecting the interventricular 
septum and free left ventricular wall.
As part of Anti-SAP treatment in systemic amyloidosis, CPHPC is administered first 
intravenously (and then subcutaneously during and after anti-SAP mAb administration) 
to deplete and maintain circulating plasma SAP levels to target. This enables the safe 
administration of anti-SAP mAb to target amyloid-involved organs without the systemic 
formation of large amounts of circulating SAP / anti-SAP mAb immune complexes. The 
anti-SAP mAb can then reach and bind to residual SAP in the amyloid deposits and 
trigger the normal opsonophagocytic processes for removal of amyloid deposits from the 
extracellular space through the formation of multinucleated giant cells. 
As proof of pharmacology, GSK has shown in a first-in-human (FIH) study (SAP115570)
that Anti-SAP treatment can promote the clearance of amyloid deposits from extra-
cardiac tissues (e.g. liver and kidney) with an acceptable safety profile (Please see 
Investigator’s Brochure (IB) GlaxoSmithKline Document Number 2012N141587_06 and 
Richards 2015). 


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3.2.1.
Preliminary Evidence of Anti SAP Therapeutic Effect & Safety in 
Cardiac Amyloidosis 
A total of twenty-three patients with systemic amyloidosis received Anti-SAP treatment
in the FIH study (SAP115570). Six of these subjects had cardiac amyloidosis: three 
ATTR-CM subjects and three AL amyloidosis subjects. 
Two subjects received 3 treatment sessions (session 1: 600 mg GSK2398852 and session 
2 and 3: 1200 mg GSK2398852); the remainder received a single Anti-SAP treatment 
session  (dose of GSK2398852 ranged from 600 to 1200 mg). Of the 2 subjects who 
received more than one Anti-SAP treatment session, cardiac magnetic resonance (CMR) 
imaging in one subject showed a reduction in LVmass that was outside the variability 
associated with the test and is, therefore, considered preliminary evidence of the potential 
to remove cardiac amyloid (refer to IB: GlaxoSmithKline Document Number 
2012N141587_06).
None of the other subjects with cardiac amyloidosis had any detectable signals of 
amyloid removal on CMR imaging, however several did show a transient rise in NT-
proBNP which may represent engagement of the target mechanism in the heart (refer to 
IB: GlaxoSmithKline Document Number 2012N141587_06).
Importantly, no cardiac adverse events were observed in the First in Human (FIH) study 
(SAP115570) in any of these subjects. Overall, the adverse event profile of anti-SAP 
mAb in subjects with cardiac amyloidosis was no different to those subjects with only 
abdominal organ involvement in the FIH study.
A Phase 2 trial (Study Number 201464) evaluating the effect of Anti-SAP therapy in
ATTR-CM and cardiac AL amyloidosis has commenced in the United Kingdom, and has 
received Food and Drug Administration (FDA) approval in the United States. The Phase 
2 study is using serial CMR imaging to evaluate the potential markers of cardiac amyloid 
removal effect of up to six sessions of Anti-SAP treatment.
3.2.2.
Radiolabelled Anti-SAP mAb: 89Zr-GSK2398852
PET has been selected as the imaging modality for this because it provides sufficiently 
high spatial resolution (about 6 mm) and a high sensitivity and ability for accurate 
quantitation of radioactivity concentration throughout the body.
There are several positron emitting radionuclides which are used for human PET studies, 
but for a study like the one proposed here, the half-life of the radionuclide is a key 
selection factor. 15O (2 minutes), 11C (20 minutes), 68Ga (68 minutes), and 18F (2 hours) 
are frequently used in PET, but these short half-lives would not allow recording of 
biodistribution of labelled antibodies with plasma elimination half-lives of multiple hours 
to days and very slow anticipated penetration to the extracellular space. 89Zr with a half-
life of 3.2 days is suited for such studies since it allows a more comprehensive evaluation 
of tissue biodistribution of the radiolabelled antibody for longer than two days.
A further advantage of 89Zr is that generic labelling methods have been developed 
whereby antibodies can be labelled in a standardized procedure and with the binding and 


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distribution properties retained [Dijkers 2009, Perk 2010, Gaykema 2013, Menke-van der 
Houven van Oordt CW 2015, Pendit-Taskar 2014, Pendit-Taskar 2015, Laforest 2016].
GSK2398852 (anti-SAP mAb) has been conjugated to 89Zirconium (Zr) using a non-
cleavable linker (See Supplement to Investigator Brochure for GSK2398852 + 
GSK2315698, GlaxoSmith Kline Document Number 2017N343159_00).
In vitro experiments have shown that the binding affinity of the Fab domain of 89Zr-
GSK2398852 for SAP is similar to unlabelled anti-SAP mAb which has been 
therapeutically used in combination with CPHPC in the FIH study (SAP115570). In 
contrast, the Fc domain of 89Zr-GSK2398852 has been shown in vitro to have an 
approximate 30% reduction in C1q binding which could lead to a potential reduction in 
immunological effector function. Thus the small dose of 89Zr-GSK2398852 (10 mg) is 
unlikely to substantially contribute pharmacology whether beneficial or adverse.
The local vascular distribution, tissue permeability, and PK profile of 89Zr-GSK2398852 
in the myocardium of ATTR-CM patients is predicted to be dependent upon five factors:
1. Vascular distribution of the antibody to the heart is principally via epicardial 
coronary arteries. The plasma PK profile of anti-SAP mAb may be altered by the 
presence of variable amounts of amyloid (decorated with SAP) in other organs. 
2. Intra-myocardial, locoregional, distribution of 89Zr-GSK2398852 is dependent on 
myocardial microvessel capillary endothelium patency. The capillary endothelium 
may be altered (impaired) in areas of amyloid deposition as compared to regions
unaffected by amyloid deposition.
3. The rate of extravasation across the myocardial microvessel endothelium is 
expected to be governed partly by paracellular convection of fluid and possibly by 
transcellular transport via neonatal Fc receptor (FcRn) receptors. In a first order 
description, the bulk flow is assumed to be proportional to the blood flow. In 
areas of amyloid deposition, there is likely to be a reduction of tissue blood flow, 
with potentially small areas of ischemia. 
4.
89Zr-GSK2398852 is expected to bind to SAP on amyloid accessible in the 
interstitium. The rate and duration of this bound antibody is dependent upon 
binding affinity and dissociation rate and the available concentration and its time 
course in the interstitium. 
The factors above indicate a complex chain of events mediating the resulting PET signal 
in the heart. The study has an adaptive iterative design to allow for use of prior data to 
inform future doses of unlabelled mAb and the timing of assessments. 
3.3.
Cardiac Amyloidosis Imaging
3.3.1.
89Zr-GSK2398852 PET Imaging
PET allows an accurate assessment of radioactivity distribution in the body after the 
administration of the radioactivity tracer. 


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Each PET sequence is anticipated to last 60-90 minutes and will have up to 3 scans per 
dosing session. All PET scans are expected to be performed within 5 days of 89Zr-
GSK2398852 administration.
From the time of tracer administration multiple blood samples are taken for the 
measurement of radioactivity concentration in whole blood and plasma. These data will 
be used in relation to the tissue uptake.
The images can be visually inspected but more important is that selected areas in the 
images will be used for quantitative evaluation of radioactivity concentration and further 
used for the modelling.
3.3.2.
Additional PET Imaging Procedures
Whenever possible, the following baseline PET procedures should be performed after a 
subject has passed other eligibility requirements.
3.3.2.1.
PiB PET Imaging: Cardiac Amyloid Burden
The PET tracer Carbon-11 PiB has been used extensively for the characterization of 
amyloid load in patients with Alzheimer’s disease but also in a number of publications 
for amyloid burden in the heart [Pilebro 2016, Antoni 2013]. This type of study has 
shown excellent visualization and quantitative values which identifies amyloid-loaded 
hearts as compared to hearts without amyloid. The studies have also identified 
differences in the anatomical location of the amyloid deposits, information which can be 
of great importance for the interpretation of the 89Zr-GSK2398852 distribution in the 
heart.
If logistically possible, this PiB PET procedure will be introduced at a time point which is 
suitable in relation to technical aspects such as availability of cyclotron and 
radiochemistry or logistical aspects related to patient handling. It includes a single IV
bolus administration of the tracer followed by about 30 minutes scanning over the heart. 
3.3.2.2.
15O-labelled Water PET Imaging: Myocardial Blood Flow 
15-Oxygen-labelled water (WAT) has been used extensively in PET studies for the 
characterization and quantitative evaluation of regional tissue blood flow [Antoni 2013, 
Dorbala 2014]. Such or similar studies have demonstrated marked and regionally 
different reductions in the blood flow in the heart of patients with systemic amyloidosis. 
This is additional information which can be important for the interpretation of the signal 
in the 89Zr-GSK2398852 study.
This PET procedure may be introduced at up to two time points which are suitable in 
relation to technical aspects such as availability of cyclotron and radiochemistry or 
logistical aspects related the patient handling.
The procedure includes the bolus administration of WAT followed by scanning across the 
heart for a few minutes.


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3.3.3.
Cardiac Magnetic Resonance (CMR) Imaging
CMR methods precisely and specifically quantify the left ventricle (LV) mass and the 
cardiac 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 ATTR-CM [Martinez-Naharro 2017].
However, the specificity of ECV as a measure of amyloid involvement in myocardial 
tissue remains to be determined. In this study, contrast-enhanced CMR will be used to 
determine the amyloid load and myocardial perfusion in ATTR-CM patients at baseline. 
Baseline CMR will also enable exploratory investigations to co-localise regions of 89Zr-
GSK2398852 cardiac uptake on PET imaging with anatomical sites of TTR amyloid 
deposition within the myocardium, as well as potentially loco-regional intramyocardial 
perfusion parameters since myocardial blood flow is expected to be an important 
determinant of 89Zr-GSK2398852 myocardial uptake and distribution.
Whenever possible, the baseline contrast-enhanced CMR should be performed after a 
subject has passed other eligibility requirements. 
3.4.
Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of Anti-SAP treatment may be found in the 
Investigator’s Brochure.
Summaries of the pre-clinical and clinical studies conducted with CPHPC alone and with 
CPHPC + anti-SAP mAb are presented in the Investigator’s Brochure [GlaxoSmithKline 
Document Number 2012N141587_06].
3.4.1.
Risk Assessment for Anti-SAP mAb
Given that the administered dose of 89Zr-GSK2398852 per anti-SAP dosing session will 
be low (10 mg), the principal risks associated with anti-SAP mAb in this PET study are 
likely to be associated with the administration of unlabelled anti-SAP mAb. 
At this time, there are two main identified risks for administration of unlabelled anti-SAP 
mAb in this PET study, based on observations in the FIH study: i) skin rash (Section 
3.4.1.1); ii) anti-SAP mAb infusion-related reactions (IRR). 
3.4.1.1.
Rashes 
Many subjects who received 582 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 distribution, severity and persistence; all but one of these 
rashes, were self-limiting. Skin biopsy in two other affected AL amyloidosis patients 
demonstrated pathological changes consistent with an early leukocytoclastic vasculitis 
(LCV). 


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The pathophysiological mechanism for these rashes is not known to date 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. The potential  mechanisms will be thoroughly investigated 
in the ongoing Phase 2 study (Study Number 201464).
GSK will also inform the study site as to the emerging immuno-toxicological / skin 
pathological findings from the Anti-SAP Phase 2 study since this might assist the 
evaluation and management of any rashes which are observed during this PET 
imaging study.
See Section 3.4.3 for risk mitigation strategy.
3.4.1.2.
Potential for mAb Infusion-Related Reactions (IRR) 
Most subjects receiving more than 200 mg of anti-SAP mAb in the FIH study 
experienced infusion-related reactions varying in type 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 hydrocortisone and chlorphenamine.
See Section 3.4.3 for risk mitigation strategy.
3.4.1.3.
Potential for Cardiotoxicity 
Cardiac amyloidosis (ATTR & AL) patients have been dosed in the FIH study. This was 
associated with an overall acceptable safety profile.
Since the minimum effective dose for anti-SAP mAb dependent amyloid removal in the 
heart of ATTR-CM patients has not yet been established, and because there is a known 
high background incidence of arrhythmias in this patient population, there remains the 
theoretical potential for engagement of complement and macrophage mechanisms within 
the myocardium of subjects receiving anti-SAP mAb TMD up to and including ≤500 mg. 
Therefore, this yields a potential risk of cardiotoxicity through disturbance of 
electrophysiology and / or myocardial contractility, or perfusion.
See Section 3.4.3 for risk mitigation strategy.
3.4.2.
Radiation exposure
The study will involve radiation exposure from up to 2 separate administrations of 89Zr 
labelled anti-SAP (89Zr-GSK2398852) to patients, each associated with 3 low-dose 
whole-body CT imaging scans, plus potential PET procedures with PiB and WAT.  
In oncology 89Zr-labelled mAb studies, a minimum administration of 37 MBq is regarded 
as adequate for good image quality. In some studies, this administration has been 
repeated up to 3 times. Some of the studies have been associated with other PET studies, 
notably Fludeoxyglucose (FDG). The studies conducted in the United States (US) have 


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typically been associated with much higher administrated doses such as 185 MBq 
[Pendit-Taskar 2014, Ulaner 2016].
The prognosis of ATTR-CM is similar to that of metastatic cancers, in that the life 
expectancy is less than 4 years from diagnosis, and the older age at presentation for wild-
type ATTR (median 75 years), means that the subjects can be exposed to higher levels of 
radiation without significantly increasing the risk of developing secondary tumors 
[Shuryak 2010]. 
Based on the above information and rationales, the proposed 89Zr-GSK2398852 dose is 
approximately 37 MBq for each administration, 2 dosing sessions per subject, with a total 
of approximately 74 MBq. The mean effective dose for 89Zr-mAb PET study was 
reported to be 0.53 mSv/MBq [Börjesson 2009], hence 37 MBq of 89Zr-GSK3128349 in
this study would provide approximately 19.61 mSv (37 MBq x 0.53 mSv/MBq) of 
exposure, which together with the low-dose CT scans (0.5 mSv/CT scan x 3 CT scans) 
yield approximately 21.11 mSv. The single PiB procedure including its CT component is 
expected to add 1.5 mSv, and the two WAT procedures to add a total of 1 mSv in 
radiation exposure. 
Total radiation dose exposure per subject is therefore expected to be a maximum of up to
44.7 mSv. With some residual radioactivity in the injection syringe and considering
radioactive decay till time of injection, we will aim to be below 44 mSv across the study. 
Reference Appendix 9 for additional information.


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3.4.3.
Risk Assessment
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 582 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 / urticarial rash after being 
administered 600 mg anti-SAP mAb on the first treatment 
session was reported as a LCV. In this biopsy sample, 
there was no demonstrable deposition of immunoglobulins, 
complement, immune complexes, or amyloid in the 
tissues. 
A second AL amyloidosis patient with improving liver load 
(after 1st treatment session) had a diffuse rash after 
receiving 1000 mg anti-SAP mAb on the 2nd treatment 
session. The dermato-pathological changes on this 
subject’s skin biopsy was consistent with a lymphocytic / 
leucocytoclastic vasculitis.
Administration of TMDs ≤500 mg per dosing session
Dermatological (skin) monitoring 
Prompt clinical dermatology review dependent on the 
presenting Grade, persistence and overall temporal evolution 
of the rash (see Section 12.7)
Use of topical or systemic anti-inflammatory medications, 
including but not restricted to corticosteroids and anti-
histamines, at the discretion of Investigator, designee, or 
dermatologist (as necessary)
Subjects will be withdrawn from the study after the 1st dosing 
session if a rash has not completely resolved by the 
scheduled time of the 2nd dosing session, or if the rash has 
been designated as >Grade 2 following session 1 (see 
Section 8.1.7)


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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 repeatedly experienced 
acute rashes with repeat anti-SAP mAb dosing ≥582 mg 
developed variable PIH.
PIH is benign but may only resolve completely 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.
Anti-SAP mAb TMD ≤500 mg per dosing session to 
mitigate risk of acute rashes
All subjects who develop PIH will be monitored clinically 
Dermatology review for all PIH occurrences
Infusion Reactions
Most subjects receiving more than 200 mg of anti-SAP 
antibody in the FIH study experienced infusion 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 hydrocortisone and chlorphenamine.
Unlabelled anti-SAP mAb will be given as a single 
infusion slowly over at least 6 hours where the intended 
mass dose per dosing session will be >200 mg range.
(i.e. TMD range: 200 mg < TMD ≤500 mg)
Interrupting the infusion and/or reducing the rate of 
administration of each mAb infusion
Hydrocortisone premedication 
Antihistamine premedication 
Careful monitoring of blood pressure, and appropriate clinical 
management if required (e.g. fluid balance and urine output 
with immediate access to IV fluids).
Use of anti-emetics for nausea & vomiting
Myocarditis
The intended and desired pharmacodynamics (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 
Administration of anti-SAP mAb TMD during each 
session which will be up to approximately 12-fold lower
than anti-SAP mAb doses administered to cardiac 
amyloidosis subjects in the FIH study (SAP115570)


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
deposits in the heart, activation of complement and 
attraction of macrophage infiltration and fusogenic 
activation to form multinucleate giant cells (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.
(i.e. 80 mg ≤TMD ≤500 mg per dosing session)
Comprehensive inpatient cardiac monitoring comprising:
Serial heart rate and blood pressure measurement
Continuous inpatient telemetry during and after each anti-
SAP treatment session
Serial 12-lead ECG recording
Serial inpatient evaluations of cardiac troponin T and NT-
proBNP 
2D-ECHO will be performed at Screening to provide 
reference cardiac functional data in the event of cardiac 
adverse event(s) during the study which might perturb 
cardiac function.
Non-implantable cardiac monitoring devices (e.g. 
BodyGuardian) will be used to evaluate the background 
electrophysiology of subjects at Screening. The same 
monitoring device will be used for at least 7 consecutive days 
after in-patent discharge to detect potential later-onset
cardiac electrophysiology changes associated with 
administration of an anti-SAP mAb TMD.
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. 
No causal relationship to Anti-SAP treatment has been 
Serial haemoglobin & platelet monitoring, and Screening 
coagulation test. 
These investigations may be repeated if an epistasis event 
occurs.


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
identified at this time.
Serial heart rate and blood pressure measurement
CMR Contrast Agent - gadolinium (Gd) 
Delayed excretion and 
tissue accumulation of 
gadolinium contrast after 
CMR scan
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
Gd-contrast CMR will be only performed once during the 
study, at Screening
Exclusion of patients with eGFR <50 mL/min 
eGFR will be checked prior to Gd-contrast CMR
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 estimated glomerular filtration rate 
(eGFR) <50 mL/min (see exclusion criteria)
Monitoring of serum creatinine before and after 
administration of Gd contrast agent.
Dermatological inspection for rashes.
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.


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Potential Risk of Clinical 
Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Procedural risks 
Subjects exposed to 
ionising radiation as a 
consequence of
participation in this study
(e.g. 89Zr-GSK2398852 
imaging).
Ionising radiation exposure from PET scanning comes 
from the administered radioligand and CT examination. 
The total radiation burden per subject is calculated as 
21.1 mSv per 89Zr-GSK2398852 scan session; and the 
single PiB and two WAT scans together 2.5 mSv; up to
total 44.7 mSv for all PET scans and this corresponds to a 
lifetime risk of a fatal malignancy of about 1 in 600 [ICRP
2007].
Subjects who participate will receive a radiation exposure 
up to a maximum of 44.7 mSv across two separate dosing 
sessions. 
The ceiling radiation exposure of 44.7 mSv is judged as 
safe to the individual, and justified on a trial basis due to 
the clinically severe and life-limiting nature of ATTR 
cardiomyopathy, and the importance to the study 
objectives of optimising the signal-noise ratio from the 
myocardium during each PET scan
The study has been designed to keep the radiation dose 
as low as reasonably practicable (ALARP) whilst obtaining 
images of sufficient quality to meet the objectives. 
Subjects <65 years of age will not be eligible
The study will exclude women of childbearing potential. 
Subjects who have been exposed to ionising radiation in 
excess of 10 mSv above background over the previous 
three-year period as a result of occupational exposure to 
radiation or as a result of research studies are excluded. 
Clinically justified (therapeutic or diagnostic) exposures are 
not included in the exposure calculation. Subjects are 
asked about any occupational exposure or previous 
participation in research studies at screening so that dose 
estimates can be obtained where necessary. 


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3.4.4.
Benefit Assessment
The purpose of this study is to provide an assessment of the myocardial uptake of anti-
SAP mAb using a radiotracer technique. Unlabelled anti-SAP mAb is also given because 
the ratio of tracer to total body amyloid is low. In order to minimise the risk of dose-
dependent adverse effects the maximum total dose of anti-SAP mAb has been capped at 
500 mg. In the first in human study the lowest dose associated with objective evidence of 
amyloid removal (in the liver) was 246 mg in a single subject. Thus the doses of anti-
SAP mAb given in this study have the potential to pharmacologically active and to 
trigger amyloid removal however they are low and are not expected to result in 
therapeutic removal. Thus participants in this study are not expected to derive direct 
therapeutic benefit but the information from this and the ongoing phase 2 study will be 
combined to inform rational dose selection for future development.  
3.4.5.
Overall Benefit:Risk Conclusion
Although ATTR-CM subjects recruited into this PET study are unlikely to derive any 
overall therapeutic benefit from Anti-SAP treatment, their participation in this PET study 
will however help the overall development of Anti-SAP treatment for cardiac 
amyloidosis.
The total radiation exposure (up to a maximum of 44.7 mSv) per subject ensures optimal
myocardial signal-to-noise ratio per PET scan and is considered justified given the 
limited survival from diagnosis of ATTR-CM patients. 
The dose of anti-SAP mAb in this study will be adjusted to optimise information on 
myocardial uptake but is set at a level that, based on previous clinical experience, is 
likely to be well tolerated
Therefore, overall the 89Zr-GSK2398852 PET imaging study is justified given the safety 
mitigation strategies in place for each subject during the study.
4.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
Assessment of 89Zr-GSK2398852 cardiac 
uptake as evaluated by PET imaging at different 
mass doses
Standardized Uptake Values (SUV) [i.e. 
Radioactivity concentrations] in focal anatomical 
locations within the heart, as well as SUV of the 
whole heart at different time points after 89Zr-
GSK2398852 administration and at different 
anti-SAP mAb TMDs.
Secondary
Assessment of 89Zr-GSK2398852 biodistribution 
in non-cardiac tissues and organs 
Focal and total radioactivity uptake (including, 
but not limited to SUV) in different tissues 


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Objectives
Endpoints
(including potentially at those peripheral tissue 
sites where transthyretin amyloidosis (TTR)
amyloid deposition can be clinically occult) at 
different time points and after different TMDs.
Characterisation of the plasma 
pharmacokinetics of total mAb (unlabelled 
GSK2398852 and 89Zr-GSK2398852)
Descriptive PK parameters, including the 
maximum concentration in plasma (Cmax), the 
time associated with Cmax (Tmax), clearance, 
terminal half-life (T½) and the area under the 
concentration-time profile (AUC).
Characterisation of the plasma 
pharmacokinetics of radioactivity (89Zr-
GSK2398852 radio-PK)
Descriptive PK parameters including the Cmax, 
Tmax, T½ and AUC based on scintillation
counter.
Safety & tolerability of Anti-SAP treatment 
including administration of 89Zr-GSK2398852 
All AEs including the incidence and grading of 
skin rashes, cardiac adverse events and 
infusion-related reactions, as well as other AEs 
utilizing standard pharmacovigilance practices.
Absolute changes in safety lab parameters, 
including cardiac troponin and NT-proBNP. 
Other safety information, including ECG, 
inpatient and outpatient cardiac telemetry, vital 
signs, and physical exam data.
Exploratory
Correlation of regional pattern of 89Zr-
GSK2398852 uptake in the heart with the 
pattern of amyloid load by PiB scan and blood 
flow by WAT scan or MRI signal pattern
Maps of regional PET signals or MRI signals 
over the myocardium will be visually compared 
and scored.
Regional derived PET and MRI parameters 
correlated within and across ATTR-CM patients.
Assess feasibility of patients to operate remote 
data collection equipment. This may include 
ECGs, vital signs, and streaming video device.
Number of “virtual visits” and number of 
additional remote assessments collected.
5.
STUDY DESIGN
5.1.
Overall Design
This is an open-label, non-randomised 89Zr-GSK2398852 PET imaging study in 
clinically stable patients with cardiac dysfunction caused by ATTR-CM. A screening 
visit and baseline assessments will be conducted prior to the first dosing session. Subjects 
will participate in up to two Anti-SAP dosing sessions in combination with 89Zr-


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GSK2398852 over approximately a two-month interval with at least 4 weeks between 
each 89Zr-GSK2398852 dose.
At a suitable time point, depending on technical and logistic aspects, each subject will 
undergo one PET scan with the administration of PiB for the characterization of the 
regional amyloid burden in the heart and up to two PET scans with the administration of 
WAT for the characterization of the regional blood flow in the heart.
5.2.
Part A and Part B
The study will be divided into two parts. Part A will complete up to 3 subjects who 
participate in up to two anti-SAP dosing sessions. The first two subjects in Part A will 
have up to three 89Zr PET scans, while the remaining subject will undergo up to two 89Zr 
PET scans. 
Part B will complete up to three subjects who participate in only one anti-SAP dosing 
session. Subjects will undergo up to two 89Zr PET scans.
Part B will be triggered by the sponsor in consultation with the Principal Investigator. 
This will be based on data obtained in Part A, which includes but is not restricted to 
equivocal myocardial uptake of 89Zr-GSK2398852 in all subjects treated in Part A. This 
decision will also be contingent based on emerging data from the concurrent Phase 2 trial 
(Study Number 201464).
Should Part B not be triggered, then the study will conclude with Part A.


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5.3.
Study Schematic
A single dosing session in this study constitutes treatment with CPHPC, TMD
administration of anti-SAP mAb consisting of in vivo mixing of a single infusion of 
unlabelled anti-SAP mAb and a separate infusion of 89Zr-GSK2398852 via a different 
peripheral venous line, and up to 3 serial PET scanning procedures after administration of 
89Zr-GSK2398852 (Figure 1).
Figure 1
Study Schematic – Part A


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Figure 2
Study Schematic – Part B
See Section 9.3.4 for details about cardiac safety monitoring during and after Anti-SAP
& 89Zr-GSK2398852 dosing
5.3.1.
Timing of 89Zr-GSK2398852 PET scans
Up to three serial 89Zr-GSK2398852 PET scans will be performed during each dosing
session. 
For the 1st subject in Part A, PET scans for each dosing session will be performed at the 
following times in relation to administration of the 89Zr-GSK2398852 infusion on Day 3:
1st PET scan: Day 3 5 ± 2 hours from the end of 89Zr-GSK2398852 infusion
2nd PET scan: Day 4 24 ± 4 hours from the end of  89Zr-GSK2398852 infusion
3rd PET scan: Day 6 72 ± 6 hours from the end of  89Zr-GSK2398852 infusion
For subsequent subjects in Part A and Part B, the timing and number of the PET scans 
may be varied after the 1st subject in Part A has completed both dosing sessions based on 
emerging SUV & radiolabel PK data. This information will be communicated to the site 
in a file note prior to the start of each subsequent dosing session.
Further details on PET procedures and analyses are given in the Imaging Acquisition and 
Analysis Manual.
5.4.
Administration of CPHPC
Subjects will begin IV CPHPC infusion on Day 1 and continue the infusion for a 
minimum of approximately 48 hours until Day 3. The infusion will be stopped prior to 
the anti-SAP mAb infusion. It is critical that the subject’s plasma SAP level is below the
target prior to beginning the anti-SAP mAb infusion. 


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Figure 3
IV CPHPC Infusion Schematic
SC CPHPC injections will be administered thrice daily, with the first SC CPHPC dose 
administered approximately 5 hours after the end of the IV CPHPC infusion. It is 
possible this may overlap with anti-SAP mAb administration.
It is important that the SC CPHPC doses are administered after the administration 
of anti-SAP mAb to ensure circulating SAP remains low to prevent the formation of 
large amounts of anti-SAP mAb / SAP immune complex formation, even if the 
subject withdraws from the study.
If a subject is unable to tolerate SC CPHPC injections, the investigator should consider 
administration of CPHPC via an IV infusion. 
If anti-SAP mAb dosing is delayed (e.g. due to PET scanner availability or delay in 89Zr-
GSK2398852 transport), the subject may continue IV CPHPC infusion for an additional 
day. Should this occur, an additional plasma SAP specimen should be collected, and the 
result confirmed to be below target prior to administering anti-SAP mAb, in effect 
repeating all Day 2 procedures. This should only be done if logistics permit and PET 
camera availability is confirmed.
Should the delay be any longer than 1 day, IV CPHPC administration will be stopped, 
and subject may be invited to return at a later date to re-start the dosing session. The 
Medical Monitor should be notified in such instances.
5.5.
Plasma SAP Target
Plasma SAP concentration must be below target prior to administering anti-SAP mAb. If 
plasma SAP levels are not below target then continue CPHPC IV and do not administer 
anti-SAP mAb. This test may be repeated if required (Section 9.5.1).


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5.6.
Administration of 89Zr-GSK2398852 in relation to 
administration of unlabelled anti-SAP mAb
For each TMD, 89Zr-GSK2398852 and anti-SAP mAb will be mixed in vivo via two 
separate peripheral venous lines. 
For TMDs ≤200 mg: For the first patient in Part A Dosing Session 1, 89Zr-GSK2398852 
will be administered simultaneously with unlabelled anti-SAP mAb, over 1 hour, such 
that both infusions finish at the same time. For subsequent patients, based on emerging 
data, 89Zr-GSK2398852 may be initiated at any time during the unlabelled anti-SAP mAb 
infusion or after the unlabelled anti-SAP mAb infusion has completed. The exact timing
of infusions will be communicated to the site in a file note.
For total anti-SAP mAb mass doses >200 mg (range: 200 < TMD ≤500 mg): Refer to
Table 6. The exact timing of infusions will be communicated to the site in a file note.
Table 6
Proposed Duration and Timing of anti-SAP mAb and 89Zr-
GSK2398852 administration
Total Mass 
Doses of anti-
SAP mAb
Proposed Duration 
of Unlabelled anti-
SAP mAb Infusions
Planned Timing of 89Zr-GSK2398852 
Administration in Relation to Unlabelled anti-
SAP mAb Infusion1, 2
80 – 200 mg
1 Hour
Simultaneous administration:
Both infusions administered over 1 hour & 
finishing at approximately the same time3
200 mg < Total 
Mass Dose 
≤500 mg
6 Hours
Co-administration:
89Zr-GSK2398852 administered over 1 hour, 
commencing any time after start of unlabelled 
anti-SAP mAb, including after its completion
1If a subject experiences infusion reaction, dosing may be paused and resumed at investigator discretion.
2Unlabelled anti-SAP mAb and 89Zr-GSK2398852 will be administered via two separate peripheral venous lines
3After the first subject, there is an option (based on emerging data) that administration of 89Zr-GSK2398852 may be 
initiated at any time during the infusion or after the unlabelled anti-SAP mAb infusion has completed.


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Table 7
Anti-SAP Treatment Dosing Sessions 1 and 2
Dosing Sessions 1 and 2
Day
Day
1 & 2
Day
3
Up to Day
11
Day 11-18
Day 20 1d
Day
26 2d
Setting
Inpatient
Outpatient
Activity
Plasma SAP 
depletion 
Administration 
of IV CPHPC 
for 
approximately 
48 hours 
Plasma SAP 
concentration 
confirmed 
before anti-
SAP mAb 
infusion.
Administration 
of anti-SAP 
mAb and 89Zr-
GSK2398852
Each infusion of 
unlabelled 
anti-SAP mAb 
either over 1 
hour or 6 hours 
dependent on 
unlabelled mass 
doses
CPHPC 
continues SC.
Subjects closely 
monitored.
Inpatient 
safety follow 
up
Administration 
of CPHPC SC 
continues until 
up to Day 11
Subject 
discharged to 
home.
Outpatient Cardiac 
monitoring
(approximately 1 
week after 
discharge)
Outpatient 
contact 
assessment 
with 
preliminary 
review of 
Remote 
Cardiac 
Telemetry 
device data 
feedback to 
subject (if 
available).
Safety 
follow up
If possible, subject will have 
option to conduct Day 20 and 
Day 26 visits via telephone or
video link using study-
approved device. Optional 
remote ECG and vital signs 
collection device may be 
used.
5.7.
Number of Subjects
Sufficient ATTR-CM subjects will be screened such that 3 subjects complete at least one 
Dosing Session in both Part A and Part B (3 subjects in each part).
If a subject prematurely discontinues the study, additional replacement subject(s) may be 
recruited at the discretion of the Sponsor in consultation with the Investigator.
5.8.
Treatment Groups and Duration
The treatment group will consist of ATTR-CM subjects: Wild-type & mutant genotypes 
primarily associated with familial amyloidotic cardiomyopathy (FAC).
The length of time between dosing sessions should be no less than 4 weeks. This is 
calculated as 4 weeks from administration of anti-SAP mAb.
Participation will last approximately 2-4 months, depending the subject’s participation in 
Part A or Part B, and length of time between dosing sessions.


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5.9.
Length of Time Between Dosing Sessions
There must be a minimum of 4 weeks between each dose of anti-SAP mAb, to allow for 
plasma SAP levels to return to baseline.
5.10.
Periodic Meeting with Investigators
5.10.1.
Individual Subject Safety Review 
Prior to beginning the next dosing session in each subject, there will be a review of the 
available data by:
1. Principal Investigator (or appropriate designee) having consulted with local 
cardiologist, and / or any other appropriate clinical colleague (e.g. dermatologist)
regarding any findings or concerns; additional attendees will be invited as 
required.
2. GSK team including Medical Monitor, GSK Safety Representative, GSK Study 
Team Leader, additional attendees will be invited as required.
The purpose of this review is to consider whether it is appropriate to administer a second 
dose to confirm the unlabelled anti-SAP mAb dose. The review will be a holistic review 
of the case, but the following safety parameters will be considered specifically:

Adverse events

Whether the subject has experienced a rash

Cardiac safety, including outpatient cardiac monitoring recording and cardiac 
biomarkers

Biochemistry & Haematology

When imaging and PK data are available, these will be reviewed to consider 
potential need to change imaging and PK time points. 
5.11.
Subject and Study Completion
A subject is considered to have completed the study if he/she has completed all planned 
dosing sessions, including the follow-up visit.
A Subject in Part A who participates in only one dosing session, and complete the final 
follow-up visit, may also be considered to have completed the study.
The end of the study is defined as the date of the last visit of the last subject in the study.


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5.12.
Scientific Rationale for Study Design
5.12.1.
Justification for the administration of CPHPC & unlabelled anti-
SAP mAb 
5.12.1.1.
CPHPC
Pharmacologically, IV CPHPC is a highly predictable drug as demonstrated in FIH study 
(SAP115570) where all systemic amyloidosis subjects attained plasma SAP depletion 
below the specified target level. 
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 both effective and consistently predictable in depleting circulating SAP to 
<2 mg/L (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 
formation of potentially harmful (i.e. high titres of) circulating immune complexes. 
Safety evaluation in the FIH study did not identify any signals suggestive of adverse 
effects from residual plasma SAP, such as clinical manifestations of systemic/organ 
vasculitis. 
CPHPC is predominantly cleared from the plasma by the kidneys and excreted in the 
urine. CPHPC doses will therefore be adjusted (see Section 7.2.1, Table 8) based on 
individual renal function as measured by 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. 
Subjects with overall low amyloid load, such as ATTR-CM patients in this study, are 
likely to deplete their plasma SAP level to target within 48 hours of administration of IV 
CPHPC. The first plasma SAP concentration will be checked after 24 hours of 
administration of IV CPHPC to confirm whether the anti-SAP mAb and 89Zr-
GSK2398852 can be administered at approximately 48 hours after initiation of IV 
CPHPC. 
The total duration of administration of maintenance SC CPHPC in this study will be 8 
days (i.e. last dose per session on Day 11), and is in line with the schedule of 
administration in the Phase 2 study (201464). 
5.12.1.2.
Unlabelled Anti-SAP mAb 
The dose level of unlabelled anti-SAP mAb in each dosing session will be selected to 
ensure the TMD will not exceed 500 mg
Given that SAP is known to be constitutively present in normal tissues and that TTR 
amyloid deposits might also be present in a clinically occult manner within peripheral 


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soft tissues, skeletal muscle, and nerve fibre sheaths of ATTR-CM subjects, unlabelled 
anti-SAP mAb will be administered during each dosing session in order to 'block' the 
extra-cardiac SAP in tissues. This will enable sufficient 89Zr-GSK2398852 in the 
systemic circulation to be distributed to SAP-containing amyloid deposits within the 
heart rather than being distributed to well vascularised extra-cardiac tissue sites (e.g. liver 
and skin) where circulating 89Zr-GSK2398852 could potentially be more accessible to 
tissue-bound SAP.
The rationale to start with a relatively low mass dose of unlabelled anti-SAP mAb in the 
first ATTR CM subject (e.g. 70 mg) is that a higher mass dose of unlabelled mAb could 
potentially be distributed to the myocardium, such that the binding of 89Zr-GSK2398852 
to cardiac amyloid deposits could be attenuated, therefore leading to a lower probability 
of detecting a PET imaging signal indicative of cardiac tissue uptake of 89Zr-
GSK2398852. 
Due to the complex relationship between allowing better “targeting” to cardiac amyloid 
at lower doses and potential attenuation of SAP-amyloid binding at higher doses, we 
suggest that up to two different mass doses are evaluated in each individual ATTR-CM 
subject from the perspective of both the (radiolabel) PK profile of 89Zr-GSK2398852 and 
the cardiac SUV/ extra-cardiac SUV ratio determined by the final PET scan per dosing
session. 
By comparing the 89Zr-GSK2398852 uptake within the same patient, we expect to 
significantly reduce the variability which could come from very different amyloid load in 
different subjects. Furthermore, the design includes the potential to have different TMDs 
in different patients and to guide the selection of the dose of unlabelled anti-SAP mAb 
adaptively by review of results from previous subjects.
5.13.
Study Overview of Anti-SAP Treatment and 89Zr-
GSK2398852
5.13.1.
Unlabelled anti-SAP mAb Dose Selection
The study aims to identify the dose range leading to “optimal” 89Zr-mAb radiotracer 
uptake in the heart. 
It is anticipated that at very low doses of unlabelled anti-SAP mAb, the clearance of 
radio-labelled PK may be fast and the expected slow penetration from plasma to heart 
muscle interstitium may therefore lead to a low uptake of 89Zr-GSK2398852 in heart 
tissue. This may give a low radioactivity signal in the heart impairing the possibility to 
obtain a good measurement.
On the other hand, a low unlabelled anti-SAP mAb dose may be beneficial to the binding 
of 89Zr-GSK2398852 to amyloid-SAP complexes in the myocardium because of lack of 
competition with binding of radiolabelled compound from a possible excess of unlabelled 
mAb within the interstitial space.
At higher TMDs of anti-SAP mAb, the plasma clearance of 89Zr-GSK2398852 is 
expected to be slower, facilitating an increased uptake in the tissue interstitium, while at 


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the same time this may be associated with an increased risk of unlabelled anti-SAP mAb 
competing with binding of the radiolabelled mAb.
The search for “optimal dose” needs to consider an expected inter-subject variability in 
the read-out due to biological factors (Figure 4).
Figure 4
Examples of inter- and intra-subject relationships between tissue / 
plasma SUV ratio across a range of unlabelled (“cold”) anti-SAP 
mAb mass doses
In order to increase the probability of obtaining data which provides a good cardiac signal 
we propose the following concept:

The first subject in Part A, Dosing Session 1 is investigated with the TMD
80 mg (70 mg unlabelled anti-SAP mAb plus 10 mg 89Zr-GSK2398852). 
The 80 mg dose is selected because this is the lowest dose in which we 
have previous adequate human PK data, and these data indicate a terminal 
elimination half-life in the range of 15 hours. This relatively short plasma 
residence may hamper the cardiac uptake but is still predicted to have a 
potential for adequate cardiac signal. 
o
The TMD for this subject’s Dosing Session 2 will be determined 
by the central study team based on data from Dosing Session 1. 
This will be communicated to the clinical site by filenote prior to 
Dosing Session 2.

Subsequent subjects will receive up to two doses, selected based on the 
following criteria:
o
The combined and individual doses should be below the highest 
single dose which in the therapeutic trials has been found to be safe


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o
Up to 6 fully evaluated subjects will be included (N=3 in Part A, 
and N=3 in Part B)
o
Doses in subsequent subjects will be selected based on previous 
subject’s data and decided upon by the project team with advice 
from the GSK statistician and modeler
o
The guiding principle is to have as many subjects as possible 
having at least one mass dose which is within a perceived 
“optimal” mass dose range.
5.13.2.
Justification of serial PET scanning per Anti-SAP session
The time course of the radiolabel mAb PK profile, and the temporal pattern of 89Zr-
GSK2398852 uptake in the myocardium are the two key parameters guiding anti-SAP 
mAb TMD selection in this PET study.
A total of up to 3 serial 89Zr-GSK2398852 PET scanning procedures will be performed 
per dosing session. The scanning times will be predefined only for the first patient, but 
may be different for the following patients, guided by previous results. 
In Part A, the first two subjects will have 3 PET scans per dosing session. The first two 
scans in these two subjects will be performed over approximately the first 24 hours after 
89Zr-GSK2398852 administration. The third scan will be performed at a later time
(timing to be determined from emerging data during the initial part of the study). 
After the first two subjects have completed Part A, the subsequent subjects are planned to 
undergo only two PET scans, the timing of which will be determined by emerging data.
Up to 3 PET scans per dosing session in Part A are justified after administration of 89Zr-
GSK2398852 because the timing of each of these three scanning procedures is a 
reflection of the predicted time-related whole body biodistribution of 89Zr-GSK2398852. 
That is, a later PET scan performed at approximately 72 hours after administration of 
89Zr-GSK2398852 is more likely to detect myocardial tissue specific uptake compared to 
PET scans performed at earlier time points which are more likely to detect 89Zr-
GSK2398852 within the blood pool of the cardiac chambers.
6.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1.
Inclusion Criteria
Subjects are eligible to be included in the study only if all of the following criteria apply:
Age
1.
Subject must be 65 to 80 years of age inclusive, at the time of signing the informed 
consent.


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Type of Subject and Disease Characteristics
2.
Subjects with a diagnosis of ATTR-CM 
a.
Wild-type ATTR status must be confirmed by genotyping AND have one 
of the following:
i. 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
ii. Scintigraphy Technetium-99m-labelled 3,3-diphosphono-1,2-
propanodicarboxylic acid (99mTc-DPD) with confirmed myocardial
uptake.
b. Hereditary ATTR amyloidosis (e.g. TTR Val30Met) should have a known 
amyloidogenic TTR mutation demonstrated by genotyping AND is 
recognised to be primarily associated with cardiomyopathy AND one of 
the following:
i. 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
ii. Scintigraphy: 99mTc-DPD with confirmed myocardial uptake. 
Sex
3.
Both male and female subjects are eligible to participate.
a. Male subjects:
A male subject must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and for at least 3 months after the last scan and 
refrain from donating sperm during this period.
b. Female subjects: 
A female subject is eligible to participate if she is not of childbearing potential as 
defined in Appendix 5.


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Informed Consent
4.
Capable of giving signed informed consent as described in Appendix 3 which 
includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol.
Other
5.
New York Heart Association (NYHA) up to class 3; subjects should be clinically 
stable for at least 3 months preceding to Screening.
6.2.
Exclusion Criteria
Subjects are excluded from the study if any of the following criteria apply:
Medical Conditions
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 (at a rate of ≥120 beats per min for ≥30 seconds), or symptomatic
monomorphic ventricular tachycardia (VT), or rapid polymorphic VT, at 
screening/baseline cardiac monitoring.
4.
Systolic blood pressure ≤100 mm/Hg based on triplicate readings at screening.
5.
Unstable heart failure defined as emergency hospitalization for worsening, or 
decompensated heart failure, or syncopal episode within 1 month of screening.
6.
Implantable cardiac defibrillator (ICD) or permanent pacemaker (PPM) at screening.
7.
Estimated Glomerular filtration rate (eGFR) at Screening <50 mL/min calculated 
using modification of diet in renal disease (MDRD).
8.
Any active and persistent dermatological condition, which in the opinion of the 
Investigator and Medical Monitor would preclude safe participation.
9.
History of allogeneic stem cell transplantation, prior solid organ transplant, or 
anticipated to undergo solid organ transplantation, or left ventricular assist device 
(LVAD) implantation.
10. 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.
11. Acute coronary syndrome, or any form of coronary revascularization procedure 
(including coronary artery bypass grafting [CABG]), within 6 months of screening. 
12. Symptomatic, clinically significant autonomic neuropathy which the Principal 
Investigator (PI) feels will preclude administration of study treatment.
13. Uncontrolled hypertension during Screening.


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14. Alanine transaminase (ALT) >3x upper limit of normal (ULN) OR bilirubin 
>1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and 
direct bilirubin <35%).
15. Peripheral oedema at Screening that in the opinion of the PI or designee might 
prevent adequate absorption of subcutaneously administered CPHPC.
16. Presence of any co-morbid (e.g. steroid refractory rheumatoid arthritis), 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.
17. 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.
18. Clinically significant multiple or severe drug allergies, intolerance to topical 
corticosteroids, or severe post-treatment hypersensitivity reactions (including, but 
not limited to, erythema multiforme major, linear immunoglobulin A [IgA] 
dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis).
19. Inability to comprehend and / or understand the study patient information sheet, and / 
or unwillingness or inability to follow the procedures outlined in the protocol.
ATTR-CM Specific Criteria
20. Has any of the following:
a.
Fulfilment of diagnostic criteria for AL amyloidosis
b. Fulfilment of diagnostic criteria for amyloid A (AA) or non-TTR hereditary
amyloidosis 
21. ATTR Disease Load:
c.
Histologically proven or clinically suspected gastrointestinal TTR amyloidosis
d. Diffuse skeletal muscle uptake of 99m(Tc)-DPD on Single-photon emission 
computed tomography (SPECT) imaging (where available)
e.
Peripheral neuropathy causing more than mild morbidity (e.g. walking disability; 
neuropathic pain affecting activities of daily living)
f.
Proven or clinically suspected intracranial TTR involvement including 
ophthalmological disease
22. 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
Prior/Concomitant Therapy
23. Participation in a separate clinical trial involving CPHPC within 3 months of 
screening


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24. Any prohibited concomitant medication as per Section 7.7.2 within referenced 
timeframe
Prior/Concurrent Clinical Study Experience
25. 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.
Diagnostic assessments for PET & Cardiac Magnetic Resonance (CMR) Scanning
26. Orthopnoea of sufficient severity to preclude supine scanning as determined at 
screening
27. Inability to fit inside scanner due to body size (girth) 
28. History of claustrophobia
29. Contraindication to MRI contrast agents
30. 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
Other Exclusions
31. Donation of blood or blood products in excess of 500 mL within 84 days of 
screening
32. Poor or unsuitable venous access
6.3.
Lifestyle Restrictions
The following restrictions apply:
6.3.1.
Caffeine, Alcohol, and Tobacco

Subjects will abstain from caffeine (e.g. tea, coffee, cola, chocolate) from Day 1 until 
final PET scan of dosing session, and 24 hours prior to any imaging scan.

During each dosing session, subjects will abstain from alcohol for 24 hours prior to 
any imaging scan and for 24 hours prior to and during inpatient stays. 

Subjects who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted 24 hours prior to any 
imaging scan or PK sample. Subjects will be required to adhere to clinical unit policy 
on tobacco/nicotine use.


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6.3.2.
Activity
Subjects will abstain from strenuous exercise for at least 24 hours before each blood 
collection for clinical laboratory tests. Subjects may participate in light recreational 
activities during studies (e.g., watching television, reading).
6.3.3.
In-person Social Interaction
Following administration of 89Zr-GSK2398852, subjects will be advised to maintain a 
safe distance from young children and pregnant women consistent with local radiation 
safety guidelines. The clinical site should adhere to local hospital policy regarding in-
person social interaction.
6.4.
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study but 
are not subsequently enrolled. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) 
may be rescreened. 
7.
TREATMENTS
Study treatment is defined as any investigational treatments intended to be administered 
to a study subject according to the study protocol.
7.1.
Treatments Administered
Study 
Treatment 
Name:
GSK2315698 (CPHPC)
GSK2398852 
(unlabelled anti-
SAP mAb)
89Zr-GSK2398852 (89Zr-Df-
labelled anti-SAP mAb)
Dosage 
formulation:
GSK2315698 Solution for 
Subcutaneous Injection or 
Intravenous Infusion, 
200 mg/mL
GSK2398852 
Concentrate for 
Solution for Infusion, 
100 mg/mL
Solution containing 10 mg 
89Zr-GSK2398852 for 
Infusion, 10 mg/10mL or 
10 mg/20mL


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Study 
Treatment 
Name:
GSK2315698 (CPHPC)
GSK2398852 
(unlabelled anti-
SAP mAb)
89Zr-GSK2398852 (89Zr-Df-
labelled anti-SAP mAb)
Unit dose 
strength(s)/
Dosage 
level(s):
200 mg/mL provided as 2 mL 
solution per vial
Dosage levels: variable 
dependent on renal function
100 mg/mL provided 
as 1 mL solution per 
vial.
Variable total mass 
doses of anti-SAP
mAb not exceeding
500 mg per dosing
session
37 MBq 89Zr-GSK2398852 
associated with a mass of 
10 mg GSK2398852
Route of 
Administration 
Intravenous infusion usually 
for approximately 48 hours 
but up to 72 hours
Subcutaneous injection up to 
3x daily for up to 8 days after
unlabelled anti-SAP mAb 
dose per dosing session
Intravenous infusion
of variable duration.
Refer to
Table 6
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
Study medication will 
be diluted in 
0.9% w/v sodium 
chloride and 
administered by 
intravenous infusion 
by study personnel 
following specified 
regimens
To be administered via 
separate intravenous 
cannula.
Refer to
Table 6 See local Standard 
operating procedure (SOP)
to protect from ionising 
radiation
Packaging and 
Labelling
Study Treatment will be 
provided in Type 1 clear 
glass vials sealed with grey 
polymer coated rubber 
stoppers that meet 
extractable criteria for sterile 
dosage forms. A silver 
aluminium overseal is placed 
over each vial and crimped. 
Each vial will be labelled as 
required per country 
requirement.
Study Treatment will 
be provided in glass 
vials. Each vial will 
be labelled as 
required per country 
requirement.
Study Treatment will be 
provided in glass vials. 
Each vial will be labelled as 
required per country 
requirement.


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Study 
Treatment 
Name:
GSK2315698 (CPHPC)
GSK2398852 
(unlabelled anti-
SAP mAb)
89Zr-GSK2398852 (89Zr-Df-
labelled anti-SAP mAb)
Manufacturer
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]
VU University Medical 
Center
Radiology & Nuclear 
Medicine
Anti-SAP mAb must not be administered until plasma SAP level has reached target. See 
Section 5.5.
See Section 5.4, Section 5.5, and Section 5.13 for additional dosing information.
7.2.
Dose Modification
7.2.1.
CPHPC dosing regimen according to renal function
Table 8
CPHPC dosing regimen according to renal function
Renal Function
IV dose level
SC dose regimen
eGFRa
(mL/min/1.73 m2)
64
20 mg/hour
60 mg t.i.d 
46 and< 64b
10 mg/hour
60 mg t.i.d 
<46
Consult Medical Monitor
Consult Medical Monitor
a.
eGFR determined by MDRD (Modification of Diet in Renal Disease) must be used to define CPHPC dose based 
on renal function
b.
Note renal withdrawal criteria in Section 8.1.3
t.i.d. = three times daily, approximately 8 hours apart.
7.2.2.
CPHPC Route of Administration Change
If the subject is unable to tolerate SC CPHPC injections post anti-SAP mAb infusion, in 
order to continue CPHPC, the investigator may switch the route of administration from 
SC injection to IV infusion. The Medical Monitor should be consulted in this instance.
7.3.
Method of Treatment Assignment
Subjects will be identified by a unique subject number at screening that will remain 
consistent for the duration of the study. Upon completion of screening subjects will will 
commence study treatments as described in Section 7. There will be no control group in 
this study.
The study has a non-randomised design. However, for internal study reporting, subjects 
will be assigned randomisation numbers for database/programming purposes, e.g. to flag 
screened subjects who commence study treatment and therefore are to be included in the 
All-Treated Population (see Section 10.3.1).


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7.4.
Blinding
This is a non-randomised open-label study. All investigators and GSK Study Team 
members, have direct access to the subject’s individual study treatment and dosing 
schedules for each constituent drug.
Analyses for PET imaging data per subject will not be blinded.
7.5.
Preparation/Handling/Storage/Accountability
A description of the methods and materials required for preparation of GSK2398852, 
89Zr-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.
1.
The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
2.
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 labeled storage conditions with access limited to the 
investigator and authorized site staff.
3.
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).
4.
Further guidance and information for the final disposition of unused study treatment 
are provided in the Study Reference Manual.

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 of 
unintentional occupational exposure notify the monitor, Medical Monitor and/or 
GSK study contact.

A Material Safety Data Sheet (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.
7.6.
Treatment Compliance
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 
treatments 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.


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7.7.
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the subject is receiving at the time of 
enrollment or receives during the study must be recorded along with:

reason for use

dates of administration including start and end dates

dosage information including dose and frequency
Subjects usual medication can be continued during this study with the exception of those 
listed in Section 7.7.2.
New chronic concomitant medication should be discussed with the GSK Medical 
Monitor.
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
7.7.1.
Pre-medication prior to unlabelled 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 unlabelled anti-SAP 
mAb. Additional administrations of either or both medications are permitted at discretion 
of Investigator or designee if symptoms require this.
Given that the infusion of 89Zr-GSK2388852 will commence during or shortly after the
infusion of the unlabelled anti-SAP mAb infusion, administration of a separate 
premedication schedule is not required before the radiolabelled mAb infusion 
commences.
7.7.2.
Prohibited Medications and Non-Drug Therapies
The following restrictions apply from pre-screening up to the final visit.


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Table 9
Restricted Medications
Medication
Pre-screen restriction
Tafamidis, diflunisal, tauroursodeoxycholic acid (TUDCA)
Initiation of, or change of 
dose, within 28 days
Green tea extract
Initiation of, or change of 
dose, within 28 days
Silencing therapies (e.g. small interfering ribonucleic acid [siRNA]) for ATTR 
protein synthesis
3 months
Disease-modifying drug for any type of autoimmune disease, including but not 
restricted to, methotrexate, cyclophosphamide, or anti-cytokine antibodies
(e.g. anti tumor necrosis factor (TNF)-α monoclonal antibody)
At any time
Antibody therapy for amyloidosis treatment 
At any time
Where these are deemed to be clinically necessary by the treating physician the 
individual subject will be withdrawn from the study.
7.8.
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 
ATTR-CM, treatment will not be provided after the end of the study. This may be 
reviewed once more information is available. 
8.
DISCONTINUATION CRITERIA
8.1.
Discontinuation of Study Treatment
8.1.1.
Discontinuation for failure to deplete plasma SAP levels with IV 
CPHPC
Subjects will be withdrawn from the study if they are unable to deplete plasma SAP 
levels to target (Section 5.4 and Section 5.5).
8.1.2.
Adverse Event Discontinuation Criteria
Subjects with any adverse event(s) (e.g. skin rash) that have arisen during the 1st dosing 
session and is potentially attributable to administration of any component of Anti-SAP 
treatment or 89Zr-GSK2398852, and that has not completely resolved by the time the 2nd 
dosing session is expected to commence, will be withdrawn from the study. 


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8.1.3.
Renal Function Discontinuation Criteria
Subjects will not receive anti-SAP mAb if 

The eGFR calculated by the MDRD equation has reduced to <40 mL/min/1.73m2
after Screening, 
or 

There has been a reduction in eGFR from baseline by >50%. 
If the eGFR falls to between 40 – 50 during the trial, the subject can continue 
participation at the investigator/designee’s discretion. 
Dose adjustment of IV and / or SC CPHPC may be necessary for subjects with reduced 
eGFR at baseline, before administration of anti-SAP mAb in the 2nd dosing session, or at 
any time during the study; refer to Section 7.2.1 and Table 8 for CPHPC renal dosing 
regimen.
8.1.4.
Cardiovascular Safety Discontinuation Criteria
8.1.4.1.
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 (≥ 120 beats/min for ≥ 30 seconds), or 
development of new rapid polymorphic VT, or new ventricular fibrillation (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 either 
prophylaxis or treatment with a permanent cardiac pacemaker, or ICD
8.1.5.
Liver Chemistry Stopping Criteria
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology.
Discontinuation of study treatment for abnormal liver tests is required when:


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
a subject meets one of the conditions outlined in the algorithm (Figure 5)

when in the presence of abnormal liver chemistries not meeting protocol-specified 
stopping rules, the investigator believes study treatment discontinuation is in the 
best interest of the subject. 
Figure 5
Phase I Liver Chemistry Stopping Criteria – Liver Stopping Event 
Algorithm
Continue Study Treatment 
Discontinue Study Treatment 
*INR value not applicable to subjects on anticoagulants 
ALT ≥3xULN 
No
Yes
Must refer to Liver Safety Required Actions and Follow up Assessments  section in the Appendix
Report as an SAE if possible Hy’s Law case: ALT≥3xULN and  Bilirubin≥2xULN (>35% direct)  or 
INR>1.5, if measured*
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 6.
8.1.6.
QTc Stopping Criteria

The same QT correction formula must be used for each individual subject to 
determine eligibility for and discontinuation from the study. This formula may not be 
changed or substituted once the subject has been enrolled.

For example, if a subject is eligible for the protocol based on QTcF, then QTcF
must be used for discontinuation of this individual subject as well.

Once the QT correction formula has been chosen for a subject’s eligibility, the 
same formula must continue to be used for that subject for all QTc data being 
collected for data analysis. Safety ECGs and other non-protocol specified ECGs 
are an exception.

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.
A subject who meets either criterion below will be withdrawn from the study treatment:
1. QTc ≥530 msec, irrespective of bundle branch block status


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or,
2. Increase from baseline: change in QTc >60 msec
8.1.7.
Dermatological Toxicity Stopping Criteria
8.1.7.1.
Individual subject dermatological stopping criteria
A subject who meets any criterion below will be withdrawn from further treatment
sessions:

Any skin rash >Grade 2

Any grade of skin rash which has not completely resolved before dosing session 2

Peripheral oedema which is deemed by the Investigator to be affecting the 
systemic absorption of SC CPHPC (i.e. CPHPC administration should continue 
by IV infusion to Day 11)

Skin toxicity of any grade which is refractory to dermatological treatment

Clinical evidence of skin necrosis, irrespective of 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)
8.1.8.
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 Grade 4 rash (see Appendix 7)
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.
See the SoA for data to be collected at the time of treatment discontinuation (i.e. all 
follow-up procedures).


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8.1.9.
Rechallenge
8.1.9.1.
Study Treatment Restart or Rechallenge
Study treatment restart or rechallenge after liver chemistry stopping criteria are met by 
any subject in this study is not allowed.
8.2.
Withdrawal from the Study

A subject may withdraw from the study at any time at his/her own request, or 
may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, compliance or administrative reasons.

If the subject withdraws consent for disclosure of future information, the 
sponsor may retain and continue to use any data collected before such a 
withdrawal of consent.

If a subject withdraws from the study, he/she may request destruction of any 
samples taken and not tested, and the investigator must document this in the site 
study records.

Withdrawal of study treatment does not necessarily require withdrawal from 
study.

Refer to Day 26 assessments in the SoA for data to be collected at the time of 
study discontinuation and follow-up and for any further evaluations that need to 
be completed.
Whenever possible, subjects should complete SC CPHPC maintenance following
administration of anti-SAP mAb to prevent circulating anti-SAP mAb / SAP
immune complexes.
8.3.
Lost to Follow Up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit:

The site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and 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.

Before a 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 known mailing 
address or local equivalent methods). These contact attempts should be 
documented in the subject’s medical record.


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
Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
9.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 2). 

Protocol waivers or exemptions are not allowed 

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the subject should continue or discontinue 
study treatment.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
subjects meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all subjects screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 

Procedures conducted as part of the subject’s routine clinical management (e.g., 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and was 
performed within the time frame defined in the SoA.

The maximum amount of blood collected from each subject over the duration of the 
study, including any extra assessments that may be required, will not exceed 
500 mL.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
9.1.
Adverse Events
The definitions of an AE or SAE can be found in Appendix 4.
The investigator and any designees are responsible for detecting, documenting, and 
reporting events that meet the definition of an AE or SAE and remain responsible for 
following up AEs that are serious, considered related to the study treatment or the study, 
or that caused the subject to discontinue the study (see Section 8). 
9.1.1.
Time Period and Frequency for Collecting AE and SAE 
Information

All AEs will be collected from the signing of the ICF until the final visit at the 
time points specified in the SoA (Section 2).

All SAEs will be recorded and reported to the sponsor or designee immediately
and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 4. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.


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
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 to be reasonably related to the study treatment or study 
participation, the investigator must promptly notify the sponsor.

The method of recording, evaluating, and assessing causality of AEs and SAEs
and the procedures for completing and transmitting SAE reports are provided in 
Appendix 4.
9.1.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. 
9.1.3.
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 will be followed until the event is 
resolved, stabilized, otherwise explained, or the subject is lost to follow-up (as defined in 
Section 8.3). Further information on follow-up procedures is given in Appendix 4.
9.1.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so 
that legal obligations and ethical responsibilities towards the safety of subjects 
and the safety of a study treatment under clinical investigation are met. 

The sponsor has a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment 
under clinical investigation. The sponsor will comply with country-specific 
regulatory requirements relating to safety reporting to the regulatory authority, 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC), and 
investigators.

Investigator safety reports must be prepared for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or 
other specific safety information e.g., summary or listing of SAE) from the 
sponsor will review and then file it along with the Investigator’s Brochure and 
will notify the IRB/IEC, if appropriate according to local requirements.
9.1.5.
Cardiovascular and Death Events
For any cardiovascular events detailed in Appendix 4 and all deaths, whether or not they 
are considered SAEs, specific Cardiovascular (CV) and Death sections of the case report 


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form (CRF) will be required to be completed. These sections include questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death. 
The CV CRFs are presented as queries in response to reporting of certain CV Medical 
Dictionary for Regulatory Activities (MedDRA) terms. The CV information should be 
recorded in the specific cardiovascular section of the CRF within one week of receipt of a 
CV Event data query prompting its completion.
The Death CRF is provided immediately after the occurrence or outcome of death is 
reported. Initial and follow-up reports regarding death must be completed within one 
week of when the death is reported.
9.1.6.
Pregnancy

Details of all pregnancies in female subjects and female partners of male subjects 
will be collected after baseline and until 3 months after last PET scan.
If a pregnancy is reported, the investigator should inform GSK within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 5.

Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAE.
9.2.
Treatment of Overdose
For this study, any dose of CPHPC, unlabelled anti-SAP mAb, or 89Zr-GSK2398852
greater than the intended dose within the scheduled dosing period will be considered an 
overdose.
GSK does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1.
Contact the Medical Monitor immediately.
2.
Closely monitor the subject for AE/SAE and laboratory abnormalities.
3.
Obtain a plasma sample for PK analysis if requested by the Medical Monitor 
(determined on a case-by-case basis).
4.
Document the quantity of the excess dose as well as the duration of the overdosing in 
the CRF.
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Medical Monitor based on the clinical evaluation of the subject.
9.3.
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.


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9.3.1.
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
Skin, Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
Height and weight 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).

Investigators should pay special attention to clinical signs related to previous 
serious illnesses.
9.3.2.
Vital Signs

Vital signs will be measured in a semi-supine position after 5 minutes of rest and
will include temperature, systolic and diastolic blood pressure, pulse, and 
respiratory rate. 
9.3.3.
Electrocardiograms

Single or triplicate 12-lead ECGs will be obtained as outlined in the SoA using 
an ECG machine that automatically calculates the heart rate and measures PR, 
QRS, QT, and QTcF or QTc corrected by Bazett's formula (QTcB) intervals. 
Refer to Section 8.1.4 for QTc withdrawal criteria and additional readings that 
may be necessary.

At each time point at which triplicate ECG are required, 3 individual ECG 
tracings should be obtained as closely as possible in succession, but no more 
than 2 minutes apart. The full set of triplicates should be completed in less than 
4 minutes.

12-lead ECGs should be measured in a semi-supine position after approximately 
5 minutes of rest.
9.3.4.
Cardiac Safety Monitoring 
9.3.4.1.
Electrophysiology
Given that cardiac amyloidosis patients have a high background incidence of arrhythmias 
[Boldrini 2013, Barbhaiya 2016], ATTR-CM subjects in this PET study will have a 
thorough evaluation of their background disposition to arrhythmias by performing 
electrophysiological cardiac monitoring at Screening and at Baseline. During each dosing
session, continuous in-patient cardiac telemetry will be performed up to Day 11 (see 
Figure 6, below).
Screening: 7-day outpatient electrophysiological cardiac monitoring using an appropriate 
non-implantable recording device (e.g. BodyGuardian) – this will evaluate the arrhythmic 
background of eligible ATTR-CM patients such that false positive attribution of 
arrhythmias to anti-SAP mAb TMDs will be minimized.
Inpatient Lead II Cardiac Telemetry: Continuous telemetry will be performed to 
detect any arrhythmias which are proximate to the administration of Anti-SAP treatment 


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and 89Zr-GSK2398852 in ATTR-CM patients including worsening of known patient-
specific arrhythmias from Screening and / or Baseline assessments. This should be 
continued until remote continuous cardiac monitoring is initiated.
At investigator discretion, in consultation with the Medical Monitor, Inpatient Lead II 
Cardiac Telemetry can be substituted to the BodyGuardian device.
Outpatient Remote Continuous Cardiac Monitoring: Monitoring will be performed 
using a non-implantable remote cardiac telemetry device. This device will be started
before discharge.
Review of Remote Cardiac Telemetry: Outpatient electrophysiological data should be 
downloaded and reviewed by a cardiologist at the local study site no longer than 48 
hours after the 1-week recording period has completed. Therefore, the preliminary report 
from 7-day outpatient cardiac monitoring should be available for the investigator or 
designee to discuss with the subject during their remote consultation “visit”.
All electrophysiological data, including inpatient telemetry, should be reviewed in 
comparison to Screening data after the 1st dosing session.
In the event of a cardiac AE, the investigator or designee should compare and contrast the 
emergent cardiac electrophysiological data with the Screening data as early as possible, 
and consult with the Medical Monitor as deemed necessary by the emergent clinical 
safety issues.
Optional Monitoring: Inpatient and / or outpatient electrophysiological cardiac 
monitoring can continue / reinitiated at the discretion of the Investigator or designee 
based on emerging cardiac safety data within a given ATTR-CM subject, and / or based 
on emerging collective study population data.
Based on emerging cardiac safety data, optional inpatient and / or outpatient cardiac 
monitoring can be continued for as long as deemed clinically necessary by the 
investigator or designee in consultation with the Medical Monitor.
Figure 6
Cardiac Safety Monitoring at Screening & during each dosing 
session
If remote cardiac monitoring uses BodyGuardian device: A separate “critical alert” 
arrhythmia protocol will be provided to the monitoring centre and study site. This will 


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include, for example, bradycardic and ventricular tachycardic event notification 
requirements.
9.3.4.2.
High Sensitivity Cardiac Troponin (hs-cTn) Monitoring after a Cardiac 
Arrhythmia Event
Given that the background incidence of cardiac arrhythmias in ATTR-CM patients is 
high, and that some subjects recruited into this study might have elevated troponin levels 
at baseline, ATTR-CM subjects might be particularly susceptible to myocardial ischemia 
as a result of either a disease or anti-SAP mAb-related arrhythmia.
Baseline hs-cTn Evaluation: In the event that an ATTR-CM subject has a clinically 
concerning cardiac arrhythmic event after administration of Anti-SAP treatment + 89Zr-
GSK2398852, a plasma hs-cTn level will always be measured before each administration 
of Anti-SAP treatment. 
Monitoring of hs-cTn after an Arrhythmia Event: A hs-cTn should be evaluated 
immediately at the time of onset of a cardiac arrhythmia which is deemed by the 
Investigator to be of clinical concern (see Section 3.4.1.3). 
hs-cTn levels should be serially repeated (using the same assay) following local troponin 
monitoring protocols at the study site, and with advice from a cardiologist at the local 
study site if this is deemed clinically necessary by the Investigator or designee. 
hs-cTn blood sample can also be drawn from an ATTR CM subject, at any time, for the 
evaluation of other types of cardiac adverse event where there are no associated 
electrophysiological changes – e.g. electrically silent acute chest pain.
Similarly, NT-proBNP levels can be performed more frequently during in-patient stay or 
as an out-patient if this is deemed clinically necessary for cardiac safety reasons by the 
Investigator or designee.
9.3.4.3.
Imaging for Investigation of Cardiac Adverse Events
Contrast-enhanced CMR and ECHO methodologies will be detailed in the separate Image 
Acquisition and Analysis Manual.
A single 2-D Echocardiogram will be performed at baseline for reference, in the event of 
an adverse cardiac event being detected during the study (e.g. worsening heart failure 
symptoms or an unexpected large rise in NT-proBNP levels) which in the opinion of the 
Investigator or designee would require repeat Echocardiogram to re-evaluate cardiac 
function. 
Similarly, repeat CMR(s) can also be performed at any time during the study (to compare 
against the baseline CMR) to enable a more detailed evaluation of cardiac function. 
Furthermore, at the discretion of the investigator / designee in consultation with the 
Medical Monitor, a repeat CMR can be performed in the unlikely event that there is
suspected change in cardiac amyloid load – e.g. in the clinical opinion of the investigator 


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or designee, an appreciable reduction in NT-proBNP levels from baseline during or after
any of the two Anti-SAP dosing sessions.
Wherever feasible, repeat CMR scan(s) should be performed at the local study site 
preferably using the same MRI scanner and IV contrast agent as that used at Screening.
9.3.4.4.
Insertion of a PPM or ICD for Prophylactic Reasons
Any individual subject who requires insertion of a PPM or ICD for prophylactic reasons 
during the study will be withdrawn and replaced with a new ATTR-CM subject.
All subjects who have a PPM or ICD inserted should be followed-up by their local 
cardiologist.
9.3.5.
Clinical Safety Laboratory Assessments

Refer to Appendix 2 for the list of clinical laboratory tests to be performed and 
to the SoA for the timing and frequency. 

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE 
section of the CRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator 
to be more severe than expected for the subject's condition.

All laboratory tests with values considered clinically significantly abnormal 
during participation in the study should be repeated until the values return to 
normal or baseline or are no longer considered significantly abnormal by the 
investigator or medical monitor. 

If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
9.3.6.
Additional Outpatient Safety Assessments (“Virtual Visit”)
Depending on the availability of technology, subjects may be invited to perform 
additional remote safety assessments on an outpatient basis. At a maximum, this would 
include remote ECG collection, remote vital signs collection, and the opportunity to 
conduct the Remote Safety Assessment (Day 20) and Day 26 visit via video link. 
Training on the use of this technology would be completed prior to discharge from the 
clinical unit, and would be optional. 
Experience with these technologies will enable the study team to understand the 
feasibility of incorporating remote safety assessment in future amyloidosis protocols, 
with the goal to reduce the in-person visit burden on subjects living with chronic disease.


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9.4.
Pharmacokinetics
9.4.1.
GSK2398852
Blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of GSK2398852 as specified in the SoA. The concentration will be the 
total of both radio-labelled and unlabelled mAb. The number of blood samples and 
sampling times for GSK2398852 may be modified during the study. Further details on 
the blood sample processing and their analyses are given in the study reference manual 
(SRM).
Once the plasma has been analyzed for GSK2398852, any remaining plasma may be 
stored and may be used in the development and validation of a companion diagnostic 
assay to measure SAP levels. 
9.4.2.
Plasma radioactivity
Blood samples will be collected for measurement of radioactivity as specified in the SoA. 
The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its 
radioactive metabolites. The number of blood samples and sampling times may be 
modified during the study. Further details on the blood sample processing and their 
analyses are given in the SRM.
9.5.
Pharmacodynamics
9.5.1.
SAP Concentration
Venous blood samples of approximately 4 mL will be collected for measurement of 
plasma SAP concentrations as detailed in the SoA. Further details on the blood sampling 
process and their analyses are given in the SRM.
Plasma SAP levels must reach target prior to administration of anti-SAP mAb. If there is 
suspicion that CPHPC treatment has been accidentally interrupted, an additional plasma 
SAP specimen should be collected and tested prior to administering anti-SAP mAb.

This specimen must have a fast turnaround in order to enable dosing of anti-SAP 
mAb on the following day.

Once the plasma has been analysed for SAP, any remaining plasma may be stored 
and may be used in the development and validation of a companion diagnostic 
assay to measure SAP levels.
9.6.
Imaging
9.6.1.
89Zr-GSK2398852 PET
Subjects will participate in up to two dosing sessions, each associated with the 
administration of up to 37 MBq 89Zr-GSK2398852 and up to 3 PET scans within 
approximately 5 days after the administration of radioactivity. The PET scan times for 


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each of the dosing sessions of the first patient are listed in Section 5.3.1. These times may 
then be varied for subsequent patients.
For each dosing session, the 89Zr-GSK2398852 (37 MBq radioactivity and a mass dose of
10 mg) will be administered IV in a room separate from the PET camera room. After a 
defined waiting time (defined by the time of the first PET scan) the patient will be taken 
to the PET camera room and placed in comfortable position on the PET couch. Arms are 
stretched over the head.
A low-dose CT scan is made for orientation of the heart and a PET acquisition of 4-5 
scans of about 20 minutes is started. This can be associated with cardiac gating if 
feasible.
Thereafter a whole body (head to upper thighs) low dose CT scan is made for anatomical 
orientation and for attenuation correction.
Sequential PET acquisitions will be made with about 3-5 minutes per bed position, 
covering the head to the upper thigh. The duration is of the order of 45 minutes.
The total duration of the scanning procedure is expected to be less than 2 hours.
Further details on scanning procedure are provided in a dedicated Image Acquisition and 
Analysis Manual.
9.6.2.
Cardiac Magnetic Resonance (CMR) Imaging 
Subjects will be asked to refrain from alcohol, caffeine, and nicotine on the days of CMR 
exams. Each baseline enhanced CMR imaging session will take approximately 45-60 
minutes, with a maximum scan time inside of the scanner of approximately 90 minutes. If 
a scanning failure occurs, there will be a minimum of 24 hours prior to rescan. 
As far as it is practicable, the local study site will use the same CMR imaging sequences, 
software acquisition, and contrast agent (i.e. DotaremTM) that is currently being used in 
the Phase 2 trial.
Whenever possible, the baseline contrast enhanced MRI scan will be performed 
after a subject has passed other eligibility requirements. 
For each subject, if follow-up CMR examination(s) are clinically indicated for evaluation 
of potential cardiac adverse event(s) the same scanner as to the one used at the baseline 
examination should be used wherever feasible. 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 local study site for disease and potential anti-SAP 
mAb-related clinical abnormalities. 


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However, image analysis for key CMR parameters which might be determinant for 89Zr-
GSK2398852 myocardial uptake (e.g. extracellular volume [ECV] and myocardial 
perfusion) will be performed by a qualified imaging laboratory.
9.6.3.
Access to Historical Patient ATTR-CM Cardiac Imaging 
Since it is likely that ATTR-CM subjects on enrolment into this PET study have had 
previous cardiac imaging, possibly including 2D-ECHO, CMR, bone tracer SPECT, and / 
or PET imaging (e.g. PiB or WAT), either at diagnosis and / or at follow-up, the images 
from these investigations and their respective reports should be available to GSK 
wherever feasible. 
Availability of this patient data would enable a more comprehensive evaluation of 89Zr-
GSK2398852 cardiac uptake in relation to cardiac amyloid load and myocardial coronary 
microvessel function.
9.7.
Additional Assessments
9.7.1.
Access to Diagnostic Patient Cardiac Biopsy Tissue
Where a ATTR-CM subject has had a cardiac (endomyocardial) biopsy, as part of a 
previous diagnostic workup, a sample of the tissue will be sent to GSK where possible. 
Routine and special histopathological investigations, including but not restricted to 
histochemical and / or immunohistochemical stains will be performed to assess for 
amyloid deposits and SAP levels, respectively.
9.8.
Efficacy
9.8.1.
Safety/exploratory Biomarkers
In the unlikely event of cardiac amyloid removal triggered by an anti-SAP mAb TMD(s) 
during this PET study, change in plasma NT-proBNP levels from baseline may provide 
surrogate biomarker evidence of cardiac amyloid clearance. 
However, it is important that any reduction in plasma NT-proBNP levels are evaluated 
alongside any change in LV mass and / or ECV from any repeat CMR imaging which is 
performed at the local study site.
10.
STATISTICAL CONSIDERATIONS
10.1.
Hypothesis
This is an exploratory study where the primary objective is to assess cardiac uptake of 
89Zr-GSK2398852 evaluated by PET imaging at different mass doses. No formal 
hypotheses will be tested as part of this study.


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10.2.
Sample Size Considerations
At the time of writing no empirical data was available to offer a suitable estimate for the 
expected between subject variability; therefore, the sample size has been determined 
primarily by feasibility.
A total of 6 subjects are expected to complete up to two dosing sessions. The study is 
split into two parts: 

in Part A up to 3 subjects will participate in up to two anti-SAP dosing sessions

in Part B up to 3 subjects will participate in one anti-SAP dosing session. 
Data will be reviewed in-stream with a view to inform subsequent unlabelled anti-SAP 
mAb mass dose levels. 
10.2.1.
Sample Size Re-estimation or Adjustment
No sample size re-estimation is planned for this study; however, at the interim (i.e. at 
completion of Part A) the team may decide to stop the study early and not recruit any 
subjects into Part B
10.3.
Data analysis considerations
Statistical analyses will be performed by, or under the direct auspices of Clinical 
Statistics, GSK.
10.3.1.
Populations for Analyses
For purposes of analysis, the following populations are defined:

All Treated Population: defined as all subjects who receive at least one Anti-
SAP treatment including 89Zr-GSK2398852. All safety analyses will be evaluated 
on this analysis population.

The PK Population: defined as all subjects from the All Treated Population for 
whom a PK sample is obtained and analysed.
Additional analysis populations may be defined in the Reporting and Analysis Plan 
(RAP).
10.3.2.
Interim Analyses
Decision making for the development programme is time critical and therefore there are 
two types of interim analysis planned in this study:

In-stream data review(s): any emergent PET imaging data from the current 
study will be complementary to the ongoing phase II study (Study Number 
201464) and its associated interim(s), as well as the broader Anti-SAP program. 
In addition, during the current study, changes may be made to a number of design 


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parameters based on the emerging data, including: (i) intra and inter mass dose 
levels; and (ii) the timing of PET scan, all based on the accruing data.

Interim analysis at the end of Part A: once the last subject in Part A has 
completed their final dosing session, a formal review of all available safety data 
(including AEs, clinical laboratory data, vital signs, ECGs), PK, ECHO/CMR and 
PET imaging data will be conducted before deciding whether to trigger Part B.
10.3.3.
Inter-Subject Reproducibility of 89Zr-GSK2398852 Myocardial 
Uptake
In any one subject in Part A, where the radiolabel PK and cardiac SUV profile of 89Zr-
GSK2398852 is consistent with myocardial uptake during either the 1st or 2nd dosing 
session (i.e. cardiac / plasma SUV ratio ≥0.5), the reproducibility of this specific 
unlabelled anti-SAP mAb dose in enabling myocardial uptake of 89Zr-GSK2398852 may
be evaluated by treating further subjects with the same unlabelled anti-SAP mAb mass 
dose. This is an optional evaluation that is at the discretion of the Investigator or designee 
in consultation with the Medical Monitor (Figure 7, below).
10.3.4.
Intra-subject confirmation of 89Zr-GSK2398852 Myocardial SAP 
Binding
In any one subject in Part A where the radiolabel PK and cardiac SUV profile of 89Zr-
GSK2398852 is consistent with myocardial uptake during the 1st dosing session (i.e. 
cardiac / plasma SUV ratio ≥0.5), 89Zr-GSK2398852 binding to myocardial SAP can be 
confirmed by performing an intra-subject mAb displacement evaluation. 
This will be attained by escalating the unlabelled anti-SAP mAb dose in the same subject 
on their 2nd dosing session (provided the AE profile from the 1st dosing session is 
acceptable) to evaluate whether a higher unlabelled anti-SAP mAb mass dose can 
attenuate the cardiac SUV signal compared to their 1st dosing session; this would be 
indicative of displacement of 89Zr-GSK2398852 from SAP binding sites on amyloid 
myocardial deposits. 
This is an optional evaluation that is at the discretion of the Investigator or designee in 
consultation with the Medical Monitor (Figure 7, below).


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Figure 7
Optional evaluations of Intra-subject 89Zr-GSK2398852 binding
Reproducibility of myocardial 89Zr-GSK2398852 uptake at a specific unlabelled anti-
SAP mAb mass dose between different ATTR-CM subjects (vertical lines), and intra-
subject dose escalation to confirm 89Zr-GSK2398852 binding to SAP on amyloid 
myocardial deposits (horizontal lines).
10.3.5.
Key Elements of Analysis Plan
Data will be listed and summarized according to the GSK reporting standards, where 
applicable. Complete details will be documented in the RAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP and final study report. 
The following is planned for the primary endpoints:
Analysis
Study Objective
Endpoints

Assessment of 89Zr-GSK2398852 cardiac uptake as evaluated by PET imaging 
at different unlabelled anti-SAP mAb mass doses
Analysis 
(Raw Data)

All data will be listed.

Descriptive statistics, where appropriate, will be calculated for all generated 
PET imaging endpoints over time grouped by total mass. 
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.
Demographic and baseline characteristics will be summarised.


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10.3.6.
Pharmacokinetics
Plasma concentrations of GSK2398852, which is the total of both 89Zr-labelled and 
unlabelled mAb, will be analysed using non-compartmental methods. PK parameters will 
be summarised by dose with/without treatment period stratification. Dose proportionality 
will be explored with/without treatment period stratification.
Plasma radioactive concentration - measured by scintillation counter, corrected by 
radioactivity decay and expressed in molar concentration of the mAb - will be analysed 
by non-compartmental methods. This radioactive concentration will reflect the total of 
both labelled-mAb and its metabolites. PK parameters will be summarised by TMD, 
with/without stratification by treatment period.
The time profile and AUC of the plasma radioactive concentration, resulting from the 
10-mg labelled-dose, will be scaled to the TMD and compared to the time profile and 
AUC of the plasma total mAb concentration.
For each anatomical region defined in the heart, the 3 PET scans will generate 3 values 
on radioactivity concentration (SUV), and the plasma radio-PK values will function as a 
marker of plasma clearance. The mechanistic model will probe the combination of tissue 
SUV and radio-PK as compatible with contributions by a vascular component, a free 
distribution to interstitium and a component related to tracer bound to amyloid-SAP 
complexes. The extracted parameters will be summarised for each subject and each mass 
dose.
10.3.7.
Evaluation of PET images
The acquired PET information is reconstructed into PET images with due corrections for 
attenuation, scattered radiation,etc.
The PET images are visually reviewed to identify the general features of body 
distribution and especially anatomical localization in the heart.
Regions of Interest (RoI) are outlined in the images to define radioactivity distribution. 
All organ and blood analyses are expressed as SUV (Measured radioactivity 
concentration corrected for radioactive decay and normalized for administered amount of 
radioactivity per body weight).
These SUV have a few different definitions depending on organ and selection of 
interesting tissue components:
Local tissue radioactivity concentration in organs in Regions of Interest (RoI)
SUVpeak: 
A small sphere of 10-12 mm diameter placed in a representative location as seen in the 
image or transferred from the CT scan. Average of voxel (picture element) values within 
this volume is calculated.


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SUVmean:
A larger outline of the whole organ or representative area or volume as seen in the image 
or transferred from the CT scan. Average voxel values (picture elements) within this 
volume is calculated.
Total organ radioactivity amount in Regions of Interest (RoI)
SUVtotal_organ:
An outline of the whole volume of the organ attempting to capture the total amount of 
radioactivity in that organ, as defined in the PET images or transferred from CT scan. 
Average of voxel (picture element) values within this volume is calculated.
VOLUMEtotal_organ:
Corresponding total volume of the organs above
The SUVtotal_organ and VOLUMEtotal_organ are used for calculation of fraction of 
administered dose in that organ.
The organs/tissues of interest for analysis include:
Local tissue radioactivity concentration in organs in Regions of Interest (RoI)
Where relevant and depending on radioactivity uptake pattern:
•
A minimum of 5 anatomical positions within the heart (only in the specific heart 
scans)
•
Up to 3 focal and 1 larger location in each of the lungs
•
Up to 3 focal and 1 larger location in the liver
•
One focal and one large area in spleen 
•
One focal and one large area in pancreas
•
One cortex and one medulla focal area in each of the kidneys
•
One large area in the brain
•
One large area in one thigh muscle
•
Up to 5 small areas of the skin
Other focal or larger areas may be included depending on features in the images
For the regions in the 4*5 scans focused over the heart, separate and average values will 
be generated for each of the RoIs.


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Total organ radioactivity amount in Regions of Interest (RoI)
•
Heart
•
Liver
•
Spleen
•
One lung
•
Both kidneys
Other organs may be included depending on features in the images 
The PiB studies, performed only across the heart will be evaluated regionally and as 
“polar maps” using an extracted parameter called “retention index” which indicates the 
degree of retention as compared to washout.
The WAT studies will be evaluated regionally with automatic software which generates 
values and “polar maps” representing absolute blood flow values.
Further details on the analysis of the images are given in the Imaging Acquisition and 
Analysis Manual.
10.3.7.1.
Analysis of PET data
The tissue SUV and plasma radio-PK values generated will constitute the primary 
information from the studies. Since plasma radio-PK will be dependent upon time after 
administration plus mass dose, it will be necessary to relate the tissue SUV to the instant 
and possibly also to the AUC of the plasma radio-PK.
It is expected that the tissue-to-plasma ratio of the mAb in the heart will be 
approximately 0.1-0.2 after equilibration between plasma and tissue interstitium. This is 
guided by an expected plasma space plus interstitium relative space of 0.1-0.2. Within the 
blood pool of the heart chambers the ratio is expected to be 0.5 (hematocrit about 0.5). 
We have placed a limit by which the tissue-to-plasma ratio in the cardiac muscle is 
indicative of entry to the interstitium and binding to amyloid-SAP complexes at 0.5 in 
balance between a sufficient increase as compared to passive distribution and avoidance 
of “spill-over” from cardiac blood pools.
More complex models of distribution between plasma and tissue will be explored.
10.3.7.2.
Storage and potential further analyses of images
The primary PET and CT images in digital form will be anonymized and stored in an 
image repository under the control of GSK and may be used for further analyses


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10.3.8.
Safety
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g. laboratory tests, vital signs, ECGs) will be summarised 
according to the scheduled, nominal visit at which they were collected and across all on-
treatment time points using a “worst-case” analysis. Complete details of the safety 
analyses will be provided in the RAP.


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11.
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Barbhaiya CR, Kumar S, Baldinger SH, Michaud GF, Stevenson WG, Falk R, et al. 
Electrophysiological assessment of conduction abnormalities and atrial arrhythmias 
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Boldrini M, Salinaro F, Mussinelli R, Raimolndi A, Alogna A, Musca F, et al. Prevalence 
and prognostic value of conduction disturbances at the time of diagnosis of cardiac AL 
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Börjesson PK, Jawu YW, de Bree R, Roos JC, Castelijns JA, Leemans CR, et al. 
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Immuno-PET in Head and Neck Cancer Patients. The Journal of nuclear medicine. 2009; 
50(11):1828-1836.
Dijkers EC, Kosterink JG, Rademaker AP, Perk LR, van Dongen GA, Bart J, et al. 
Development and characterization of clinical-grade 89Zr-trastuzumab for HER2/neu 
immunoPET imaging. J Nucl Med. 2009 Jun; 50(6):974-81.
Dijkers EC, Oude Munnink TH, Kosterink JG, Brouwes AH, Jager PL, de Jong JR, et al. 
Biodistribution of 89Zr-trastuzumab and PET Imaging of HER2-Positive Lesions in 
Patients With Metastatic Breast Cancer. Clinical pharmacology & Therapeutics. 2010, 
87(5).
Dorbala S, Vangala D, Bruyere J Jr, Quarta C, Kruger J, Padera R, et al. Coronary 
microvascular dysfunction is related to abnormalities in myocardial structure and 
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Gaykema SBM, Brouwers AH, Lub-de Hooge MN, Pleihuis RG, Timmer-Bosscha H, Pot 
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GSK2315698 in patients with systemic amyloidosis (SAP115570). Effective 09 NOV 
2016.
GlaxoSmith Kline Document Number 2017N343159_00. Supplement to GSK2398852 + 
GSK2315698 Investigator’s Brochure. Effective: Pending Publication.
GlaxoSmithKline Document Number 2012N141587_06. GSK2398852 + GSK2315698 
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[89Zr]Trastuzumab: Evaluation of Radiation Dosimetry, Safety, and Optimal Imaging 
Parameters in Women with HER2-Positive Breast Cancer. Mol Imaging Biol (2016) 
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Magnetic Resonance in Transthyretin Cardiac Amyloidosis. JACC. 2017; 70(4):466-477.
Menke-van der Houven van Oordt CW, Goorjes EC, Huisman MC, Vugts DJ, Roth C, 
Luik AM, et al.  89Zr-cetuximab PET imaging in patients with advanced colorectal 
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(99m)Tc-DPD scintigraphy in diagnosis and prognosis of hereditary transthyretin-related 
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Clearance of Amyloid by Antibodies to Serum Amyloid P Component. N Engl J Med. 
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Drug Disposition Model of CPHPC in Patients with Systemic Amyloidosis. CPT: 
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12.
APPENDICES
12.1.
Appendix 1 Abbreviations and Trademarks
Abbreviations
89Zr-GSK2398852
89-Zirconium-labelled anti-
SAP mAb
99mTc-DPD
Technetium-99m-labelled 
3,3-diphosphono-1,2-
propanodicarboxylic acid
AE
Adverse Event
AL
Amyloid Light-chain
ALARP
As Low as Reasonably 
Practicable
ALT
Alanine transaminase
anti-SAP
anti-Serum Amyloid P 
component
aPTT
activated partial 
thromboplastin time
AST
Aspartate transaminase
ATTR-CM
Transthyretin amyloidosis 
restrictive cardiomyopathy
AUC
Area Under the Curve 
Bq
Becquerel
BSA
Body surface area
BUN
Blood urea nitrogen
CABG
Coronary Artery Bypass 
Grafting
CIOMS
Council for International 
Organizations of Medical 
Sciences
cm
Centimetre
Cmax
Maximum Concentration
CMR
Cardiac Magnetic 
Resonance Imaging
CPK
Creatine phosphokinase
Cold anti-SAP mAb
Unlabelled anti-SAP mAb
CONSORT
Consolidated Standards of 
Reporting Trials
CPHPC
GSK2315698 (Carboxy 
pyrrolidine hexanoyl 
pyrrolidine carboxylate)
CRF
Case report form
CRNA
Complementary 
ribonucleic acid
CSR
Clinical Study Report
CT
Computerised 
Tomography
CV
Cardiovascular
Df
desferrioxamine
ECG
Electrocardiogram (12-
lead)
ECHO
Echocardiogram
ECV
Cardiac Extracellular 
Volume
eGFR
Estimated Glomerular 
Filtration Rate
FAC
Familial Amyloidotic 
Cardiomyopathy
FcRn
neonatal Fc receptor
FDA
Food and Drug 
administration
FDG
Fludeoxyglucose
FIH
First in Human
FSH
Follicle stimulating 
hormone
GBM
Glomerulus basement 
membrane
GCP
Good Clinical Practice
Gd
Gadolinium
GSK
GlaxoSmithKline
GSK2315698
CPHPC (Carboxy 
pyrrolidine hexanoyl 
pyrrolidine carboxylate).
GSK2398852
Unlabelled anti-SAP mAb
h
hour
HBsAg
Hepatitis B surface 
antigen
HCG
Human chorionic 
gonadotropin
HFpEF
Heart failure with 
preserved ejection fraction
HIPAA
Health Insurance 
Portability and 
Accountability Act
HIV
Human Immunodeficiency 
Virus
HPLC
High performance liquid 
chromatography
HRT
Hormonal replacement 
therapy
hs-cTn
High Sensitivity Cardiac 
Troponin
IB
Investigator’s Brochure


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ICD
Implantable Cardiac 
Defibrillator
ICF
Informed Consent Form 
IEC
Independent ethics 
committee
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IMP
Investigational Medical 
Product
INR
International normalized 
ratio
IP
Investigational Product
IRB
Institutional Review Board
IRR
Infusion Related Reaction
IUD
Intrauterine device
IUS
Intrauterine hormone-
releasing system
IV
Intravenous
L
Litre
LCV
Leukocytoclastic vasculitis
LDH
Lactate dehydrogenase
LV
Left ventricle
LVAD
Left Ventricular Assist 
Device
mAb
Monoclonal antibody
MBq
Megabecquerel 
MCH
Mean corpuscular 
hemoglobin
MDRD
Modification of Diet in 
Renal Disease
MedDRA
Medical Dictionary for 
Regulatory Activities
mg
Milligram
Mg/dL
Milligram per decilitre
MGC
Multinucleate giant cells
μmol/L
Micromol/litre
mL
Millilitre 
mm
Millimetre
mmHg
Millimetre of mercury
MRI
Magnetic Resonance 
Imaging
MSDS
Material Safety Data
Sheet
msec
Millisecond
mSv
Millisievert 
NSD
Nephrogenic systemic 
dermatopathy
NSF
Nephrogenic systemic 
fibrosis
NT-proBNP
N-terminal prohormone of 
brain natriuretic peptide
NYHA
New York Heart 
Association
O
Oxygen
PD
Pharmacodynamics
PET
Positron Emission 
Tomography
PET/CT
Positron Emission 
Tomography and 
Computed Tomography 
(combined scan)
PI
Principal Investigator
PiB
Pittsburgh Compound B 
(binds to amyloid deposit)
PIH
Post-Inflammatory 
Hyperpigmentation
PK
Pharmacokinetic
PPM
Permanent Pacemaker
PT
Prothrombin time
QTcF
Interval from the Q wave 
on the ECG to point T 
using Fredericia's formula
QTcB
QTc corrected by Bazett's 
formula
RAP
Reporting and Analysis 
Plan
RoI
Regions of Interest
SAE
Serious Adverse Event
SAP
Serum Amyloid P
Component
SC
Subcutaneous
SCr
Serum Creatinine
SD
Starting dose
SGOT
Serum Glutamic-
Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic 
Transaminase
Sec
Seconds
siRNA
Small interfering 
ribonucleic acid
SoA
Schedule of Activities
SOP
Standard Operating 
Procedure
SPECT imaging
Single-photon emission 
computed tomography
SRM
Study Reference Manual
SUSAR
Suspected Unexpected 
Serious Adverse 
Reactions


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SUV
Standardized Uptake 
Values (Measured 
radioactivity concentration 
corrected for radioactive 
decay and normalized for 
administered amount of 
radioactivity per body 
weight)
T½ 
Half-life
Tc-DPD
Technetium-99m-labelled 
3,3-diphosphono-1,2-
propanodicarboxylic acid
TID
Thrice daily
Tmax
Time to reach maximum 
concentration
TMD
Total Mass Dose
TNF
Tumor necrosis factor
TTR
Transthyretin amyloidosis
TTS
Study Specific Technical 
Agreement/Memo
TUDCA
Tauroursodeoxycholic acid
ULN
Upper Limit of Normal
Unlabelled anti-
SAP mAb
GSK2398852
US
United States
VF
Ventricular Fibrillation 
VT
Ventricular Tachycardia
WAT
15-Oxygen labelled water
WBC
White blood cell
WOCBP
Woman of Childbearing 
Potential
w/v
Weight by volume
Zr
Zirconium
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
None
BodyGuardian
Dotarem


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12.2.
Appendix 2 Clinical Laboratory Tests

The tests detailed in Table 10 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of subjects are detailed 
in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 10
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:
Mean corpuscular 
volume (MCV)
Mean corpuscular 
hemoglobin (MCH)
%Reticulocytes
White blood cell (WBC)
count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Red blood cell (RBC)
Count
Hemoglobin
Hematocrit
Clinical 
Chemistry1
Blood urea 
nitrogen (BUN)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase
(SGOT)
Total and direct 
bilirubin
Creatinine
Sodium
ALT/ Serum 
Glutamic-Pyruvic 
Transaminase
(SGPT)
Total Protein
Glucose (non-
fasting)
Calcium
Alkaline 
phosphatase
Albumin
Cardiac Safety

Troponin-T

NT-proBNP
Pregnancy 
testing

Urine Human chorionic gonadotropin (HCG) (female subjects only)
Routine 
Urinalysis

Specific gravity, pH, glucose, protein, blood, and ketones by dipstick

Urine microscopy may be performed if indicated
Other 
Screening 
Tests

Clotting tests: prothrombin time (PT) and activated partial thromboplastin 
time (APTT)


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Laboratory 
Assessments
Parameters

Follicle-stimulating hormone and estradiol (all female subjects only)

Urine alcohol & drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines)

Viral serology (HIV antibody, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody) 
The results of each test must be entered into the CRF.
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 8.1.5 and Appendix 6 All events of ALT 3 × ULN and bilirubin 2 × ULN 
(>35% direct bilirubin) or ALT 3 × ULN and international normalized ratio (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).


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12.3.
Appendix 3 Study Governance Considerations
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with:

Consensus ethical principles derived from international guidelines 
including the Declaration of Helsinki and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other 
relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by 
the investigator and reviewed and approved by the IRB/IEC before the study is 
initiated. 

Any amendments to the protocol will require IEC/IRB approval before 
implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects. 

The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC 
annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/EC

Notifying the IRB/IEC of SAE or other significant safety findings as 
required by IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to 
the subject or his/her legally authorized representative and answer all questions 
regarding the study. 

Subjects must be informed that their participation is voluntary. Subjects or their 
legally authorized representative will be required to sign a statement of informed 


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consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent 
must also sign the ICF.

Subjects must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 

A copy of the ICF(s) must be provided to the subject or the subject’s legally 
authorized representative. 

Subjects who are rescreened are required to sign a new ICF.
The ICF may contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research in accordance with SOP-GSKF-410. The 
investigator or authorized designee will explain to each subject the objectives of the 
exploratory research. Subjects will be told that they are free to refuse to participate and 
may withdraw their consent at any time and for any reason during the storage period. A 
separate signature will be required to document a subject's agreement to allow any 
remaining specimens to be used for exploratory research. Subjects who decline to 
participate will not provide this separate signature.
Data Protection

Subjects will be assigned a unique identifier by the sponsor. Any subject records 
or datasets that are transferred to the sponsor will contain the identifier only; 
subject names or any information which would make the subject identifiable 
will not be transferred. 

The subject must be informed that his/her personal study-related data will be 
used by the sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the subject. 

The subject must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by
the sponsor, by appropriate IRB/IEC members, and by inspectors from 
regulatory authorities.
Publication Policy

The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to 
the sponsor before submission. This allows the sponsor to protect proprietary 
information and to provide comments.

The sponsor will comply with the requirements for publication of study results. 
In accordance with standard editorial and ethical practice, the sponsor will 
generally support publication of multicenter studies only in their entirety and not 


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as individual site data. In this case, a coordinating investigator will be 
designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with 
International Committee of Medical Journal Editors authorship requirements.
Data Quality Assurance

All subject data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the sponsor or designee electronically (e.g., 
laboratory data). The investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the CRF. 

The investigator must maintain accurate documentation (source data) that 
supports the information entered in the CRF. 

The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 

The sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 

Study monitors will perform ongoing source data verification to confirm that 
data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of subjects are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 

Records and documents, including signed ICF, pertaining to the conduct of this 
study must be retained by the investigator for 25 years from the issue of the final 
Clinical Study Report (CSR)/ equivalent summary unless local regulations or 
institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the 
sponsor. No records may be transferred to another location or party without 
written notification to the sponsor. 
Source Documents

Source documents provide evidence for the existence of the subject and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site.

Data reported on the CRF or entered in the eCRF that are transcribed from 
source documents must be consistent with the source documents or the 
discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the study. Also, current 
medical records must be available.

Definition of what constitutes source data can be found in the Study Reference 
Manual.


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Study and Site Closure
GSK or its designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of GSK. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include 
but are not limited to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of subjects by the investigator

Discontinuation of further study treatment development


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12.4.
Appendix 4 Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition

An AE is any untoward medical occurrence in a clinical study subject, temporally 
associated with the use of a study treatment, whether or not considered related to the 
study treatment.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
Events Meeting the AE Definition 

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (e.g., ECG, radiological scans, vital signs 
measurements), including those that worsen from baseline, considered clinically 
significant in the medical and scientific judgment of the investigator (i.e., not related 
to progression of underlying disease).

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 before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/self-
harming intent. Such overdoses should be reported regardless of sequelae.
Events NOT Meeting the AE Definition 

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the 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 
condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 


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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.
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, 
death due to progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
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 inpatient hospitalization or prolongation of existing hospitalization
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 outpatient 
setting. Complications that occur during hospitalization are AE. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in
doubt as to whether “hospitalization” occurred or was necessary, the AE should be 
considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the subject or may require medical or surgical intervention to prevent one 


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of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
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

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
Recording AE and SAE
AE 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) 
related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the subject’s medical 
records to GlaxoSmithKline (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 case, all subject identifiers, with the exception of the 
subject number, will be redacted on the copies of the medical records before 
submission to GSK.

The investigator will attempt to establish a diagnosis of the event based on signs, 


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symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 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 causes sufficiently discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. Severe is a category utilized for rating 
the intensity of an event; and both AE and SAE can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study treatment and 
each occurrence of each AE/SAE.

A "reasonable possibility" of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study treatment 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to GSK. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to GSK.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.


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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by GSK to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other 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 24 hours of 
receipt of the information.
Reporting of SAE to GSK
SAE Reporting to GSK via Electronic Data Collection Tool

The primary mechanism for reporting SAE to GSK will be the electronic data 
collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

The investigator or medically-qualified sub-investigator must show evidence within 
the eCRF (e.g., check review box, signature, etc.) of review and verification of the 
relationship of each SAE to IP/study participation (causality) within 72 hours of SAE 
entry into the eCRF.

After the study is completed at a given site, the electronic data collection tool 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, then the site can report this information on a paper SAE form (see next 
section) or to the medical monitor by telephone.

Contacts for SAE reporting can be found in the SRM.
SAE Reporting to GSK via Paper CRF

Email or facsimile transmission of the SAE paper CRF is the preferred method to 
transmit this information to the medical monitor or the SAE coordinator.

In rare circumstances and in the absence of email or facsimile equipment, 


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notification by telephone is acceptable with a copy of the SAE data collection tool 
sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the Study Reference Manual.


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12.5.
Appendix 5 Contraceptive Guidance and Collection of 
Pregnancy Information
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below).
Women in the following categories are not considered WOCBP
1. Premenarchal
2. Premenopausal female with ONE of the following:

Documented hysterectomy

Documented bilateral salpingectomy

Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of subject’s 
medical records, medical examination, or medical history interview.
3. Postmenopausal female

A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in 
the postmenopausal range may be used to confirm a postmenopausal state in 
women not using hormonal contraception or hormonal replacement therapy 
(HRT). However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient. 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
Contraception Guidance
Male subjects

Male subjects with female partners of child-bearing potential are eligible to 
participate if they agree to ONE of the following from Day 1 until 3 months 
after last PET scan:

Are abstinent from penile-vaginal intercourse as their usual and preferred 
lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent 

Agree to use a male condom plus an additional method of contraception 
with a failure rate of <1% per year as described in Table 11 when having 
penile-vaginal intercourse with a woman of childbearing potential 


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
Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of 
penile penetration for up to three months after last scan.

In addition, male subjects must refrain from donating sperm for duration of 
study and for 3 months after last scan.
Female subjects
Female subjects of childbearing potential are not eligible to participate.


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Table 11
Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationa
oral
intravaginal 
transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulationa
injectable 
Highly Effective Methods That Are User Independent 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationa
Intrauterine device (IUD)
Intrauterine hormone-releasing system (IUS)
bilateral tubal occlusion
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used.)
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration 
of the study and the preferred and usual lifestyle of the subject.)
NOTES: 
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for subjects in clinical studies. 


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Pregnancy Testing

WOCBP are not eligible for the study. However, all women will undergo a negative 
highly sensitive urine pregnancy test prior to each dosing session.

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 

Pregnancy testing will be performed and assayed in a certified laboratory OR by the 
clinical site using a test kit in accordance with instructions provided in its package 
insert.
Collection of Pregnancy Information
Male subjects with partners who become pregnant

Investigator will attempt to collect pregnancy information on any male subject’s 
female partner of a male study subject who becomes pregnant while participating in 
this study. This applies only to subjects who receive study treatment.

After obtaining the necessary signed informed consent from the pregnant female 
partner directly, the investigator will record pregnancy information on the 
appropriate form and submit it to GSK within 24 hours 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 fetal 
status (presence or absence of anomalies) or indication for procedure. 
Female Subjects who become pregnant

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 
24 hours 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 subject and neonate, 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.


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
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 4 While the investigator is not obligated to actively seek 
this information in former study subjects, he or she may learn of an SAE through 
spontaneous reporting. 
Any female subject who becomes pregnant while participating

will discontinue study treatment or be withdrawn from the study.


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12.6.
Appendix 6 Liver Safety: Required Actions and Follow-up 
Assessments 
Phase I liver chemistry stopping criteria have been designed to assure subject safety and 
to evaluate liver event etiology 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
Phase I 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, 
Report as an SAE.
See additional Actions and Follow Up Assessments listed below
Required Actions and Follow up Assessments 
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 chemistry event follow up 
assessments 

Monitor the subject until liver chemistries resolve, 
stabilise, or return to within baseline (see 
MONITORING below)

Do not restart/rechallenge subject with study 
treatment unless allowed per protocol and GSK 
Medical Governance approval is granted (see 
below). If restart/rechallenge not allowed per 
protocol or not granted, permanently 
discontinue study treatment and continue subject
in the study for any protocol specified follow up 
assessments 
MONITORING:
If ALT≥3xULN AND bilirubin 2xULN or INR 
>1.5:

Repeat liver chemistries (include ALT, AST, 

Viral hepatitis serology3

Obtain INR and recheck with each 
liver chemistry assessment until the 
transaminases values show 
downward trend

Obtain blood sample for 
pharmacokinetic (PK) analysis, 
obtained within 5 days of last dose of 
CPHPC or anti-SAP mAb.4

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 case report 
form (CRF)

Record use of concomitant 
medications on the concomitant 
medications CRF page including 


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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
acetaminophen, herbal remedies, 
other over the counter medications.

Record alcohol use on the liver event 
alcohol intake CRF page
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 high 
performance liquid chromatography 
(HPLC) assay (quantifies potential 
acetaminophen contribution to liver 
injury in subjects with definite or likely 
acetaminophen use in the preceding 
week [James 2009]). NOTE: not 
required in China

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; HbsAg and Hepatitis B Core Antibody (IgM); Hepatitis complementary 
ribonucleic acid 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 
PK 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, et al. 
Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen Overdose 
and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.


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12.7.
Appendix 7 Guidance on the Clinical Management of Rash 
Associated with Anti-SAP mAb
12.7.1.
Background 
In the FIH study, anti-SAP mAb administration, at doses ≥582 mg 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 600 mg on their first treatment. Their skin biopsy showed 
an active 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 1000 mg 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 consistent with a lymphocytic vasculitis/LCV picture.
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 - which arose after an anti-
SAP mAb dose of 1200mg at the 3rd dosing session - was associated with the highest 
measured plasma concentration of anti-SAP mAb, albeit this subject was concomitantly 
receiving an immunomodulatory drug.
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.
12.7.2.
Management of Rash
Rash will be graded using the following criteria based on symptoms and the body surface 
area (BSA) affected [Table 12].
Table 12
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 12.7.3
a.
Symptoms include: pain, itch and burning
b.
E.g. evidence of renal involvement
Local dermatological review can be sought at any time during a rash, but should be 
sought if a rash is deemed to be stable but persistent lasting ≥7 days, or is deemed to be 
rapidly worsening.
Symptomatic management of mild/moderate rash should be under the direction of the 
Investigator or designee with expert dermatological advice as appropriate. Initial 
management of rashes could include, but is not restricted to, use of emollients, topical 
corticosteroids and antihistamines.
12.7.3.
Emergency management of rash with systemic /mucosal 
involvement
Severe (Grade 4) rash, with systemic or mucosal involvement is a medical emergency.


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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.
12.7.4.
Post-Inflammatory Hyperpigmentation (PIH) 
PIH is a recognised chronic complication of acute skin inflammation, and can take weeks 
to months to completely resolve depending upon the skin layer which is principally 
involved. PIH is more prevalent in patients with African heritage, such that ATTR CM 
subjects in this PET study with the mutant V122I genotype might be more susceptible to 
PIH after an acute rash event. The Investigator or designee should report to GSK any PIH 
events as soon as possible after its onset.


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12.8.
Appendix 8 Equations and Diagnostic Criteria
Equation 1
4-variable MDRD formula for 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
Table 13
Classification- for groups


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Table 14
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.


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12.9.
Appendix 9
Radiation Dose
Subjects will be exposed to an additional dose of ionising radiation as a consequence of 
their participation in this study. The ionising radiation exposure from PET/CT scanning 
comes from two sources. A proportion of the radiation exposure comes from the 
administered radioligand 89Zr-GSK2398852 and the administration of 11C-PiB and 15O-
WAT. The remaining radiation dose comes from low dose CT scans performed in order 
to correct the PET data for tissue attenuation. If the subject needs to be removed from the 
scanner and repositioned during the PET scan, then a second low dose CT scan may be 
performed. The doses chosen for this study aim to deliver a minimal radiation exposure, 
compatible with a good quality PET and CT signal. 
The proposed 89Zr-GSK2398852 radioactivity dose is 37 MBq for each administration, 2 
sessions per subject, with total 74 MBq. The mean effective dose for 89Zr-mAb PET 
study was reported to be 0.53 mSv/MBq [Börjesson 2009], hence 37 MBq of 89Zr-
GSK3128349 in this study would provide approximately 19.61 mSv (37 MBq X 0.53 
mSv/MBq) of exposure, which together with the low-dose CT scans (0.5 mSv/CT scan X 
3 CT scans) yield approximately 21.11 mSv. 
The single PiB study with its associated low dose CT scan is expected to give 1.5 mSv 
and the WAT scans 0.5 mSv each.  (x2 WAT = 1.0 mSv)
Total radiation dose exposure per subject is therefore expected to be 44.7 mSv. With 
some residual radioactivity in the injection syringe and considering radioactive decay till 
time of injection, we will aim to be below 44 mSv across the study.
The total maximum effective dose of approximately 44 mSv in this study is equivalent to 
approximately 18 times the average annual exposure (2.4 mSv) from natural background 
radiation in Sweden (Swedish Radiation Protection Authority, SSI Report 2007-02). The 
additional risk of developing a fatal malignancy is 5.5% per Sv [ICRP37 2007] and hence 
as a result of these exposures has been estimated as approximately 1 in 400 for an adult in 
normal health. However, the reduced life expectancy of the ATTR-CM patient 
population to be studied will result in a lower risk for these individual subjects. 


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12.10.
Appendix 10 Schedule of Activities: Flow Diagram
The diagrams below provide an example order of study activities for a subject who 
receives a TMD of >200mg. This is not a comprehensive list; refer to the SoA for 
additional details.


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Dosing Session 2 will be similar to Dosing Session 1, but will include a WAT PET scan 
on Day 1 or 2 (Part A only).

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
204512
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for An Adaptive, Open-Label 
Study to Evaluate the Biodistribution of 89Zirconium-
labelled GSK2398852 in the Heart and Other Organs of 
Patients with Transthyretin Cardiomyopathy (ATTR-CM) 
using Positron Emission Tomography (PET) Imaging
Compound Number 
:
GSK2315698 + GSK2398852+ Radiolabelled 89Zr-
GSK2398852
Effective Date 
:
19-Feb-2019
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 204512.

This RAP will be provided to the study team members to convey the content of the 
Interim and Final Statistical Analysis Complete (SAC) deliverable.
Author(s):
Author
Date
Lead
01-Feb-2019
Senior Statistician (Future Pipelines Discovery, Clinical 
Statistics)
Co-Authors
Senior Director (Clinical Pharmacology Modelling and 
Simulation)
Principal Statistician (Future Pipelines Discovery, Clinical 
Statistics)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
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CONFIDENTIAL
The GlaxoSmithKline group of companies
204512
2
RAP Team Review Confirmations (Method: E-mail)
Reviewer
Date
01-Feb-2019
Programming Manager, (Future Pipelines Discovery Clinical 
Programming)
01-Feb-2019
Clinical Investigation Lead (FPD)
01-Feb-2019
Principal Statistician (Future Pipelines Discovery, Clinical 
Statistics)
04-Feb-2019
Senior Director (Clinical Pharmacology Modelling and 
Simulation)
Clinical Statistics and Clinical Programming Line Approvals (Method: Pharma 
TMF eSignature)
Approver
Date
14-Feb-2019
Director (Future Pipelines Discovery Clinical Statistics)
19-Feb-2019
Programming Manager (Future Pipelines Discovery Clinical 
Programming)
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................6
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................6
2.1.
Nomenclature ...............................................................................................6
2.2.
Changes to the Protocol Defined Statistical Analysis Plan............................6
2.3.
Study Objective(s) and Endpoint(s)...............................................................7
2.4.
Study Design ................................................................................................9
2.5.
Statistical Analyses.....................................................................................10
2.6.
Sample Size Considerations.......................................................................10
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Interim Analyses .........................................................................................12
3.2.
Final Analyses ............................................................................................12
4.
ANALYSIS POPULATIONS ...................................................................................13
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
5.1.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................14
6.
STUDY POPULATION ANALYSES .......................................................................15
6.1.
Overview of Planned Study Population Analyses........................................15
7.
PRIMARY STATISTICIAL ANALYSES...................................................................16
7.1.
Primary Analyses........................................................................................16
7.1.1.
Endpoint / Variables.....................................................................16
7.1.2.
Summary Measure ......................................................................16
7.1.3.
Population of Interest...................................................................16
7.1.4.
Statistical Analyses / Methods .....................................................16
7.2.
Secondary Analyses ...................................................................................17
7.2.1.
Endpoint / Variables.....................................................................17
7.2.2.
Summary Measure ......................................................................17
7.2.3.
Population of Interest...................................................................17
7.2.4.
Statistical Analyses / Methods .....................................................17
8.
SAFETY ANALYSES .............................................................................................18
8.1.
Adverse Events Analyses ...........................................................................19
8.2.
Adverse Events of Special Interest (AESI) Analyses...................................19
8.3.
Clinical Laboratory Analyses.......................................................................20
8.4.
Other Safety Analyses ................................................................................21
9.
PHARMACOKINETIC ANALYSES.........................................................................22
9.1.
Primary Pharmacokinetic Analyses.............................................................22
9.1.1.
Endpoint / Variables.....................................................................22
Drug Concentration Measures .....................................................22
Derived Pharmacokinetic Parameters..........................................22


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9.1.2.
Population of Interest...................................................................23
9.1.3.
Statistical Analyses / Methods .....................................................23
10. PHARMACODYNAMIC AND BIOMARKER ANALYSES........................................24
11. REFERENCES.......................................................................................................25
12. APPENDICES........................................................................................................26
12.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................26
12.1.1.
Exclusions from Per Protocol Population .....................................26
12.2.
Appendix 2: Schedule of Activities ..............................................................27
12.2.1.
Protocol Defined Schedule of Events...........................................27
12.3.
Appendix 3: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................31
12.3.1.
Treatment Phases .......................................................................31
12.3.2.
Treatment Sessions.....................................................................31
12.3.3.
AE Onset Time and Duration .......................................................32
12.4.
Appendix 4: Data Display Standards & Handling Conventions....................33
12.4.1.
Baseline Definitions .....................................................................33
Derivations and Handling of Missing Baseline Data.....................33
12.4.2.
Reporting Process .......................................................................33
12.4.3.
Reporting Standards....................................................................34
12.4.4.
Appendix 4A: Additional Endpoint Information .............................35
12.4.5.
Evaluation of PET Images ...........................................................35
12.5.
Appendix 5: Derived and Transformed Data ...............................................37
12.5.1.
General........................................................................................37
12.5.2.
Study Population..........................................................................37
12.5.3.
Safety ..........................................................................................38
12.5.4.
Triplicate ECG and Vital Sign measurements ..............................39
12.6.
Appendix 6: Reporting Standards for Missing Data.....................................40
12.6.1.
Premature Withdrawals................................................................40
12.6.2.
Handling of Missing Data.............................................................40
Handling of Missing and Partial Dates .........................................40
12.7.
Appendix 7: Values of Potential Clinical Importance ...................................42
12.7.1.
Haematology Values of Potential Clinical Importance ..................42
12.7.2.
Chemistry Values of Potential Clinical Importance.......................42
12.7.3.
Liver Function Test Values of Potential Clinical Importance.........42
12.7.4.
ECG Values and QTc Change of Potential Clinical 
Importance...................................................................................43
12.7.5.
Vital Sign Values and Changes of Potential Clinical 
Importance...................................................................................43
12.8.
Appendix 8: Abbreviations & Trade Marks ..................................................44
12.8.1.
Abbreviations...............................................................................44
12.8.2.
Trademarks .................................................................................45
12.9.
Appendix 9: List of Data Displays ...............................................................46
12.9.1.
Data Display Numbering..............................................................46
12.9.2.
Data Display Format ....................................................................46
12.9.3.
Mock Example Shell Referencing ................................................46
12.9.4.
Deliverables.................................................................................46
12.9.5.
Study Population Tables..............................................................47
12.9.6.
PD Figures...................................................................................48


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12.9.7.
Safety Tables...............................................................................49
12.9.8.
Safety Figures .............................................................................51
12.9.9.
Pharmacokinetic Tables...............................................................52
12.9.10. Pharmacokinetic Figures .............................................................53
12.9.11. ICH Listings .................................................................................54
12.9.12. Non-ICH Listings..........................................................................57
12.10. Appendix 10: Example Mock Shells for Data Displays ................................58


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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:
2016N308062_00
04-OCT-2017
Original
2.
SUMMARY OF KEY PROTOCOL INFORMATION
The principal aim of this PET imaging study is to investigate the cardiac uptake of 89Zr-
GSK2398852 in patients with transthyretin amyloidosis restrictive cardiomyopathy 
(ATTR-CM), and its biodistribution to other organs.
This is an open-label non-randomised 89Zr-GSK2398852 PET imaging study in clinically 
stable patients with either wild type or inherited ATTR-CM. Subjects will participate in 
up to two dosing sessions.
This study will be divided into two parts: Part A and an optional Part B.
All subjects will participate in a screening period of up to 35 days. Part A subjects (N=3) 
will participate in up to two dosing sessions approximately 26 days in duration (each). 
Part B subjects (N=3) will participate in one dosing session of approximately 26 days in 
duration. Total duration in the study will be approximately 3-4 months for Part A 
subjects, and approximately 2 months for Part B subjects.
2.1.
Nomenclature
In this document:

GSK2315698 is referred to as CPHPC (carboxy pyrrolidine hexanoyl pyrrolidine 
carboxylate).

GSK2398852 is referred to as unlabelled anti SAP mAb.

89Zirconium-desferrioxamine (Df) labelled anti-SAP mAb is referred to as 89Zr-
GSK2398852. 

The administration of CPHPC and anti-SAP mAb is referred to as Anti SAP 
treatment.

Total Mass Dose (TMD) of anti-SAP mAb = unlabelled anti-SAP mAb + 89Zr-
GSK2398852.

Throughout this document, the usage of Total mAb (or Total anti-SAP mAb) 
refers to both unlabelled and labelled mAb.
2.2.
Changes to the Protocol Defined Statistical Analysis Plan
For analyzing the secondary objectives of characterization of the plasma 
pharmacokinetics of total mAb (unlabelled GSK2398852 and 89Zr-GSK2398852) and 
characterization of the plasma pharmacokinetics of radioactivity (89Zr-GSK2398852 


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radio-PK), the descriptive pharmacokinetic parameter of clearance is not analyzed as it is 
deemed not useful from the CPMS perspective.
The two PET scans with the administration of Oxygen-15 labelled water (WAT) for the 
characterization of the regional blood flow in the heart were not done due to logistical 
difficulties.
The PiB PET scan for the characterization of the regional amyloid burden in the heart is 
not being done due to logistical difficulties.
Descriptive statistics are not being presented for any of the generated PET imaging 
endpoints due to a small sample size.
The summaries for the generated PET imaging parameters will not be grouped by 
common total mass dose due to a small sample size.
Correlation of regional pattern of 89Zr-GSK2398852 uptake in the heart with the pattern 
of blood flow by MRI signal will be assessed informally using a scatter plot.  Formal 
correlations will not be produced because of the small sample size.
The CMR/ECHO analysis will not be performed as this was a baseline safety 
measurement only, therefore the data were not databased.
2.3.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints
Assessment of 89Zr-GSK2398852 cardiac 
uptake as evaluated by PET imaging at 
different mass doses
Standardized Uptake Values (SUV) [i.e. Radioactivity 
concentrations] in focal anatomical locations within the heart, 
as well as SUV of the whole heart at different time points after 
89Zr-GSK2398852 administration and at different anti-SAP 
mAb TMDs.
Secondary Objectives
Secondary Endpoints
Assessment of 89Zr-GSK2398852 
biodistribution in non-cardiac tissues and 
organs
Focal and total radioactivity uptake (including, but not limited 
to SUV) in different tissues (including potentially at those 
peripheral tissue sites where TTR amyloid deposition can be 
clinically occult) at different time points and after different 
TMDs.
Characterisation of the plasma 
pharmacokinetics of total mAb (unlabelled 
GSK2398852 and 89Zr-GSK2398852)
Descriptive pharmacokinetic (PK) parameters, including the 
maximum concentration in plasma (Cmax), the time 
associated with Cmax (Tmax), clearance, terminal half-life 
(T½) and the area under the concentration-time profile (AUC).
Characterisation of the plasma 
pharmacokinetics of radioactivity (89Zr-
GSK2398852 radio-PK)
Descriptive PK parameters including Cmax, Tmax, clearance, 
T½ and AUC based on scintillation counter.
Safety & tolerability of Anti-SAP treatment 
including administration of 89Zr-
GSK2398852
All adverse events (AEs) including the incidence and grading 
of skin rashes, cardiac adverse events and infusion-related 
reactions, as well as other AEs utilizing standard 
pharmacovigilance practices.


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Objectives
Endpoints
Absolute changes in safety lab parameters, including cardiac 
troponin and N-terminal prohormone of brain natriuretic 
peptide (NT-ProBNP). Other safety information, including 
electrocardiogram (ECG), inpatient and outpatient cardiac 
telemetry, vital signs, and physical exam data.
Exploratory Objectives
Exploratory Endpoints
Correlation of regional pattern of 89Zr-
GSK2398852 uptake in the heart with the
pattern of amyloid load by PiB scan and 
blood flow by WAT scan or MRI signal 
pattern
Maps of regional PET signals or MRI signals over the 
myocardium will be visually compared and scored.
Regional derived PET and MRI parameters correlated within 
and across ATTR-CM patients.
Assess feasibility of patients to operate 
remote data collection equipment. This 
may include ECGs, vital signs, and 
streaming video device.
Number of “virtual visits” and number of additional remote 
assessments collected.


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2.4.
Study Design
Overview of Study Design and Key Features
Figure 1
Study Schematic – Part A
Figure 2
Study Schematic – Part B
Design 
Features

This is an open-label, non-randomised 89Zr-GSK2398852 PET imaging study in 
clinically stable patients with cardiac dysfunction caused by ATTR-CM.

The study will be divided into two parts, Part A and an optional Part B. 
o
Part A will complete up to 3 subjects who participate in up to two anti-SAP dosing 


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Overview of Study Design and Key Features
sessions (Figure 1). The first two subjects in Part A will have up to three 89Zr PET 
scans, while the remaining subject will undergo up to two 89Zr PET scans.
o
Part B will complete up to three subjects who participate in only one anti-SAP 
dosing session (Figure 2). Subjects will undergo up to two 89Zr PET scans.
Part B will be triggered by the sponsor in consultation with the Principal Investigator. This 
will be based on data obtained in Part A, which includes but is not restricted to equivocal 
myocardial uptake of 89Zr-GSK2398852 in all subjects treated in Part A. This decision will 
also be contingent based on emerging data from the concurrent Phase 2 trial (Study 
Number 201464). Should Part B not be triggered, then the study will conclude with Part A.
Dosing

Details of the administration of CPHPC is provided in the protocol Section 5.4

Details of the administration and dosing or Anti-SAP Treatment and 89Zr-GSK2398852 
is provided in the protocol Section 5.6 & Section 5.13
Time & 
Events

Details of the Schedule of Activities can be found in Appendix 2, Section 12.2
Treatment 
Assignment
This is an open-label, non-randomised, adaptive, dose-ranging study.
Interim 
Analysis
There are two types of interim analysis planned in this study:

In-stream data reviews: Data will be reviewed on an ongoing basis throughout the 
study (including, but not limited to: safety, imaging (PET), PK data) to make decisions 
on: (i) intra (i.e. subsequent dose administered within a given subject) and inter (i.e. 
dose administered in a separate subject) mass dose levels; and (ii) the timing of PET 
scan.

Interim analysis at the end of Part A: once the last subject in Part A has completed 
their final dosing session, a formal review of all available safety data (including AEs, 
clinical laboratory data, vital signs, ECGs), PK, PET imaging data will be conducted 
before deciding whether to trigger Part B.
2.5.
Statistical Analyses
This is an exploratory study where the primary objective is to assess cardiac uptake of 
89Zr-GSK2398852 evaluated by PET imaging at different mass doses. No formal 
hypotheses will be tested as part of this study.
All generated PET imaging endpoints (e.g., SUVpeak, SUVmean, SUVtotal_organ etc.) 
over time will be listed to identify the potential for cardiac uptake of 89Zr-GSK2398852 
in ATTR-CM patients.
2.6.
Sample Size Considerations
At the time of writing no empirical data was available to offer a suitable estimate for the 
expected between subject variability; therefore, the sample size has been determined 
primarily by feasibility.


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A total of 6 subjects are expected to complete up to two dosing sessions. The study is 
split into two parts:

in Part A up to 3 subjects will participate in up to two anti-SAP dosing sessions

in Part B up to 3 subjects will participate in one anti-SAP dosing session.
Data will be reviewed in-stream with a view to inform subsequent unlabelled anti-SAP 
mAb mass dose levels.
No sample size re-estimation is planned for this study; however, at the interim (i.e. at 
completion of Part A) the team may decide to stop the study early and not recruit any 
subjects into Part B.


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
Decision making for the development programme is time critical and therefore there are 
two types of interim analysis planned in this study:

In-stream data review(s): Data will be reviewed on an ongoing basis throughout 
the study (including, but not limited to: safety, imaging (PET), PK data). Any
emergent PET imaging data from the current study will be complementary to the 
ongoing phase II study (Study Number 201464) and its associated interim(s), as 
well as the broader Anti-SAP program. In addition, during the current study, team 
review of listings of accruing uncleaned study data (provided directly by Data 
Management or obtained from site) may trigger changes being made to a number 
of design parameters, including: (i) subsequent dose levels for the same or future 
subjects; and (ii) the timing of PET scan, all based on the emerging data. The 
foreseen primary parameters for this in-stream review is anticipated to be cardiac 
SUV values plus plasma radio-PK in relation to administered mass dose.

Interim analysis at the end of Part A: once the last subject in Part A has 
completed their final dosing session, a formal review of all available safety data 
(including AEs, clinical laboratory data, vital signs, ECGs), PK, PET imaging 
data will be conducted before deciding whether to trigger Part B. Study data 
included as part of this interim will be cleaned prior to analysis.
Details for end of Part A interim include

Plots of individual profiles, listings and tabulated descriptive statistics where 
appropriate for: blood pressure, heart rate, AEs, clinical chemistry, hematology, 
urinalysis, cardiac monitoring, NT-ProBNP, Troponin T, serum Creatinine, eGFR

Listings of PET imaging parameters

Plots of plasma concentration of GSK2398852, for radioactive assays, versus 
time.
3.2.
Final Analyses
The final planned primary analyses (which will comprise both Part A and the optional 
Part B together) will be performed after the completion of the following sequential steps:
1.
All participants have completed the study as defined in the protocol (which may or 
may not include participants from Part B following the decision as to whether to 
trigger Part B based on the interim analysis at the end of Part A).
2.
All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management.
3.
The study has a non-randomised open label design, however, for internal study 
reporting, subjects will be assigned randomisation numbers. Therefore, the formal 
process for unblinding the randomization codes will need to be also met.
4.
Randomization codes have been distributed according to RandAll NG procedures.


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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)
All Treated
All subjects who receive at least one Anti-SAP treatment 
including 89Zr-GSK2398852
PET
Safety1
All subjects who receive at least one dose of GSK2315698, 
GSK2398852, or 89Zr-GSK2398852.  As all patients who 
receive GSK2398852, or 89Zr-GSK2398852 will also have 
received GSK2315698 (as mandated by the protocol), this 
definition is equivalent to all subjects who received at least 
one dose of GSK2315698
Study Population
Safety
PD/Biomarkers
Pharmacokinetic 
(PK)
All subjects from the All Treated Population for whom a PK 
sample is obtained and analysed
PK
Refer to Appendix 9: List of Data Displays which details the population used for each display.
Notes
[1] Population identified separate from “All Treated” as described in protocol. Here exposure to any administered GSK 
compound warrants belonging to the “Safety” population
4.1.
Protocol Deviations
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient 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.

Data will be reviewed prior to the DBF (database freeze) milestone for each study 
part (Part A and Part B) to ensure all important deviations are captured and 
categorised on the protocol deviations dataset. 

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.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Other Considerations for Data Analyses and Data Handling 
Conventions
The table below provides an overview of appendices within the RAP for outlining 
general considerations for data analyses and data handling conventions:
Section
Component
12.3
Appendix 3: Study Phases and Treatment Emergent Adverse Events
12.4
Appendix 4: Data Display Standards & Handling Conventions
12.5
Appendix 5: Derived and Transformed Data
12.6
Appendix 6: Reporting Standards for Missing Data
12.7
Appendix 7: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population 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.
Table 1 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 9: List of Data Displays.
Table 1
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 Discontinuation of Study Treatment
Y
Y
Number of Participant
Y
Reasons for Withdrawals
Y
Study Population
Study Populations
Y
Participants Excluded from any Population
Y
Protocol Deviations
Important Protocol Deviations
Y
Y
Inclusion and Exclusion Criteria Deviations
Y
Demography
Demography Characteristics
Y
Y
Age Ranges
Y
Race and Racial Combinations
Y
Y
Concomitant Medications
Concomitant Medication
Y
Y
Past Medical Conditions
Y
Y
Current Medical Conditions
Y
Y
Exposure
Exposure to Total anti-SAP mAb*
Y
Y
Exposure to GSK2315698
Y
Y
NOTES :
Y = Yes display generated.
*Total Mass Dose (TMD) of anti-SAP mAb = unlabelled anti-SAP mAb + 89Zr-GSK2398852.


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7.
PRIMARY STATISTICIAL ANALYSES
7.1.
Primary Analyses
7.1.1.
Endpoint / Variables

Standardized Uptake Values (SUV) [i.e. Radioactivity concentrations] in focal 
anatomical locations within the heart, as well as SUV of the whole heart at different 
time points after 89Zr-GSK2398852 administration and at different anti-SAP mAb 
TMDs.
7.1.2.
Summary Measure
Data will be listed according to the GSK reporting standards, where applicable. All PET 
imaging parameters will be listed. Individual subject plots for the PET imaging 
parameters will also be produced. 
Note that, in any one subject in Part A, where the radiolabel PK and cardiac SUV profile 
of 89Zr-GSK2398852 is consistent with myocardial uptake during either the 1st or 2nd 
dosing session (i.e. cardiac / plasma SUV ratio ≥0.5), the reproducibility of this specific
unlabelled anti-SAP mAb dose in enabling myocardial uptake of 89Zr-GSK2398852 may
be evaluated by treating further subjects with the same unlabelled anti-SAP mAb mass
dose.
7.1.3.
Population of Interest 
The analyses in this section will be based on the “All Treated” population, unless 
otherwise specified.
7.1.4.
Statistical Analyses / Methods
Table 2 provides an overview of the planned primary analyses, with full details of data 
displays being presented in Appendix 9: List of Data Displays which will be based on
GSK data standards and statistical principles.
Table 2
Overview of Planned Primary Analyses
Endpoint / Parameter / Display Type
Absolute
Summary
Individual
T
F
F
L
PET (cardiac images)
For the whole heart: SUVmean and volume
For each cardiac focal anatomical location:  SUVpeak over the 
entire 20-minute scan period, and volume 
Y1
Y
NOTES :
[1] Figures will be restricted to SUVmean values and SUVpeak values over the entire 20-minute scan period.
T = Table, F = Figure, L = Listing, Y = Yes display generated.


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7.2.
Secondary Analyses
7.2.1.
Endpoint / Variables
Focal and total radioactivity uptake (including, but not limited to SUV) in different 
tissues (including potentially at those peripheral tissue sites where transthyretin 
amyloidosis (TTR) amyloid deposition can be clinically occult) at different time points 
and after different TMDs. 
7.2.2.
Summary Measure
Data will be listed according to the GSK reporting standards, where applicable. All PET 
imaging parameters will be listed
7.2.3.
Population of Interest 
The analyses in this section will be based on the “All Treated” population, unless 
otherwise specified.
7.2.4.
Statistical Analyses / Methods
Table 3 provides an overview of the planned secondary analyses, with full details of data 
displays being presented in Appendix 9: List of Data Displays which will be based on
GSK data standards and statistical principles.
Table 3
Overview of Planned Secondary Analyses
Endpoint / Parameter / Display Type
Absolute
Summary
Individual
T
F
F
L
PET (non-cardiac images)
For each organ/ tissue: SUVmean and volume
Y1
Y
NOTES :
[1] Figure will be restricted to SUVmean values.
T = Table, F = Figure, L = Listing, Y = Yes display generated.


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8.
SAFETY ANALYSES
The safety analyses will be based on the Safety population, unless otherwise specified. 
Analyses detailed in this section will be performed on data from each study part 
separately.
Table 4 provides an overview of the planned safety analyses, with full details of data 
displays being presented in Appendix 9: List of Data Displays.
Table 4
Overview of Planned Adverse Events Analyses
Endpoint / Parameter / Display Type
Absolute
Summary
Individual
T
L
Adverse Events (AEs)
All AEs by System Organ Class (SOC) and Preferred Term (PT)
Y
Y
Common (≥5%) Adverse Events by Overall Frequency
Y
Common (≥5%) Grade 2-4 Adverse Events by Overall Frequency
Y
Drug-Related AEs by SOC and PT 
Y
Common (≥5%)   Non-Serious AEs by SOC and PT (Subjects & No. of 
Occurrences)
Y
Common (≥5%) Drug Related Grade 2-4 Adverse Events by SOC and PT
Y
Subject Numbers for Individual AEs
Y
Relationship Between Adverse Event System Organ Classes, Preferred Terms, 
and Verbatim Text
Y
Serious and Other Significant AEs
Fatal Serious AEs
Y
Non-Fatal Serious AEs
Y
Reasons for Considering as a Serious AE
Y
Serious AEs by SOC and PT (Subjects & No. of Occurrences)
Y
AEs Related to Treatments other than the Study Drug
Y
AEs Leading to Withdrawal from Study / Permanent Discontinuation of Study 
Treatment by SOC and PT
Y
Y
Temporally-Associated, Potential mAb-Related Infusion Events1
Y
Anti-SAP mAb Infusion Related Reactions1
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] Further details provided in Section 8.2


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8.1.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 9: List of Data Displays. Tables will present 
AEs in the treatment phase.  Listings will present all AEs
8.2.
Adverse Events of Special Interest (AESI) Analyses
The following categories of AESIs associated with GSK2398852 have been identified to 
date:
- Rash, Rash AESI will be identified based on the eCRF rash question and flagged in the 
general AE listing.
- Anti-SAP mAb Infusion-related reaction (IRR).
The identification of anti-SAP mAb IRR will follow a two-step process.
Step 1
A listing of temporally-associated, potential mAb-related infusion events (TPMI) will be 
produced. 
TPMIs will only include AEs that correspond to the following list of preferred terms:

“Headache”, “Flushing”, “Feeling hot”, “Feeling cold”, “Chest discomfort”, 
“Chills”, “Face oedema”, “Oedema peripheral”, “Orbital oedema”, “Nausea”, 
“Vomiting”, “Diarrhoea”, “Fatigue”, “Tachycardia”, “Presyncope”, “Infusion 
related reaction”.
In addition, TPMIs will be restricted to AEs that occurred during the mAb infusion or 
within 24 hours of the end of the mAb infusion. If the AE start time is missing, the AE 
will be included as TPMI if the AE start date is the same as the mAb infusion start date or 
end date (either dates if not the same), or if the AE start date is the next day after the end 
of the mAb infusion. 
Step 2
This initial selection of AEs will be manually reviewed by the clinical team to identify 
the subset of TPMI events that qualify as IRR.
As a result, a listing of IRR (only including AEs flagged by this clinical review) will be 
displayed. If there is no AE identified as IRR as part of the clinical review, this listing 
will not be produced.
The details of the planned displays are provided in Appendix 9: List of Data Displays.


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8.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, Hematology 
laboratory tests, Urinalysis, and liver function tests will be based on GSK Core Data 
Standards.
Table 5 provides an overview of the planned clinical laboratory analyses, with full details 
of data displays being presented in Appendix 9: List of Data Displays.
Table 5
Overview of Clinical Laboratory Analyses
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F
L
Chemistry
Chemistry Changes from Baseline
Y
Chemistry Shifts from Baseline Relative to Normal Range
Y
Hematology
Hematology Changes from Baseline
Y
Clinically-Relevant Changes in Haemoglobin
Y
Hematology Shifts from Baseline Relative to Normal Range
Y
Urinalysis
Urinalysis Changes from Baseline
Y
Urinalysis Parameters Shifts from Baseline Relative to Normal Range
Y
All Laboratory
All Laboratory Data for Subjects with any Value of PCI
Y
Laboratory Values of PCI
Y
Laboratory Data with Character Results
Y
Liver Monitoring/Stopping Event Reporting
Y
Medical Conditions for Participants with Liver Stopping Events
Y
Substance Use for Participants with Liver Stopping Events
Y
Hepatobiliary Laboratory Abnormalities
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.


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8.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. 
Table 6 provides an overview of the planned other safety analyses, with full details of 
data displays being presented in Appendix 9: List of Data Displays.
Table 6
Overview of Other Safety Analyses
Endpoint / Parameter/ Display Type
Absolute
Summary
Individual
T
F[1]
L
ECG
ECG Findings
Y
All ECG Values for Subjects with any Value of PCI
Y
ECG Values of PCI
Y
Abnormal ECG Findings
Y
Maximum QTc Values Post-Baseline Relative to Baseline by Category
Y
Change from Baseline in ECG Values by Visit
Y
Maximum Increase in QTc Values Post-Baseline Relative to Baseline by 
Category
Y
Echocardiogram and Cardiac Monitoring [2]
Cardiac Telemetry
Y
Vital Signs
Change from Baseline in Vital Signs
Y 
Y
All Vital Signs for Subjects with any Value 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.


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9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
The analyses in this section will be based on the “Pharmacokinetic (PK)” population, 
unless otherwise specified. Data will be listed and summarized according to the GSK 
reporting standards, where applicable. Table 7 provides an overview of the planned PK 
analyses, with full details of data displays being presented in Appendix 9: List of Data 
Displays.
Table 7
Overview of Planned Pharmocokinetic Analyses
Endpoints
Absolute
Summary
Individual
T
F
F
L
PK
Total mAb
Y
Y
Y
Y
89Zr-GSK2398852
Y
Y
Y
Y
NOTES :
T = Table, F = Figure, L = Listing, Y = Yes display generated.
9.1.1.
Endpoint / Variables
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin. All calculations of non-compartmental parameters will be based on actual 
sampling times. Pharmacokinetic parameters listed will be determined from the plasma 
concentration-time data of both GSK2398852 and 89Zr-GSK2398852, as data permits.
Parameter
Parameter Description
Cmax
Maximum observed concentration
Tmax
Time of first observation of maximum concentration
AUCt
Area under the concentration time course till last observation
T1/2
Terminal phase half life
AUCinf
Area under the concentration time course till time infinity
NOTES:

Additional parameters may be included as required.


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9.1.2.
Population of Interest 
The pharmacokinetic analyses will be based on the “Pharmacokinetic (PK)” population, 
unless otherwise specified.
9.1.3.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 9: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. No formal statistical models will be fit as part of the PK analysis.
Plasma concentrations of Total mAb, which is the total of both 89Zr-labelled and 
unlabelled mAb, will be analysed using non-compartmental methods. PK parameters will
be summarised by TMD. 
Plasma radioactive concentration - measured by scintillation counter, corrected by
radioactivity decay and expressed in molar concentration of the mAb - will be analysed
by non-compartmental methods. This radioactive concentration will reflect the total of
both labelled-mAb and its metabolites. PK parameters will be summarised by TMD,
with/without stratification by treatment period.
For each anatomical region defined in the heart, the PET scans will generate up to 3 
values on tissue radioactivity concentration (SUV), and the plasma radio-PK values will 
function as a marker of plasma clearance. The mechanistic model will probe the 
combination of tissue SUV and radio-PK as compatible with contributions by a vascular 
component, a free distribution to interstitium and a component related to tracer bound to 
amyloid-SAP complexes. The extracted parameters will be summarised for each subject 
and each mass dose.


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10.
PHARMACODYNAMIC AND BIOMARKER ANALYSES
The analyses in this section will be based on the “Safety” population, unless otherwise 
specified. Data will be listed and summarized according to the GSK reporting standards, 
where applicable. Table 8 provides an overview of the planned PD analyses, with full 
details of data displays being presented in Appendix 9: List of Data Displays.
Table 8
Overview of Planned Pharmacodynamic Analyses
Endpoints
Absolute
Summary
Individual
T
F
F
L
Cardiac biomarker
Troponin T, NT-ProBNP
Y
Plasma SAP Concentration
Y
NOTES :
T = Table, F = Figure, L = Listing, Y = Yes display generated.


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11.
REFERENCES
Not Applicable


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12.
APPENDICES
12.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
12.1.1.
Exclusions from Per Protocol Population
There is no per protocol population defined for this study.


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12.2.
Appendix 2: Schedule of Activities
12.2.1.
Protocol Defined Schedule of Events
Table 9
Part A and Part B Overview
Dosing Session 1
Dosing Session 2
Part A
X
X
Part B
X
Table 10
Overview All Groups 
Dosing Sessions 1 and 2
Screening1
Baseline2
Day 1: pre- dose
Day 1
Day 2
Day 3: pre-dose mAb
Day 3: anti-SAP mAb dosing 
Day 3: end of mAb infusion18
Day 3: 4 hours post end mAb infusion18
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 11-18
Day 2018
Day 2616, 18
Inpatient stay at unit
-------------------------------------------------------- X ---------------------------------
Discharge from 
inpatient
X
Outpatient visit
X
X
X
Remote Contact for 
Safety Assessment
X
Informed consent
X
Medical history/risk 
factors/demographics
X
Inclusion/exclusion 
criteria
X
Safety Assessments
Physical examination3
X
X
X
X
X
X
X
Adverse event (AE)/ 
serious adverse event 
(SAE) Assessment
------------------------------------------------------- X -------------------------------------------------------
Concomitant 
Medications
------------------------------------------------- X -------------------------------------------------------
12-lead 
electrocardiogram 
(ECG)
X
13
X
13
X
X
X
X
X
X
X
X
X
X
X
X 
21
X
Continuous Lead II 
Telemetry20
-------------------------------------------------------- X ------------------------------------


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Dosing Sessions 1 and 2
Screening1
Baseline2
Day 1: pre- dose
Day 1
Day 2
Day 3: pre-dose mAb
Day 3: anti-SAP mAb dosing 
Day 3: end of mAb infusion18
Day 3: 4 hours post end mAb infusion18
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 11-18
Day 2018
Day 2616, 18
Remote Continuous 
Cardiac Monitoring4
X
X
X
Vital signs
X
13
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
21
X
Screening Laboratory 
Assessments5
X
Haem/clin chem/ 
urinalysis
X
X
X
X
X
X
X
Troponin T/ N-terminal 
prohormone of brain 
natriuretic peptide (NT-
ProBNP)
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
X
15
X
15
Investigational medicinal product (IMP) Administration
Carboxy pyrrolidine 
hexanoyl pyrrolidine 
carboxylate (CPHPC) 
IV
---  X10  ---
CPHPC SC12
X
11
X
X
X
X
X
X
X
X
Premedication 
(hydrocortisone/anti-
histamine)
X
Unlabelled anti-SAP 
mAb
X
7
89Zr-GSK2398852
X
7
Pharmacokinetics 
(PK)/SAP9
Blood sampling for 
plasma SAP
X
X
6
Anti-SAP mAb PK17
X
X
X
X
X
X
X
89Zr-GSK2398852 
radio-PK (for 
scintillation)14
X
X
X
X
X
X


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Dosing Sessions 1 and 2
Screening1
Baseline2
Day 1: pre- dose
Day 1
Day 2
Day 3: pre-dose mAb
Day 3: anti-SAP mAb dosing 
Day 3: end of mAb infusion18
Day 3: 4 hours post end mAb infusion18
Day 4
Day 5
Day 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 11-18
Day 2018
Day 2616, 18
Imaging Procedures
Cardiac Magnetic 
Resonance Imaging 
(MRI) with contrast
X
Echocardiogram 
(ECHO)
X
Pittsburgh Compound 
B (PIB) Positron 
Emission Tomography 
(PET)
X
15-Oxygen labelled 
water (WAT PET)
X
X
8
89Zr-GSK2398852 PET 
/ Computerised 
Tomography (CT)
X
9
X
9 
X
9, 
19
Note: If anti-SAP mAb dosing is delayed by one day, then Day 2 assessments should be repeated, 
and all subsequent assessments should be delayed by one day.
Footnotes:
1.
Screening to take place within 35 days of start of Anti-SAP treatment.
2.
Baseline will be any time after eligibility confirmed and before Anti-SAP treatment starts. Procedures may be 
done on different days.
3.
Full examination at screening only, brief examination at all other time-points.
4.
Out-patient cardiac recording (see Protocol Section 3.4.1.3): Baseline for approximately 1 week, and from 
Day 11 for approximately 1 week after discharge.
5.
See Other Screening Tests in Protocol Appendix 2
6.
Requires rapid turnaround. See Protocol Section 5.5
7.
See Protocol Section 5.6 for timing of administration of unlabelled anti-SAP mAb and 89Zr-GSK2398852.
8.
Dosing Session 2 only, if logistically feasible. Can be done any day/time prior to anti-SAP mAb.
9.
Exact timing in relation to end of 89Zr-GSK2398852 infusion will change based on emerging data. See 
Protocol Section 5.3.1 
10. CPHPC IV infusion for a minimum of approximately 48 hours. To be stopped prior to mAb infusion.
11. First SC dose to be administered approximately 5 hours after end of IV CPHPC infusion. 
12. Administered three times daily. See Protocol Section 7.1 and Section 7.2
13. In triplicate.
14. See Protocol Table 5 
15. Female Subjects Only.
16. The last visit of the final study session will be considered the final follow-up visit. This may be conducted in-
person, or by “virtual visit”.
17. See Protocol Table 4for sampling times and windows.


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18. See Protocol Table 3for allowable time/visit windows.
19. Third 89Zr PET-CT to be done in first two subjects who complete Part A, only. Subsequent subjects to 
undergo only two 89Zr PET-CT scans.
20. From Day 6 onward, at investigator discretion, inpatient cardiac monitoring can be performed via remote 
cardiac telemetry device (e.g. BodyGuardian® device)
21. If logistically possible.
Table 11
Allowable Assessment/Visit Windows 
Day 3: End 
mAb Infusion
Day 3: 4 hours 
post end-mAb 
infusion
Day 20
Day 26
Window
+10 minutes
±10 minutes
±1 day
±2 days
Table 12
Unlabelled anti-SAP mAb PK Sampling (Dosing Sessions 1 and 2)
Pre anti-
SAP 
mAb 
infusion
Halfway 
through 
infusion 
End of 
unlabelled 
anti-SAP 
mAb 
infusion 
7 hours 
post end 
of anti-
SAP 
mAb 
infusion
24 hours 
after end 
of 
infusion 
(Day 4)
48 hours 
after end 
of 
infusion 
(Day 5)
72 hours 
after end 
of 
infusion 
(Day 6)
96 hours 
after end 
of 
infusion 
(Day 7)
Anti-SAP 
mAb PK
X
X
X
X
X
X
X
X
Time 
window
±10 
minutes
+10 
minutes
±30 
minutes
±1 hour
±2 hours
±2 hours
±2 hours
Note: Up to three additional samples may be collected and sampling times may be modified based on emerging data. 
Table 13
89Zr-GSK2398852 Radio-PK Sampling (Dosing Sessions 1 and 2)
Time after 89Zr-GSK2398852 infusion end
10 
minutes
60 
minutes
4 hours
7 hours
24 hours
(Day 4)
48 hours
(Day 5)
72 hours
(Day 6)
89Zr-GSK2398852 
radio-PK (for 
scintillation)
X
X
X
X
X
X
X
Time Window
± 5 
minutes
± 10 
minutes
± 1 hour
± 2 hours
± 4 hours
± 4 hours
± 4 hours
Note: Up to three additional samples may be collected and sampling times may be modified based on emerging data. 
Time windows are for guidance; non-adherence to these times will not constitute a protocol deviation.


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12.3.
Appendix 3: Study Phases and Treatment Emergent 
Adverse Events
12.3.1.
Treatment Phases
Treatment phases are defined for the purpose of AE summaries and listings. 
AEs will be assigned to pre-treatment, on-treatment, and post-treatment phases according 
to the date/time of occurrence relative to Dates/Times of First and Last Doses of Study 
Drug.
Treatment Phase
Definition
Pre-Treatment 
Date/Time of AE < First Dose Date/Time of Study Drug1
On-Treatment
First Dose Date/Time of Study Drug1 ≤ Date/Time of AE ≤ Last Dose Date/Time of 
Study Drug2 + 56 Days
Post-Treatment
Date/Time of AE> Last Dose Date/Time of Study Drug2 + 56 Days
1Earliest dose of GSK2315698 or GSK2398852 or 89Zr-GSK2398852 in the study
2Latest dose of GSK2315698 or GSK2398852 or 89Zr-GSK2398852 in the study
Unless stated otherwise, AE summaries will only include AEs assigned to the on-
treatment phase. All AE listings will include treatment phase assignment.
12.3.2.
Treatment Sessions
Treatment sessions are defined for the purpose of AE listings.
AEs 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.
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 2 Last 
Dose Date/Time of Study Drug2 + 56 Days 
1Earliest treatment session dose of GSK2315698 or GSK2398852 or 89 Zr-GSK2398852
2Latest treatment session dose of GSK2315698 or GSK2398852 or 89Zr-GSK2398852


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12.3.3.
AE Onset Time and Duration
The following AE onset times and duration will be included in all AE listings.
Definition
AE 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 subject is not exposed to any study drug
AE 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
AE 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 (labelled or unlabelled) First Dose Date
If Session mAb First Dose Date/Time of study drug ≤ AE 
Onset Date/Time, Onset Day = AE Onset Date – Session 
mAb (labelled or unlabelled) 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 or 89Zr-GSK2398852
in the study


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12.4.
Appendix 4: Data Display Standards & Handling 
Conventions
12.4.1.
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 (labelled or unlabelled). 
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 12.4.1 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.
12.4.2.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: uk1salx00175
HARP Compound
: \arprod\gsk2398852\mid204512\final
Analysis Datasets 

Analysis datasets will be created according to CDISC standards.
Generation of RTF Files

RTF files will be generated for all the tables


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12.4.3.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

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, unless otherwise stated.

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:

Planned time relative to dosing will be used in summary figures, summaries, statistical analyses 
and calculation of any derived parameters.

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.

Actual times relative to the first study dose of anti-SAP treatment (CPHPC or labelled mAb or 
unlabelled mAb) will be used in individual subject plots

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing (first dose of either GSK2315698 or anti-
SAP mAb (labelled and unlabelled)) 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. Post-baseline 
unscheduled visits will not be included in summary tables, with the exception of the following 
summaries: Summary of Hematology/Chemistry/ Urinalysis Shifts from Baseline Relative to 
normal range (worst case post baseline). Summary of Haemoglobin Change from Baseline 
Relative to Clinical Importance Range, Summary of Maximum QTc Values Post-Baseline Relative 
to Baseline by Category, Summary of Maximum Increase in QTc Values Post-Baseline Relative to 
Baseline by Category, Summary of hepatobiliary laboratory abnormalities, Summary of ECG 
findings.

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, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


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12.4.4.
Appendix 4A: Additional Endpoint Information
All the PET imaging variables are derived by the PET imaging centre and not the 
responsibility of S&P.
12.4.5.
Evaluation of PET Images
The acquired PET information is reconstructed into PET images with due corrections for 
attenuation, scattered radiation, etc.
The PET images are visually reviewed to identify the general features of body distribution and 
especially anatomical localization in the heart.
Regions of Interest (RoI) are outlined in the images to define radioactivity distribution.
All organ and blood analyses are expressed as SUV (Measured radioactivity concentration 
corrected for radioactive decay and normalized for administered amount of radioactivity per body 
weight).
Depending on organ and selection of tissue components, SUV may have different definitions.
Local tissue radioactivity concentration in organs in Regions of Interest (RoI)
SUVpeak:
A small sphere of 10-12 mm diameter placed in a representative location as seen in the image or 
transferred from the CT scan. Average of voxel (picture element) values within this volume is 
calculated.
SUVmean:
A larger outline of the whole organ or representative area or volume as seen in the image or 
transferred from the CT scan. Average voxel values (picture elements) within this volume is 
calculated.
Total organ radioactivity amount in Regions of Interest (RoI)
SUVtotal_organ:
An outline of the whole volume of the organ attempting to capture the total amount of radioactivity 
in that organ, as defined in the PET images or transferred from CT scan. Average of voxel (picture 
element) values within this volume is calculated.
VOLUMEtotal_organ:
Corresponding total volume of the organs above.
The SUVtotal_organ and VOLUMEtotal_organ are used for calculation of fraction of administered 
dose in that organ.


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The organs/tissues of interest for analysis include:
Local tissue radioactivity concentration in organs in Regions of Interest (RoI)
Where relevant and depending on radioactivity uptake pattern:
•
A minimum of 5 anatomical positions within the heart (only in the specific heart scans)
•
Up to 3 focal and 1 larger location in each of the lungs
•
Up to 3 focal and 1 larger location in the liver
•
One focal and one large area in spleen
•
One focal and one large area in pancreas
•
One cortex and one medulla focal area in each of the kidneys
•
One large area in one thigh muscle
•
Up to 5 small areas of the skin
Other focal or larger areas may be included depending on features in the images.
For the regions in the 4*5 scans focused over the heart, separate and average values will be 
generated for each of the RoIs.
Total organ radioactivity amount in Regions of Interest (RoI)
•
Heart
•
Liver
•
Spleen
•
One lung
•
Each kidney
Other organs may be included depending on features in the images.
Analysis of PET Data
The tissue SUV and plasma radio-PK values generated will constitute the primary information from 
the studies. Since plasma radio-PK will be dependent upon time after administration plus mass 
dose, it will be necessary to relate the tissue SUV to the instant and possibly also to the AUC of the 
plasma radio-PK.
It is expected that the tissue-to-plasma ratio of the mAb in the heart will be approximately 0.1-0.2 
after equilibration between plasma and tissue interstitium. This is guided by an expected plasma 


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space plus interstitium relative space of 0.1-0.2. Within the blood pool of the heart chambers the 
ratio is expected to be 0.5 (hematocrit about 0.5).
We have placed a limit by which the tissue-to-plasma ratio in the cardiac muscle is indicative of 
entry to the interstitium and binding to amyloid-SAP complexes at 0.5 in balance between a 
sufficient increase as compared to passive distribution and avoidance of “spill-over” from cardiac 
blood pools.
More complex models of distribution between plasma and tissue may be explored.
Storage and potential further analyses of images
The primary PET and CT images in digital form will be anonymized and stored in an image 
repository under the control of GSK and may be used for further analyses.
12.5.
Appendix 5: Derived and Transformed Data
12.5.1.
General
Multiple Measurements at One Analysis 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

Calculated as the number of days from the first study dose of aSAP treatment (GSK2315698 or 
labelled mAb or unlabelled mAb):

Ref Date or Study Dose Date = Missing                         → Study Day = Missing 

Ref Date < aSAP treatment first study Dose Date   → Study Day = Ref Date – aSAP 
treatment First Study Dose Date    

Ref Data ≥ aSAP treatment first study dose date Dose Date   → Study Day = Ref Date –
(aSAP treatment First Study Dose Date) + 1    
12.5.2.
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
Calculated as Weight (kg) / [Height (m)2]


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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 
administered in each dosing session and over the study as a whole.

Number of days of exposure to total anti-SAP mAb will be calculated as the number of doses 
administered.  

The cumulative dose of total aSAP mAb will be calculated from the sum of the individual doses 
administered (over all dosing sessions).
12.5.3.
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 : 
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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12.5.4.
Triplicate ECG and Vital Sign measurements
ECG measurements are performed in triplicate at Screening and at the Day 1 Pre-dose 
timepoint of each dosing session. Vital signs are performed in triplicate at screening. The 
average of the triplicate measurements will be used for all summary tables, whereas 
individual measurements will be displayed in figures and listings.  As a consequence, the 
average of the 3 Session 1 Day 1 Pre-dose measurements will be used as the baseline 
value for ECG summary tables.  In case of missing Session 1 Day 1 Pre-dose ECG 
measurement, the average of the 3 Screening values will be used as the baseline value 
instead.


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12.6.
Appendix 6: Reporting Standards for Missing Data
12.6.1.
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.
12.6.2.
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 participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
Handling of Missing and 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 anti-SAP 
mAb (labelled or unlabelled)); in this case the study treatment start date will 
be used and hence the event is considered On-treatment as per Appendix 
3: 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 3: 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 
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 


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Element
Reporting Detail
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.
o
If the entire date is missing it is assumed that the concomitant medication occurred 
in all phases.

The recorded partial date will be displayed in listings.


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12.7.
Appendix 7: Values of Potential Clinical Importance
12.7.1.
Haematology Values of Potential Clinical Importance
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
12.7.2.
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
Magnesium (mmol/L)
0.50
1.20
Potassium (mmol/L)
0.77
1.17
Sodium (mmol/L)
0.92
1.07
Creatinine (mmol/L)
1.6
12.7.3.
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


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12.7.4.
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
12.7.5.
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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12.8.
Appendix 8: Abbreviations & Trade Marks
12.8.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DBF
Database Freeze
DBR
Database Release
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
EMA
European Medicines Agency
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GSK
GlaxoSmithKline
IA
Interim Analysis
ICH
International Conference on Harmonization
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
PopPK
Population PK
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
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDSP
Study Data Standardization Plan


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Abbreviation
Description
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
12.8.2.
Trademarks
Trademarks of the 
GlaxoSmithKline Group of 
Companies
Trademarks not owned by 
the GlaxoSmithKline 
Group of Companies
NONE
[WinNonlin]
[SAS]


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12.9.
Appendix 9: List of Data Displays
12.9.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.14
NA
PD
NA
2.1 to 2.2
Safety
3.1 to 3.22
3.1 to 3.1
Pharmacokinetic
4.1 to 4.5
4.1 to 4.6
Section
Listings
ICH Listings
1 to 31
Other Listings
32 to 41
12.9.2.
Data Display Format
For all summaries PART A, Part B and Part A+B will be summarised as separate column 
headers. If Part B does not occur, then only PART A will be summarised, and the column 
header will be “Anti-SAP”.
For listings and figures the Part will be displayed only if PART A and PART B occur.
12.9.3.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 10: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
PD
PD_Fn
PD_Tn
PD_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
12.9.4.
Deliverables
Delivery [Priority] [1]
Description
IA SAC
Interim Analysis Statistical Analysis Complete
SAC
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


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12.9.5.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
Safety
ES1
Summary of Participant Disposition for the Participant
Conclusion Record
IA, SAC
1.2.
Safety
SD1
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment
IA, SAC
1.3.
Screened
ES6
Summary of Screening Status and Reasons for Screen Failure
IA, SAC
1.4.
Enrolled
NS1
Summary of Number of Participant
IA, SAC
Protocol Deviation
1.5.
Safety
DV1
Summary of Important Protocol Deviations
SAC
Population Analysed
1.6.
Screened
SP1
Summary of Study Populations 
SAC
Demographic and Baseline Characteristics
1.7.
Safety
DM1
Summary of Demographic Characteristics
Please include BMI in this table.
SAC
1.8.
Enrolled
DM11
Summary of Age Ranges
SAC
1.9.
Safety
DM5
Summary of Race and Racial Combinations
SAC
Prior and Concomitant Medications and Medical Conditions
1.10.
Safety
CM1
Summary of Concomitant Medications
All medications that are collected will be 
included in this table.
SAC
1.11.
Safety
MH1
Summary of Past Medical Conditions
SAC
1.12.
Safety
MH1
Summary of Current Medical Conditions
SAC
Exposure and Treatment Compliance


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Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
1.13
Safety
POP_T1
Summary of Exposure to Study Treatment (CPHPC)
Display overall and by treatment 
session
SAC
1.14
Safety
POP_T1
Summary of Exposure to Study Treatment (anti-SAP mAb
(unlabelled and labelled))
Display overall and by treatment 
session
SAC
12.9.6.
PD Figures
PET Figures
No.
Population
IDSL /  
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.1.
All Treated
PD_F1
Individual Subject Plot: SUVpeak Over Time for Cardiac Focal 
Anatomical Locations
Display by page for different cardiac 
focal anatomical locations
Panel by subject and dosing session
X axis: Actual time (days)
Y axis: SUVpeak
IA, SAC
2.2.
All Treated
PD_F1
Individual Subject Plot: SUVmean Over Time for Each Organ/ 
Tissue
Display by page for different organs/ 
tissues
Panel by subject and dosing session
X axis: Actual time (days)
Y axis: SUVmean
IA, SAC


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12.9.7.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
Safety
AE1
Summary of All Adverse Events by System Organ Class and 
Preferred Term - On-treatment
IA, SAC
3.2.
Safety
AE3
Summary of Common (>=5%) Adverse Events by Overall 
Frequency – On-treatment
IA, SAC
3.3.
Safety
AE3
Summary of Common (>=5%) Grade 2-4 Adverse Events by 
Overall Frequency – On-treatment
IA, SAC
3.4.
Safety
AE1
Summary All Drug-Related Adverse Events by System Organ 
Class and Preferred Term/by Overall Frequency – On-treatment
IA, SAC
3.5.
Safety
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences) – On-treatment
IA, SAC
3.6.
Safety
AE3
Summary of Common (>=5%) Drug-Related Grade 2-4 Adverse 
Events by Overall Frequency – On-treatment
IA, SAC
Serious and Other Significant Adverse Events
3.7.
Safety
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences) –
On-treatment
IA, SAC
3.8.
Safety
AE1
Summary of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment or Withdrawal from Study by 
System Organ Class and Preferred Term – On-treatment
IA, SAC
Laboratory: Chemistry 
3.9.
Safety
LB1
Summary of Chemistry Changes from Baseline 
IA, SAC
3.10.
Safety
LB4
Summary of Chemistry Shifts from Baseline Relative to Normal 
Range
IA, SAC


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Hematology
3.11.
Safety
LB1
Summary of Hematology Changes from Baseline
IA, SAC
3.12.
Safety
LB4
Summary of Hematology Shifts from Baseline Relative to 
Normal Range
IA, SAC
3.13.
Safety
LB15
Summary of Haemoglobin Change from Baseline Relative to 
Clinical Importance Ranges
IA, SAC
Laboratory: Urinalysis
3.14.
Safety
LB1
Summary of Urinalysis Changes from Baseline
IA, SAC
3.15.
Safety
LB4
Summary of Urinalysis Parameters Shifts from Baseline Relative 
to Normal Range
IA, SAC
Laboratory: Hepatobiliary (Liver)
3.16.
Safety
LIVER1
Summary of Liver Monitoring/Stopping Event Reporting
IA, SAC
3.17.
Safety
LIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IA, SAC
ECG
3.18.
Safety
EG1
Summary of ECG Findings 
IA, SAC
3.19.
Safety
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
IA, SAC
3.20.
Safety
EG2
Summary of Change from Baseline in ECG Values by Visit
IA, SAC
3.21.
Safety
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
IA, SAC
Vital Signs
3.22.
Safety
VS1
Summary of Change from Baseline in Vital Signs
IA, SAC


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12.9.8.
Safety Figures
Safety: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Vital Signs
3.1
Safety
PD_F1
Profile Plot of Vital Signs Parameters Over Time by Subject
Panel by subject and dosing session
X axis: Study day
Y axis: Value of vitals parameter.
IA, SAC


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12.9.9.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Plasma Concentration
4.1.
PK
PK01
Summary of Plasma concentration of 89Zr-GSK2398852 
Pharmacokinetic Concentration-Time Data by TMD
Please rename the “Treatment” column 
as “Dose”.
IA, SAC
4.2.
PK
PK01
Summary of Plasma Concentration of Total mAb
Pharmacokinetic Concentration-Time Data by TMD
Please rename the “Treatment” column 
as “Dose”.
IA, SAC
4.3.
PK
PK01
Summary of 89Zr-GSK2398852 PK parameters by TMD, 
with/without period stratification
IA, SAC
4.4.
PK
PK01
Summary of Total mAb PK parameters by TMD, with/without 
period stratification 
IA, SAC
4.5.
PK
PK_T1
Summary of Plasma concentration of 89Zr-GSK2398852 
Pharmacokinetic Concentration-Time Data by focal anatomical 
region
IA, SAC


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12.9.10.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1.
PK
PK16a
Individual Plasma Concentration-Time Plots of 89Zr-
GSK2398852 (Linear and Semi-log)
IA, SAC
4.2.
PK
PK16a
Individual Plasma Concentration-Time Plots of
Total mAb (Linear and Semi-log)
IA, SAC
4.3.
PK
PK17
Mean Plasma Concentration-Time Plots of 89Zr-GSK2398852
(Linear and Semi-log) by TMD
IA, SAC
4.4.
PK
PK17
Mean Plasma Concentration-Time Plots of Total mAb (Linear 
and Semi-log) by TMD
IA, SAC
4.5.
PK
PK18
Median Plasma Concentration-Time Plots of 89Zr-GSK2398852
(Linear and Semi-log) by TMD
IA, SAC
4.6.
PK
PK18
Median Plasma Concentration-Time Plots of Total mAb (Linear 
and Semi-log) by TMD
IA, SAC


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12.9.11.
ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
Screened
ES7
Listing of Reasons for Screen Failure
IA, SAC
2.
Safety
ES2
Listing of Reasons for Study Withdrawal
IA, SAC
3.
Safety
SD2
Listing of Reasons for Study Treatment Discontinuation
IA, SAC
Protocol Deviations
4.
Safety
DV2
Listing of Important Protocol Deviations 
IA, SAC
5.
Safety
IE3
Listing of Participants with Inclusion/Exclusion Criteria Deviations
IA, SAC
Populations Analysed
6.
Enrolled
SP3
Listing of Participants Excluded from Any Population
IA, SAC
Demographic and Baseline Characteristics
7.
Safety
DM2
Listing of Demographic Characteristics
Please include BMI.
IA, SAC
8.
Safety
DM9
Listing of Race
IA, SAC
Prior and Concomitant Medications and Medical Conditions
9.
Safety
CP_CM3
Listing of Concomitant Medications
IA, SAC
10.
Safety
MH2
Listing of Medical Conditions
IA, SAC
Exposure and Treatment Compliance
11.
Safety
EX3 
Listing of Exposure to CPHPC
IA, SAC
12.
Safety
EX3 
Listing of Exposure to anti-SAP mAb
Please present the cumulative dose as 
labelled+unlabelled. Add a footnote 
explaining the same: “ The cumulative 
doses presented comprises both 
labelled and unlabelled mAb”.
SAC


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events
13.
Safety
AE8CP
Listing of All Adverse Events
The AE listing should include a column 
for rash and a column for the grade
IA, SAC
14.
Safety
AE7
Listing of Subject Numbers for Individual Adverse Events
IA, SAC
15.
Safety
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IA, SAC
Serious and Other Significant Adverse Events
16.
Safety
AE8CP
Listing of Fatal Serious Adverse Events
IA, SAC
17.
Safety
AE8CP
Listing of Non-Fatal Serious Adverse Events
IA, SAC
18.
Safety
AE14
Listing of Reasons for Considering as a Serious Adverse Event
IA, SAC
19.
Safety
AE8CP
Listing of Adverse Events Leading to Withdrawal from Study / 
Permanent Discontinuation of Study Treatment
IA, SAC
20.
Safety
AE8CP
Listing of Temporally-Associated, Potential mAb-Related Infusion 
Events
See RAP Section 8.2 for further details 
on AE selection process
IA, SAC
21.
Safety
AE8CP
Listing of Anti-SAP mAb Infusion Related Reactions
See RAP Section 8.2 for further details 
on AE selection process
22.
Safety
AE8CP
Listing of Adverse Events Related to Treatments other than Study 
Drug
IA, SAC
Hepatobiliary (Liver)
23.
Safety
MH2
Listing of Medical Conditions for Participants with Liver Stopping 
Events
IA, SAC
24.
Safety
SU2
Listing of Substance Use for Participants with Liver Stopping 
Events
IA, SAC
All Laboratory


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
25.
Safety
LB5
Listing of All Laboratory Data for Subjects with Any Value of 
Potential Clinical Concern/Potential Clinical Importance
IA, SAC
26.
Safety
LB5
Listing of Laboratory Values of Potential Clinical Importance
IA, SAC
27.
Safety
LB14
Listing of Laboratory Data with Character Results
IA, SAC
ECG
28.
Safety
EG3
Listing of All ECG Values for Participants with Any Value of 
Potential Clinical Importance
IA, SAC
29.
Safety
EG3
Listing of ECG Values of Potential Clinical Importance
IA, SAC
30.
Safety
EG5
Listing of Abnormal ECG Findings
IA, SAC
Vital Signs
31.
Safety
VS4
Listing of All Vital Signs Data for Participants with Any Value of 
Potential Clinical Importance
IA, SAC
32.
Safety
VS4
Listing of Vital Signs of Potential Clinical Importance
IA, SAC


CONFIDENTIAL
204512
57
12.9.12.
Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Pharmacodynamic and Biomarkers
33.
All Treated
PD_L1
Listing of Quantitative Derived Parameters of Cardiac PET 
Images of Focal Anatomical Locations
IA, SAC
34.
All Treated
PD_L2
Listing of Quantitative Derived Parameters of PET Images of 
Different Organs/ Tissues
IA, SAC
35.
Safety
PD_L3
Listing of Troponin T and NT-ProBNP
IA, SAC
36.
Safety
PK07
Listing Plasma SAP concentrations
IA, SAC
Safety
37.
Safety
SAFE_L1
Listing of Cardiac Telemetry
IA, SAC
PK
38.
PK
PK07
Listing of Plasma Concentration Time Data of 89Zr-
GSK2398852
IA, SAC
39.
PK
PK07
Listing of Whole Blood Concentration Time Data of 89Zr-
GSK2398852
IA, SAC
40.
PK
PK07
Listing of Plasma Concentration Time Data of Total mAb
IA, SAC
41.
PK
PK13
Listing of Derived Pharmacokinetic Parameters for Plasma
Concentration of 89Zr-GSK2398852
IA, SAC
42.
PK
PK13
Listing of Derived Pharmacokinetic Parameters for Plasma
Concentration of Total mAb
IA, SAC


CONFIDENTIAL
204512
58
12.10.
Appendix 10: Example Mock Shells for Data Displays
Example POP_T1
Protocol: 204512                                                                     Page 1 of x
Population: Safety
                               Table 1.12
                       Summary of Exposure to Study Treatment (CPHPC)
                                                                 Anti-SAP             
Planned Period                                                    
  (N=xx)
-----------------------------------------------------------------------------
SESSION 1        Duration of Exposure (days)     n               
xx
                                                 Mean
xx.x
                                                 SD              
xx.xx
                                                 Median         
xx.x
                                                 Min.            
xx
                                                 Max.           
xx
                 Cumulative Dose (mg)            n               
xx
                                                 Mean         
xxxx.x
                                                 SD           
xxxx.xx
                                                 Median       
xxxx.x
                                                 Min.          
xxxx
                                                 Max.         
xxxx
SESSION 2        Duration of Exposure (days)     n               
xx
                                                 Mean           
xx.x
                                                 SD              
xx.xx
                                                 Median         
xx.x
                                                 Min.           
xx
                                                 Max.           
xx
                 Cumulative Dose (mg)            n               
xx
                                                 Mean         
xxxx.x
                                                 SD            
xxxx.xx


CONFIDENTIAL
204512
59
                                                 Median       
xxxx.x
                                                 Min.         
xxxx
                                                 Max.         
xxxx
Overall          Duration of Exposure (days)     n              
xx
                                                 Mean           
xx.x
                                                 SD              
xx.xx
                                                 Median         
xx.x
                                                 Min.           
xx
                                                 Max.           
xx
                 Cumulative Dose (mg)            n               
xx
                                                 Mean         
xxxx.x
                                                 SD            
xxxx.xx
                                                 Median       
xxxx.x
                                                 Min.         
xxxx
                                                 Max.         
xxxx
Time on study treatment[1]        n               
xx
                                                 Mean         
xxxx.x
                                                 SD            
xxxx.xx
                                                 Median       
xxxx.x
                                                 Min.         
xxxx
                                                 Max.         
xxxx
[1] The time on study drug does not exclude dose interruptions. In other words, it is the total time span of exposure to
treatment. It is calculated as the total number of days between first dosing date of GSK2315698 and last dosing date of
GSK2315698 (both days inclusive).
PPD


CONFIDENTIAL
204512
60
Example PD_F1
Protocol: 201452
Population: All Treated
Figure x.x
Individual Subject Plot: <SUVpeak/SUVmean> Over Time <for Cardiac Focal Anatomical Regions / 
for Each Organ/ Tissue>
Location: <Location>
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
204512
61
Example PK_T1
Protocol: AAA111111
     Page 1 of xx
Population: PK
Table x.x
Summary of [Analyte] [Matrix] Pharmacokinetic Concentration-Time Data [units]
{by Group}
Focal 
Anatomica
l Region of 
the heart
Dose
N
{Add. 
time
var.}
Planned 
Relative
Time
n
No.
Imputed
[1]
Mean
{95% CI
(Lower,Upper)}
SD
Median
Min.
Max.
Region 1
50mg
24
Pre-dose
24
20
xxxx.x
(xxxx.x,xxxx.x)
xxxx.x
xxxx
xxxx
30 min
24
  1
xxxx.x
(xxxx.x,xxxx.x)
xx.xx
xxxx.x
xxxx
xxxx
1 hr
23
  0
xxxx.x
(xxxx.x,xxxx.x)
xx.xx
xxxx.x
xxxx
xxxx
2 hr
24
  0
xxxx.x
(xxxx.x,xxxx.x)
xx.xx
xxxx.x
xxxx
xxxx
100mg
24
Pre-dose
24
  3
xxxx.x
(xxxx.x,xxxx.x)
xx.xx
xxxx.x
xxxx
xxxx
30 min
21
  0 
xxxx.x
(xxxx.x,xxxx.x)
xx.xx
xxxx.x
xxxx
xxxx
1 hr
21
  0
xxxx.x
(xxxx.x,xxxx.x)
xx.xx
xxxx.x
xxxx
xxxx
2 hr
21
  0
xxxx.x
(xxxx.x,xxxx.x)
xx.xx
xxxx.x
xxxx
xxxx
200mg
24
Pre-dose
24
  0
xxxx.x
(xxxx.x,xxxx.x)
xx.xx
xxxx.x
xxxx
xxxx
30 min
23
  0
xxxx.x
(xxxx.x,xxxx.x)
xx.xx
xxxx.x
xxxx
xxxx
1 hr
24
  0
xxxx.x
(xxxx.x,xxxx.x)
xx.xx
xxxx.x
xxxx
xxxx
2 hr
24
  0
xxxx.x
(xxxx.x,xxxx.x)
xx.xx
xxxx.x
xxxx
xxxx
Region 2
………
“[1] Original result values which are NQ have been imputed as per IDSL Standards
and counts are displayed in No.Imputed column
PPD


CONFIDENTIAL
204512
62
Example 
: PD_L1
Page 1 of n
Protocol
: 204512
Population
: All Treated
Listing x
Listing of Quantitative Derived Parameters of Cardiac PET Images of focal anatomical locations
Site Id./
Unique 
Subject Id.
Planned Period/
Planned Visit
Date/
Study Day
Parameter 
(unit)
LA 
Blood
LV 
Blood
LVW 
High
LVW 
Low
MS High
MS Low
RV 
Blood
Session 1/
Day 3
DDMMMYY/
3
Volume 
(mm3)
xxx
xxx
xxx
xxx
xxx
xxx
xxx
SUVpeak
(<unit>)
x.xx
x.xx
x.xx
x.xx
x.xx
x.xx
x.xx
Session 1/
Day 4
DDMMMYY/
4
Etc.
Note: SUVpeak is averaged over the entire 20-minute scan period. LA Blood = blood pool left atrium; LV Blood = Blood pool left ventricle; LVW High = 
Left ventricle wall, high intake; LVW Low = Left ventricle wall, low intake; MS High = Mid septum, high intake; MS Low = Mid septum, low intake; RV 
Blood = Blood pool right ventricle.
PPD


CONFIDENTIAL
204512
63
Example 
: PD_L2
Page 1 of n
Protocol
: 204512
Population
: All Treated
Listing x
Listing of Quantitative Derived Parameters of PET Images of Different Organs/ Tissues
Site Id./
Unique Subject Id.
Planned Period/
Planned Visit
Date/
Study Day
Organ / Tissue
SUVmean
(<unit>)
Volume
(mm3)
Session 1/
Day 3
DDMMMYY/
3
Adrenal sinister
x.xx
xxxx
Aorta
x.xx
xxxx
Bone marrow
x.xx
xxxx
Brain
x.xx
xxxx
Gut
x.xx
xxxx
Heart
x.xx
xxxx
Etc.
PPD


CONFIDENTIAL
204512
64
Example 
: PD_L3
Page 1 of n
Protocol
: 204512
Population
: Safety
Listing x.x
Listing of <Endpoint or Endpoint Type>
<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
204512
65
SAFE_L1
Protocol: MID204512
   Pages 1 of 1
Population: Safety
Listing X
Listing of Cardiac Telemetry
Site Id./
Unique 
Subject Id.
Age(y)/
Sex/
Race
Planned
Period/
Planned 
Visit
Start Date/
Start Time/
Study Day
Stop Date/
Stop Time/
Study Day 
Result
Holter 
monitoring 
method
Other - description
57/
Male/
WHITE
/
Baseline
09:00/
1
20:00/
1
ABNORMAL - NOT 
CLINICALLY 
SIGNIFICANT
TELEMETRY 
Session 1/
Day 11
09:00/
30
20:00/
30
NORMAL
OTHER 
BODYGUARDIAN TELEMETRY
Session 2/
Day 11
09:00/
60
20:00/
60
ABNORMAL -
CLINICALLY 
SIGNIFICANT
TELEMETRY
PPD
PPD
PPD
PPD