Clinical trial NCT02312206
Conditions: Primary Systemic (AL) Amyloidosis
Sponsor: Prothena Biosciences Ltd.
Start date: 2015-02-01; Completion date: 2018-05-01
Enrollment: 260 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multi-center, international, randomized, double-blind, placebo-controlled, two-arm efficacy and safety study in subjects newly diagnosed with AL amyloidosis. Subjects will remain on-study until study completion, which will occur when all primary endpoint events (all-cause mortality or cardiac hospitalizations) have been reached.

Detailed description:
This is a multi-center, international, randomized, double-blind, placebo-controlled, two-arm efficacy and safety study in subjects newly diagnosed with AL amyloidosis. Approximately 236 subjects will be enrolled in \~60 centers, with approximately 118 subjects per arm.

This is an event driven trial, therefore subjects will remain on-study until study completion, which will occur when all primary endpoint events (all-cause mortality or cardiac hospitalizations) have been reached. All subjects who discontinue will be followed until the last event is adjudicated. The estimated overall study duration is approximately 42 months, including the enrollment and treatment periods

Study drug will be administered once every 28 days as a 60-120 minute IV infusion.

First-line chemotherapy must be a bortezomib-containing regimen, with bortezomib administered weekly. The number of cycles of first-line chemotherapy that are administered are at the discretion of the Investigator, and subsequent chemotherapy regimens may be prescribed as per standard of care at the Investigator's discretion.

An independent Data Monitoring Committee (DMC) will review data on a regular basis.

Arms: arm 1: 24 mg/kg (maximum dose of 2500 mg) of NEOD001 administered once every 28 days. arm 2: Placebo will be administered as a 250 mL bag of normal saline once every 28 days.
Interventions: intervention 1: NEOD001 intervention 2: Placebo
Intervention descriptions: intervention 1: NEOD001, is a humanized immunoglobulin G1 monoclonal antibody, which specifically targets misfolded light chain aggregates and amyloid deposits. NEOD001 is proposed for use to target the misfolded light chain protein in subjects with AL amyloidosis. intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
 
Document Type: Study Protocol 
Official Title: 
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-
Controlled, 2-Arm, Efficacy and Safety Study of NEOD001 Plus 
Standard of Care vs. Placebo Plus Standard of Care in Subjects with 
Light Chain (AL) Amyloidosis 
NCT Number: 
NCT02312206 
Document Date: 
06 November 2017 
 


This protocol for Study NEOD001-CL002 was amended three times. 
Date of Original Protocol: 
23 October 2014 
Date of Amendment 1: 
24 February 2015 
Date of Amendment 2: 
28 April 2016 
Date of Amendment 3: 
06 November 2017 
 
The following key changes were made between amendments: 
Overview of Major/Substantial Changes in Amendment 1: 
• Addressed Sponsor name change 
• Clarified standard of care to include bortezomib 
• Revised and clarified eligibility criteria and study assessments 
• Added renal stage as a stratification factor 
• Clarified the role of the Clinical Events Committee in adjudicating primary endpoint 
events 
 
Overview of Major/Substantial Changes in Amendment 2: 
• Revised and clarified eligibility criteria and study assessments 
• Revised and reordered secondary and exploratory objectives and endpoints 
• Revised windows for post-dose monitoring, sampling times, and visit dates 
• Aligned to Clinical Events Committee manual of operations and Data Monitoring 
Committee charter 
• Updated appendices to consolidate and provide additional organ response and 
progression criteria; rename the “Peripheral Neuropathy Assessment Form” to the 
“Neuropathy Impairment Scale – Lower Limbs (NIS-LL)” and update the content; 
delete Borg Scale, add a sample VASPI tool, and add an appendix with a list of 
coagulation indices 
 
Overview of Major/Substantial Changes in Amendment 3: 
• Aligned with updated case report form and statistical analysis plan 
• Removed requirement for monthly collection of additional coagulation indices 
• Removed sample collection for quantitative/renal biomarkers 
• Allowed postbaseline 6MWT to be administered on the same calendar day that study 
drug is administered 
• Increased the number of subjects 
• Clarified timing of serious adverse event collection 


CLINICAL RESEARCH PROTOCOL 
Study Title: 
A Phase 3, Randomized, Multicenter, Double-Blind, 
Placebo-Controlled, 2-Arm, Efficacy and Safety Study of 
NEOD001 Plus Standard of Care vs. Placebo Plus 
Standard of Care in Subjects with Light Chain (AL) 
Amyloidosis 
Protocol Number: 
NEOD001-CL002 
Investigational Product: 
NEOD001 
US IND Number: 
122,912 
EudraCT Number: 
2014-003865-11 
Indication: 
Light Chain (AL) Amyloidosis 
Sponsor: 
Prothena Therapeutics Limited 
Adelphi Plaza, Upper George's Street 
Dun Laoghaire, Co. Dublin 
A96 T927, Ireland 
Sponsor Representative: 
Prothena Biosciences Inc 
331 Oyster Point Boulevard  
South San Francisco, CA 94080 USA 
Sponsor’s Chief Medical Officer: ______________________ 
Medical Monitor: 
Contact information available in the Study File Notebook 
Development Phase: 
Phase 3 
Date of Original Protocol: 
23 October 2014 
Date of Amendment 1: 
24 February 2015 
Date of Amendment 2: 
28 April 2016 
Date of Amendment 3: 
06 November 2017 
Confidential
The information contained in this document and all information provided to you related to NEOD001 is the confidential and 
proprietary information of Prothena Therapeutics Limited (Prothena). It is intended solely for the recipient clinical investigator(s) 
and must not be disclosed to any other party. This material may be used only for evaluating or conducting clinical investigations; 
any other proposed use requires written consent from Prothena.




Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 3 of 135 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title:  A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, 
2-Arm, Efficacy and Safety Study of NEOD001 Plus Standard of Care vs. Placebo Plus Standard 
of Care in Subjects with Light Chain (AL) Amyloidosis 
Protocol Number: NEOD001-CL002 
Date of Original Protocol: 23 October 2014 
Date of Amendment 1:  24 February 2015 
Date of Amendment 2:  28 April 2016 
Date of Amendment 3:  06 November 2017 
 
 
 
 
 
 
 
I have read the foregoing protocol and agree to conduct this study in accordance with the current 
protocol. 
 
 
 
Investigator Signature 
 
Date 
 
 
Investigator Name (Print) 
 
 
 
Please sign, date, and return this form to Prothena or its designee. Contact details will be 
provided to the Investigator. Please retain a copy for your study files. 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 4 of 135 
TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE ...............................................................................................2 
INVESTIGATOR SIGNATURE PAGE......................................................................................3 
TABLE OF CONTENTS ..............................................................................................................4 
LIST OF TABLES .........................................................................................................................8 
LIST OF FIGURES .......................................................................................................................8 
PROTOCOL SYNOPSIS ..............................................................................................................9 
1 
INTRODUCTION............................................................................................................32 
1.1 
Light Chain (AL) Amyloidosis ..............................................................................32 
1.2 
Rationale for Clinical Study...................................................................................33 
1.3 
Background on NEOD001 .....................................................................................34 
1.3.1 
Nonclinical Safety .................................................................................35 
1.3.2 
Clinical Experience ...............................................................................37 
1.4 
Rationale for Dose Selection .................................................................................38 
2 
OBJECTIVES ..................................................................................................................39 
2.1 
Primary Objective ..................................................................................................39 
2.2 
Key Secondary Objectives .....................................................................................39 
2.3 
Additional Secondary Objectives ..........................................................................39 
2.4 
Exploratory Objectives ..........................................................................................39 
3 
STUDY PLAN ..................................................................................................................40 
3.1 
Study Design ..........................................................................................................40 
3.2 
Rationale for Study Design ....................................................................................41 
3.3 
Number of Sites and Subjects ................................................................................41 
3.4 
Endpoints ...............................................................................................................41 
3.4.1 
Efficacy Endpoints ................................................................................41 
3.4.1.1 
Primary Efficacy Endpoints ...........................................................41 
3.4.1.2 
Key Secondary Efficacy Endpoints ...............................................41 
3.4.1.3 
Additional Secondary Efficacy Endpoints .....................................41 
3.4.1.4 
Exploratory Efficacy Endpoints .....................................................41 
3.4.2 
Safety Endpoints ...................................................................................45 
3.5 
Estimated Study Duration ......................................................................................45 
3.6 
Definition of Primary Endpoint and End of Study ................................................45 
3.7 
Termination of the Clinical Study..........................................................................45 
4 
SUBJECT SELECTION .................................................................................................46 
4.1 
Inclusion Criteria ...................................................................................................46 
4.2 
Exclusion Criteria ..................................................................................................47 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 5 of 135 
5 
SUBJECT SCREENING AND RANDOMIZATION ..................................................50 
6 
INVESTIGATIONAL MEDICINAL PRODUCT AND TREATMENT ...................51 
6.1 
Formulation, Packaging, and Labeling of NEOD001 ............................................51 
6.2 
Shipping, Storage, and Handling of NEOD001 .....................................................51 
6.3 
Placebo ...................................................................................................................51 
6.4 
Accountability and Return of Study Drug Supplies ..............................................51 
6.5 
Dosage, Administration, and Schedule ..................................................................52 
6.5.1 
Study Drug ............................................................................................52 
6.5.2 
Study Drug Premedication ....................................................................53 
6.5.3 
Standard of Care Chemotherapy ...........................................................53 
6.6 
Dosage Adjustments ..............................................................................................54 
6.6.1 
Withholding of Study Drug ...................................................................54 
6.6.2 
Management of Suspected Infusion-Related/Hypersensitivity 
Adverse Events......................................................................................54 
6.6.3 
Dose Reductions ...................................................................................55 
6.7 
Treatment Compliance ...........................................................................................55 
6.8 
Concomitant Therapy.............................................................................................55 
6.8.1 
Allowed Concomitant Therapy .............................................................55 
6.8.2 
Prohibited Concomitant Therapy ..........................................................56 
7 
STUDY PROCEDURES .................................................................................................57 
7.1 
Study Visits and Assessments ................................................................................57 
7.1.1 
First Screening Visit: Day -28 to Day -1 ..............................................57 
7.1.2 
Second Screening Visit:  Day -2 or Day -1 ...........................................59 
7.1.3 
Randomization ......................................................................................60 
7.1.4 
Treatment Visits ....................................................................................60 
7.1.4.1 
Month 1-Day 1 ...............................................................................60 
7.1.4.2 
Month 1-Days 8, 15, 22 (±2 Days) ................................................62 
7.1.4.3 
Month 2-Day 1 (±2 Days) ..............................................................63 
7.1.4.4 
Month 2-Days 8, 15, 22 (±2 days) .................................................65 
7.1.4.5 
Month 3-Day 1 (±2 Days) ..............................................................66 
7.1.4.6 
Month 3-Days 8, 15, and 22 (±2 days) ..........................................68 
7.1.4.7 
Every Third Month-Day 1 (±5 Days):  Month 6-Day 1, Month 
9-Day 1, Month 12-Day 1, etc. ......................................................69 
7.1.4.8 
All Other Months-Day 1 (±5 Days):  Month 4-Day 1, Month 5-
Day 1, Month 7-Day 1, Month 8-Day 1, etc. .................................72 
7.1.5 
Concomitant Chemotherapy Visits .......................................................74 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 6 of 135 
7.1.6 
End of Treatment (EOT)/Early Treatment Discontinuation (ETD) 
(28-35 days post-final dose) ..................................................................75 
7.1.7 
90-day Postdose Pregnancy Test ...........................................................77 
7.1.8 
Telephone Follow-Up Every Three Months .........................................77 
7.2 
Order of Assessments ............................................................................................77 
7.3 
Laboratory Evaluations ..........................................................................................78 
7.4 
Peripheral Neuropathy Assessment .......................................................................78 
7.5 
6-Minute Walk Test ...............................................................................................81 
7.6 
Liver Imaging.........................................................................................................81 
7.7 
Monitoring Anti-NEOD001 Antibodies During the Study ....................................82 
8 
EMERGENCY UNBLINDING OF STUDY DRUG, EARLY 
DISCONTINUATION, OR TERMINATION FROM STUDY...................................83 
8.1 
Emergency Unblinding ..........................................................................................83 
8.2 
Early Treatment Discontinuation ...........................................................................83 
8.3 
Early Termination from the Study .........................................................................84 
8.4 
Replacement of Subjects ........................................................................................84 
9 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS AND REPORTING .............85 
9.1 
Definitions..............................................................................................................85 
9.2 
Recording of Adverse Events ................................................................................87 
9.3 
Assessment of AEs:  Severity ................................................................................88 
9.4 
Assessment of AEs:  Relationship to Study Drug .................................................88 
9.5 
Assessment of AEs:  Outcome ...............................................................................90 
9.6 
Reporting of Serious Adverse Events ....................................................................90 
9.7 
Follow-up of Adverse Events ................................................................................90 
9.8 
Pregnancy ...............................................................................................................91 
9.9 
Urgent Safety Measures .........................................................................................91 
10 
STATISTICAL CONSIDERATIONS ...........................................................................92 
10.1 
Analysis Populations ..............................................................................................92 
10.2 
General Considerations ..........................................................................................92 
10.3 
Efficacy Analyses ..................................................................................................93 
10.3.1 
Primary Analysis ...................................................................................93 
10.3.2 
Key Secondary Efficacy Analyses ........................................................93 
10.3.3 
Additional Secondary Efficacy Analyses..............................................94 
10.3.4 
Exploratory Efficacy Analyses .............................................................94 
10.3.5 
Handling of Missing Data .....................................................................94 
10.3.6 
Subgroup Analyses ...............................................................................94 
10.4 
Safety Analyses ......................................................................................................95 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 7 of 135 
10.4.1 
Adverse Events......................................................................................95 
10.4.2 
Clinical Laboratory Evaluations ...........................................................95 
10.4.3 
Additional Safety Analysis ...................................................................95 
10.5 
Pharmacokinetic Analyses .....................................................................................95 
10.6 
Immunogenicity .....................................................................................................95 
10.7 
Interim Analysis .....................................................................................................96 
10.8 
Determination of Sample Size ...............................................................................96 
11 
STUDY COMMITTEES .................................................................................................97 
11.1 
Data Monitoring Committee (DMC) .....................................................................97 
11.2 
Clinical Events Committee (CEC) .........................................................................97 
11.3 
Hepatic Response Committee ................................................................................97 
12 
DATA RECORDING, RETENTION, AND MONITORING .....................................98 
12.1 
Case Report Forms .................................................................................................98 
12.2 
Availability and Retention of Records ...................................................................98 
12.3 
Quality Control and Quality Assurance .................................................................98 
12.4 
Subject Confidentiality ..........................................................................................99 
13 
ETHICAL AND LEGAL ISSUES ................................................................................100 
13.1 
Ethical Conduct of the Study ...............................................................................100 
13.2 
Regulatory Approval ............................................................................................100 
13.3 
Independent Review Board / Ethics Committee (EC) Approval .........................100 
13.4 
Subject Informed Consent....................................................................................100 
13.5 
Subject Compensation for Adverse Effects on Health ........................................101 
13.6 
Protocol Amendments and Study Termination ....................................................101 
13.7 
Finance, Insurance and Indemnity .......................................................................101 
14 
PUBLICATION .............................................................................................................102 
15 
REFERENCES ...............................................................................................................103 
16 
APPENDICES ................................................................................................................106 
 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 8 of 135 
LIST OF TABLES 
Table 1: 
Schedule of Events .....................................................................................24 
Table 2: 
Peripheral Neuropathy Assessments ..........................................................80 
 
LIST OF FIGURES 
Figure 1: 
Proposed Mechanism of Action for NEOD001 .........................................34 
 
LIST OF APPENDICES 
Appendix 1: 
Organ Response and Progression Criteria ...............................................107 
Appendix 2: 
Stratification Details ................................................................................108 
Appendix 3: 
Schedule Of Events For Subjects Who Discontinue Study Drug Early 
but Agree to Return For Assessments After the ETD Visit .....................109 
Appendix 4: 
Examples of Highly Effective Contraception Methods ...........................111 
Appendix 5: 
Revised International Myeloma Working Group Diagnostic Criteria 
for Multiple Myeloma ..............................................................................112 
Appendix 6: 
Hematologic Response and Progression Criteria .....................................113 
Appendix 7: 
Short Form-36 Questionnaire (SF-36v2) .................................................114 
Appendix 8: 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ............................125 
Appendix 9: 
Functional Assessment of Cancer Therapy – Gynecologic Oncology 
Group Neurotoxicity Subscale (FACT-GOG NTX) ................................129 
Appendix 10: 
Neuropathy Impairment Scale – Lower Limbs (NIS-LL) .......................130 
Appendix 11: 
Visual Analog Scale – Pain Intensity (VASPI) .......................................131 
Appendix 12: 
Coagulation Indices .................................................................................132 
Appendix 13: 
Eastern Cooperative Oncology Group (ECOG) Performance Status ......133 
Appendix 14: 
New York Heart Association (NYHA) Functional Classification ...........134 
Appendix 15: 
Package Inserts for Chemotherapeutic Agents Commonly Prescribed 
for Individuals with AL Amyloidosis ......................................................135 
 
 
 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 9 of 135 
PROTOCOL SYNOPSIS 
Title 
A Phase 3, Randomized, Multicenter, Double-Blind, 
Placebo-Controlled, 2-Arm, Efficacy and Safety Study of 
NEOD001 Plus Standard of Care vs. Placebo Plus Standard of 
Care in Subjects with Light Chain (AL) Amyloidosis 
Study Phase 
Phase 3 
Indication 
NEOD001 is indicated for the treatment of patients with AL 
amyloidosis.  
Primary Objective 
To evaluate the efficacy of NEOD001 plus standard of care vs. 
placebo plus standard of care when administered intravenously 
in subjects with AL amyloidosis by assessing time to all-cause 
mortality or cardiac hospitalization. 
Key Secondary Objectives 
To evaluate NEOD001 plus standard of care compared to 
placebo plus standard of care on the following: 
• Change from baseline in health-related quality of life using 
the Short Form-36 questionnaire (SF-36v2) 
• Change from baseline in cardiac functional response using 
the 6-Minute Walk Test (6MWT) 
• Cardiac best response rate as assessed by N-terminal 
pro-brain natriuretic peptide (NT-proBNP; Appendix 1) 
Additional Secondary 
Objectives 
To evaluate NEOD001 plus standard of care compared to 
placebo plus standard of care in the organ-specific populations 
below. In addition, the safety and tolerability of NEOD001 
plus standard of care will be evaluated. 
• Renal best response rate using established criteria 
(Appendix 1) in subjects with renal involvement at baseline 
• Change from baseline in peripheral neurological function 
using the Neuropathy Impairment Score – Lower Limbs 
(NIS-LL; Appendix 10) in subjects with peripheral 
neuropathy involvement at baseline 
• Hepatic best response rate according to consensus criteria 
(Appendix 1) in subjects with hepatic involvement at 
baseline 
Exploratory Objectives 
To evaluate NEOD001 plus standard of care compared to 
placebo plus standard of care on other cardiac, renal, 
peripheral neuropathy, hepatic, and disease-related clinical 
outcome measures. 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 10 of 135 
Study Design 
This is a multicenter, international, randomized, double-blind, 
placebo-controlled, two-arm efficacy and safety study in 
subjects with AL amyloidosis. 
Newly diagnosed subjects with AL amyloidosis will be 
randomized in a 1:1 ratio to NEOD001 or placebo. Subjects 
will be stratified at randomization based on three factors: 
• Mayo Clinic Stage (Appendix 2):  Stages I and II vs. 
Stages III and IV 
• Renal Stage (Appendix 2):  Stage I vs. Stages II and III 
• 6MWT distance:  < 300 meters vs. ≥ 300 meters 
Subjects will remain on study until study completion, which 
will occur when approximately 156 primary endpoint events 
(all-cause mortality or cardiac hospitalizations as adjudicated 
by the Clinical Events Committee [CEC]) have been reached.  
If the subject discontinues study drug prior to the end of the 
study but is willing to continue to participate in study visits, 
the subject should have an Early Treatment Discontinuation 
(ETD) Visit within 28-35 days after the last study drug 
administration (per Table 1 and Section 7.1.6) and then have 
assessments every third month per Appendix 3. The most 
important visit is the Month 9-Day 1 Visit, so if a subject is 
unwilling to continue visits every third month, every effort 
should be made for the subject to return and complete the 
Month 9-Day 1 Visit on schedule. All visits after the ETD 
Visit should occur on schedule, that is, at the time when the 
visit would have occurred had the subject remained on study 
drug.  
New SAEs occurring beyond the EOT/ETD Visit or >28 days 
after the last administration of study drug, whichever is later, 
will be reported to the Sponsor or its designee only if, in the 
judgment of the Investigator, the SAE is associated with any 
protocol intervention (i.e., related to study procedure or 
previous study drug exposure).  
Follow-up phone calls should be made to randomized subjects 
(or their caregivers) who received a dose of study drug and are 
no longer receiving study drug every 3 months, beginning 
approximately 3 months from the subject’s last visit. The 
subject’s health status, as well as details of any 
hospitalizations will be collected accordingly in the study 
database to ensure adequate capture of primary endpoint 
events.  


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 11 of 135 
At the time of study completion (i.e., once approximately 
156 events have been reached), all subjects still on study 
(i.e., subjects still receiving study drug [NEOD001 or placebo] 
treatment, subjects who discontinue study drug early but agree 
to return for assessments after the ETD Visit, and subjects 
participating in the vital status phone call follow up) may be 
considered for entry into a separate open-label extension study 
of NEOD001. 
Outline of Procedures 
Subject screening will occur during the 28 days prior to the 
first administration of study drug on Month 1-Day 1. The 
Screening period may be extended upon approval by the 
Medical Monitor. Screening assessments are listed in 
Table 1. Individual test results that do not meet eligibility 
requirements may be repeated, with the exception of 
6MWT; full rescreening is allowed once per subject.  
Two Screening 6MWTs are required before the first 
administration of study drug. The first Screening 6MWT is 
required to be performed between Days -28 and -5, at least 
4 days prior to the second Screening 6MWT, which should 
be performed within 2 days prior to Month 1-Day 1. The 
postbaseline 6MWTs may be performed on the same day as 
study drug administration, if the 6MWT is completed 
before initiation of the study drug infusion.  
If all eligibility requirements are met, the subject will be 
randomized, Month 1-Day 1 assessments will be 
completed, and treatment will be initiated. 
Each visit will be denoted by its “month” and “day” such 
that the first study drug (NEOD001 or placebo) infusion 
day is denoted as Month 1-Day 1; subsequent months will 
use sequential numbers (e.g., the second dose is 
administered on Month 2-Day 1). “Cycle” is reserved to 
denote administration of chemotherapy. Assessment and 
visit windows are described in the Schedule of Events 
(Table 1). 
Each month, subjects will receive their study drug infusion 
on Day 1 at the study site. For Months 1 through 3, subjects 
will be assessed weekly, although not all visits are required 
to be at the study site. For Month 3 and all subsequent 
months until the end of the study, subjects will only be 
required to return to the study site every 28 days for Day 1 
dosing of study drug.  
First-line chemotherapy must be a bortezomib-containing 
regimen, with bortezomib administered subcutaneously 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 12 of 135 
(SC), weekly. The first administration of chemotherapy, 
including bortezomib, will be administered after 
Month 1-Day 1 study drug administration (following the 
post-study drug infusion observation period) such that 
Month 1-Day 1 of the study will be equivalent to 
Cycle 1-Day 1 of chemotherapy. In addition to the visits 
outlined above, during the first cycle of chemotherapy, the 
subject must return to the study site for each weekly 
administration of bortezomib and for assessments prior to 
the administrations. During the second and third cycles of 
chemotherapy, bortezomib must be administered at the 
study site during the Month 2-Day 1, Month 2-Day 15, and 
Month 3-Day 1 visits (i.e., Cycle 2-Day 1, Cycle 2-Day 15, 
and Cycle 3-Day 1, respectively). If, for any reason in the 
opinion of the Investigator, the subject should continue to 
be seen weekly at the study site (e.g., toxicity that appears 
to exceed the anticipated side effects of the chemotherapy), 
then the other Cycle 2 and Cycle 3 weekly bortezomib 
administrations may be performed at the study site, as well. 
At the Investigator’s discretion, if the subject is not 
experiencing any unanticipated or significant toxicity, the 
subject may be administered the Cycle 2-Days 8 and 22 and 
the Cycle 3-Days 8, 15 and 22 bortezomib by their local 
physician, rather than by the Investigator. Within 1 day 
prior to or on the day of each administration of bortezomib 
by the local physician, a Prothena-sponsored healthcare 
professional must administer the FACT-GOG NTX and 
obtain pre-dose vital signs and central laboratory samples. 
However, if bortezomib is administered on a Monday (or 
there is an intervening holiday), then it is acceptable for the 
Homecare visit to take place on the previous Friday. 
The number of cycles of first-line chemotherapy that is 
administered is at the discretion of the Investigator, and 
subsequent chemotherapy regimens may be prescribed as 
per standard of care at the Investigator’s discretion. Details 
regarding commonly accepted treatment practice are 
provided in Section 6.5.3.  
In the event that bortezomib doses are missed, the 
chemotherapy cycles may become misaligned with the 
monthly study drug dosing. In this case, the weekly visits 
during Months 1 through 3 should continue as described 
above in order to closely monitor subjects’ health during 
the initial months of concomitant chemotherapy. 
Throughout the study, monthly doses of study drug should 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 13 of 135 
not be delayed or skipped due to adjustments that are made 
to chemotherapy dosing. 
Safety and efficacy assessments will be performed at each 
visit as outlined in the Schedule of Events (Table 1). 
Autologous stem cell transplant (ASCT) is not allowed 
while on study. 
Number of Sites and 
Subjects 
This is a multicenter, international study in approximately 
75 centers. Up to 260 subjects will be enrolled in the study, 
with approximately 130 subjects per arm. 
Estimated Study Duration 
This is an event-driven trial that will continue until 
approximately 156 primary endpoint events have occurred. All 
subjects who discontinue will be followed until the last event 
is adjudicated. The estimated overall study duration is 
approximately 42 months, including the enrollment and 
treatment periods. 
Summary of Subject 
Eligibility Criteria 
Inclusion Criteria (subjects must meet all of the following 
criteria): 
1. Aged ≥ 18 years 
2. Newly diagnosed and AL amyloidosis treatment naïve 
3. Bone marrow demonstrating clonal plasma cells 
4. Confirmed diagnosis of AL amyloidosis by the following: 
• Histochemical diagnosis of amyloidosis determined 
by polarizing light microscopy of green birefringent 
material in Congo red-stained tissue specimens OR 
characteristic electron microscopy appearance  
AND 
• Confirmatory immunohistochemistry OR mass 
spectroscopy of AL amyloidosis 
5. Confirmed diagnosis of AL amyloidosis by mass 
spectrometry or immunoelectron microscopy of amyloid 
material in tissue biopsy if the subject meets any of the 
following: 
• Is black or African American 
• Is over 75 years of age with concurrent monoclonal 
gammopathy 
• Has a history of familial amyloidosis and has 
concurrent monoclonal gammopathy 
OR 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 14 of 135 
• If the subject meets any of the above 
3 conditions and has echocardiographic 
evidence of amyloidosis, biopsy-proven 
amyloidosis with a monoclonal gammopathy 
and no tissue is available for mass spectrometry 
or immunoelectron microscopy, the subject 
must have gene sequencing consistent with 
transthyretin (TTR) wild type (e.g., no TTR 
mutation present) AND must score 0 in 
technetium-99m-3,3-diphosphono-1,2 
propanodicarboxylic acid (99mTc-DPD; Rapezzi 
2011), hydroxymethylenediphosphonate 
(99mTc-HMDP; Galat 2015), or pyrophosphate 
(99mTc-PYP; Bokhari 2013) scintigraphy  
6. Cardiac involvement as defined by all of the following: 
• Past documented or presently noted clinical signs and 
symptoms supportive of a diagnosis of heart failure in 
the setting of a confirmed diagnosis of AL 
amyloidosis in the absence of an alternative 
explanation for heart failure 
• Either an endomyocardial biopsy demonstrating AL 
amyloidosis or an echocardiogram demonstrating a 
mean left ventricular wall thickness at diastole 
> 12 mm in the absence of other causes (e.g., severe 
hypertension, aortic stenosis), which would 
adequately explain the degree of wall thickening 
• NT-proBNP ≥ 650 pg/mL and ≤ 8500 pg/mL  
7. Planned first-line chemotherapy contains bortezomib 
administered weekly and subcutaneously (SC) 
8. Adequate bone marrow reserve, hepatic function, and 
renal function, as demonstrated by: 
• Absolute neutrophil count (ANC) ≥ 1.0 × 109/L 
• Platelet count ≥ 75 × 109/L 
• Hemoglobin ≥ 9 g/dL 
• Total bilirubin ≤ 2 times the upper limit of normal 
(× ULN) 
• Aspartate aminotransferase (AST)/serum glutamic 
oxaloacetic transaminase (SGOT) ≤ 3 × ULN  
• Alanine aminotransferase (ALT)/serum glutamic 
pyruvic transaminase (SGPT) ≤ 3 × ULN 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 15 of 135 
• Alkaline phosphatase (ALP) ≤ 5 × ULN (except for 
subjects with hepatomegaly and isozymes specific to 
liver, rather than bone) 
• Estimated glomerular filtration rate (eGFR) 
≥ 30 mL/min/1.73 m2 as estimated by the Chronic 
Kidney Disease Epidemiology Collaboration (CKD-
EPI) equation 
9. Seated systolic blood pressure 90-180 mmHg 
10. Distance walked during each Screening 6MWT is 
> 30 meters and < 550 meters 
11. Women of childbearing potential (WOCBP) must have 
two negative pregnancy tests during Screening, the 
second within 24 hours prior to the first administration of 
study drug, and must agree to use highly effective 
physician-approved contraception (Appendix 4) from 
Screening to 90 days following the last study drug 
administration  
12. Male subjects must be surgically sterile or must agree to 
use highly effective physician-approved contraception 
(Appendix 4) from Screening to 90 days following the 
last study drug administration 
13. Ability to understand and willingness to sign an informed 
consent form prior to initiation of any study procedures 
 
Exclusion Criteria (subjects must meet none of the following 
criteria): 
1. Non-AL amyloidosis 
2. NT-proBNP < 650 pg/mL or > 8,500 pg/mL 
3. Meets the International Myeloma Working Group 
(IMWG) definition of Multiple Myeloma (Appendix 5) 
*Note that subjects who meet the IMWG definition of 
symptomatic multiple myeloma with signs and/or 
symptoms attributable only to associated amyloidosis are 
potentially eligible upon approval of the Sponsor. 
4. Subject is eligible for and plans to undergo ASCT or 
organ transplant 
5. Symptomatic orthostatic hypotension that in the medical 
judgment of the Investigator would interfere with 
subject’s ability to safely receive treatment or complete 
study assessments 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 16 of 135 
6. Myocardial infarction, uncontrolled angina, severe 
uncontrolled ventricular arrhythmias, or 
electrocardiographic (ECG) evidence of acute ischemia, 
within 6 months prior to the Month 1-Day 1 Visit 
7. Severe valvular stenosis (e.g. aortic or mitral stenosis 
with a valve area <1.0 cm2) or severe congenital heart 
disease 
8. ECG evidence of acute ischemia or active conduction 
system abnormalities with the exception of any of the 
following: 
• First degree AV-block 
• Second degree AV-block Type 1 (Mobitz Type 1 / 
Wenckebach type) 
• Right or left bundle branch block 
• Atrial fibrillation with a controlled ventricular rate 
(uncontrolled [i.e., >110 bpm] ventricular rate is not 
allowed [determined by an average of three beats in 
Lead II or three representative beats if Lead II is not 
representative of the overall EKG]) 
9. Peripheral neuropathy assessed as National Cancer 
Institute-Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) Grade 2 with pain, Grade 3, or 
Grade 4 
10. Subject is receiving oral or IV antibiotics, antifungals or 
antivirals within 1 week of Month 1-Day 1 with the 
exception of prophylactic oral agents 
11. Prior treatment with hematopoietic growth factors, 
transfusions of blood or blood products within 1 week of 
Month 1-Day 1 
12. Prior radiotherapy within 4 weeks of Month 1-Day 1 
13. Major surgery within 4 weeks of Month 1-Day 1 or 
planned major surgery during the study 
14. Active malignancy with the exception of any of the 
following: 
• Adequately treated basal cell carcinoma, squamous 
cell carcinoma, or in situ cervical cancer 
• Adequately treated Stage I cancer from which the 
subject is currently in remission and has been in 
remission for 2 years 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 17 of 135 
• Low-risk prostate cancer with Gleason score < 7 and 
prostate-specific antigen < 10 mg/mL 
• Any other cancer from which the subject has been 
disease-free for ≥ 2 years 
15. History of severe allergy to any of the components of 
NEOD001 such as histidine/L histidine hydrochloride 
monohydrate, trehalose dehydrate, or polysorbate 20 or 
history of Grade ≥ 3 infusion-related AEs or 
hypersensitivity to another monoclonal antibody, or 
known hypersensitivity to diphenhydramine (or an 
equivalent H1 antihistamine) or acetaminophen (or its 
equivalent, paracetamol) 
16. Known or history of uncontrolled, active HIV, hepatitis B 
or hepatitis C infection 
17. Prior treatment with plasma cell-directed chemotherapy, 
NEOD001, 11-1F4, anti-serum amyloid P antibody, 
doxycycline for amyloid, or other investigational 
treatment directed at amyloid 
18. Treatment with another investigational agent within 
30 days of Month 1-Day 1 
19. Women who are pregnant or lactating 
20. Any condition which could interfere with, or the 
treatment for which might interfere with, the conduct of 
the study or which would, in the opinion of the 
Investigator, unacceptably increase the subject’s risk by 
participating in the study 
21. Subject is under legal custodianship 
22. History of epilepsy or seizure disorder with the exception 
of childhood febrile seizures 
23. Waldenström's macroglobulinemia and/or 
immunoglobulin M (IgM) monoclonal gammopathy  
Drug, Drug Dosage and 
Formulation 
Study Drug: 
Study drug consists of NEOD001 (24 mg/kg) or placebo. The 
active study drug, NEOD001, is supplied as a sterile, 
lyophilized dosage form in a 20/25 mL vial containing 500 mg 
NEOD001. Each vial will be reconstituted with 9.6 mL sterile 
water for injection (WFI) to a concentration of 50 mg/mL 
resulting in a buffered, isotonic, preservative-free solution.  
Study drug will be administered once every 28 days as an 
initial 120 (±10)-minute IV infusion. If the subject tolerates 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 18 of 135 
the initial infusion, subsequent infusions may be administered 
over 60 (±10) minutes. The length of the infusion may be 
extended over a longer period of time if and when it is 
clinically indicated per Section 6.5.1. Every effort must be 
made to ensure doses are given 28 days from the previous 
dose. If logistic considerations intervene, a minimum of 
21 days between doses is required. 
Premedication: 
All subjects will be premedicated for each dose of study drug 
with 25 mg diphenhydramine (or an equivalent dose of a H1 
antihistamine) and 650 mg acetaminophen (or an equivalent 
paracetamol dose) within 30-90 minutes prior to study drug 
administration. 
Standard of Care Chemotherapy: 
All subjects will receive concomitant standard of care 
chemotherapy, which must include bortezomib administered 
subcutaneously on a weekly basis for the initial, first-line 
chemotherapy regimen. Subsequent chemotherapy regimens 
may be prescribed as per standard of care at the Investigator’s 
discretion (see Section 6.5.3). Antiviral prophylaxis is 
required. 
Control Group 
Normal saline will be used as the placebo control. 
Route of Administration 
(Study Drug) 
Intravenous infusion 
Primary Efficacy Endpoint 
Time to all-cause mortality or cardiac hospitalization as 
adjudicated by the CEC  
Key Secondary Efficacy 
Endpoints 
• Change from baseline to Month 9 in the Physical 
Component Summary (PCS) score of the SF-36v2 
• Change from baseline to Month 9 in the 6MWT distance 
(meters) 
• NT-proBNP (cardiac) best response from baseline through 
Month 9  
Additional Secondary 
Efficacy Endpoints 
• For renal evaluable subjects, renal best response from 
baseline through Month 9 
• For peripheral neuropathy evaluable subjects, change from 
baseline to Month 9 in NIS-LL total score 
• For hepatic evaluable subjects, hepatic best response from 
baseline to Month 9 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 19 of 135 
Exploratory Efficacy 
Endpoints 
See Section 3.4.1.4 for a list of exploratory efficacy endpoints. 
Safety Endpoints 
• Safety as assessed by vital signs, 12-lead ECGs, routine 
laboratory assessments, frequency and severity of AEs, 
and immunogenicity 
Statistical Considerations 
Analysis Populations 
The Intent-to-Treat (ITT) Population will include all 
randomized subjects with AL amyloidosis who receive any 
amount of study drug (NEOD001 or placebo). The ITT 
Population will be the primary population used for efficacy 
analyses. The Safety Population will include all subjects with 
AL amyloidosis who receive any amount of study drug 
(NEOD001 or placebo). The Safety Population will be the 
primary population used for safety analyses.  
Efficacy Subset Populations: 
The Renal Evaluable Population will include subjects who had 
renal involvement (i.e., proteinuria >0.5 g/24 hours [measured 
by 24-hour urine total protein excretion]) at baseline and at 
least 1 postbaseline assessment of proteinuria. 
The Peripheral Neuropathy Evaluable Population will include 
subjects who had peripheral nerve involvement at baseline 
(only if the subject had ascending sensorimotor neuropathy at 
screening due to AL amyloidosis etiologies answered as yes) 
and had a baseline NIS-LL total score of 2 or greater and at 
least 1 postbaseline peripheral neuropathy assessment. 
The Hepatic Evaluable Population will include subjects who 
had hepatic involvement defined as one of the following: 
1) >1.5 × ULN alkaline phosphatase at baseline and at least 
1 postbaseline assessment of alkaline phosphatase or 
2) baseline total liver size (i.e., craniocaudal dimension) 
>15 cm and at least 1 postbaseline assessment total liver size. 
Efficacy Analyses 
Primary Analysis - The primary endpoint is time to all-cause 
mortality or cardiac hospitalization as adjudicated by the CEC. 
For all-cause mortality, all deaths occurring after the first 
infusion of study drug (i.e., Study Day 1) through the study’s 
last subject last visit (LSLV) will be included. Cardiac 
hospitalization occurring ≥91 days after a subject’s first 
infusion of study drug through LSLV will be included. Each 
subject will be counted only once in the primary analysis, 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 20 of 135 
based on their first adjudicated occurrence of an endpoint 
event. The distribution of the primary endpoint in the two 
treatment groups will be summarized using the Kaplan-Meier 
method. The two treatment groups will be compared using a 
two-sided stratified (by the randomization stratification 
factors) log-rank test at the alpha=0.05 level of significance. 
Each component of the primary endpoint will be analyzed as 
well. 
Key Secondary Efficacy Analyses – If the primary analysis is 
statistically significant (p<0.05) in favor of NEOD001, the 
following key secondary endpoints will be analyzed using a 
fixed-sequence testing procedure in the order specified below 
to control the overall level of significance: 
• Change from baseline to Month 9 in the PCS score of the 
SF-36v2 
• Change from baseline to Month 9 in the 6MWT distance 
(meters) 
• NT-proBNP (cardiac) best response from baseline through 
Month 9  
For each of these endpoints, the treatment groups will be 
compared using a two-sided test at the alpha=0.05 level of 
significance. However, once a nonsignificant result (p>0.05) 
occurs, the results of all subsequent analyses will be 
considered nominal, descriptive, and exploratory rather than 
confirmatory. 
The SF-36v2 PCS score change from baseline at Month 9 will 
be analyzed using a restricted maximum likelihood (REML) 
based mixed-effect model for repeated measures (MMRM) 
model including fixed effects for randomization strata, 
treatment group, categorical time point, and the treatment 
group × time point interaction, and with the baseline value 
included as a covariate. The unstructured covariance model 
will be used. The 6MWT distance (meters) change from 
baseline at Month 9 will be analyzed using a rank analysis of 
covariance (ANCOVA) model including fixed effects for 
randomization strata and treatment group, with the ranked 
baseline value included as a covariate. The Hodges-Lehman 
estimate of the median treatment difference with associated 
95% CI will be presented. The NT-proBNP (cardiac) best 
response rates in the 2 treatment groups will be compared using 
the Cochran-Mantel-Haenszel (CMH) test stratified by the 
randomization stratification factors. 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 21 of 135 
Additional Secondary Efficacy Analyses - For the Renal 
Evaluable Population, renal best response will be analyzed in the 
same manner described for NT-proBNP (cardiac) best response. 
For the Peripheral Neuropathy Evaluable Population, the change 
from baseline in NIS-LL total score will be analyzed in the same 
manner described for the SF-36v2 PCS score. For the Hepatic 
Evaluable Population, hepatic best response will be analyzed in 
the same manner described for NT-proBNP (cardiac) best 
response. 
Exploratory Efficacy Analyses - Endpoints that are defined as 
time-to-event variables will be analyzed in the same manner as 
the primary endpoint. Quantitative exploratory endpoints will 
be analyzed in the same manner as described for the SF-36v2 
PCS score. Exploratory endpoints that are defined as 
proportions will be analyzed in the same manner described for 
NT-proBNP (cardiac) best response. All exploratory analyses 
will be carried out using two-sided tests at the alpha=0.05 
level of significance. 
Safety Analyses 
Safety data, including AEs, and clinical laboratory 
observations will be summarized by treatment group using the 
Safety Population.  
Adverse Events - AEs will be coded using the Medical 
Dictionary of Regulatory Activities. Summary tables of 
treatment-emergent AEs (TEAEs) will be provided. The 
incidence of TEAEs will be tabulated by system organ class 
and preferred term for each treatment group, and by severity 
and relationship to treatment. Tables of TEAEs leading to 
study drug discontinuation and serious adverse events (SAEs) 
will be provided.  
Clinical Laboratory Evaluations - Descriptive statistics 
summarizing central laboratory data will be presented for all 
study visits. Changes from baseline to each study visit will 
also be summarized by treatment group. In addition, mean 
change from baseline will be summarized for the maximum 
and minimum post-treatment values and for the values at the 
EOT/ETD Visit. The number and percent of subjects with a 
lab value with CTCAE Grade ≥3 and the number and percent 
of subjects with a CTCAE shift of ≥2 grades will be presented. 
Additional Safety Analyses - Additional safety assessments 
include vital signs and ECGs. Descriptive statistics of the vital 
sign and ECG parameters will be presented by treatment group 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 22 of 135 
and study visit, as well as the change from baseline at each 
visit. 
Pharmacokinetic Analyses 
Serum NEOD001 concentrations and elapsed time from the 
preceding NEOD001 dose will be listed. Serum NEOD001 
concentrations from this study will be pooled with data from 
similar samples from other NEOD001 studies in a population 
PK analysis. There will be no PK analyses for this protocol. 
Immunogenicity 
Serum anti-NEOD001 antibody titers will be listed and, if 
sufficient data exist, summarized by treatment group. Serum 
anti-NEOD001 antibody titers may be correlated with serum 
NEOD001 concentrations and select safety endpoints, if 
sufficient data exist.  
Determination of Sample Size 
For the endpoint of time to all-cause mortality or cardiac 
hospitalization, the assumed 18-month event rate in the control 
arm is 60%, based on Kumar 2012. The 18-month event rate in 
the active arm is assumed to be 42%, a relative reduction of 
30%. These assumptions correspond to a hazard ratio of 0.594. 
For a two-arm study with 1:1 randomization, and based on the 
use of a two-sided test at the alpha=0.05 level of significance, 
a total of 156 events (both arms combined) are required for 
90% power. The study is designed to have 90% power in 
accordance with common practice for the design of 
confirmatory trials. Assuming an accrual period of 24 months, 
and a treatment/follow-up period of 18 months (i.e., a total 
study duration of 42 months), a total sample size of 
approximately 236 subjects will be required to attain 
156 events. 
Data Monitoring Committee 
An independent DMC will review data on a regular basis at 
selected intervals to ensure that NEOD001 is safe and 
well-tolerated. The guidelines for the DMC operations will be 
reported in a separate DMC Charter.  
Clinical Events Committee 
An independent CEC blinded to treatment groups, will provide 
independent central adjudication of deaths and 
hospitalizations. The members of this committee will not 
participate in the enrollment or treatment of subjects in this 
trial, nor will they participate in the DMC. The guidelines for 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 23 of 135 
the adjudication process will be reported in a separate Manual 
of Procedures. 
Sponsor 
Prothena Therapeutics Limited 
 
 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 24 of 135 
Table 1: 
Schedule of Events 
 
Screening1 
Month 1 
Month 2 
Month 3 
Months 6, 9, 
12, etc. (Every 
3rd Month) 
All Other 
Months 
 
Assessments 
Day-28 to 
Day -1 
Day -2 or 
Day -1  
Day 1 
Days 8,  
15, 22 
(±2) 
Day 1 
(±2) 
Days 82,  
15, 222 
(±2) 
Day 1 
(±2) 
Days 82, 
152, 222 
(±2) 
Day 1 
(±5) 
Day 1 
(±5) 
EOT/ 
ETD3 
Written Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Review 
X 
 
 
 
 
 
 
 
 
 
 
Medical History4 
X 
 
 
 
 
 
 
 
 
 
 
Confirmation of AL Amyloidosis5 
X 
 
 
 
 
 
 
 
 
 
 
SF-36v2 Health Survey6 
 
X 
 
 
X 
 
X 
 
X 
 
X 
KCCQ6 
 
X 
 
 
X 
 
X 
 
X 
 
X 
FACT-GOG NTX6,7 
X 
X 
X 
X 
X 
X 
X 
X 
Per Section 7.4 & Table 2 
X 
Echocardiogram 
X8 
 
 
 
 
 
 
 
Every 6th mo8 
 
X8 
Liver Imaging (CT) 
X9 
 
 
 
 
 
 
 
Every 6th mo10 
X10 
X10 
12-lead Triplicate ECG11 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Complete PE12 
X 
 
 
 
 
 
 
 
 
 
X 
Symptom-Directed PE13 
 
 
X 
 
X 
 
X 
 
X 
X 
 
ECOG PS & NYHA Class 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
NIS-LL14 
X 
 
X 
 
X 
 
X 
 
Per Section 7.4 & Table 2 
X 
VASPI15 
X 
 
X 
 
X 
 
X 
 
Per Section 7.4 & Table 2 
X 
Local Laboratory 
 
 
 
 
 
 
 
 
 
 
 
Hematology & Chemistry16 
 
 
 
X 
X 
X17 
X 
X17 
X 
X 
 
Serum Pregnancy (WOCBP) 
 
 
X18 
 
X 
 
X 
 
X 
X 
X19 
Central Laboratory20 
 
 
 
 
 
 
 
 
 
 
 
Hematology & Chemistry 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Amylase 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Coagulation21 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Complements C3, C4 
 
X 
 
 
 
 
X 
 
X 
 
X 
Troponin T 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
NT-proBNP22 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 25 of 135 
 
Screening1 
Month 1 
Month 2 
Month 3 
Months 6, 9, 
12, etc. (Every 
3rd Month) 
All Other 
Months 
 
Assessments 
Day-28 to 
Day -1 
Day -2 or 
Day -1  
Day 1 
Days 8,  
15, 22 
(±2) 
Day 1 
(±2) 
Days 82,  
15, 222 
(±2) 
Day 1 
(±2) 
Days 82, 
152, 222 
(±2) 
Day 1 
(±5) 
Day 1 
(±5) 
EOT/ 
ETD3 
Tryptase 
 
X 
 
 
 
 
 
 
 
 
 
Serum Free Light Chains (sFLCs) 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Serum Pregnancy (WOCBP) 
X 
 
 
 
 
 
 
 
 
 
X 
Serum IFE/PEP23 
X 
 
 
 
 
 
X 
 
X24 
X24 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
24-hour Urine Collection for: 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Protein Excretion25 
X 
X 
 
 
 
 
X 
 
Odd months 
Odd months 
X 
Urine IFE/PEP23,25 
X 
 
 
 
 
 
X 
 
Odd months26 Odd months26
X 
6-Minute Walk Test (6MWT)22,27 
X28 
X28 
 
 
 
 
X 
 
X 
 
X 
Bioanalytical Laboratory 
 
 
 
 
 
 
 
 
 
 
 
PK Samples29 
 
 
X 
Day 15 
X 
 
X 
Day 8 
X 
X 
X 
Anti-NEOD001 Antibody Sample 
(pre-dose)  
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Archive Sample (pre-dose)30 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Premedication Administration31 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Vital Signs32 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Infusion33 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Chemotherapy & Antiviral 
Prophylaxis34 
 
 
X35 
X35 
X35 
X35,36 
X35 
X36 
X35 
X35 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X17 
X 
X17 
X 
X 
X37 
Concomitant Medications 
X 
X 
X 
X 
X 
X17 
X 
X17 
X 
X 
X 
Vital Status Phone Call 
 
 
 
 
 
 
 
 
 
 
X38 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 26 of 135 
ALP = alkaline phosphatase; BP = blood pressure; CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; 
EOI = end of infusion; EOT = End of Treatment; ETD = Early Treatment Discontinuation; FACT-GOG NTX = Functional Assessment of Cancer Therapy – Gynecologic 
Oncology Group Neurotoxicity Subscale; HR = heart rate; IFE = immunofixation electrophoresis; KCCQ = Kansas City Cardiomyopathy Questionnaire; NGAL = neutrophil 
gelatinase-associated lipocalin; NIS-LL = Neuropathy Impairment Score – Lower Limbs; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart 
Association; PE = physical exam; PEP = protein electrophoresis; PK = pharmacokinetic; RBP = retinol-binding protein; RR = respiratory rate; SC = subcutaneous; 
6MWT = 6-minute walk test; SF-36v2 = Short Form-36 Version 2; ULN = upper limit of normal; VASPI = Visual Analog Scale – Pain Intensity; WOCBP = women of 
childbearing potential. 
1. The 28-day Screening period may be extended upon approval by the Medical Monitor. Individual test results that do not meet eligibility requirements may be repeated, with the 
exception of 6MWT; full rescreening is allowed once per subject. 
2. Cycle 2-Days 8 and 22 and Cycle 3-Days 8, 15 and 22 bortezomib-containing chemotherapy should be administered by the Investigator at the study site if subject had 
significant toxicity; otherwise, it may be administered by local physician at Investigator’s discretion. See more detail in Footnote 35. 
3. EOT/ETD Visit to occur 28-35 days after the last study drug administration. 
4. Obtain comprehensive cardiac, hematologic, and oncologic medical history; additionally for all other conditions obtain relevant medical history for the past 5 years (including 
all major hospitalizations and surgeries), as well as the subject’s current medical status. 
5. Results from mass spectrometry tissue typing, immunoelectron microscopy, gene sequencing, and/or 99mTc scintigraphy must be obtained prior to randomization to assess 
eligibility for subjects identified in Inclusion Criterion #5.  
6. At visits where one or more questionnaires are to be administered, the following order occurs prior to the performance of any other study assessments on the day they are 
administered: SF-36v2 (Appendix 7), KCCQ (Appendix 8), and FACT-GOG NTX (Appendix 9). 
7. Administer the FACT-GOG NTX (Appendix 9) per Table 2. 
8. If an echocardiogram has been conducted within 90 days prior to Screening Day -28, it does not need to be repeated during Screening and the previous result can be used for 
eligibility. After Screening, perform echocardiograms every 6 months within 10 days prior to Day 1; repeat at EOT/ETD if not performed within 60 days prior to visit. To be 
eligible for the additional cardiac imaging analysis, the subject must have had a 4-chamber view, 2-dimensional echocardiogram with Doppler.  
9. Perform CT imaging of the abdomen for liver measurement for subjects with an ALP > 1.5 × ULN at Screening per Section 7.6 (Exception: not required in Germany). If CT 
imaging has been conducted within 60 days prior to Screening Day -28 and it meets acquisition guidelines, it does not need to be repeated during Screening and the previous 
result can be used for eligibility. 
10. For subjects with liver involvement at Screening, perform scheduled repeat CT imaging of the abdomen for liver measurement every sixth month and unscheduled repeat CT 
imaging as needed per Section 7.6 (Exception: not required in Germany). Repeat at EOT/ETD as needed per Section 7.6. 
11. ECG to be performed in triplicate as follows: Month 1-Day 1: within 30 minutes before dosing and 1 hour (±15 min) post-EOI; All Other Visits:  within 30 minutes before 
dosing or any time on non-infusion days. Medications given for prophylaxis chemotherapy-induced side effects should not be administered prior to completion of the 
postinfusion ECG. 
12. Complete PE includes height (Screening only), weight, and examination of the following:  general appearance; head, ears, eyes, nose, and throat; neck; skin; cardiovascular 
system; respiratory system; gastrointestinal system; and nervous system. Assess macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, liver/spleen size 
(palpable +/-), ascites (+/-), and edema (which should be quantified on a scale of 0-4). 
13. Symptom-directed PE should be as clinically indicated and also include weight, and assessment of macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, 
liver/spleen size (palpable +/-), ascites (+/-), and edema (which should be quantified on a scale of 0-4). 
14. Administer NIS-LL (Appendix 10) per Table 2. 
15. Administer VASPI (Appendix 11) per Table 2. 
16. Local laboratory results for hematology and chemistry will be used for subject management and should be reviewed for safety assessment prior to administration of 
chemotherapy, but will not be collected in the electronic case report forms or the clinical database. 
17. Perform only if subject returns to study site for this visit. 
18. Use local lab for serum pregnancy test within 24 hours prior to Month 1-Day 1 study drug administration. 
19. Obtain local laboratory serum pregnancy test 90 (±5) days after the last study drug administration. 
20. Collect central laboratory samples before 6MWT, if being performed on the same day. 
21. Collect PT/INR and PTT at each time point. At the second Screening visit, EOT/ETD visit, and as clinically indicated, citrated plasma samples may be collected for freezing 
and for potential analysis of coagulation indices at a later date; these analyses may include, but may not be limited to, the indices listed in Appendix 12. 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 27 of 135 
22. NT-proBNP should be drawn before conducting 6MWT if being performed on the same calendar day. 
23. The serum and urine PEP must be conducted before the NEOD001 infusion, if being performed on the same calendar day. 
24. Perform serum IFE/PEP monthly. If a subject’s first on-study hematologic complete response was assessed at the previous visit, perform serum IFE/PEP (and 24-hour urine 
IFE/PEP) at least 28 days after the initial assessment of response to confirm response. 
25. The 24-hour urine protein excretion and 24-hour urine IFE/PEP tests will be performed using the same 24-hour urine collection sample when required at the same visit. 
26. If a subject’s first on-study hematologic complete response was assessed at the previous visit, perform 24-hour urine IFE/PEP (and serum IFE/PEP) at least 28 days after the 
initial assessment of response to confirm response. Repeat every odd-numbered month (to correspond with 24-hour urine protein excretion collection) to assess for continuing 
response or progression. If the initial response confirmation needs to occur on an even-numbered month, perform an additional 24-hour urine collection. 
27. Subjects should plan to be able to return to the same clinical site for each 6MWT from first Screening through Month 9. The postbaseline 6MWT may be administered on the 
same calendar day that study drug is administered (i.e., Months 3, 6, 9, etc.) as long as the NT-proBNP sample is drawn before conducting the 6MWT and the 6MWT is 
completed before initiation of the study drug infusion. Collect BP and HR pre- and post-6MWT administration. 
28. The first Screening 6MWT must be performed between Days -28 and -5, at least 4 days prior to the second Screening 6MWT, which should be performed within 2 days prior 
to the Month 1-Day 1 visit (i.e., on Day -2 or Day -1).  
29. Collect PK samples pre-dose on study drug or chemotherapy dosing days, anytime during EOT/ETD Visit, and at these additional time points: Month 1-Day 1: EOI (+5 min), 
0.5 hour (±5 min) post-EOI, and 1 hour (±10 min) post-EOI; Month 2-Day 1: EOI (+5 min), and 1 hour (±10 min) post-EOI; Month 6-Day 1 and Month 12-Day 1: EOI 
(+5 min), 0.5 hour (±5 min) post-EOI, and 1 hour (±10 min) post-EOI. Additional samples may be collected as clinically indicated, such as when significant toxicity occurs. 
30. Archive serum samples will only be collected from those subjects who have consented to the collection and archiving of their samples for future correlative testing. 
31. All subjects are to receive 25 mg diphenhydramine (or an equivalent dose of a H1 antihistamine) and 650 mg acetaminophen (or an equivalent paracetamol dose) within 
30-90 minutes prior to the start of infusion. 
32. Vital signs include BP, HR, RR, and temperature; assess in same position for all time points after the subject has been at rest for ≥5 minutes. Pre-dose assessments should be 
performed after administration of premedication. Screening and non-infusion days: any time; Month 1-Day 1: Within 30 minutes before dosing, halfway through infusion 
(i.e., approximately 60 minutes after the start of the infusion), immediately at EOI (+10 min), 0.5 hour (±10 min) post-EOI, and 1 hour (±10 min) post-EOI. All Other 
Months-Day 1: Within 30 minutes before dosing, EOI (+10 min), and 1 hour (±10 min) post-EOI. 
33. Administer per Section 6.5.1. Subjects should be closely monitored for 90 (±10) minutes following completion of the study drug infusion. The Investigator may increase this 
standard monitoring time if deemed appropriate or per local standards. In the event of any clinical concerns or suspicious signs or symptoms after the infusion, the subject will 
remain under observation for as long as the Investigator deems it appropriate. 
34. First-line chemotherapy must be a bortezomib-containing regimen, with bortezomib administered weekly, SC, according to the approved prescribing information and local 
institutional practices. Antiviral prophylaxis is required. When chemotherapy is administered on same day as study drug, the chemotherapy must be administered AFTER the 
post-study drug infusion observation period. Number of first-line chemotherapy cycles and subsequent chemotherapy regimens will be administered per standard of care at the 
Investigator’s discretion. 
35. Bortezomib must be administered at the study site for Cycle 1-Days 1, 8, 15, and 22; Cycle 2-Days 1 and 15; and on Day 1 of subsequent cycles, after review of local labs, 
study drug administration, and the post-study drug infusion observation period.  
36. Cycle 2-Days 8 and 22, and Cycle 3-Days 8, 15, and 22 chemotherapy may be administered by local physician with a Homecare visit by a Prothena-sponsored healthcare 
professional to the subject within 1 day prior to or pre-dose on the day of each bortezomib administration to administer FACT-GOG NTX, and to obtain vital signs, blood 
samples for central laboratory testing, and bioanalytical samples (if applicable). If bortezomib is administered on a Monday, the Homecare visit may occur on the previous 
Friday. If significant toxicity occurs during Cycle 1, subject should return to the study site for Cycle 2 and Cycle 3 visits until Investigator deems it appropriate for local 
administration.  
37. New SAEs occurring beyond the EOT/ETD Visit or >28 days after the last administration of study drug, whichever is later, will be reported to the Sponsor or its designee only 
if, in the judgement of the Investigator, the SAE is associated with any protocol intervention (i.e., related to study procedure or previous study drug exposure). 
38. For all subjects who are randomized and received a dose of study drug: Conduct vital status phone call per Section 7.1.8 approximately 3 months after the subject’s last visit 
and approximately every 3 months thereafter. 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 28 of 135 
GLOSSARY OF TERMS 
Abbreviation/Acronym 
Definition 
AA 
Amyloid A 
ADA(s) 
Anti-drug antibody(ies) 
ADL 
Activities of Daily Living 
AE(s) 
Adverse event(s) 
AEF 
Amyloid-enhancing factor 
AL 
Amyloid light chain 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCT 
Autologous stem cell transplant 
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
BSA 
Bovine serum albumin 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CEC 
Clinical Events Committee (previously referred to as the Clinical 
Adjudication Committee [CAC]) 
CFR 
Code of Federal Regulations 
CR 
Complete response 
CT 
Computerized tomography 
D 
Aspartic acid 
dFLC 
Difference between involved and uninvolved free light chain 
DMC 
Data Monitoring Committee 
E 
Glutamic acid 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECL 
Electrochemiluminescent 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 29 of 135 
Abbreviation/Acronym 
Definition 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EOI 
End of Infusion 
EOT 
End of Treatment 
ETD 
Early Treatment Discontinuation 
EU 
European Union 
FACT-GOG NTX 
Functional Assessment of Cancer Therapy – Gynecologic 
Oncology Group Neurotoxicity Subscale 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
Hct 
Hematocrit 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IFE 
Immunofixation electrophoresis 
IgG1 
Immunoglobulin G1 
IL-6 
Interleukin-6 
IMWG 
International Myeloma Working Group 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent to Treat 
IV 
Intravenous 
IXRS 
Interactive Voice and Web Response System 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 30 of 135 
Abbreviation/Acronym 
Definition 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LDH 
Lactate dehydrogenase 
LSLV 
Last subject last visit 
MMRM 
Mixed-effect model for repeated measures 
N 
Number of observations 
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events  
NGAL 
Neutrophil gelatinase-associated lipocalin 
NOAEL 
No-observable-adverse-effect-level 
NR 
No response 
NT-proBNP 
N-terminal pro-brain natriuretic peptide  
NYHA 
New York Heart Association 
PCD 
Plasma cell dyscrasia 
PCS 
Physical Component Summary 
PE 
Physical examination 
PEP 
Protein electrophoresis 
PK 
Pharmacokinetic(s) 
PN 
Peripheral neuropathy 
PR 
Partial response 
PS 
Performance status 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RBP 
Retinol-binding protein 
REML 
Restricted maximum likelihood 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous(ly) 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 31 of 135 
Abbreviation/Acronym 
Definition 
sFLC 
Serum-free light chain 
SF-36v2 
Short Form-36 questionnaire Version 2 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
6MWT 
6-Minute Walk Test 
TEAE(s) 
Treatment emergent adverse event(s) 
TRIAD 
Transgenic Rapidly Inducible Amyloid Disease 
ULN 
Upper limit of normal 
US 
United States 
USP 
United States Pharmacopeial Convention 
VGPR 
Very good partial response 
WFI 
Water for Injection 
WOCBP 
Women of childbearing potential 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 32 of 135 
1 
INTRODUCTION 
1.1 
Light Chain (AL) Amyloidosis 
Systemic amyloidoses are a complex group of diseases caused by tissue deposition of misfolded 
proteins that result in progressive organ damage. The most common type, light chain (AL) 
amyloidosis or primary systemic amyloidosis, involves a hematologic disorder caused by clonal 
plasma cells that produce misfolded immunoglobulin light chains. Overproduction of misfolded 
light chains by plasma cells results in both soluble, aggregated forms of light chains and 
insoluble, fibrillar deposits of abnormal AL protein (amyloid), in the tissues and organs of 
individuals with AL amyloidosis. Clinical features of AL amyloidosis include a constellation of 
symptoms and organ dysfunction including cardiac, renal, and hepatic dysfunction, 
gastrointestinal involvement, neuropathy, and macroglossia. The mechanisms by which 
amyloidogenic immunoglobulin light chains result in organ dysfunction are not well 
characterized, however, it is hypothesized that both amyloid deposits and prefibrillar aggregates 
may contribute to cytotoxic effects on organs observed in patients with AL amyloidosis.  
AL amyloidosis is a rare disorder. Although the exact incidence of AL amyloidosis in the United 
States (US) is unknown, a weighted average from 5 sources (Kyle 1992) (Kyle 2002) 
(Kyle 2006) (Simms 1994) (Junicon Study) estimates the incidence to be 7.6 new cases per 
million population per year, which is approximately 2,300 new cases per year. By comparison, 
the estimated minimum incidence of systemic amyloidosis in England in 2008 was calculated to 
be 0.4/100,000 based on new referrals to the National Amyloidosis Centre with a peaked 
incidence at age 60-79 years. However, other data suggest that the incidence of systemic 
amyloidosis in England exceeds 0.8/100,000 (8 cases per million) of the population 
(Pinney 2013), which is similar to estimates from other countries. With an estimated total 
population of 63.7 million, the overall incidence of systemic amyloidosis in England may be 
approximately 500 per year. 
Approximately, three-fourths of AL amyloidosis patients present with one or two major organ 
systems involved (e.g., cardiac, renal, gastrointestinal tract, hepatic, autonomic nervous system, 
peripheral nervous system, soft tissues) while a quarter of patients present with more than two 
systems involved (Palladini 2005) (Gertz 2010). AL amyloidosis is most commonly associated 
with cardiac and/or renal dysfunction, with overt restrictive cardiomyopathy observed in 
approximately 50% of all cases, and subclinical cardiac involvement detected in almost every 
case at autopsy or on endomyocardial biopsy (Falk 2010).  
AL amyloidosis has two important disease components. The first component is the plasma cell 
dyscrasia (PCD), which results in the overproduction of immunoglobulin light chain, and the 
second component is the impact of the soluble and insoluble amyloid on organ structure and 
function, leading to the clinical manifestations of the disease. While there are currently no 
approved treatments for AL amyloidosis, the current standard of care for these patients is aimed 
at reducing or eliminating the bone marrow disorder, the PCD. The most aggressive treatment 
options include autologous stem cell transplant (ASCT) and high-dose chemotherapy for those 
patients who can tolerate it. Other treatment regimens include combinations of drugs often used 
to treat hematological malignancies including melphalan, prednisone, dexamethasone and 
proteasome inhibitors (e.g., bortezomib), in an attempt to reduce light chain production. There 


Study Drug:  NEOD001  
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 33 of 135 
are no currently approved treatments for AL amyloidosis, and none that directly target 
potentially toxic forms of the amyloidogenic proteins. 
1.2 
Rationale for Clinical Study 
Unlike other hematologic disorders such as multiple myeloma, the morbidity and mortality of 
AL amyloidosis is almost entirely related to organ dysfunction and not hematologic parameters. 
One of the major determinants of prognostic outcome in AL amyloidosis patients is the extent of 
cardiac involvement; 75% of the deaths are due to cardiac amyloidosis (Merlini 2011). The 
process of amyloid formation results in cellular injury, tissue damage, and organ dysfunction 
through mechanisms that are not completely understood. Because the current available treatment 
options are limited to treatment for the PCD component of the disease, the rate of organ function 
improvement or stabilization (“organ response”) after achieving hematologic response from 
chemotherapy regimens is highly variable, ranging from 25% to 78% based on published 
information (Michael 2010) (Cibeira 2011) (Cohen 2007). Furthermore, the incidence of 
treatment-related mortality following high dose melphalan and ASCT was 13% within the first 
100 days in patients with AL amyloidosis (Skinner 2004) and with the greatest mortality in 
patients with cardiac involvement. Though the ASCT approach is effective and results in rapid 
hematologic response, the average treatment related mortality in four single-center studies 
ranged from 21% to 39% (Falk 2010). Therefore, there is an urgent need to develop a treatment 
that can directly target the misfolded proteins to increase their clearance and to alleviate direct 
organ toxicity. Treatments that reduce or eliminate PCD in conjunction with treatments that 
target toxic soluble aggregates and insoluble amyloid may be of great clinical benefit in the 
treatment of AL amyloidosis. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 34 of 135 
1.3 
Background on NEOD001 
Prothena Therapeutics Limited (Prothena) is developing NEOD001, a humanized 
immunoglobulin G1 (IgG1), kappa version of 2A4, the parent murine monoclonal antibody, 
which is directed against a cryptic epitope on amyloid fibrils. NE0D001 specifically targets 
misfolded light chain aggregates and amyloid deposits. Nonclinical studies to date suggest little 
cross-reactivity of the antibody with normal immunoglobulins of the immune system. 
NEOD001, administered by intravenous (IV) infusion, is proposed for use to target the misfolded 
light chain protein in subjects with AL amyloidosis. (Refer to the Investigator’s Brochure for 
detailed NEOD001 nonclinical and clinical information.) 
The proposed mechanism of action for NEOD001 is thought to be two-pronged (Figure 1). First, 
is the direct interaction of NEOD001 with soluble aggregates resulting in the neutralization of 
the soluble, toxic aggregated moieties. The second is clearing the insoluble toxic amyloid 
deposited in organs/tissues. Here, it is believed that NEOD001 attaches to the amyloid deposits 
and the intact Fc portion of NEOD001 signals monocytes/macrophages to the area; and via 
phagocytosis, clearance of the insoluble, toxic deposits occurs (e.g., opsonization of the 
deposited amyloid). It is believed that both mechanisms may contribute to potential clinical 
benefit. 
Figure 1: 
Proposed Mechanism of Action for NEOD001 
 
 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 35 of 135 
Since NEOD001 and 2A4 recognize a conserved epitope in both the AL and amyloid A (AA) 
proteins, nonclinical efficacy was evaluated in mouse models of both systemic serum AA 
amyloidosis (H2/hIL-6 Transgenic Rapidly Inducible Amyloid Disease [TRIAD] mouse model) 
and AL (amyloidoma xenograft model) using the parent murine monoclonal antibody, 2A4. In 
the AL xenograft model, treatment with ~5 mg/kg of 2A4 subcutaneously (SC), 3 times a week 
resulted in a statistically significant reduction in the size of the amyloidomas that were formed 
(by weight and volume). Efficacy studies in the TRIAD mouse model at the same dose 
demonstrated improvements in survival and, in some experiments, reductions in amyloid load. A 
single experiment using high doses of 2A4 (40 mg/kg) at either 1 week after disease induction 
vs. 3 weeks after disease induction (when organ amyloid burden is well established) generated 
conflicting results; with increased organ amyloid burden in the early treatment arm, but 
decreased organ amyloid burden in the late treatment arm. At this time, no explanation for these 
differences has been found. 
The pharmacokinetic (PK) parameters of NEOD001 as determined in the cynomolgus monkey 
were typical of humanized monoclonal antibodies within this species, with a terminal elimination 
half-life of 12-20 days and a clearance of 0.150 to 0.179 mL/h/kg. However, the target of 
NEOD001 is absent in the monkey. Pharmacokinetics in the TRIAD mouse where large amounts 
of amyloid target are available demonstrated rapid binding of the antibody to its target in 
amyloid burdened organs with resultant loss of antibody from the circulating blood pool, 
initially. Available evidence indicates that this is a saturable phenomenon. The PK of second or 
later administrations may, therefore, not exhibit the same profile, particularly for the early 
distribution phase, until this saturation is achieved.  
Imaging, autoradiography, and biodistribution studies demonstrated specific binding of 
NEOD001 and 2A4 to their amyloid target in the TRIAD and AL xenograft models. No evidence 
has been found that would indicate relevant off-target binding of NEOD001 (e.g., to endogenous 
parent proteins of the amyloid), consistent with the results of the human tissue cross-reactivity 
study with NEOD001 discussed below. 
1.3.1 
Nonclinical Safety 
Nonclinical safety was evaluated in the cynomolgus monkey, the TRIAD mouse model, and an 
in vitro study examining binding to human tissue. 
Cynomolgus monkey:  Important amino acid contributions to the epitope in AL amyloidosis are 
glutamic acid (E) and aspartic acid (D) at positions 81 and 82, respectively, on IgG light chain 
and these are conserved in this species; i.e., the incidence of E and D at these positions is > 90% 
in both cynomolgus monkey and human. Though the aspartic acid is buried in the normally 
folded light chain, if physiologic conditions arise that result in the revealing of this epitope, or if 
there is binding to similar epitopes on other proteins, then the consequence would be evaluable in 
this species. 
In a 28-day, weekly IV dose study of NEOD001 in cynomolgus monkeys with a 28-day 
dose-free period for control and high dose animals, treatment was well-tolerated at all dose levels 
(10, 50, and 100 mg/kg/week). There were no NEOD001-related changes in any of the study 
parameters evaluated and thus the no-observable-adverse-effect-level (NOAEL) for NEOD001 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 36 of 135 
in this species was 100 mg/kg. Serum levels of NEOD001 were maintained throughout the 
treatment period. The data suggest a low risk of off-target toxicity. 
H2/hIL-6 TRIAD mice:  The TRIAD mouse model of AA amyloidosis has limitations relative 
to safety assessment for AL amyloidosis; e.g., 1) this transgenic model overexpresses human 
interleukin-6 (IL-6), creating a proinflammatory baseline state that is important for disease 
progression but can confound safety evaluation, 2) the disease state is also promoted by injection 
with an amyloid extract, called amyloid enhancing factor (AEF), intended to seed tissue with 
amyloid, and 3) it involves an amyloid protein (AA) that is different than the one targeted in this 
population (AL), despite the fact that 2A4 recognizes both proteins. However, this model 
contributes to the safety assessment of NEOD001 as it is the only nonclinical model available 
that offers the ability to assess the potential hazards of antibody binding to amyloid embedded in 
various vital organs, primarily liver, spleen, and kidney. The murine homologue of NEOD001, 
2A4, maintains full effector function and was used in these studies. 
Two TRIAD mouse studies were used in the nonclinical safety assessment:  a 22-day toxicity 
study by the IV route of administration and a 28-day toxicity study by IV and SC routes of 
administration. In addition, a 22-day special immunogenicity/toxicity study in H2/hIL-6 mice 
(no AEF) was conducted to compare 2A4 against the immunogenic potential of an unrelated 
protein, bovine serum albumin (BSA). These are detailed in the Investigator’s Brochure and the 
key points are summarized below. 
As intended for this disease model, the TRIAD mouse has background pathology. Appropriate 
controls demonstrated the effect of the IL-6 transgene (plasmacytosis in spleen, thrombus 
formation in mesenteric vessels) and the effect of the IL-6 transgene with AEF added (amyloid 
deposition in kidney, liver, spleen, and other tissues; inflammatory infiltrates in the heart; and 
renal pathology, including tubular degenerative changes and papillary necrosis). Importantly, no 
additional pathology was observed that was attributable to 2A4 treatment at the doses studied, 4 
and 40 mg/kg/week. 
In both toxicity studies, mortality was observed acutely following the third weekly dose 
(Study Day 15) when 2A4 was administered by bolus IV administration. No pathology was 
present to indicate mechanism of the cause of death. The timing of the adverse reaction being 
within minutes to hours of the third weekly dose, and the presence of anti-drug antibodies 
(ADAs), suggest that the effect is an ADA-mediated phenomenon in this model. In animals that 
survived, there were no adverse effects described surrounding deposited amyloid, or in other 
tissues. ADA reactions in animal species are not predictive of human responses and therefore 
these effects are not considered to contribute to human risk assessment (Bugelski 2004) 
(Pimm 1992). Additionally, while it is possible that ADAs might develop, it is not known 
whether or not this would be associated with any clinical significance. 
A special immunogenicity/toxicity study was conducted to explore whether the mortality 
observed following IV dosing of 2A4 in the TRIAD mouse can be observed with an unrelated, 
but immunogenic, protein. Nontransgenic/wild-type mice and H2/hIL-6 transgenic mice (no AEF 
administered) were treated once weekly by IV administration with 2A4 at 4 mg/kg. The 
nontransgenic mice showed no systemic effects; however, the IL-6 overproducing mice 
developed profound signs (decreased motor activity, hunched posture, ataxia, cold to touch) 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 37 of 135 
immediately after dosing on Days 15 and 22, replicating what was observed in the TRIAD 
mouse safety studies above. Mortality and moribundity occurred post-dosing on Day 22. Another 
group of H2/hIL-6 transgenic mice was treated once weekly by IV administration with BSA at 
50 mg/kg. A similar clinical course occurred although signs began one week earlier; i.e. after 
dosing on Day 8 (the second dose). Again, mortality was observed in some animals after dosing 
on Day 22. This study demonstrates the importance of elevated IL-6 in the morbidity and 
mortality observed in this model and further demonstrates that the mortality is not unique to 2A4 
but can be seen with other proteins that are immunogenic in this mouse model. 
Human tissue cross-reactivity:  In a human tissue cross-reactivity study of NEOD001 designed 
to examine potential off-target effects, a limited number of tissues demonstrated any binding. 
Cytoplasmic staining was observed in the heart, kidney, pancreas, pituitary, and testis. 
Cytoplasmic staining is generally not considered to be relevant to IV dosing as these sites are not 
accessible to the administered antibody. Rare to occasional, mild-intensity membrane staining 
was observed on ductular and tubular epithelial cells of the pancreas and testis, respectively. No 
pathologic changes were observed in these organs in the repeat-dose studies suggesting limited 
safety liabilities from potential binding in these tissues. Overall, these data confirm the 
prediction of a low potential for binding of NEOD001 to normal tissue. 
In summary, the available nonclinical data support clinical development of NEOD001 for the 
treatment of AL amyloidosis. No target organ toxicity has been described. Based on available 
models, there are limitations on the ability to assess the interaction of NEOD001 with deposited 
or soluble AL amyloid. The investigations in an AA amyloidosis model (the TRIAD mouse) 
provide some reassurance that binding of 2A4, an antibody with full effector function, does not 
appear to adversely react with deposited amyloid in tissue. Nevertheless, monitoring for changes 
in disease pathology, as would typically be performed in clinical development, is warranted. 
1.3.2 
Clinical Experience 
The safety and tolerability of NEOD001 are being investigated in an ongoing, open-label, dose 
escalation Phase 1/2 study (Study NEOD001-001) of the IV administration of single-agent 
NEOD001 in subjects with AL amyloidosis in the US. Further details can be found in the latest 
edition of the NEOD001 Investigator’s Brochure. 
As of an interim analysis with a data cutoff date of 30 September 2015, 27 subjects were enrolled 
and treated in the Escalation Phase of the study and 42 subjects were enrolled and treated in the 
Expansion Phase.  
As of the data cutoff, the most frequently reported TEAEs overall in Study NEOD001-001 
(occurring in ≥ 10% of subjects [N=69], regardless of relationship to NEOD001) were fatigue, 
upper respiratory tract infection, diarrhea, nausea, edema, anemia, cough, increased blood 
creatinine, headache, peripheral edema, and rash. No dose limiting toxicities (DLTs) or related 
SAEs have been reported. No systemic hypersensitivity reactions have been reported and there 
have been no clinically significant changes solely attributable to NEOD001 in clinical laboratory 
determinations, vital signs, electrocardiogram (ECG) changes, or physical exams. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 38 of 135 
Based on the data available to date, NEOD001 is safe and well-tolerated in subjects with AL 
amyloidosis and no clinically significant safety signals have been identified.  
1.4 
Rationale for Dose Selection 
The majority of subjects with AL amyloidosis present late in the course of their disease with 
significant organ involvement, especially subjects with cardiac involvement. The amyloid burden 
in each individual subject cannot be determined at baseline and may vary significantly. With 
cardiac involvement, the amyloid burden remains significant and there is an urgency to treat 
cardiac subjects as quickly as possible in an attempt to reduce or reverse the significant cardiac 
morbidity and mortality associated with cardiac AL amyloidosis. Therefore, administering the 
safest, highest tolerated dose is recommended. The highest dose tested in the Phase 1/2 study 
was 24.0 mg/kg, which was deemed to be safe and well-tolerated.  


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 39 of 135 
2 
OBJECTIVES 
2.1 
Primary Objective 
To evaluate the efficacy of NEOD001 plus standard of care vs. placebo plus standard of care 
when administered intravenously in subjects with AL amyloidosis by assessing time to all-cause 
mortality or cardiac hospitalization.  
2.2 
Key Secondary Objectives 
To evaluate NEOD001 plus standard of care compared to placebo plus standard of care on the 
following: 
• Change from baseline in health-related quality of life using the Short Form-36 questionnaire 
(SF-36v2) 
• Change from baseline in cardiac functional response using the 6-Minute Walk Test (6MWT) 
• Cardiac best response rate as assessed by N-terminal pro-brain natriuretic peptide 
(NT-proBNP) (Appendix 1) 
2.3 
Additional Secondary Objectives 
To evaluate NEOD001 plus standard of care compared to placebo plus standard of care in the 
organ-specific populations below. In addition, the safety and tolerability of NEOD001 plus 
standard of care will be evaluated. 
• Renal best response rate using established criteria (Appendix 1) in subjects with renal 
involvement at baseline 
• Change from baseline in peripheral neurological function using the Neuropathy Impairment 
Score – Lower Limbs (NIS-LL; Appendix 10) in subjects with peripheral neuropathy 
involvement at baseline 
• Hepatic best response rate according to consensus criteria (Appendix 1) in subjects with 
hepatic involvement at baseline 
2.4 
Exploratory Objectives 
To evaluate NEOD001 plus standard of care compared to placebo plus standard of care on other 
cardiac, renal, peripheral neuropathy, hepatic, and disease-related clinical outcome measures. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 40 of 135 
3 
STUDY PLAN 
3.1 
Study Design 
This is a multicenter, international, randomized, double-blind, placebo-controlled, two-arm 
efficacy and safety study in subjects with AL amyloidosis. 
Newly diagnosed subjects with AL amyloidosis will be randomized in a 1:1 ratio to NEOD001 
or placebo. Subjects will be stratified at randomization based on three factors: 
• Mayo Clinic Stage (Appendix 2):  Stages I and II vs. Stages III and IV 
• Renal Stage (Appendix 2):  Stage I vs. Stages II and III 
• 6MWT distance:  < 300 meters vs. ≥ 300 meters 
Subjects will remain on study until study completion, which will occur when approximately 
156 primary endpoint events (all-cause mortality or cardiac hospitalizations as adjudicated by the 
CEC) have been reached.  
Each visit will be denoted by its “month” and “day” such that the first study drug (NEOD001 or 
placebo) infusion day is denoted as Month 1-Day 1; subsequent months will use sequential 
numbers (e.g., the second dose is administered on Month 2-Day 1). “Cycle” is reserved to denote 
administration of chemotherapy. Assessment and visit windows are described in the Schedule of 
Events (Table 1). 
If the subject discontinues study drug prior to the end of the study, but is willing to continue to 
participate in study visits, the subject should have an Early Treatment Discontinuation (ETD) 
Visit within 28-35 days after the last study drug administration (per Table 1 and Section 7.1.6) 
and then have assessments every third month per Appendix 3. The most important visit is the 
Month 9-Day 1 Visit, so if a subject is unwilling to continue visits every third month, every 
effort should be made for the subject to return and complete the Month 9-Day 1 Visit on 
schedule. All visits after the ETD Visit should occur on schedule, that is, at the time when the 
visit would have occurred had the subject remained on study drug. 
New SAEs occurring beyond the EOT/ETD Visit or >28 days after the last administration of 
study drug, whichever is later, will be reported to the Sponsor or its designee only if, in the 
judgment of the Investigator, the SAE is associated with any protocol intervention (i.e., related to 
study procedure or previous study drug exposure). 
Follow-up phone calls should be made to randomized subjects (or their caregivers) who received 
a dose of study drug and are no longer receiving study drug every 3 months, beginning 
approximately 3 months from the subject’s last visit (Section 7.1.8). The subject’s health status, 
as well as details of any hospitalizations will be collected accordingly in the study database to 
ensure adequate capture of primary endpoint events. 
At the time of study completion (i.e., once approximately 156 events have been reached), all 
subjects still on study (i.e., subjects still receiving study drug [NEOD001 or placebo] treatment, 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 41 of 135 
subjects who discontinue study drug early but agree to return for assessments after the ETD 
Visit, and subjects participating in the vital status phone call follow up) may be considered for 
entry into a separate open-label extension study of NEOD001. 
3.2 
Rationale for Study Design 
As a pivotal study to support potential licensure, a randomized, double-blind, placebo-controlled, 
parallel-group design was selected as an adequate and well-controlled study to demonstrate the 
safety and efficacy of NEOD001 vs. placebo against a background of standard of care in subjects 
with AL amyloidosis.  
3.3 
Number of Sites and Subjects 
This is a multicenter, international study in approximately 75 centers. Up to 260 subjects will be 
enrolled in the study, with approximately 130 subjects per arm. 
3.4 
Endpoints 
3.4.1 
Efficacy Endpoints 
3.4.1.1 
Primary Efficacy Endpoints 
• Time to all-cause mortality or cardiac hospitalization as adjudicated by the CEC 
3.4.1.2 
Key Secondary Efficacy Endpoints 
• Change from baseline to Month 9 in the Physical Component Summary (PCS) score of the 
SF-36v2 
• Change from baseline to Month 9 in the 6MWT distance (meters) 
• NT-proBNP (cardiac) best response from baseline through Month 9 
3.4.1.3 
Additional Secondary Efficacy Endpoints 
• For renal-evaluable subjects, renal best response from baseline through Month 9  
• For peripheral neuropathy evaluable subjects, change from baseline to Month 9 in the 
NIS-LL total score  
• For hepatic evaluable subjects, hepatic best response from baseline to Month 9  
3.4.1.4 
Exploratory Efficacy Endpoints 
3.4.1.4.1 
Cardiac Endpoints 
3.4.1.4.1.1 
Cardiac Biomarkers (NT-proBNP and Troponin T) 
• Cardiac response (Appendix 1), as assessed by NT-proBNP response criteria, at each visit 
• Cardiac best response (Section 3.4.1.2), as assessed by NT-proBNP response criteria, through 
Month 3 visit, Month 6 visit, and Month 12 visit, and over course of study 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 42 of 135 
• Change and percent change from baseline in NT-proBNP and troponin T at each visit 
3.4.1.4.1.2 
Select Echocardiogram Cardiac Parameters 
• Change and percent change from baseline to each visit in selected cardiac parameters, as 
determined by a 4-chamber view from a 2-dimensional echocardiogram with Doppler, as 
follows: 
o 
LVEF = Left ventricular ejection fraction 
o 
IVSd = Intraventricular septal at end diastole 
o 
LPWd = Left posterior wall at end diastole 
3.4.1.4.2 
Functional Endpoint 
3.4.1.4.2.1 
6MWT Distance 
• Change and percent change from baseline in the 6MWT distance (meters) to each visit 
(except Month 9 [key secondary endpoint]) 
3.4.1.4.3 
Quality of Life Endpoints 
3.4.1.4.3.1 
SF-36v2 
• Change and percent change from baseline in SF-36v2 PCS score (except Month 9 [key 
secondary endpoint]), Mental Component Summary score, and the 8 subscales to each visit 
3.4.1.4.3.2 
KCCQ 
• Change and percent change from baseline in KCCQ subscores and overall summary score to 
each visit 
3.4.1.4.4 
Renal Endpoints 
The following endpoints will be evaluated in the Renal Evaluable Population. 
3.4.1.4.4.1 
Renal Response 
• Renal response (Appendix 1) at each visit 
• Renal best response through Month 3 visit, Month 6 visit, and Month 12 visit, and over 
course of study 
3.4.1.4.4.2 
Creatinine, Proteinuria, and Estimated Glomerular Filtration Rate (eGFR) 
• Change and percent change from baseline to each visit in creatinine, proteinuria, and eGFR 
• Time to eGFR ≤15 mL/min/1.73m2 (Chronic Kidney Stage 5) 
• Shifts from baseline in Chronic Kidney Stage 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 43 of 135 
• Time to doubling of creatinine 
3.4.1.4.5 
Peripheral Neuropathy Endpoints 
The following endpoints will be evaluated in the Peripheral Neuropathy Evaluable Population. 
3.4.1.4.5.1 
NIS-LL Total Score 
• Change and percent change from baseline in the NIS-LL total score to each visit (except 
Month 9 [additional secondary endpoint] 
• Peripheral neuropathy response (Appendix 1) at each visit 
• Peripheral neuropathy best response through Month 3 visit, Month 6 visit, Month 9 visit, and 
Month 12 visit, and over course of study 
3.4.1.4.5.2 
NIS-LL Component Scores 
• Change and percent change from baseline in the 3 NIS-LL component scores (sensory 
function, reflexes, muscle strength) to each visit 
3.4.1.4.5.3 
Visual Analog Score – Pain Intensity (VASPI) 
• Change and percent change from baseline to each visit in the VASPI score (for peripheral 
neuropathy evaluable subjects with painful neuropathy, defined as a baseline VASPI score 
>0) 
3.4.1.4.6 
Hepatic Endpoints 
The following endpoints will be evaluated in the Hepatic Evaluable Population. 
3.4.1.4.6.1 
Hepatic Response 
• Hepatic response (Appendix 1) at each visit 
• Hepatic best response through Month 3 visit, Month 6 visit, and Month 12 visit, and over 
course of study 
• Change and percent change in ALP to each visit 
3.4.1.4.6.2 
Liver Size 
• Change and percent change from baseline to each visit in liver size (i.e., craniocaudal 
dimension) 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 44 of 135 
3.4.1.4.7 
Additional Time-to-Event Endpoints 
• Time to cardiac mortality at any time or cardiac hospitalization (occurring ≥91 days after a 
subject’s first infusion of study drug) as adjudicated by the CEC 
• Time to cardiac mortality as adjudicated by the CEC 
• Progression-free survival 
• Time to hematologic progression 
• Time to derived organ progression (Appendix 1) for each organ (cardiac/NT-proBNP, renal, 
peripheral neuropathy, hepatic) separately and to any organ progression 
• Time to first organ response (Appendix 1) for each organ (cardiac/NT-proBNP, renal, 
peripheral neuropathy, hepatic) separately and to any organ response 
3.4.1.4.8 
Other Efficacy Endpoints 
3.4.1.4.8.1 
Cardiac Hospitalizations 
• Frequency of cardiac hospitalizations over the course of the study 
3.4.1.4.8.2 
ECOG Performance Status, NYHA Class, Mayo Clinic Stage, Renal Stage 
• ECOG Performance Status, NYHA Class, Mayo Clinic Stage, and Renal Stage at each visit 
including any changes from baseline 
3.4.1.4.8.3 
Selected Hematologic and Urine Analyte Endpoints 
• Change and percent change from baseline in serum free light chains (sFLCs), serum and 
24-hour urine PEP, and serum and urine IFE to each visit 
• Hematologic response (Appendix 6) at each visit 
• Hematologic best response through Month 3 visit, Month 6 visit, Month 9 visit, and 
Month 12 visit, and over course of study 
3.4.1.4.8.4 
Disease-Related Symptoms 
• Change from baseline in disease-related symptoms at each visit 
3.4.1.4.8.5 
Pharmacokinetics 
Data on serum NEOD001 concentrations from this study will be pooled with data from similar 
samples from other studies in a population PK analysis.  


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 45 of 135 
3.4.2 
Safety Endpoints 
• Safety as assessed by vital signs, 12-lead ECGs, routine laboratory assessments, frequency 
and severity of AEs, and immunogenicity 
3.5 
Estimated Study Duration 
Subject’s participation in the study will begin with a 28-day Screening period; if they are 
assessed as eligible for enrollment, they will be randomized and will receive study drug 
intravenously every 28 days. Subjects will remain on study until study completion, which will 
occur when approximately 156 primary endpoint events have been reached. Therefore, subjects 
who enroll at the beginning of the study may remain on study for a longer period of time (as long 
as approximately 3.5-4 years) than subjects enrolled closer to the end of the study, who may only 
be on study for up to approximately 1.5-2 years. At the time of study completion (i.e., once 
approximately 156 primary endpoint events have been reached), all subjects still on study 
(i.e., subjects still receiving study drug [NEOD001 or placebo] treatment, subjects who 
discontinue study drug early but agree to return for assessments after the ETD Visit, and subjects 
participating in the vital status phone call follow up) may be considered for entry into a separate 
open-label extension study of NEOD001. 
3.6 
Definition of Primary Endpoint and End of Study 
The study will end when approximately 156 primary endpoint events have occurred and EOT 
Visits have been completed for all subjects who remain on study at that time. Events are defined 
as deaths due to any cause, and AL amyloidosis-related cardiac hospitalizations as adjudicated 
by the CEC. 
3.7 
Termination of the Clinical Study 
If the Investigator, the Sponsor, or the Medical Monitor becomes aware of conditions or events 
that suggest a possible hazard to subjects if the clinical study continues, then the clinical study 
may be terminated. The clinical study may also be terminated at the Sponsor’s discretion in the 
absence of such a finding, at any time and for any reason. 
Conditions that may warrant termination of the clinical study include, but are not limited to: 
• The discovery of an unexpected, relevant, or unacceptable risk to the subjects enrolled in the 
clinical study 
• Failure to enroll subjects at the required rate 
• A decision by the Sponsor to suspend the study, or to suspend or discontinue development of 
the study drug, for any reason 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 46 of 135 
4 
SUBJECT SELECTION 
4.1 
Inclusion Criteria 
Subjects must meet all of the following criteria: 
1. 
Aged ≥ 18 years 
2. 
Newly diagnosed and AL amyloidosis treatment naïve 
3. 
Bone marrow demonstrating clonal plasma cells 
4. 
Confirmed diagnosis of AL amyloidosis by the following: 
o 
Histochemical diagnosis of amyloidosis determined by polarizing light microscopy of 
green birefringent material in Congo red-stained tissue specimens OR characteristic 
electron microscopy appearance  
 
AND 
o 
Confirmatory immunohistochemistry OR mass spectroscopy of AL amyloidosis 
5. 
Confirmed diagnosis of AL amyloidosis by mass spectrometry or immunoelectron 
microscopy of amyloid material in tissue biopsy if the subject meets any of the following: 
o 
Is black or African American 
o 
Is over 75 years of age with concurrent monoclonal gammopathy 
o 
Has a history of familial amyloidosis and has concurrent monoclonal gammopathy 
OR 
o 
If the subject meets any of the above 3 conditions and has echocardiographic evidence 
of amyloidosis, biopsy-proven amyloidosis with a monoclonal gammopathy and no 
tissue is available for mass spectrometry or immunoelectron microscopy, the subject 
must have gene sequencing consistent with transthyretin (TTR) wild type (e.g., no TTR 
mutation present) AND must score 0 in technetium-99m-3,3-diphosphono-1,2 
propanodicarboxylic acid (99mTc-DPD; Rapezzi 2011), 
hydroxymethylenediphosphonate (99mTc-HMDP; Galat 2015), or pyrophosphate 
(99mTc-PYP; Bokhari 2013) scintigraphy 
6. 
Cardiac involvement as defined by all of the following: 
o 
Past documented or presently noted clinical signs and symptoms supportive of a 
diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in 
the absence of an alternative explanation for heart failure 
o 
Either an endomyocardial biopsy demonstrating AL amyloidosis or an echocardiogram 
demonstrating a mean left ventricular wall thickness at diastole > 12 mm in the absence 
of other causes (e.g., severe hypertension, aortic stenosis), which would adequately 
explain the degree of wall thickening  
o 
NT-proBNP ≥ 650 pg/mL and ≤ 8500 pg/mL 
7. 
Planned first-line chemotherapy contains bortezomib administered weekly and SC 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 47 of 135 
8. 
Adequate bone marrow reserve, hepatic function, and renal function, as demonstrated by: 
o 
Absolute neutrophil count (ANC) ≥ 1.0 × 109/L 
o 
Platelet count ≥ 75 × 109/L 
o 
Hemoglobin ≥ 9 g/dL 
o 
Total bilirubin ≤ 2 times the upper limit of normal (× ULN) 
o 
Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) 
≤ 3 × ULN  
o 
Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) 
≤ 3 × ULN 
o 
Alkaline phosphatase (ALP) ≤ 5 × ULN (except for subjects with hepatomegaly and 
isozymes specific to liver, rather than bone) 
o 
Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 as estimated by the 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation  
9. 
Seated systolic blood pressure (BP) 90-180 mmHg 
10. 
Distance walked during each Screening 6MWT is > 30 meters and < 550 meters 
11. 
Women of childbearing potential (WOCBP) must have two negative pregnancy tests 
during Screening, the second within 24 hours prior to the first administration of study drug, 
and must agree to use highly effective physician-approved contraception (Appendix 4) 
from Screening to 90 days following the last study drug administration  
12. 
Male subjects must be surgically sterile or must agree to use highly effective physician-
approved contraception (Appendix 4) from Screening to 90 days following the last study 
drug administration 
13. 
Ability to understand and willingness to sign an informed consent form prior to initiation 
of any study procedures 
4.2 
Exclusion Criteria 
Subjects must meet none of the following criteria: 
1. Non-AL amyloidosis 
2. NT-proBNP < 650 pg/mL or > 8,500 pg/mL 
3. Meets the International Myeloma Working Group (IMWG) definition of Multiple 
Myeloma (Appendix 5)  
*Note that subjects who meet the IMWG definition of symptomatic multiple myeloma with 
symptoms attributable only to associated amyloidosis are potentially eligible upon approval 
of the Sponsor. 
4. Subject is eligible for and plans to undergo ASCT or organ transplant 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 48 of 135 
5. Symptomatic orthostatic hypotension that in the medical judgment of the Investigator 
would interfere with subject’s ability to safely receive treatment or complete study 
assessments 
6. Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias, 
or ECG evidence of acute ischemia, within 6 months prior to the Month 1-Day 1 Visit 
7. Severe valvular stenosis (e.g. aortic or mitral stenosis with a valve area <1.0 cm2) or severe 
congenital heart disease 
8. ECG evidence of acute ischemia or active conduction system abnormalities with the 
exception of any of the following: 
• First degree AV-block 
• Second degree AV-block Type 1 (Mobitz Type 1 / Wenckebach type) 
• Right or left bundle branch block 
• Atrial fibrillation with a controlled ventricular rate (uncontrolled [i.e., >110 bpm] 
ventricular rate is not allowed [determined by an average of three beats in Lead II or 
three representative beats if Lead II is not representative of the overall EKG]) 
9. Peripheral neuropathy assessed as National Cancer Institute-Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) Grade 2 with pain, Grade 3, or Grade 4 
10. Subject is receiving oral or IV antibiotics, antifungals or antivirals within 1 week of 
Month 1-Day 1 with the exception of prophylactic oral agents 
11. Prior treatment with hematopoietic growth factors, transfusions of blood or blood 
products within 1 week of Month 1-Day 1 
12. Prior radiotherapy within 4 weeks of Month 1-Day 1 
13. Major surgery within 4 weeks of Month 1-Day 1 or planned major surgery during the 
study 
14. Active malignancy with the exception of any of the following: 
• Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical 
cancer 
• Adequately treated Stage I cancer from which the subject is currently in remission 
and has been in remission for 2 years 
• Low-risk prostate cancer with Gleason score < 7 and prostate specific antigen 
< 10 ng/mL 
• Any other cancer from which the subject has been disease-free for ≥ 2 years 
15. History of severe allergy to any of the components of NEOD001 such as histidine/L 
histidine hydrochloride monohydrate, trehalose dehydrate, or polysorbate 20 or history of 
Grade ≥ 3 infusion-related AEs or hypersensitivity to another monoclonal antibody, or 
known hypersensitivity to diphenhydramine (or an equivalent H1 antihistamine) or 
acetaminophen (or its equivalent, paracetamol) 
16. Known or history of uncontrolled, active HIV, hepatitis B or hepatitis C infection 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 49 of 135 
17. Prior treatment with plasma cell-directed chemotherapy, NEOD001, 11-1F4, anti-serum 
amyloid P antibody, doxycycline for amyloid, or other investigational treatment directed 
at amyloid 
18. Treatment with another investigational agent within 30 days of Month 1-Day 1 
19. Women who are pregnant or lactating 
20. Any condition which could interfere with, or the treatment for which might interfere 
with, the conduct of the study or which would, in the opinion of the Investigator, 
unacceptably increase the subject’s risk by participating in the study 
21. Subject is under legal custodianship 
22. History of epilepsy or seizure disorder with the exception of childhood febrile seizures 
23. Waldenström's macroglobulinemia and/or immunoglobulin M (IgM) monoclonal 
gammopathy 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 50 of 135 
5 
SUBJECT SCREENING AND RANDOMIZATION 
A 4-digit Subject Screening Number will be assigned via a phone- and web-based registration for 
each subject who has signed an informed consent. This Screening Number will be utilized for 
submission of lab samples, Screening ECGs, and other Screening procedures.  
After a subject has completed all Screening requirements and meets all of the eligibility criteria, 
a Patient Registration Form should be submitted within several days prior to Month 1-Day 1 for 
eligibility review and approval by the Medical Monitor or designee. If approved, randomization 
will be implemented through a phone call or via the Internet connection to an Interactive Voice 
and Web Response System (IXRS) utilizing results from Screening assessments. Eligible 
subjects will be randomized in a 1:1 ratio into one of two arms, NEOD001 24 mg/kg or placebo. 
The randomization will be stratified by three factors: 
• Mayo Clinic Stage (Appendix 2):  Stages I and II vs. Stages III and IV 
• Renal Stage (Appendix 2):  Stage I vs. Stages II and III 
• 6MWT distance:  < 300 meters vs. ≥ 300 meters 
Upon successful randomization, the subject will be assigned a 6-digit Subject ID consisting of 
the 3-digit site number plus the 3-digit subject number, and the Unblinded Pharmacist or their 
designee (henceforth collectively referred to as the Unblinded Pharmacy Staff) will be provided 
access to the treatment assignment. Subject IDs that are assigned to subjects who are randomized 
but do not receive study drug will not be re-utilized. Each arm of this 2-arm study will consist of 
approximately 130 subjects for an estimated total of 260 subjects. 
Refer to the Study File Notebook for additional details. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 51 of 135 
6 
INVESTIGATIONAL MEDICINAL PRODUCT AND TREATMENT 
6.1 
Formulation, Packaging, and Labeling of NEOD001 
The active study drug, NEOD001, is supplied as a sterile, single-use, lyophilized dosage form in 
a 20/25 mL vial containing 500 mg/vial NEOD001. After reconstitution with 9.6 mL of sterile 
water for injection (WFI), the vial will contain 50 mg/mL of NEOD001, 25 mM L-Histidine, 
230 mM Trehalose, and 0.02% Polysorbate 20.  
At a minimum, the label for each vial shipped to a clinical site will provide the following 
information:  batch number/lot number, required storage conditions, directions for use, and any 
region-specific caution statements, e.g. “New Drug - Limited by United States Federal Law to 
Investigational Use.” 
6.2 
Shipping, Storage, and Handling of NEOD001 
NEOD001 will be shipped to clinical sites in individual cartons (one vial per carton). Upon 
receipt, a study staff member will place the study drug in a refrigerator at a temperature ranging 
from 2 to 8°C in a secure, locked location. Access to the study drug should be strictly limited to 
the Unblinded Pharmacy Staff. Neither the Investigator nor any member of the study staff will 
distribute any of the study supplies to any person who is not participating in this study.  
If a study staff member becomes aware that the study drug has not been properly handled (e.g., 
physical damage to carton/vial, temperature outside the 2ºC to 8ºC range in transit, or not stored 
at 2ºC to 8ºC in the clinic), follow the procedure outlined in the Pharmacy Manual or 
immediately contact the Unblinded Monitor (contact information available in the Study File 
Notebook). In such an event, study drug should be quarantined in a 2 to 8°C refrigerator and 
must not be administered to any subject until the drug has been approved for use. 
It is expected that the site staff will maintain refrigerator temperature logs in the investigational 
product storage area, recording the temperature at least once each working day.  
See the Pharmacy Manual for further details about shipping, storage, and handling of NEOD001.  
6.3 
Placebo 
A matching placebo will not be provided for this study. Subjects who are randomized to the 
placebo arm will be administered a 250 mL IV bag of 0.9% saline, which will look identical to 
the NEOD001 infusion bag.  
6.4 
Accountability and Return of Study Drug Supplies 
The study drug will be dispensed at the discretion of the Investigator under the direction of the 
Unblinded Pharmacy Staff, in accordance with the conditions specified in this protocol. It is the 
Unblinded Pharmacy Staff’s responsibility to ensure that accurate records of study drug 
disposition and return are maintained. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 52 of 135 
6.5 
Dosage, Administration, and Schedule 
6.5.1 
Study Drug 
Study drug consists of IV NEOD001 or placebo. The NEOD001 dose is 24 mg/kg; however, the 
maximum dose administered is not to exceed 2500 mg. Therefore, subjects with a weight of 
104.2 kg or greater will receive the maximum dose of 2500 mg. The subject’s weight during 
Screening may be used for calculation of the first dose. Subsequent doses may be calculated 
based on the current weight at that visit or by using the baseline weight, based on the site’s 
institutional guidelines. A change of ±10% from the weight being used for dosing should trigger 
recalculation of the dose based on the new weight. 
Each vial of 500 mg of NEOD001 will be reconstituted with 9.6 mL sterile WFI to a 
concentration of 50 mg/mL resulting in a buffered, isotonic, preservative-free solution with a 
total extractable volume of 10 mL. Study drug will be prepared in a 250-mL IV bag of 0.9% 
saline. The equivalent volume of reconstituted NEOD001 will be withdrawn prior to transferring 
the drug solution into the IV bag, such that the total IV bag volume will be 250 mL. Each vial of 
NEOD001 is single-use – if there is residual drug in a vial after treating a subject, it should not 
be used for another subject and must be destroyed. Refer to the Pharmacy Manual for complete 
information on preparing and administering the study drug. 
Subjects who are randomized to the placebo arm will be administered a 250 mL IV bag of 0.9% 
saline, which will look identical to the NEOD001 infusion bag.  
The Unblinded Pharmacy Staff at each site will be responsible for preparing the study drug; all 
other study team members, including the Sponsor and site monitor, must remain blinded to study 
drug assignment. The Unblinded Pharmacy Staff will obtain the treatment assignment 
information from the IXRS, and will then prepare and reconstitute the study drug, providing the 
prepared IV bag to the Investigator for administration. The Unblinded Pharmacy Staff will 
maintain the records for drug accountability for audits or inspections. An Unblinded Monitor will 
be assigned as the Sponsor’s designee to perform drug accountability and as such, will be the 
Unblinded Pharmacy Staff’s primary point of contact for any study drug-related issues. 
The study drug should only be administered in settings where emergency resuscitative equipment 
and personnel trained in the management of anaphylaxis are immediately available to treat 
systemic reactions under the direct supervision of a physician.  
The study drug will be administered once every 28 days from the time the subject is randomized 
until the EOT/Early Treatment Discontinuation (ETD) Visit, as an initial 120 (±10) minute IV 
infusion on Month 1-Day 1. If the subject tolerates the initial administration without 
infusion-related AEs, subsequent infusions may be administered over 60 (±10) minutes. If there 
is concern about infusing 250 mL over 60 (±10) minutes in any specific subject, the length of the 
infusion may be extended over a longer period of time as clinically indicated. If it is anticipated 
that the infusion will extend beyond 4 hours, the reconstituted and diluted study drug should be 
split into multiple bags to ensure that no amount of reconstituted study drug will be at room 
temperature for longer than 4 hours (i.e., from the time of reconstitution of the vial to end of the 
infusion of a bag). The additional bag(s) should remain refrigerated until ready for use. The 
volume contained in the administration tubing should be completely flushed using approximately 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 53 of 135 
30 mL of 0.9% Sodium Chloride Injection (USP) after administration of study drug. The infusion 
line should NOT be used for blood draws.  
Every effort must be made to ensure doses are given 28 days from the previous dose. If logistic 
considerations intervene, a minimum of 21 days between doses is required. All subjects will be 
closely monitored for 90 (±10) minutes after completion of the study drug infusion. The 
Investigator may increase this standard monitoring time if deemed appropriate or per local 
standards. In the event of any clinical concerns or suspicious signs or symptoms after the 
infusion, the subject will remain under observation for as long as the Investigator deems it 
appropriate. 
6.5.2 
Study Drug Premedication 
All subjects will be premedicated with 25 mg diphenhydramine (or an equivalent dose of a H1 
antihistamine) and 650 mg acetaminophen (or an equivalent paracetamol dose) within 
30-90 minutes prior to study drug administration. 
6.5.3 
Standard of Care Chemotherapy 
All subjects will receive concomitant standard of care chemotherapy. The initial first-line 
chemotherapy regimen must include bortezomib, which must be administered SC on a weekly 
basis. Subsequent chemotherapy regimens may be prescribed as per standard of care at the 
Investigator’s discretion. Bortezomib should be administered according to the approved 
prescribing information and local institutional practices. Antiviral prophylaxis is required. When 
chemotherapy is administered on same day as study drug, the chemotherapy must be 
administered after the 90 (±10)-minute post-study drug infusion observation period. 
The number of cycles of first-line chemotherapy that is administered is at the discretion of the 
Investigator; however, commonly accepted treatment practice suggests that a change in plasma 
cell-directed chemotherapy may occur in any of the following circumstances: 
In subjects who are at high risk for complications due to Mayo Stage III or IV (Appendix 2):  a 
change in therapy should be considered if they fail to attain at least a hematologic partial 
response by 6 weeks or a very good partial response by 3 months. 
• In subjects who are Mayo Stage I or II (Appendix 2):  a change in therapy should be 
considered if they fail to attain at least a hematologic partial response by 3 months or a very 
good partial response by 6 months. 
• Withdrawal of consent 
• Unacceptable toxicity 
• Investigator decision 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 54 of 135 
The Investigator may prescribe subsequent chemotherapy at his/her discretion as per standard of 
care. Particular care must be taken to accurately report chemotherapy administration, including 
missed or delayed doses, and dose reductions. The Sponsor does not intend to provide 
reimbursement for standard of care chemotherapy. 
In the event that bortezomib doses are missed, the chemotherapy cycles may become misaligned 
with the monthly study drug dosing. In this case, the weekly visits during Months 1 through 3 
should continue as described above in order to closely monitor subjects’ health during the initial 
months of concomitant chemotherapy. Throughout the study, monthly doses of study drug 
should not be delayed or skipped due to adjustments that are made to chemotherapy dosing. 
Study drug dosing adjustments are described in Section 6.6. 
6.6 
Dosage Adjustments 
6.6.1 
Withholding of Study Drug 
Subjects with symptomatic orthostatic hypotension which in the medical judgment of the 
Investigator would interfere with subject’s ability to safely receive treatment will have study 
drug withheld until the next scheduled monthly administration, but should still have all other 
study visit assessments completed. Subjects who have had study drug withheld for two 
consecutive scheduled monthly treatments and who require study drug to be withheld during the 
subsequent, third consecutive scheduled monthly treatment visit will have study drug 
permanently discontinued and have an ETD Visit per Section 7.1.5. 
Throughout the study, monthly doses of study drug should not be delayed or skipped due to 
adjustments that are made to chemotherapy dosing. 
6.6.2 
Management of Suspected Infusion-Related/Hypersensitivity Adverse Events 
In the event of a suspected infusion-related and/or hypersensitivity adverse event (AE), the 
infusion should be immediately discontinued and appropriate supportive therapy should be 
administered per institutional practice, which may include epinephrine, IV fluids, corticosteroids, 
vasopressors, oxygen, bronchodilators, antihistamines or acetaminophen/paracetamol. Subjects 
should be evaluated and carefully monitored until there is complete resolution of the AE (i.e., all 
hypersensitivity signs and symptoms have resolved). In addition to the institution’s 
recommended assessments, blood samples should be obtained in the event of a suspected 
infusion-related and/or hypersensitivity AE for assessment of the following:  tryptase, 
complements C3 and C4, PK, and anti-NEOD001 antibody levels. 
For subjects with a Grade 2 infusion-related AE, if it is appropriate to restart the infusion, then 
this should be done at 50% of the original rate (i.e., if the initial infusion is administered over 
120 minutes, the new rate should be based on administering 250 mL over at least 180 minutes). 
If the subject is to receive additional infusions in subsequent weeks, then the rate of these 
infusions should be discussed with and agreed upon prospectively by the Investigator and the 
Medical Monitor. 
If a subject experiences a Grade 3 infusion-related and/or hypersensitivity AE, the infusion 
should not be restarted. The decision to continue dosing this subject at their next scheduled 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 55 of 135 
administration should be discussed with the Medical Monitor. If the decision is made to proceed 
with dosing, the dose will be reduced by 50%, in addition to a 50% reduction of the original 
infusion rate (i.e., 250 mL over at least 180 minutes). In addition, maximal premedication must 
be administered according to institutional practice and should include an H1 blocker, an H2 
blocker, an antipyretic such as acetaminophen/paracetamol and a steroid (e.g., 25-50 mg 
hydrocortisone IV). Subjects who have an infusion-related and/or hypersensitivity AE at the 
subsequent scheduled study drug administration must have study drug permanently discontinued 
and have an ETD Visit per Section 7.1.5. 
Subjects who experience a Grade 4 infusion-related and/or hypersensitivity AE must have study 
drug permanently discontinued and have an ETD Visit per Section 7.1.5. 
6.6.3 
Dose Reductions 
Dose reductions may be allowed in the event that AEs are observed that are believed to be 
related to study drug, and which in consultation between the Investigator and the Medical 
Monitor, may be managed by a 50% reduction in dose. The duration of the dose reduction will 
be at the Investigator’s discretion. 
6.7 
Treatment Compliance 
Treatment compliance is assured as study drug will be administered at the study site. Any 
changes in volume or rate of administration will be recorded on the eCRF, along with reasons 
why treatment was adjusted or not administered, if applicable. 
6.8 
Concomitant Therapy 
Concomitant medication includes any drug (prescription or over-the-counter) or biological 
product (such as vaccines, blood or blood components) including herbal remedies or 
preparations. All medications that are taken by a subject within the 28 days prior to the 
Month 1-Day 1 Visit through the EOT/ETD Visit, and any changes to concomitant medications 
during the study will be recorded on the appropriate eCRF. 
6.8.1 
Allowed Concomitant Therapy 
• All supportive concomitant therapy 
• Medications such as anti-emetics required for prophylaxis of emesis for the subsequent 
chemotherapy are allowed, but should be administered after the post-infusion ECG has been 
completed 
• Radiation therapy for the removal of local amyloid deposits 
• Steroids are allowed for the treatment of AL amyloidosis during the study. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 56 of 135 
6.8.2 
Prohibited Concomitant Therapy 
• Other investigational agents (e.g., drugs not approved for any indication) 
• Myeloablative chemotherapy with ASCT 
• Organ transplant 
• Doxycycline 
• Steroids are not allowed PRIOR to study entry for the treatment of AL amyloidosis 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 57 of 135 
7 
STUDY PROCEDURES 
7.1 
Study Visits and Assessments 
7.1.1 
First Screening Visit: Day -28 to Day -1 
Screening will take place within the 28 days prior to the first administration of study drug on 
Month 1-Day 1. The Screening period may be extended upon approval by the Medical Monitor. 
Individual test results that do not meet eligibility requirements may be repeated, with the 
exception of 6MWT; full rescreening is allowed once per subject. 
Subjects should have bone marrow demonstrating clonal plasma cells within 90 days prior to 
Screening Day -28. 
Two pre-treatment 6MWTs are required before the first administration of study drug. The first 
Screening 6MWT is required to be performed between Days -28 and -5, at least 4 days prior to 
the second Screening 6MWT, which should be performed within 2 days prior to Month 1-Day 1 
(i.e., on Day -2 or Day -1). Although the entire Screening period does not need to be utilized, a 
minimum of 5 days must be allowed to accommodate the required 4-day interval between the 
two Screening 6MWTs. Subjects should plan to be able to return to the same clinical site for 
each 6MWT from first Screening through Month 9. 
Written informed consent must be obtained before any study-specific screening evaluations are 
performed and should be documented in the subject’s medical chart. 
The following will be performed between Days -28 and -1 prior to the Month 1-Day 1 Visit, 
unless otherwise noted: 
• Obtain written informed consent 
• Review inclusion and exclusion criteria to assess eligibility 
• Obtain comprehensive cardiac, hematologic and oncologic medical history; additionally for 
all other conditions obtain relevant medical history for the past 5 years (including all major 
hospitalizations and surgeries), as well as the subject’s current medical status 
• Confirmation of AL amyloidosis by mass spectrometry tissue typing, immunoelectron 
microscopy, gene sequencing, and/or 99mTc scintigraphy must be completed, and results 
obtained prior to randomization, for subjects who meet Inclusion Criterion #5 
• Functional Assessment of Cancer Therapy – Gynecologic Oncology Group Neurotoxicity 
Subscale (FACT-GOG NTX) - should be performed prior to any other study assessments on 
the day it is administered 
• Echocardiogram - To be eligible for the additional cardiac imaging analysis, the subject must 
have had a 4-chamber view, 2-dimensional echocardiogram with Doppler. If an 
echocardiogram has been conducted within 90 days prior to Screening Day -28, it does not 
need to be repeated during Screening and the previous result can be used for eligibility. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 58 of 135 
• CT imaging of the abdomen for liver measurement for subjects with liver involvement based 
on ALP >1.5 × ULN (Section 7.6) (Exception: not required in Germany). The dimension that 
is measured at Screening (i.e., craniocaudal) should be consistently measured for all 
subsequent assessments for the same subject. If CT imaging of the abdomen for liver 
measurement has been conducted within 60 days prior to Screening Day -28 and it meets 
acquisition guidelines, it does not need to be repeated during Screening and the previous 
result can be used for eligibility. 
• 12-lead ECG performed in triplicate 
• Complete physical exam (PE) including height (Screening only), weight, and examination of 
general appearance; head, ears, eyes, nose, and throat; neck; skin; cardiovascular system; 
respiratory system; gastrointestinal system; and nervous system. The following should be 
assessed:  macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, liver/spleen 
size (palpable +/-), ascites (+/-), and edema (which should be quantified on a scale of 0-4).  
• ECOG PS (Appendix 13) 
• NYHA class (Appendix 14) 
• Determine if a subject has AL amyloidosis disease-related peripheral neuropathy prior to 
administration of study drug and administer the following to all subjects: 
o 
NIS-LL (Section 7.4 and Appendix 10) 
o 
VASPI (Section 7.4 and Appendix 11) 
• Central Laboratory Assessments – Collect samples prior to 6MWT, if being performed on the 
same day: 
o 
Hematology:  complete blood count (CBC) with differential, hemoglobin (Hgb), 
hematocrit (Hct), and platelet count 
o 
Chemistry:  sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), 
creatinine, creatinine clearance, glucose, ALT, AST, ALP, total bilirubin, direct 
bilirubin, lactate dehydrogenase (LDH), eGFR, total protein, albumin, calcium, 
phosphate, and magnesium (and isozymes for subjects with ALP > 5 × ULN) 
o 
Amylase 
o 
Troponin T 
o 
NT-proBNP  
o 
sFLCs 
o 
Serum pregnancy test for women of childbearing potential (WOCBP); note that women 
with tubal ligations are considered to be of childbearing potential but women who are 
surgically sterile (hysterectomy) or post-menopausal ≥ 2 years are not considered to be 
of childbearing potential 
o 
Serum immunofixation electrophoresis (IFE) and protein electrophoresis (PEP) 
o 
Urinalysis 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 59 of 135 
o 
24-hour urine collection (see Section 7.3) for:  
 Urine protein excretion 
 Urine IFE and PEP 
• First Screening 6MWT – must be performed between Days -28 and -5, at least 4 days prior to 
the second Screening 6MWT, which should be performed within 2 days prior to Month 
1-Day 1 (i.e., on Day -2 or Day -1); collect BP and HR pre- and post-6MWT administration 
• Vital signs, including BP, heart rate (HR), respiratory rate (RR), and temperature – after the 
subject has been at rest for ≥ 5 minutes 
• Record all medications and therapy beginning with Day -28 
• Assess for AEs after written informed consent is obtained 
7.1.2 
Second Screening Visit:  Day -2 or Day -1 
The following assessments will be conducted on Day -2 or Day -1 (i.e., 1-2 days prior to dosing 
on Month 1-Day 1):  
• Administer questionnaires in the following order, prior to conducting any other assessments 
on the day they are administered: 
o 
SF-36v2 Questionnaire (Appendix 7) 
o 
KCCQ (Appendix 8) 
o 
FACT-GOG NTX (Section 7.4 and Appendix 9) 
• Central Laboratory Assessments – Collect samples prior to 6MWT, if being performed on the 
same day: 
o 
Hematology:  CBC with differential, Hgb, Hct, and platelet count 
o 
Chemistry:  sodium, potassium, chloride, bicarbonate, BUN, creatinine, creatinine 
clearance, glucose, ALT, AST, ALP, total bilirubin, direct bilirubin, LDH, eGFR, total 
protein, albumin, calcium, phosphate, and magnesium 
o 
Amylase 
o 
PT/INR and PTT 
o 
Additional coagulation samples per Appendix 12 
o 
Complements C3 and C4 
o 
Troponin T 
o 
NT-proBNP 
o 
Tryptase 
o 
sFLCs 
o 
Urinalysis 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 60 of 135 
o 
24-hour urine collection (see Section 7.3) for urine protein excretion 
• Second Screening 6MWT; collect BP and HR pre- and post-6MWT administration 
• Ensure all medications and therapy beginning with Day -28 have been recorded 
• Assess for AEs as of the first Screening visit 
7.1.3 
Randomization 
If the subject meets all eligibility criteria after completion of Screening assessments, 
randomization will occur per Section 5. After the subject is randomized, Month 1-Day 1 
assessments will be completed and treatment will be initiated.  
7.1.4 
Treatment Visits 
Subjects will receive study drug as an IV infusion every 28 days. Assessment and visit windows 
are described in the Schedule of Events (Table 1) and in the sections below; the study drug 
dosing window is described in Section 6.5.1. The pre-dose assessments for each visit may be 
performed within the 2 days prior to the visit.  
Although central laboratory assessments will be performed each month for study analysis, local 
laboratory assessments, including hematology and chemistry, will be performed for subject 
management. Results will be reviewed prior to dosing and prior to in-clinic bortezomib 
administration, to confirm that continued dosing is appropriate.  
Subjects who present with symptomatic orthostatic hypotension, which in the medical judgment 
of the Investigator would interfere with the subject’s ability to safely receive treatment, will have 
the study drug withheld. If the study drug is withheld and subsequently rescheduled, central 
laboratory assessments required for that visit will need to be repeated if they were drawn more 
than 7 days prior to the rescheduled dosing date. However, a symptom-directed PE and vital 
signs need to be repeated prior to each dosing. Subjects who have had study drug withheld for 
more than two consecutive scheduled treatments (i.e., if a third consecutive infusion needs to be 
withheld) will be withdrawn from the study.  
Additional anti-NEOD001 antibody and PK samples should be collected if significant toxicity is 
observed (e.g., an infusion reaction in the clinic, anaphylaxis, etc.) and if possible, should be 
collected while the acute symptoms persist.  
If the subject discontinues study drug treatment prior to the end of the study, refer to Section 8.2.  
7.1.4.1 
Month 1-Day 1 
The subject must return to the study site for the following procedures: 
Prior to Study Drug Infusion: 
• FACT-GOG NTX (Section 7.4 and Appendix 9) – prior to any other study assessments on 
the day it is administered 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 61 of 135 
• Symptom-directed PE should be as clinically indicated and also include weight and 
assessment of macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, 
liver/spleen size (palpable +/-), ascites (+/-), and edema (which should be quantified on a 
scale of 0-4) 
• ECOG PS (Appendix 13) 
• NYHA class (Appendix 14) 
• NIS-LL (Section 7.4 and Appendix 10) 
• VASPI (Section 7.4 and Appendix 11)  
• Local Laboratory Assessment: 
o 
Serum Pregnancy Test for WOCBP within 24 hours prior to Month 1-Day 1 study drug 
administration; test results must be obtained prior to dosing and must be negative 
• Bioanalytical Laboratory Assessments – any time on Month 1-Day 1, prior to the start of the 
infusion: 
o 
Pre-dose PK sample  
o 
Pre-dose anti-NEOD001 antibody sample  
o 
Pre-dose serum sample for archiving (only for those subjects who have consented to the 
collection and archiving of their samples for future correlative testing) 
• Administer premedication within 30-90 minutes prior to the start of the infusion: 
o 
25 mg diphenhydramine or an equivalent dose of a H1 antihistamine 
o 
650 mg acetaminophen or an equivalent paracetamol dose 
• 12-lead ECG performed in triplicate – within 30 minutes prior to infusion 
• Vital signs including BP, HR, RR, and temperature – within the 30 minutes prior to dosing 
after premedications have been administered and subject has been at rest for ≥ 5 minutes. 
Vital signs should be assessed in the same position at each assessment (i.e., pre-dose, during 
infusion, and after the infusion); if the subject will be supine during the infusion, then all of 
the vital signs should be assessed in the supine position. 
Study Drug Administration: 
• The initial dose of study drug will be delivered over 120 (±10) minutes (Section 6.5.1) 
• Vital signs, including BP, HR, RR, and temperature – halfway through the infusion (i.e., 
approximately 60 minutes after the start of the infusion) 
Assessments After Infusion: 
• Bioanalytical Laboratory Assessments – PK samples are to be collected at the following time 
points and should take priority over collection of vital signs for this time point: 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 62 of 135 
o 
Immediately at the End of Infusion (EOI) (+5 minutes), which includes completion of 
the saline flush 
o 
0.5 hour (±5 minutes) post-EOI 
o 
1 hour (±10 minutes) post-EOI 
• Vital signs, including BP, HR, RR, and temperature – in the same position as assessed pre-
dose and during the infusion, at the following time points: 
o 
Immediately at the EOI (+ 10 minutes), which includes completion of the saline flush 
o 
0.5 hour (±10 minutes) post-EOI 
o 
1 hour (±10 minutes) post-EOI 
• 12-lead ECG performed in triplicate 1 hour (±15 minutes) after the EOI; medications given 
for prophylaxis chemotherapy-induced side effects should not be administered prior to 
completion of the post-infusion ECG 
• Closely monitor subject for 90 (±10) minutes following completion of the study drug 
infusion per Section 6.5.1 
• Administer Cycle 1-Day 1 bortezomib, antiviral prophylaxis, and other scheduled 
chemotherapy following the post-study drug infusion observation period 
• Assessment of AEs 
• Record all changes to concomitant medications and therapy 
7.1.4.2 
Month 1-Days 8, 15, 22 (±2 Days) 
The subject must return to the study site for the following procedures: 
Prior to Chemotherapy Administration: 
• FACT-GOG NTX (Section 7.4 and Appendix 9) – prior to any other study assessments on 
the day it is administered 
• Local Laboratory Assessments: 
o 
Perform pre-dose local laboratory assessments, including hematology and chemistry, 
and review results prior to dosing 
• Central Laboratory Assessments: 
o 
Hematology:  CBC with differential, Hgb, Hct, and platelet count 
o 
Chemistry:  sodium, potassium, chloride, bicarbonate, BUN, creatinine, creatinine 
clearance, glucose, ALT, AST, ALP, total bilirubin, direct bilirubin, LDH, eGFR, total 
protein, albumin, calcium, phosphate, and magnesium 
• Bioanalytical Laboratory Assessment – Month 1-Day 15 only: 
o 
PK sample 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 63 of 135 
• Vital signs, including BP, HR, RR, and temperature – after the subject has been at rest for 
≥ 5 minutes 
Chemotherapy Administration: 
• Administer bortezomib, antiviral prophylaxis, and other scheduled chemotherapy 
• Assessment of AEs 
• Record all changes to concomitant medications and therapy 
7.1.4.3 
Month 2-Day 1 (±2 Days) 
• The subject must return to the study site for the following procedures: 
Prior to Study Drug Infusion: 
• Administer questionnaires in the following order, prior to conducting any other assessments 
on the day they are administered: 
o 
SF-36v2 Questionnaire (Appendix 7) 
o 
KCCQ (Appendix 8)  
o 
FACT-GOG NTX (Section 7.4 and Appendix 9) 
• 12-lead ECG performed in triplicate – within 30 minutes prior to infusion 
• Symptom-directed PE should be as clinically indicated and also include weight and 
assessment of macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, 
liver/spleen size (palpable +/-), ascites (+/-), and edema (which should be quantified on a 
scale of 0-4) 
• ECOG PS (Appendix 13) 
• NYHA class (Appendix 14) 
• NIS-LL (Section 7.4 and Appendix 10) 
• VASPI (Section 7.4 and Appendix 11)  
• Local Laboratory Assessments: 
o 
Perform local laboratory assessments, including hematology and chemistry, and review 
results prior to dosing 
o 
WOCBP: Serum pregnancy test  
• Central Laboratory Assessments: 
o 
Hematology:  CBC with differential, Hgb, Hct, and platelet count 
o 
Chemistry:  sodium, potassium, chloride, bicarbonate, BUN, creatinine, creatinine 
clearance, glucose, ALT, AST, ALP, total bilirubin, direct bilirubin, LDH, eGFR, total 
protein, albumin, calcium, phosphate, and magnesium 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 64 of 135 
o 
Amylase 
o 
PT/INR and PTT 
o 
Troponin T 
o 
NT-proBNP 
o 
sFLCs 
o 
Urinalysis 
• Bioanalytical Laboratory Assessments – any time on Month 2-Day 1, prior to the start of the 
infusion: 
o 
Pre-dose PK sample  
o 
Pre-dose anti-NEOD001 antibody sample 
o 
Pre-dose serum sample for archiving (only for those subjects who have consented to the 
collection and archiving of their samples for future correlative testing) 
• Administer premedication within 30-90 minutes prior to the start of the infusion: 
o 
25 mg diphenhydramine or an equivalent dose of a H1 antihistamine 
o 
650 mg acetaminophen or an equivalent paracetamol dose 
• Vital signs, including BP, HR, RR, and temperature – after the subject has been at rest for 
≥ 5 minutes, within the 30 minutes prior to dosing, after premedication has been 
administered.  
Study Drug Administration 
• The dose of study drug may be delivered over 60 (±10) minutes if the Month 1-Day 1 
infusion was well tolerated without infusion-related AEs (Section 6.5.1)  
Assessments After Infusion: 
• Bioanalytical Laboratory Assessments – PK samples are to be collected at the following time 
points; the PK sample collection should take priority over collection of vital signs for this 
time point: 
o 
Immediately at the EOI (+5 minutes), which includes completion of the saline flush 
o 
1 hour (±10 minutes) post-EOI 
• Vital signs, including BP, HR, RR, and temperature – in the same position as those assessed 
pre-dose and during the infusion, at the following time points: 
o 
Immediately at the EOI (+10 minutes), which includes completion of the saline flush 
o 
1 hour (±10 minutes) post-EOI 
• Closely monitor subject for 90 (±10) minutes following completion of the study drug 
infusion per Section 6.5.1 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 65 of 135 
• Administer Cycle 2-Day 1 bortezomib, antiviral prophylaxis, and other scheduled 
chemotherapy following the post-study drug infusion observation period 
• Assessment of AEs 
• Record all changes to concomitant medications and therapy 
7.1.4.4 
Month 2-Days 8, 15, 22 (±2 days) 
If the subject had significant toxicities associated with previous chemotherapy administrations, 
then the subject should return to the study site for the following procedures and Cycle 2-Day 8 
and/or Cycle 2-Day 22 bortezomib administration. If there were no significant toxicities 
associated with previous chemotherapy administration, then Cycle 2-Day 8 and/or 
Cycle 2-Day 22 chemotherapy may be administered by the subject’s local physician, at the 
Investigator’s discretion, and a Homecare visit performed. The subject must return to the study 
site for Cycle 2-Day 15 bortezomib administration and assessments, regardless of previous 
tolerability. 
Prior to Chemotherapy Administration: 
The following assessments will be performed whether the visit is conducted at the study site or at 
the subject’s local physician’s clinic. If the visit is performed at the subject’s local physician’s 
clinic, a Prothena-sponsored Homecare visit will take place either within 1 day prior to or 
pre-dose on the same day as bortezomib administration to administer the FACT-GOG NTX, to 
perform vital signs and to collect central laboratory assessments. If bortezomib is administered 
on a Monday, then it is acceptable for the Homecare visit to take place on the previous Friday. 
• FACT-GOG NTX (Section 7.4 and Appendix 9) – prior to any other study assessments on 
the day it is administered 
• Vital signs, including BP, HR, RR, and temperature – after the subject has been at rest for 
≥ 5 minutes 
• Central Laboratory Assessments: 
o 
Hematology:  CBC with differential, Hgb, Hct, and platelet count 
o 
Chemistry:  sodium, potassium, chloride, bicarbonate, BUN, creatinine, creatinine 
clearance, glucose, ALT, AST, ALP, total bilirubin, direct bilirubin, LDH, eGFR, total 
protein, albumin, calcium, phosphate, and magnesium 
The following assessments will only be performed if the subject returns to the study site for the 
visit: 
• Local Laboratory Assessments: 
o 
Perform local laboratory assessments, including hematology and chemistry, and review 
results prior to dosing 
• Assessment of AEs 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 66 of 135 
• Record all changes to concomitant medications and therapy 
Chemotherapy Administration (Investigator or local physician): 
• Administer bortezomib, antiviral prophylaxis, and other scheduled chemotherapy 
7.1.4.5 
Month 3-Day 1 (±2 Days) 
The postbaseline 6MWT may be administered on the same day as study drug administration as 
long as the NT-proBNP sample is drawn before conducting the 6MWT and the 6MWT is 
completed before initiation of the study drug infusion. Questionnaires and collection of central 
laboratory samples are to be performed prior to the 6MWT, if being performed on the same day.  
The subject must return to the study site for the following procedures: 
Prior to Study Drug Infusion: 
• Administer questionnaires in the following order, prior to conducting any other assessments 
on the day they are administered: 
o 
SF-36v2 Questionnaire (Appendix 7) 
o 
KCCQ (Appendix 8)  
o 
FACT-GOG NTX (Section 7.4 and Appendix 9) 
• 12-lead ECG performed in triplicate - within 30 minutes prior to infusion 
• Symptom-directed PE should be as clinically indicated and also include weight and 
assessment of macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, 
liver/spleen size (palpable +/-), ascites (+/-), and edema (which should be quantified on a 
scale of 0-4) 
• ECOG PS (Appendix 13) 
• NYHA class (Appendix 14) 
• NIS-LL (Section 7.4 and Appendix 10) 
• VASPI (Section 7.4 and Appendix 11)  
• Local Laboratory Assessments: 
o 
Perform local laboratory assessments, including hematology and chemistry, and review 
results prior to dosing 
o 
WOCBP: Serum pregnancy test 
• Central Laboratory Assessments – Collect samples prior to 6MWT, if being performed on the 
same day: 
o 
Hematology:  CBC with differential, Hgb, Hct, and platelet count 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 67 of 135 
o 
Chemistry:  sodium, potassium, chloride, bicarbonate, BUN, creatinine, creatinine 
clearance, glucose, ALT, AST, ALP, total bilirubin, direct bilirubin, LDH, eGFR, total 
protein, albumin, calcium, phosphate, and magnesium 
o 
Amylase 
o 
PT/INR and PTT 
o 
Complements C3 and C4 
o 
Troponin T 
o 
NT-proBNP 
o 
sFLCs 
o 
Serum IFE and PEP 
o 
Urinalysis 
o 
24-hour urine collection (see Section 7.3) for:  
 Urine protein excretion 
 Urine IFE and PEP 
• 6MWT; collect BP and HR pre- and post-6MWT administration 
• Bioanalytical Laboratory Assessments – any time on Month 3-Day 1, prior to the start of the 
infusion: 
o 
Pre-dose PK sample  
o 
Pre-dose anti-NEOD001 antibody sample 
o 
Pre-dose serum sample for archiving (only for those subjects who have consented to the 
collection and archiving of their samples for future correlative testing) 
• Administer premedication within 30-90 minutes prior to the start of the infusion: 
o 
25 mg diphenhydramine or an equivalent dose of a H1 antihistamine 
o 
650 mg acetaminophen or an equivalent paracetamol dose 
• Vital signs, including BP, HR, RR, and temperature – within 30 minutes before dosing  
Study Drug Administration: 
• The dose of study drug may be delivered over 60 (±10) minutes if the previous infusions 
were well tolerated without infusion-related AEs (Section 6.5.1)  
Assessments After Infusion: 
• Vital signs, including BP, HR, RR and temperature – in the same position as those assessed 
pre-dose, at the following time points: 
o 
Immediately at the EOI (+10 minutes), which includes completion of the saline flush 
o 
1 hour (±10 minutes) post-EOI 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 68 of 135 
• Closely monitor subject for 90 (±10)  minutes following completion of the study drug 
infusion per Section 6.5.1 
• Administer bortezomib, antiviral prophylaxis, and other scheduled chemotherapy following 
the post-study drug infusion observation period 
• Assessment of AEs 
• Record all changes to concomitant medications and therapy 
7.1.4.6 
Month 3-Days 8, 15, and 22 (±2 days) 
If the subject had significant toxicities associated with Cycles 1 or 2 chemotherapy 
administrations, then the subject should return to the study site for the following procedures and 
Cycle 3-Days 8, 15, and 22 bortezomib administration. If there were no significant toxicities 
associated with previous chemotherapy administrations, Cycle 3-Days 8, 15, and 22 
chemotherapy may be administered by the subject’s local physician, at the Investigator’s 
discretion, and a Homecare visit performed within 1 day prior to or on the same day as 
bortezomib administration to conduct the following pre-chemotherapy assessments. If 
bortezomib is administered on a Monday, then it is acceptable for the Homecare visit to take 
place on the previous Friday. 
Prior to Chemotherapy Administration: 
The following assessments will be performed whether the visit is conducted at the study site or at 
the subject’s local physician’s clinic:  
• FACT-GOG NTX (Section 7.4 and Appendix 9) – prior to any other study assessments on 
the day it is administered 
• Vital signs, including BP, HR, RR and temperature – after the subject has been at rest for 
≥ 5 minutes 
• Central Laboratory Assessments: 
o 
Hematology:  CBC with differential, Hgb, Hct, and platelet count 
o 
Chemistry:  sodium, potassium, chloride, bicarbonate, BUN, creatinine, creatinine 
clearance, glucose, ALT, AST, ALP, total bilirubin, direct bilirubin, LDH, eGFR, total 
protein, albumin, calcium, phosphate, and magnesium 
• Bioanalytical Laboratory Assessment– Month 3-Day 8 only: 
o 
PK sample 
The following assessments will only be performed if the subject returns to the study site for this 
visit: 
• Local Laboratory Assessments: 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 69 of 135 
o 
Perform local laboratory assessments, including hematology and chemistry, and review 
results prior to dosing 
• Assessment of AEs 
• Record all changes to concomitant medications and therapy 
Chemotherapy Administration (Investigator or local physician): 
• Administer bortezomib, antiviral prophylaxis, and other scheduled chemotherapy 
7.1.4.7 
Every Third Month-Day 1 (±5 Days):  Month 6-Day 1, Month 9-Day 1, 
Month 12-Day 1, etc. 
The postbaseline 6MWT may be administered on the same day as study drug administration as 
long as the NT-proBNP sample is drawn before conducting the 6MWT and the 6MWT is 
completed before initiation of the study drug infusion. Questionnaires and collection of central 
laboratory samples are to be performed prior to the 6MWT, if being performed on the same day.  
The subject must return to the study site for the following procedures: 
Prior to Study Drug Infusion: 
• Administer questionnaires in the following order, prior to conducting any other assessments 
on the day they are administered: 
o 
SF-36v2 Questionnaire (Appendix 7) 
o 
KCCQ (Appendix 8) 
o 
FACT-GOG NTX (Appendix 9) – if applicable per Table 2 
• Echocardiogram – every sixth month only (i.e., Month 6, Month 12, etc.); may be completed 
within 10 days prior to Day 1. To be eligible for the additional cardiac imaging analysis, the 
subject must have a 4-chamber view, 2-dimensional echocardiogram with Doppler. 
• For subjects with liver involvement at Screening (Exception:  not required in Germany):  
perform scheduled CT imaging of the abdomen for liver measurement every sixth month 
and/or unscheduled CT imaging at any other month per Section 7.6; imaging may be 
completed within the 10 days prior to Day 1. The dimension that was measured at Screening 
(i.e., craniocaudal) should be consistently measured for all subsequent assessments for the 
same subject. 
• 12-lead ECG performed in triplicate - within 30 minutes prior to infusion 
• Symptom-directed PE should be as clinically indicated and also include weight and 
assessment of macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, 
liver/spleen size (palpable +/-), ascites (+/-), and edema (which should be quantified on a 
scale of 0-4) 
• ECOG PS (Appendix 13) 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 70 of 135 
• NYHA class (Appendix 14) 
• NIS-LL (Section 7.4 and Appendix 10) – if applicable per Table 2  
• VASPI (Section 7.4 and Appendix 11) – if applicable per Table 2 
• Local Laboratory Assessments: 
o 
If administering chemotherapy during the visit:  Perform local laboratory assessments, 
including hematology and chemistry, and review results prior to dosing with 
chemotherapy 
o 
WOCBP:  Serum pregnancy test 
• Central Laboratory Assessments – Collect samples prior to 6MWT, if being performed on 
the same day: 
o 
Hematology:  CBC with differential, Hgb, Hct, and platelet count 
o 
Chemistry:  sodium, potassium, chloride, bicarbonate, BUN, creatinine, creatinine 
clearance, glucose, ALT, AST, ALP, total bilirubin, direct bilirubin, LDH, eGFR, total 
protein, albumin, calcium, phosphate, and magnesium 
o 
Amylase 
o 
PT/INR and PTT 
o 
Complements C3 and C4 
o 
Troponin T 
o 
NT-proBNP  
o 
sFLCs 
o 
Serum IFE and PEP: Perform monthly. If a subject’s first on-study hematologic 
complete response was assessed at the previous visit, perform serum IFE/PEP (and 
24-hour urine IFE/PEP) at least 28 days after the initial assessment of response to 
confirm response.  
o 
Urinalysis 
o 
24-hour urine collection (see Section 7.3) for:  
 Urine protein excretion – odd-numbered months only 
 Urine IFE and PEP - If a subject’s first on-study hematologic complete response 
was assessed at the previous visit, perform 24-hour urine IFE/PEP (and serum 
IFE/PEP) at least 28 days after the initial assessment of response to confirm 
response. Repeat every odd-numbered month (to correspond with 24-hour urine 
protein excretion collection) to assess for continuing response or progression. If the 
initial response confirmation needs to occur on an even-numbered month, perform 
an additional 24-hour urine collection. 
• 6MWT; collect BP and HR pre- and post-6MWT administration 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 71 of 135 
• Bioanalytical Laboratory Assessments – any time on Day 1, prior to the start of the infusion: 
o 
Pre-dose PK sample  
o 
Pre-dose anti-NEOD001 antibody sample 
o 
Pre-dose serum sample for archiving (only for those subjects who have consented to the 
collection and archiving of their samples for future correlative testing) 
• Administer premedication within 30-90 minutes prior to the start of the infusion: 
o 
25 mg diphenhydramine or an equivalent dose of a H1 antihistamine 
o 
650 mg acetaminophen or an equivalent paracetamol dose 
• Vital signs, including BP, HR, RR and temperature – within the 30 minutes prior to dosing, 
after premedication has been administered  
Study Drug Administration: 
• The dose of study drug may be delivered over 60 (±10) minutes if previous infusions have 
been well tolerated without infusion-related AEs (Section 6.5.1) 
Assessments After Infusion: 
• Bioanalytical Laboratory Assessments – PK samples are to be collected post-infusion at the 
following time points at Month 6-Day 1 and Month 12-Day 1: 
o 
EOI (+5 minutes) 
o 
0.5 hour (±5 minutes) 
o 
1 hour (±10 minutes) post-EOI  
• Vital signs, including BP, HR, RR and temperature – assessed in the same position as 
assessed pre-dose, at the following time points: 
o 
Immediately at the EOI (+10 minutes), which includes completion of the saline flush 
o 
1 hour (±10 minutes) post-EOI 
• Closely monitor subject for 90 (±10) minutes following completion of the study drug 
infusion per Section 6.5.1 
• If standard of care chemotherapy is being administered, it may be administered following the 
post-study drug infusion observation period, and the review of local laboratory tests 
• Assessment of AEs 
• Record all changes to concomitant medications and therapy 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 72 of 135 
7.1.4.8 
All Other Months-Day 1 (±5 Days):  Month 4-Day 1, Month 5-Day 1, Month 
7-Day 1, Month 8-Day 1, etc. 
The following assessments will be done on Day 1 of all other months (e.g., Months 4, 5, 7, 8, 10, 
11, 13, etc.), unless otherwise noted: 
Prior to Study Drug Infusion: 
• For subjects with liver involvement at Screening (Exception: not required in Germany): 
perform unscheduled CT imaging of the abdomen for liver measurement, if applicable per 
Section 7.6  
• Symptom-directed PE should be as clinically indicated and also include weight and 
assessment of macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, 
liver/spleen size (palpable +/-), ascites (+/-), and edema (which should be quantified on a 
scale of 0-4) 
• ECOG PS (Appendix 13) 
• NYHA class (Appendix 14) 
• FACT-GOG NTX (Appendix 9) - if applicable per Table 2 
• NIS-LL (Section 7.4 and Appendix 10) - if applicable per Table 2 
• VASPI (Section 7.4 and Appendix 11) - if applicable per Table 2 
• Local Laboratory Assessments: 
o 
If administering chemotherapy during this visit:  Perform local laboratory assessments, 
including hematology and chemistry, and review results prior to dosing with 
chemotherapy 
o 
WOCBP:  serum pregnancy test 
• Central Laboratory Assessments: 
o 
Hematology:  CBC with differential, Hgb, Hct, and platelet count 
o 
Chemistry:  sodium, potassium, chloride, bicarbonate, BUN, creatinine, creatinine 
clearance, glucose, ALT, AST, ALP, total bilirubin, direct bilirubin, LDH, eGFR, total 
protein, albumin, calcium, phosphate, and magnesium 
o 
Amylase 
o 
PT/INR and PTT 
o 
Troponin T 
o 
NT-proBNP 
o 
sFLCs 
o 
Serum IFE and PEP: Perform monthly. If a subject’s first on-study hematologic 
complete response was assessed at the previous visit, perform serum IFE/PEP (and 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 73 of 135 
24-hour urine IFE/PEP) at least 28 days after the initial assessment of response to 
confirm response. 
o 
Urinalysis 
o 
24-hour urine collection (see Section 7.3) for:  
 Urine protein excretion – odd-numbered months only 
 Urine IFE and PEP - If a subject’s first on-study hematologic complete response 
was assessed at the previous visit, perform 24-hour urine IFE/PEP (serum IFE/PEP) 
at least 28 days after the initial assessment of response to confirm response. Repeat 
every odd-numbered month (to correspond with 24-hour urine protein excretion 
collection) to assess for continuing response or progression. If the initial response 
confirmation needs to occur on an even-numbered month, perform an additional 24-
hour urine collection. 
• Bioanalytical Laboratory Assessments – any time on Day 1, prior to the start of the infusion: 
o 
Pre-dose PK sample  
o 
Pre-dose anti-NEOD001 antibody sample  
o 
Pre-dose serum sample for archiving (only for those subjects who have consented to the 
collection and archiving of their samples for future correlative testing) 
• Administer premedication within 30-90 minutes prior to the start of the infusion: 
o 
25 mg diphenhydramine or an equivalent dose of a H1 antihistamine 
o 
650 mg acetaminophen or an equivalent paracetamol dose 
• 12-lead ECG performed in triplicate - within 30 minutes prior to infusion 
• Vital signs, including BP, HR, RR and temperature – within the 30 minutes prior to dosing, 
after premedication has been administered.  
Study Drug Administration: 
• The dose of study drug may be delivered over 60 (±10) minutes if previous infusions have 
been well tolerated without infusion-related AEs (Section 6.5.1)  
Assessments After Infusion: 
• Vital signs including BP, HR, RR and temperature – in the same position as assessed pre-
dose, at the following time points: 
o 
Immediately at the EOI (+10 minutes), which includes completion of the saline flush 
o 
1 hour (±10 minutes) post-EOI 
• Closely monitor subject for 90 (±10) minutes following completion of the study drug 
infusion per Section 6.5.1  
• If standard of care chemotherapy is being administered, it may be administered following the 
post-study drug infusion observation period, and the review of local laboratory tests 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 74 of 135 
• Assessment of AEs 
• Record all changes to concomitant medications and therapy 
7.1.5 
Concomitant Chemotherapy Visits 
The first cycle of first-line, bortezomib-containing chemotherapy should be initiated on 
Month 1-Day 1, following administration of study drug and completion of the post-study drug 
observation period. Month 1-Day 1 is equivalent to Cycle 1-Day 1 of chemotherapy. Bortezomib 
should be given SC weekly on Days 1, 8, 15, and 22 according to the approved prescribing 
information and local institutional practices. Antiviral prophylaxis is required.  
The subject must be closely monitored during at least the first 3 cycles of the first-line, 
bortezomib-containing chemotherapy regimen. During the first cycle of chemotherapy (i.e., 
Month 1 of the study), the subject must return to the study site for each administration of 
bortezomib and for assessments prior to each administration. In addition, subjects must receive 
Cycle 2-Day 1, Cycle 2-Day 15, and Cycle 3-Day 1 (i.e., Month 2-Day 1, Month 2-Day 15, and 
Month 3-Day 1, respectively) of bortezomib, along with any other chemotherapy, at the study 
site.  
During the second and third cycles, Cycle 2-Day 1, Cycle 2-Day 15, and Cycle 3-Day 1 will 
correspond to the Month 2-Day 1, Month 2-Day 15, and Month 3-Day 1 visits, respectively, 
during which visits, bortezomib, along with any other chemotherapy, will be administered at the 
study site and assessments will be performed prior to each administration. For chemotherapy on 
Cycle 2-Days 8 and 22, as well as Cycle 3-Days 8, 15, and 22, the subject should return to the 
study site for bortezomib administration and assessments if, in the opinion of the Investigator, 
the subject is experiencing any significant toxicity that appears to exceed the anticipated side 
effects of the chemotherapy. At the Investigator’s discretion, if the subject is not experiencing 
any unanticipated or significant toxicity, the subject may be administered bortezomib by their 
local physician, rather than by the Investigator.  
In the event that bortezomib doses are missed, the chemotherapy cycles may become misaligned 
with the monthly study drug dosing. In this case, the weekly visits during Months 1 through 3 
should continue as described above in order to closely monitor subjects’ health during the initial 
months of concomitant chemotherapy. Throughout the study, monthly doses of study drug 
should not be delayed or skipped due to adjustments that are made to chemotherapy dosing. 
Study drug dosing adjustments are described in Section 6.6. 
When bortezomib administration takes place at the subject’s local physician’s office, the 
FACT-GOG NTX assessment, vital signs, and central laboratory sample collection must be 
performed by a Prothena-sponsored healthcare professional within 1 day prior to or pre-dose on 
the same day as each administration of bortezomib. If bortezomib is administered on a Monday, 
then it is acceptable for the Homecare visit to take place on the previous Friday. 
The number of cycles of first-line chemotherapy that is administered is at the discretion of the 
Investigator, and subsequent chemotherapy regimens may be prescribed as per standard of care 
at the Investigator’s discretion. The Sponsor does not intend to provide reimbursement for 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 75 of 135 
standard of care chemotherapy. Refer to Section 6.5.3 for guidance regarding cycles of 
chemotherapy beyond Month 3. 
7.1.6 
End of Treatment (EOT)/Early Treatment Discontinuation (ETD) (28-35 
days post-final dose) 
After approximately 156 primary endpoint events have occurred, the study will conclude and all 
subjects will have an EOT Visit. Subjects who discontinue study drug before the EOT should 
have an ETD Visit after they decide to end their treatment. The EOT/ETD Visit should be 
completed 28-35 days after the subject’s final administration of study drug. Subjects who are 
willing to participate in additional visits after the ETD Visit should have assessments every third 
month per Appendix 3 (see also Section 8.2). 
• Administer questionnaires in the following order, prior to conducting any other assessments 
on the day they are administered: 
o 
SF-36v2 Questionnaire (Appendix 7) 
o 
KCCQ (Appendix 8) 
o 
FACT-GOG NTX (Section 7.4 and Appendix 9)  
• Echocardiogram – unless it has been performed within the 60 days prior to the EOT/ETD 
Visit. To be eligible for the additional cardiac imaging analysis, the subject must have a 
4-chamber view, 2-dimensional echocardiogram with Doppler. 
• For subjects with liver involvement at Screening (Exception:  not required in Germany): 
Perform CT imaging of the abdomen for liver measurement per Section 7.6, in any of the 
following situations: 
o 
If not done within the previous 60 days 
o 
If a ≥50% reduction from baseline in ALP is newly observed 
o 
To confirm a hepatic response (i.e., reduction in liver size) ≥ 28 days after the 
assessment of response 
If the initial occurrence of response based on liver size is assessed at the EOT/ETD Visit, 
then unscheduled imaging should be scheduled ≥ 28 days after that imaging was completed 
to confirm the assessment of response. 
• 12-lead ECG performed in triplicate 
• Complete PE including weight and examination of general appearance; head, ears, eyes, 
nose, and throat; neck; skin; cardiovascular system; respiratory system; gastrointestinal 
system; and nervous system. The following should be assessed:  macroglossia, 
submandibular nodes/fullness, adenopathy, ecchymoses, liver/spleen size (palpable +/-), 
ascites (+/-), and edema (which should be quantified on a scale of 0 4). 
• ECOG PS (Appendix 13) 
• NYHA class (Appendix 14) 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 76 of 135 
• NIS-LL (Section 7.4 and Appendix 10) 
• VASPI (Section 7.4 and Appendix 11) 
• Central Laboratory Assessments - Collect samples prior to 6MWT, if being performed on 
the same day: 
o 
Hematology:  CBC with differential, Hgb, Hct, and platelet count 
o 
Chemistry:  sodium, potassium, chloride, bicarbonate, BUN, creatinine, creatinine 
clearance, glucose, ALT, AST, ALP, total bilirubin, direct bilirubin, LDH, eGFR, total 
protein, albumin, calcium, phosphate, and magnesium 
o 
Amylase 
o 
PT/INR and PTT 
o 
Additional coagulation samples, per Appendix 12 
o 
Complements C3 and C4 
o 
Troponin T 
o 
NT-proBNP 
o 
sFLCs 
o 
WOCBP: Serum pregnancy test 
o 
Serum IFE and PEP 
o 
Urinalysis 
o 
24-hour urine collection (see Section 7.3) for:  
 Urine protein excretion 
 Urine IFE and PEP 
• 6MWT; collect BP and HR pre- and post-6MWT administration 
• Bioanalytical Laboratory Assessments: 
o 
PK sample 
o 
Anti-NEOD001 antibody blood sample 
o 
Serum sample for archiving (only for those subjects who have consented to the 
collection and archiving of their samples for future correlative testing) 
• Vital signs, including BP, HR, RR, and temperature – after the subject has been at rest for 
≥ 5 minutes  
• Assessment of AEs 
• Record all changes to concomitant medications and therapy  


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 77 of 135 
7.1.7 
90-day Postdose Pregnancy Test 
For WOCBP only:  Obtain a local laboratory serum pregnancy test 90 (±5) days after the last 
administration of study drug. 
7.1.8 
Telephone Follow-Up Every Three Months 
Follow-up phone calls should be made to randomized subjects (or their caregivers) who received 
a dose of study drug and are no longer receiving study drug every 3 months, beginning 
approximately 3 months from the subject’s last visit. The subject’s health status, as well as 
details of any hospitalizations will be collected accordingly in the study database to ensure 
adequate capture of primary endpoint events. New SAEs reported to the Investigator during this 
period will be reported to the Sponsor or its designee only if, in the judgment of the Investigator, 
the SAE is associated with any protocol intervention (i.e., related to study procedure or previous 
study drug exposure). 
7.2 
Order of Assessments 
At each study visit, there are certain assessments that must be performed in a prescribed order, as 
follows:  
• Questionnaires:  At visits where one or more questionnaires are to be administered, the 
following order occurs prior to the performance of any other study assessments on the day 
they are administered: 
1. SF-36v2 
2. KCCQ 
3. FACT-GOG NTX 
• 6MWT:  The postbaseline 6MWT may be administered on the same day as study drug 
administration as long as the NT-proBNP sample is drawn before conducting the 6MWT and 
the 6MWT is completed before initiation of the study drug infusion. Questionnaires and 
collection of central laboratory samples must be performed prior to administering the 
6MWT, if being performed on the same day. 
• Chemotherapy: Blood samples for local laboratory assessments must be collected per 
institutional practice prior to administration of chemotherapy. Within 3 days prior to the first 
day of a new regimen of chemotherapy, conduct an unscheduled central laboratory 
collection, including hematology, chemistry, and coagulation factors. If standard of care 
chemotherapy is administered on the same day as study drug, the chemotherapy must be 
administered after the 90 (±10)-minute post-study drug infusion observation period.  
• ECGs:  Medications given for prophylaxis chemotherapy-induced side effects should not be 
administered prior to completion of the post-infusion ECG. 
• Vital Signs:  Pre-dose vital sign assessments should be performed within the 30 minutes 
prior to dosing, after administration of study drug premedication. PK sample collection 
should take priority over collection of vital signs. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 78 of 135 
7.3 
Laboratory Evaluations 
A central laboratory will be used for analysis of hematology, chemistry, amylase, coagulation, 
NT-proBNP, troponin T, sFLCs, serum IFE/PEP, urinalysis, and 24-hour urine collection for 
urine IFE/PEP and urine protein excretion. Central and local pregnancy testing will be conducted 
as shown in Table 1. 
Local laboratory results (e.g., hematology, chemistry) will be obtained for subject management 
when necessary for obtaining results on a more immediate basis. Local laboratory results should 
also be obtained and reviewed for a safety assessment prior to each administration of 
chemotherapy. Results from these local laboratory tests will not be collected in the eCRFs or the 
clinical database. 
Citrated plasma samples may be collected and frozen for potential analysis of coagulation 
indices at a later date. These analyses may include but may not be limited to the indices listed in 
Appendix 12. 
The 24-hour urine protein excretion and 24-hour urine IFE/PEP tests will be performed using the 
same 24-hour urine collection sample, when required at the same visit. Details regarding the 
24-hour urine sample collection are provided in the Laboratory Manual. 
In addition, a bioanalytical laboratory will be used for the analysis of PK and anti-NEOD001 
antibody samples, as well as for the storage of serum samples for future correlative testing. 
Serum samples will be collected and archived at the bioanalytical laboratory for those subjects 
who have consented to the collection and use of their samples for future correlative studies. 
Samples will be stored for up to 5 years after completion of the study, after which point any 
remaining samples will be destroyed. Approximately 146 mL of blood will be collected from 
each subject during the first year of participation in the study for bioanalytical testing. Each 
month thereafter, 10 mL of blood will be collected from each subject for bioanalytical 
assessments. 
One or more laboratories will be used for mass spectrometry of tissue samples, immunoelectron 
microscopy, gene sequencing, and/or 99mTc scintigraphy, which are required for a subset of 
subjects who meet Inclusion Criterion #5 (Section 4.1).  
Details for the processing of laboratory specimens are provided in the Laboratory Manual. 
7.4 
Peripheral Neuropathy Assessment 
In addition to assessing peripheral neuropathy adverse events using NCI-CTCAE grading as 
shown in Appendix 9, the following three assessments will be utilized to assess peripheral 
neuropathy: 
• The FACT-GOG NTX (Appendix 9) assesses subject-reported neurotoxicity symptoms and 
concerns that evaluate Activities of Daily Living (ADL) with an 11-item scale with a range 
of possible scores of 0 to 44. The FACT-GOG NTX should be performed after the SF-36v2 
and KCCQ (if being performed on the same day) and prior to any other study assessments on 
the day it is administered. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 79 of 135 
• The NIS-LL (Appendix 10) assesses reflexes, sensation, and motor strength to determine a 
peripheral neuropathy score, with a range of possible scores of 0 to 88.  
• The VASPI (sample tool in Appendix 11) assesses a subject’s level of pain related to 
peripheral neuropathy. 
Peripheral neuropathy assessments will be performed as shown in Table 2. After Month 3, 
subjects who do not meet the criteria listed in the “Months 4-12” and “Months 13+” columns do 
not need to have the peripheral neuropathy assessments conducted until their EOT/ETD Visit.


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
Date: 06 November 2017 
Page 80 of 135 
Table 2: 
Peripheral Neuropathy Assessments 
Assessment 
Screening 
Months 1-3 
Months 4-12 
Months 13+ 
EOT/ETD 
FACT-GOG 
NTX  
(Appendix 9) 
All Subjects:  
Once between 
Days -28 and -1 
and again on 
Day -2 or Day -1 
All Subjects:  
Weekly 
(Day 1, 8a, 
15a, and 22a 
Visits) 
• 
Subjects who had positive scores at 
Screening and/or Month 3: 
Months 6, 9, and 12 (Day 1 Visit) 
• 
Subjects who are receiving 
identified concomitant 
medicationb: 
Monthly (Day 1 Visit) 
• 
Subjects who had negative scores 
at Screening and Month 3 and new 
PN signs and symptoms develop:  
Monthly (Day 1 Visit) 
• 
Subjects who had positive scores at 
Screening and/or Month 3: 
Every sixth month (e.g., Months 18, 
24 [Day 1 Visit]) 
• 
Subjects who are receiving 
identified concomitant medicationb: 
Monthly (Day 1 Visit) 
• 
Subjects who had negative scores at 
Screening and Month 3 and new PN 
signs and symptoms develop:  
Monthly (Day 1 Visit) 
All Subjects 
NIS-LL 
(Appendix 10) 
and 
VASPI 
(Appendix 11) 
All Subjects:  
Once between 
Days -28 and -1 
All Subjects:  
Monthly 
(Day 1 Visit) 
• 
Subjects who had positive scores at 
Screening and/or Month 3: 
Months 6, 9, and 12 (Day 1 Visit) 
• 
Subjects who are receiving 
identified concomitant 
medicationb: 
Monthlya (Day 1 Visit) until 
completion of concomitant 
medication & then at Months 6, 9, 
and 12 (Day 1 Visit) or whatever 
remains of these months 
• 
Subjects who had negative scores 
at Screening and Month 3 and new 
PN signs and symptoms develop:  
At the next scheduled visit and then 
at Months 6, 9, and 12 (Day 1 Visit) 
or whatever remains of these months 
• 
Subjects who had positive scores at 
Screening and/or Month 3: 
Every sixth month (e.g., Months 18, 
24 [Day 1 Visit]) 
• 
Subjects who are receiving 
identified concomitant medicationb: 
Monthly (Day 1 Visit) until 
completion of concomitant medication 
& then every sixth month (e.g., 
Months 18, 24 [Day 1 Visit]) 
• 
Subjects who had negative scores at 
Screening and Month 3 and new PN 
signs and symptoms develop:  
At the next scheduled visit and then 
every third month (e.g., Months 15, 18 
[Day 1 Visit]) 
All Subjects 
EOT/ETD = End of Treatment/Early Treatment Discontinuation; FACT-GOG NTX = Functional Assessment of Cancer Therapy – Gynecologic Oncology Group Neurotoxicity 
Subscale; NIS-LL = Neuropathy Impairment Score – Lower Limbs; PN = peripheral neuropathy; VASPI = Visual Analog Scale – Pain Intensity. 
a 
Subjects who have discontinued study drug prior to the end of the study but are willing to return for visits will be assessed every third month (i.e., Months 3, 6, 9, and 12 or 
whatever remains of these visits) per Appendix 3. 
b 
Bortezomib, another proteasome inhibitor, or other drug with the propensity to cause peripheral neuropathy. 
Note: After Month 3, subjects who do not meet the criteria listed in the “Months 4-12” and “Months 13+” columns do not need to have the peripheral neuropathy assessments 
conducted until the EOT/ETD Visit. 
 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 81 of 135 
7.5 
6-Minute Walk Test 
The 6MWT will be assessed twice during Screening, every third month, and at the EOT/ETD 
Visit (per Table 1). The postbaseline 6MWT may be administered on the same day that study 
drug is administered, if the 6MWT is completed before initiation of the study drug infusion. At 
least 4 days are required between the two Screening 6MWTs; therefore, the first Screening 
6MWT must be performed between Day -28 and Day -5 and the second Screening 6MWT 
should be performed within 2 days prior to Month 1-Day 1 (i.e., on Day -2 or Day -1). Subjects 
should plan to be able to return to the same clinical site for each 6MWT from first Screening 
through Month 9. 
Questionnaires and collection of central clinical laboratory samples must be performed prior to 
administering the 6MWT, if being performed on the same day. 
As part of the 6MWT, BP and HR will be collected pre- and post-6MWT administration. 
If the subject discontinues study drug prior to the Month 9 Visit, every effort should be made for 
the subject to return to the study site at the Month 9 time point for completion of all of the 
Month 9-Day 1 assessments, in particular, the 6MWT. 
Details regarding the requirements for proper administration of the 6MWT are described in a 
separate manual.  
7.6 
Liver Imaging 
CT imaging of the abdomen for liver measurement will be conducted as follows (Exception:  
subjects in Germany are not required to have study-specific liver imaging; any liver imaging 
performed for these subjects will be at the discretion of the Investigator and will be considered 
standard of care): 
• Perform Screening CT imaging if a subject has an ALP >1.5 × ULN (Note: If CT imaging 
has been conducted within 60 days prior to Screening Day -28 and it meets acquisition 
guidelines, it does not need to be repeated during Screening and the previous result can be 
used for eligibility) 
• Perform CT imaging every sixth month (i.e., Months 6, 12, 18, etc.), within the 10 days prior 
to Day 1 
• When there is a ≥50% reduction from baseline in ALP, perform unscheduled CT imaging 
within the 10 days prior to Day 1 of the applicable month 
o 
If the 50% reduction from baseline in ALP is maintained, yet no hepatic response based 
on liver measurement (i.e., ≥ 2 cm reduction in liver size from baseline 
radiographically) is observed, repeat CT imaging 3 months later to determine if 
response or progression is observed 
• When there is a ≥ 2 cm reduction in liver size from baseline radiographically (Appendix 1) 
repeat CT imaging ≥ 28 days later to confirm the reduced liver size, and then revert back to 
the usual imaging schedule of every sixth month (i.e., Months 6, 12, 18, etc.) 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 82 of 135 
• If no response or progression is observed, then the CT imaging schedule will continue every 
sixth month (i.e., Months 6, 12, 18, etc.) 
• If CT imaging was performed within the 30 days of the next scheduled visit, that scan can be 
skipped until the following scheduled visit  
• If imaging was completed within the 60 days prior to the EOT/ETD Visit, it does not need to 
be repeated unless: 
o 
a ≥ 50% reduction from baseline in ALP is newly observed OR 
o 
imaging is required for confirmation of a response observed at the previous assessment 
• If the initial occurrence of response based on liver size is assessed at the EOT/ETD Visit, 
then unscheduled CT imaging should be scheduled ≥ 28 days after that imaging was 
completed to confirm the assessment of response 
The dimension that was measured at Screening (i.e., craniocaudal) should be consistently 
measured for all subsequent assessments for the same subject. CT imaging should be done as per 
the imaging acquisition guidelines provided by the central imaging laboratory. Measurements 
will be performed by the central imaging laboratory and provided to the site.  
7.7 
Monitoring Anti-NEOD001 Antibodies During the Study 
Serum anti-NEOD001 antibody levels will be measured on Day 1 of each month and at the 
EOT/ETD Visit. Additional serum samples to test for anti-NEOD001 antibodies should be 
collected if significant toxicity is observed (e.g., an infusion reaction in the clinic, anaphylaxis) 
and if possible, should be collected while the acute symptoms persist. Anti-NEOD001 antibody 
levels will be correlated with NEOD001 exposure level to assess potential dose concentration 
related associations when anti-NEOD001 antibody and corresponding PK data are available.  


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 83 of 135 
8 
EMERGENCY UNBLINDING OF STUDY DRUG, EARLY 
DISCONTINUATION, OR TERMINATION FROM STUDY  
8.1 
Emergency Unblinding 
The Investigator has the ability to break the blind for a specific subject in the event of an 
immediate medical emergency, where knowledge of the subject’s treatment (NEOD001 or 
placebo) must be known in order to provide adequate medical treatment. In these situations, the 
breaking of the blind must be reported to the Sponsor within 24 hours. The procedure for the 
unblinding of a specific subject using the IXRS is provided in the Study File Notebook. 
Any other requests to reveal a subject’s treatment must be requested of, and approved by, the 
Medical Monitor.  
8.2 
Early Treatment Discontinuation 
If the subject discontinues study drug prior to the end of the study, but is willing to continue to 
participate in study visits, the subject should have an ETD Visit within 28-35 days after his/her 
final administration of study drug (per Table 1 and Section 7.1.6) and then have assessments 
every third month per Appendix 3. The most important visit is the Month 9-Day 1 Visit, so if a 
subject is unwilling to continue visits every third month, every effort should be made for the 
subject to return and complete the Month 9-Day 1 Visit on schedule. All visits after the ETD 
Visit should occur on schedule, that is, at the time when their visit would have occurred had they 
remained on study drug.  
If the subject discontinues study drug prior to the end of the study and is not willing to continue 
to participate in study visits, the subject should return for an ETD Visit 28-35 days after his/her 
final administration of study drug (per Table 1 and Section 7.1.6). If a subject fails to return for 
the scheduled visit, a documented effort must be made to determine the reason. If the subject 
cannot be reached by phone after two attempts, a certified letter will be sent to the subject (or the 
subject’s legally authorized representative, if appropriate) requesting contact with the 
Investigator. This information will be recorded in the study records. 
Reasons for early discontinuation from study drug treatment may include, but are not limited to: 
• A suspected NEOD001-related immunologic reaction – collect additional serum samples, if 
possible, during the period following the treatment stoppage to allow for the determination of 
the persistence of anti-NEOD001 antibodies. At a minimum, samples should be collected at 
the ETD Visit and at the every third month visits through Month 12, if the subject agrees to 
return to the clinic.  
• Occurrence of an AE or clinically significant laboratory abnormality that, in the opinion of 
the Investigator, warrants the subject’s permanent discontinuation from study drug treatment; 
the Medical Monitor should be notified as soon as possible of any discontinuation of study 
drug due to an AE 
• Suspected or confirmed pregnancy or nursing during study treatment period. Female subjects 
who has a positive pregnancy test at the ETD Visit must be followed to term or until 
termination of the pregnancy (Section 9.8). 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 84 of 135 
At any point in the study, if a subject who was randomized and received a dose of study drug is 
unwilling to return to the study site for further visits but is willing to discuss his/her health status 
by phone, follow-up phone calls should be made to the subject or their caregiver, per 
Section 7.1.8.  
8.3 
Early Termination from the Study 
Subject participation in this study will continue until the end of the study (i.e., after 
approximately 156 primary endpoint events have occurred). Early termination occurs if the 
subject fails to complete the entire study and is no longer participating in study visits. Subjects 
may withdraw their consent to participate in this study at any time without prejudice. The 
Investigator must withdraw from the study any subject who requests to be withdrawn. A 
subject’s participation in the study may be discontinued at any time at the discretion of the 
Investigator in accordance with his/her clinical judgment. The Sponsor should be notified in a 
timely manner of all subject discontinuations. 
Early termination from the study may occur if: 
• Subject needs to receive any of the prohibited concomitant therapies listed in Section 6.8.2 
• In the opinion of the Investigator, the subject cannot safely participate in the procedures 
required by the protocol 
• Subject withdraws consent 
• Subject is unwilling or unable to comply with the study requirements 
• Subject is lost to follow-up 
• Prothena reserves the right to discontinue the study at any time for any reason, including but 
not limited to, clinical or administrative reasons, or to discontinue participation of an 
individual Investigator or site for any reason, including but not limited to, poor enrollment or 
noncompliance. 
Vital status will be collected within legal and ethical boundaries for all randomized subjects 
receiving at least one dose of study drug and will be searched in public sources. During the study 
close-out period, survival status will be collected within legal and ethical boundaries for all 
randomized subjects who withdrew participation from the study. If vital status is determined, the 
subject will not be considered lost to follow-up. 
8.4 
Replacement of Subjects 
Randomized subjects who drop out of the study for any reason will not be replaced. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 85 of 135 
9 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS AND REPORTING 
Adverse events, both reported and observed, will be recorded in the source documents and on the 
appropriate eCRF page from the time initial eligibility is established during Screening (upon 
signature of the informed consent form) until the EOT/ETD Visit or for 28 days after the last 
dose, whichever is later. New SAEs (per definition in Section 9.1) occurring beyond the 
EOT/ETD Visit or >28 days after the last administration of study drug, whichever is later, will be 
reported to the Sponsor or its designee only if, in the judgment of the Investigator, the SAE is 
associated with any protocol intervention (i.e., related to study procedure or previous study drug 
exposure). 
9.1 
Definitions 
Consistent with the current regulatory guidance provided by the US Code of Federal Regulations 
(CFR) and the International Conference on Harmonisation (ICH) Guideline for Good Clinical 
Practices, AEs and SAEs are defined below. 
AE Definition:  Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, syndrome, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. The AE may involve any organ or system and can be represented by the new 
onset, or the deterioration, of a disease, a syndrome, a symptom, or a physical sign, as well as by 
findings and results of instrumental examinations and laboratory tests. Any medically relevant 
and untoward change, including frequency or pattern changes for a fluctuating condition (e.g., 
migraine), occurring during the reporting period is considered an AE. All such occurrences must 
be recorded and reported to the Sponsor, or the Sponsor’s designee, accordingly, whether or not 
they appear causally related to the study medication.  
Examples include: 
• The emergence of any signs and symptoms that were not present at baseline (an event present 
at baseline that has not changed is not considered an AE) 
• Pre-existing conditions that are marked by a worsening from the subject’s baseline/entry 
status (i.e., an increase in severity or frequency of the pre-existing abnormality or disorder) 
• Reactions to study drug, abuse of drug, withdrawal phenomena, sensitivity, or toxicity to 
study drug 
• Apparently unrelated illnesses 
• Injuries or accidents 
• Extensions or exacerbations or symptomatology, subjective events reported by the subject, or 
new clinically significant abnormalities in clinical laboratory tests, physiological tests or PE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 86 of 135 
SAE Definition:  Any AE occurring at any dose that results in any of the following outcomes is 
an SAE: 
• Death 
• Life threatening 
• Inpatient hospitalization, or prolongation of existing hospitalization 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect 
• 
Important medical events 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject and/or may require medical or surgical intervention to prevent one of 
the outcomes listed in the definition of SAEs. Examples of such events are: 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Convulsions that do not result in hospitalization 
• 
Development of drug dependency or drug abuse 
An SAE may also include any other event that the Investigator or Medical Monitor judges to be 
serious, or that suggests a significant hazard, contraindication, side effect, or precaution. 
Important Note:  The concepts of AEs and SAEs represent regulatory instruments used to 
evaluate and monitor the safety of clinical trial subjects. Therefore, these terms only apply in 
light of their regulatory definition. The term “serious,” in a regulatory sense, does not necessarily 
mean “severe.” All AEs (serious and non-serious) reported during a study will be taken into 
account when analyzing the study data and establishing the safety profile of the investigational 
drug.  
Death:  Death, in and of itself, is not an AE; it is only an outcome. The cause of death is the AE. 
Therefore, the Investigator should make every effort to obtain and document the cause of death 
for all subjects who die during the study. If, despite all efforts, the cause of death remains 
unknown, the SAE should be documented as an “unspecified fatal event.” 
Life-threatening AE:  Any AE that places the subject, in the view of the Investigator, at 
immediate risk of death from the event as it occurred. This does not include an event that, had it 
occurred in a more severe form, might have caused death. 
Hospitalization:  Hospitalization is defined by the Sponsor as a full admission to the hospital for 
diagnosis and treatment. This includes prolongation of an existing inpatient hospitalization. 
Examples of visits to a hospital facility that do not meet the serious criteria for hospitalization 
include: 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 87 of 135 
• 
Emergency room visits that do not result in a full hospital admission or that last for a period 
of less than 24 hours 
• 
Outpatient surgery 
• 
Preplanned or elective procedures 
• 
Protocol procedures 
A pre-scheduled elective procedure or a routinely scheduled treatment is not to be considered an 
SAE, even if the subject is hospitalized, provided the site stipulates that: 
• 
The condition requiring the pre-scheduled elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress between the subject’s consent to 
participate in the clinical trial and the time of the procedure or treatment 
• 
The pre-scheduled elective procedure or routinely scheduled treatment is the sole reason for 
admission and intervention 
An untoward medical event occurring during the pre-scheduled elective procedure or routinely 
scheduled treatment should be recorded as an AE or an SAE, as appropriate.  
Disability:  A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
9.2 
Recording of Adverse Events 
Subjects should be instructed to report to the study staff any AE that they experience, even those 
that may not be related to the study drug, and to discuss potential treatment. Subjects should be 
instructed to call the appropriate emergency response telephone number (911 if within the US) if 
they experience an AE that requires immediate attention or could, if untreated, have potentially 
serious consequences.  
At each visit, the Investigator will prompt the subject with non-leading questions to determine if 
any AEs were experienced since the last visit. The Investigator must follow all AEs until the 
events have resolved or until the condition has stabilized and no further medical follow-up is 
warranted. 
It is the responsibility of the Investigator to document all AEs that occur during the reporting 
period. Pre-existing conditions (noted before Screening) should not be reported as AEs unless 
they worsen (i.e., become more severe or more frequent) after beginning participation in the 
study (upon signing the informed consent form).  
Whenever feasible, AEs should be documented as medical diagnoses and a unifying diagnosis 
should be provided. For example, symptoms including fever, productive cough, opacity in the 
left lower lobe of the lung on x-ray would be reported as a single AE of pneumonia. Otherwise, 
if reported AEs do not appear clearly inter-related, individual signs or symptoms may be 
reported as separate AEs. Information recorded on the appropriate page of the eCRF will include 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 88 of 135 
the description of the AE, the date and time of onset and resolution (if applicable), severity, 
seriousness, relationship to the study drug, action taken, and the outcome.  
When an AE resulting from disease progression meets the requirements to be considered serious 
the SAE verbatim term should be reported as the sign/symptom that best describes the event 
rather than as disease progression. For example, a subject presents with worsening shortness of 
breath due to a pleural effusion resulting from disease progression. The event term should be 
reported as “pleural effusion” instead of as disease progression.  
9.3 
Assessment of AEs:  Severity 
AEs will be assessed according to the NCI-CTCAE version 4.0. AEs that do not have a 
corresponding NCI-CTCAE term will be assessed according to their impact on the participant’s 
ability to perform daily activities as listed below. 
The severity of each AE should be characterized and then classified into one of five clearly 
defined categories as follows: 
• 
Grade 1 (Mild):  the AE does not interfere in a significant manner with the subject’s normal 
functioning level; it may be an annoyance 
• 
Grade 2 (Moderate): the AE produces some impairment of functioning, but is not hazardous 
to health; it is uncomfortable or an embarrassment 
• 
Grade 3 (Severe):  the AE produces significant impairment of functioning or incapacitation 
and is a definite hazard to the subject’s health 
• 
Grade 4 (Life threatening):  Life threatening or disabling 
• 
Grade 5 (Fatal):  Causes death of the participant 
These five categories are based on the Investigator’s clinical judgment, which in turn depends on 
consideration of various factors such as the subject’s reports, the Investigator’s observations, and 
the Investigator’s prior experience. The severity of the AE should be recorded in the appropriate 
section of the eCRF. The evaluation of severity is distinguished from the evaluation of 
“seriousness.” A severe event might not meet the criteria for seriousness and a serious event 
might be evaluated as mild. For example, a subject might have a severe headache that does not 
require hospitalization and is consequently not serious; or a subject might have a mild 
myocardial infarction that requires hospitalization and is, therefore, serious. 
9.4 
Assessment of AEs:  Relationship to Study Drug 
The causality of each adverse event should be assessed and classified by the Investigator as 
“related” or “not related.” An event is considered related if there is “a reasonable possibility” that 
the event may have been caused by the product under investigation (i.e., there are facts, 
evidence, or arguments to suggest possible causation). 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 89 of 135 
Guidelines for “Related” Events 
• There is clear evidence to suggest a causal relationship, and other possible contributing 
factors can be ruled out 
• There is evidence to suggest a causal relationship, and the influence of other factors is 
unlikely 
• There is some evidence to suggest a causal relationship (e.g., the event occurred within a 
reasonable time after administration of the study drug). However, the influence of other 
factors may have contributed to the event (e.g., the subject’s clinical condition, other 
concomitant events). 
Guidelines for “Not related” Events 
• There is little evidence to suggest there is a causal relationship. There is another reasonable 
explanation for the event. 
• An adverse event will be considered “not related” to the use of the product if any of the 
following tests are met: 
o 
An unreasonable temporal relationship between administration of the product and the 
onset on the AE (e.g., the event occurred either before, or too long after administration 
of the product for it to be considered product-related) 
o 
A causal relationship between the product and the AE is biologically implausible (e.g., 
death as a passenger in an automobile accident) 
o 
A clearly more likely alternative explanation for the AE is present (e.g., typical adverse 
reaction to a concomitant drug and/or typical disease-related event) 
Consider the Following When Assessing Causality 
• Temporal associations between the agent and the event 
• Effect of dechallenge and/or rechallenge 
• Compatibility with known class effect 
o 
The likelihood the AE can be attributed to the use of concomitant drugs, in particular 
chemotherapeutic agents used in treating the subject’s underlying PCD (see the current 
prescribing information for chemotherapeutic products used as standard of care; refer to 
Appendix 15) 
• Pre-existing risk factors 
• A plausible mechanism 
• Concurrent illnesses 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 90 of 135 
9.5 
Assessment of AEs:  Outcome 
Recovered/Resolved: 
The event has improved or recuperated. 
Recovered/Resolved with Sequelae: The subject recuperated but retained pathological 
conditions resulting from the prior disease or injury. 
Recovering/Resolving: 
Event is improving. 
Not Recovered/Not Resolved: 
Event has not improved or recuperated.  
Fatal:  
The termination of life as a result of an AE. 
Unknown:  
 
Not known, not observed, not recorded, or refused. 
(Source: Clinical Data Interchange Standards Consortium [CDISC] in collaboration with the 
National Cancer Institute’s Enterprise Vocabulary Services.) 
9.6 
Reporting of Serious Adverse Events 
It is the responsibility of the Principal Investigator to report SAEs to the Sponsor or its designee. 
Any SAE that occurs at any time during the study (Screening until the EOT/ETD Visit or for 
28 days after the last dose of study drug, whichever is later) whether or not related to study drug, 
must be reported within 24 hours of discovery to the Sponsor or its designee. New SAEs 
occurring beyond the EOT/ETD Visit or >28 days after the last administration of study drug, 
whichever is later, will be reported to the Sponsor or its designee only if, in the judgment of the 
Investigator, the SAE is associated with any protocol intervention (i.e., related to study 
procedure or previous study drug exposure). Do not delay in the reporting of an SAE in order to 
obtain additional information. Any additional information, if collected, can be reported to the 
Sponsor as a follow-up to the initial report. The SAE report should include the subject 
identification number or other appropriate terminology and the narrative should be 
comprehensive, including a chronology and assessment of the event. The SAE report should also 
include the Investigator’s assessment of the relationship of the event to the use of study drug. 
This assessment can be changed as more information becomes available. 
The Investigator is encouraged to discuss with the Medical Monitor any AEs for which the 
assessment of seriousness is unclear or questionable. Contact information for the Medical 
Monitor is found in the Study Manual. 
9.7 
Follow-up of Adverse Events 
All AEs experienced by a subject, regardless of the suspected causality, will be followed until 
the event has resolved, until the Investigator and/or the Medical Monitor deems the event to be 
chronic or stable, until there is a satisfactory explanation for the changes observed, or until the 
subject is lost to follow-up. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 91 of 135 
9.8 
Pregnancy 
The Sponsor has a responsibility to monitor the outcome of all pregnancies reported during the 
clinical study. Although pregnancy is not considered an SAE, an abnormal outcome of 
pregnancy is an SAE. Therefore, the Pregnancy Form should be used to report to the Sponsor the 
pregnancy of a female subject, or the pregnancy of the female partner of a male subject.  
Each pregnancy must be reported by the Investigator to the Sponsor within 24 hours after 
becoming aware of the pregnancy. The Investigator must follow-up and document the course and 
the outcome of all pregnancies even if the subject was withdrawn from the clinical study or if the 
clinical study has ended. Pregnancies must be followed until birth, termination of the pregnancy, 
or loss of the subject to follow-up. 
9.9 
Urgent Safety Measures 
The Sponsor is required to follow global regulations including EU regulations which state that 
the appropriate regulatory bodies, including IRBs/ECs/REBs, be notified according to their 
respective regulations of any new event resulting in the Sponsor and Investigator taking urgent 
safety measures to protect subjects against any immediate hazards.  
The reporting period for these events, which may require the implementation of urgent safety 
measures, is the period from the time the ICF is signed through the completion of the EOT/ETD 
Visit or for 28 days after the last dose of study drug, whichever is later. Investigators are required 
to report any events which may require the implementation of urgent safety measures to Sponsor 
within 24 hours. Examples of situations that may require urgent safety measures include the 
following: 
• 
Immediate need to revise the study drug administration (e.g., modified dose amount or 
frequency not defined in protocol) 
• 
Change in the study which has a significant impact on the scientific value of the clinical trial 
• 
Detrimental study conduct or management 
• 
Discovery that the quality or safety of the study drug does not meet established safety 
requirements 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 92 of 135 
10 
STATISTICAL CONSIDERATIONS 
A statistical analysis plan (SAP), providing details about the specific planned analyses and 
hypothesis tests, will be prepared and approved by the Sponsor and its designees prior to study 
database lock and unblinding of double blind subject treatment assignments.  
10.1 
Analysis Populations 
The Intent to Treat (ITT) Population will include all randomized subjects with AL amyloidosis 
who receive any amount of study drug (NEOD001 or placebo). The ITT Population will be the 
primary population used for efficacy analyses. The Safety Population will include all subjects 
with AL amyloidosis who receive any amount of study drug (NEOD001 or placebo). The Safety 
Population will be the primary population used for safety analyses.  
Additional analysis populations may be defined in the SAP. 
Efficacy Subset Populations: 
The Renal Evaluable Population will include subjects who had renal involvement 
(i.e., proteinuria >0.5 g/24 hours [measured by 24-hour urine total protein excretion]) at baseline 
and at least 1 postbaseline assessment of proteinuria. 
The Peripheral Neuropathy Evaluable Population will include subjects who had peripheral nerve 
involvement at baseline (only if the subject had ascending sensorimotor neuropathy at screening 
due to AL amyloidosis etiologies answered as yes) and had a baseline NIS-LL total score of 2 or 
greater and at least 1 postbaseline peripheral neuropathy assessment. 
The Hepatic Evaluable Population will include subjects who had hepatic involvement defined as 
one of the following: 1) >1.5 × ULN alkaline phosphatase at baseline and at least 1 postbaseline 
assessment of alkaline phosphatase or 2) baseline total liver size (i.e., craniocaudal dimension) 
>15 cm and at least 1 postbaseline assessment total liver size. 
10.2 
General Considerations 
Subject disposition will be summarized for all screened subjects and will include the number of 
subjects screened, the number screened but not randomized with reasons for screen failure, the 
number randomized, the number randomized and not treated, the number in each subject 
population for analysis, the number who withdraw from study prior to completing the study and 
reason(s) for withdrawal, and the number who discontinued treatment early and reason(s) for 
discontinuation of treatment. The demographic and baseline characteristics will be presented by 
treatment group and overall for the ITT and Safety populations. Duration of study drug exposure 
will be summarized using descriptive statistics by treatment group for the Safety Population. 
Continuous variables will be summarized by the number of subjects, mean, standard deviation 
(SD), standard error of the mean (SEM), median, 25th quartile (Q1), 75th quartile (Q3), 
minimum, and maximum values. Categorical variables will be summarized using frequency 
counts and percentages. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 93 of 135 
10.3 
Efficacy Analyses 
10.3.1 
Primary Analysis 
The primary endpoint is time to all-cause mortality or cardiac hospitalization as adjudicated by 
the CEC (Section 3.4.1 and Section 11.2). 
For all-cause mortality, all deaths occurring after the first infusion of study drug (i.e., Study 
Day 1) through the study’s last subject last visit (LSLV) will be included. Cardiac hospitalization 
occurring ≥91 days after a subject’s first infusion of study drug through LSLV will be included. 
All primary endpoint events will be adjudicated. Each subject will be counted only once in the 
primary analysis, based on their first adjudicated occurrence of an endpoint event.  
In addition, each component of the primary efficacy endpoint will be evaluated separately. 
The distribution of the primary endpoint of time to all-cause death or cardiac hospitalization in 
the two treatment groups will be summarized using the Kaplan-Meier method. The two treatment 
groups will be compared using a two-sided stratified (by the randomization stratification factors) 
log-rank test at the alpha=0.05 level of significance. 
10.3.2 
Key Secondary Efficacy Analyses 
If the primary analysis is statistically significant (p<0.05) in favor of NEOD001, the following 
key secondary endpoints will be analyzed using a fixed-sequence testing procedure in the order 
specified below to control the overall level of significance: 
• Change from baseline to Month 9 in the PCS score of the SF-36v2 
• Change from baseline to Month 9 in the 6MWT distance (meters) 
• NT-proBNP (cardiac) best response from baseline through Month 9 
For each of these endpoints, the treatment groups will be compared using a two-sided test at the 
alpha=0.05 level of significance. However, once a nonsignificant result (p>0.05) occurs, the 
results of all subsequent analyses will be considered nominal, descriptive, and exploratory rather 
than confirmatory. 
The SF-36v2 PCS score change from baseline at Month 9 will be analyzed using a restricted 
maximum likelihood (REML) based mixed-effect model for repeated measures (MMRM) model 
including fixed effects for randomization strata, treatment group, categorical time point, and the 
treatment group × time point interaction, and with the baseline value included as a covariate. The 
unstructured covariance model will be used. The 6MWT distance (meters) change from baseline 
at Month 9 will be analyzed using a rank ANCOVA model including fixed effects for 
randomization strata and treatment group, with the ranked baseline value included as a covariate. 
The Hodges-Lehman estimate of the median treatment difference with associated 95% CI will be 
presented. The NT-proBNP (cardiac) best response rates in the 2 treatment groups will be 
compared using the Cochran-Mantel-Haenszel (CMH) test stratified by the randomization 
stratification factors. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 94 of 135 
10.3.3 
Additional Secondary Efficacy Analyses 
For the Renal Evaluable Population, renal best response will be analyzed in the same manner 
described for NT-proBNP (cardiac) best response. For the Peripheral Neuropathy Evaluable 
Population, the change from baseline in NIS-LL total score will be analyzed in the same manner 
described for the SF-36v2 PCS score. For the Hepatic Evaluable Population, hepatic best 
response will be analyzed in the same manner described for NT-proBNP (cardiac) best response. 
10.3.4 
Exploratory Efficacy Analyses 
Endpoints that are defined as time-to-event variables will be analyzed in the same manner as the 
primary endpoint. Quantitative exploratory endpoints will be analyzed in the same manner 
described for the SF-36v2 PCS score. Exploratory endpoints that are defined as proportions will 
be analyzed in the same manner described for NT-proBNP (cardiac) best response. All 
exploratory analyses will be carried out using two-sided tests at the alpha=0.05 level of 
significance. 
10.3.5 
Handling of Missing Data 
Every effort must be made to avoid missing data. For all time-to-event endpoints, subjects with 
no data after randomization will be censored on Day 1 (first day of study drug dosing). As a 
sensitivity analysis, subjects with no data after randomization will be considered to have an event 
on Day 1 (first day of study drug dosing).  
Missing data for quantitative endpoints will not be imputed; all available data from each subject 
will be included in the linear mixed model analysis. Additional approaches for sensitivity 
analyses of the effects of missing data for primary, secondary, and exploratory endpoints may be 
provided in the SAP. 
For proportion endpoints, missing data will be replaced by the least favorable response. 
10.3.6 
Subgroup Analyses 
The primary and key secondary efficacy endpoints will be analyzed for subject subgroups using 
the ITT Population including the interaction between treatment group and the subgroup. In 
addition, select safety analyses will also be analyzed for subject subgroups using the Safety 
Population. Subgroups will be defined based on baseline values and only if there is a sufficient 
number of subjects in each category of the subgroup (e.g., >5 subjects per treatment group). 
Baseline subgroups of interest are as follows:  
• 
Age (<65, ≥65 years; <75, ≥75 years) 
• 
Sex (males, females) 
• 
Race (White, Non-White [Black or African American, Asian, Native Hawaiian or Other 
Pacific Islander, American Indian or Alaska Native]) 
• 
Geographic Region (North America, Rest of World) 
• 
IWRS Stratification Factor Mayo Clinic Stage (I/II vs. III/IV) 
• 
Baseline NYHA Class (I/II vs. III/IV) 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 95 of 135 
• 
IWRS Stratification Factor Renal Stage (I vs. II/III) 
• 
IWRS Stratification Factor 6MWT distance (<300 meters vs. ≥300 meters) 
• 
Baseline NT-proBNP (<1800 pg/mL vs. ≥1800 pg/mL) 
10.4 
Safety Analyses 
Safety data, including AEs, and clinical laboratory observations will be summarized by treatment 
group using the Safety Population. A comparison of safety will be made between the two arms of 
the study. 
10.4.1 
Adverse Events 
AEs will be coded using the Medical Dictionary for Regulatory Activities. Summary tables of 
TEAEs will be provided. The incidence of TEAEs will be tabulated by system organ class and 
preferred term for each treatment group, and by severity and relationship to treatment. Tables of 
TEAEs leading to study drug discontinuation and SAEs will be provided. TEAEs are defined as 
those AEs or SAEs that occur from the initiation of the first study drug infusion through the 
28-day period following the last dose of study drug. 
10.4.2 
Clinical Laboratory Evaluations 
Descriptive statistics summarizing central laboratory data will be presented for all study visits. 
Changes from baseline to each study visit will also be summarized by treatment group. In 
addition, mean change from baseline will be summarized for the maximum and minimum 
post-treatment values and for the values at the EOT/ETD Visit. 
The number and percent of subjects with a lab value with CTCAE Grade ≥3 and the number and 
percent of subjects with a CTCAE shift of ≥2 grades will be presented. 
10.4.3 
Additional Safety Analysis 
Additional safety assessments include vital signs and ECGs. Descriptive statistics of the vital 
sign and ECG parameters will be presented by treatment group and study visit, as well as the 
change from baseline at each visit. 
10.5 
Pharmacokinetic Analyses 
Serum NEOD001 concentrations and elapsed time from the preceding NEOD001 dose will be 
listed. Serum NEOD001 concentrations from this study will be pooled with data from similar 
samples from other NEOD001 studies in a population PK analysis. There will be no PK analyses 
for this protocol. 
10.6 
Immunogenicity 
Serum anti-NEOD001 antibody titers will be listed and, if sufficient data exist, summarized by 
treatment group. Serum anti-NEOD001 antibody titers may be correlated with serum NEOD001 
concentrations and select safety endpoints, if sufficient data exist.  


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 96 of 135 
An electrochemiluminescent (ECL) assay format will be used to detect serum anti-NEOD001 
antibodies in the study.  
10.7 
Interim Analysis 
No interim analyses are planned for this study. 
10.8 
Determination of Sample Size 
For the endpoint of time to all-cause mortality or cardiac hospitalization, the assumed 18-month 
event rate in the control arm is 60%, based on Kumar 2012. The 18-month event rate in the 
active arm is assumed to be 42%, a relative reduction of 30%. These assumptions correspond to a 
hazard ratio of 0.594. For a two-arm study with 1:1 randomization, and based on the use of a 
two-sided test at the alpha=0.05 level of significance, a total of 156 events (both arms combined) 
are required for 90% power. The study is designed to have 90% power in accordance with 
common practice for the design of confirmatory trials. Assuming an accrual period of 24 months, 
and a treatment/follow-up period of 18 months (i.e., a total study duration of 42 months), a total 
sample size of approximately 236 subjects will be required to attain 156 events.  


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 97 of 135 
11 
STUDY COMMITTEES 
11.1 
Data Monitoring Committee (DMC) 
The primary objective of the independent DMC is to safeguard the interests of subjects in the 
study and to help ensure the integrity and credibility of the study. The DMC abides by the 
principles set forth in the Food and Drug Administration (FDA) Guidance for Clinical Trial 
Sponsors, Establishment and Operation of Clinical Trial Data Monitoring Committees. The 
DMC is composed of individuals external to the study organizers, Sponsors, and Investigators 
and operates under the DMC’s written Charter that includes standard operating guidelines. The 
DMC will conduct reviews of accumulating data from the study on a regular basis and will 
advise the Sponsor regarding the continuing safety of trial subjects and those yet to be recruited 
to the trial, as well as the continuing validity and scientific merit of the trial. It is possible that the 
DMC may advise the Sponsor to stop the study based on its review of the accruing data that 
indicate clear harm to subjects participating in the study. A DMC Charter will be drafted to 
provide the guidelines for its operations and monitoring plans.  
The DMC members will review safety reports on a monthly basis. After the first 20 subjects 
have completed 3 cycles of randomized treatment, the DMC will conduct a review to confirm the 
safety and tolerability of the administration of NEOD001 and concomitant chemotherapy. This 
will include review of aggregated data to assess SAEs. The DMC will meet at least twice a year 
starting when the first subject is exposed to study medication, and continuing until the study is 
terminated and the database is locked and finalized.  
11.2 
Clinical Events Committee (CEC) 
An independent CEC, previously referred to as the Cardiovascular Adjudication Committee 
(CAC), blinded to treatment groups, will provide independent central adjudication of all deaths 
and hospitalizations. The CEC will define in its Manual of Procedures (MOP) cardiac events for 
use in the primary and secondary outcome analyses. The members of this committee will be 
experts in cardiac event adjudication and will be responsible for determining if hospitalizations 
meet the adjudication standard to be considered as a primary endpoint. The members of the CEC 
will not directly participate in this trial, nor will they participate as a member of the DMC.  
Any potential endpoint event (i.e., death or hospitalization) must be reported to the Sponsor or 
designee within 24 hours after the site staff learns of the clinical event. Study sites should collect 
the required documents, including the relevant completed endpoint eCRFs and the requested 
source documentation for submission to the CEC in a timely fashion for adjudication of the 
event.  
Further details regarding endpoint event submission guidelines, the CEC responsibilities, and the 
process of adjudication are described in the CEC MOP. 
11.3 
Hepatic Response Committee 
Hepatic responses according to consensus criteria (Comenzo 2012) may be subject to 
independent review by a Hepatic Response Committee.  


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 98 of 135 
12 
DATA RECORDING, RETENTION, AND MONITORING 
12.1 
Case Report Forms 
The clinical sites participating in this study are required to submit clinical data for each enrolled 
subject via an electronic data capture (EDC) system, using an eCRF. Site personnel will be 
trained on the EDC system before receiving access to it. The Sponsor or its designee is 
responsible for maintaining a record of all system users. The participants of the study will not be 
identified by name on any study documents to be collected by the Sponsor. 
All clinical information requested in this protocol will be recorded on the eCRFs provided by the 
Sponsor or their designee (or via other data collection methods, e.g., electronic laboratory data 
transfer). The Principal Investigator is responsible for reviewing all eCRFs for their subjects, 
verifying them for accuracy, and approving them via an electronic signature. Copies of the 
completed eCRFs, saved to disk in pdf format, will be sent to the Investigator’s site at the 
completion of the study. 
12.2 
Availability and Retention of Records 
The Investigator must make study data accessible to the study monitor, other authorized 
representatives of the Sponsor, and Regulatory Agency inspectors upon request. A file for each 
subject must be maintained that includes the signed Informed Consent Form (ICF) and the 
Investigator’s copies of all source documentation related to that subject. The Investigator must 
ensure the reliability and availability of source documents from which the information on the 
eCRF was derived. 
Investigators are required to maintain all study documentation, including documents created or 
modified in electronic format, for at least 15 years following the completion of the study. ICFs 
and adequate records for the receipt and disposition of all study drug must be retained for a 
period of 2 years following the date a marketing application is approved for the drug for the 
indication for which it is being investigated, or if no application is to be filed or if the application 
is not approved for such indication, until 2 years after the investigation is discontinued and FDA 
and other applicable Regulatory Authorities are notified, unless a longer period is required by 
applicable law or regulation. The Investigator must not discard any records unless given written 
authorization by the Sponsor. 
Subject identity information will be maintained for 15 years unless applicable law or regulation 
requires a longer period. 
12.3 
Quality Control and Quality Assurance 
Sponsor representatives and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the study (e.g., eCRFs and other pertinent data), provided that subject 
confidentiality is respected. 
The study monitor is responsible for inspecting the eCRFs at regular intervals throughout the 
study to verify the following:  adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical research. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 99 of 135 
The monitor should have access to subject medical records and other study-related records 
needed to verify the entries on the eCRFs. The Investigator must agree to cooperate with the 
monitor to ensure that any problems detected in the course of these monitoring visits are 
resolved. 
In accordance with ICH Good Clinical Practice (GCP) and Sponsor’s (or designee’s) audit plans, 
this study may be selected for an audit. Inspection of site facilities (e.g., pharmacy, drug storage 
areas, laboratories, etc.) and review of study-related records may occur in order to evaluate the 
trial conduct and compliance with the protocol, ICH GCP, and applicable regulatory 
requirements. 
12.4 
Subject Confidentiality 
The Investigator must ensure that each subject’s anonymity is maintained as described below. On 
the eCRFs or other documents submitted to the Sponsor or its designee, subjects must be 
identified by no more than their initials, date of birth, and a Subject Identification Number. 
Documents that are not for submission to the Sponsor (e.g., signed ICFs) should be kept in strict 
confidence by the Investigator in compliance with applicable regulations and ICH GCP 
Guidelines. The Investigator and institution must permit authorized representatives of the 
Sponsor, of regulatory agencies, and the IRB/EC direct access to review the subject’s original 
medical records for verification of study-related procedures and data. Direct access includes 
examining, analyzing, verifying, and reproducing any records and reports that are needed for the 
evaluation of the study. The Investigator is obligated to inform the subject in the ICF that the 
above named representatives may review study-related records from subjects. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 100 of 135 
13 
ETHICAL AND LEGAL ISSUES 
13.1 
Ethical Conduct of the Study 
The Investigator and Sponsor will ensure that this study is conducted in full compliance with the 
“Declaration of Helsinki” ICH guidelines, the CFR and/or with the laws and regulations of the 
country in which the research is conducted, whichever affords the greater protection to the study 
subject.  
13.2 
Regulatory Approval 
The Sponsor/designee will make the appropriate applications to the Regulatory Authority in each 
participating country for regulatory approval of the study and, if necessary, approval to import 
Investigational Product. The study will not start in a given region until the required regulatory 
approvals have been obtained in the appropriate jurisdiction. 
13.3 
Independent Review Board / Ethics Committee (EC) Approval 
The Investigator at the site is responsible for obtaining Institutional Review board/Ethics 
Committee (IRB/EC) approval for the final protocol, the Sponsor or designee-approved ICF, and 
any materials provided to or used to recruit subjects. Written approval of these documents must 
be obtained from the IRB/EC before any subject may be enrolled at the site. 
The Investigator is also responsible for the following interactions with the IRB/EC: 
• Obtaining IRB/EC approval for any protocol amendments and ICF revisions before 
implementing the changes 
• Providing the IRB/EC with any required information before or during the study 
• Submitting progress reports to the IRB/EC, as required during the conduct of the study, 
requesting re-review and approval of the study, as needed, and for providing copies of all 
IRB/EC re-approvals and relevant communication to the Sponsor or its designee 
• Notifying the IRB/EC of all serious and unexpected AEs related to the study medication 
reported by the Sponsor or its designee, as required by local regulations 
13.4 
Subject Informed Consent 
The Sponsor or its designee must review and approve the draft ICF and any amended ICFs 
prepared by the Investigator prior to submission to the IRB/EC for approval. An IRB/EC-
approved copy of the ICF and all amendments will be forwarded to Prothena. 
The ICF documents the study-specific information the Investigator provides to the subject and 
the subject’s agreement to participate. Among other things, the Investigator will fully explain in 
layman’s terms the nature of the study, along with the aims, methods, potential risks, and any 
discomfort participation in the study may entail. The subject must voluntarily, personally sign 
and date the ICF before any study-related procedures are performed. The original and any 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 101 of 135 
amended, signed and dated ICF(s) must be retained in the subject’s file at the study site and a 
copy of the signed ICF must be provided to the subject. 
13.5 
Subject Compensation for Adverse Effects on Health 
The Sponsor or its designee will adhere to local regulations regarding clinical trial compensation 
guidelines to subjects whose health is adversely affected by taking part in the study. 
13.6 
Protocol Amendments and Study Termination 
The Sponsor or its designee may amend the protocol as needed to ensure that the clinical 
investigation is being conducted as intended. The Sponsor or its designee will initiate protocol 
amendments in writing if any change significantly affects the safety of subjects, the scope of the 
investigation, or the scientific quality of the study. Protocol changes must be submitted to the 
IRB/EC as a protocol amendment. If necessary, the ICF will be revised to reflect the changes in 
the amendment and will be submitted to the IRB/EC for review and approval. A copy of the 
amendment signature page must be signed by the Investigator and returned to the Sponsor or its 
designee. Written documentation of IRB/EC approval is required before the amendment is 
implemented. 
Both the Sponsor and the Investigator reserve the right to terminate the study, according to the 
study contract. The Investigator should notify the IRB/EC in writing of the trial’s completion or 
early termination and send a copy of the notification to the Sponsor and/or their designee. 
13.7 
Finance, Insurance and Indemnity 
A study center will not initiate study participation until a fully executed Clinical Study 
Agreement is in place between the study center and the Sponsor. All details associated with 
finance, insurance and indemnity will be delineated in the Clinical Study Agreement. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 102 of 135 
14 
PUBLICATION 
All publication rights are delineated in the Clinical Study Agreement. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 103 of 135 
15 
REFERENCES 
American Heart Association. Classes of heart failure (last reviewed 06Apr2015). Available from: 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-
Heart-Failure_UCM_306328_Article.jsp. Accessed 31 Oct 2015. 
Bokhari S, Castaño A, Pozniakoff T, et al. (99m)Tc-pyrophosphate scintigraphy for 
differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile 
cardiac amyloidoses. Circ Cardiovasc Imaging. 2013;6(2):195-201. 
Bugelski PJ and Treacy G. Predictive power of preclinical studies in animals for the 
immunogenicity of recombinant therapeutic proteins in humans. Cur Opin Mol Ther. 
2004;6(1):10–6. 
Cibeira MT, Sanchorawala V, Seldin DC, et al. Outcome of AL amyloidosis after high-dose 
melphalan and autologous stem cell transplantation: long term results in a series of 421 patients. 
Blood. 2011;118(16):4346-52. 
Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid 
polyneuropathy: a randomized, controlled trial. Neurology. 2012;79(8):785-92. 
Cohen AD, Zhou P, Chou J, et al. Risk-adapted autologous stem cell transplantation with 
adjuvant dexamethasone+/-thalidomide for systemic light-chain amyloidosis: results of a phase II 
trial. Br J Haematol. 2007;139(2):224-33. 
Comenzo RL, Reece D, Palladini G, et al. Consensus guidelines for the conduct and reporting of 
clinical trials in systemic light-chain amyloidosis. Leukemia. 2012;26(11):2317-25. 
Dyck PJ, LitchyWJ, Lehman KA, et al. Variables influencing neuropathic endpoints: the 
Rochester Diabetic Neuropathy Study of Healthy Subjects. Neurology. 1995;45(6):1115-21. 
Falk RH and Dubrey SW. Amyloid Heart Disease. Prog Cardiovasc Dis. 2010;52:347-61. 
Galat A, Rosso J, Guellich A, et al. Usefulness of (99m)Tc-HMDP scintigraphy for the etiologic 
diagnosis and prognosis of cardiac amyloidosis. Amyloid. 2015(4):210-20. 
Gertz MA, Lacy MQ, Dispenzieri A, et al. Autologous stem cell transplant for immunoglobulin 
light chain amyloidosis: a status report. Leuk Lymphoma. 2010;51(12):2181-7. 
Gertz MA, Landau H, Comenzo RL, et al. First-in-human phase 1/2 study of NEOD001 in 
patients with light chain amyloidosis and persistent organ dysfunction. J Clin Oncol. 
2016;34(10):1097-103. 
Junicon Study: Relatively little published data exists on the incidence or prevalence of AL 
amyloidosis. Prothena contracted Juniper Consulting Group to conduct an amyloidosis 
opportunity evaluation and clinical landscape assessment. This study was completed in 
September 2011 and the review of the available literature was the basis for the estimated 
amyloidosis populations in the United States and Europe that formed the basis of the Orphan 
Drug Designation granted by the US FDA’s Office of Orphan Drug Products on  
17 February 2012 for NEOD001 in the treatment of AA and AL Amyloidosis and by the 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 104 of 135 
European Committee on Orphan Medicinal Products (COMP) on 09 January 2013 for NEOD001 
for the treatment of AL Amyloidosis. 
Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain 
amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin 
Oncol. 2012;30(9):989-95. 
Kyle R, Linos A, Beard C, et al. Incidence and natural history of primary systemic amyloidosis 
in Olmsted County, Minnesota, 1950 through 1989. Blood. 1992;79:1817-22. 
Kyle R, Therneau T, Rajkumar S, et al. A long-term study of prognosis in monoclonal 
gammopathy of undetermined significance. N Engl J Med. 2002;346(8):564-9. 
Kyle R, Therneau T, Rajkumar S, et al. Prevalence of Monoclonal Gammopathy of 
Undetermined Significance. N Engl J Med. 2006;354(13):1362-9. 
Merlini G, Seldin D, Gertz M. Amyloidosis: pathogenesis and new therapeutic options. J Clin 
Oncol. 2011;29(14):1924-33. 
Michael M, Kastritis E, Delimpassi S, et al. Clinical characteristics and outcome of primary 
systemic light-chain amyloidosis in Greece. Clin Lymphoma Myeloma Leuk. 2010;10(1):56-61. 
National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0 NCI, NIH, 
DHHS. NIH publication # 09-7473. 29 May 2009. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
Palladini G, Kyle RA, Larson DR, et al. Multicentre versus single centre approach to rare 
diseases: the model of systemic light chain amyloidosis. Amyloid. 2005;12(2):120-6. 
Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers 
of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124(15):2325-32.  
Palladini G, Sachchithanantham S, Milani P, et al. A European collaborative study of 
cyclophosphamide, bortezomib, and dexamethasone in upfront treatment of systemic AL 
amyloidosis. Blood. 2015;126(5):612-5. 
Pimm MV and Gribben SJ. Toxicity associated with the formation and clearance of immune 
complexes between antitumour monoclonal antibodies and syngeneic anti idiotype antibodies in 
mice. J Cancer Res Clin Oncol. 1992;119:41–5. 
Pinney J, Smith C, Taube J, et al. Systemic amyloidosis in England: an epidemiological study. Br 
J Haematol. 2013;161(4):525-32. 
Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group 
updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-48. 
Rapezzi C, Quarta CC, Guidalotti PL, et al. Role of (99m)Tc-DPD scintigraphy in diagnosis and 
prognosis of hereditary transthyretin-related cardiac amyloidosis. JACC Cardiovasc Imaging. 
2011;4(6):659-70. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 105 of 135 
Simms R, Prout M, Cohen A. The epidemiology of AL and AA amyloidosis. Baillieres Clin 
Rheumatol. 1994;8(3):627-34. 
Skinner M, Sanchorawala V, Seldin DC, et al. High-dose melphalan and autologous stem-cell 
transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med. 
2004;140(2):85-93. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 106 of 135 
16 
APPENDICES 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 107 of 135 
APPENDIX 1: 
ORGAN RESPONSE AND PROGRESSION CRITERIA 
Organ 
Response 
Progression 
Heart/Cardiac1 
NT-proBNP response (> 30% and > 300 ng/L 
decrease in patients with baseline NT-proBNP 
≥ 650 ng/L) or NYHA class response (≥ 2 class 
decrease in subjects with baseline NYHA class III 
or IV) 
NT-proBNP progression (> 30% and 
> 300 ng/L increase)2  
Kidney/Renal3 
≥ 30% decrease in proteinuria or drop of proteinuria 
below 0.5 g/24 hours in the absence of renal 
progression 
≥ 25% decrease in eGFR 
Peripheral 
Nerve4 
NIS-LL increase from baseline of <2 points 
NIS-LL increase from baseline of 
≥ 2 points 
Liver/Hepatic1 
50% decrease in abnormal ALP value 
OR 
≥ 2 cm reduction in liver size radiographically 
≥ 50% increase in ALP above lowest 
value 
ALP = alkaline phosphatase; eGFR = estimated glomerular filtration rate (as estimated by the Chronic Kidney Disease 
Epidemiology Collaboration [CKD-EPI] equation); NIS-LL = Neuropathy Impairment Score–Lower Limbs; 
NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association.  
1 
Modified from Table 2 in Comenzo 2012. In addition to the progression criteria listed above, Investigators will use their 
best clinical judgment in circumstances that do not meet the specifically referenced criteria above in assessing the 
progression. A repeated assessment at an interval that is determined by the investigator is required to confirm the 
progression. 
2 
Patients with progressively worsening renal function cannot be scored for NT-proBNP progression. 
3 
Palladini 2014. 
4 
Coelho 2012. 
 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 108 of 135 
APPENDIX 2: 
STRATIFICATION DETAILS 
Stratification Details for Mayo Staging Criteria 
Test 
Value 
Score 
NT-proBNP 
< 1,800 pg/mL 
0 
 
≥1,800 pg/mL 
1 
Troponin-T 
≤0.03 ng/mL1 
0 
 
>0.03 ng/mL1 
1 
dFLC 
<18 mg/dL 
0 
 
≥18 mg/dL 
1 
Total Score 
0 = Mayo Stage I 
1 = Mayo Stage II 
2 = Mayo Stage III 
3 = Mayo Stage IV 
1 
Modified from the value of 0.025 ng/mL cited in Kumar et al, to 0.03 ng/mL, which is the lowest validated determination 
for this commercially available test. 
Source:  Kumar 2012. 
 
Stratification Details for Renal Staging 
Test 
Value 
Score 
Proteinuria 
≤5 g/24 hours 
0 
 
>5g/24 hours 
1 
eGFR 
≥50 mL/min/1.73 m2 
0 
<50 mL/min/1.73 m2 
1 
Total Score 
0 = Renal Stage I 
1 = Renal Stage II 
2 = Renal Stage III 
eGFR = estimated glomerular filtration rate. 
Source:  Palladini 2014. 
 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 109 of 135 
APPENDIX 3: 
Schedule Of Events For Subjects Who Discontinue Study Drug Early 
but Agree to Return For Assessments After the ETD Visit 
Assessments 
Months 3, 6, 9, 12 
Day 1 (±5)1 
Every Third Month 
After Month 122 
(e.g., Months 15, 18, 21) 
Day 1 (±5) 
Every 3 
Months after 
Last Visit 
SF-36v2 Health Survey3 
X 
 
 
KCCQ3 
X 
 
 
FACT-GOG NTX3,4 
Per Section 7.4 & Table 2 
 
 
Echocardiogram 
Months 6 and 125 
 
 
Liver Imaging (CT) 
Months 6 and 126 
 
 
12-lead Triplicate ECG7 
X 
 
 
Symptom-Directed PE8 
X 
 
 
ECOG PS & NYHA Class 
X 
 
 
NIS-LL9 
Per Section 7.4 & Table 2 
 
 
VASPI10 
Per Section 7.4 & Table 2 
 
 
Local Laboratory 
 
 
 
Serum Pregnancy (WOCBP) 
X11 
 
 
Central Laboratory12 
 
 
 
Hematology & Chemistry 
X 
 
 
Amylase 
X 
 
 
Coagulation13 
X 
 
 
Complements C3, C4 
X 
 
 
Troponin T 
X 
 
 
NT-proBNP 
X 
 
 
Serum Free Light Chains (sFLCs) 
X 
 
 
Serum IFE/PEP 
X14 
 
 
Urinalysis 
X 
 
 
24-hour Urine Collection for: 
 
 
 
 
Urine Protein Excretion15 
Months 3 and 9 
 
 
Urine IFE/PEP15 
Months 3 and 916 
 
 
6-Minute Walk Test (6MWT) 
X 
X17 
 
Bioanalytical Laboratory 
 
 
 
Anti-NEOD001 Antibody Sample18 
X 
 
 
Vital Signs 
X19 
X17 
 
Adverse Event Assessment 
X20 
X17, 20 
 
Concomitant Medications 
X 
X17 
 
Health Status & Hospitalizations 
X21 
X17, 21 
X17, 20, 21 
Vital Status Phone Call 
 
 
X22 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 110 of 135 
 BP = blood pressure; CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
performance status; ETD = Early Treatment Discontinuation; FACT-GOG NTX = Functional Assessment of Cancer 
Therapy – Gynecologic Oncology Group Neurotoxicity Subscale; HR = heart rate; IFE = immunofixation electrophoresis; 
KCCQ = Kansas City Cardiomyopathy Questionnaire; NGAL = neutrophil gelatinase-associated lipocalin; 
NIS-LL = Neuropathy Impairment Score – Lower Limbs; NT-proBNP = N-terminal pro-brain natriuretic peptide; 
NYHA = New York Heart Association; PE = physical exam; PEP = protein electrophoresis; RBP = retinol-binding protein; 
RR = respiratory rate; 6MWT = 6-minute walk test; SF-36v2 = Short Form-36 Version 2; VASPI = Visual Analog Scale – 
Pain Intensity; WOCBP = women of childbearing potential. 
1. If a subject discontinues study drug prior to the end of the study, but is willing to continue to participate in study visits, the 
subject should have an ETD Visit within 28-35 days after the last study drug administration (per Table 1 and Section 7.1.6) 
and then have assessments performed every third month (i.e., Months 3, 6, 9, and 12, or whatever remains of these visits). 
The most important visit is the Month 9-Day 1 Visit, so if a subject is unwilling to continue visits every third month, every 
effort should be made for the subject to return and complete the Month 9-Day 1 Visit on schedule. All visits after the ETD 
Visit should occur on schedule, that is, at the time when the visit would have occurred had the subject remained on study 
drug. 
2. If subject is willing to return to the study site, otherwise, subjects will receive vital status phone calls per Footnote 22. 
3. Administer questionnaires in the following order prior to the performance of any other study assessments on the day they are 
administered: SF-36v2 (Appendix 7), KCCQ (Appendix 8), and FACT-GOG NTX (Appendix 9). 
4. Administer the FACT-GOG NTX (Appendix 9) per Table 2. 
5. Perform echocardiograms within 10 days prior to Day 1 of Months 6 and 12. To be eligible for the additional cardiac imaging 
analysis, the subject must have had a 4-chamber view, 2-dimensional echocardiogram with Doppler. 
6. For subjects with liver involvement at Screening (Exception: not required in Germany), perform scheduled repeat CT imaging 
of the abdomen for liver measurement at Months 6 and 12 and unscheduled repeat CT imaging as needed per Section 7.6.  
7. ECG to be performed in triplicate. 
8. Symptom-directed PE should be as clinically indicated and also include weight, and assessment of macroglossia, 
submandibular nodes/fullness, adenopathy, ecchymoses, liver/spleen size (palpable +/-), ascites (+/-), and edema (which 
should be quantified on a scale of 0-4). 
9. Administer NIS-LL (Appendix 10) per Table 2. 
10. Administer VASPI (Appendix 11) per Table 2. 
11. Obtain local laboratory serum pregnancy test 90 (±5) days after the last study drug administration. 
12. Collect central laboratory samples before 6MWT, if being performed on the same day. 
13. Collect PT/INF and PTT at each time point. As clinically indicated, collect citrated plasma samples for freezing and for 
potential analysis of coagulation indices at a later date; these analyses may include, but may not be limited to, the indices 
listed in  Appendix 12. 
14. Perform serum IFE/PEP at each visit. If a subject’s first on-study hematologic complete response was assessed at the previous 
visit, perform serum IFE/PEP (and 24-hour urine IFE/PEP) at least 28 days after the initial assessment of response to confirm 
response. 
15. The 24-hour urine protein excretion and 24-hour urine IFE/PEP tests will be performed using the same 24-hour urine 
collection sample, when required at the same visit.  
16. If a subject’s first on-study hematologic complete response was assessed at the previous visit, perform 24-hour urine IFE/PEP 
(and serum IFE/PEP) at least 28 days after the initial assessment of response to confirm response. Repeat every odd-
numbered month (i.e., Months 3 and 9 to correspond with 24-hour urine protein excretion collection) to assess for continuing 
response or progression. If the initial response confirmation needs to occur on an even-numbered month, perform an 
additional 24-hour urine collection. 
17. After Month 12, if the subject is willing to return to the study site, perform or collect the following every third month (e.g., 
Months 15, 18, 21): 6MWT (which includes BP and HR pre- and post-6MWT administration), adverse events, concomitant 
medications, overall health status, as well as details of any hospitalizations. 
18. Collect if an earlier sample established the presence of anti-NEOD001 antibodies or if a subject discontinued treatment due to 
a suspected immunologic reaction. 
19. Collect BP, HR, RR, and temperature any time during visit. 
20. New SAEs occurring beyond the EOT/ETD Visit or >28 days after the last administration of study drug, whichever is later, 
will be reported to the Sponsor or its designee only if, in the judgement of the Investigator, the SAE is associated with any 
protocol intervention (i.e., related to study procedure or previous study drug exposure). 
21. All hospitalizations and deaths occurring during this period need to be reported to the Sponsor or its designee. 
22. Conduct a vital status phone call per Section 7.1.8 approximately 3 months after the subject’s last visit and approximately 
every 3 months thereafter. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 111 of 135 
APPENDIX 4: 
EXAMPLES OF HIGHLY EFFECTIVE CONTRACEPTION 
METHODS 
Contraception methods that can achieve a failure rate of <1% per year when used consistently 
and correctly are considered to be highly effective. Such methods include: 
 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation1: 
o Oral 
o Intravaginal 
o Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1: 
o Oral 
o Injectable 
o Implantable2 
• Intrauterine device (IUD)2 
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2 
• Vasectomized partner2,3 
• Sexual abstinence4 
 
1 Hormonal contraception may be susceptible to interaction with the Investigational Medicinal Product ( IMP), 
which may reduce the efficacy of the contraception method. 
2 Contraception methods that in the context of this guidance are considered to have low user dependency. 
3 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of 
the WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical 
success. 
4 In the context of this guidance 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 treatments. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the subject. 
 
Source:  Clinical Trial Facilitation Group (CTFG): Recommendations related to contraception and pregnancy testing 
in clinical trials (Final Version 15Sep2014). Available from: 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. Accessed 02Aug2015. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 112 of 135 
APPENDIX 5: 
REVISED INTERNATIONAL MYELOMA WORKING GROUP 
DIAGNOSTIC CRITERIA FOR MULTIPLE MYELOMA 
Definition of Multiple Myeloma 
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary 
plasmacytoma* and any one or more of the following myeloma deﬁning events: 
Myeloma deﬁning events: 
• Evidence of end organ damage that can be attributed to the underlying plasma cell 
proliferative disorder, speciﬁcally: 
o Hypercalcaemia:  serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper 
limit of normal (ULN) or >2.75 mmol/L (>11 mg/dL) 
o Renal insufficiency:  creatinine clearance <40 mL per min† or serum creatinine 
>177 μmol/L (>2 mg/dL) 
o Anemia:  hemoglobin value of >20 g/L below the lower limit of normal, or a 
hemoglobin value <100 g/L 
o Bone lesions:  one or more osteolytic lesions on skeletal radiography, CT, or 
PET-CT‡ 
• Any one or more of the following biomarkers of malignancy: 
o Clonal bone marrow plasma cell percentage* ≥60% 
o Involved:uninvolved serum free light chain ratio§ ≥100 
o >1 focal lesions on magnetic resonance imaging (MRI) studies¶ 
 
PET-CT=18F-ﬂuorodeoxyglucose PET with CT. *Clonality should be established by showing κ/λ-light-chain 
restriction on ﬂow cytometry, immunohistochemistry, or immunoﬂuorescence. Bone marrow plasma cell percentage 
should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core 
biopsy, the highest value should be used. †Measured or estimated by validated equations. ‡If bone marrow has less 
than 10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary plasmacytoma with 
minimal marrow involvement. §These values are based on the serum Freelite assay (The Binding Site Group, 
Birmingham, UK). The involved free light chain must be ≥100 mg/L. ¶Each focal lesion must be 5 mm or more in 
size. 
Source:  Rajkumar 2014. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 113 of 135 
APPENDIX 6: 
HEMATOLOGIC RESPONSE AND PROGRESSION CRITERIA 
Response Subcategory 
Response Criteria 
Complete Response (CR) 
• Normalization of free light chain levels and ratio, negative serum 
and urine immunofixation 
Very Good Partial Response (VGPR)* 
• Reduction in the dFLC to <40 mg/L (<4.0 mg/dL) 
Partial Response (PR)* 
• A greater than 50% reduction in the dFLC 
No Response (NR) 
• Less than a PR 
Progression 
• From CR:  any detectable monoclonal protein or abnormal free 
light chain ratio (light chain must double) 
• From PR, 50% increase in serum M protein to > 0.5 g/dL or 50% 
increase in urine M protein to > 200 mg/day (a visible peak must 
be present) or free light chain increase of 50% to > 10 mg/dL 
(100 mg/L) 
dFLC = difference between involved and uninvolved free light chains. 
*Only applicable for subjects with dFLC > 50 mg/L (5 mg/dL) at study entry. 
Source:  Comenzo 2012. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 114 of 135 
APPENDIX 7: 
SHORT FORM-36 QUESTIONNAIRE (SF-36V2) 
 
 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 115 of 135 
 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 116 of 135 
 
 
 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 117 of 135 
 
 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 118 of 135 
 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 119 of 135 
 
 
 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 120 of 135 
 
 
 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 121 of 135 
 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 122 of 135 
 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 123 of 135 
 
 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 124 of 135 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 125 of 135 
APPENDIX 8: 
KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE (KCCQ) 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 126 of 135 
 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 127 of 135 
 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 128 of 135 
 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 129 of 135 
APPENDIX 9: 
FUNCTIONAL ASSESSMENT OF CANCER THERAPY – 
GYNECOLOGIC ONCOLOGY GROUP NEUROTOXICITY 
SUBSCALE (FACT-GOG NTX) 
Circle or mark one number per line to indicate your response as it applies to the past 7 days: 
 
Instructions for Healthcare Professionals: 
This assessment tool is to help you evaluate peripheral neuropathy in subjects receiving chemotherapy. You may 
find discussion of subject responses helpful in determining the grade of neuropathy as defined by the NCI-CTCAE 
listed below; there is no direct correlation between assessment scores and toxicity grades. 
 
NCI-CTCAE for Peripheral Neuropathy and Neuropathic Pain 
 
Grade 
 
1 
2 
3 
4 
5 
Peripheral 
motor 
neuropathy 
Asymptomatic; clinical or 
diagnostic observations 
only; intervention not 
indicated 
Moderate 
symptoms; limiting 
instrumental ADL 
Severe symptoms; 
limiting self-care 
ADL; assistive 
device indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Peripheral 
sensory 
neuropathy 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia 
Moderate 
symptoms; limiting 
instrumental ADL 
Severe symptoms; 
limiting self-care 
ADL 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Neuralgia 
Mild pain 
Moderate 
symptoms; limiting 
instrumental ADL 
Severe pain; 
limiting self-care 
ADL 
 
 
ADL = activities of daily living; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events. 
Source: NCI-CTCAE (version 4.03) 2009. 
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 130 of 135 
APPENDIX 10: 
NEUROPATHY IMPAIRMENT SCALE – LOWER LIMBS 
(NIS-LL) 
  
SAMPLE 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 131 of 135 
APPENDIX 11: 
VISUAL ANALOG SCALE – PAIN INTENSITY (VASPI) 
 
 
 
 
VISUAL ANALOG SCALE – PAIN INTENSITY 
 
 
 
 
 
 
Over the last week, on average, my lower extremity pain would be described as: 
 
 
 
 
 
 
 
 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 132 of 135 
APPENDIX 12: 
COAGULATION INDICES 
For each coagulation time point in Table 1, citrated plasma samples may be collected and frozen 
for potential analysis of coagulation indices at a later date; these analyses may include, but may 
not be limited to, the indices listed in the following table: 
Antithrombin Activity (ATIII Activity) 
Fibrinogen Antigen 
Partial Thromboplastin Time Mixing Studies 
High-Molecular Weight Kininogen 
D-dimer, quantitative 
Prekallikrein 
Euglobulin Lysis Time  
Plasminogen Activator Inhibitor-1 Antigen 
Factor II Activity 
Plasminogen Activator Inhibitor-1 Activity 
Factor V Activity 
Plasmin-antiplasmin Complex 
Factor VII Activity 
Plasminogen Activity 
Factor VIII Activity  
Protein C Activity 
Factor VIII Antigen Quantitation 
Protein S Antigen Free 
Factor IX Activity 
Thrombin Time 
Factor X Activity 
Tissue Plasminogen Activator Activity 
Factor XI Activity 
Tissue Plasminogen Activator Antigen 
Factor XII Activity 
von Willebrand Factor Activity (Ristocetin Cofactor) 
Factor XIII Activity 
von Willebrand Factor Antigen 
Fibrin Monomer 
von Willebrand Factor Multimers 
Fibrinogen Activity 
 
 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 133 of 135 
APPENDIX 13: 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
Grade 
Eastern Cooperative Oncology Group 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 
Source:  Oken 1982. 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 134 of 135 
APPENDIX 14: 
NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION 
NYHA Class 
Symptoms 
I 
No symptoms and no limitation in ordinary physical activity, e.g. shortness of breath when 
walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during ordinary 
activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. 
walking short distances (20–100 m). Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound patients. 
NYHA = New York Heart Association. 
Source:  American Heart Association 2015. 
 
 


Study Drug:  NEOD001 
CONFIDENTIAL 
Study Protocol:  NEOD001-CL002 Amendment 3 
 
 
Date: 06 November 2017 
Page 135 of 135 
APPENDIX 15: 
PACKAGE INSERTS FOR CHEMOTHERAPEUTIC AGENTS 
COMMONLY PRESCRIBED FOR INDIVIDUALS WITH AL 
AMYLOIDOSIS 
Package Inserts for many chemotherapeutic agents commonly prescribed for individuals with AL 
amyloidosis and which have been approved by the US Food and Drug Administration (FDA) 
may be found at the FDA website, Drugs@FDA, at the following link:  
http://www.accessdata.fda.gov/scripts/cder/drugsatfda/ 
The Summary of Product Characteristics for all products approved via the Centralized procedure 
in the European Union (EU) can be found on the European Medicines Agency (EMA) website as 
follows: 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=
WC0b01ac058001d124  
The above website states that EMA does not evaluate all medicines currently in use in Europe. If 
a specific medicine cannot be found on the website, it may be found on that of the national health 
authority of a specific EU country. For example, in the United Kingdom, refer to the electronic 
Medicines Compendium (https://www.medicines.org.uk/emc/about-the-emc). 
For countries outside of the US and EU, the package inserts may be found on the website of the 
country’s national health authority, such as: 
• Australia: https://www.tga.gov.au/australian-register-therapeutic-goods 
• Canada: http://webprod5.hc-sc.gc.ca/dpd-bdpp/index-eng.jsp 
• Israel: http://www.old.health.gov.il/units/pharmacy/trufot/index.asp?safa=e 
 
 

SAP_001.pdf: 
Document Type:
Statistical Analysis Plan
Official Title:
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-
Controlled, 2-Arm, Efficacy and Safety Study of NEOD001 Plus 
Standard of Care vs. Placebo Plus Standard of Care in Subjects with 
Light Chain (AL) Amyloidosis
NCT Number:
NCT02312206
Document Date:
13 June 2018


TITLE PAGE 
 
Statistical Analysis Plan for Protocol NEOD001-CL002 (VITAL) 
 
A Phase 3, Randomized, Multicenter, Double-Blind, Placebo-Controlled, 2-
Arm, Efficacy and Safety Study of NEOD001 Plus Standard of Care vs. 
Placebo Plus Standard of Care in Subjects with Light Chain (AL) Amyloidosis 
 
Investigational Product: 
NEOD001 
US IND Number: 
122,912 
EudraCT Number: 
2014-003865-11 
Protocol Version and Date: 
Amendment 2, 28 April 2016 
Phase: 
Phase 3 
Methodology: 
Double-Blind, Randomized, Placebo-Controlled Study 
Sponsor: 
Prothena Therapeutics Limited 
Adelphi Plaza, Upper George’s Street 
Dun Laoghaire, Co. Dublin 
A96 T927, Ireland 
Sponsor Representative: 
Prothena Biosciences Inc 
331 Oyster Point Boulevard 
South San Francisco, CA 94080 USA 
Analysis Plan Date: 
13 June 2018 
Analysis Plan Version: 
Final v1.0  
 
CONFIDENTIAL 
 This document and its contents are confidential and proprietary to Prothena. Any unauthorized 
use, disclosure, or copying of this document is prohibited. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 2 
 
Confidential and Proprietary 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES 
TITLE PAGE ...................................................................................................................................1 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
INTRODUCTION .......................................................................................................12 
2. 
INFORMATION FROM THE STUDY PROTOCOL ................................................12 
2.1. 
Study Objective ......................................................................................................12 
2.1.1. 
Primary Objective ......................................................................................12 
2.1.2. 
Key Secondary Objectives .........................................................................12 
2.1.2.1. 
Change in Health-Related Quality of Life ................................................. 12 
2.1.2.2. 
Change in Cardiac Functional Response .................................................... 12 
2.1.2.3. 
Cardiac Response Rate ............................................................................... 12 
2.1.3. 
Additional Secondary Objectives ..............................................................13 
2.1.3.1. 
Renal Response Rate .................................................................................. 13 
2.1.3.2. 
Change in Peripheral Neurological Function ............................................. 13 
2.1.4. 
Exploratory Objectives ..............................................................................13 
2.2. 
Study Design ..........................................................................................................13 
2.2.1. 
Overall Study Design .................................................................................13 
2.2.2. 
Study Design Diagram ...............................................................................14 
2.2.3. 
Study Drug .................................................................................................16 
2.2.4. 
Randomization Methodology.....................................................................16 
2.2.5. 
Study Procedures .......................................................................................16 
2.3. 
Study Endpoints .....................................................................................................22 
2.3.1. 
Primary Efficacy Endpoint ........................................................................22 
2.3.2. 
Key Secondary Efficacy Endpoints ...........................................................22 
2.3.2.1. 
Change from Baseline to Month 9 in the Physical Component Score of the 
SF-36v2 ...................................................................................................... 22 
2.3.2.2. 
Change from Baseline to Month 9 in the 6-Minute Walk Test (6MWT) 
Distance (meters) ....................................................................................... 23 
2.3.2.3. 
NT-proBNP (Cardiac) Best Response from Baseline Through Month 9 ... 23 
2.3.3. 
Additional Secondary Efficacy Endpoints .................................................24 
2.3.3.1. 
Renal Evaluable Subjects: Renal Best Response from Baseline through 
Month 9 ...................................................................................................... 24 
2.3.3.2. 
Peripheral Neuropathy Evaluable Subjects: Change from Baseline to 
Month 9 in Neuropathy Impairment Score–Lower Limbs (NIS-LL) Total 
Score .......................................................................................................... 24 
2.3.4. 
Exploratory Efficacy Endpoints .................................................................25 
2.3.4.1. 
Cardiac Endpoints ...................................................................................... 25 
2.3.4.2. 
Functional Endpoint - 6MWT Distance ..................................................... 25 
2.3.4.3. 
Quality of Life Endpoints - SF-36v2 ......................................................... 25 
2.3.4.4. 
Renal Endpoints ......................................................................................... 25 
2.3.4.5. 
Peripheral Neuropathy Endpoints .............................................................. 25 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 3 
 
Confidential and Proprietary 
2.3.4.6. 
Additional Time-to-Event Endpoints ......................................................... 26 
2.3.4.7. 
Other Efficacy Endpoints ........................................................................... 26 
2.3.5. 
Safety Endpoints ........................................................................................26 
3. 
SAMPLE SIZE JUSTIFICATION ..............................................................................27 
4. 
GENERAL STATISTICAL METHODS ....................................................................27 
4.1. 
Reporting Conventions ..........................................................................................27 
4.2. 
Computing Environment ........................................................................................28 
4.3. 
Definition of Baseline ............................................................................................28 
4.4. 
Partial Dates ...........................................................................................................28 
4.5. 
Data Conventions ...................................................................................................30 
4.6. 
Standard Calculations ............................................................................................30 
4.7. 
Visit Windows .......................................................................................................31 
5. 
ANALYSIS POPULATIONS .....................................................................................32 
6. 
EXAMINATION OF SUBGROUPS ..........................................................................33 
7. 
STUDY POPULATION ..............................................................................................33 
7.1. 
Subject Disposition ................................................................................................33 
7.2. 
Demographics and Baseline Characteristics ..........................................................33 
7.3. 
Baseline AL Amyloidosis Disease Characteristics ................................................34 
7.4. 
Disease Specific AL Symptoms.............................................................................35 
7.5. 
General Medical History ........................................................................................35 
7.6. 
Protocol Deviations ................................................................................................35 
7.7. 
Pre-Treatment, Prior, and New Concomitant Medications ....................................35 
7.8. 
Chemotherapy ........................................................................................................36 
8. 
EFFICACY ANALYSES ............................................................................................36 
8.1. 
Adjustments for Covariates....................................................................................36 
8.2. 
Handling of Dropouts or Missing Data ..................................................................36 
8.2.1. 
Time to Event Endpoints ...........................................................................36 
8.2.2. 
Parametric Analyses ...................................................................................37 
8.2.2.1. 
Missing Not at Random (MNAR): Imputation for Deaths ........................ 37 
8.2.2.2. 
Missing at Random (MAR): Multiple Imputation ..................................... 37 
8.2.3. 
Non-Parametric Analyses ..........................................................................37 
8.2.3.1. 
Ranking ...................................................................................................... 37 
8.2.4. 
Responder Endpoints .................................................................................38 
8.2.5. 
Observed Cases ..........................................................................................38 
8.3. 
Interim Analyses and Data Monitoring ..................................................................38 
8.3.1. 
Data Monitoring Committee (DMC) .........................................................38 
8.3.2. 
Interim Analysis .........................................................................................38 
8.3.3. 
Adjudication Committee ............................................................................39 
8.4. 
Multicenter Studies ................................................................................................39 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 4 
 
Confidential and Proprietary 
8.5. 
Use of an “Efficacy Subset” of Patients ................................................................39 
8.6. 
Multiple Comparisons/Multiplicity .......................................................................39 
8.7. 
Primary Efficacy Analysis .....................................................................................40 
8.7.1. 
Sensitivity Analyses of the Primary Endpoint ...........................................41 
8.7.1.1. 
Time to Event Methods .............................................................................. 41 
8.7.1.2. 
Finkelstein–Schoenfeld Method ................................................................ 42 
8.7.2. 
Analyses of Each Component of the Primary Endpoint ............................43 
8.7.2.1. 
Time to All-Cause Mortality (Overall Survival) ........................................ 43 
8.7.2.2. 
Time to Cardiac Hospitalization ................................................................ 43 
8.8. 
Key Secondary Efficacy Analyses .........................................................................44 
8.8.1. 
SF-36v2 PCS Score ...................................................................................44 
8.8.2. 
6MWT Distance .........................................................................................45 
8.8.3. 
NT-proBNP (Cardiac) Best Response .......................................................46 
8.9. 
Additional Secondary Efficacy Analyses ..............................................................47 
8.9.1. 
Renal Evaluable Subjects: Renal Best Response .......................................47 
8.9.2. 
Peripheral Neuropathy Evaluable Subjects: NIS-LL Score .......................47 
8.10. 
Exploratory Efficacy Analyses ..............................................................................47 
8.10.1. 
Cardiac Endpoint Analyses ........................................................................47 
8.10.2. 
Functional Endpoint Analyses ...................................................................48 
8.10.2.1. 
6MWT Distance ......................................................................................... 48 
8.10.3. 
Quality of Life Endpoint Analyses ............................................................49 
8.10.3.1. 
SF-36v2 PCS Score .................................................................................... 49 
8.10.4. 
Renal Endpoint Analyses ...........................................................................49 
8.10.4.1. 
Renal Response .......................................................................................... 49 
8.10.4.2. 
Creatinine, Proteinuria, and eGFR ............................................................. 49 
8.10.5. 
Peripheral Neuropathy Endpoint Analyses ................................................49 
8.10.6. 
Additional Time-to-Event Analyses ..........................................................49 
8.10.6.1. 
Time to Cardiac Mortality or Cardiac Hospitalization .............................. 49 
8.10.6.2. 
Time to Cardiac Mortality .......................................................................... 50 
8.10.6.3. 
Time to Cardiac Hospitalization ................................................................ 50 
8.10.6.4. 
Time to Derived Organ Progression .......................................................... 50 
8.10.6.5. 
Time to First Derived Organ Response ...................................................... 51 
8.10.7. 
Other Efficacy Endpoints ...........................................................................51 
9. 
SAFETY ANALYSES.................................................................................................51 
9.1. 
Extent of Exposure .................................................................................................52 
9.1.1. 
Study Drug .................................................................................................52 
9.1.2. 
Premedication ............................................................................................52 
9.1.3. 
Standard of Care Chemotherapy ................................................................52 
9.2. 
Adverse Events ......................................................................................................52 
9.2.1. 
Types of Incidence Rates ...........................................................................53 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 5 
 
Confidential and Proprietary 
9.2.1.1. 
Crude Incidence Rates ............................................................................... 53 
9.2.1.2. 
Exposure-Adjusted Incidence Rates .......................................................... 53 
9.2.2. 
Overall Summary of Adverse Events ........................................................54 
9.2.3. 
Treatment-Emergent Adverse Events ........................................................54 
9.2.4. 
Serious Adverse Events and Deaths ..........................................................54 
9.2.5. 
Adverse Events Leading to Study Drug Withdrawal .................................55 
9.2.6. 
Adverse Events of Special Interest ............................................................55 
9.2.6.1. 
Infusion Associated Adverse Events .......................................................... 55 
9.3. 
FACT-GOG NTX ..................................................................................................55 
9.4. 
Clinical Laboratory Evaluations ............................................................................55 
9.4.1. 
Pregnancy Testing and Urinalysis Dipstick ...............................................55 
9.5. 
Weight and BMI ....................................................................................................56 
9.6. 
Vital Signs ..............................................................................................................56 
9.7. 
Electrocardiograms ................................................................................................56 
9.8. 
Physical Examination.............................................................................................56 
9.9. 
Immunogenicity Analyses .....................................................................................56 
10. 
CHANGES TO PROTOCOL PLANNED ANALYSES .............................................56 
10.1. 
Changes from Protocol Planned Analyses .............................................................56 
10.2. 
Changes Due to Discontinuation of the NEOD001 Program ................................57 
11. 
REFERENCES ............................................................................................................59 
12. 
APPENDICES .............................................................................................................61 
Appendix 1: 
Organ Response and Progression Criteria .................................................62 
Appendix 2: 
Stratification Details ..................................................................................63 
Appendix 3: 
Schedule of Events For Subjects Who Discontinue Study Drug Early but 
Agree to Return For Assessments After the ETD Visit .............................64 
Appendix 4: 
Hematologic Response and Progression Criteria .......................................66 
Appendix 5: 
SF-36V2 Health Survey .............................................................................67 
Appendix 6: 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ..............................78 
Appendix 7: 
Functional Assessment of Cancer Therapy – Gynecologic Oncology 
Group Neurotoxicity Subscale (FACT-GOG NTX) ..................................81 
Appendix 8: 
Neuropathy Impairment Scale – Lower Limbs (NIS-LL) .........................82 
Appendix 9: 
Visual Analog Scale – Pain Intensity (VASPI) .........................................83 
Appendix 10: 
Coagulation Indices ...................................................................................84 
Appendix 11: 
Eastern Cooperative Oncology Group (ECOG) Performance Status ........85 
Appendix 12: 
New York Heart Association (NYHA) Functional Classification .............86 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 6 
 
Confidential and Proprietary 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures .................................................................................... 17 
Table 2: 
Peripheral Neuropathy Assessments .......................................................................... 21 
Table 3: 
1-Month Interval Visit Windows (Days) .................................................................... 32 
Table 4: 
3-Month Interval Visit Windows (Days) .................................................................... 32 
Table 5: 
Finkelstein–Schoenfeld Scoring Algorithm ............................................................... 42 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic ............................................................................................. 15 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 7 
 
Confidential and Proprietary 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
6MWT 
6-minute walk test 
99mTc 
Radioisotope of Technetium  
ADL 
activities of daily living 
AE 
adverse event 
AIC 
Akaike’s information criterion 
AL 
amyloid light chain 
ALP 
alkaline phosphatase 
ANCOVA 
analysis of covariance 
AR(1) 
first-order autoregressive 
ATC  
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BP 
blood pressure 
C 
Celsius 
CAC 
Cardiovascular Adjudication Committee 
CEC 
Clinical Events Committee 
CI 
confidence interval 
cm 
centimeter 
CMH 
Cochran-Mantel-Haenszel 
CR 
complete response 
CRF 
case report form 
CRP 
C-reactive protein 
CS 
compound symmetry 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DOB 
date of birth 
DOIC 
date of informed consent 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 8 
 
Confidential and Proprietary 
Abbreviation 
Term 
dFLC 
difference between involved and uninvolved free light chains 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eGFR 
estimated glomerular filtration rate 
EOI 
end of infusion 
EOS 
end of study 
ETD 
early treatment discontinuation 
FACT-GOG NTX  
Functional Assessment of Cancer Treatment Gynecologic Oncology Group - 
Neurotoxicity 
FDA 
Food and Drug Administration 
FLC 
free light chain 
g/24 hours 
grams per day (24 hours) 
g 
gram 
GH 
General Health (SF-36v2) 
HCS 
heterogeneous compound symmetry 
HR 
heart rate 
ICH 
International Council for Harmonisation 
ID 
identification 
IFE 
immunofixation electrophoresis  
in 
inches 
IQR 
interquartile range 
IRT 
item response theory 
IV 
intravenous  
IVSd 
intraventricular septal thickness at diastole 
ITT 
Intent-to-Treat 
IXRS 
interactive voice and web response system 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 9 
 
Confidential and Proprietary 
Abbreviation 
Term 
kg 
kilogram  
KM 
Kaplan-Meier 
L 
liter 
lb 
pounds 
LN 
lymph node 
LPWd 
left ventricular posterior wall in end-diastole 
LS 
least-square 
LVEF 
left ventricular ejection fraction 
LVSd 
intraventricular septal at diastole 
m 
meter 
m2 
meters squared 
MCS 
Mental Component Score (SF-36v2) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram  
mg/dL 
milligrams per deciliter 
MH 
Mental Health (SF-36v2) 
min 
minimum 
mL 
milliliters 
mmHg 
millimeters of mercury 
MMRM 
mixed-effect repeated measures model 
MOP 
manual of procedures 
msec 
milliseconds 
NCS 
not clinically significant 
ng 
nanogram 
ng/L 
nanograms per liter 
NGAL 
neutrophil gelatinase-associated lipocalin 
NIS-LL 
Neuropathy Impairment Score-Lower Limbs 
NR 
no response 
NT-proBNP 
N-terminal pro-brain natriuretic peptide 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 10 
 
Confidential and Proprietary 
Abbreviation 
Term 
NYHA 
New York Heart Association 
PCS 
Physical Component Score (SF-36v2) 
PE 
physical examination 
PEP 
protein electrophoresis 
PF 
Physical Functioning (SF-36v2) 
PK 
pharmacokinetic 
pg/mL 
picogram per milliliter 
PN 
peripheral neuropathy 
PR 
partial response 
PS 
performance status 
PT 
preferred term 
PT/INR 
prothrombin time/international normalized ratio 
PTT 
partial thromboplastin time 
QT 
measure of time between start of Q wave and end of T wave  
QTcB 
QT formula corrected by Bazett’s formula 
QTcF 
QT interval corrected by Fridericia’s formula 
RBP 
retinol-binding protein 
RE 
Role-Emotional Limitations (SF-36v2) 
REML 
restricted maximum likelihood  
RP 
Role-Physical Limitations (SF-36v2) 
RR 
respiratory rate or time between 2 consecutive R waves 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
standard deviation 
SF 
Social Functioning (SF-36v2) 
SEM 
standard error of the mean 
SF-36v2 
Short Form-36 version 2 Health Survey   
sFLC 
serum free light chains 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 11 
 
Confidential and Proprietary 
Abbreviation 
Term 
SI 
standard international unit 
SOC 
system organ class 
StdErr 
least squares standard error 
TEAE 
treatment-emergent adverse event 
temp 
temperature 
ULN 
upper limit of normal 
VASPI 
Visual Analogue Scale – Pain Intensity 
VGPR 
very good partial response 
vs 
versus 
VT 
Vitality (SF-36v2) 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 12 
 
Confidential and Proprietary 
1. 
INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of Study 
NEOD001-CL002 (VITAL) data collected within the scope of the Prothena-sponsored protocol. 
The purpose of this plan is to provide specific guidelines from which the analyses will proceed. 
Any deviations from these guidelines will be documented in the clinical study report (CSR).  
2. 
INFORMATION FROM THE STUDY PROTOCOL 
2.1. 
Study Objective 
2.1.1. 
Primary Objective 
The primary objective is to evaluate the efficacy of NEOD001 plus standard of care versus 
placebo plus standard of care when administered intravenously in subjects with AL amyloidosis 
by assessing time to all-cause mortality or cardiac hospitalization. 
The primary estimand is the difference in survival distributions of the time-to all-cause mortality 
or cardiac hospitalization in all randomized subjects with AL amyloidosis who received any 
amount of study drug. 
2.1.2. 
Key Secondary Objectives 
The secondary efficacy objectives include the evaluation of NEOD001 plus standard of care 
compared to placebo plus standard of care on the following:  
2.1.2.1. 
Change in Health-Related Quality of Life  
Objective: Change from baseline in health-related quality of life using the Short Form 36 
questionnaire (SF-36v2) 
Estimand: The mean difference in SF-36v2 physical functioning score (PCS) change from 
baseline between treatment groups at Month 9 in all randomized subjects with AL amyloidosis 
who received any amount of study drug.  
2.1.2.2. 
Change in Cardiac Functional Response 
Objective: Change from baseline in cardiac functional response using the 6-Minute Walk Test 
(6MWT) 
Estimand: The median difference in 6MWT distance change from baseline between treatment 
groups at Month 9 in all randomized subjects with AL amyloidosis who received any amount of 
study drug. 
2.1.2.3. 
Cardiac Response Rate 
Objective: Cardiac best response rate as assessed by N-terminal pro-brain natriuretic peptide 
(NT-proBNP) (Appendix 1) 
Estimand: The difference in cardiac best response rate between treatment groups through Month 
9 in all randomized subjects with AL amyloidosis who received any amount of drug. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 13 
 
Confidential and Proprietary 
2.1.3. 
Additional Secondary Objectives 
Additional secondary efficacy objectives include the evaluation of NEOD001 plus standard of 
care compared to placebo plus standard of care in the organ-specific populations below.  In 
addition, the safety and tolerability of NEOD001 plus standard of care will be evaluated.  
2.1.3.1. 
Renal Response Rate 
Objective: Renal best response rate using established criteria (Appendix 1) in subjects with renal 
amyloid involvement at baseline 
Estimand: The difference in renal best response rate between treatment groups through Month 9 
in all randomized subjects with AL amyloidosis and renal amyloid involvement at baseline who 
received any amount of drug. 
2.1.3.2. 
Change in Peripheral Neurological Function 
Objective: Change from baseline in peripheral neurological function using the Neuropathy 
Impairment Score – Lower Limbs (NIS-LL; Appendix 8) in subjects with peripheral neuropathy 
due to amyloidosis at baseline. 
Estimand: The mean difference in NIS-LL total score change from baseline between treatment 
groups at Month 9 in all randomized subjects with AL amyloidosis and peripheral nerve 
involvement at baseline who received any amount of study drug. 
2.1.4. 
Exploratory Objectives 
The exploratory efficacy objectives include the evaluation of NEOD001 plus standard of care 
compared to placebo plus standard of care on other cardiac, renal, peripheral neuropathy, and 
disease-related clinical outcome measures. 
2.2. 
Study Design 
2.2.1. 
Overall Study Design 
This is a multicenter, international, randomized, double-blind, placebo-controlled, two-arm 
efficacy and safety study in subjects with AL amyloidosis. 
Newly diagnosed subjects with AL amyloidosis will be randomized in a 1:1 ratio to NEOD001 
or placebo. Subjects will be stratified at randomization based on three factors: 
x Mayo Clinic Stage (Appendix 2):  Stages I and II vs. Stages III and IV 
x Renal Stage (Appendix 2):  Stage I vs. Stages II and III    
x 6MWT distance:  < 300 meters vs. ≥ 300 meters 
Subjects will remain on study until study completion, which will occur when approximately 
156 primary endpoint events (all-cause mortality or cardiac hospitalizations as adjudicated by the 
clinical endpoint committee [CEC]) have been observed. As the number of adjudicated primary 
endpoints events get closer to 156, a data base cutoff date will be determined. Therefore, the 
final number of adjudicated primary endpoint events for analysis will be the number of 
adjudicated events as of that data cutoff date. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 14 
 
Confidential and Proprietary 
Each visit will be denoted by its “month” and “day” such that the first study drug (NEOD001 or 
placebo) infusion day is denoted as Month 1-Day 1; subsequent months will use sequential 
numbers (e.g., the second dose is administered on Month 2-Day 1). “Cycle” is reserved to denote 
administration of chemotherapy. Assessment and visit windows are described in the Schedule of 
Events (Table 1). 
If the subject discontinues study drug prior to the end of the study, but is willing to continue to 
participate in study visits, the subject should have an Early Treatment Discontinuation (ETD) 
Visit within 28-35 days after the last study drug administration (per Table 1 and protocol section 
7.1.6) and then have assessments every third month per Appendix 3. The most important visit is 
the Month 9-Day 1 Visit, so if a subject is unwilling to continue visits every third month, every 
effort should be made for the subject to return and complete the Month 9-Day 1 Visit on 
schedule. All visits after the ETD Visit should occur on schedule, that is, at the time when the 
visit would have occurred had the subject remained on study drug. 
Follow-up phone calls should be made to randomized subjects (or their caregivers) who received 
a dose of study drug and are no longer receiving study drug every 3 months, beginning 
approximately 3 months from the subject’s last treatment visit (protocol section 7.1.7). The 
subject’s health status, as well as details of any hospitalizations will be collected accordingly in 
the study database to ensure adequate capture of primary endpoint events. 
At the time of study completion (i.e., once approximately 156 events have been observed), 
subjects still receiving study drug (i.e., NEOD001 or placebo) may be considered for entry into a 
separate open-label extension study of NEOD001. 
2.2.2. 
Study Design Diagram 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 15 
Confidential and Proprietary 
Figure 1: 
Study Design Schematic 
 
Screening
Treatment (N=~236a)
Terminationa
Days -28 to -1
Monthly Day 1
(±2 days Months 1-3; ±5 days all other months)
28-35 Days 
After Last Dose
Population:
Confirmed AL 
amyloidosis – 
Newly diagnosed and 
treatment naïve
 
 Cardiac involvement
Adequate bone 
marrow reserve,
hepatic and renal
 function
ICF &
Screening
Assessments
ICF & 
Screening 
Assessments
24 mg/kgb IV NEOD001 every 28 days
- PLUS -
SOC 1st line chemotherapy
(must contain bortezomib)c
EOS/ETD
Visit
EOS/ETD 
Visit
CEC = Clinical Events Committee; dFLC=difference between involved and uninvolved free light chains; eGFR = estimated glomerular filtration rate; EOS/ETD = End of Study/Early Treatment Discontinuation; ICF = informed consent 
form; IV = intravenous; NIS-LL =Neuropathy Impairment Scale – Lower Limbs; NT-proBNP=N-terminal pro B-type natriuretic peptide; PCS = Physical Component Score; SF-36 = Short Form-36; 6MWT = 6-minute walk test; 
SOC=standard of care.
a An estimated sample size of approximately 236 subjects will be required to attain 156 events; after approximately 156 primary endpoint events have occurred, the study will conclude and all subjects will have an EOS Visit. 
b Maximum dose not to exceed 2500 mg.
c Number of cycles per Investigator’s discretion.
d Subjects may be considered for entry into a separate open-label extension study.
e Renal-evaluable subjects, peripheral neuropathy-evaluable subjects, and hepatic-evaluable subjects, respectively.
IV placebo every 28 days
- PLUS -
SOC 1st line chemotherapy
(must contain bortezomib)c
Randomization 1:1
Randomization Stratification:
x
Mayo Clinic Stage: Stages I and II vs. Stages III and IV
¾
NT-proBNP: <1800 pg/mL = 0; ≥1800 pg/mL = 1
¾
Troponin-T: ≤0.03 ng/mL = 0; >0.03 ng/mL = 1
¾
dFLC: <18 mg/dL = 0; ≥18 mg/dL = 1
¾
Total Score: 0 = Mayo Stage I; 1 = Mayo Stage II; 2 = Mayo Stage III; 3 = Mayo Stage IV
x
Renal Stage: Stage I vs. Stages II and III
¾
Proteinuria: ≤5 g/24 hours = 0; >5g/24 hours = 1
¾
eGFR: ≥50 mL/min/1.73 m2 = 0; <50 mL/min/1.73 m2 = 1
¾
Total Score: 0 = Renal Stage I; 1 = Renal Stage II; 2 = Renal Stage III
x
6MWT distance: <300 meters vs. ≥300 meters
Randomization Stratification:
x
Mayo Clinic Stage:  Stages I and II vs. Stages III and IV
¾ NT-proBNP: <1800 pg/mL = 0; ≥1800 pg/mL = 1
¾ Troponin-T: ≤0.03 ng/mL = 0; >0.03 ng/mL = 1
¾ dFLC: <18 mg/dL = 0; ≥18 mg/dL = 1
¾ Total Score: 0 = Mayo Stage I; 1 = Mayo Stage II; 2 = Mayo Stage III; 3 = Mayo Stage IV
x
Renal Stage:  Stage I vs. Stages II and III
¾ Proteinuria: ≤5 g/24 hours = 0; >5g/24 hours = 1
¾ eGFR: ≥50 mL/min/1.73 m2 = 0; <50 mL/min/1.73 m2 = 1
¾ Total Score: 0 = Renal Stage I; 1 = Renal Stage II; 2 = Renal Stage III
x
6MWT distance:  <300 meters vs. ≥300 meters
Primary Endpoint:
x
Time to all-cause mortality or cardiac hospitalization
Key Secondary Endpoints:
x
SF-36 PCS change from baseline to Month 9
x
6MWT distance change from baseline to Month 9
x
NT-proBNP best response from baseline through Month 9
Secondary Endpoints in Efficacy Subset Populationse:
x
Renal best response from baseline through Month 9
x
NIS-LL Total Score change from baseline to Month 9
x
Hepatic best response from baseline through Month 9
Primary Endpoint: 
x
Time to all-cause mortality or cardiac hospitalization
Key Secondary Endpoints: 
x
SF-36 PCS change from baseline to Month 9
x
6MWT distance change from baseline to Month 9
x
NT-proBNP best response from baseline through Month 9
Secondary Endpoints in Efficacy Subset Populationse:
x
Renal best response from baseline through Month 9
x
NIS-LL Total Score change from baseline to Month 9
x
Hepatic best response from baseline through Month 9
Open-
label 
Extension 
Studyd
156a
events


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 16 
Confidential and Proprietary 
2.2.3.
Study Drug 
Study drug consists of NEOD001 or placebo. The NEOD001 dose is 24 mg/kg (not to exceed 
2500 mg). Each vial of 500 mg of NEOD001 will be reconstituted with 9.6 mL sterile water for 
injection to a concentration of 50 mg/mL, resulting in a buffered, isotonic, preservative-free 
solution with a total extractable volume of 10 mL. Study drug will be prepared in a 250 mL 
intravenous (IV) bag of 0.9% saline. The equivalent volume of reconstituted NEOD001 will be 
withdrawn from the IV bag prior to transferring the drug solution into the IV bag, such that the 
total IV bag volume will be 250 mL. A separate placebo will not be provided for this study. 
Subjects who are assigned to the placebo group will be administered a 250 mL IV bag of 0.9% 
saline, which will look identical to the NEOD001 infusion bag. 
Please refer to the protocol for complete product details. 
2.2.4.
Randomization Methodology 
After a subject has completed all Screening requirements and meets all of the eligibility criteria, 
a Patient Registration Form should be submitted within several days prior to Month 1-Day 1 for 
eligibility review and approval by the Medical Monitor or designee. If approved, randomization 
will be implemented through a phone call or via the Internet connection to an Interactive Voice 
and Web Response System (IXRS) utilizing results from Screening assessments. Eligible 
subjects will be randomized in a 1:1 ratio into one of two arms, NEOD001 24 mg/kg or placebo. 
The randomization will be stratified by three factors: 
x Mayo Clinic Stage (Appendix 2):  Stages I and II vs. Stages III and IV 
x Renal Stage (Appendix 2):  Stage I vs. Stages II and III 
x 6MWT distance:  < 300 meters vs. ≥ 300 meters
Upon successful randomization, the subject will be assigned a 6-digit Subject ID consisting of 
the 3-digit site number plus the 3-digit subject number, and the Unblinded Pharmacist or their 
designee (henceforth collectively referred to as the Unblinded Pharmacy Staff) will be provided 
access to the treatment assignment. Subject IDs that are assigned to subjects who are randomized 
but do not receive study drug will not be re-utilized. Each arm of this 2-arm study will consist of 
approximately 118 subjects for an estimated total of 236 subjects. 
2.2.5.
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is presented in Table 1. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 17 
 
Confidential and Proprietary 
 
Table 1: 
Schedule of Study Procedures  
 
Screening1 
Month 1 
Month 2 
Month 3 
Months 6, 9, 12, 
etc. (Every 3rd 
Month) 
All Other 
Months 
 
Assessments 
Day-28 to 
Day -1 
Day -2 or 
Day -1  
Day 1 
Days 8,  15
22 
(±2) 
Day 1 
(±2) 
Days 82,  15
222 
(±2) 
Day 1 
(±2) 
Days 82, 
152, 222 
(±2) 
Day 1 
(±5) 
Day 1 
(±5) 
EOS/ 
ETD3 
Written Informed Consent  
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Review 
X 
 
 
 
 
 
 
 
 
 
 
Medical History4 
X 
 
 
 
 
 
 
 
 
 
 
Confirmation of AL Amyloidosis5 
X 
 
 
 
 
 
 
 
 
 
 
SF-36v26 
 
X 
 
 
X 
 
X 
 
X 
 
X 
KCCQ6 
 
X 
 
 
X 
 
X 
 
X 
 
X 
FACT-GOG NTX6,7 
X 
X 
X 
X 
X 
X 
X 
X 
Per Protocol Section 7.4 
X 
Echocardiogram 
X8 
 
 
 
 
 
 
 
Every 6th mo8 
 
X8 
Liver Imaging (CT) 
X9 
 
 
 
 
 
 
 
Every 6th mo10 
X10 
X10 
12-lead Triplicate ECG11 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Complete PE12 
X 
 
 
 
 
 
 
 
 
 
X 
Symptom-Directed PE13 
 
 
X 
 
X 
 
X 
 
X 
X 
 
ECOG PS & NYHA Class 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
NIS-LL14 
X 
 
X 
 
X 
 
X 
 
Per Protocol Section 7.4  
X 
VASPI15 
X 
 
X 
 
X 
 
X 
 
Per Protocol Section 7.4  
X 
Local Laboratory 
 
 
 
 
 
 
 
 
 
 
 
Hematology & Chemistry16 
 
 
 
X 
X 
X17 
X 
X17 
X 
X 
 
Serum Pregnancy (WOCBP) 
 
 
X18 
 
X 
 
X 
 
X 
X 
X19 
Central Laboratory20 
 
 
 
 
 
 
 
 
 
 
 
Hematology & Chemistry 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Amylase 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Coagulation – PT/INR, PTT, & 
Indices21 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
Complements C3, C4 
 
X 
 
 
 
 
X 
 
X 
 
X 
Troponin T 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
NT-proBNP 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 18 
 
Confidential and Proprietary 
 
 
Screening1 
Month 1 
Month 2 
Month 3 
Months 6, 9, 12, 
etc. (Every 3rd 
Month) 
All Other 
Months 
 
Assessments 
Day-28 to 
Day -1 
Day -2 or 
Day -1  
Day 1 
Days 8,  15
22 
(±2) 
Day 1 
(±2) 
Days 82,  15
222 
(±2) 
Day 1 
(±2) 
Days 82, 
152, 222 
(±2) 
Day 1 
(±5) 
Day 1 
(±5) 
EOS/ 
ETD3 
Tryptase 
 
X 
 
 
 
 
 
 
 
 
 
Serum Free Light Chains (sFLCs) 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Serum Pregnancy (WOCBP) 
X 
 
 
 
 
 
 
 
 
 
X 
Serum IFE/PEP 
X 
 
 
 
 
 
X 
 
X22 
X22 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
Urine Sample for Quantitative/Renal 
Biomarkers23 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
24-hour Urine Collection for: 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Protein Excretion24 
X 
X 
 
 
 
 
X 
 
Odd months 
Odd months 
X 
Urine IFE/PEP24 
X 
 
 
 
 
 
X 
 
Odd months25 
Odd months25 
X 
6-Minute Walk Test (6MWT)26 
X27 
X27 
 
 
 
 
X 
 
X 
 
X 
Bioanalytical Laboratory 
 
 
 
 
 
 
 
 
 
 
 
PK Samples28 
 
 
X 
Day 15 
X 
 
X 
Day 8 
X 
X 
X 
Anti-NEOD001 Antibody Sample 
(pre-dose)  
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Archive Sample (pre-dose)29 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
Premedication Administration30 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Vital Signs31 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study Drug Infusion32 
 
 
X 
 
X 
 
X 
 
X 
X 
 
Chemotherapy & Antiviral 
Prophylaxis33 
 
 
X34 
X34 
X34 
X34,35 
X34 
X35 
X34 
X34 
 
Adverse Event Assessment 
X 
X 
X 
X 
X 
X17 
X 
X17 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X17 
X 
X17 
X 
X 
X 
Vital Status Phone Call 
 
 
 
 
 
 
 
 
 
 
X36 
 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 19 
 
Confidential and Proprietary 
 
ALP = alkaline phosphatase; BP = blood pressure; CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance status; 
EOI = end of infusion; EOS = End of Study; ETD = Early Treatment Discontinuation; FACT-GOG NTX = Functional Assessment of Cancer Therapy – Gynecologic Oncology 
Group Neurotoxicity Subscale; HR = heart rate; IFE = immunofixation electrophoresis; KCCQ = Kansas City Cardiomyopathy Questionnaire; NGAL = neutrophil gelatinase-
associated lipocalin; NIS-LL = Neuropathy Impairment Score – Lower Limbs; NT-proBNP = N-terminal pro B-type natriuretic peptide; NYHA = New York Heart Association; 
PE = physical exam; PEP = protein electrophoresis; PK = pharmacokinetic; PT/INR = prothrombin time/ international normalized ratio; PTT = partial thromboplastin time; 
RBP = retinol-binding protein; RR = respiratory rate; SC = subcutaneous; 6MWT = 6-minute walk test; SF-36v2 = SF-36v2® Health Survey; ULN = upper limit of normal; 
VASPI = Visual Analog Scale – Pain Intensity; WOCBP = women of childbearing potential. 
1. The 28-day Screening period may be extended upon approval by the Medical Monitor. Individual test results that do not meet eligibility requirements may be repeated, with the 
exception of 6MWT; full rescreening is allowed once per subject. 
2. Cycle 2-Days 8 and 22 and Cycle 3-Days 8, 15 and 22 bortezomib-containing chemotherapy should be administered by the Investigator at the study site if subject had 
significant toxicity; otherwise, it may be administered by local physician at Investigator’s discretion. See more detail in Footnote 35. 
3. EOS/ETD Visit to occur 28-35 days after the last study drug administration. 
4. Obtain comprehensive cardiac, hematologic, and oncologic medical history; additionally for all other conditions obtain relevant medical history for the past 5 years (including 
all major hospitalizations and surgeries), as well as the subject’s current medical status. 
5. Results from mass spectrometry tissue typing, immunoelectron microscopy, gene sequencing, and/or 99mTc scintigraphy must be obtained prior to randomization to assess 
eligibility for subjects identified in Inclusion Criterion #5.  
6. At visits where one or more questionnaires are to be administered, the following order occurs prior to the performance of any other study assessments on the day they are 
administered: SF-36v2 (Appendix 5), KCCQ (Appendix 6), and FACT-GOG NTX (Appendix 7). 
7. Administer the FACT-GOG NTX (Appendix 7) per Table 2. 
8. If an echocardiogram has been conducted within 90 days prior to Screening Day -28, it does not need to be repeated during Screening and the previous result can be used for 
eligibility. After Screening, perform echocardiograms every 6 months within 10 days prior to Day 1; repeat at EOS/ETD if not performed within 60 days prior to visit. To be 
eligible for the additional cardiac imaging analysis, the subject must have had a 4-chamber view, 2-dimensional echocardiogram with Doppler.  
9. Perform CT imaging of the abdomen for liver measurement for subjects with an ALP > 1.5 × ULN at Screening per protocol Section 7.6 (Exception: not required in Germany). 
If CT imaging has been conducted within 60 days prior to Screening Day -28 and it meets acquisition guidelines, it does not need to be repeated during Screening and the 
previous result can be used for eligibility. 
10. For subjects with liver involvement at Screening, perform scheduled repeat CT imaging of the abdomen for liver measurement every sixth month and unscheduled repeat CT 
imaging as needed per protocol Section 7.6 (Exception: not required in Germany). Repeat at EOS/ETD as needed per protocol Section 7.6. 
11. ECG to be performed in triplicate as follows: Month 1-Day 1: within 30 minutes before dosing and 1 hour (±15 min) post-EOI; All Other Visits:  within 30 minutes before 
dosing or any time on non-infusion days. Medications given for prophylaxis chemotherapy-induced side effects should not be administered prior to completion of the 
postinfusion ECG. 
12. Complete PE includes height (Screening only), weight, and examination of the following:  general appearance; head, ears, eyes, nose, and throat; neck; skin; cardiovascular 
system; respiratory system; gastrointestinal system; and nervous system. Assess macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, liver/spleen size 
(palpable +/-), ascites (+/-), and edema (which should be quantified on a scale of 0-4+). 
13. Symptom-directed PE should be as clinically indicated and also include weight, and assessment of macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, 
liver/spleen size (palpable +/-), ascites (+/-), and edema (which should be quantified on a scale of 0-4+). 
14. Administer NIS-LL (Appendix 8) per Table 2.  
15. Administer VASPI (Appendix 9) per Table 2. 
16. Local laboratory results for hematology and chemistry will be used for subject management and should be reviewed for safety assessment prior to administration of 
chemotherapy, but will not be collected in the electronic case report forms or the clinical database. 
17. Perform only if subject returns to study site for this visit. 
18. Use local lab for serum pregnancy test within 24 hours prior to Month 1-Day 1 study drug administration. 
19. Obtain local laboratory serum pregnancy test 90 (±5) days after the last study drug administration. 
20. Collect central laboratory samples before 6MWT, if being performed on the same day. 
21. Collect citrated plasma samples for coagulation indices at each time point; per Appendix 10, samples will be frozen for potential analysis of coagulation indices at a later date. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 20 
 
Confidential and Proprietary 
 
22. Perform serum IFE/PEP monthly. If a subject’s first on-study hematologic complete response was assessed at the previous visit, perform serum IFE/PEP (and 24-hour urine 
IFE/PEP) at least 28 days after the initial assessment of response to confirm response. 
23. Urine sample will be collected per protocol Section 7.3 and frozen for potential analysis of quantitative/renal biomarkers (i.e., urine albumin/creatinine ratio, urine NGAL, and 
urine RBP) at a later date. Collect the final sample within 1 week prior to EOS/ETD Visit. 
24. The 24-hour urine protein excretion and 24-hour urine IFE/PEP tests will be performed using the same 24-hour urine collection sample when required at the same visit. 
25. If a subject’s first on-study hematologic complete response was assessed at the previous visit, perform 24-hour urine IFE/PEP (and serum IFE/PEP) at least 28 days after the 
initial assessment of response to confirm response. Repeat every odd-numbered month (to correspond with 24-hour urine protein excretion collection) to assess for continuing 
response or progression. If the initial response confirmation needs to occur on an even-numbered month, perform an additional 24-hour urine collection. 
26. Subject should plan to be able to return to the same clinical site for each 6MWT from first Screening through Month 9. The 6MWT must not be administered on the same day 
as study drug administration at any visit; therefore, it should be performed within 2 days prior to the Day 1 visit. Collect BP and HR pre- and post-6MWT administration. 
27. The first Screening 6MWT must be performed between Days -28 and -5, at least 4 days prior to the second Screening 6MWT, which should be performed within 2 days prior 
to the Month 1-Day 1 visit (i.e., on Day -2 or Day -1).  
28. Collect PK samples pre-dose on study drug or chemotherapy dosing days, anytime during EOS/ETD Visit, and at these additional time points: Month 1-Day 1: EOI (+5 min), 
0.5 hour (±5 min) post-EOI, and 1 hour (±10 min) post-EOI; Month 2-Day 1: EOI (+5 min), and 1 hour (±10 min) post-EOI; Month 6-Day 1 and Month 12-Day 1: EOI 
(+5 min), 0.5 hour (±5 min) post-EOI, and 1 hour (±10 min) post-EOI. Additional samples may be collected as clinically indicated, such as when significant toxicity occurs. 
29. Archive serum samples will only be collected from those subjects who have consented to the collection and archiving of their samples for future correlative testing. 
30. All subjects are to receive 25 mg diphenhydramine (or an equivalent dose of a H1 antihistamine) and 650 mg acetaminophen (or an equivalent paracetamol dose) within 
30-90 minutes prior to the start of infusion. 
31. Vital signs include BP, HR, RR, and temperature; assess in same position for all time points after the subject has been at rest for ≥5 minutes. Pre-dose assessments should be 
performed after administration of premedication. Screening and non-infusion days: any time; Month 1-Day 1: Within 30 minutes before dosing, halfway through infusion 
(i.e., approximately 60 minutes after the start of the infusion), immediately at EOI (+10 min), 0.5 hour (±10 min) post-EOI, and 1 hour (±10 min) post-EOI. All Other 
Months-Day 1: Within 30 minutes before dosing, EOI (+10 min), and 1 hour (±10 min) post-EOI. 
32. Administer per protocol Section 6.5.1. Subjects should be closely monitored for 90 (±10) minutes following completion of the study drug infusion. The Investigator may 
increase this standard monitoring time if deemed appropriate or per local standards. In the event of any clinical concerns or suspicious signs or symptoms after the infusion, the 
subject will remain under observation for as long as the Investigator deems it appropriate. 
33. First-line chemotherapy must be a bortezomib-containing regimen, with bortezomib administered weekly, SC, according to the approved prescribing information and local 
institutional practices. Antiviral prophylaxis is required. When chemotherapy is administered on same day as study drug, the chemotherapy must be administered AFTER the 
post-study drug infusion observation period. Number of first-line chemotherapy cycles and subsequent chemotherapy regimens will be administered per standard of care at the 
Investigator’s discretion. 
34. Bortezomib must be administered at the study site for Cycle 1-Days 1, 8, 15, and 22; Cycle 2-Days 1 and 15; and on Day 1 of subsequent cycles, after review of local labs, 
study drug administration, and the post-study drug infusion observation period.  
35. Cycle 2-Days 8 and 22, and Cycle 3-Days 8, 15, and 22 chemotherapy may be administered by local physician with a Homecare visit by a Prothena-sponsored healthcare 
professional to the subject within 1 day prior to or pre-dose on the day of each bortezomib administration to administer FACT-GOG NTX, and to obtain vital signs, blood 
samples for central laboratory testing, and bioanalytical samples (if applicable). If bortezomib is administered on a Monday, the Homecare visit may occur on the previous 
Friday. If significant toxicity occurs during Cycle 1, subject should return to the study site for Cycle 2 and Cycle 3 visits until Investigator deems it appropriate for local 
administration.  
36. For all subjects who are randomized and received a dose of study drug: Conduct vital status phone call per protocol Section 7.1.8 approximately 3 months after the subject’s 
last visit and approximately every 3 months thereafter. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL) 
Page 21 
 
Confidential and Proprietary 
 
Table 2: 
Peripheral Neuropathy Assessments  
Assessment 
Screening 
Months 1-3 
Months 4-12 
Months 13+ 
EOS/ETD 
FACT-GOG 
NTX  
(Appendix 7) 
All Subjects:  
Once between 
Days -28 and -1 
and again on 
Day -2 or Day -1 
All Subjects:  
Weekly 
(Day 1, 8a, 
15a, and 22a 
Visits) 
x 
Subjects who had positive scores at 
Screening and/or Month 3: 
Months 6, 9, and 12 (Day 1 Visit) 
x 
Subjects who are receiving 
identified concomitant 
medicationb: 
Monthly (Day 1 Visit) 
x 
Subjects who had negative scores 
at Screening and Month 3 and new 
PN signs and symptoms develop:  
Monthly (Day 1 Visit) 
x 
Subjects who had positive scores at 
Screening and/or Month 3: 
Every sixth month (e.g., Months 18, 
24 [Day 1 Visit]) 
x 
Subjects who are receiving 
identified concomitant medicationb: 
Monthly (Day 1 Visit) 
x 
Subjects who had negative scores at 
Screening and Month 3 and new PN 
signs and symptoms develop:  
Monthly (Day 1 Visit) 
All Subjects 
NIS-LL 
(Appendix 8) 
and 
VASPI 
(Appendix 9) 
All Subjects:  
Once between 
Days -28 and -1 
All Subjects:  
Monthly 
(Day 1 Visit) 
x 
Subjects who had positive scores at 
Screening and/or Month 3: 
Months 6, 9, and 12 (Day 1 Visit) 
x 
Subjects who are receiving 
identified concomitant 
medicationb: 
Monthlya (Day 1 Visit) until 
completion of concomitant 
medication & then at Months 6, 9, 
and 12 (Day 1 Visit) or whatever 
remains of these months 
x 
Subjects who had negative scores 
at Screening and Month 3 and new 
PN signs and symptoms develop:  
At the next scheduled visit and then 
at Months 6, 9, and 12 (Day 1 Visit) 
or whatever remains of these months 
x 
Subjects who had positive scores at 
Screening and/or Month 3: 
Every sixth month (e.g., Months 18, 
24 [Day 1 Visit]) 
x 
Subjects who are receiving 
identified concomitant medicationb: 
Monthly (Day 1 Visit) until 
completion of concomitant medication 
& then every sixth month (e.g., 
Months 18, 24 [Day 1 Visit]) 
x 
Subjects who had negative scores at 
Screening and Month 3 and new PN 
signs and symptoms develop:  
At the next scheduled visit and then 
every third month (e.g., Months 15, 18 
[Day 1 Visit]) 
All Subjects 
EOS/ETD = End of Study/Early Treatment Discontinuation; FACT-GOG NTX = Functional Assessment of Cancer Therapy – Gynecologic Oncology Group Neurotoxicity 
Subscale; NIS-LL = Neuropathy Impairment Score – Lower Limbs; PN = peripheral neuropathy; VASPI = Visual Analog Scale – Pain Intensity. 
a Subjects who have discontinued study drug prior to the end of the study but are willing to return for visits will be assessed every third month (i.e., Months 3, 6, 9, and 12 or 
whatever remains of these visits) per Appendix 3. 
b Bortezomib, another proteasome inhibitor, or other drug with the propensity to cause peripheral neuropathy. 
Note: After Month 3, subjects who do not meet the criteria listed in the “Months 4-12” and “Months 13+” columns do not need to have the peripheral neuropathy assessments 
conducted until the EOS/ETD Visit. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 22 
Confidential and Proprietary 
 
2.3.
Study Endpoints 
2.3.1.
Primary Efficacy Endpoint
The primary efficacy endpoint is the time to all-cause mortality or cardiac hospitalization as 
adjudicated by the CEC.  
For all-cause mortality, all deaths occurring after the first infusion of study drug (i.e. study day 
1) through the study’s last subject last visit (LSLV; see Section 2.2.1) will be included. Cardiac 
hospitalizations occurring ≥91 days after a subject’s first infusion of study drug through LSLV 
will be included. All primary endpoint events will be adjudicated. Each subject will be counted 
only once in the primary analysis, based on their first adjudicated occurrence of an endpoint 
event. 
The following censoring rules will apply: 
x Subjects who complete the study and experience a confirmed CEC cardiac hospitalization on 
or after study day 1 but prior to study day 91, have no other confirmed CEC cardiac 
hospitalizations on or after study day 91, and are not known to have died, will be censored at 
their last assessment (visit or phone call) known to be alive.  
x Subjects who complete the study and do not experience any confirmed CEC cardiac 
hospitalization and are not known to have died will be censored at their last assessment (visit 
or phone call) known to be alive. 
x Subjects who withdraw from the study or are lost to follow-up prior to experiencing a 
confirmed CEC cardiac hospitalization on or after study day 91 or death will be censored at 
their last assessment (visit or phone call) where both vital status and hospitalization 
information was available.  
In addition, each component of the primary efficacy endpoint will be evaluated separately. 
2.3.2.
Key Secondary Efficacy Endpoints  
The following secondary efficacy endpoints are considered key in evaluating subjects’ response 
to treatment in terms of how s/he feels, how s/he functions, and survival time. The key secondary 
endpoints, in order of priority are as follow. 
2.3.2.1. 
Change from Baseline to Month 9 in the Physical Component Score of the SF-
36v2  
The SF-36v2 is a 36-item self-report instrument that measures generic health-related quality of 
life in eight specific dimensions plus one additional question that asks respondents to rate the 
amount of change experienced in their health in general (Maruish 2011; Appendix 5; 
https://campaign.optum.com/optum-outcomes.html). It allows for the scoring of two component 
summary indices: the Physical Component Score (PCS) and the Mental Component Score 
(MCS). The SF-36v2 is scored as eight subscales representing separate domains of functional 
health and well-being:  
x Physical Functioning (PF: 10 questions, # 3a to 3j) 
x Role-Physical (RP; role limitations due to physical problems: 4 questions, # 4a to 4b) 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 23 
Confidential and Proprietary 
 
x Bodily Pain (BP: 2 questions, # 7 to 8) 
x General Health Perceptions (GH: 5 questions, # 1, 11a to 11d) 
x Vitality (VT: 4 questions,# 9a, 9e, 9g, and 9i) 
x Social Functioning (SF: 2 questions, # 6 and 10) 
x Role-Emotional (RE; role limitations due to emotional problems: 3 questions, # 5a to 5c) 
x Mental Health (MH: 5 questions, # 9b to 9d, 9f, 9h) 
Responses to items allow for direct calculation of subscales for each of the eight dimensions, 
while PCS and MCS scores are computed from weighted subscale scores (Maruish 2011). The 
lower the score the more disability; the higher the score the less disability. A score of 50 is the 
mean in the US General Population. The standard deviation is 10 for all scales and both 
summary measures. The SF-36v2 will be scored using the algorithm provided by Optum with the 
instrument license (Health Outcomes™ Scoring Software 4.5). Algorithms that allow for the 
evaluation of summary component scores in the presence of missing data have been developed 
using Item Response Theory (IRT) and regression methods. Scores for respondents with 
incomplete answers can be derived using the maximum data recovery approach for the missing 
data estimation for all scales except the PF scale. For the PF scale, an estimated score based on 
an IRT model is utilized as long as at least one of its items has valid data, otherwise the scale 
score will be missing. Both the PCS score and the MCS score can be calculated if (1) at least 
seven scale scores are available, (2) the PF scale is not missing when evaluating the PCS, and (3) 
the MH scale is not missing when calculating the MCS. The scoring algorithm to apply to the 
calculation of the summary scores depends upon which particular scale score is missing from the 
eight-scale profile. 
The key secondary endpoint will include data from PCS score only, including all visits in the 
model (Section 8.8.1), with the primary comparison at the Month 9 visit.  
2.3.2.2. 
Change from Baseline to Month 9 in the 6-Minute Walk Test (6MWT) Distance 
(meters)  
The 6MWT is a test that requires a minimum walking length of 25 meters but no exercise 
equipment or advanced training for technicians. The walking track or area should be the same for 
all tests for a subject. Walking is an activity performed daily by all but the most severely 
impaired subjects. This test measures the distance that a subject can quickly walk on a flat, hard 
surface in a period of 6 minutes. The primary comparison will be at the Month 9 visit. 
2.3.2.3. 
NT-proBNP (Cardiac) Best Response from Baseline Through Month 9 
Cardiac response as defined by NT-proBNP best response from baseline through Month 9. All 
visits after the first infusion of study drug up to and through the Month 9 visit will be included. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 24 
Confidential and Proprietary 
 
NT-proBNP response categories (modified from Table 2 in Comenzo 2012; Appendix 1) are 
defined as:   
Response 
Stable Disease 
Progression 
Decrease in NT-proBNP from 
baseline >30% and from 
baseline >300 ng/L (pg/mL) 
Assessment was 
neither Response 
nor Progression 
Increase in NT-proBNP from 
baseline >30% and from 
baseline >300 ng/L (pg/mL) 
Best response is defined as the most favorable category (response, stable disease, or progression) 
up to and through the Month 9 visit. Subjects will be classified as responders or non-responders. 
Non-response is defined as either stable disease or progression.  
2.3.3.
Additional Secondary Efficacy Endpoints 
2.3.3.1. 
Renal Evaluable Subjects: Renal Best Response from Baseline through Month 9  
The Renal Evaluable Population will include subjects who had renal involvement (i.e., 
proteinuria >0.5g/24 hours [measured by 24-hour urine total protein excretion]) at baseline and at 
least one post-baseline assessment of proteinuria. All visits after the first infusion of study drug 
up to and through the Month 9 visit will be included. 
For these subjects, renal response categories (modified from Palladini 2014; Appendix 1) are 
defined as:  
Response 
Stable Disease 
Progression 
≥30% decrease from baseline 
or <0.5g/24 hours post-
baseline result of proteinuria 
(measured by 24-hour urine 
total protein excretion) in the 
absence of renal progression 
Assessment was 
neither Response 
nor Progression 
≥25% decrease in eGFR from 
baseline 
Note: if assessment qualifies as 
both Response and Progression, 
then assessments will be 
counted as progression 
Best response is defined as the most favorable category (response, stable disease, or progression) 
up to and through the Month 9 visit. Subjects will be classified as responders or non-responders. 
Non-response is defined as either stable disease or progression.  
2.3.3.2. 
Peripheral Neuropathy Evaluable Subjects: Change from Baseline to Month 9 in 
Neuropathy Impairment Score–Lower Limbs (NIS-LL) Total Score  
The Peripheral Neuropathy Evaluable Population will include subjects who had peripheral nerve 
involvement at baseline (only if the subject had ascending sensorimotor neuropathy at screening 
due to AL amyloidosis etiologies answered as yes) and had a baseline NIS-LL score of 2 or 
greater and at least one post-baseline peripheral neuropathy assessment. All visits will be 
included in the model (Section 8.9.2), with the primary comparison at the Month 9 visit. 
NIS-LL is a scoring system graduated from 0 points to a maximum of 88 points (the absence of 
all motor, sensory, and reflex activity in the lower extremities) (Dyck 1995; Appendix 8). The 
scale is an additive of all deficits (64 potential points for muscle strength, 8 points for reflexes, 
and 16 points for sensory function) in the lower extremities. The component scores will be 
calculated by summing the values of the following assessments: 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 25 
Confidential and Proprietary 
 
x Sensory Function (in the great toe) = Sum of (touch pressure, pinprick, vibration, joint 
position) 
x Reflexes = Sum of (knee, ankle) 
x Muscle Strength = Sum of (hip flexion, hip extension, knee flexion, knee extension, ankle 
dorsiflexion, ankle plantar flexion, toe extension, toe flexion) 
x Total score = Sum of (sensory function, reflexes, muscle strength)  
2.3.4.
Exploratory Efficacy Endpoints 
The following exploratory efficacy endpoints will evaluate NEOD001 plus standard of care 
compared to placebo plus standard of care. 
2.3.4.1. 
Cardiac Endpoints 
2.3.4.1.1. Cardiac Biomarkers (NT-proBNP) 
x Cardiac response (Appendix 1), as assessed by NT-proBNP response criteria, at each visit  
x Cardiac best response (Section 2.3.2.3), as assessed by NT-proBNP response criteria, 
through Month 3 visit, Month 6 visit, and Month 12 visit, and over course of study 
x Change and percent change from baseline in NT-proBNP at each visit 
2.3.4.2. 
Functional Endpoint - 6MWT Distance 
x Change and percent change from baseline in the 6MWT distance (meters) to each visit 
(except Month 9 [the key secondary endpoint])  
2.3.4.3. 
Quality of Life Endpoints - SF-36v2 
x Change and percent change from baseline in SF-36v2 PCS (except Month 9 [the key 
secondary endpoint]), MCS, and the eight subscales to each visit  
2.3.4.4. 
Renal Endpoints 
The following endpoints may be evaluated in the Renal Evaluable Population.  
2.3.4.4.1. Renal Response 
x Renal response (Appendix 1) at each visit  
x Renal best response through Month 3 visit, Month 6 visit, and Month 12 visit, and over 
course of study 
2.3.4.4.2. Creatinine, Proteinuria, and Estimated Glomerular Filtration Rate (eGFR)
x Change and percent change from baseline to each visit in creatinine, proteinuria, and 
eGFR  
2.3.4.5. 
Peripheral Neuropathy Endpoints 
The following endpoints may be evaluated in the Peripheral Neuropathy Evaluable Population.  


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 26 
Confidential and Proprietary 
 
x Change and percent change from baseline in the NIS-LL total score and the 3 deficit 
component scores to each visit (except Month 9 [the additional secondary endpoint]) 
2.3.4.6. 
Additional Time-to-Event Endpoints 
Details regarding events, time derivations, and censoring methods are included in the 
corresponding endpoint analysis Section 8.10.6. 
x Time to cardiac mortality at any time or cardiac hospitalization (occurring ≥91 days after 
a subject’s first infusion of study drug) as adjudicated by the CEC 
x Time to cardiac mortality as adjudicated by the CEC 
x Time to derived organ progression (Appendix 1) 
x Time to first derived organ response (Appendix 1) 
2.3.4.7. 
Other Efficacy Endpoints 
Below are the other efficacy data collected in NEOD001-CL002 study: 
x Echocardiogram Cardiac Parameters: Left ventricular ejection fraction (LVEF), 
Intraventricular septal at end diastole (LVSd), Left posterior wall at end diastole
(LPWd) 
x Cardiac Biomarker: Troponin T (μg/L) 
x Kansas City Cardiomyopathy Questionnaire (KCCQ) 
x Visual Analog Scale – Pain Intensity (VASPI) 
x Liver size 
x Eastern Cooperative Oncology Group (ECOG) performance, New York Heart 
Association (NYHA) Class, Mayo Clinic Stage, and Renal Stage 
x Free light chains (sFLCs), serum and 24-hour urine protein electrophoresis (PEP), 
and serum and urine immunofixation electrophoresis (IFE)  
x Disease-related symptoms  
x Pharmacokinetics (PK)  
2.3.5.
Safety Endpoints 
Safety evaluations performed during the study include:  
x Vital signs 
x 12-lead ECGs 
x Routine laboratory assessments 
x AEs 
x Immunogenicity  


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 27 
Confidential and Proprietary 
 
3.
SAMPLE SIZE JUSTIFICATION 
For the endpoint of time to all-cause mortality or cardiac hospitalization, the assumed 18-month 
event rate in the control arm is 60%, based on Kumar 2012. The 18-month event rate in the 
active arm is assumed to be 42%, a relative reduction of 30%. These assumptions correspond to a 
hazard ratio of 0.594. For a two-arm study with 1:1 randomization, and based on the use of a 
two-sided test at the alpha=0.05 level of significance, a total of 156 events (both arms combined) 
are required for 90% power. The study is designed to have 90% power in accordance with 
common practice for the design of confirmatory trials. Assuming an accrual period of 24 months, 
and a treatment/follow-up period of 18 months (i.e., a total study duration of 42 months), a total 
sample size of approximately 236 subjects will be required to attain 156 events. 
4.
GENERAL STATISTICAL METHODS 
4.1.
Reporting Conventions 
Individual subject data obtained from electronic case report forms (eCRFs), central laboratories, 
external sources, and any derived data will be presented in data listings by subject. The primary 
data source will be used for all analyses. All data listings that contain an evaluation date will 
contain a relative study day. Pre-treatment and on-treatment study days are numbered relative to 
the day of the first dose of study drug which is designated as Day 1. The preceding day is Day -1, 
the day before that is Day -2, etc.  
All output will be incorporated into Microsoft Word rich text format (.rtf) files, sorted and 
labeled according to the International Council for Harmonisation (ICH) recommendations, and 
formatted to the appropriate page size(s). 
For categorical variables, summary tabulations of the number and percentage of subjects within 
each category (with a category for missing data) of the parameter will be presented. Percentage 
calculations will be based on non-missing data, unless otherwise specified. Percentages are 
rounded to 1 decimal place, unless otherwise specified.  
For frequency counts of categorical variables, categories whose counts are zero will be displayed 
for the sake of completeness. For example, if none of the subjects discontinue due to “lost to 
follow-up,” this reason will be included in the table with a count of 0. Percentages based on 
frequency counts will be presented to one decimal place, and values less than 1% will be 
presented as “<1%.” Values less than 100% but greater than 99% will be presented as “>99%.”   
For continuous variables, the number of subjects, mean, standard deviation (SD), median, 25th 
quartile (Q1), 75th quartile (Q3), minimum, and maximum values will be presented. The 
precision of summary statistics, unless otherwise, specified will be as follows:  mean and median 
to 1 more decimal place than the raw data, and SD and SEM to 2 decimal places more than the 
raw data. In general, the number of decimal places should not exceed 3 decimal places unless 
appropriate. Confidence intervals (CIs) will be provided and will be rounded to 1 decimal place, 
unless otherwise specified, in the table and listing shell.  
For tables where rounding is required, rounding will be done to the nearest round-off unit. For 
example, when rounding to the nearest integer, values ≥XX.5 will be rounded up to XX+1 (e.g., 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 28 
Confidential and Proprietary 
 
97.5 will round up to 98), while values <XX.5 will be rounded down to XX (e.g., 97.4 will round 
down to 97). 
Time-to-event data will be summarized using Kaplan-Meier methodology using 25th, 50th 
(median), and 75th percentiles with associated 2-sided 95% CIs (where estimable), as well as 
percentage of censored observations. 
All statistical tests comparing groups will be conducted at the 2-sided, 0.05 level of significance, 
unless otherwise specified. Summary statistics for each treatment group will be presented, as 
well as 95% CIs comparing groups will be provided. 
4.2.
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.4 
or higher, unless otherwise noted. Medical history and AEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) version 19.0. Concomitant medications will be 
coded using World Health Organization (WHO) Drug Dictionary, B2 Enhanced September 
2015.
4.3.
Definition of Baseline 
To minimize the impact of variability in the 6MWT distance, the baseline for the 6MWT 
distance (meters) will be defined as the longest distance walked prior to first study drug infusion. 
If only one valid assessment is available prior to first study drug infusion, it will be used as the 
baseline value. Baseline for all other efficacy and safety parameters will be defined as the last 
non-missing assessment prior to the first study drug infusion.  
4.4.
Partial Dates 
If only a partial date is available and is required for calculation, the following standards will be 
applied: 
x Birth Date 
o For missing day only – Day will be imputed as the middle of the month (i.e., 15).
o For missing day and month – Day and month will be imputed as the middle of the 
year (i.e., 15 June). 
x Death Date  
o The last date that each subject was known to be alive will be identified as the 
greatest date associated with the subject’s completed assessments, including 
telephone contacts at which the subject was confirmed to be alive.  
o For missing day only – Day will be imputed as the first day of the month (i.e., 1) 
with the following exception:  if the partial date falls in the same month as the last 
known alive date, then the partial date will be imputed to equal the last known 
alive date. 
o For missing day and month – Day and month will be imputed as the first day of 
the year (i.e., 1 January) with the following exception:  if the partial date falls in 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 29 
Confidential and Proprietary 
 
the same year as the last known alive date, then the partial date will be imputed to 
equal the last known alive date.  
x Diagnostic Date  
o For missing day only – Day will be imputed as the first day of the month (i.e., 1). 
o For missing day and month – Day and month will be imputed as the first day of 
the year (i.e., 1 January). 
x Start Dates (e.g., event date, adverse event [AE] onset date, start date of medication, or 
hospitalization admission date) 
o For missing start day only – Day will be imputed as the first day of the month 
(i.e., 1) with the following exception:  if the partial date falls in the same month 
and year as the date being used in the calculation (e.g., first infusion date, 
informed consent date), then the partial date will be imputed to equal the date 
being used for the calculation. 
o For missing start day and month – Day and month will be imputed as the first day 
of the year (i.e., 1 January) with the following exception: if the partial date falls 
in the same year as the date being used in the calculation (e.g., first infusion date, 
informed consent date), then the partial date will be imputed to equal the date 
being used for the calculation. 
o When applicable, imputed start dates must be prior to the stop date. 
x Stop Dates (e.g., AE resolution date or stop date of medication) 
o For missing stop day only – Day will be imputed as the last day of the month (i.e., 
28, 29, 30, or 31).
o For missing stop day and month – Day and month will be imputed as the last day 
of the year (i.e., 31 December). 
o Imputed stop dates must be on or after the start date. 
If a time required for calculation related to exposure is missing, the following standards will be 
applied: 
x If start time is missing for an infusion where the volume recorded on the eCRF is greater 
than 0 mL then start time will be imputed as the pre-dose time of vital signs at the same 
visit + 1 minute. This should only be done for the first dose time within a given visit 
should there be more than one record. 
x If stop time is missing for an infusion where the volume is greater than 0 mL then stop 
time will be imputed as the ‘immediately after infusion’ time of the vital signs at the 
same visit - 1 minute. This will only be done for the last dose time within a given visit 
should there be more than one record. 
x If vital sign assessment times are not available, infusion start date/time is missing, and 
infusion stop date/time is non-missing then the start date/time will be imputed as stop 
date/time - 2 hours at the Month 1 Day 1 visit or as the stop date/time - 1 hour for all 
other visits 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 30 
Confidential and Proprietary 
 
If vital sign assessment times are not available, infusion stop date/time is missing, and infusion 
start date/time is non-missing then the stop date/time will be imputed as start date/time + 2 hours 
at the Month 1 Day 1 visit or as the start date/time + 1 hour for all other visits. 
All data recorded on the case report form will be included in data listings that will accompany 
the CSR. 
4.5.
Data Conventions 
The precision of original measurements will be maintained in summaries, when possible. 
Quantitative laboratory tests containing less than (<) and greater than (>) symbols are test results 
that are below and above quantifiable limits, respectively. In order to retain these values for 
analysis purpose, the numeric portion of the result will be imputed and stored within the analysis 
datasets.
Variables (e.g., urine albumin/creatinine ratio) with a non-normal distribution that impacts the 
interpretation or validity of the planned analysis may have a data transformation applied (e.g., ln, 
log10). Only transformations that lead to clinically meaningful interpretations will be used. 
4.6.
Standard Calculations 
Variables requiring calculation will be derived using the following formulas:
x Days – A duration expressed in days between one date (date1) and another later date 
(date2) will be calculated using the following formulas:  
duration in days = date2 – date1 + 1, where date1 ≥first infusion date 
duration in days = date2 – date1, where date1 <first infusion date 
x Months – A duration expressed in months is calculated as the number of days divided by 
30.4375 
x Years – A duration expressed in years between one date (date1) and another date (date2) 
is calculated using the following formulas: 
duration in years = (date2 – date1 + 1)/365.25, where date1 ≥first infusion date
duration in years = (date2 – date1)/365.25, where date1<first infusion date 
x Age – Age is calculated as the number of years from the date of birth (DOB) to the 
specified date, e.g., date of informed consent (DOIC).  
            age (years) = (DOIC –DOB + 1) / 365.25. 
x Height – Height entries made in inches (in) are converted to centimeters (cm) using the 
following formula: 
height (cm) = height (in) × 2.54 
x
Weight – Weight entries made in pounds (lb) are converted to kilograms (kg) using the
following formula: 
weight (kg) = weight (lb) / 2.205 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 31 
Confidential and Proprietary 
 
x Temperature – Temperature entries in degrees Fahrenheit are converted to degrees 
Celsius using the following formula:
temp (degrees Celsius) = 5 / 9 × (temp [degrees Fahrenheit] – 32) 
x Body Mass Index (BMI) – BMI is calculated using height (cm) and weight (kg) using the
following formula: 
BMI (kg/m2) = weight (kg) / ([height (cm)/100]2) 
x Change from baseline – Change from baseline will be calculated as: 
Change = post baseline value – baseline value 
x Percent change from baseline – Change from baseline will be calculated as: 
Percent change from baseline = ([post baseline value – baseline value] / baseline 
value) × 100 
4.7.
Visit Windows   
Each visit will be denoted by its “month” and “day” such that the first dose day is denoted as 
Month 1-Day 1; subsequent months will use sequential numbers (e.g., the second dose is 
administered on Month 2-Day 1). Each infusion is scheduled to be 28 days from the previous 
infusion (±2 days for Months 2 and 3; ±5 days for Months 4 and beyond). All visits, including 
scheduled visits,  unscheduled visits, re-test, and ETD assessments, will be remapped to a 
scheduled visit for analysis purposes according to visit window as described in Table 3 and 
Table 4 below, the nominal visits will not be used for any by-visit analyses.   
If multiple visits occur within a single visit window, unique assessment will be selected step by 
step as follows: 
1. Choose the assessments with shortest distance from the target day. 
2. If multiple assessments are the same distance from the target day for a particular analysis 
window, the later assessments are chosen. 
3. If there are 2 or more assessments taken on the same date or same date and time, the rules 
for choosing the assessment are: 
a. First take the assessment from the scheduled visit, then take the assessment from the re-
test visit (applicable to laboratory tests), then take the assessment from the 
discontinuation visit, then take the assessment from the unscheduled visit. 
b. Take the assessment with the most abnormal value. Most abnormal value is determined 
by taking the value that is the further from the lower limit of normal (LLN) or ULN. 
Table 3 defines the visit windows for assessments taken at 1-month intervals to be established 
with respect to relative day from the start of study drug.  


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 32 
Confidential and Proprietary 
 
Table 3: 
1-Month Interval Visit Windows (Days)  
Target 
Study 
Day a 
Analysis Window Study Day a 
Low 
High 
Baselineb 
1 
Closest visit to Day 1, prior to first NEOD001 dose 
Month 2 
28 
2 
42 [= 28 + 28/2] 
Month 3 
56 
43 [= (28 + 28/2 + 1] 
70 [= 56 + 28/2] 
Month x 
28*(x-1) 
(x-2)*28 + 28/2 + 1 
(x-1)*28 + 28/2  
a Study day will be calculated from first dose date.  
b Baseline is defined Section 4.3. 
Table 4 defines the visit windows for assessments taken at 3-month intervals to be established 
with respect to relative day from the start of study drug.  
Table 4: 
3-Month Interval Visit Windows (Days)  
Months 
Target 
Study 
Day a 
Analysis Window Study Day a 
Low 
High 
Baselineb 
1 
Closest visit to Day 1, prior to first NEOD001 dose b 
Month 3 
56 
2 
98 
Month 6 
140 
99 
182 
Month x 
28*(x-1) 
(x-4)*28 + 84/2 + 1 
(x-1)*28 + 84/2  
a Study day will be calculated from first dose date.  
b Baseline is defined in Section 4.3 . 
“Cycle” is reserved to denote administration of chemotherapy. It is expected that all visits should 
occur according to the protocol schedule.  
In data listings, the relative study day from first infusion of all dates will be presented. 
5.
ANALYSIS POPULATIONS  
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
x The Intent-to-Treat (ITT) Population will include all randomized subjects who receive 
any amount of study drug (NEOD001 or placebo). The ITT Population will be the 
primary population used for efficacy analyses. Treatment assignment will be based on the 
randomized treatment. 
x The Safety Population will include all subjects who received any amount of study drug 
(NEOD001 or placebo). The Safety Population will be the primary population used for 
safety analyses. Treatment assignment will be based on the randomized treatment.  


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 33 
Confidential and Proprietary 
 
6.
EXAMINATION OF SUBGROUPS 
No subgroup analyses will be done for this study.  
7.
STUDY POPULATION 
7.1.
Subject Disposition 
Subject disposition will be tabulated for all screened subjects and will include the number of 
subjects screened, the number screened but not randomized with reasons for screen failure, 
number randomized, the number randomized and not treated, the number in each subject 
population for analysis, the number who withdraw from study prior to completing the study and 
reason(s) for withdrawal, and the number who discontinued treatment early and reason(s) for 
discontinuation of treatment. 
Time on study in months will be calculated as (last known date of contact minus date of 
randomization plus one)/30.4375. Time on treatment in months will be calculated as (last 
infusion date minus first infusion date plus one)/30.4375.  
The number and percentage of subjects randomized by geographical region and site will also be 
presented by treatment group and for ITT subjects.  
A summary table will be produced of the stratification factors and the combined stratum groups: 
x Mayo Clinic Stage (Kumar 2012):  Stage I/II vs Stage III/IV 
x Renal Stage (Palladini 2014):  Stage I vs Stages II and III 
x 6MWT distance:  <300 meters vs ≥300 meters
x Stratum Group 1:  Mayo Clinic Stage I/II, Renal Stage I, 6MWT <300 meters 
x Stratum Group 2:  Mayo Clinic Stage I/II, Renal Stage I, 6MWT ≥300 meters 
x Stratum Group 3:  Mayo Clinic Stage I/II, Renal Stage II/III, 6MWT <300 meters 
x Stratum Group 4:  Mayo Clinic Stage I/II, Renal Stage II/III, 6MWT ≥300 meters 
x Stratum Group 5:  Mayo Clinic Stage III/IV, Renal Stage I, 6MWT <300 meters 
x Stratum Group 6:  Mayo Clinic Stage III/IV, Renal Stage I, 6MWT ≥300 meters 
x Stratum Group 7:  Mayo Clinic Stage III/IV, Renal Stage II/III, 6MWT <300 meters 
x Stratum Group 8:  Mayo Clinic Stage III/IV, Renal Stage II/III, 6MWT ≥300 meters. 
In addition, in case the site accidentally stratified a subject using the wrong stratification value, 
the derived stratification value reported in the eCRF or central lab data versus the one the site 
entered in the IWRS during randomization process will be presented. 
By-subject data listings of all the above study disposition data including study completion and 
any reasons for premature treatment and/or study withdrawal will be presented. 
7.2.
Demographics and Baseline Characteristics
Demographic variables will include the following: 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 34 
Confidential and Proprietary 
 
x Age at informed consent 
x Sex 
x Race 
x Ethnicity
Other baseline characteristics will include the following: 
x Weight (kg) 
x Height (cm) 
x BMI (kg/m2) including frequency of the following subgroups:  
o <20, ≥20 - <25, ≥25 - <30, ≥30 kg/m2 
Both conventional BMI and modified BMI (mBMI [kg/m2 g/L], defined as subject’s weight (kg) 
x subjects squared height (meters) x serum albumin (g/L)) will be presented.  
Demographics and baseline characteristics will be presented by treatment group and overall for 
ITT and Safety populations.  
No inferential statistical comparisons will be performed. 
All demographic and baseline characteristics data will be presented in by-subject data listings. 
7.3.
Baseline AL Amyloidosis Disease Characteristics 
Baseline disease characteristics will be presented by treatment group and all subjects for the ITT 
and Safety populations and the efficacy subsets as described in Section 8.5. No inferential 
statistical comparisons will be performed.  
Baseline disease characteristics will be presented in by-subject data listings. 
The following disease histories will be summarized: 
x Age at AL amyloidosis diagnosis 
x Duration (months) since AL amyloidosis diagnosis 
x Increase in light chains identified prior to bone marrow biopsy (yes/no) 
x Concurrent Monoclonal Gammopathy (yes/no) 
x History of Familial Amyloidosis (yes/no/unknown)  
x Number of involved organs (1, 2, 3, or 4 organs: cardiac, renal, peripheral neuropathy) as 
defined in Section 8.5 
x Screening NT-proBNP:  <1800 pg/mL, ≥1800 pg/mL 
x Mayo Clinic Stage:  I, II, III, IV; I/II, III/IV; I/II/III, IV 
x Renal Stage:  I, II, III; I/II, III; I, II/III 
x NYHA Class:  I, II, III, IV; I/II vs III/IV
x 6MWT distance:  < 300 meters vs. ≥ 300 meters


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 35 
Confidential and Proprietary 
 
x Baseline FLC:  
o Ratio: Low (<0.26), Normal (0.26 – 1.65), High (>1.65) 
o dFLC: <18 mg/dL, ≥18 mg/dL 
Historical NT-proBNP results will be listed including the date of assessment, number of days 
from first dose of study since the historical result, result, and result unit will be included in a by-
subject data listing. 
7.4.
Disease Specific AL Symptoms 
Disease specific AL symptoms verbatim terms as recorded on the Disease-Specific Medical 
History eCRF will be mapped to preferred terms (PT) and system organ classes (SOC) using 
MedDRA version 19.0.  
Disease specific AL symptoms will be presented in a by-subject data listing. 
7.5.
General Medical History 
Verbatim terms on eCRFs will be mapped to PTs and SOCs using MedDRA version 19.0.  
General medical history will be presented in a by-subject data listing. 
7.6.
Protocol Deviations 
The Investigator is not permitted to deviate from the protocol in any significant way without 
notification to the Sponsor (or designee) as described in the protocol.  
All protocol deviations will be collected by the clinical research associates. 
Important protocol deviations that could potentially affect the efficacy or safety conclusions of 
the study will be identified prior to database lock and unblinding of individual subject treatment 
information. Important protocol deviations will be summarized by deviation category and 
treatment group using the ITT Population. 
All protocol deviations will be presented in a by-subject data listing. 
7.7.
Pre-Treatment, Prior, and New Concomitant Medications 
Verbatim terms on eCRFs will be mapped to Anatomical Therapeutic Chemical (ATC) class and 
Preferred Name using the WHO Drug Dictionary, B2 Enhanced December 2015.  
Pretreatment medications, recorded on the Concomitant Medications eCRF, are those 
medications with start and stop dates prior to the first infusion of study drug. Prior concomitant 
medications are those medications started prior and continued after the first infusion of study 
drug. New concomitant medications are those medications that were started on or after the first 
infusion of study drug.  
Pretreatment medications, prior and new concomitant medications will be listed. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 36 
Confidential and Proprietary 
 
7.8.
Chemotherapy 
Chemotherapy regimens will be prescribed as per standard of care at the Investigator’s discretion. All 
chemotherapy recorded on the Prescribed Chemotherapy Regimens and Concomitant Chemotherapy 
Treatment Medications eCRFs will be listed.  
8.
EFFICACY ANALYSES  
All efficacy analyses will use the ITT Population, except where noted for the Efficacy Subset 
Populations (Section 8.5). All efficacy endpoints, recorded and derived, will be presented in by-
subject data listings. For applicable efficacy analyses, if the assumptions of the planned 
parametric analyses are violated and inhibit the interpretation of the results, appropriate data 
transformations or non-parametric analyses will be performed to support the interpretation of the 
treatment effect. 
8.1.
Adjustments for Covariates 
For comparison of treatment groups with respect to change and percent change from baseline, 
restricted maximum likelihood (REML) based mixed-effect model for repeated measures 
(MMRM) and analysis of covariance (ANCOVA) models will be used. The corresponding 
baseline value will be used as a covariate in the model.  
8.2.
Handling of Dropouts or Missing Data 
At any point in the study, if a subject who was randomized and received any amount study drug 
is unwilling to return to the study site for further visits but is willing to provide his/her health 
status (AEs if during treatment emergent period, mortality, and hospitalizations) by phone, 
follow-up phone calls should be made to the subject or their caregiver, per protocol Section 7.1.7 
and Appendix 3. If a subject discontinues study drug prior to the end of the study, but is willing 
to continue to participate in study visits, the subject should have an ETD Visit within 28-35 days 
after the last study drug administration and then have assessments performed every third month. 
Vital status will be collected within legal and ethical boundaries for all randomized subjects 
receiving any amount of study drug and will be searched in public sources. During the study 
close-out period, survival status will be collected within legal and ethical boundaries for all 
randomized subjects who withdrew participation from the study. If vital status is determined, the 
subject will not be considered lost to follow-up and the vital status will be included in relevant 
analyses.  
For the SF-36v2, missing data conventions for partially completed questionnaires are specified in 
Section 2.3.2.1. 
The following methods will be implemented to address missing data for relevant primary, key 
secondary, other secondary efficacy endpoint analyses, and select exploratory efficacy endpoints. 
8.2.1.
Time to Event Endpoints 
Censoring rules are defined in the applicable study endpoint section (Section 8.10.6). Subjects 
with no data after randomization will be censored on Day 1 (first day of study drug dosing). 
Methods for handling missing data for time to event endpoints are included in the applicable 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 37 
Confidential and Proprietary 
 
study endpoint section because the censoring and event dates are specific to the events being 
analyzed. 
8.2.2.
Parametric Analyses 
8.2.2.1. 
Missing Not at Random (MNAR): Imputation for Deaths 
For the primary analysis of the SF-36v2 PCS and NIS-LL total score, subjects who are missing 
Month 9 due to death, will be imputed as the worst Month 9 value in the total population.  
8.2.2.2. 
Missing at Random (MAR): Multiple Imputation 
For the primary analysis of the SF-36v2 PCS and NIS-LL total score, subjects who are missing 
Month 9 for reasons other than death, will be imputed using multiple imputation (MI) 
methodology using the total study sample. MI will be performed under the assumption of MAR. 
Intermittent missing value(s) will also be replaced using MI. MI will impute 10 integer values 
using Markov Chain Monte Carlo (MCMC) methods assuming nonmontone missing, a seed of 
100201, 500 burn-in iterations, 100 iterations between imputations, and a non-informative prior. 
The imputation models based on all subjects (regardless of treatment group) will include 
randomization stratification factors, and baseline value of the endpoint and all previous values of 
the endpoint at each time point. Change from baseline to each post-baseline visit will be 
calculated based on observed and imputed data. Data will be analyzed using the primary REML 
based MMRM model. Results from the analysis of each of the 10 imputed datasets will be 
combined using Rubin’s imputation rules (Rubin 1987) to produce a pooled least squares mean 
(LSM) estimate of treatment difference. 
8.2.3.
Non-Parametric Analyses 
8.2.3.1. 
Ranking 
For the primary analysis of 6MWT, subjects will be ranked as follows ordered from worst to 
best: 
1. Subjects who died prior to Month 9 where time to death is used to rank earlier deaths 
worse than later deaths, 
2. Subjects who are missing Month 9 and vital status is unknown at Month 9 
3. Subjects who are missing Month 9 because they are hospitalized for cardiac reasons (as 
adjudicated by the CEC) where duration of hospitalization is used to rank longer length 
of stay (LOS) worse than shorter LOS 
4. Subjects who are missing Month 9 because the subject physically cannot perform the test, 
due to physical incapacity, non-cardiac hospitalization, or other reason 
5. Subjects who are missing Month 9, known to be alive, but it is unknown if they are 
missing due to a cardiac hospitalization 
6. Subjects who are missing Month 9, known to be alive, and are known not to be in the 
hospital
7. Completed subject’s values will be ranked from worst (lowest distance) to best (highest 
distance) performance
Exploratory analyses at other visits (i.e. not Month 9) will use the same ranking methodology.   


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 38 
Confidential and Proprietary 
 
8.2.4.
Responder Endpoints 
The primary analysis for best response analyses, will consider a subject as a non-responder until 
a response is achieved.
For other categorical efficacy endpoints in which subjects are classified as either a responder or a 
non-responder (binary outcome) based on dichotomizing a continuous variable at each visit, 
analyses will use “observed cases,” where subjects who do not provide an assessment at the 
specified time point for the defining of response will not be included. That is, for the percentage 
of responders, the subject will not be included in the numerator or the denominator.  
8.2.5.
Observed Cases 
In order to estimate the effect in those who survive, analyses of continuous efficacy endpoints 
will be presented where no imputations are made for missing values.  
8.3.
Interim Analyses and Data Monitoring 
8.3.1.
Data Monitoring Committee (DMC) 
The primary objective of the independent DMC is to safeguard the interests of subjects in the 
study and to help ensure the integrity and credibility of the study. The DMC abides by the 
principles set forth in the Food and Drug Administration (FDA) Guidance for Clinical Trial 
Sponsors, Establishment and Operation of Clinical Trial Data Monitoring Committees. The 
DMC is composed of individuals external to the study organizers, Sponsors, and Investigators 
and operates under the DMC’s written Charter that includes standard operating guidelines. The 
DMC will conduct reviews of accumulating data from the study on a regular basis and will 
advise the Sponsor regarding the continuing safety of trial subjects and those yet to be recruited 
to the trial, as well as the continuing validity and scientific merit of the trial. It is possible that the 
DMC may advise the Sponsor to stop the study based on its review of the accruing data that 
indicate clear harm to subjects participating in the study. A DMC Charter provides the guidelines 
for its operations and monitoring plans.  
The DMC members will review safety reports on a monthly basis. After the first 20 subjects 
have completed 3 cycles of randomized treatment, the DMC will conduct a review to confirm the 
safety and tolerability of the administration of NEOD001 and concomitant chemotherapy. This 
will include review of aggregated data to assess serious adverse events (SAEs). The DMC will 
meet at least twice a year starting when the first subject is exposed to study medication, and 
continuing until the study is terminated and the database is locked and finalized.  
8.3.2.
Interim Analysis  
No interim analyses were planned for this study. Based on the results from a separate Phase 2b 
PRONTO study (NEOD001-201) in the same indication, which did not meet its primary or 
secondary endpoints, the DMC was requested to review an unplanned interim efficacy and 
futility analysis of the ongoing VITAL study (NEOD001-CL002). The unplanned interim 
efficacy and futility analysis was conducted using a Lan-DeMets spending function with non-
binding futility and Pocock monitoring (stopping) boundaries based on 103 adjudicated events. 
The analysis needed to yield a HR of less than 0.664 for efficacy and greater than 0.739 for 
futility.  The interim analysis HR was 0.84, leading the DMC to recommend the discontinuation 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 39 
Confidential and Proprietary 
 
of the VITAL study for futility.  It was therefore decided to discontinue all development of 
NEOD001, including the VITAL study as well as the open label extension studies.   
8.3.3.
Adjudication Committee 
An independent clinical events committee (CEC), previously referred to as the Cardiovascular 
Adjudication Committee (CAC), blinded to treatment groups, will provide independent central 
adjudication of all deaths and hospitalizations. The CEC will define in its Manual of Procedures 
(MOP) cardiac events for use in the primary and secondary outcome analyses. The members of 
this committee will be experts in cardiac event adjudication and will be responsible for 
determining if hospitalizations meet the adjudication standard to be considered as a primary 
endpoint. The members of the CEC will not directly participate in this trial, nor will they 
participate as a member of the DMC.  
Any potential endpoint event (i.e., death or hospitalization) must be reported to the Sponsor or 
designee within 24 hours after the site staff learns of the clinical event. Study sites should collect 
the required documents, including the relevant completed endpoint eCRFs and the requested 
source documentation for submission to the CEC in a timely fashion for adjudication of the 
event. 
8.4.
Multicenter Studies
The randomization is not stratified by site. Likewise, analyses of efficacy data will not be 
stratified by study site. The number and percentage of subjects randomized by geographical 
region and study site will be summarized by treatment group and for all subjects. 
8.5.
Use of an “Efficacy Subset” of Patients 
The Renal Evaluable Population will include subjects who had renal involvement, i.e.,
proteinuria >0.5g/24 hours (measured by 24-hour urine total protein excretion), at baseline and at 
least one post-baseline assessment of proteinuria.  
The Peripheral Neuropathy Evaluable Population will include subjects who had peripheral nerve 
involvement at baseline (only if the subject had ascending sensorimotor neuropathy due to AL 
amyloidosis etiologies answered as yes) and had a baseline NIS-LL score of 2 or greater and at 
least one post-baseline NIS-LL total score. 
8.6.
Multiple Comparisons/Multiplicity 
For the primary and the key secondary efficacy analyses, the overall 2-sided level of 
significance will be alpha = 0.05. The hypothesis testing of key secondary endpoints will be 
conducted using a gatekeeping procedure based on a closed fixed-sequence test, provided the 
primary efficacy endpoint comparison is statistically significant at an alpha level 0.05. If this 
comparison is not statistically significant, then the comparison of key secondary efficacy 
endpoints will be considered nominal, descriptive and exploratory. This procedure controls 
the study-wise type I error and is described below. 
1. First placebo and NEOD001 will be compared with respect to the primary efficacy endpoint. 
If the comparison achieves statistical significance at the 2-sided 0.05 level in favor of 
NEOD001, then 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 40 
Confidential and Proprietary 
 
2. Placebo and NEOD001 will be compared with respect to change from baseline to Month 9 in 
the SF-36v2 PCS. If the comparison achieves statistical significance at the 2-sided 0.05 level 
in favor of NEOD001, then 
3. Placebo and NEOD001 will be compared with respect to change from baseline to Month 9 in 
the 6MWT distance (meters). If the comparison achieves statistical significance at the 
2-sided 0.05 level in favor of NEOD001, then 
4. Placebo and NEOD001 will be compared with respect to NT-proBNP (cardiac) best response 
from baseline through Month 9.  
If at any step defined above, the comparison is not statistically significant at the 2-sided 
0.05 level, then the remaining comparisons in the stated hierarchy will be considered 
nominal, descriptive and exploratory. The study-wise type I error will be maintained with the 
above closed procedure.  
8.7.
Primary Efficacy Analysis 
The primary efficacy endpoint (defined in Section 2.3.1) is the time to all-cause mortality or 
cardiac hospitalization as determined by the CEC.  
The primary estimand is the difference in survival distributions of the time-to all-cause mortality 
or cardiac hospitalization in all randomized subjects with AL amyloidosis who received any 
amount of study drug. 
Time (months) to event for each subject will be calculated as the (earliest date of first cardiac 
hospitalization admission occurring ≥91 days after first study drug infusion or death - the date of 
first study drug infusion + 1) / 30.4375. The censoring rules are defined in Section 2.3.1. 
NEOD001 will be compared to placebo using the log rank test stratified by the randomization 
stratification factors. Kaplan-Meier (KM) estimates of the survival distributions of the time-to-
event will be tabulated and graphed by treatment group. The tabulation will include the KM 
estimate of the medians, 25th and 75th quartiles, and corresponding 95% CIs, if they can be 
estimated. The tabular and graphical summaries will include the at-risk counts for every visit. 
The number and percent of subjects censored, reason for censoring, and with events will be 
presented overall and for each visit, using last day of the visit window by treatment group.  
The log rank test uses a weight of 1, where all time intervals are weighted equally. 
The log rank test and KM methods have the following assumptions. 
1. Independence of censoring and the event, i.e. the reason why cases are censored does not 
relate to the event: A scatter plot of the censored and event values against survival time 
will be presented together and separately to evaluate if any patterns arise and if the 
patterns are similar across treatment groups. 
2. Censoring is random, with a similar amount and pattern of censorship per group: In 
addition to the above scatter plot, the percentage of censoring between treatment groups 
will be compared. 
The hazard ratio and 95% CI will be determined based on the semi-parametric Cox regression 
model stratified by randomization strata to estimate the magnitude of the effect. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 41 
Confidential and Proprietary 
 
8.7.1.
Sensitivity Analyses of the Primary Endpoint 
8.7.1.1. 
Time to Event Methods  
In order to assess the effect of weight assignment used by the log rank test, the analyses will be 
repeated using the Peto-Peto test (weight=KM survival function), Modified Peto-Peto test 
(weight=survival function multiplied by the ratio of the number at risk over the number at risk 
plus one), Wilcoxon test (weight=number at risk, where gives more weight to differences that 
occur earlier in the follow-up time), and the likelihood ratio test which assumes exponentially 
distributed survival times.
As the independence assumption is not easily verified, the cumulative incidence curve will be 
presented estimating the marginal probability of an event to assess treatment utility regardless of 
independence assumption. 
In order to assess constant survival probabilities and the effects of including cardiac 
hospitalizations on or after study day 91, the following sensitivity analyses may be conducted in 
the same manner as specified for the primary endpoint (Section 8.7): 
1. Removing any time constraints on cardiac hospitalizations, i.e., including all 
confirmed CEC cardiac hospitalizations regardless of when they occur from study 
day 1 until end of study. Subjects will be censored at their last contact date with who 
do not have a confirmed CEC cardiac hospitalization prior to the end of the study, 
withdraw consent, or are lost to follow-up. 
2. Including only cardiac hospitalizations within the first 90 days after first study drug 
dosing, i.e. on or after study day 1 before study day 91. If a subject has a cardiac 
hospitalization after study day 91, then the subject will be censored at study day 91 or 
if they withdraw from the study or are lost to follow-up prior to documented cardiac 
hospitalization.  
In addition to the semi-parametric Cox model, different parametric regression models 
(lognormal, Weibull, and exponential) will be assessed.  If the graph of the hazard functions is U 
shaped, first increasing and then decreasing, the lognormal distribution will be chosen.  If the 
graph of the log of the survival function, against time appears as a straight line passing through 
the origin, the exponential distribution will be chosen. If a graph of the log of the log of the 
survival function against the log of time appears as a straight line, the Weibull distribution will 
be chosen.  
In order to test assess the effects of the stratification factors, the unadjusted/not stratified hazard 
ratio with associated 95% CI will be presented. KM plots will also be presented for each 
stratification factor by treatment group.  
The frequency and percentage of subjects who died with their reported primary cause of death 
from the Death eCRF and the adjudicated cause of death will be summarized by treatment group 
and for all subjects. Similarly, the frequency and percentage of subjects who were hospitalized 
with their reported cause of hospitalization from the Hospitalization eCRF and the adjudicated 
cause of hospitalization will be summarized by treatment group and for all subjects for 
hospitalizations occurring <91 days and ≥91 days and overall. 
A by-subject listing will present all events which were adjudicated. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 42 
Confidential and Proprietary 
 
8.7.1.2. 
Finkelstein–Schoenfeld Method  
Finkelstein–Schoenfeld method is a modified Wilcoxon rank sum test, may be used to analyze 
the impact of treatment on all-cause mortality and frequency of cardiac hospitalization during the 
course of study.  
The analysis will test the following hypotheses: 
x H0:  Neither all-cause mortality nor frequency of cardiac hospitalizations is different 
between placebo and NEOD001.
x H1:  At least one and possibly both mortality and frequency of cardiac hospitalizations are 
different between placebo and NEOD001.  
Table 5: 
Finkelstein–Schoenfeld Scoring Algorithm  
Scenario
Mortality
Survival 
Timea 
Cardiac 
Hospitalization 
Frequency
Score
1 
Dead 
… 
… 
-1 
Alive 
… 
… 
+1 
2 
Dead 
Low 
… 
-1 
Dead  
High 
… 
+1 
3
Dead 
Tied 
High 
-1 
Dead 
Tied 
Low 
+1 
4 
Dead  
Tied 
Tied 
0 
Dead 
Tied 
Tied 
0 
5 
Alive 
 
High 
-1 
Alive 
 
Low 
+1 
6 
Alive 
 
Tied 
0 
Alive 
 
Tied 
0 
a Survival time will be derived as date of death - the date of first study drug infusion + 1. 
In each scenario as presented in Table 5, a pairwise comparison of patients is made by first taking 
mortality into account. If there is a clear difference (scenario 1), then a score is assigned. If both 
subjects died (scenario 2), then survival time is considered, and a score is assigned if there is a 
difference between the patients. If there is no difference between the 2 patients in survival time, 
then the frequency of cardiac hospitalization (scenario 3) is considered, and a score is assigned. 
If there is no difference in cardiac hospitalization frequency between the 2 patients (scenario 4), 
then a score of 0 is assigned. If both subjects are alive, then the frequency of cardiovascular 
related hospitalization (scenario 5) is considered, and a score is assigned. If there is no difference 
in cardiovascular related hospitalization (scenario 6), then a score of 0 is assigned. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 43 
Confidential and Proprietary 
 
The Finkelstein–Schoenfeld method increases the sensitivity and power of the analysis while 
also preserving the importance of the all-cause mortality end point. The test is based on the 
principle that each patient in the clinical study is compared with every other patient within each 
stratum in a pairwise manner. The method recognizes the higher importance of all-cause 
mortality. The pairwise comparison proceeds in a hierarchical fashion using all-cause mortality 
first, assigning a +1 to the better patients and a −1 to the worse patients. The test statistic is based 
on the sum of these scores within each stratum and then summed across the all strata.  
Number and percentage of subjects who died will be presented.  Percentage will be based on ITT 
population. Descriptive statistics for frequency of cardiac hospitalization will be summarized for 
patients who are alive.  A p-value (Dianne 1999) will be presented to compare NEOD001 and 
Placebo on all-cause mortality and frequency of cardiac hospitalization.  
8.7.2.
Analyses of Each Component of the Primary Endpoint 
In order to assess the contribution of each component of the primary endpoint, the primary 
analyses will be repeated for each component of the primary endpoint. 
8.7.2.1. 
Time to All-Cause Mortality (Overall Survival) 
Time (months) to all-cause mortality will be calculated as: (date of death - the date of first study 
drug infusion + 1) / 30.4375. All adjudicated deaths will be included in analyses. Subjects who 
do not die will be censored at the date last known to be alive.  
8.7.2.2. 
Time to Cardiac Hospitalization 
Time (months) to cardiac hospitalization, as adjudicated by the CEC, will be calculated as: (date 
of first cardiac hospitalization admission - the date of first study drug infusion + 1) / 30.4375. 
Only adjudicated cardiac hospitalizations occurring ≥91 days after a subject’s first infusion of 
study drug will be included. Sensitivity analyses are specified in Section 8.10.6.3. 
The following censoring rules will apply: 
1. If a subject withdraws from the study and is no longer being followed for hospitalization 
information, the subject will be censored at their last known date of contact at which both 
vital status and hospitalization information is available. 
2. If a subject dies while on study and does not have a prior cardiac hospitalization, the 
subject will be censored at date of death (regardless of cause). 
3. If a subject completes the study and never has a confirmed CEC cardiac hospitalization 
that occurred on or after study day 91, then the subject will be censored at the last 
assessment (visit or phone call). 
4. If a subject completes the study and experiences a confirmed CEC cardiac hospitalization 
on or after study day 1 but prior to study day 91, has no other confirmed CEC cardiac 
hospitalizations on or after study day 91, then the subject will be censored at their last 
assessment (visit or phone call). 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 44 
Confidential and Proprietary 
 
8.8.
Key Secondary Efficacy Analyses 
Key secondary efficacy endpoints are described in Section 2.3.2, multiplicity adjustments in 
Section 8.6, and missing data conventions in Section 8.2.
8.8.1.
SF-36v2 PCS Score 
The estimand for the SF-36v2 PCS is the mean difference in SF-36v2 PCS change from baseline 
between treatment groups at Month 9 in all randomized subjects with AL amyloidosis who 
received any amount of study drug. 
The key secondary efficacy analysis will test the following hypotheses: 
x H0:  The mean change from baseline at Month 9 in SF-36v2 PCS score is equal between 
placebo and NEOD001. 
x H1:  The mean change from baseline at Month 9 in SF-36v2 PCS score is different 
between placebo and NEOD001. 
For the primary analysis of the SF-36v2 PCS, subjects who are missing Month 9 due to death, 
will be imputed as the worst Month 9 value in the total population. Subjects who are missing 
Month 9 for reasons other than death, will be imputed using MI methodology using the total 
study sample.  
NEOD001 and placebo will be compared on change from baseline using a REML based MMRM 
model including fixed effects for randomization strata, treatment group, categorical time point, 
and the treatment group × time point interaction, and with the baseline value included as a 
covariate. The unstructured covariance model will be used. If the computational algorithm fails 
to converge, the following structures will be executed:  heterogeneous Toeplitz, Toeplitz, 
heterogeneous First-Order Autoregressive [AR (1)], AR(1), heterogeneous compound symmetry 
(HCS), and compound symmetry (CS). The covariance structure converging to the best fit, as 
determined by Akaike’s information criterion (AIC), will be used. The Kenward and Roger 
method will be used to calculate the denominator degrees of freedom for the test of fixed effects. 
All visits will be included in the model, with the primary comparison at the Month 9 visit. 
The assumption for a REML based MMRM model without missing data is that the data are 
normally distributed.  In the presence of missing data, the REML based MMRM assumes the 
missing data are missing at random. The use of an unstructured covariance model assumes 
independence over the repeated measurements, where variances and covariances are estimated 
individually from the data.  
Estimates of least-square (LS) means, standard errors (StdErr), and 95% CIs will be presented by 
treatment group. In addition, the LS mean difference comparisons between NEOD001 and 
placebo, the StdErr of the difference, and 95% CI of the difference will be presented. 
Descriptive statistics for SF-36v2 PCS scores, change from baseline, and percent change from 
baseline will be presented by visit for each treatment group.  


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 45 
Confidential and Proprietary 
 
8.8.2.
6MWT Distance  
The estimand for the 6MWT is the median difference in 6MWT distance change from baseline 
between treatment groups at Month 9 in all randomized subjects with AL amyloidosis who 
received any amount of study drug.  
The key secondary efficacy analysis will test the following hypotheses: 
x H0:  The distribution of change from baseline at Month 9 in 6MWT distance (meters) is 
equal between placebo and NEOD001. 
x H1:  The distribution of change from baseline at Month 9 in 6MWT distance (meters) is 
different between placebo and NEOD001.  
For the primary analysis of 6MWT, subjects will be ranked as follows ordered from worst to 
best: 
1. Subjects who died prior to Month 9 where time to death is used to rank earlier deaths 
worse than later deaths, 
2. Subjects who are missing Month 9 6MWT and vital status is unknown at Month 9 will be 
ranked according to time on study drug from worst (shortest time) to best (longest time) 
3. Subjects who are missing Month 9 6MWT because they are hospitalized for cardiac 
reasons (as adjudicated by the CEC) where duration of hospitalization is used to rank 
longer length of stay (LOS) worse than shorter LOS
4. Subjects who are missing Month 9 6MWT because the subject physically cannot perform 
the test, due to physical incapacity, non-cardiac hospitalization, or other reason, will be 
ranked according to time on study drug from worst (shortest time) to best (longest time) 
5. Subjects who are missing Month 9 6MWT, known to be alive, but it is unknown if they 
are missing due to a cardiac hospitalization, will be ranked according to time on study 
drug from worst (shortest time) to best (longest time) 
6. Subjects who are missing Month 9 6MWT, known to be alive, and are known not to be in 
the hospital, will be ranked according to time on study drug from worst (shortest time) to 
best (longest time) 
7. Completed subject’s values will be ranked from worst (lowest distance) to best (highest 
distance) performance
Descriptive statistics for 6MWT distance, change from baseline, and percent change from 
baseline will be presented by visit for each treatment group. The change and percent change from 
baseline at Month 9 in 6MWT distance (meters) will be analyzed using a rank ANCOVA model 
including fixed effects for randomization strata and treatment group, with the ranked baseline 
value included as a covariate.  
Estimates of least-square (LS) means, standard errors (StdErr), and 95% CIs will be presented by 
treatment group. In addition, the LS mean difference comparisons between NEOD001 and 
placebo, the StdErr of the difference, and 95% CI of the difference will be presented. The 
Hodges-Lehman estimate of the median treatment difference with associated 95% CI will be 
presented. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 46 
Confidential and Proprietary 
 
The rank ANCOVA assumes the ranked data are normally distributed and homogenous variance.   
If above assumptions are violated and inhibit the interpretation of the results, appropriate data 
transformations or non-parametric analyses will be performed. 
Only valid assessments 6MWT distance will be included in analysis. Reasons for results being 
invalid will be presented in a listing and will be finalized prior to database lock. Reasons for 
results being invalid may include:  
x Incorrect course length 
x Use of unapproved course 
x Unapproved administrator of test 
x A site staff member has stopped the stopwatch either inadvertently or incorrectly before 
the 6 minutes are complete and the subject is still able to walk 
The percent change from baseline will be analyzed is the same manner. 
8.8.3.
NT-proBNP (Cardiac) Best Response 
The key secondary estimand for NT-proBNP (cardiac) best response is the difference in cardiac 
best response rate between treatment groups through Month 9 in all randomized subjects with 
AL amyloidosis who received any amount of drug. 
The key secondary efficacy endpoint of cardiac best response is assessed by cardiac best 
response from baseline through Month 9. All visits after the first infusion of study drug up to and 
through the Month 9 visit will be included. The key secondary efficacy analysis will test the 
following hypothesis: 
x H0:  The percentage of cardiac best responders from baseline through Month 9 is equal 
between placebo and NEOD001.
x H1:  The percentage of cardiac best responders from baseline through Month 9 is different 
between placebo and NEOD001. 
The primary analysis of cardiac best response will consider subjects with missing values 
through Month 9 as a non-responder. 
The key secondary efficacy analyses will compare placebo and NEOD001 on the percentage 
of cardiac best responders from baseline through Month 9, using a CMH test stratified by the 
randomization stratification factors. The number and percentage, with associated two-sided 
95% confidence intervals (CI), of subjects in each category of best response (response, 
nonresponse) will be presented by treatment group. The proportional treatment difference 
with associated two-sided 95% CI will be presented.  
The CMH test assumes the effect of the treatment is homogeneous in all strata. The Breslow-
Day test will be used to test this assumption. 
In addition, an analysis using a logistic regression will be performed with best response as 
the dependent variable and factors for treatment group and randomization strata. Estimates of 
the odds ratio comparing NEOD001 to placebo and the two-sided 95% CI of the odds ratio 
will be presented. An odds ratio greater than 1 favors the NEOD001 treatment group. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 47 
Confidential and Proprietary 
 
8.9.
Additional Secondary Efficacy Analyses
8.9.1.
Renal Evaluable Subjects: Renal Best Response 
The estimand for renal best response is the difference in renal best response rate between 
treatment groups through Month 9 in randomized subjects with AL amyloidosis and renal 
involvement (Section 8.5) who received any amount of drug. 
The secondary efficacy analysis will test the following hypotheses: 
x H0:  The percentage of renal best response from baseline through Month 9 is equal 
between placebo and NEOD001.
x H1:  The percentage of renal best response from baseline through Month 9 is different 
between placebo and NEOD001. 
All visits after the first dose of study drug up to and through the Month 9 visit will be included. 
The primary analysis of best response will consider subjects with missing values through Month 
9 as a non-responder.  Best renal response will be analyzed in the same manner described in 
Section 8.8.3. 
If an assessment qualifies as both response and progression (Section 2.3.3.1), then assessments 
will be counted as progression for the primary analysis.  
8.9.2.
Peripheral Neuropathy Evaluable Subjects: NIS-LL Score 
The estimand for peripheral neurological function is the mean difference in NIS-LL total score 
change from baseline between treatment groups at Month 9 in randomized subjects with AL 
amyloidosis and peripheral neuropathy involvement (Section 8.5) who received any amount of 
study drug. 
The secondary efficacy analysis will test the following hypotheses: 
x H0:  The mean change from baseline at Month 9 in NIS-LL total score is equal between 
placebo and NEOD001. 
x H1:  The mean change from baseline at Month 9 in NIS-LL total score is different 
between placebo and NEOD001. 
For the primary analysis of the NIS-LL total score, subjects who are missing Month 9 NIS-LL 
score will have their score imputed as the worst Month 9 value in peripheral neuropathy 
evaluable subjects. Subjects who are missing Month 9 for reasons other than death, will be 
imputed using MI methodology using peripheral neuropathy evaluable subjects.  
The change from baseline in NIS-LL total score will be analyzed in the same manner described 
above in Section 8.8.1.
8.10.
Exploratory Efficacy Analyses  
8.10.1. 
Cardiac Endpoint Analyses  
Cardiac (NT-proBNP) best response (response, nonresponse) will be determined for different 
time intervals, such as through Month 3 visit, Month 6 visit, and Month 12 visit, and over course 
of study. Best response at each of these time points (in addition to Month 9 as described above 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 48 
Confidential and Proprietary 
 
for the key secondary endpoint) and response (response, nonresponse) at each visit may be 
analyzed using the CMH test and logistic regression analysis methods described in Section 8.8.3.  
Cardiac best response and response as 3 categories (response, stable disease, and progression) 
may be analyzed in the same manner described above, except ordinal logistic regression will be 
used to analyze the 3 category response. 
Observed NT-proBNP results, change from baseline, and percentage change from baseline may 
be analyzed in the same manner described in Section 8.8.1.  
An analysis of the rate of decrease (ie, slope) of NT-proBNP may be performed for different 
time intervals, such as through Month 9 visit, and Month 12 visit, and over course of study, 
using a general linear mixed effects model to compare treatment groups. The model will fit a 
random intercept and slope for each subject and will include fixed effects for treatment 
group, time, randomization strata, and treatment group × time interaction. Time will be 
expressed in months as a continuous variable and will include all scheduled time points 
including baseline. An unstructured covariance structure will be used to model the within-
subject errors. If the computational algorithm fails to converge, the following structures will 
be executed:  heterogeneous Toeplitz, Toeplitz, heterogeneous First-Order Autoregressive 
[AR (1)], AR(1), heterogeneous compound symmetry (HCS), and compound symmetry (CS). 
The covariance structure converging to the best fit, as determined by Akaike’s information 
criterion (AIC), will be used. The Kenward and Roger method will be used to calculate the 
denominator degrees of freedom for the test of fixed effects. The null hypothesis of no 
difference in slopes between the treatment groups will be determined by testing the 
significance of the treatment group by time interaction term.  
Estimates of the slope will be presented by treatment group along with corresponding 95% CIs. 
The estimate of the difference between slopes (NEOD001-Placebo) and the 95% CI of the 
difference between slopes will also be presented. Appropriate contrasts for pairwise differences 
in coefficients at time points of interest between NEOD001 and placebo with corresponding 95% 
CIs will be estimated from the model and tested for significance. 
8.10.2. 
Functional Endpoint Analyses 
8.10.2.1. 6MWT Distance 
In addition to the key secondary endpoint, 6MWT distance, change from baseline, and percent 
change from baseline to all visits will be analyzed in the same manner described in Section 8.8.2.  
Descriptive statistics will be presented for observed values, changes from baseline and percent 
change from baseline at each post-baseline time point. 
The change from baseline to Month 9 will be categorized as follows: 
x ≤30 meter decline (Worsening) 
x >30 meter decline to <30 meter improvement (No Change) 
x
≥30 meter improvement (Improvement).
The categorical change from baseline may be analyzed in the same manner described in Section 
8.8.3.


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 49 
Confidential and Proprietary 
 
8.10.3. 
Quality of Life Endpoint Analyses 
8.10.3.1. SF-36v2 PCS Score 
In addition to the key secondary endpoint, the SF-36v2 PCS, MCS scores and the eight subscales 
to all visits will be analyzed in the same manner described in Section 8.8.1 using observed value.
The rate of increase (i.e. slopes) may be analyzed in the same manner described in 
Section 8.10.1. 
8.10.4. 
Renal Endpoint Analyses 
The following endpoints may be evaluated in the Renal Evaluable Population.  
8.10.4.1. Renal Response 
In addition to the secondary endpoint, for the Renal Evaluable Population, the renal best 
response may be determined for different time intervals, including through Month 3 visit, 
Month 6 visit, and Month 12 visit, and over course of study. Best response at each of these time 
points (in addition to Month 9 as described above for the secondary endpoint) may be analyzed 
in the same manner described in Section 8.9.1. 
Renal response at each visit may be analyzed in the same manner described in Section 8.9.1.  
8.10.4.2. Creatinine, Proteinuria, and eGFR
Proteinuria, measured by 24-hour urine protein excretion, and estimated glomerular filtration rate 
(eGFR) to all visits may be analyzed in the same manner described in Section 8.8.1 using 
observed value. 
8.10.5. 
Peripheral Neuropathy Endpoint Analyses  
In addition to the secondary endpoint, for subjects in the Peripheral Neuropathy Evaluable 
Population, the NIS-LL total scores and the 3 deficit component scores (sensory function, 
reflexes, muscle strength) to all visits may be analyzed in the same manner described in Section 
8.9.2 using observed value. 
8.10.6. 
Additional Time-to-Event Analyses 
The following additional time-to event endpoints may be analyzed in the same manner described 
in Section 8.7 for the primary endpoint.  
8.10.6.1. Time to Cardiac Mortality or Cardiac Hospitalization 
Time (months) to cardiac mortality or cardiac hospitalization, as adjudicated by the CEC, will be 
calculated as: (earliest date of cardiac hospitalization /cardiac death - the date of first study drug 
infusion + 1) / 30.4375. Only adjudicated events will be included in these analyses.  
For cardiac mortality, all deaths adjudicated as “cardiac”, occurring after the first infusion of 
study drug will be included. Cardiac hospitalizations as defined for the primary endpoint will be 
used in this analysis.  
The following censoring rules will apply: 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 50 
Confidential and Proprietary 
 
x Subjects who die for any reason other than cardiac, will be censored at their date of death. 
x Subjects who complete the study and experience a cardiac hospitalization on or after 
study day 1 but prior to study day 91, have no other cardiac hospitalizations on or after 
study day 91, and are not known to have died from a cardiac cause, will be censored at 
their last assessment (visit or phone call) known to be alive.  
x Subjects who complete the study and do not experience any cardiac hospitalization and 
are not known to have died from cardiac cause will be censored at their last assessment 
(visit or phone call) known to be alive. 
x Subjects who withdraw from the study or are lost to follow-up prior to experiencing a 
cardiac hospitalization on or after study day 91 or death will be censored at their last 
assessment (visit or phone call) where both vital status and hospitalization information 
was available. 
In addition, the following sensitivity analyses may be conducted in the same manner: 
1) Removing any time constraints on cardiac hospitalizations, i.e., including all cardiac 
hospitalizations regardless of when they occur. 
2) Including only cardiac hospitalizations within the first 90 days after first study drug 
dosing.
8.10.6.2. Time to Cardiac Mortality  
Time (months) to cardiac mortality, as adjudicated by the CEC, will be calculated as: (date of 
cardiac death - the date of first study drug infusion + 1) / 30.4375. Only adjudicated events will 
be included in analyses.  
For cardiac mortality, all deaths adjudicated as “cardiac”, occurring after the first infusion of 
study drug will be included. Subjects who do not die will be censored at the date of last contact. 
If a subject dies for any reason other than cardiac, then the subject will be censored at their date 
of death.  
8.10.6.3. Time to Cardiac Hospitalization 
The following sensitivity analyses may be conducted in the same manner as specified for the 
primary endpoint (Section 8.7): 
1) Removing any time constraints on cardiac hospitalizations, i.e., including all cardiac 
hospitalizations regardless of when they occur. 
2) Including only cardiac hospitalizations within the first 90 days after first study drug 
dosing.
8.10.6.4. Time to Derived Organ Progression 
The following time-to progression endpoints may be analyzed in the same manner described in 
Section 8.7. For all of the endpoints below, subjects who die prior to having documented disease 
progression will be assumed to have progressed at their date of death and subjects who 
discontinue due to disease progression, as reported on the ETD or EOS eCRF, will be assumed to 
have progressed at the date of their last contact. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 51 
Confidential and Proprietary 
 
x Time (months) to NT-proBNP progression calculated as: (date first assessed with 
progression (Section 2.3.2.3) - the date of first study drug infusion + 1) / 30.4375. 
Subjects who do not progress will be censored at the date of last NT-proBNP assessment.  
x For renal evaluable subjects, time (months) to renal progression calculated as: (date first 
assessed with progression (Section 2.3.3.1) - the date of first study drug infusion + 1) / 
30.4375. Subjects who do not progress will be censored at the date of last eGFR 
assessment.  
8.10.6.5. Time to First Derived Organ Response 
The following time-to response endpoints may be analyzed in the same manner described in 
Section 8.7.  
x Time (months) to first NT-proBNP response calculated as: (date first assessed with 
response (Section 2.3.2.3) - the date of first study drug infusion + 1) / 30.4375. Subjects 
who do not respond will be censored at the date of last NT-proBNP assessment.  
x For renal evaluable subjects, time (months) to first renal response calculated as: (date first 
assessed with response (Section 2.3.3.1) - the date of first study drug infusion + 1) / 
30.4375. Subjects who do not respond will be censored at the date of last proteinuria 
(measured by 24-hour urine total protein excretion), assessment.  
8.10.7. 
Other Efficacy Endpoints 
Below efficacy data will be presented in by-subject data listings: 
x Echocardiogram Cardiac Parameters: Left ventricular ejection fraction (LVEF), 
Intraventricular septal at end diastole (LVSd), Left posterior wall at end diastole 
(LPWd) 
x Cardiac Biomarker: Troponin T (μg/L) 
x Kansas City Cardiomyopathy Questionnaire (KCCQ) 
x Visual Analog Scale – Pain Intensity (VASPI) 
x
Liver size
x Eastern Cooperative Oncology Group (ECOG) performance, New York Heart 
Association (NYHA) Class, Mayo Clinic Stage, and Renal Stage 
x Free light chains (sFLCs), serum and 24-hour urine protein electrophoresis (PEP), 
and serum and urine immunofixation electrophoresis (IFE)  
x Disease-related symptoms  
x Pharmacokinetics (PK)  
9.
SAFETY ANALYSES   
Safety analyses will be conducted using the Safety Population.  
No inferential comparison of safety endpoints will be performed, unless otherwise specified.  


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 52 
Confidential and Proprietary 
 
9.1.
Extent of Exposure 
9.1.1.
Study Drug 
The total patient exposure years (PEY) for each subject is defined as the time interval between 
the first dose and the last dose, inclusive, of study drug based on the subject’s study drug
administration information. One PEY is the equivalent of 1 subject exposed to study drug for 
1 year. Two subjects who are exposed to study drug for half a year together contribute one PEY. 
The total PEY is the sum of the person exposure years of each subject in that treatment group.
Duration of exposure is defined in days as the date of the last infusion of study drug – the date of 
the first infusion of study drug + 1. 
Study drug exposure summaries will include:
x The number of subjects exposed to NEOD001, the total PEY, and duration of 
exposure will be summarized using descriptive statistics. 
x Total Number of Infusions received will be determined for each subject by number of 
times the start time of drug infused is reported. If multiple infusion start times are 
reported on a single day, then only 1 infusion will be counted for that day. If the start 
time of drug infused is missing but total volume infused is greater than 0 mL, 
1 infusion will be counted for that day.  The number of infusions received will be 
summarized using descriptive statistics. In addition, cumulative number of subjects 
receiving infusions at each visit will be presented. 
All recorded and derived exposure data will be presented in a by-subject data listing. 
9.1.2.
Premedication 
All subjects will be premedicated for each dose of study drug with 25 mg diphenhydramine (or 
an equivalent dose of a H1 antihistamine) and 650 mg acetaminophen (or an equivalent 
paracetamol dose) within 30-90 minutes prior to study drug administration. Pretreatment 
medications will be mapped to Anatomical Therapeutic Chemical (ATC) class and Preferred 
Name using the WHO Drug Dictionary, B2 Enhanced December 2015 and listed. 
9.1.3.
Standard of Care Chemotherapy
All subjects will receive concomitant standard of care chemotherapy, which must include 
bortezomib administered subcutaneously on a weekly basis for the initial, first-line 
chemotherapy regimen. Subsequent chemotherapy regimens may be prescribed as per standard 
of care at the Investigator’s discretion (see protocol Section 7.1.5). Chemotherapy regimens 
including line of therapy, medication, date prescribed, and planned number of cycles will be 
listed. 
9.2.
Adverse Events 
Verbatim terms on eCRFs will be mapped to PT and SOC using MedDRA version 19.0. AEs 
will be reported and severity will be categorized using the Common Terminology Criteria for 
Adverse Events (CTCAE, Version 4.03).


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 53 
Confidential and Proprietary 
 
Pretreatment AEs are those AEs with a start date prior to the first infusion of study drug. All AE 
summaries will be restricted to TEAEs, which are defined as any AE that newly appears, 
increases in frequency, or worsens in severity following initiation of study drug and up to the 
ETD / EOS Visit or 28 days after date of last dose. If it cannot be determined whether the AE is 
treatment emergent due to a partial onset date, then it will be counted as such.  
Each AE summary will be displayed by treatment group. Summaries that are displayed by SOC 
and PT will be ordered by descending order of NEOD001 incidence of SOC and PT within each 
SOC.  
The following listings will be presented by treatment group and subject: 
x All AEs 
x SAEs (this is a subset of the AEs where serious is marked as “Yes”) 
x CTCAE Grade 3 or higher AEs (this is a subset of AEs where severity is missing or 
marked as CTCAE grade 3, 4, or 5) 
x Related AEs (this is a subset of the AEs where relationship marked as “Related” or 
relationship is missing) 
x AEs leading to Study Drug Withdrawal (this is a subset of the AEs where Action Taken 
with Study Treatment is checked as “Drug Discontinued”) 
x AEs leading to death (this is a subset of the AEs where outcome is indicated as “Fatal” or 
the CTCAE grade is 5) 
x AEs resulting in any dose change (i.e., interruption, reduction, held, or prolongation) All 
adverse events for subjects who received the wrong treatment 
9.2.1.
Types of Incidence Rates 
9.2.1.1. 
Crude Incidence Rates 
The crude rate for a particular AE is defined as the number of subjects with the AE divided by 
the number of subjects exposed to the study drug. All crude incidence tables will be repeated 
only for MedDRA PT, excluding MedDRA SOC. 
9.2.1.2. 
Exposure-Adjusted Incidence Rates 
Crude AE incidence will be corrected for differences in study drug exposure by using person-
time in the denominator to calculate incidence rates. Adjusted incidence per 100 PEY is the 
number of subjects with an event for whom person-time is available divided by the total PEY for 
each treatment group and multiplied by 100. Each subject’s PEY will be calculated as the last 
infusion date minus the first infusion date plus 1 divided by 365.25 days/year. One PEY is the 
equivalent of one subject exposed to study drug for one year. Two subjects who are exposed to 
study drug for half a year together contribute one PEY. The total PEY of a treatment group is the 
sum of the person exposure years of each subject in that treatment group. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 54 
Confidential and Proprietary 
 
9.2.2.
Overall Summary of Adverse Events
An overall summary of crude AE incidences will be presented including the number and percent 
of subjects with at least one of: 
o Any TEAE 
o TEAE by maximum CTCAE Grade 
o CTCAE Grade ≥3 TEAE 
o Serious TEAE 
o TEAE leading to death (outcome=“Fatal” or severity=CTCAE grade 5) 
o Treatment-related TEAE 
o Treatment-related serious TEAE 
o Treatment-related TEAE of CTCAE ≥Grade 3 
o Treatment-related TEAE leading to death 
o TEAE leading to interruption of study treatment 
o TEAE leading to dose reduction of study treatment 
o TEAE leading to dose being held 
o TEAE leading to prolongation of infusion time (>2.5 hours) 
o Infusion associated TEAE overall 
o TEAE leading to study drug withdrawal  
9.2.3.
Treatment-Emergent Adverse Events 
The crude incidences of TEAEs will be summarized by treatment group. In addition, the 
exposure-adjusted incidences of TEAEs will be summarized. The following summaries will be 
presented: 
x Subject incidence of TEAEs by MedDRA SOC and PT 
x Subject incidence of TEAEs by MedDRA SOC and PT occurring in ≥5% of NEOD001 
subjects with greater frequency than placebo 
x Subject incidence of TEAEs by MedDRA SOC and PT occurring in ≥10% of NEOD001 
subjects with greater frequency than placebo 
x Subject incidence of TEAEs by MedDRA SOC and PT occurring with greater frequency 
than placebo 
9.2.4.
Serious Adverse Events and Deaths 
The crude incidences of serious TEAEs and deaths will be summarized by treatment group. In 
addition, the exposure-adjusted incidences of serious TEAEs and deaths will be summarized. 
The following summaries will be presented: 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 55 
Confidential and Proprietary 
 
x Subject incidence of serious TEAEs by MedDRA SOC and PT 
x Subject incidence of serious related TEAEs by MedDRA SOC and PT 
9.2.5.
Adverse Events Leading to Study Drug Withdrawal  
AEs leading to study drug withdrawal are those AEs where Action Taken with Study Treatment 
is checked as “Drug Discontinued”. The crude incidences of AEs leading to study drug 
withdrawal will be summarized by treatment group. The following summaries will be presented: 
x Subject incidence of TEAEs leading to study drug withdrawal by MedDRA SOC and PT.  
9.2.6.
Adverse Events of Special Interest 
9.2.6.1. 
Infusion Associated Adverse Events 
The crude incidence of infusion associated TEAEs by MedDRA SOC and PT will be 
summarized by treatment group. This is a subset of the AEs where the question “Was the event 
an infusion-associated adverse event?” is checked “Yes”. In addition, the exposure-adjusted 
incidences of TEAEs will be summarized.  
If applicable, the crude incidence anaphylactic reaction, defined as the broad algorithmic 
standardized MedDRA query (SMQ) of “Anaphylactic reaction” will be summarized by 
treatment group. 
9.3.
FACT-GOG NTX 
The Functional Assessment of Cancer Therapy – Gynecologic Oncology Group Neurotoxicity 
Subscale (FACT-GOG NTX) assesses subject-reported neurotoxicity symptoms and concerns 
that evaluate Activities of Daily Living (ADL) with an 11-item scale with a range of possible 
scores of 0 to 44. The FACT-GOG NTX score to all visits will be listed. 
9.4.
Clinical Laboratory Evaluations 
Laboratory parameters include serum chemistry, hematology and coagulation.  
All clinical laboratory data will be presented in by-subject data listings using standard 
international (SI) system of units. In addition, separate listings will be presented for any subject 
with a post-baseline CTCAE grade 3 or 4 laboratory value, or with a post-baseline value outside 
the normal range where CTCAE criteria cannot be applied to an analyte. 
The following normal ranges will be used where not provided in the central laboratory data: 
x INR Upper Limit of Normal (ULN) = 1.1 
x eGFR LLN = 90 mL/min/1.73m2 
9.4.1.
Pregnancy Testing and Urinalysis Dipstick 
All pregnancy test results and urinalysis dipstick results will be provided in a by-subject data 
listing.  


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 56 
Confidential and Proprietary 
 
9.5.
Weight and BMI 
Weight (kg), BMI (kg/m2), and mBMI (kg/m2 g/L), defined as a subject’s weight (kg) × subjects 
squared height (meters) × serum albumin (g/L), will be provided in a by-subject data listing.  
9.6.
Vital Signs  
Vital sign parameters including temperature (C), systolic and diastolic pressure (mmHg), pulse 
(beats/min), and respiratory rate (breaths/min) will be presented in a data listing.  
9.7.
Electrocardiograms 
ECGs measurements will be made in triplicate, 5 to 10 minutes apart and assessed by a central 
reader. ECG parameters including, time between 2 consecutive R waves [RR], PR interval, QRS 
duration, QT (uncorrected) interval, QT interval corrected by the Bazett’s formula [QTcB], and 
QT interval corrected by the Fridericia’s formula [QTcF]. 
Overall interpretation results for ECGs and the investigator interpretation results are collected as 
normal, abnormal not clinically significant, and abnormal clinically significant.  
All ECG results will be presented in by-subject data listings. 
9.8.
Physical Examination 
Physical examination findings will be included in a data listing. 
9.9.
Immunogenicity Analyses 
Immunogenicity of NEOD001 will be assessed by anti-NEOD001 antibody levels. Serum anti-
NEOD001 antibody levels will be listed.  
10.
CHANGES TO PROTOCOL PLANNED ANALYSES 
10.1.
Changes from Protocol Planned Analyses 
The following describes the changes to any protocol planned analyses: 
1) The protocol describes a Modified Intent-to-Treat (MITT) Population, which has been 
updated to the Intent-to-Treat (ITT) Population within this analysis plan. 
2) The Safety Population is described in the protocol as only including randomized subjects, 
however, should a subject be dosed prior to randomization or without randomization, all 
subjects treated regardless of randomization will be included in the Safety Population. In 
addition, subjects will be analyzed as randomized. For any subject who receives a 
treatment different than that to which they were randomized, their AEs will be listed 
separately.  
3) An Efficacy Evaluable Population was added. 
4) The interim futility analysis was removed. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 57 
Confidential and Proprietary 
 
5) For the primary endpoint, cardiac hospitalizations occurring ≥91 days after a subject’s 
first infusion of study drug through the last subject’s last visit (LSLV) will be included. 
6) The first key secondary endpoint, NT-proBNP best response from baseline to Month 9 
was moved to the third key secondary endpoint.  
7) The secondary endpoints for population subsets have been changed to efficacy subset 
populations to evaluate the following additional secondary endpoints:  
i. 
For renal evaluable subjects, renal best response from baseline through the 
Month 9 visit  
ii. 
For peripheral neuropathy evaluable subjects, change from baseline at the 
Month 9 in the NIS-LL total score 
iii. 
For hepatic evaluable subjects, hepatic best response from baseline through 
the Month 9 visit  
 
8) Two previous secondary endpoints have been changed to exploratory endpoints to assess 
the utility of these endpoints in AL amyloidosis: 
i. 
For subjects with painful peripheral neuropathy due to AL amyloidosis, 
change in the Visual Analog Scale – Pain Intensity (VASPI) score from 
baseline to Month 9 of treatment 
ii. 
Change from baseline to Month 9 in the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) 
 
9) The following secondary endpoints, that are subsets of the primary endpoint, will be 
analyzed as components of the primary endpoint: 
i. 
Time to cardiac hospitalization (occurring ≥91 days after a subject’s first 
infusion of study drug administered) 
ii. 
Time to all-cause mortality 
 
10) The following secondary endpoint will be analyzed as exploratory time-to-event 
endpoint: 
i. 
Time to cardiac mortality or cardiac hospitalization (occurring ≥91 days after 
a subject’s first infusion of study drug administered) 
11) The protocol includes the following cardiac parameters from echocardiogram: left 
ventricular strain, atrial size, and atrial function. The following cardiac parameters were 
collected and will be summarized: LVEF = Left ventricular ejection fraction, IVSd = 
Intraventricular septal at end diastole, and LPWd = Left posterior wall at end diastole. 
12) Additional exploratory endpoints and analyses have been included. 
13) Subgroup analyses for ethnicity were removed. 
10.2.
Changes Due to Discontinuation of the NEOD001 Program 
Based on the results from a separate Phase 2b PRONTO study (NEOD001-201) in the same 
indication, which did not meet its primary or secondary endpoints, the DMC was requested to 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 58 
Confidential and Proprietary 
 
review an unplanned interim efficacy and futility analysis of the ongoing VITAL study 
(NEOD001-CL002). The unplanned interim efficacy and futility analysis was conducted using a 
Lan-DeMets spending function with non-binding futility and Pocock monitoring (stopping) 
boundaries based on 103 adjudicated events. The analysis needed to yield a HR of less than 
0.664 for efficacy and greater than 0.739 for futility.  The interim analysis HR was 0.84, leading 
the DMC to recommend the discontinuation of the VITAL study for futility.  It was therefore 
decided to discontinue all development of NEOD001, including the VITAL study as well as the 
open label extension studies.   
Due to the discontinuation of the NEOD001 program, the following changes were made to any 
protocol planned analyses:
1) The Efficacy Evaluable Population was removed.
2) All subgroup analyses were removed. 
3) Hepatic related analyses were removed. 
4) Most exploratory endpoints and analyses were removed. 
5) Safety analyses were removed except the summary tables described in Section 9.2 for 
TEAEs and SAEs 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 59 
Confidential and Proprietary 
 
11.
REFERENCES 
American Heart Association. Classes of heart failure (last reviewed 06Apr2015). Available from: 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-
Heart-Failure_UCM_306328_Article.jsp. Accessed 31 Oct 2015. 
Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid 
polyneuropathy: a randomized, controlled trial. Neurology. 2012;79(8):785-92. 
Comenzo RL, Reece D, Palladini G, et al. Consensus guidelines for the conduct and reporting of 
clinical trials in systemic light-chain amyloidosis. Leukemia. 2012;26(11):2317-25. 
Dyck PJ, Litchy WJ, Lehman KA, et al. Variables influencing neuropathic endpoints: the 
Rochester Diabetic Neuropathy Study of Healthy Subjects. Neurology. 1995;45(6):1115-21. 
Dianne F, David S. Combing mortality and longitudinal measures in clinical trials.  
Statistics in medicine. 1999, 18: 1341-1354. 
Falk RH, Dubrey SW. Amyloid heart disease. Prog Cardiovasc dis. 2010;52(4):347-61. Erratum 
in: Prog Cardiovasc Dis. 2010 Mar-Apr;52(5):445-7. 
Guidance for Industry E9: Statistical Principles for Clinical Trials. U.S. Department of Health 
and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research 
(CDER), Center for Biologics Evaluation and Research (CBER), September 1998. 
Guidance for Industry E14: The Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-antiarrhythmic Drugs. U.S. Department of Health and Human 
Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), 
October 2005. 
Kumar S, Dispenzieri A, Lacy MQ, et al. Revised prognostic staging system for light chain 
amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin 
Oncol. 2012;30(9):989-95. 
Maruish ME. User’s manual for the SF36v2 health survey (3rd ed.). Lincoln, RI: QualityMetric, 
Inc.; 2011. Available from: https://campaign.optum.com/optum-outcomes/what-we-do/health-
surveys/sf-36v2-health-survey.html. Accessed 08 Jun 2017. 
National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0 NCI, NIH, 
DHHS. NIH publication # 09-7473. 28 May 2009. 
O’Neill RT. Postmarketing safety assessment and surveillance. In Peace KE, editor. 
Biopharmaceutical statistics for drug development. New York and Basel: Marcel Dekker, Inc. 
1988. p 543–73. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-55. 
Palladini G, Hegenbart U, Milani P, et al. A staging system for renal outcome and early markers 
of renal response to chemotherapy in AL amyloidosis. Blood. 2014;124(15):2325-32. 
Ratitch B and O’Kelly M. Implementation of pattern-mixture models using standard SAS/STAT 
procedures, PharmaSUG2011 – Paper SP04 Available from: 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 60 
Confidential and Proprietary 
 
http://www.pharmasug.org/proceedings/2011/SP/PharmaSUG-2011-SP04.pdf. Accessed 
08 Jun 2017. 
Reboussin DM, DeMets DL, Kim KM, et al. Computations for group sequential boundaries 
using the Lan-DeMets spending function method. Control Clin Trials. 2000;21(3):190-207. 
Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley & Sons; 
1987.


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 61 
Confidential and Proprietary 
 
12.
APPENDICES 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 62 
Confidential and Proprietary 
 
APPENDIX 1: 
ORGAN RESPONSE AND PROGRESSION CRITERIA 
Organ 
Response 
Progression 
Heart/Cardiac1
NT-proBNP response (>30% and >300 ng/L 
decrease in subjects with baseline NT-proBNP 
≥650 ng/L) or NYHA class response (≥2 class 
decrease in subjects with baseline NYHA class III 
or IV) 
NT-proBNP progression (>30% and 
>300 ng/L increase)2  
Kidney/Renal3 
≥30% decrease in proteinuria or drop of proteinuria 
below 0.5 g/24 hours in the absence of renal 
progression 
≥25% decrease in eGFR 
Liver/Hepatic1 
50% decrease in abnormal ALP value 
OR 
≥2 cm reduction in liver size radiographically 
≥50% increase in ALP above lowest 
value 
Peripheral 
Nerve4 
NIS-LL increase from baseline of <2 points 
NIS-LL increase from baseline of 
≥2 points 
ALP = alkaline phosphatase; eGFR = estimated glomerular filtration rate (as estimated by the Chronic Kidney Disease 
Epidemiology Collaboration [CKD-EPI] equation); NIS-LL = Neuropathy Impairment Score–Lower Limbs; NT-proBNP = N-
terminal pro B-type natriuretic peptide; NYHA = New York Heart Association.  
1 
Modified from Table 2 in Comenzo 2012. 
2 
Subjects with progressively worsening renal function cannot be scored for NT-proBNP progression. 
3 
Palladini 2014. 
4 
Coelho 2012. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 63 
Confidential and Proprietary 
 
APPENDIX 2: 
STRATIFICATION DETAILS 
Stratification Details for Mayo Staging Criteria 
Test 
Value 
Score 
NT-proBNP 
<1,800 pg/mL 
0 
 
≥1,800 pg/mL 
1 
Troponin-T 
≤0.03 ng/mL1 
0 
 
>0.03 ng/mL1 
1 
dFLC 
<18 mg/dL 
0 
 
≥18 mg/dL 
1 
Total Score 
0 = Mayo Stage I 
1 = Mayo Stage II 
2 = Mayo Stage III 
3 = Mayo Stage IV 
1 
Modified from the value of 0.025 ng/mL cited in Kumar et al, to 0.03 ng/mL, which is the lowest validated 
determination for this commercially available test. 
Source:  Kumar 2012. 
 
Stratification Details for Renal Staging 
Test 
Value 
Score 
Proteinuria 
≤5 g/24 hours 
0 
 
>5g/24 hours 
1 
eGFR 
≥50 mL/min/1.73 m2 
0 
<50 mL/min/1.73 m2 
1 
Total Score 
0 = Renal Stage I 
1 = Renal Stage II 
2 = Renal Stage III 
eGFR = estimated glomerular filtration rate. 
Source: Palladini 2014. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 64 
Confidential and Proprietary 
 
APPENDIX 3: 
Schedule of Events For Subjects Who Discontinue Study Drug Early 
but Agree to Return For Assessments After the ETD Visit 
Assessments 
Months 3, 6, 9, 12 
Day 1 (±5)1 
Every Third Month 
After Month 122 
(e.g., Months 15, 18, 21) 
Day 1 (±5) 
Every 3 
Months after 
Last Visit 
SF-36v2 3 
X 
 
 
KCCQ3 
X 
 
 
FACT-GOG NTX3,4 
Per Protocol 7.4 & Table 2 
 
 
Echocardiogram 
Months 6 and 125 
 
 
Liver Imaging (CT) 
Months 6 and 126 
 
 
12-lead Triplicate ECG7 
X 
 
 
Symptom-Directed PE8 
X 
 
 
ECOG PS & NYHA Class 
X 
 
 
NIS-LL9 
Per Protocol 7.4 & Table 2 
 
 
VASPI10 
Per Protocol 7.4 & Table 2 
 
 
Local Laboratory 
 
 
 
Serum Pregnancy (WOCBP) 
X11 
 
 
Central Laboratory12 
 
 
 
Hematology & Chemistry 
X 
 
 
Amylase 
X 
 
 
Coagulation – PT/INR, PTT, & 
Indices13 
X 
 
 
Complements C3, C4 
X 
 
 
Troponin T 
X 
 
 
NT-proBNP 
X 
 
 
Serum Free Light Chains (sFLCs) 
X 
 
 
Serum IFE/PEP 
X14 
 
 
Urinalysis 
X 
 
 
Urine Sample for 
Quantitative/Renal Biomarkers15 
X 
 
 
24-hour Urine Collection for: 
 
 
 
 
Urine Protein Excretion16 
Months 3 and 9 
 
 
Urine IFE/PEP16 
Months 3 and 917 
 
 
6-Minute Walk Test (6MWT)
X
X18
Bioanalytical Laboratory 
 
 
 
Anti-NEOD001 Antibody Sample19 
X 
 
 
Vital Signs 
X20 
X18 
 
Adverse Event Assessment 
X 
X18 
 
Concomitant Medications 
X 
X18 
 
Health Status & Hospitalizations 
 
X18 
 
Vital Status Phone Call 
 
 
X21 
BP = blood pressure; CT = computed tomography; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
performance status; ETD = Early Treatment Discontinuation; FACT-GOG NTX = Functional Assessment of Cancer Therapy – 
Gynecologic Oncology Group Neurotoxicity Subscale; HR = heart rate; IFE = immunofixation electrophoresis; KCCQ = Kansas 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 65 
Confidential and Proprietary 
 
City Cardiomyopathy Questionnaire; NGAL = neutrophil gelatinase-associated lipocalin; NIS-LL = Neuropathy Impairment 
Score – Lower Limbs; NT-proBNP = N-terminal pro B-type natriuretic peptide; NYHA = New York Heart Association; 
PE = physical exam; PEP = protein electrophoresis; RBP = retinol-binding protein; RR = respiratory rate; 6MWT = 6-minute 
walk test; SF-36v2 = SF-36v2 Health Survey; VASPI = Visual Analog Scale – Pain Intensity; WOCBP = women of childbearing 
potential. 
1. If a subject discontinues study drug prior to the end of the study, but is willing to continue to participate in study visits, the 
subject should have an ETD Visit within 28-35 days after the last study drug administration (per protocol section 7.1.6) and 
then have assessments performed every third month (i.e., Months 3, 6, 9, and 12, or whatever remains of these visits). The 
most important visit is the Month 9-Day 1 Visit, so if a subject is unwilling to continue visits every third month, every 
effort should be made for the subject to return and complete the Month 9-Day 1 Visit on schedule. All visits after the ETD 
Visit should occur on schedule, that is, at the time when the visit would have occurred had the subject remained on study 
drug. 
2. If subject is willing to return to the study site, otherwise, subjects will receive vital status phone calls per Footnote 21. 
3. Administer questionnaires in the following order prior to the performance of any other study assessments on the day they are 
administered: SF-36v2 (Appendix 5), KCCQ (Appendix 6), and FACT-GOG NTX (Appendix 7). 
4. Administer the FACT-GOG NTX (Appendix 7). 
5. Perform echocardiograms within 10 days prior to Day 1 of Months 6 and 12. To be eligible for the additional cardiac imaging 
analysis, the subject must have had a 4-chamber view, 2-dimensional echocardiogram with Doppler. 
6. For subjects with liver involvement at Screening (Exception: not required in Germany), perform scheduled repeat CT imaging 
of the abdomen for liver measurement at Months 6 and 12 and unscheduled repeat CT imaging as needed per protocol Section 
7.6.  
7. ECG to be performed in triplicate. 
8. Symptom-directed PE should be as clinically indicated and also include weight, and assessment of macroglossia, 
submandibular nodes/fullness, adenopathy, ecchymoses, liver/spleen size (palpable +/-), ascites (+/-), and edema (which 
should be quantified on a scale of 0-4+). 
9. Administer NIS-LL (Appendix 8). 
10. Administer VASPI (Appendix 9). 
11. Obtain local laboratory serum pregnancy test 90 (±5) days after the last study drug administration. 
12. Collect central laboratory samples before 6MWT, if being performed on the same day. 
13. Collect citrated plasma samples at each time point; per Appendix 10, samples will be frozen for potential analysis of 
coagulation indices at a later date. 
14. Perform serum IFE/PEP at each visit. If a subject’s first on-study hematologic complete response was assessed at the previous 
visit, perform serum IFE/PEP (and 24-hour urine IFE/PEP) at least 28 days after the initial assessment of response to confirm 
response. 
15. Urine sample will be collected per protocol Section 7.3 and frozen for potential analysis of quantitative/renal biomarkers (i.e., 
urine albumin/creatinine ratio, urine NGAL, and urine RBP) at a later date. 
16. The 24-hour urine protein excretion and 24-hour urine IFE/PEP tests will be performed using the same 24-hour urine 
collection sample, when required at the same visit.  
17. If a subject’s first on-study hematologic complete response was assessed at the previous visit, perform 24-hour urine IFE/PEP 
(and serum IFE/PEP) at least 28 days after the initial assessment of response to confirm response. Repeat every odd-
numbered month (i.e., Months 3 and 9 to correspond with 24-hour urine protein excretion collection) to assess for continuing 
response or progression. If the initial response confirmation needs to occur on an even-numbered month, perform an 
additional 24-hour urine collection. 
18. After Month 12, if the subject is willing to return to the study site, perform or collect the following every third month (e.g., 
Months 15, 18, 21): 6MWT (which includes BP and HR pre- and post-6MWT administration), adverse events, concomitant 
medications, overall health status, as well as details of any hospitalizations. 
19. Collect if an earlier sample established the presence of anti-NEOD001 antibodies or if a subject discontinued treatment due to 
a suspected immunologic reaction. 
20. Collect BP, HR, RR, and temperature any time during visit. 
21. Conduct a vital status phone call per protocol Section 7.1.8 approximately 3 months after the subject’s last visit and 
approximately every 3 months thereafter. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 66 
Confidential and Proprietary 
 
APPENDIX 4: 
HEMATOLOGIC RESPONSE AND PROGRESSION CRITERIA 
Response Subcategory 
Response Criteria 
Complete Response (CR) 
x Normalization of free light chain levels and ratio, negative 
serum and urine immunofixation
Very Good Partial Response (VGPR)* 
x Reduction in the dFLC to <40 mg/L (<4.0 mg/dL) 
Partial Response (PR)* 
x A greater than 50% reduction in the dFLC 
No Response (NR) 
x Less than a PR 
Progression 
x From CR:  any detectable monoclonal protein or abnormal free 
light chain ratio (light chain must double)
x From PR, 50% increase in serum M protein to > 0.5 g/dL or 
50% increase in urine M protein to > 200 mg/day (a visible 
peak must be present) or free light chain increase of 50% to 
> 10 mg/dL (100 mg/L)
dFLC = difference between involved and uninvolved free light chains. 
*Only applicable for subjects with dFLC > 50 mg/L (5 mg/dL) at study entry. 
Source:  Comenzo 2012. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 67 
Confidential and Proprietary 
 
APPENDIX 5: 
SF-36V2 HEALTH SURVEY 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 68 
Confidential and Proprietary 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 69 
Confidential and Proprietary 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 70 
Confidential and Proprietary 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 71 
Confidential and Proprietary 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 72 
Confidential and Proprietary 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 73 
Confidential and Proprietary 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 74 
Confidential and Proprietary 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 75 
Confidential and Proprietary 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 76 
Confidential and Proprietary 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 77 
Confidential and Proprietary 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 78 
Confidential and Proprietary 
 
APPENDIX 6: 
KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE (KCCQ) 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 79 
Confidential and Proprietary 
 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 80 
Confidential and Proprietary 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 81 
Confidential and Proprietary 
 
APPENDIX 7: 
FUNCTIONAL ASSESSMENT OF CANCER THERAPY – 
GYNECOLOGIC ONCOLOGY GROUP NEUROTOXICITY 
SUBSCALE (FACT-GOG NTX) 
Circle or mark one number per line to indicate your response as it applies to the past 7 days: 
 
Instructions for Healthcare Professionals: 
This assessment tool is to help you evaluate peripheral neuropathy in subjects receiving chemotherapy. You may 
find discussion of subject responses helpful in determining the grade of neuropathy as defined by the NCI-CTCAE 
listed below; there is no direct correlation between assessment scores and toxicity grades. 
NCI-CTCAE for Peripheral Neuropathy and Neuropathic Pain 
 
Grade 
 
1
2 
3 
4 
5 
Peripheral 
motor 
neuropathy 
Asymptomatic; clinical or 
diagnostic observations 
only; intervention not 
indicated 
Moderate 
symptoms; limiting 
instrumental ADL 
Severe symptoms; 
limiting self-care 
ADL; assistive 
device indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Peripheral 
sensory 
neuropathy 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia 
Moderate 
symptoms; limiting 
instrumental ADL 
Severe symptoms; 
limiting self-care 
ADL 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Neuralgia
Mild pain
Moderate 
symptoms; limiting 
instrumental ADL 
Severe pain; 
limiting self-care 
ADL 
ADL = activities of daily living; NCI-CTCAE = National Cancer Institute-Common Terminology Criteria for Adverse Events. 
Source: NCI-CTCAE (version 4.03) 2009. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 82 
Confidential and Proprietary 
 
APPENDIX 8: 
NEUROPATHY IMPAIRMENT SCALE – LOWER LIMBS 
(NIS-LL) 
  


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 83 
Confidential and Proprietary 
 
APPENDIX 9: 
VISUAL ANALOG SCALE – PAIN INTENSITY (VASPI) 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 84 
Confidential and Proprietary 
 
APPENDIX 10: 
COAGULATION INDICES 
For each coagulation time point, citrated plasma samples will be collected and frozen for 
potential analysis of coagulation indices at a later date; these analyses may include, but may not 
be limited to, the indices listed in the following table: 
Antithrombin Activity (ATIII Activity) 
Fibrinogen Antigen 
Partial Thromboplastin Time Mixing Studies 
High-Molecular Weight Kininogen 
D-dimer, quantitative 
Prekallikrein 
Euglobulin Lysis Time  
Plasminogen Activator Inhibitor-1 Antigen 
Factor II Activity 
Plasminogen Activator Inhibitor-1 Activity 
Factor V Activity 
Plasmin-antiplasmin Complex 
Factor VII Activity 
Plasminogen Activity 
Factor VIII Activity  
Protein C Activity 
Factor VIII Antigen Quantitation 
Protein S Antigen Free
Factor IX Activity 
Thrombin Time 
Factor X Activity 
Tissue Plasminogen Activator Activity 
Factor XI Activity 
Tissue Plasminogen Activator Antigen 
Factor XII Activity 
von Willebrand Factor Activity (Ristocetin Cofactor) 
Factor XIII Activity 
von Willebrand Factor Antigen 
Fibrin Monomer 
von Willebrand Factor Multimers 
Fibrinogen Activity 
 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 85 
Confidential and Proprietary 
 
APPENDIX 11: 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
Grade 
Eastern Cooperative Oncology Group 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. 
5 
Dead 
Source:  Oken 1982. 


Statistical Analysis Plan   
13 June 2018 
NEOD001-CL002 (VITAL)
Page 86 
Confidential and Proprietary 
 
APPENDIX 12: 
NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
CLASSIFICATION 
NYHA Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. 
shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g. 
walking short distances (20–100 m). Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound subjects. 
NYHA = New York Heart Association. 
Source:  American Heart Association 2015.