Conditions: AL Amyloidosis
Keywords: amyloidosis ntprobnp NEOD001 Prothena PRONTO amyloid plasma cell dyscrasia immunotherapy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 129
Healthy volunteers: no

Brief summary:
This is a global, multicenter, Phase 2b, randomized, double-blind, placebo-controlled, two-arm, parallel-group efficacy and safety study of NEOD001 as a single agent administered intravenously in adults with AL amyloidosis who had a hematologic response to previous treatment for their amyloidosis (e.g., chemotherapy, autologous stem cell transplant \[ASCT\]) and have persistent cardiac dysfunction.

Detailed description:

Arms:
arm 1: Study Drug given IV every 28 days at 24mg/kg arm 2: Placebo

Interventions: intervention 1: NEOD001 intervention 2: Placebo
Intervention descriptions: intervention 1: NEOD001 is a monoclonal antibody directed at soluble and insoluble light chain aggregates intervention 2: Saline Bag

Protocol document:
Prot_000.pdf: 
 
Document Type: Study Protocol 
Official Title: 
A Phase 2b, Randomized, Double-blind, Placebo-controlled Study of 
NEOD001 in Previously Treated Subjects with Light Chain (AL) 
Amyloidosis who have Persistent Cardiac Dysfunction 
NCT Number: 
NCT02632786 
Document Date: 
22 October 2017 
 


This protocol for Study NEOD001-201 was amended three times. 
Date of Original Protocol: 
06 November 2015 
Date of Amendment 1: 
28 June 2016 
Date of Amendment 2: 
25 April 2017 
Date of Amendment 3: 
22 October 2017 
 
The following key changes were made between amendments: 
Overview of Major/Substantial Changes in Amendment 1: 
• 
Corrected and clarified eligibility criteria. 
• 
Clarified study populations, including the Modified Intent-to-Treat population and 
subjects considered to have AL amyloidosis-related peripheral neuropathy. 
• 
Removed select study procedures to reduce patient burden and clarified various study 
procedures, including the importance of consistency in administration of the 6-minute 
walk test. 
Overview of Major/Substantial Changes in Amendment 2: 
• 
Added new and modified existing study endpoints. 
• 
Increased the number of subjects 
• 
Removed requirement for monthly collection of additional coagulation indices 
• 
Corrected Inclusion Criterion #7 to align with existing stratification factor 
• 
Updated analysis populations and statistical analyses to align with statistical analysis 
plan 
Overview of Major/Substantial Changes in Amendment 3: 
• 
Modified existing study endpoints based on updates to the statistical analysis plan 
• 
Updated statistical analyses to align with statistical analysis plan 






Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 3 of 111 
INVESTIGATOR SIGNATURE PAGE 
 
Protocol Title:  A Phase 2b, Randomized, Double-blind, Placebo-controlled Study of NEOD001 
in Previously Treated Subjects with Light Chain (AL) Amyloidosis who have Persistent Cardiac 
Dysfunction 
Protocol Number: 
 
NEOD001-201 
Sponsor:  
 
 
Prothena Therapeutics Limited 
Date of Original Protocol: 06 November 2015 
Date of Amendment 1: 
28 June 2016 
Date of Amendment 2: 
25 April 2017 
Date of Amendment 3: 
22 October 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 your Study Monitor. Please retain a copy for your 
study files. 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 4 of 111 
TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................4 
LIST OF TABLES .........................................................................................................................7 
LIST OF FIGURES .......................................................................................................................7 
1 
INTRODUCTION............................................................................................................26 
1.1 
Light Chain (AL) Amyloidosis ..............................................................................26 
1.2 
Study Rationale ......................................................................................................27 
1.3 
Background on NEOD001 .....................................................................................28 
1.3.1 
Nonclinical Safety .................................................................................29 
1.3.2 
Clinical Experience ...............................................................................31 
1.4 
Rationale for Study Design and Dose Selection ....................................................33 
2 
OBJECTIVES ..................................................................................................................34 
3 
STUDY PLAN ..................................................................................................................35 
3.1 
Study Design ..........................................................................................................35 
3.2 
Endpoints ...............................................................................................................35 
3.2.1 
Primary Efficacy Endpoint ....................................................................35 
3.2.2 
Key Secondary Efficacy Endpoints ......................................................35 
3.2.3 
Additional Secondary Efficacy Endpoints ............................................35 
3.2.4 
Exploratory Efficacy Endpoints ............................................................36 
3.2.5 
Safety Endpoints ...................................................................................38 
3.3 
Number of Sites and Subjects ................................................................................38 
3.4 
Randomization and Blinding .................................................................................38 
3.4.1 
Randomization ......................................................................................38 
3.4.2 
Emergency Unblinding .........................................................................38 
3.5 
Safety Monitoring Committee ...............................................................................39 
3.6 
Estimated Study Duration ......................................................................................39 
3.7 
Definition of End of Study .....................................................................................39 
4 
SELECTION, DISCONTINUATION, AND WITHDRAWAL OF SUBJECTS ......40 
4.1 
Inclusion Criteria ...................................................................................................40 
4.2 
Exclusion Criteria ..................................................................................................42 
4.3 
Early Treatment Discontinuation ...........................................................................44 
4.4 
Early Termination from the Study .........................................................................45 
4.5 
Replacement of Subjects ........................................................................................45 
4.6 
Termination of the Clinical Study..........................................................................45 
5 
TREATMENT OF SUBJECTS ......................................................................................47 
5.1 
Study Drug .............................................................................................................47 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 5 of 111 
5.1.1 
Formulation, Packaging, and Labeling of NEOD001 ...........................47 
5.1.2 
Shipping, Storage, and Handling of NEOD001 ....................................47 
5.2 
Accountability and Return of Study Supplies ........................................................47 
5.3 
Dosage, Preparation, and Administration ..............................................................48 
5.4 
Dosage Adjustments ..............................................................................................49 
5.4.1 
Withholding of Study Drug ...................................................................49 
5.4.2 
Management of Suspected Systemic Infusion-
Related/Hypersensitivity Adverse Events .............................................49 
5.4.3 
Dose Reductions ...................................................................................50 
5.5 
Treatment Compliance ...........................................................................................50 
5.6 
Prior and Concomitant Medication/Therapy .........................................................50 
5.6.1 
Allowed (Concomitant) .........................................................................50 
5.6.2 
Prohibited (Concomitant) ......................................................................50 
6 
STUDY PROCEDURES .................................................................................................52 
6.1 
Evaluations by Visit ...............................................................................................52 
6.1.1 
Screening ...............................................................................................52 
6.1.2 
Treatment Visits ....................................................................................54 
6.1.2.1 
Month 1-Day 1 ...............................................................................55 
6.1.2.2 
Months 2 through 12 – Day 1 (±5 Days) .......................................57 
6.2 
End of Study/Early Treatment Discontinuation (EOS/ETD):  30 (±5) Days 
AFTER Final Dose ................................................................................................60 
6.3 
90-day Postdose Pregnancy Test ...........................................................................62 
6.4 
Vital Status Follow-Up Phone Call........................................................................62 
6.5 
Order of Assessments of Specific Tests.................................................................62 
6.6 
Methods of Assessment .........................................................................................63 
6.6.1 
Safety.....................................................................................................63 
6.6.1.1 
Clinical Laboratory Evaluations ....................................................63 
6.6.1.2 
Vital Signs ......................................................................................63 
6.6.1.3 
Physical Examination.....................................................................64 
6.6.1.4 
Echocardiograms............................................................................64 
6.6.1.5 
12-Lead ECGs ................................................................................64 
6.6.2 
Efficacy .................................................................................................64 
6.6.2.1 
Organ Response (i.e., cardiac, renal, peripheral nerve) .................64 
6.6.2.2 
Short Form-36v2® Health Survey (SF-36v2) ...............................64 
6.6.2.3 
6-Minute Walk Test (6MWT) ........................................................65 
6.6.2.4 
Kansas City Cardiomyopathy Questionnaire (KCCQ) ..................65 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 6 of 111 
6.6.2.5 
Peripheral Neuropathy Assessment ...............................................65 
6.6.3 
Pharmacokinetics ..................................................................................66 
6.6.4 
Immunogenicity ....................................................................................66 
7 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS AND REPORTING .............67 
7.1 
Adverse Events—Definition ..................................................................................67 
7.2 
Adverse Events—Severity Rating .........................................................................68 
7.3 
Adverse Events—Causality Rating........................................................................68 
7.4 
Serious Adverse Events and Unexpected Adverse Events ....................................69 
7.4.1 
Elective Procedures and Surgeries ........................................................71 
7.4.2 
Other Reportable Information ...............................................................72 
7.4.3 
Disease Progression and Death .............................................................72 
7.4.4 
Serious Adverse Events—Reporting.....................................................72 
8 
STATISTICAL METHODS AND CONSIDERATIONS ............................................74 
8.1 
Analysis Populations ..............................................................................................74 
8.2 
Analysis of Study Population and Subject Characteristics ....................................74 
8.3 
Analysis of Efficacy Endpoints .............................................................................75 
8.3.1 
Primary Efficacy Analysis ....................................................................75 
8.3.2 
Key Secondary Efficacy Analyses ........................................................75 
8.3.3 
Additional Secondary Efficacy Analyses..............................................76 
8.3.4 
Exploratory Efficacy Analyses .............................................................76 
8.4 
Analysis of Safety Endpoints .................................................................................76 
8.5 
Analysis of Other Endpoints ..................................................................................77 
8.5.1 
Pharmacokinetics ..................................................................................77 
8.5.2 
Immunogenicity ....................................................................................77 
8.6 
Determination of Sample Size ...............................................................................77 
8.7 
Handling of Dropouts and Missing Data ...............................................................77 
9 
DATA RECORDING, RETENTION, AND MONITORING .....................................78 
9.1 
Case Report Forms .................................................................................................78 
9.2 
Availability and Retention of Records ...................................................................78 
9.3 
Quality Control and Quality Assurance .................................................................78 
9.4 
Subject Confidentiality ..........................................................................................79 
10 
ETHICAL AND LEGAL ISSUES ..................................................................................80 
10.1 
Ethical Conduct of the Study .................................................................................80 
10.2 
Regulatory Approval ..............................................................................................80 
10.3 
Ethics Committee Approval ...................................................................................80 
10.4 
Subject Informed Consent......................................................................................80 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 7 of 111 
10.5 
Subject Compensation for Adverse Effects on Health ..........................................81 
10.6 
Protocol Amendments and Study Termination ......................................................81 
10.7 
Finance, Insurance, and Indemnity ........................................................................81 
10.8 
Publication Policy ..................................................................................................81 
11 
REFERENCES .................................................................................................................82 
12 
APPENDICES ..................................................................................................................84 
Appendix 1 
Hematologic Response and Progression Criteria ..................................85 
Appendix 2 
Examples of Highly Effective Contraception Methods ........................86 
Appendix 3 
Revised International Myeloma Working Group (IMWG) 
Diagnostic Criteria for Multiple Myeloma ............................................................87 
Appendix 4 
Organ Response and Progression Criteria ............................................88 
Appendix 5 
Neuropathy Impairment Scale – Lower Limbs .....................................89 
Appendix 6 
Visual Analog Scale – Pain Intensity (VASPI).....................................90 
Appendix 7 
Eastern Cooperative Oncology Group (ECOG) Performance Status ...91 
Appendix 8 
New York Heart Association (NYHA) Functional Classification ........92 
Appendix 9 
Short Form-36v2 Health Survey ...........................................................93 
Appendix 10 
Kansas City Cardiomyopathy Questionnaire (KCCQ) .......................104 
Appendix 11 
Laboratory Tests..................................................................................108 
Appendix 12 
Coagulation Indices .............................................................................109 
Appendix 13 
Schedule Of Events For Subjects Who Discontinue Study Drug 
Early but Agree to Return For Assessments After the ETD Visit .......................110 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments ...........................................................................18 
Table 2 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 1-
5 for Peripheral Neuropathy and Neuropathic Pain ...................................66 
 
LIST OF FIGURES 
Figure 1 
NEOD001-201 Study Design ....................................................................21 
Figure 2 
Proposed Mechanism of Action for NEOD001 .........................................28 
 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 8 of 111 
PROTOCOL SYNOPSIS 
Title 
A Phase 2b, Randomized, Double-blind, Placebo-controlled 
Study of NEOD001 in Previously Treated Subjects with Light 
Chain (AL) Amyloidosis who have Persistent Cardiac 
Dysfunction 
Phase 
2b 
Planned Number of 
Study Centers 
Approximately 35 centers globally 
Objective 
The objective of this study is to determine the efficacy and 
safety of NEOD001 versus placebo in subjects with AL 
amyloidosis who have persistent cardiac dysfunction. 
Study Design 
This is a global, multicenter, Phase 2b, randomized, double-
blind, placebo-controlled, two-arm, parallel-group efficacy 
and safety study of NEOD001 as a single agent administered 
intravenously in adults with AL amyloidosis who had a 
hematologic response (Appendix 1) to previous treatment 
for their amyloidosis (e.g., chemotherapy, autologous stem 
cell transplant [ASCT]) and have persistent cardiac 
dysfunction. 
Subject screening will occur during the 28 days prior to the 
first administration of study drug (i.e., Month 1-Day 1 
Visit). If all eligibility requirements are met, the subject will 
be enrolled and Screening assessments will be completed. 
Screening assessments are listed in Table 1. 
Study visits will occur every 28 days based on scheduling from 
Month 1-Day 1. A ±5-day window is allowed for visits starting 
after Month 1. Subjects may receive up to 12 infusions of study 
drug. Subjects who discontinue study drug before the End of 
Study (EOS) Visit should have an Early Treatment 
Discontinuation (ETD) Visit 30 (±5) days after their final 
administration of study drug. 
Number of Subjects and 
Cohort Specifications 
Up to 130 subjects will be enrolled and randomized (1:1) to 
NEOD001 or placebo. The randomization will be stratified 
according to: 
• 
Hematologic response; that is, complete response/very 
good partial response (CR/VGPR) vs partial response 
(PR) to first-line therapy 
• 
N-terminal pro-brain natriuretic peptide (NT-proBNP) 
<1800 pg/mL vs ≥1800 pg/mL 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 9 of 111 
Study Drug, Dose, and 
Mode of Administration 
Study drug consists of NEOD001 24 mg/kg (dose not to exceed 
2500 mg) or placebo. 
Study drug will be administered once every 28 (±5) days; a 
minimum of 21 days between doses is required. Subjects may 
receive up to 12 infusions of study drug. 
Study drug will be administered as an initial 120 (±10)-minute 
intravenous (IV) infusion. If, in the opinion of the Investigator, 
the subject tolerates 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 5.3. In the case of a 
suspected systemic infusion-related reaction, follow 
instructions in Section 5.4.2. 
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. Beginning with the 
third infusion, the Investigator may decrease the monitoring 
time to no less than 60 minutes, if no infusion-related reactions 
were observed in the previous infusions and allowed per the 
IRB/IEC. 
Control Group 
Normal saline will be used as the placebo control. 
Estimated Study and 
Treatment Duration 
Each subject’s study duration may be up to 14 months, 
consisting of a Screening Phase (1 month), Treatment Phase 
(12 months), and the EOS Visit 30 (±5) days after the last dose. 
Subjects who complete the study and meet the eligibility 
criteria will be considered for entry into a separate open-label 
extension study, during which subjects will receive active 
treatment and may receive concurrent chemotherapy. 
Subject Eligibility 
Criteria 
Inclusion Criteria (subjects must meet all of the following 
criteria): 
1. Age ≥18 years 
2. Confirmed diagnosis of systemic AL amyloidosis by the 
following: 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 10 of 111 
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 electron microscopy OR 
immunohistochemistry OR mass spectrometry of AL 
amyloidosis 
3. If the subject meets any of the following criteria, confirm 
diagnosis of AL amyloidosis by mass spectrometry OR 
immunoelectron microscopy of amyloid material in tissue 
biopsy:  
o Is black or African American 
o Is over 75 years of age (at time of diagnosis) 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 et al, 2011), 
hydroxymethylenediphosphonate (99mTc-HMDP; 
Galat et al, 2015), or pyrophosphate (99mTc-PYP; 
Bokhari et al, 2013) scintigraphy 
4. Cardiac involvement as defined by BOTH 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 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 11 of 111 
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 
5. NT-proBNP ≥650 pg/mL and ≤5000 pg/mL (i.e., 
≥76.7 pmol/L and ≤590 pmol/L) 
6. Received at least one prior systemic chemotherapeutic 
regimen, which may include stem cell transplant, for AL 
amyloidosis 
7. Achieved at least a partial hematologic response (per 
Appendix 1) to a first-line therapy resulting in a stable 
hematologic condition not currently requiring additional 
active treatment against the plasma cell dyscrasia 
component of their AL disease 
8. Adequate bone marrow reserve, hepatic 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 × upper limit of normal (ULN) 
o Aspartate aminotransferase (AST) ≤3 × ULN  
o Alanine aminotransferase (ALT) ≤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. Systolic blood pressure 90-180 mmHg 
10. Distance walked during each of the two Screening 6-
minute walk tests (6MWTs) is >100 meters and 
<600 meters 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 12 of 111 
11. Women of childbearing potential (WOCBP) must have 
2 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 2) 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 2) 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 not meet any of the 
following criteria): 
1. Diagnosis of non-AL amyloidosis 
2. Meets the International Myeloma Working Group 
(IMWG) definition of Multiple Myeloma (Appendix 3) 
3. 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 
4. Myocardial infarction, uncontrolled angina, uncontrolled 
ventricular arrhythmias, or electrocardiographic evidence 
of acute ischemia, within 6 months prior to the Month 1-
Day 1 Visit 
5. Severe valvular stenosis (e.g. aortic or mitral stenosis with 
a valve area <1.0 cm2) or severe congenital heart disease 
6. Electrocardiographic (ECG) evidence of acute ischemia 
or active conduction system abnormalities with the 
exception of any of the following: 
o First degree atrioventricular (AV) block 
o Second degree AV block Type 1 (Mobitz Type 1/ 
Wenckebach type) 
o Right or left bundle branch block 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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o 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 3 representative beats if Lead II is not 
representative of the overall ECG]) 
7. Has not recovered (i.e., equivalent to a Common 
Terminology Criteria for Adverse Events [CTCAE] 
≥Grade 2) from the clinically significant toxic effects of 
prior anticancer therapy. Exception: subjects with prior 
bortezomib treatment may have CTCAE Grade 2 
neuropathy. 
8. Received any of the following within the specified time 
frame prior to the Month 1-Day 1 Visit: 
o  Oral or intravenous antibiotics, antifungals, or 
antivirals within 1 week, with the exception of 
prophylactic oral agents. Note:  In the event that a 
subject requires the chronic use of antivirals, Medical 
Monitor permission is required for entry into the study. 
o Hematopoietic growth factors, transfusions of blood or 
blood products within 1 week 
o Chemotherapy, radiotherapy, or other plasma cell 
directed therapy within 6 months 
o ASCT within 12 months 
o Major surgery within 4 weeks 
o Planned major surgery or organ transplant during the 
study 
o Any other investigational agent within 4 weeks 
o Prior treatment with NEOD001, 11-1F4, anti-serum 
amyloid P [SAP] antibody (exception: allowed as part 
of established diagnostic procedures such as SAP 
scintigraphy), or other investigational treatment 
directed at amyloid  
o Doxycycline within 6 weeks 
9. Active malignancy with the exception of any of the 
following: 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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o Adequately treated basal cell carcinoma, squamous cell 
carcinoma, or in situ cervical cancer 
o Adequately treated Stage I cancer from which the 
subject is currently in remission and has been in 
remission for ≥2 years 
o Low-risk prostate cancer with Gleason score <7 and 
prostate-specific antigen <10 mg/mL 
o Any other cancer from which the subject has been 
disease-free for ≥2 years 
10. History of Grade ≥3 infusion-related adverse events 
(AEs) or hypersensitivity to another monoclonal antibody 
11. History of severe allergy to any of the components of 
NEOD001 such as histidine/L-histidine hydrochloride 
monohydrate, trehalose dehydrate, or polysorbate 20 
12. Currently known uncontrolled bacterial, viral, fungal, 
HIV, hepatitis B, or hepatitis C infection 
13. Women who are breastfeeding 
14. 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 
15. Unable or unwilling to adhere to the study-specified 
procedures and restrictions 
16. Subject is under legal custodianship 
17. Waldenström's macroglobulinemia and/or 
immunoglobulin M (IgM) monoclonal gammopathy 
Study Procedures and 
Assessments 
See Schedule of Assessments (Table 1) 
Endpoints 
Primary Efficacy Endpoint: 
• 
NT-proBNP best response from baseline through 12 
months of treatment 
Key Secondary Efficacy Endpoints: 
• 
Change from baseline to 12 months of treatment in the 
Physical Component Score of the Short Form-36 Version 
2 (SF-36v2) 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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• 
Change from baseline to 12 months of treatment in the 
6MWT distance (meters) 
• 
NT-proBNP Slope over 12 months of treatment 
Additional Secondary Efficacy Endpoints: 
• 
Renal evaluable subjects: renal best response from 
baseline through 12 months of treatment  
• 
Peripheral neuropathy evaluable subjects: change from 
baseline to 12 months of treatment in NIS-LL total score  
• 
Hepatic evaluable subjects: hepatic best response from 
baseline through 12 months of treatment 
 
Exploratory Efficacy Endpoints: 
See Section 3.2.4 for a list of exploratory efficacy endpoints 
Safety Endpoints:  
Safety and tolerability of NEOD001 as assessed by vital signs, 
12-lead ECGs, routine clinical laboratory assessments, AEs, 
and immunogenicity by measurement of anti-NEOD001 
antibodies 
Statistical 
Considerations and 
Methods 
Analysis Populations: 
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. The 
Safety Population will include all subjects who receive 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. 
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 
one 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 due 
to AL amyloidosis etiologies answered as yes) and had a 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 16 of 111 
baseline NIS-LL total score of 2 or greater and at least one 
postbaseline NIS-LL total score. 
The Hepatic Evaluable Population will include subjects who 
had hepatic involvement defined as >1.5 × ULN alkaline 
phosphatase at baseline and at least one postbaseline 
assessment of alkaline phosphatase. 
Primary Efficacy Analysis: 
The NT-proBNP best response rates in the two arms will be 
compared using the Cochran-Mantel-Haenszel (CMH) test at 
the alpha=0.05 (two-sided) level of significance. The analysis 
will be stratified by the randomization stratification factors. 
Key Secondary Efficacy Analyses: 
NEOD001 and placebo will be compared on change from 
baseline in the SF-36v2 Physical Component Summary (PCS) 
score after 12 months of treatment 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 NEOD001 and placebo distributions of change from 
baseline in 6MWT distance (meters) after 12 months of 
treatment will be analyzed using a van Elteren test with 
stratification by randomization strata.  
The analysis of NT-proBNP slope will be performed using a 
general linear mixed effects model to compare the rate of 
change (i.e., slope) of NT-proBNP over 12 months of treatment 
between treatment groups.  
For the primary and 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 in a sequential closed testing gate-keeping procedure 
separately, 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. 
Additional Secondary Efficacy Analyses: 
For the Renal Evaluable Population, renal best response will be 
analyzed in the same manner described for the primary efficacy 
endpoint. For the Peripheral Neuropathy Evaluable Population, 
the change from baseline in NIS-LL total score will be analyzed 


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 17 of 111 
in the same manner described for the SF-36v2. For the Hepatic 
Evaluable Population, hepatic best response will be analyzed in 
the same manner described for the primary efficacy endpoint. 
Safety Analyses: 
Safety will be assessed through summaries of AEs, changes in 
laboratory test results, and changes in vital signs. In addition, 
all SAEs, including deaths, will be listed and summarized 
separately. 
Sample Size Justification 
 
For the primary endpoint, the assumed true rates for NEOD001 
vs placebo are 50% and 22.5%, respectively. Based on a two-
sample comparison of proportions at the alpha=0.05 level of 
significance, a total sample size of 100 subjects (50 in the 
NEOD001 arm, 50 in the placebo arm) will provide >80% 
power based on a two-sided CMH test. Based on the actual 
enrolled sample size (N~130), the final power is 91%. 
Sponsor 
Prothena Therapeutics Limited 
 


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 18 of 111 
Table 1 
Schedule of Assessments 
  
Screening1 
Treatment 
Termination 
 Assessment or Procedure 
Days -28 
through -1 
Month 1 
Day 1 
Months 2 through 12 
Day 1 (±5 days)2 
EOS/ETD3 
 
Written Informed Consent  
X 
 
 
 
Eligibility Review 
X 
 
 
 
Clinical 
Medical History4 
X 
 
 
 
Historical NT-proBNP/BNP5 Levels 
X 
 
 
 
Prior/Concomitant Medications/Therapy 
X 
X 
X 
X 
Adverse Event Assessment6 
X 
X 
X 
X 
Confirmation of AL Amyloidosis7 
X 
 
 
 
Physical Exam8 
X 
X 
X 
X 
Vital Signs9 
X 
X 
X 
X 
ECOG PS/NYHA Class9 
X 
X 
X 
X 
NIS-LL & VASPI11 
X 
X 
X (Months 3, 6, 9, 12) 
X 
SF-36v212 
X 
 
X (Months 3, 6, 9, 12) 
X 
KCCQ13 
X 
 
X (Months 3, 6, 9, 12) 
X 
6MWT14,15 
X, X16 
 
X (Months 3, 6, 9, 12)17 
X 
Echocardiogram18 
X 
 
X (Month 12) 
X 
ECG (12-lead triplicate) 
X 
X19 
X (Months 3, 6, 9, 12) 19 
X 
Laboratory24 
Hematology & Chemistry (including amylase 
and creatine kinase)20 
X 
X 
X 
X 
Coagulation21 
X 
 
X 
X 
Inflammatory Biomarkers22,23 
 
X 
X (Month 3)23 
X 
Troponin T  
X 
 
X 
X 
NT-proBNP14  
X 
X 
X 
X 
Pregnancy (WOCBP)25 
X  
X 
X 
X 
Serum Free Light Chain 
X 
 
X (Months 3, 6, 9, 12) 
X 
Serum IFE & PEP26 
X 
 
X (Months 3, 6, 9, 12) 
X 
Urinalysis – Dipstick27 
X 
X 
X (Months 3, 6, 9, 12) 
X 
Urinalysis - Quantitative/Renal Biomarkers28 
X 
 
X (Months 3, 6, 9, 12) 
 
24-hour Urine Collection: 
 
 
 
 
Urine IFE & PEP26 
X 
 
X (Months 3, 6, 9, 12)  
X 
Urine Protein Excretion 
X 
 
X (Months 3, 6, 9, 12) 
X 
Other 
Serum NEOD001 Sample23,29 
 
X 
X (Months 3, 6, 9, 12)23 
X 
Anti-NEOD001 Serum Sample23,30  
 
X 
X (Months 3, 6, 9, 12)23 
X 
Archive Sample31 
X 
 
X (Months 6, 12) 
 
 Randomization 
 
X 
 
 
 Study Drug Infusion32 
 
X 
X 
 
 Vital Status Phone Call 
 
 
 
X33 


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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 19 of 111 
BNP = B-type natriuretic peptide; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
performance status; EOI = end of infusion; EOS = End of Study; ETD = Early Treatment Discontinuation; 
IFE = immunofixation electrophoresis; KCCQ = Kansas City Cardiomyopathy Questionnaire; 
NIS-LL = neuropathy impairment score – lower limbs; NT-proBNP = N-terminal pro-brain natriuretic peptide; 
NYHA = New York Heart Association; PEP = protein electrophoresis; PK = pharmacokinetic; 
6MWT = 6-minute walk test; SF-36v2 = Short Form-36v2® Health Survey; VASPI = visual analog scale – pain 
intensity; WOCBP = women of childbearing potential. 
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. 
2. 
Study visits will occur every 28 days based on scheduling from Month 1-Day 1. A ±5-day window is allowed 
for visits starting after Month 1. The predose assessments for each visit may be performed within the 3 days 
before the visit unless otherwise specified. 
3. 
Conduct the EOS Visit 30 (±5) days after last administration of study drug. Subjects who discontinue study 
drug before the end of the study should have an ETD Visit 30 (±5) days after their final administration of study 
drug, and if willing, have assessments monthly per Appendix 13 (see also Section 4.3). Every effort should be 
made for the subject to return to the clinic and complete the Month 12-Day 1 Visit on schedule. The 
assessments shown for EOS/ETD should also be conducted for any unscheduled visit (i.e., a visit not specified 
by the protocol) as clinically indicated or if deemed necessary.  
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. 
If available, record results of at least 2 prior NT-proBNP or 2 BNP measures from within the previous 6 
months; NT-proBNP is preferred, but BNP may be used if it is the institution’s historical standard. 
6. 
Adverse events will be collected from the time that the informed consent form is signed through 30 days after 
the last dose of study drug or last study visit, whichever is later. 
7. 
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 #3. 
8. 
Screening and EOS/ETD: conduct a complete physical examination, including 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. All other visits: 
conduct a directed physical examination, including weight, and the components of the exam will be as clinically 
indicated. All visits: assess macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, liver/spleen 
size (palpable +/-), ascites (+/-), and edema (which should be quantified on a scale of 0-4). 
9. 
Vital signs include heart rate (HR), respiratory rate (RR), blood pressure (BP), and body temperature; assess 
after subject has been at rest ≥5 minutes; within a visit, assess in the same position for all time points. Month 1: 
Within 30 minutes before dosing, 60 (±10) minutes after the start of the infusion, at EOI (+5 minutes), 30 (±5) 
minutes after EOI, and 60 (±10) minutes after EOI. All Other Months: Within 30 minutes before dosing, at 
EOI (+5 minutes), and 60 (±10) minutes after EOI. 
10. See Appendix 7 (ECOG) and Appendix 8 (NYHA). 
11. See Appendix 5 (NIS-LL; for all subjects with peripheral neuropathy at Screening) and Appendix 6 (VASPI; for 
subjects with painful peripheral neuropathy at Screening). 
12. See Appendix 9; SF-36v2 should be administered before performing any other study assessments on the same 
calendar day it is administered. 
13. See Appendix 10; administer KCCQ after the SF-36v2, but before conducting any other assessments on the 
same calendar day it is administered. 
14. NT-proBNP should be drawn before conducting 6MWT if being performed on the same calendar day.  
15. Collect blood pressure and heart rate pre- and post-6MWT administration. Subject should plan to be able to 
return to the same clinical site for each 6MWT from first Screening through Month 12. 
16. Two pretreatment 6MWTs are required before the first administration of study drug, with a minimum of 4 days 
in between the two tests. 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). 


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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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17. The postbaseline 6MWTs may be administered on the same calendar day that study drug is administered (i.e., 
Months 3, 6, 9, 12) 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. 
18. Perform echocardiogram locally; Screening: If an echocardiogram was conducted within 90 days prior to 
Screening Day -28, it does not need to be repeated during Screening and the previous result may be used for 
eligibility; however, to be eligible for the additional cardiac imaging analysis, the subject must have had a 
4-chamber view, 2-dimensional echocardiogram with Doppler. Month 12: may be conducted within 10 days 
before Day 1; EOS/ETD: repeat if not performed within 60 days prior to visit.  
19. Months 1, 3, 6, 9, 12: perform ECGs centrally within 30 minutes before dosing and within 15 minutes after 
EOI.  
20. Hematology and chemistry per Appendix 11. 
21. Collect PT/INR and PTT at each time point. At Screening, EOS/ETD, and 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. 
22. Inflammatory biomarkers per Appendix 11. 
23. Collect additional samples as clinically indicated, such as when significant toxicity occurs per Section 5.4.2. 
24. All laboratory tests to be done centrally, unless otherwise noted. Please refer to Laboratory Manual for details. 
25. Pregnancy tests for WOCBP as follows: Screening: serum test (central) within 28 days before Month 1-Day 1; 
Month 1: serum test (local) within 24 hours before Month 1-Day 1; Months 2-12: serum test (local) 
preinfusion; EOS/ETD: serum test (central); 90 (±5) days after the last study drug administration: serum 
test (local). 
26. The serum and urine PEP must be conducted before the NEOD001 infusion, if being performed on the same 
calendar day. 
27. Per Appendix 11. 
28. Per Appendix 11. It is important that the sample be taken before exercising and at approximately the same time 
for each collection; therefore, the first morning void is recommended. Urine samples will be collected and 
frozen for potential analysis at a later date.  
29. NEOD001 serum samples (for population PK analysis): collect within 2 hours before infusion and within 
4 hours after EOI. 
30. Anti-NEOD001 serum samples: collect preinfusion. 
31. Archive samples (only subjects who consented to the collection and archiving of their samples for future 
correlative testing): collect preinfusion. 
32. A minimum of 21 days between doses is required. 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. 
Beginning with the third infusion, the Investigator may decrease the monitoring time to no less than 60 minutes, 
if no infusion-related reactions were observed in the previous infusions and allowed per the IRB/IEC. 
33. For randomized subjects who received at least 1 dose of study drug, conduct vital status telephone call 
approximately 3 months after last visit and approximately every 3 months thereafter or until subject enrolls in a 
separate open-label study, death, or for up to 5 years. 


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 21 of 111 
Figure 1 
NEOD001-201 Study Design 
 
Screening
Treatment (N~130)
Termination
Days -28 to -1
Months 1 through 12
Day 1 (±5 daysd)
30 (±5) Days 
After Last Dose
Population:
Previously
treated AL 
amyloidosis
Response to 
first-line PCD 
therapy,
6-month 
treatment-free 
intervala
Cardiac
involvement
ICF & 
Screening 
Assessments
24 mg/kgb IV NEOD001 every 28 days
EOS/ETD 
Visit
CR = complete response; EOS/ETD = End of Study/Early Treatment Discontinuation; ICF = informed consent form; IV = intravenous; M12 = Month 12; NT-proBNP = N-terminal pro B-type natriuretic peptide; NIS-LL = 
Neuropathy Impairment Score-Lower Limbs; PCD = plasma cell dyscrasia; PCS = Physical Component Summary; PR = partial response; SF-36 = Short Form-36; 6MWT = 6 minute walk test; VGPR = very good partial response.
a 6 months chemotherapy or 12 months stem cell transplant treatment-free. 
b Maximum dose not to exceed 2500 mg.
c Eligible subjects will receive active treatment and may receive concurrent chemotherapy.
d ±5-day window applicable to Months 2-12.
e Renal-evaluable subjects, peripheral neuropathy-evaluable subjects, and hepatic-evaluable subjects, respectively.
IV Placebo every 28 days
Randomization 1:1
Randomization Stratification:
• 
Hematologic response; i.e., CR+VGPR vs PR to first-line therapy
• 
NT-proBNP <1800 pg/mL vs ≥1800 pg/mL
Primary Endpoint: 
• 
NT-proBNP best response from baseline through 12 months of treatment
Key Secondary Endpoints:
• 
SF-36 PCS change from baseline to 12 months of treatment
• 
6MWT distance change from baseline to 12 months of treatment
• 
NT-proBNP slope over 12 months of treatment
Secondary Endpoints in Efficacy Subset Populationse:
• 
Renal best response from baseline through 12 months of treatment
• 
NIS-LL Total Score change from baseline to 12 months of treatment
• 
Hepatic best response from baseline through 12 months of treatment
Open-label 
Extension 
Studyc


Study Drug: NEOD001 
CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 22 of 111 
GLOSSARY OF TERMS 
Abbreviation/Acronym 
Definition 
6MWT 
6-minute walk test 
99mTc 
Radioisotope of technetium 
AA 
Amyloid A 
ADA(s) 
Anti-drug antibody(ies) 
ADL 
Activities of daily living 
AE(s) 
Adverse event(s) 
AEF 
Amyloid-enhancing factor 
ALP 
Alkaline phosphatase 
AL 
Amyloid light chain 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ASCT 
Autologous stem cell transplant 
A-SAA 
Acute phase serum amyloid A 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
BNP 
B-type natriuretic peptide 
BP 
Blood pressure 
BSA 
Bovine serum albumin 
BUN 
Blood urea nitrogen 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CMH 
Cochran-Mantel-Haenszel 
CR 
Complete response 
CRP 
C-reactive protein 
CT 
Computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events  
D 
Aspartic acid 


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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 23 of 111 
Abbreviation/Acronym 
Definition 
dFLC 
Difference between involved and uninvolved free light chains 
E 
Glutamic acid 
ECG 
Electrocardiogram 
ECL 
Electrochemiluminescent 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EOI 
End of infusion 
EOS 
End of Study 
ETD 
Early Treatment Discontinuation 
FDA 
Food and Drug Administration 
FLC 
Free light chain 
GCP 
Good Clinical Practice 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Institutional Ethics Committee 
IFE 
Immunofixation electrophoresis 
Ig 
Immunoglobulin 
IgG1 
Immunoglobulin G1 
IL-6 
Interleukin-6 
IMWG 
International Myeloma Working Group 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 


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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 24 of 111 
Abbreviation/Acronym 
Definition 
IV 
Intravenous or intravenously 
IVSd 
Intraventricular septal at diastole 
IWRS 
Interactive Web Response System 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LDH 
Lactate dehydrogenase 
LPWd 
Left posterior wall at diastole 
LVEF 
Left ventricular ejection fraction 
MCS 
Mental Component Summary 
MMRM 
Mixed models for repeated measurements 
NGAL 
Neutrophil gelatinase-associated lipocalin 
NIS-LL 
Neuropathy Impairment Score–Lower Limbs 
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 
PEP 
Protein electrophoresis 
PK 
Pharmacokinetic(s) 
PR 
Partial response 
PS 
Performance status 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RBP 
Retinol-binding protein 
RR 
Respiratory rate 
SAA 
Serum amyloid A 
SAE 
Serious adverse event 


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CONFIDENTIAL 
Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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Abbreviation/Acronym 
Definition 
SC 
Subcutaneous(ly) 
SF-36v2 
Short Form-36v2® Health Survey 
SMC 
Safety Monitoring Committee 
TEAE(s) 
Treatment-emergent adverse event(s) 
TRIAD 
Transgenic Rapidly Inducible Amyloid Disease 
ULN 
Upper limit of normal 
US(A) 
United States (of America) 
USP 
United States  Pharmacopeial Convention 
VASPI 
Visual Analog Scale – Pain Intensity 
VGPR 
Very good partial response 
WFI 
Water for injection 
WOCBP 
Women of childbearing potential 
WT 
Wild-type 
 


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 26 of 111 
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. The overall incidence of AL amyloidosis is estimated to be 
8.9/million persons/year (CI: 5.1, 12.8) (Kyle et al, 1992; Pinney et al, 2013). NEOD001 was 
designated as an Orphan Medicinal Product in the European Union on 08 February 2013 for the 
treatment of AL amyloidosis and in the US on 17 February 2012 for the treatment of AA 
amyloidosis and AL amyloidosis.  
Approximately three-fourths of AL amyloidosis patients present with 1 or 2 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 >2 systems 
involved (Palladini et al, 2005; Gertz et al, 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 and Dubrey, 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 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 
are no currently approved treatments for AL amyloidosis, and none that directly target 
potentially toxic forms of the amyloidogenic proteins. 


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 27 of 111 
1.2 
Study Rationale 
The pathobiology of AL amyloidosis results from PCD, which causes the overproduction of 
immunoglobulin light chain, and soluble aggregates and insoluble amyloid that have a profound 
impact on organ structure and function, leading to the clinical manifestations of the disease. 
Unlike other hematologic disorders such as multiple myeloma, the morbidity and mortality of 
AL amyloidosis is related to organ dysfunction rather than the PCD. In all patients with AL 
amyloidosis, disease outcome is highly dependent on the severity of organ involvement, 
especially cardiac involvement; and prognosis can be defined by N–terminal pro-brain natriuretic 
peptide (NT-proBNP). For this study, NT-proBNP was chosen as the primary endpoint because 
it is a validated cardiac functional biomarker of injury and dysfunction and decreasing NT-
proBNP levels predict lower mortality rates (Comenzo et al, 2012). NT-proBNP can also be used 
for early assessment of cardiac response, allowing treatment modification (Palladini et al, 2014).  
In the completed Phase 1/2 study of NEOD001 in subjects with AL amyloidosis, monthly 
infusions of NEOD001 resulted in clinically meaningful reductions in NT-proBNP  
(Gertz et al, 2016). 
Currently, there are no approved treatments for AL amyloidosis and no existing treatments that 
directly neutralize the toxic soluble aggregates or remove the organ deposited misfolded amyloid 
that are thought to cause organ dysfunction (Falk and Dubrey, 2010). Current treatment 
approaches are aimed at reducing or eliminating the PCD, which produces the toxic amyloid 
(i.e., eliminating or reducing the plasma cells responsible for producing light chains, thereby 
reducing or halting production of the toxic protein). These include high-dose chemotherapy and 
ASCT for patients who can tolerate those treatments. Indeed, the incidence of treatment-related 
mortality following ASCT is high (although variable and treatment center dependent) with the 
greatest mortality in patients with cardiac involvement (Falk and Dubrey, 2010).  Falk and 
colleagues noted that although complete hematologic responses could be achieved in 
approximately 40% of treated patients (Falk and Dubrey, 2010), the rate of any organ function 
improvement or stabilization (“organ response”) after achieving hematologic response from 
ASCT or chemotherapy regimens is highly variable (Cibeira et al, 2011; Cohen et al, 2007; 
Michael et al, 2010). This is significant in as much as hematologic response in the absence of 
organ benefit provides limited if any, clinical benefit to patients with AL amyloidosis  
(Kaufman et al, 2015) and underscores the fact that the major determinant of morbidity and 
mortality is end organ damage.  
NEOD001 is currently being studied in a double-blind, randomized, placebo-controlled Phase 3 
study (The VITAL Amyloidosis Study; Study NEOD001-CL002) in newly diagnosed patients 
with AL amyloidosis disease receiving chemotherapy to treat the underlying PCD. In addition, 
Study NEOD001-OLE001, a Phase 2 open-label extension study for subjects who completed 
9 months of treatment in the Phase 1/2 Study NEOD001-001, allows subjects to receive 
NEOD001 and concomitant chemotherapy for treatment of their underlying PCD. Study 
NEOD001-201 is designed to evaluate the efficacy and safety of NEOD001 as a single agent in 
AL amyloidosis subjects whose underlying PCD is stable but who still exhibit significant organ 
impairment.  


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 28 of 111 
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. NEOD001 specifically targets 
misfolded light chain aggregates and amyloid deposits. In the course of specificity 
characterization of NEOD001, the antibody was found to also react with high affinity and in a 
conformation-dependent manner with the misfolded light chain found in soluble aggregates and 
deposited light chain amyloid fibrils, however not with immunoglobulin (Ig) or free non-amyloid 
light chain in circulation. NEOD001, administered by intravenous (IV) infusion, is proposed for 
use to target the misfolded light chain protein in subjects with AL amyloidosis. See the current 
NEOD001 Investigator’s Brochure for detailed nonclinical and clinical information.  
The proposed mechanism of action for NEOD001 is thought to be two-pronged (Figure 2). 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 2 
Proposed Mechanism of Action for NEOD001 
 


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 29 of 111 
Because NEOD001 and 2A4 (the parent murine monoclonal antibody for NEOD001) recognize a 
conserved epitope in both the AL and serum 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 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.  
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 
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. 


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 30 of 111 
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. Anti-drug antibody reactions in animal species are not predictive of human responses 
and, therefore, these effects are not considered to contribute to human risk assessment  
(Bugelski and Treacy, 2004; Pimm and Smith, 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.  


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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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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 (WT) 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) 
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 
Study NEOD001-001 was a Phase 1/2 open-label, dose escalation study of the IV administration 
of single-agent NEOD001 in subjects with AL amyloidosis previously treated for their plasma 
cell dyscrasia (PCD), which enrolled 27 subjects in the Escalation Phase in 7 cohorts (evaluating 
dose levels from 0.5 mg/kg to 24.0 mg/kg) and enrolled an additional 42 subjects in the 
Expansion Phase. The most frequently reported treatment-emergent adverse events (TEAEs) 
overall in Study NEOD001-001 (occurring in ≥20% of subjects [N=69], regardless of 
relationship to NEOD001) were fatigue, nausea, upper respiratory tract infection, edema 
peripheral, diarrhea, and anemia. No confirmed anti-NEOD001 antibodies were detected. No 
dose-limiting toxicities (DLTs) or treatment-related serious TEAEs were reported. 


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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Efficacy data from the completed Study NEOD001-001 were previously reported by Gertz et al. 
(2016) and final data are summarized herein. Cardiac response was assessed by the clinically 
relevant cardiac biomarker, NT proBNP, using Comenzo 2012 criteria (Appendix 4). Thirty-six 
subjects were considered cardiac evaluable (i.e., Screening NT-proBNP ≥650 pg/mL). Among 
cardiac evaluable subjects, 50% (n=18) met the criteria for cardiac best response and 50% (n=18) 
met cardiac best response category of stable disease. Renal response was defined according to 
Palladini 2014 criteria (Appendix 4). Thirty-six subjects were considered renal evaluable (i.e., 
Screening proteinuria ≥0.5 g/24 hours). Among renal evaluable subjects, 64% (n=23) met the 
criteria for renal best response and 36% (n=13) met renal best response category of stable 
disease. Peripheral neuropathy response was defined according to Coelho 2012 criteria 
(Appendix 4). Eleven subjects (all in the Peripheral Neuropathy Expansion Cohort) were 
considered peripheral neuropathy evaluable. At Month 10, 82% (n=9) of the peripheral 
neuropathy evaluable subjects met the criteria for peripheral nerve response (i.e., <2-point 
increase in Neuropathy Impairment Score–Lower Limbs [NIS-LL] score [88-point scale] from 
Screening) and 18% (n=2) were progressors. Two of the responders had complete resolution of 
peripheral neuropathy at Month 10. 
Eligible subjects from Study NEOD001-001 enrolled in Study NEOD001-OLE001, an open-
label extension study to evaluate the long-term safety and tolerability of NEOD001 in subjects 
with AL amyloidosis. Subjects receive 24 mg/kg NEOD001 once every 28 days using the 
infusion duration established for the individual subject in Study NEOD001 001 or over 60 (±10) 
minutes. As of the data lock point, 11 subjects experienced TEAEs and no treatment-related 
TEAEs, serious TEAEs, discontinuations due to TEAEs, or deaths were reported. 
Study NEOD001-CL002 (VITAL) is an ongoing Phase 3, multicenter, international, randomized, 
double-blind, placebo-controlled, two-arm efficacy and safety study in subjects with AL 
amyloidosis. Newly diagnosed subjects with AL amyloidosis are randomized in a 1:1 ratio to 
received either NEOD001 (24 mg/kg) plus standard of care or placebo plus standard of care, 
administered once every 28 days as a 1- to 2-hour IV infusion. All subjects are premedicated 
with 25 mg diphenhydramine (or an equivalent dose of an H1 antihistamine) and 650 mg 
acetaminophen (or an equivalent dose of paracetamol) within 30 to 90 minutes prior to the start 
of the infusion. As of the data lock point and including late-breaking events, 68 (52.7%) subjects 
experienced at least 1 serious TEAE, 2 of which had events considered related to study drug 
(treatment blinded), 19 (14.7%) subjects had died, none of which were considered by the 
Investigator to be related to study drug treatment, and 5 (3.9%) subjects had TEAEs that lead to 
study drug discontinuation.  
In an overabundance of caution, premedication is required in Study NEOD001-CL002 because 
subjects are also receiving standard of care chemotherapy. But, due to the limited number of 
infusion-related reactions (IRRs) reported to date, premedication will not be routinely 
administered in the ongoing Studies NEOD001-201, NEOD001-OLE001, and NEOD001-
OLE251, unless the Investigator observed an IRR with a prior infusion of study drug in an 
individual subject.  


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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As of 30 September 2016, 221 subjects had been dosed with a total of 1638 infusions of 
NEOD001 or placebo in the 4 completed or ongoing studies. In the completed Study 
NEOD001-001, <1% of infusions administered were associated with IRRs (e.g., rash, 
hypotension). These IRRs were Common Terminology Criteria for Adverse Events (CTCAE) 
Grades 1 or 2, nonserious, considered possibly or probably related to study drug, and most 
resolved within 24 hours. In the ongoing Study NEOD001-CL002 (VITAL), <1% of infusions of 
study drug (treatment blinded) were associated with infusion-related TEAEs. These TEAEs, 
experienced by 5 subjects, were Grade 1 or 2, nonserious, and most were considered related to 
study drug (treatment blinded), and 2 were ongoing at the time of the data lock point. Two events 
required interruption of the infusion. 
Based on the data available to date, NEOD001 has been well tolerated as single-agent therapy in 
subjects with AL amyloidosis and limited clinically significant safety signals have been 
identified. 
Further details can be found in the latest edition of the NEOD001 Investigator’s Brochure. 
1.4 
Rationale for Study Design and Dose Selection 
Since preliminary data have indicated that NEOD001 as a single agent in previously treated 
subjects appears to improve NT-proBNP (Gertz et al, 2016), a randomized, double-blind, 
placebo-controlled, two-arm, parallel-group design was selected to evaluate the safety and 
efficacy of NEOD001 vs placebo in subjects with AL amyloidosis. 


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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2 
OBJECTIVES 
The objective of this study is to determine the efficacy and safety of NEOD001 versus placebo in 
subjects with AL amyloidosis who have persistent cardiac dysfunction. 


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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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3 
STUDY PLAN 
3.1 
Study Design 
This is a global, multicenter, Phase 2b, randomized, double-blind, placebo-controlled, two-arm, 
parallel-group efficacy and safety study of NEOD001 as a single agent administered 
intravenously in adults with AL amyloidosis who had a hematologic response (Appendix 1) to 
previous treatment for their amyloidosis (e.g., chemotherapy, ASCT) and have persistent cardiac 
dysfunction. 
Subject screening will occur during the 28 days prior to the first administration of study drug 
(i.e., Month 1-Day 1 Visit). If all eligibility requirements are met, the subject will be enrolled 
and Screening assessments will be completed. Screening assessments are listed in Table 1.  
Study visits will occur every 28 days based on scheduling from Month 1-Day 1. A ±5-day 
window is allowed for visits starting after Month 1. Subjects may receive up to 12 infusions of 
study drug. Subjects who discontinue study drug before the End of Study (EOS) Visit should 
have an Early Treatment Discontinuation (ETD) Visit 30 (±5) days after their final 
administration of study drug (per Section 6.2). If willing, subjects may continue in the study and 
have monthly assessments, through Month 12, per Appendix 13. Subjects who complete the 
study and meet the eligibility criteria will be considered for entry into a separate open-label 
extension study, during which subjects will receive active treatment and may receive concurrent 
chemotherapy. 
3.2 
Endpoints 
3.2.1 
Primary Efficacy Endpoint 
• NT-proBNP best response from baseline through 12 months of treatment  
3.2.2 
Key Secondary Efficacy Endpoints 
• Change from baseline to 12 months of treatment in the Physical Component Summary (PCS) 
score of the Short Form-36 Version 2 (SF-36v2) 
• Change from baseline to 12 months of treatment in the 6MWT distance (meters) 
• NT-proBNP slope over 12 months of treatment 
3.2.3 
Additional Secondary Efficacy Endpoints 
• Renal evaluable subjects: renal best response from baseline through 12 months of treatment  
• Peripheral neuropathy evaluable subjects: change from baseline to 12 months of treatment in 
NIS-LL total score  
• Hepatic evaluable subjects: hepatic best response from baseline through 12 months of 
treatment  


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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3.2.4 
Exploratory Efficacy Endpoints 
• Cardiac response, as assessed by NT-proBNP response criteria, at each visit  
• Cardiac best response, as assessed by NT-proBNP response criteria, through 3, 6, and 9 
months of treatment 
• Change and percent change from baseline to each visit in NT-proBNP and troponin T  
• 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 diastole 
o LPWd = Left posterior wall at diastole 
• Change and percent change from baseline to each visit (except the key secondary endpoint) 
in the 6MWT distance (meters)  
• Change and percent change from baseline to each visit in SF-36v2 PCS score (except the key 
secondary endpoint), Mental Component Summary (MCS) score, and the 8 subscales 
• Change and percent change from baseline to each visit in the Kansas City Cardiomyopathy 
Questionnaire (KCCQ) subscores and overall summary score  
• Renal Evaluable Subjects:  
o Renal response at each visit 
o Renal best response through 3, 6, and 9 months of treatment 
o Change and percent change from baseline to each visit in renal biomarkers (urine 
albumin/creatinine ratio, urinary neutrophil gelatinase-associated lipocalin [NGAL], and 
urinary retinol-binding protein [RBP]) 
o Change and percent change from baseline to each visit in creatinine, proteinuria, and 
eGFR  
o Time to eGFR ≤15 mL/min/1.73 m2 (Chronic Kidney Stage 5) 
o Shifts from baseline in Chronic Kidney Stage 
o Time to doubling of creatinine  
• Peripheral Neuropathy Evaluable Subjects:  


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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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o Change and percent change from baseline to each visit in the NIS-LL total score (except 
the additional secondary endpoint) 
o Peripheral neuropathy response at each visit  
o Peripheral neuropathy best response through 3, 6, 9, and 12 months of treatment  
o Change and percent change from baseline to each visit in the 3 NIS-LL component 
scores (sensory function, reflexes, muscle strength)  
o For peripheral neuropathy evaluable subjects with painful peripheral neuropathy, 
defined as a baseline VASPI score >0, change and percent change from baseline to each 
visit in the VASPI score 
• Hepatic Evaluable Subjects: 
o Hepatic response at each visit 
o Hepatic best response through 3, 6, and 9 months of treatment  
o Change and percent change from baseline to each visit in ALP  
• Time to all-cause mortality (overall survival) 
• Progression-free survival 
• Duration of response 
• Time to derived organ progression for each organ (cardiac/NT-proBNP, renal, peripheral 
neuropathy, hepatic) separately and to any organ progression 
• Time to first organ response for each organ (cardiac/NT-proBNP, renal, peripheral 
neuropathy, hepatic) separately and to any organ response 
• Frequency of cardiac hospitalizations over the course of the study 
• ECOG Performance Status, NYHA Class, Mayo Clinic Stage, and Renal Stage at each visit 
including any changes from baseline 
• Change and percent change from baseline to each visit in serum free light chains (FLCs), 
serum and 24-hour urine PEP, and serum and urine IFE 
• Hematologic response at each visit 
• Hematologic best response through 3, 6, 9, and 12 months of treatment   


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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• Disease-related symptoms (including macroglossia, submandibular nodes/fullness, 
adenopathy, ecchymoses, edema, ascites, and liver/spleen size) at each visit and changes 
from baseline 
3.2.5 
Safety Endpoints 
Safety and tolerability of NEOD001 as assessed by vital signs, 12-lead ECGs, routine laboratory 
assessments, AEs, and immunogenicity by measurement of anti-NEOD001 antibodies. 
3.3 
Number of Sites and Subjects 
This is a global, multicenter study in approximately 35 centers. Up to 130 subjects will be 
enrolled and randomized (1:1) to NEOD001 or placebo. 
3.4 
Randomization and Blinding 
3.4.1 
Randomization 
A subject number will be assigned via a web-based registration for each subject who has signed 
an informed consent form (ICF). If a subject has completed all Screening requirements and 
meets all of the eligibility criteria, a Subject Registration Form will be submitted for eligibility 
review and approval. If approved, randomization will be implemented through an internet 
connection to an Interactive Web Response System (IWRS) utilizing results from Screening 
assessments. Up to 130 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 two factors: 
• Hematologic response; that is, complete response/very good partial response (CR/VGPR) vs 
partial response (PR) to first-line therapy 
• NT-proBNP <1800 pg/mL vs ≥1800 pg/mL 
Upon successful randomization, the Unblinded Pharmacist or their designee (henceforth 
collectively referred to as the Unblinded Pharmacy Staff) will be provided with the treatment 
assignment. Numbers assigned to subjects who do not receive study drug will not be re-used. 
Refer to the Study Manual for additional details. 
3.4.2 
Emergency Unblinding 
The Investigator has the ability to break the blind for a specific subject in the event of an 
immediate medical emergency, wherein 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 or its designee within 24 hours. The 
procedure for the unblinding of a specific subject using the IWRS is provided in the Study 
Manual. 
Any other requests to reveal a subject’s treatment must be requested of, and approved in writing 
by the Sponsor or its designee. 


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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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In addition, in the event of any safety concern, the Safety Monitoring Committee (SMC) will 
have the option to unblind the treatment of any subject. In this situation, only the SMC will have 
access to the unblinded data. 
3.5 
Safety Monitoring Committee 
An independent Safety Monitoring Committee (SMC), consisting of at least 2 clinicians and a 
biostatistician not directly involved with the conduct of the trial, will meet to review specified 
blinded subject data during the conduct of the study. The purpose of these independent data 
reviews is to assess the totality of the safety data and provide a recommendation to the Sponsor 
for continuation of dosing or protocol modifications. Details will be provided in the SMC 
Charter. 
3.6 
Estimated Study Duration 
Each subject’s study duration may be up to 14 months, consisting of a Screening Phase 
(1 month), Treatment Phase (12 months), and the EOS Visit 30 (±5) days after the last dose. 
3.7 
Definition of End of Study 
The study will end when the last subject completes 12 months of study treatment and the 30-day 
safety follow-up period (i.e., EOS Visit). Subjects who complete the study and meet the 
eligibility criteria will be considered for entry into a separate open-label extension study, during 
which subjects will receive active treatment and may receive concurrent chemotherapy. 


Study Drug: NEOD001 
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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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4 
SELECTION, DISCONTINUATION, AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
Subjects must meet all of the following criteria: 
1. Age ≥18 years 
2. Confirmed diagnosis of systemic 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 electron microscopy OR immunohistochemistry OR mass spectrometry of 
AL amyloidosis 
3. If the subject meets any of the following criteria, confirm diagnosis of AL amyloidosis by 
mass spectrometry or immunoelectron microscopy of amyloid material in tissue biopsy: 
o Is black or African American 
o Is over 75 years of age (at time of diagnosis) 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 et al, 2011), 
hydroxymethylenediphosphonate (99mTc-HMDP; Galat et al, 2015), or pyrophosphate 
(99mTc-PYP; Bokhari et al,  2013) scintigraphy 
4. Cardiac involvement as defined by BOTH 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  


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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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5. NT-proBNP ≥650 pg/mL and ≤5000 pg/mL (i.e., ≥76.7 pmol/L and ≤590 pmol/L) 
6. Received at least one prior systemic chemotherapeutic regimen, which may include stem cell 
transplant, for AL amyloidosis 
7. Achieved at least a partial hematologic response (per Appendix 1) to a first-line therapy 
resulting in a stable hematologic condition not currently requiring additional active treatment 
against the PCD component of their AL disease 
8. Adequate bone marrow reserve, hepatic and renal function, as demonstrated by:   
o Absolute neutrophil count (ANC) ≥1.0 x109/L 
o Platelet count ≥75 × 109/L 
o Hemoglobin ≥9 g/dL 
o Total bilirubin ≤2 × upper limit of normal (ULN) 
o Aspartate aminotransferase (AST) ≤3 × ULN  
o Alanine aminotransferase (ALT) ≤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. Systolic blood pressure (BP) 90-180 mmHg 
10. Distance walked during each of the two Screening 6MWTs is >100 meters and <600 meters   
11. Women of childbearing potential (WOCBP) must have 2 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 2) 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 2) from Screening to 90 days following the last study 
drug administration 
13. Ability to understand and willingness to sign an ICF prior to initiation of any study 
procedures 


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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
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4.2 
Exclusion Criteria 
Subjects must not meet any of the following criteria: 
1. Diagnosis of non-AL amyloidosis 
2. Meets the International Myeloma Working Group (IMWG) definition of Multiple Myeloma 
(Appendix 3) 
3. 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 
4. Myocardial infarction, uncontrolled angina, uncontrolled ventricular arrhythmias, or 
electrocardiographic evidence of acute ischemia, within 6 months prior to the Month 1-Day 1 
Visit 
5. Severe valvular stenosis (e.g. aortic or mitral stenosis with a valve area <1.0 cm2) or severe 
congenital heart disease 
6. ECG evidence of acute ischemia or active conduction system abnormalities with the 
exception of any of the following: 
o First degree atrioventricular (AV) block 
o Second degree AV block Type 1 (Mobitz Type 1/Wenckebach type) 
o Right or left bundle branch block 
o 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 
3 representative beats if Lead II is not representative of the overall ECG]) 
7. Has not recovered (i.e., equivalent to a CTCAE ≥Grade 2) from the clinically significant 
toxic effects of prior anticancer therapy. Exception: subjects with prior bortezomib treatment 
may have CTCAE Grade 2 neuropathy. 
8. Received any of the following within the specified time frame prior to the Month 1-Day 1 
Visit: 
o Oral or intravenous antibiotics, antifungals, or antivirals within 1 week, with the 
exception of prophylactic oral agents. Note:  In the event that a subject requires the 
chronic use of antivirals, Medical Monitor permission is required for  entry into the 
study. 
o Hematopoietic growth factors, transfusions of blood or blood products within 1 week 
o Chemotherapy, radiotherapy, or other plasma cell directed therapy within 6 months 
o ASCT within 12 months 


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Date:  22 October 2017 
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o Major surgery within 4 weeks 
o Planned major surgery or organ transplant during the study 
o Any other investigational agent within 4 weeks 
o Prior treatment with NEOD001, 11-1F4, anti-SAP antibody (exception: allowed as part 
of established diagnostic procedures such as SAP scintigraphy), or other investigational 
treatment directed at amyloid 
o Doxycycline within 6 weeks 
9. Active malignancy with the exception of any of the following: 
o Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical 
cancer 
o Adequately treated Stage I cancer from which the subject is currently in remission and 
has been in remission for ≥2 years 
o Low-risk prostate cancer with Gleason score <7 and prostate-specific antigen 
<10 mg/mL 
o Any other cancer from which the subject has been disease-free for ≥2 years 
10. History of Grade ≥3 infusion-related AEs or hypersensitivity to another monoclonal antibody 
11. History of severe allergy to any of the components of NEOD001 such as histidine/L-histidine 
hydrochloride monohydrate, trehalose dehydrate, or polysorbate 20 
12. Currently known uncontrolled bacterial, viral, fungal, HIV, hepatitis B, or hepatitis C 
infection 
13. Women who are breastfeeding 
14. 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 
15. Unable or unwilling to adhere to the study-specified procedures and restrictions 
16. Subject is under legal custodianship 
17. Waldenström's macroglobulinemia and/or immunoglobulin M (IgM) monoclonal 
gammopathy 


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Date:  22 October 2017 
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4.3 
Early Treatment Discontinuation 
If the subject discontinues study drug prior to the EOS Visit, they should return for an ETD Visit 
30 (±5) days after their final administration of study drug as per Section 6.2. 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 telephone after 2 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. 
If the subject discontinues study drug prior to the EOS, but is willing to continue to participate in 
study visits, the subject should have an ETD Visit 30 (±5) days after his/her final administration 
of study drug (per Section 6.2) and then have assessments monthly, through Month 12 per 
Appendix 13. The subject will not have an EOS Visit. The most important visit is the Month 12-
Day 1 Visit, so if a subject is unwilling to continue monthly visits, every effort should be made 
for the subject to return to the clinic and complete the Month 12-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. Following the Month 12-Day 1 Visit, subjects 
will be followed for vital status per Section 6.4. 
Reasons for early discontinuation from study drug treatment may include, but are not limited to: 
• Hematologic progression and initiation of chemotherapy is required; chemotherapy regimen 
should be documented on the appropriate electronic case report form (eCRF). 
• Need for organ transplant or major surgery. 
• 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 3 months after the ETD Visit, 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 
whose pregnancy test is positive at the ETD Visit must be followed to term or until 
termination of the pregnancy (Section 7.4.2). 
At any point in the study, if the subject is unwilling to return to the clinic for further visits but is 
willing to discuss their health status by phone, follow-up phone calls should be made to the 
subject or their caregiver every 3 months (Section 6.4). 


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4.4 
Early Termination from the Study 
Early termination occurs if the subject fails to complete the entire study, through the EOS Visit. 
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 or its designee should be 
notified in a timely manner of all subject discontinuations. When possible, the tests and 
evaluations listed for the ETD Visit should be carried out. 
Early termination from the study may occur if: 
• 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. 
4.5 
Replacement of Subjects 
Randomized subjects who drop out of the study for any reason will not be replaced. 
4.6 
Termination of the Clinical Study 
If the Investigator, the Sponsor or its designee, 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 


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• A decision by the Sponsor to suspend the study, or to suspend or discontinue development of 
the study drug, for any reason 


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5 
TREATMENT OF SUBJECTS 
5.1 
Study Drug 
Study drug consists of NEOD001 or placebo. 
5.1.1 
Formulation, Packaging, and Labeling of NEOD001 
The active study drug, NEOD001, is supplied as a sterile, 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.  
The labelling will comply with applicable regulatory requirements. 
5.1.2 
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 NEOD001 in a refrigerator at a temperature ranging 
from 2°C to 8°C in a secure, locked location. Access to the NEOD001 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 NEOD001 has not been properly handled (e.g., 
physical damage to carton/vial, temperature outside the 2°C to 8°C range in transit, or not stored 
at 2°C to 8°C in the clinic), follow the procedure outlined in the Pharmacy Manual or 
immediately contact the Unblinded Monitor (contact information available in the Study Manual). 
In such an event, NEOD001 should be quarantined in a 2°C 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 Section 5.3 and the Pharmacy Manual for further details about shipping, storage and 
handling of NEOD001. 
5.2 
Accountability and Return of Study 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. 


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5.3 
Dosage, Preparation, and Administration 
Study drug consists of 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 using the Screening 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 unless thought to be exclusively due to fluid 
fluctuation (e.g., edema). 
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. A separate 
placebo will not be provided for this study. Subjects who receive placebo will be administered a 
250 mL IV bag of 0.9% saline, which will look identical to the NEOD001 infusion bag. Refer to 
the Pharmacy Manual for complete information on preparing and administering the study drug.  
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 IWRS, and will then prepare and reconstitute the study drug, providing it 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.  
Study drug will be administered as an initial 120 (±10)-minute IV infusion on Month 1-Day 1. If, 
in the opinion of the Investigator, the subject tolerates the initial administration, subsequent 
infusions may be administered over 60 (±10) minutes once every 28 (±5) days; a minimum of 
21 days between doses is required. Subjects may receive up to 12 infusions of study drug.  
NEOD001 contains no antimicrobial preservatives. Once reconstituted, storage of study drug, 
inclusive of dilution and administration, should be limited to 24 hours under refrigerated conditions 
or 4 hours at room temperature. If it is anticipated that the infusion will extend beyond 4 hours, 
the reconstituted 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 30 mL of 0.9% Sodium Chloride Injection (USP) after 
administration of study drug. The infusion line should NOT be used for blood draws. 


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All subjects will be closely monitored for approximately 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. Beginning with the third infusion, the Investigator may 
decrease the monitoring time to no less than 60 minutes, if no infusion-related reactions were 
observed in the previous infusions and allowed per the Institutional Review Board/Institutional 
Ethics Committee (IRB/IEC). 
5.4 
Dosage Adjustments 
5.4.1 
Withholding of Study Drug 
Subjects with symptomatic orthostatic hypotension and/or systolic BP <85 mmHg, which in the 
medical judgment of the Investigator would interfere with subject’s ability to safely receive 
study drug, will have study drug withheld until the next scheduled monthly administration, but 
should still have all other study visit assessments completed. 
5.4.2 
Management of Suspected Systemic Infusion-Related/Hypersensitivity Adverse 
Events 
In the event of a suspected systemic infusion-related and/or hypersensitivity AE, the infusion 
should be immediately discontinued and appropriate supportive therapy should be administered 
per institutional practice, which may include, but is not limited to, 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 systemic infusion-related and/or hypersensitivity AE for assessment of the 
following: cytokine levels (IL-6, IL-8, TNF-alpha, and INF-gamma) complements C3, C4, and 
CH50; C-reactive protein (CRP), serum amyloid A/acute phase serum amyloid A (SAA/A-
SAA); tryptase (serial levels: within 30 to 120 minutes of onset AND at 48 to 72 hours); serum 
NEOD001; and anti-NEOD001 antibody levels. 
For subjects with a Grade 2 infusion-related AE, if it is appropriate to restart the infusion, the 
infusion rate should be decreased by 50% (e.g., if the infusion was previously administered over 
60 minutes, the new rate should be based on administering 250 mL over at least 90 minutes). If 
the subject is to receive additional infusions in subsequent weeks, the rate of these infusions 
should be discussed with and agreed upon prospectively by the Investigator and the Medical 
Monitor. In addition, for all subsequent infusions, 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). 


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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 
administration should be discussed with the Medical Monitor. If the decision is made to proceed 
with subsequent dosing, both the dose and infusion rate will be reduced by 50% from the 
original dose (i.e., 12.5 mg/kg in 250 mL) and infusion rate (i.e., over at least 90 minutes [if the 
previous infusion time was 60 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 6.2. 
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 6.2. 
5.4.3 
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. 
5.5 
Treatment Compliance 
Treatment compliance will be documented in the eCRF by recording the date, time, and whether 
or not each IV dose of study drug was completely infused, along with reasons why treatment was 
adjusted or not administered, if applicable. 
5.6 
Prior and Concomitant Medication/Therapy 
Prior and concomitant medications include any drug (investigational, prescription, or over-the-
counter) or biological product (such as vaccines, blood or blood components) including herbal 
remedies or preparations. All prior/concomitant medications taken or received by a subject 
within the 28 days prior to the Month 1-Day 1 Visit through the EOS/ETD Visit, and any 
changes to concomitant medications during the study will be recorded on the appropriate eCRF. 
5.6.1 
Allowed (Concomitant) 
• Radiation therapy for the treatment of local amyloid deposits 
• Calcium channel blockers (if on stable dose) 
• Steroids (exception: not allowed for treatment of AL amyloidosis) 
5.6.2 
Prohibited (Concomitant) 
• Chemotherapy 
• Other investigational agents (e.g., drugs not approved for any indication) 


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• Myeloablative chemotherapy with ASCT 
• Organ transplant 
• Histone deacetylase (HDAC) inhibitors 
• Doxycycline use (if required for treatment of infection, contact the Medical Monitor) 
• Gadolinium contrast agents are only permitted in exceptional circumstances. If a patient 
requires the use of gadolinium contrast agents, contact the Medical Monitor. 
• Experimental imaging of amyloid  


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6 
STUDY PROCEDURES 
6.1 
Evaluations by Visit 
6.1.1 
Screening 
With the exception of the assessments to be considered standard of care (e.g., NT-proBNP/BNP, 
tissue samples, and echocardiograms), a signed ICF must be obtained before any study-specific 
screening evaluations are performed and should be documented in the subject’s medical chart. 
Screening evaluations and procedures will be performed within 28 days prior to the first study 
drug administration on Month 1-Day 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.  
The following will be performed within the 28 days prior to the Month 1-Day 1 Visit: 
• Signed ICF 
• Review inclusion and exclusion criteria to assess eligibility 
• Medical History - 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 
• If available, record results of at least 2 prior NT-proBNP or 2 prior BNP measures from 
within the previous 6 months; NT-proBNP is preferred, but BNP may be used if it is the 
institution’s historical standard 
• Prior and concomitant medications/therapy 
• Assessment of AEs 
• Confirmation of AL amyloidosis by mass spectrometry tissue typing, immunoelectron 
microscopy, gene sequencing, and/or 99mTc scintigraphy for subjects who meet Inclusion 
Criterion #3 
• Complete physical examination - including height, 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). 
• Vital signs – heart rate (HR), BP, respiratory rate (RR), and body temperature after the 
subject has been at rest for ≥5 minutes 
• ECOG PS (Appendix 7) 


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• NYHA class (Appendix 8) 
• NIS-LL (Appendix 5 and Section 6.6.2.5) and VASPI (Appendix 6 and Section 6.6.2.5) 
o Note: NIS-LL is for all subjects with peripheral neuropathy at Screening and the addition 
of the VASPI is only for subjects with painful peripheral neuropathy at Screening 
• SF-36v2 (Appendix 9) 
o Note: Administer SF-36v2 before conducting any other assessments on the same calendar 
day it is administered 
• KCCQ (Appendix 10)  
o Note: Administer KCCQ after the SF-36v2, but before conducting any other assessments 
on the same calendar day it is administered 
• 6MWT (Section 6.6.2.3); collect HR and BP pre- and post-6MWT administration 
o Notes: Two pretreatment 6MWTs are required before the first administration of study 
drug, with a minimum of 4 days in between the two tests. 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). NT-proBNP should be drawn before conducting 6MWT if 
being performed on the same calendar day. 
• Echocardiogram (perform locally) 
o Note: If an echocardiogram was conducted within 90 days prior to Screening Day -28, it 
does not need to be repeated during Screening and the previous result may be used for 
eligibility; however, to be eligible for the additional cardiac imaging analysis, the 
subject must have had a 4-chamber view, 2-dimensional echocardiogram with Doppler 
• 12-lead ECG performed in triplicate (perform centrally) 
• Laboratory Assessments (central laboratory, unless otherwise noted): 
o Hematology and chemistry (including amylase and creatine kinase) per Appendix 11  
o PT/INR and PTT 
o Additional coagulation samples per Appendix 12 
o Troponin T 
o NT-proBNP 


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 Note: NT-proBNP should be drawn before 6MWT if being performed on the same 
calendar day 
o Serum pregnancy test for WOCBP within 28 days before Month 1-Day 1 study drug 
administration 
 Note: Women with tubal ligations are considered to be of childbearing potential but 
women who are surgically sterile (hysterectomy) or postmenopausal ≥2 years are not 
considered to be of childbearing potential 
o Serum free light chains 
o Serum immunofixation electrophoresis (IFE) and protein electrophoresis (PEP) 
o Urinalysis - dipstick per Appendix 11  
o Urinalysis - quantitative analysis/renal biomarkers per Appendix 11  
 Notes: It is important that the sample be taken before exercising and at approximately 
the same time for each collection; therefore, the first morning void is recommended. 
Urine samples will be collected and frozen for potential analysis at a later date.  
o 24-hour urine collection for: 
 Urine IFE and PEP 
 Urine protein excretion 
• Other Assessments (see Laboratory Manual) 
o  Archive sample – collect only from those subjects who have consented to the collection 
and archiving of their samples for future correlative testing 
6.1.2 
Treatment Visits 
Study visits will occur every 28 days based on scheduling from Month 1-Day 1. A ±5-day 
window is allowed for visits starting after Month 1. Subjects may receive up to 12 infusions of 
study drug; a minimum of 21 days between doses is required. 
The predose assessments for each visit may be performed within the 3 days before the visit  
unless otherwise specified. Although central laboratory assessments will be performed each 
month for study analysis, local laboratory assessments may be performed for subject 
management when necessary for obtaining results on a more immediate basis. Results will be 
reviewed prior to dosing at each month’s Day 1 visit to confirm that continued dosing is 
appropriate.  


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Subjects who present with symptomatic orthostatic hypotension and/or systolic BP <85 mmHg, 
which in the medical judgment of the Investigator would interfere with the 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. If study drug is 
withheld and subsequently rescheduled, central laboratory assessments required for that visit will 
need to be repeated if they were drawn >7 days prior to the rescheduled dosing date. However, a 
symptom-directed physical exam and vital signs need to be repeated prior to each dosing.  
6.1.2.1 
Month 1-Day 1 
Prior to Study Drug Infusion: 
The following assessments will be done prior to dosing on Month 1-Day 1: 
• Concomitant medications/therapies 
• Assessment of AEs 
• Directed physical examination - including 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. The components of the physical exam 
will be as clinically indicated; however, 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).  
• Vital signs including HR, BP, RR, and body temperature (per Section 6.6.1.2) – within 
30 minutes before dosing, after subject has been at rest ≥5 minutes; assess in same position 
for all time points 
• ECOG PS (Appendix 7) 
• NYHA class (Appendix 8) 
• NIS-LL (Appendix 5) and VASPI (Appendix 6) 
o Note: NIS-LL is for all subjects with peripheral neuropathy at Screening and the addition 
of the VASPI is only for subjects with painful peripheral neuropathy at Screening 
• 12-lead ECG in triplicate (perform centrally) within 30 minutes before study drug 
administration 
• Laboratory Assessments (central laboratory, unless otherwise noted): 
o Hematology and chemistry (including amylase) per Appendix 11 
o Inflammatory biomarkers per Appendix 11  
o NT-proBNP 


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o Serum pregnancy test within 24 hours before study drug administration (local laboratory) 
o Urinalysis - dipstick per Appendix 11  
• Other Assessments (see Laboratory Manual) 
o NEOD001 serum sample – within 2 hours before infusion 
o Anti-NEOD001 serum sample 
• Randomization – After the subject is randomized, study drug treatment may be initiated  
• Ensure subject continues to meet eligibility criteria before administration of study drug 
Study Drug Administration: 
• Administer study drug IV over 120 (±10) minutes (Section 5.3) 
• Vital signs including HR, BP, RR, and body temperature (per Section 6.6.1.2) – assess 
60 (±10) minutes after the start of the infusion; assess in same position for all time points  
Assessments After Infusion: 
• Monitor subjects 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. 
• Vital signs including HR, BP, RR, and body temperature (per Section 6.6.1.2) after subject 
has been at rest ≥5 minutes; assess in same position for all time points: 
o At the end of infusion (EOI) (+5 minutes) 
o 30 (±5) minutes after EOI 
o 60 (±10) minutes after EOI 
• 12-lead ECG in triplicate (perform centrally): 
o Within 15 minutes after EOI 
• Other Assessments (see Laboratory Manual): 
o NEOD001 serum sample within 4 hours after EOI 


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o Collect additional blood samples if a significant toxicity is observed (e.g., a systemic 
infusion-related reaction, anaphylaxis, hypersensitivity reaction; Section 5.4.2) and if 
possible, samples should be collected while the acute symptoms persist 
• Discharge subject from clinic if no immediate safety concerns and/or hypersensitivities are 
present after the postdose assessments and monitoring period. In the event of any clinical 
concerns or suspicious signs or symptoms after the infusion, the subject will remain with the 
Investigator and study staff for further observation until the Investigator deems the subject 
can safely leave the clinic. 
6.1.2.2 
Months 2 through 12 – Day 1 (±5 Days) 
Prior to Study Drug Infusion: 
The following assessments will be done prior to dosing on Day 1: 
• Concomitant medications/therapies 
• Assessment of AEs 
• Directed physical examination - including 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. The components of the physical exam 
will be as clinically indicated; however, 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).  
• Vital signs including HR, BP, RR, and body temperature (per Section 6.6.1.2) – within 
30 minutes before dosing, after subject has been at rest ≥5 minutes; assess in same position 
for all time points 
• ECOG PS (Appendix 7) 
• NYHA class (Appendix 8) 
• NIS-LL (Appendix 5) and VASPI (Appendix 6) – Months 3, 6, 9, 12 
o Note: NIS-LL is for all subjects with peripheral neuropathy at Screening and the addition 
of the VASPI is only for subjects with painful peripheral neuropathy at Screening 
• SF-36v2 (Appendix 9) – Months 3, 6, 9, 12 
o Note: administer SF-36v2 before performing any other study assessments on the same 
calendar day it is administered 
• KCCQ (Appendix 10) – Months 3, 6, 9, 12 


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o Note: Administer after the SF-36v2, but prior to conducting any other assessments on the 
same calendar day it is administered 
• 6MWT (Section 6.6.2.3) and collect HR and BP pre- and post-6MWT administration – 
Months 3, 6, 9, 12 
o Notes: NT-proBNP should be drawn before conducting 6MWT if being performed on the 
same calendar day. If the 6MWT is conducted on the same calendar day as the study 
drug infusion, the 6MWT must be completed before initiation of the infusion 
• Echocardiogram (perform locally) – Month 12 only 
o Notes: May be conducted within 10 days before Day 1. To be eligible for the additional 
cardiac imaging analysis, the subject must have a 4-chamber view, 2-dimensional 
echocardiogram with Doppler. 
• 12-lead ECG in triplicate (perform centrally) – within 30 minutes before dosing – Months 3, 
6, 9, 12 
• Laboratory Assessments (central laboratory, unless otherwise noted): 
o Hematology and chemistry (including amylase and creatine kinase) per Appendix 11  
o PT/INR and PTT 
o Additional coagulation samples if clinically indicated, per Appendix 12 
o Inflammatory biomarkers per Appendix 11 – Month 3 
o Troponin T 
o NT-proBNP 
 Note: NT-proBNP should be drawn before conducting 6MWT if being performed on 
the same calendar day (i.e., at Months 3, 6, 9, 12) 
o Serum pregnancy test (WOCBP only; local laboratory) 
o Serum free light chain – Months 3, 6, 9, 12 
o Serum IFE and PEP – Months 3, 6, 9, 12 
o Urinalysis - dipstick per Appendix 11 – Months 3, 6, 9, 12 
o Urinalysis - quantitative analysis/renal biomarkers per Appendix 11 – Months 3, 6, 9, 12 


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 Notes: It is important that the sample be taken before exercising and at approximately 
the same time for each collection; therefore, the first morning void is recommended. 
Urine samples will be collected and frozen for potential analysis at a later date. 
o 24-hour urine collection at Months 3, 6, 9, 12 for: 
 Urine IFE and PEP 
 Urine protein excretion 
• Other Assessments (see Laboratory Manual): 
o NEOD001 serum sample – within 2 hours before infusion – Months 3, 6, 9, 12 
o Anti-NEOD001 serum sample – Months 3, 6, 9, 12 
o Archive sample – Months 6 and 12 
Study Drug Administration: 
Subjects with symptomatic orthostatic hypotension and/or systolic BP <85 mmHg, which in the 
medical judgment of the Investigator would interfere with subject’s ability to safely receive 
treatment, will have study drug withheld.  
• Administer study drug IV over 60 (±10) minutes if the prior infusions were well tolerated 
(Section 5.3). If needed, see Section 5.4 for dose adjustment instructions. 
• Collect additional blood samples per Section 5.4.2 if a significant toxicity is observed  
(e.g., a suspected systemic infusion-related reaction, anaphylaxis, hypersensitivity reaction) 
and if possible, samples should be collected while the acute symptoms persist 
Assessments After Infusion: 
• Monitor subjects 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. Beginning with the third infusion, the Investigator may decrease the 
monitoring time to no less than 60 minutes, if no infusion-related reactions were observed in 
the previous infusions and allowed per the IRB/IEC. 
• Vital signs including HR, BP, RR, and body temperature (per Section 6.6.1.2) – after subject 
has been at rest ≥5 minutes; assess in same position for all time points: 
o At EOI (+5 minutes) 
o 60 (±10) minutes after EOI 


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• 12-lead ECG in triplicate (perform centrally) – Months 3, 6, 9, 12: 
o Within 15 minutes after EOI 
• NEOD001 serum sample – Months 3, 6, 9, 12: 
o Within 4 hours after EOI 
• Discharge subject from clinic if no immediate safety concerns and/or hypersensitivities are 
present after the postdose assessments and monitoring period. In the event of any clinical 
concerns or suspicious signs or symptoms after the infusion, the subject will remain with the 
Investigator and study staff for further observation until the Investigator deems the subject 
can safely leave the clinic. 
6.2 
End of Study/Early Treatment Discontinuation (EOS/ETD):  30 (±5) Days 
AFTER Final Dose 
A final visit should occur 30 (±5) days after the final administration of study drug. The 
assessments shown for EOS/ETD should also be conducted for any unscheduled visit (i.e., a visit 
not specified by the protocol) as clinically indicated or if deemed necessary. 
• Concomitant medications/therapy 
• Assessment of AEs 
• Complete physical examination - 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). 
• Vital signs including HR, BP, RR, and body temperature (per Section 6.6.1.2) - after subject 
has been at rest ≥5 minutes 
• ECOG PS (Appendix 7) 
• NYHA class (Appendix 8) 
• NIS-LL (Appendix 5) and VASPI (Appendix 6) 
o Note: NIS-LL is for all subjects with peripheral neuropathy at Screening and the addition 
of the VASPI is only for subjects with painful peripheral neuropathy at Screening 
• SF-36v2 (Appendix 9) 
o Note: Administer SF-36v2 before conducting any other assessments on the same calendar 
day it is administered 


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• KCCQ (Appendix 10)  
o  Note: Administer after the SF-36v2, but prior to conducting any other assessments on the 
same calendar day it is administered 
• 6MWT (Section 6.6.2.3); collect HR and BP pre- and post-6MWT administration  
o  Note: NT-proBNP should be drawn before conducting 6MWT if being performed on the 
same calendar day 
• Echocardiogram – perform (locally) if not done within 60 days prior to visit 
o  Note: To be eligible for the additional cardiac imaging analysis, the subject must have a 
4-chamber view, 2-dimensional echocardiogram with Doppler 
• 12-lead ECG performed in triplicate (perform centrally) 
• Laboratory Assessments (central laboratory, unless otherwise noted): 
o Hematology and  chemistry (including amylase and creatine kinase) per Appendix 11 
o PT/INR and PTT 
o Additional coagulation samples per Appendix 12 
o Inflammatory biomarkers per Appendix 11  
o Troponin T 
o NT-proBNP 
 Note: NT-proBNP should be drawn before conducting 6MWT if being performed on 
the same calendar day 
o Serum pregnancy test (WOCBP only) 
o Serum free light chains 
o Serum IFE and PEP 
o Urinalysis - dipstick per Appendix 11 
o 24-hour urine collection for: 
 Urine IFE and PEP 
 Urine protein excretion 
• Other Assessments (see Laboratory Manual): 


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o NEOD001 serum sample 
o Anti-NEOD001 serum sample 
6.3 
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. 
6.4 
Vital Status Follow-Up Phone Call 
For randomized subjects who received at least 1 dose of study drug, conduct vital status 
telephone call approximately 3 months after last visit and approximately every 3 months 
thereafter or until subject enrolls in a separate open-label study, death, or for up to 5 years. 
6.5 
Order of Assessments of Specific Tests 
SF-36v2: 
Whenever the SF-36v2 is required, it should be administered prior to any other visit assessments 
on the calendar day it is administered. 
KCCQ: 
Administer the KCCQ after the SF-36v2, but prior to conducting any other assessments on the 
calendar day it is administered. 
6MWT: 
Questionnaires and clinical laboratory samples, including NT-proBNP, should be drawn prior to 
administering the 6MWT, if being performed on the same calendar day. The postbaseline 
6MWTs must be completed before the study drug infusion is initiated, if being performed on the 
same calendar day. 
ECGs and Vitals: 
When ECGs are scheduled to be performed at the same time point as vital signs (e.g., within 
30 minutes before dosing), the ECG should be completed before the blood pressure and HR 
measurements.  
ECGs and PK Sampling: 
When ECGs are scheduled to be performed at the same visit as PK blood collection, the ECG 
should be done before the PK blood collection. 
Concomitant Medications: 
Routine medications should not be administered in the 15 minutes after the completion of the 
NEOD001 infusion. 


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6.6 
Methods of Assessment 
6.6.1 
Safety 
6.6.1.1 
Clinical Laboratory Evaluations 
A central laboratory will be used for this study for analysis of hematology, chemistry (including 
amylase), coagulation, inflammatory biomarkers, cardiac biomarkers, serum free light chains, 
serum IFE/PEP, urinalyses, 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 may be obtained at the Investigator’s discretion for subject management 
when necessary for obtaining results on a more immediate basis. Results will be reviewed prior 
to dosing at each month’s Day 1 visit to confirm that continued dosing is appropriate. Results 
from local laboratory tests will not be collected in the eCRFs or the clinical database. 
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 
Appendix 12. 
Urine samples will be collected and frozen for potential analysis of renal biomarkers at a later 
date (see Appendix 11). It is important that the sample be taken before exercising and at 
approximately the same time for each collection; therefore, the first morning void is 
recommended. 
The 24-hour urine IFE/PEP and 24-hour urine protein excretion 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 will be provided in the Laboratory Manual. 
A bioanalytical laboratory will be used for the analysis of NEOD001 and anti-NEOD001 
samples, as well as for the storage of serum samples for future correlative testing (Sections 6.6.3 
and 6.6.4). 
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 subjects who 
meet Inclusion Criterion #3.   
Details for the processing of laboratory specimens will be provided in the Laboratory Manual. 
6.6.1.2 
Vital Signs 
Predose vital signs should be assessed within 30 minutes before dosing. Vital signs should be 
measured after the subject has been at rest ≥5 minutes. Within a single visit, assess in the same 
position for all time points. 
Heart rate will be measured from the radial pulse counted manually or with an automatic BP 
monitor over at least 15 seconds and adjusted per minute.  
Blood pressure (systolic and diastolic) measurements should be taken from the same arm 
throughout the study using an automated BP monitor that uses an oscillometric method.  


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Respiratory rate will be measured over at least 15 seconds and adjusted per minute. 
Body temperature can be measured using either oral or tympanic methods, but the method should 
be consistent throughout the study for a given subject. 
Blood pressure and HR are to be collected after ECGs are completed. 
As part of the 6MWT, BP and HR will be collected pre- and post-6MWT administration. 
6.6.1.3 
Physical Examination 
Any unfavorable changes in physical examination findings considered by the Investigator as 
clinically significant will be documented in the eCRF as an AE. Physical examinations must be 
performed by the Investigator or a medically qualified delegate. 
A complete physical examination 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. A directed physical 
examination includes weight and other components, which will be as clinically indicated. At all 
visits, the following are to 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). 
6.6.1.4 
Echocardiograms 
Echocardiograms will be performed locally. Data from study centers that possess the technical 
abilities to produce a 4-chamber view from a 2-dimensional echocardiogram with Doppler will 
be used for the relevant exploratory endpoint analysis. Details will be provided in the Study 
Manual. Note that the Month 12 echocardiogram may be performed within 10 days before 
Day 1. 
6.6.1.5 
12-Lead ECGs 
The ECGs will be performed centrally. Measurements will be made in triplicate, 1 to 10 minutes 
apart and taken after the subject has rested in a supine position for ≥5 minutes. Heart rate, PQ/PR 
duration, QRS duration, QT duration, and QTcF - Fridericia's correction formula, and the 
Investigator’s overall interpretation will be recorded. When ECGs are scheduled to be performed 
at the same visit as PK blood collection, the ECG should be done before the PK blood collection. 
6.6.2 
Efficacy 
6.6.2.1 
Organ Response (i.e., cardiac, renal, peripheral nerve) 
See Appendix 4. 
6.6.2.2 
Short Form-36v2® Health Survey (SF-36v2) 
The SF-36v2 should be administered before any other study assessments are performed on the 
same calendar day it is administered. See Appendix 9. Details will be provided separately. 


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6.6.2.3 
6-Minute Walk Test (6MWT) 
The postbaseline 6MWTs may be administered on the same calendar day that study drug is 
administered, if the 6MWT is completed before initiation of the study drug infusion. The 
questionnaires and clinical laboratory samples (central and if applicable, local) should be drawn 
prior to administering the 6MWT, if being performed on the same calendar day. As part of the 
6MWT, BP and HR will be collected pre- and post-6MWT administration. Subjects should plan 
to be able to return to the same clinical site for each 6MWT from first Screening through Month 
12. 
If the subject discontinues study drug prior to the Month 12 Visit, every effort should be made 
for the subject to return to the clinic at the Month 12 time point for completion of all of the 
Month 12-Day 1 assessments, in particular, the 6MWT. 
Details regarding the requirements for proper administration of the 6MWT are described in the 
Study Manual.  
6.6.2.4 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
The KCCQ (Appendix 10) should be administered after the SF-36v2, but prior to conducting any 
other assessments on the same calendar day it is administered. Details will be provided in the 
Study Manual. 
6.6.2.5 
Peripheral Neuropathy Assessment 
Peripheral neuropathy will be assessed as follows: 
• The Neuropathy Impairment Score in Lower Limbs (NIS-LL; Appendix 5) assesses lower 
limb reflexes, sensation, and motor strength and will be administered to subjects who have 
peripheral neuropathy at Screening 
• The Visual Analog Scale – Pain Intensity (VASPI; sample tool in Appendix 6) assesses a 
subject’s level of pain related to peripheral neuropathy and will be administered to subjects 
who have painful peripheral neuropathy at Screening. Details regarding administration of the 
VASPI are described in the Study Manual.  
Peripheral neuropathy and neuropathic pain AEs will be assessed using NCI-CTCAE grading, as 
shown in Table 2. 


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Table 2 
Common Terminology Criteria for Adverse Events (CTCAE) Grade 1-5 for 
Peripheral Neuropathy and Neuropathic Pain 
 
CTCAE 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 
neuropathya 
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 
 
 
Abbreviations: ADL = activities of daily living (e.g., preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc.). 
a 
Definition: a disorder characterized by inflammation or degeneration of the peripheral sensory nerves. 
Source: National Cancer Institute, 2009. 
 
6.6.3 
Pharmacokinetics 
All subjects enrolled in the study will undergo sparse sampling for serum NEOD001 according 
to Table 1 and the Laboratory Manual. Additional samples should be collected if a significant 
toxicity is observed (per Section 5.4.2). Serum NEOD001 concentrations from this study will be 
pooled with similar samples from other studies in a population PK analysis. Details will be 
provided in a separate document. Refer to the Laboratory Manual for additional details. 
6.6.4 
Immunogenicity 
Serum ADA levels will be measured according to Table 1 and the Laboratory Manual. 
Additional samples should be collected if a significant toxicity is observed (per Section 5.4.2). 
ADA levels will be correlated with serum NEOD001 concentrations when ADA and 
corresponding serum NEOD001 concentrations are available.  
An electrochemiluminescent (ECL) assay will be used to detect serum anti-NEOD001 
antibodies. Any screening positives will be run at increasing dilutions and a titer determined 
(expressed as the reciprocal of the dilution that generates a positive response). Additionally, all 
positives will be run in a confirmatory assay to determine the response is specific to NEOD001. 
Refer to the Laboratory Manual for additional details. 


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7 
ADVERSE EVENTS/SERIOUS ADVERSE EVENTS AND REPORTING 
7.1 
Adverse Events—Definition 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. An AE can, therefore, be any unfavorable and unintended sign 
(including a laboratory finding, for example), symptom, syndrome, or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. Examples include: 
• Any treatment-emergent signs and symptoms (events that are marked by a change from the 
subject’s baseline/entry status [e.g., an increase in severity or frequency of preexisting 
abnormality or disorder]) 
• All reactions from study drug, abuse of drug, withdrawal phenomena, sensitivity, or toxicity 
to study drug 
• Apparently unrelated illnesses 
• Injury or accidents 
• Exacerbations of the underlying disease (indication) 
• Extensions or exacerbations or symptomatology, subjective events reported by the subject, 
new clinically significant abnormalities in clinical laboratory, physiological testing, or 
physical examination 
The reporting period for AEs is from the time that the ICF is signed through the last study visit 
or through 30 days after the last dose of study drug, whichever is later. All AEs, whether or not 
related to the study drug, must be fully and completely documented on the eCRF and in the 
subject’s medical notes. The following attributes must be assigned:  description, dates of onset 
and resolution, severity, assessment of relatedness to study drug (either related or not related), 
and action taken. The Investigator may be asked to provide additional follow-up information. 
In the event that a subject is withdrawn from the study because of an AE, it must be recorded on 
the eCRF. The subject should be followed and treated by the Investigator until the AE has 
resolved, stabilized, or a new chronic baseline has been established. 
The Investigator must report all AEs. At each visit the Investigator will ask the subject a 
nonspecific question (e.g., “Have you noticed anything different since your last visit?”) to assess 
whether any AEs have been experienced since the last report or visit. Adverse events will be 
identified and documented on the eCRF in appropriate medical terminology. The severity and the 
relationship to the study drug will be determined and reported on the eCRF (Sections 7.2 and 
7.3). 
Note that any intermittent or as-needed (“PRN”) use of medication (and specifically any newly 
prescribed medication) during the course of a study may indicate the occurrence of an AE that 
may need to be recorded on more than one eCRF. 


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7.2 
Adverse Events—Severity Rating 
Adverse events will be assessed according to CTCAE version 4.0 (National Cancer Institute, 
2009). Adverse events that do not have a corresponding 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): Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Grade 2 (moderate): Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activity of daily living (e.g., preparing meals, shopping 
for groceries or clothes, using the telephone, managing money). 
• Grade 3 (severe): Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living (e.g., bathing, dressing and undressing, feeding self, using the toilet, 
taking medications, and not bedridden). 
• Grade 4 (life threatening): Life-threatening consequences; urgent intervention indicated. 
• Grade 5 (fatal): Death related to AE. 
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. 
7.3 
Adverse Events—Causality Rating 
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). 
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. 


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• 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 
• Known effects of concomitant medications 
• Preexisting risk factors 
• A plausible mechanism 
• Concurrent illnesses 
7.4 
Serious Adverse Events and Unexpected Adverse Events 
In addition to the severity rating, each AE is to be classified by the Investigator as “serious” or 
“not serious.”  The seriousness of an event is defined according to the applicable regulations and 
generally refers to the outcome of an event. An SAE is one that meets one or more of the 
following: 
• Is fatal 
• Is life-threatening 


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• Is persistent or significantly incapacitating or causes substantial disruption of the ability to 
conduct normal life functions 
• Requires inpatient hospitalization 
• Prolongs existing hospitalization 
• Is a congenital anomaly or birth defect  
• Is an important medical event that may jeopardize the subject and/or may require medical or 
surgical intervention to prevent one of the outcomes listed above 
Definition of Life-threatening 
An adverse event or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the Investigator or Sponsor (and/or designee), its occurrence places the subject at 
immediate risk of death. It does not include an adverse event or suspected adverse reaction that, 
had it occurred in a more severe form, might have caused death. 
Definition of 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: 
• Emergency room visits that last for a period of <24 hours and do not result in a full hospital 
admission  
• Outpatient surgery 
• Preplanned or elective procedures (Section 7.4.1) 
• Protocol procedures 
The above events would not be reported as SAEs unless the event triggering the hospital visit is 
an SAE as defined by other SAE criteria such as life-threatening, results in persistent or 
significant disability/incapacity or as per medical judgment of the Investigator. 
Any other event fulfilling the definition of serious that develops as a result of the in-hospital 
procedure or extends the hospital stay is an SAE. 
Definition of Disability 
Disability is defined as a persistent or significant incapacity or substantial disruption of the 
ability to conduct normal life functions. 


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Definition of Medically Significant 
Important medical events (medically significant events) that may not result in death, be life-
threatening or require hospitalization may be considered to be 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 this definition. Examples of such 
events are a new diagnosis of cancer, intensive treatment in an emergency room or at home for 
allergic bronchospasm, or convulsions that do not result in hospitalization, or 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. 
Definition of Suspected Adverse Reactions 
Suspected adverse reaction is considered any AE for which there is a reasonable possibility that 
the drug caused the AE. 
Definition of Unexpected 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Investigator Brochure or is not listed at the specificity or severity that has been observed. 
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the Investigator Brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned 
as occurring with the particular drug under investigation. 
7.4.1 
Elective Procedures and Surgeries 
For the purposes of this protocol, the following conventions will apply for SAE reporting of 
elective procedures, and surgeries: 
• A prescheduled 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: 
o The condition requiring the prescheduled 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 
o The prescheduled elective procedure or routinely scheduled treatment is the sole reason 
for admission and intervention 
• An untoward medical event occurring during the prescheduled elective procedure or 
routinely scheduled treatment should be recorded as an AE or a SAE. Any concurrent 
medications should also be recorded on the eCRF. 


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7.4.2 
Other Reportable Information 
In addition, and for the purposes of monitoring, any occurrence of exposure through lactation 
and any pregnancy (with or without an AE) of a female subject or partner of a male subject 
should be reported, regardless of seriousness, according to the directions in Section 7.4.4. Any 
subject who becomes pregnant during the study must be withdrawn from study drug treatment, 
and will be followed to term. 
7.4.3 
Disease Progression and Death 
Disease progression (including progression of hematologic condition and/or organ dysfunction of 
AL amyloidosis, and death due to disease progression) is generally recorded as part of the 
efficacy evaluation and should not be reported as a specific AE or SAE term. When an AE 
resulting from disease progression meets the requirements to be considered serious, the SAE 
verbatim term should be reported as the diagnosis that best describes the event rather than as 
“disease progression.”  For instance, a subject with pleural effusion presents with shortness of 
breath. The cause of the shortness of breath is a pleural effusion resulting from disease 
progression. The event term may be reported as “pleural effusion” instead of disease progression.  
Death should not be reported as an SAE term, but as a clinical outcome of a specific SAE. The 
cause of death, reported on a source document such as the Death Certificate or autopsy report, 
should be used as the event term for the SAE. For example, in a subject with acute heart failure 
that results in death, the SAE is reported as “acute heart failure” with an outcome of “death.”   
7.4.4 
Serious Adverse Events—Reporting 
It is the responsibility of the Investigator to report SAEs to the Sponsor or its designee within 
24 hours of awareness of the event or safety information, whether initial or follow-up. 
All SAEs must be reported immediately (within 24 hours of awareness) to the Sponsor or its 
designee (see Study Manual for details). Do not delay in the reporting of a suspected SAE in 
order to obtain additional information. Any additional information, if collected, can be reported 
to the Sponsor or its designee as a follow-up to the initial report. SAEs will be reported using the 
SAE forms provided as part of the Study Manual. Please remember to give details of the subject 
identification number or other appropriate terminology and ensure the narrative is 
comprehensive and includes a chronology and assessment of the event. 
Reporting of SAEs to the IRB/IEC will be done in compliance with the standard operating 
procedures and policies of the IRB/IEC and with applicable regulatory requirements. Adequate 
information must be obtained by the Sponsor or its designee showing that the IRB/IEC was 
properly and promptly notified as required. Please refer to the Study Manual for details on 
reporting SAEs. 
The Investigator is encouraged to discuss any AEs with the Sponsor Medical Monitor for which 
the issue of seriousness is unclear or questioned. Contact information for the Medical Monitor is 
listed on the Team Roster in the Study Manual. 


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The reporting period for SAEs is the period from signing of the ICF through 30 days after the 
last administration of study drug or last study visit, whichever is later. SAEs reported to the 
Investigator outside of this reporting period will be reported to the Sponsor or its designee only 
if, in the judgment of the Investigator, there is “a reasonable possibility” that the event may have 
been caused by the product.  
All SAEs will continue to be followed until the end of the study or until such events have 
resolved or the Investigator, in conjunction with the Sponsor or its designee, deems them to be 
chronic or stable. 


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8 
STATISTICAL METHODS AND CONSIDERATIONS 
A statistical analysis plan, providing details about the specific planned analyses and hypothesis 
tests, will be prepared and approved by the Sponsor prior to study database lock and unblinding 
of double blind subject treatment assignments.  
Endpoints are listed in Section 3.2. 
8.1 
Analysis Populations 
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.  
The Safety Population will include all subjects who receive 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. 
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 one 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 due to AL 
amyloidosis etiologies answered as yes) and had a baseline Neuropathy Impairment Score–
Lower Limbs (NIS-LL) total score of 2 or greater and at least one postbaseline NIS-LL total 
score. 
The Hepatic Evaluable Population will include subjects who had hepatic involvement defined as 
>1.5 × ULN alkaline phosphatase at baseline and at least one postbaseline assessment of alkaline 
phosphatase. 
8.2 
Analysis of Study Population and Subject Characteristics 
Enrollment, important protocol deviations, and discontinuations from the study will be 
summarized. 
Demographic and baseline characteristics, such as age, sex, race, and weight at Screening will be 
summarized using means, standard deviations, medians, ranges for continuous variables, and 
proportions for categorical variables.  
Study drug administration data will be listed and any dose modifications will be flagged. Study 
drug exposure will be summarized using total number of infusions received, percentage of 
expected infusions, total dose interruptions and reductions, and dose strength. 


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8.3 
Analysis of Efficacy Endpoints 
8.3.1 
Primary Efficacy Analysis 
The NT-proBNP best response rates in the two arms will be compared using the Cochran-
Mantel-Haenszel (CMH) test at the alpha=0.05 (two-sided) level of significance. The analysis 
will be stratified by the randomization stratification factors. 
8.3.2 
Key Secondary Efficacy Analyses 
NEOD001 and placebo will be compared on change from baseline in the SF-36v2 PCS score 
after 12 months of treatment 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. 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 EOS Visit to evaluate 12 months of treatment. 
The NEOD001 and placebo distributions of change from baseline in 6MWT distance (meters) 
after 12 months of treatment will be analyzed using a van Elteren test with stratification by 
randomization strata. 
The analysis of NT-proBNP will be performed using a general linear mixed effects model to 
compare the rate of change (i.e., slope) of NT-proBNP over 12 months of treatment between 
treatment groups. 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.  
For the primary and 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 in a 
sequential closed testing gate-keeping procedure separately, 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 
2. Placebo and NEOD001 will be compared with respect to change from baseline to 12 months 
of treatment in the SF-36v2 PCS score. 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 12 months 
of treatment in the 6MWT distance (meters). If the comparison achieves statistical 
significance at the 2-sided 0.05 level in favor of NEOD001, then 


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4. Placebo and NEOD001 NT-proBNP slopes over 12 months of treatment will be compared. 
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. 
8.3.3 
Additional Secondary Efficacy Analyses  
For the Renal Evaluable Population, renal best response will be analyzed in the same manner 
described for the primary efficacy endpoint. 
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.  
For the Hepatic Evaluable Population, hepatic best response will be analyzed in the same manner 
described for the primary efficacy endpoint. 
8.3.4 
Exploratory Efficacy Analyses 
All exploratory quantitative endpoints, except the 6MWT, defined as the change and percent 
change from baseline will be analyzed in the same manner described for the SF-36v2. 
Exploratory 6MWT endpoints will be analyzed in the same manner described for the key 6MWT 
secondary endpoint.  
Proportion endpoints will be analyzed in the same manner described for the primary efficacy 
endpoint. 
Overall survival and other time-to-event endpoints will be analyzed in the same manner 
described for progression-free survival. 
8.4 
Analysis of Safety Endpoints 
Safety will be assessed through summaries of AEs, changes in laboratory test results, and 
changes in vital signs. Additional safety assessments include 12-lead ECGs. Safety data will be 
summarized by treatment group using the Safety Population. 
All collected AE data will be listed by study site, subject number, and visit. All AEs occurring on 
or after treatment on Day 1 will be summarized. TEAEs are defined as AEs or SAEs that occur 
from the initiation of the first study drug infusion through the 30-day period following the last 
dose of study drug. In addition, all SAEs, including deaths, will be listed and summarized 
separately.  
Descriptive statistics of the quantitative laboratory results, vital signs, and ECG parameters will 
be presented by treatment group and study visit, as well as the change from baseline at each visit.  
The baseline value is defined as the last non-missing value before the initial administration of 
study drug.  


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8.5 
Analysis of Other Endpoints 
8.5.1 
Pharmacokinetics 
Serum NEOD001 concentrations from this study will be pooled with similar samples from other 
studies in a population PK analysis. Details will be provided in a separate document. 
8.5.2 
Immunogenicity 
Serum anti-NEOD001 titers will be listed and correlated with clinical toxicity and serum 
NEOD001 concentrations (where available). 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. 
8.6 
Determination of Sample Size 
For the primary endpoint, the assumed true rates for NEOD001 vs placebo are 50% and 22.5%, 
respectively. Based on a two-sample comparison of proportions at the alpha=0.05 level of 
significance, a total sample size of 100 subjects (50 in the NEOD001 arm, 50 in the placebo arm) 
will provide >80% power based on a two-sided CMH test. Based on the actual enrolled sample 
size (N~130), the final power is 91%. 
8.7 
Handling of Dropouts and Missing Data 
Observed data will be included in listings and summary tables. Handling of missing data will be 
outlined in the Statistical Analysis Plan. 


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9 
DATA RECORDING, RETENTION, AND MONITORING 
9.1 
Case Report Forms 
The clinical site(s) participating in this study is (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 the system. 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 its designee (or via other data collection methods, e.g., electronic laboratory data 
transfer). The Investigator is responsible for reviewing all eCRFs, 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. 
9.2 
Availability and Retention of Records 
The Investigator must make study data accessible to the study monitor, other authorized 
representatives of the Sponsor, and Regulatory Authority inspectors upon request. A file for each 
subject must be maintained at the clinical site that includes the signed 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 medications 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. 
9.3 
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. 


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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. 
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 International Committee on Harmonisation (ICH) Good Clinical Practice 
(GCP) and the Sponsor’s (or its 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. 
9.4 
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 date of birth or age, sex, and study-specific site and subject 
numbers. 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/IEC 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. 


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10 
ETHICAL AND LEGAL ISSUES 
10.1 
Ethical Conduct of the Study 
This study will be conducted in compliance with the current ICH E6 GCP, the ethical principles 
of the Declaration of Helsinki, current FDA GCP guidelines, and any additional national or 
IRB/IEC or competent authority-required procedures, whichever represents the greater protection 
for the individual. 
10.2 
Regulatory Approval 
The Sponsor or its 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 until the required regulatory approvals 
have been obtained in the appropriate jurisdiction. 
10.3 
Ethics Committee Approval 
The Investigator at the site is responsible for obtaining IRB/IEC approval for the final protocol, 
the Sponsor-approved ICF, and any materials used to recruit subjects. Written approval of these 
documents must be obtained from the IRB/IEC before any subject is enrolled at a site. 
The Investigator is also responsible for the following interactions with the IRB/IEC: 
• Obtaining IRB/IEC approval for any protocol amendments and ICF revisions before 
implementing the changes 
• Providing the IRB/IEC with any required information before or during the study 
• Submitting progress reports to the IRB/IEC, as required, during the conduct of the study; 
requesting re-review and approval of the study, as needed; providing copies of all IRB/IEC 
re-approvals and relevant communication to the Sponsor or its designee 
• Notifying the IRB/IEC of all serious and unexpected AEs related to the study medication 
reported by the Sponsor or its designee, as required by local regulations 
10.4 
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/IEC for approval. An 
IRB/IEC-approved copy of the ICF and all amendments will be forwarded to the Sponsor. 
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 personally sign and date the 
ICF before any study-related procedures are performed. The original and any 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 given to the subject. 


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10.5 
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. 
10.6 
Protocol Amendments and Study Termination 
Protocol amendments and amendment to the Informed Consent must be made only with the prior 
approval of the Sponsor and/or its designee. The IRB/IEC must be informed of all amendments 
and give approval for any amendments likely to affect the safety of the subjects or the conduct of 
the trial. The Investigator must send a copy of the approval letter from the IRB/IEC to the 
Sponsor and/or designee. 
Both the Sponsor and the Investigator reserve the right to terminate the study (Section 4.6), 
according to the study contract. The Investigator should notify the IRB/IEC in writing of the 
trial’s completion or early termination and send a copy of the notification to the Sponsor 
and/or designee. 
10.7 
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 are delineated in the Clinical Study Agreement. 
10.8 
Publication Policy 
All publication rights are delineated in the Clinical Study Agreement. 


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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. 
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, 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. 
Clinical Trial Facilitation Group. 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 
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. 
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, Litchy WJ, Lehman KA, et al. Variables influencing neuropathic endpoints: the 
Rochester Diabetic Neuropathy Study of Healthy Subjects. Neurology. 1995;45(6):1115-21. 
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. 
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 I/II study of NEOD001 in 
patients with light chain amyloidosis and persistent organ dysfunction. J Clin Oncol. 
2016(10):1097-103. 


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Kaufman GP, Dispenzieri A, Gertz MA, et al. Kinetics of organ response and survival following 
normalization of the serum free light chain ratio in AL amyloidosis. Am J Hematol. 
2015;90(3):181-6. 
Kyle RA, Linos A, Beard CM, et al. Incidence and natural history of primary systemic 
amyloidosis in Olmsted County, Minnesota, 1950 through 1989. Blood. 1992;79(7):1817-22. 
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. 28 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. 
Pimm MV, Gribben SJ. Toxicity associated with the formation and clearance of immune 
complexes between antitumour monoclonal antibodies and syngeneic anti-idiotypic antibodies in 
mice. J Cancer Res Clin Oncol. 1992;119(1):41-5. 
Pinney JH, Smith CJ, Taube JB, 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. 


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12 
APPENDICES 


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Appendix 1 
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) 
Abbreviations:  dFLC = difference between involved and uninvolved free light chains. 
*Only applicable for subjects who had dFLC >50 mg/L (5 mg/dL) prior to treatment. 
Source: Comenzo et al, 2012. 


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Appendix 2 
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 
• Vasectomised 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 women of childbearing potential (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, 2014. 


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Appendix 3 
Revised International Myeloma Working Group (IMWG) 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, computerized 
tomography (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 positron emission tomography with computed tomography.  
*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 et al, 2014. 


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Appendix 4 
Organ Response and Progression Criteria 
Organ 
Response 
Progression 
Heart/Cardiaca 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)b  
Kidney/Renalc  ≥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 
Nerved 
NIS-LL increase from baseline of <2 
points 
NIS-LL increase from baseline of 
≥2 points 
Liver/Hepatica 50% decrease in abnormal ALP value 
≥50% increase in ALP above the 
lowest value 
Abbreviations: ALP = alkaline phosphatase; eGFR = estimated glomerular filtration rate; NIS-LL = Neuropathy Impairment 
Score–Lower Limbs; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association.  
a 
Modified from Table 2 in Comenzo et al, 2012. In addition to the progression criteria listed above, the 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. 
b 
Subjects with progressively worsening renal function cannot be scored for NT-proBNP progression. 
c 
Palladini et al, 2014. 
d 
Coelho et al, 2012. 
 
 


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Appendix 5 
Neuropathy Impairment Scale – Lower Limbs 
 
 


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Appendix 6 
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: 
 
 
 
 
 
 
 


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Date:  22 October 2017 
Page 91 of 111 
Appendix 7 
Eastern Cooperative Oncology Group (ECOG) Performance Status 
Grade 
Description 
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 et al, 1982. 


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Date:  22 October 2017 
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Appendix 8 
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. 
Source: American Heart Association, 2015. 


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Date:  22 October 2017 
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Appendix 9 
Short Form-36v2 Health Survey 
 


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Appendix 10 Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 


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Appendix 11 Laboratory Tests 
Serum Chemistry: 
• 
ALP (E)a 
• 
ALT (E) 
• 
AST (E) 
• 
Bilirubin - total  (E) and direct 
• 
GGT 
• 
BUN 
• 
LDH 
• 
Creatinine (E) 
• 
Glucose 
• 
Cholesterol 
• 
Triglycerides 
• 
Calcium 
• 
Phosphate 
• 
Protein - total 
• 
Albumin 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Magnesium 
• 
Amylase 
• 
Creatine kinase  
• 
Uric acid 
• 
Estimated glomerular filtration rate (E)e 
• 
Estimated creatinine clearance 
• 
Cystatin C 
Hematology: 
• 
Hemoglobin (E) 
• 
Hematocrit 
• 
RBC 
• 
WBC 
• 
Neutrophils (absolute [E], %) 
• 
Lymphocytes (absolute, %) 
• 
Monocytes (absolute, %) 
• 
Eosinophils (absolute, %) 
• 
Basophils (absolute, %) 
• 
Platelet count (E) 
Otherb: 
• 
Serum anti-NEOD001 antibodiesc 
• 
Serum NEOD001 concentration 
• 
Serum FLCsd 
• 
24-hr urine protein excretion & total volume 
• 
Serum & 24-hr urine PEP 
• 
Serum & urine IFE 
Inflammatory Biomarkersb: 
• 
IL-6 
• 
IL-8 
• 
TNF-alpha 
• 
INF-gamma 
• 
Complements C3, C4, and CH50 
• 
CRP 
• 
SAA (A-SAA) 
• 
Tryptase 
Urinalysis - Dipstick: 
• 
Color & clarity 
• 
Specific gravity 
• 
pH 
• 
Protein 
• 
Glucose  
• 
Ketones 
• 
Bilirubin 
• 
Urobilinogen 
• 
Blood 
• 
Nitrite 
• 
Leukocyte esterase 
• 
Microscopic 
Urinalysis - Quantitative 
Analysis/Renal Biomarkersf: 
• 
Urine albumin/creatinine 
ratio 
• 
Urine NGAL 
• 
Urine RBP  
Cardiac Biomarkers: 
• 
Troponin T 
• 
NT-proBNP  
Coagulation: 
• 
PT/INR 
• 
PTT 
• 
Additional indices - see Appendix 12 
Women of childbearing potential only: 
• 
Serum beta hCG pregnancy tests (E) 
Abbreviations: ALP = alkaline phosphatase; ALT = alanine aminotransferase; A-SAA = acute phase serum amyloid A; AST  = aspartate 
aminotransferase; BUN = blood urea nitrogen; CRP = C-reactive protein; (E) = may be used for eligibility; FLCs = free light chains; 
GGT = gamma-glutamyl transpeptidase; hCG = human chorionic gonadotropin; IFE = immunofixation electrophoresis; IL = interleukin; 
INF = interferon; LDH = lactate dehydrogenase; NGAL = neutrophil gelatinase-associated lipocalin; NT-proBNP = N-terminal pro-
brain natriuretic peptide; PEP = protein electrophoresis; PT/INR = prothrombin time/international normalized ratio; PTT = partial 
thromboplastin time; RBC = red blood cell; RBP = retinol-binding protein; SAA = serum amyloid A; TNF = tumor necrosis factor; 
WBC = white blood cell. 
a 
Including isozymes for subjects with ALP >5 × upper limit of normal.  
b 
See details in Section 5.4.2 regarding collection of samples in cases of suspected systemic infusion-related/hypersensitivity reactions. 
c 
Any sample found to be confirmed positive for anti-NEOD001 antibodies may be further evaluated by a neutralizing antibody assay. 
d 
Including dFLC (difference between involved and uninvolved FLCs) and FLC ratio. 
e 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] where: Scr = serum creatinine in 
mg/dL; κ = 0.7 for females, 0.9 for males; α = -0.329 for females, -0.411 for males; min = the minimum of Scr /κ or 1;  max = the 
maximum of Scr /κ or 1. 
f 
It is important that the sample be taken before exercising and at approximately the same time for each collection; therefore, the first 
morning void is recommended. Urine samples to be collected and frozen for potential future analysis. 


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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 109 of 111 
Appendix 12 Coagulation Indices 
At Screening, EOS/ETD, and as clinically indicated, 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: 
Test Name 
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 
 
 


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Study Protocol: NEOD001-201 Amendment 3 
 
Date:  22 October 2017 
Page 110 of 111 
Appendix 13 Schedule Of Events For Subjects Who Discontinue Study Drug Early but 
Agree to Return For Assessments After the ETD Visit  
 Assessment or Procedure 
Monthly 
Day 1 (±5 days)1 
Every 3 Months after 
Last Visit 
Clinical 
Prior/Concomitant Medications/Therapy 
X 
 
Adverse Event Assessment 
X 
 
Physical Exam2 
X 
 
Vital Signs3 
X 
 
ECOG PS/NYHA Class4 
X 
 
NIS-LL & VASPI5 
X 
 
SF-36v26 
X 
 
KCCQ7 
X 
 
6MWT8,9 
X (Months 3, 6, 9, 12) 
 
Echocardiogram10 
X (Month 12) 
 
ECG (12-lead triplicate)11 
X (Months 3, 6, 9, 12) 
 
Laboratory16 
Hematology & Chemistry (including amylase and 
creatine kinase)12 
X 
 
Coagulation13 
X 
 
Inflammatory Biomarkers14 
X (Month 3)15 
 
Troponin T 
X 
 
NT-proBNP8 
X 
 
Pregnancy (WOCBP)  
X17 
 
Serum Free Light Chain 
X (Months 3, 6, 9, 12) 
 
Serum IFE & PEP 
X (Months 3, 6, 9, 12) 
 
Urinalysis – Dipstick18 
X (Months 3, 6, 9, 12) 
 
Urinalysis - Quantitative/Renal Biomarkers19 
X (Months 3, 6, 9, 12) 
 
24-hour Urine Collection: 
 
 
Urine IFE & PEP 
X (Months 3, 6, 9, 12) 
 
Urine Protein Excretion 
X (Months 3, 6, 9, 12) 
 
Other 
Anti-NEOD001 Serum Sample 
X20 
 
Vital Status Phone Call 
 
X21 


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Date:  22 October 2017 
Page 111 of 111 
BP = blood pressure; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance 
status; ETD = Early Treatment Discontinuation; HR = heart rate; IFE = immunofixation electrophoresis; 
KCCQ = Kansas City Cardiomyopathy Questionnaire; NIS-LL = neuropathy impairment score – lower 
limbs; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; 
PEP = protein electrophoresis; RR = respiratory rate; 6MWT = 6-minute walk test; SF-36v2 = Short Form-
36v2® Health Survey; VASPI = visual analog scale – pain intensity; WOCBP = women of childbearing 
potential. 
1. 
Study visits will occur every 28 days based on scheduling from Month 1-Day 1. A ±5-day window is allowed 
for visits starting after Month 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 per Table 1 and Section 6.2 and 
then have assessments performed monthly, through Month 12, if willing. The most important visit is the 
Month 12-Day 1 Visit, so if a subject is unwilling to continue monthly visits, every effort should be made for 
the subject to return and complete the Month 12-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. An EOS Visit will not be conducted. 
2. 
Conduct a directed physical examination, including weight, and the components of the exam as clinically 
indicated. Assess macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, liver/spleen size 
(palpable +/-), ascites (+/-), and edema (which should be quantified on a scale of 0-4). 
3. 
Vital signs include HR, RR, BP, and body temperature; assess any time during visit after subject has been at 
rest ≥5 minutes. 
4. 
See Appendix 7 (ECOG) and Appendix 8 (NYHA). 
5. 
See Appendix 5 (NIS-LL; for all subjects with peripheral neuropathy at Screening) and Appendix 6 (VASPI; 
for subjects with painful peripheral neuropathy at Screening). 
6. 
See Appendix 9; SF-36v2 should be administered before performing any other study assessments on the same 
calendar day it is administered. 
7. 
See Appendix 10; administer KCCQ after the SF-36v2, but before conducting any other assessments on the 
same calendar day it is administered. 
8. 
NT-proBNP should be drawn before conducting 6MWT if being performed on the same calendar day. 
9. 
Collect BP and HR pre- and post-6MWT administration. 
10. Perform echocardiogram locally within 10 days before Day 1.  
11. Perform ECGs centrally any time during visit.  
12. Hematology and chemistry per Appendix 11. 
13. Collect PT/INR and PTT monthly. Collect citrated plasma samples as clinically indicated 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. Inflammatory biomarkers per Appendix 11. 
15. Collect additional samples as clinically indicated, such as when significant toxicity occurs per Section 5.4.2. 
16. All laboratory tests to be done centrally, unless otherwise noted. Please refer to Laboratory Manual for details. 
17. Obtain local laboratory serum pregnancy test 90 (±5) days after the last study drug administration.  
18. Per Appendix 11. 
19. Per Appendix 11. It is important that the sample be taken before exercising and at approximately the same time 
for each collection; therefore, the first morning void is recommended. Urine samples will be collected and 
frozen for potential analysis at a later date. 
20. Anti-NEOD001 serum samples: Collect if an earlier sample established the presence of anti-NEOD001 
antibodies or if a subject discontinued treatment due to a suspected immunologic reaction. 
21. For randomized subjects who received at least 1 dose of study drug, conduct vital status telephone call 
approximately 3 months after last visit and approximately every 3 months thereafter or until subject enrolls in 
a separate open-label study, death, or for up to 5 years. 
 

SAP_001.pdf: 
 
Document Type: Statistical Analysis Plan 
Official Title: 
A Phase 2b, Randomized, Double-blind, Placebo-controlled Study of 
NEOD001 in Previously Treated Subjects with Light Chain (AL) 
Amyloidosis who have Persistent Cardiac Dysfunction 
NCT Number: 
NCT02632786 
Document Date: 
15 February 2018 
 


TITLE PAGE 
 
 
 
Statistical Analysis Plan for Protocol NEOD001-201 (PRONTO) 
 
A Phase 2b, Randomized, Double-blind, Placebo-controlled Study of 
NEOD001 in Previously Treated Subjects with Light Chain (AL) Amyloidosis 
who have Persistent Cardiac Dysfunction 
 
Investigational Product: 
NEOD001 
US IND Number: 
122,912 
EudraCT Number: 
2015-004318-14 
Protocol Version and Date: 
Amendment 3, 22 October 2017 
Phase: 
Phase 2b 
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: 
15 February 2018 
Analysis Plan Version: 
Final  
 
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   
15 February 2018
NEOD001-201 (PRONTO) 
Page 2
 
Confidential and Proprietary 
TABLE OF CONTENTS 
List of Abbreviations and Definition of Terms ............................................................................. 7 
1. 
Introduction ...................................................................................................... 12 
2. 
Information from the Study Protocol ............................................................... 13 
2.1. 
Study Objective ......................................................................................................13 
2.2. 
Study Design ..........................................................................................................13 
2.2.1. 
Overall Study Design .................................................................................13 
2.2.2. 
Study Design Diagram ...............................................................................14 
2.2.3. 
Study Population ........................................................................................14 
2.2.4. 
Study Drug .................................................................................................14 
2.2.5. 
Randomization Methodology.....................................................................15 
2.2.6. 
Study Procedures .......................................................................................15 
2.2.7. 
Definition of Baseline ................................................................................18 
2.2.8. 
Definition of Efficacy End of Study Visit .................................................18 
2.3. 
Study Endpoints .....................................................................................................18 
2.3.1. 
Primary Efficacy Endpoint ........................................................................18 
2.3.2. 
Key Secondary Efficacy Endpoints ...........................................................18 
2.3.2.1. 
Change from Baseline to 12 Months of Treatment in the Physical 
Component Score of the SF-36v2 .....................................................19 
2.3.2.2. 
Change from Baseline to 12 Months of Treatment in the 6-Minute 
Walk Test (6MWT) Distance (meters) .............................................19 
2.3.2.3. 
NT-proBNP Slope over 12 Months of Treatment.............................20 
2.3.3. 
Additional Secondary Efficacy Endpoints .................................................20 
2.3.3.1. 
Renal Evaluable Subjects:  Renal Best Response from Baseline 
through 12 Months of Treatment ......................................................20 
2.3.3.2. 
Peripheral Neuropathy Evaluable Subjects:  Change from Baseline to 
12 Months of Treatment in Neuropathy Impairment Score–Lower 
Limbs (NIS-LL) Total Score ............................................................20 
2.3.3.3. 
Hepatic Evaluable Subjects:  Hepatic Best Response from Baseline 
through 12 Months of Treatment ......................................................21 
2.3.4. 
Exploratory Efficacy Endpoints .................................................................21 
2.3.4.1. 
Cardiac Endpoints .............................................................................21 
2.3.4.2. 
Functional Endpoint ..........................................................................22 
2.3.4.3. 
Quality of Life Endpoints .................................................................22 
2.3.4.4. 
Renal Endpoints ................................................................................22 
2.3.4.5. 
Peripheral Neuropathy Endpoints .....................................................23 
2.3.4.6. 
Hepatic Endpoints .............................................................................23 
2.3.4.7. 
Additional Time-to-Event Endpoints ................................................23 
2.3.4.8. 
Other Efficacy Endpoints ..................................................................24 
2.3.5. 
Safety Endpoints ........................................................................................26 
3. 
Sample Size Justification .................................................................................. 27 


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15 February 2018
NEOD001-201 (PRONTO) 
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4. 
General Statistical Methods .............................................................................. 28 
4.1. 
Reporting Conventions ..........................................................................................28 
4.2. 
Computing Environment ........................................................................................28 
4.3. 
Partial Dates and Unknown Times ........................................................................29 
4.4. 
Data Conventions ...................................................................................................30 
4.5. 
Standard Calculations ............................................................................................30 
4.6. 
Visit Windows .......................................................................................................31 
5. 
Analysis Populations ........................................................................................ 34 
6. 
Examination of Subgroups ............................................................................... 35 
7. 
Study Population .............................................................................................. 36 
7.1. 
Subject Disposition ................................................................................................36 
7.2. 
Demographics and Baseline Characteristics ..........................................................36 
7.3. 
Baseline AL Amyloidosis Disease Characteristics ................................................37 
7.4. 
Disease History Specific AL Symptoms................................................................38 
7.5. 
General Medical History ........................................................................................38 
7.6. 
Protocol Deviations ................................................................................................38 
7.7. 
Pretreatment, Prior, and New Concomitant Medications ......................................39 
8. 
Efficacy Analyses ............................................................................................. 40 
8.1. 
Adjustments for Covariates....................................................................................40 
8.2. 
Handling of Dropouts or Missing Data ..................................................................40 
8.2.1. 
Time to Event Endpoints ...........................................................................40 
8.2.2. 
Responder Endpoints .................................................................................40 
8.2.3. 
Parametric Analyses...................................................................................41 
8.2.3.1. 
Missing Not at Random (MNAR):  Imputation for Deaths ..............41 
8.2.3.2. 
Missing at Random (MAR):  Multiple Imputation ...........................41 
8.2.3.3. 
MNAR:  Multiple Imputation Placebo-Based ..................................41 
8.2.4. 
Non-Parametric Analyses ..........................................................................42 
8.2.4.1. 
Ranking .............................................................................................42 
8.2.5. 
Last Observation Carried Forward (LOCF) ...............................................43 
8.2.6. 
Complete Case Analysis ............................................................................43 
8.3. 
Interim Analyses and Data Monitoring..................................................................43 
8.3.1. 
Interim Analysis .........................................................................................43 
8.3.2. 
Safety Monitoring Committee ...................................................................43 
8.4. 
Multicenter Studies ................................................................................................43 
8.5. 
Use of an “Efficacy Subset” of Patients ................................................................44 
8.6. 
Multiple Comparisons/Multiplicity .......................................................................44 
8.7. 
Primary Efficacy Analysis .....................................................................................44 
8.7.1. 
Additional Analyses of the Primary Endpoint ...........................................45 
8.8. 
Key Secondary Efficacy Analyses .........................................................................45 


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NEOD001-201 (PRONTO) 
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8.8.1. 
SF-36v2 PCS Score to 12 Months of Treatment .......................................45 
8.8.2. 
6MWT Distance to 12 Months of Treatment .............................................47 
8.8.3. 
NT-proBNP Slope Through 12 Months of Treatment ...............................48 
8.9. 
Additional Secondary Efficacy Analysis ...............................................................49 
8.9.1. 
Renal Evaluable Subjects:  Renal Best Response ......................................49 
8.9.2. 
Peripheral Neuropathy Evaluable Subjects:  NIS-LL Total Score ............49 
8.9.3. 
Hepatic Evaluable Subjects:  Hepatic Best Response................................49 
8.10. 
Exploratory Efficacy Analyses ..............................................................................50 
8.10.1. 
Cardiac Endpoint Analyses ........................................................................50 
8.10.1.1. 
Cardiac Biomarkers:  NT-proBNP and Troponin T .........................50 
8.10.1.2. 
Select Echocardiogram Cardiac Parameters .....................................50 
8.10.2. 
Functional Endpoint Analyses ...................................................................51 
8.10.2.1. 
6MWT Distance ................................................................................51 
8.10.3. 
Quality of Life Endpoint Analyses ............................................................51 
8.10.3.1. 
SF-36v2 .............................................................................................51 
8.10.3.2. 
KCCQ ...............................................................................................52 
8.10.4. 
Renal Endpoint Analyses ...........................................................................52 
8.10.4.1. 
Renal Response .................................................................................52 
8.10.4.2. 
Renal Biomarkers..............................................................................52 
8.10.4.3. 
Creatinine, Proteinuria, and eGFR ....................................................53 
8.10.5. 
Peripheral Neuropathy Endpoint Analyses ................................................53 
8.10.5.1. 
NIS-LL Total and Component Scores ..............................................53 
8.10.5.2. 
VASPI ...............................................................................................53 
8.10.6. 
Hepatic Endpoint Analyses ........................................................................53 
8.10.6.1. 
Hepatic Response ..............................................................................53 
8.10.7. 
Additional Time-to-Event Endpoints .........................................................54 
8.10.7.1. 
Time to All-Cause Mortality (Overall Survival) ..............................54 
8.10.7.2. 
Cardiac Progression-Free Survival ...................................................54 
8.10.7.3. 
Duration of Cardiac Response ..........................................................55 
8.10.7.4. 
Time to Derived Organ Progression .................................................55 
8.10.7.5. 
Time to First Organ Response ..........................................................56 
8.10.8. 
Other Efficacy Analyses ............................................................................56 
8.10.8.1. 
Cardiac Hospitalizations ...................................................................56 
8.10.8.2. 
ECOG Performance Status, NYHA Class, Renal Stage ...................57 
8.10.8.3. 
Selected Hematological and Urine Analyte Analyses ......................57 
8.10.8.4. 
Disease-Related Symptoms ..............................................................57 
8.10.8.5. 
Pharmacokinetic Analyses ................................................................57 
8.10.8.6. 
PK/PD Analyses................................................................................57 
9. 
Safety Analyses ................................................................................................ 58 
9.1. 
Extent of Exposure .................................................................................................58 
9.1.1. 
Use of Premedication .................................................................................59 
9.2. 
Adverse Events ......................................................................................................59 


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15 February 2018
NEOD001-201 (PRONTO) 
Page 5
 
Confidential and Proprietary 
9.2.1. 
Other Adverse Events:  Infusion Reactions ...............................................62 
9.3. 
Clinical Laboratory Evaluations ............................................................................62 
9.3.1. 
Serum Chemistry, Hematology, and Coagulation .....................................63 
9.3.2. 
Inflammatory Biomarkers ..........................................................................63 
9.3.3. 
Shifts in CTCAE Grade .............................................................................63 
9.3.4. 
Shifts in Normal Range ..............................................................................63 
9.3.5. 
Pregnancy Testing and Urinalysis Dipstick ...............................................64 
9.4. 
Weight and BMI ....................................................................................................64 
9.5. 
Vital Signs ..............................................................................................................64 
9.6. 
Electrocardiograms ................................................................................................64 
9.7. 
Physical Examination.............................................................................................65 
9.8. 
Immunogenicity Analyses .....................................................................................65 
10. 
Changes to Protocol Planned Analyses ............................................................ 66 
11. 
References ........................................................................................................ 67 
12. 
Appendices ....................................................................................................... 68 
Appendix 1. 
Hematologic Response and Progression Criteria ............................................. 69 
Appendix 2. 
Organ Response and Progression Criteria ........................................................ 70 
Appendix 3. 
Neuropathy Impairment Scale – Lower Limbs ................................................ 71 
Appendix 4. 
Visual Analog Scale – Pain Intensity (VASPI) ................................................ 72 
Appendix 5. 
Eastern Cooperative Oncology Group (ECOG) Performance Status ............... 73 
Appendix 6. 
New York Heart Association (NYHA) Functional Classification ................... 74 
Appendix 7. 
SF-36v2 Health Survey .................................................................................... 75 
Appendix 8. 
Kansas City Cardiomyopathy Questionnaire (KCCQ) .................................... 86 
Appendix 9. 
Renal Stage ....................................................................................................... 90 
Appendix 10. 
Laboratory Tests ............................................................................................... 91 
Appendix 11. 
Coagulation Indices .......................................................................................... 93 
Appendix 12. 
Schedule Of Events For Subjects Who Discontinue Study Drug Early but 
Agree to Return For Assessments After the ETD Visit ................................... 94 
Appendix 13. 
Anaphylactic Reaction SMQ ............................................................................ 96 
 


Statistical Analysis Plan   
15 February 2018
NEOD001-201 (PRONTO) 
Page 6
 
Confidential and Proprietary 
LIST OF TABLES 
Table 1: 
Schedule of Study Procedures .........................................................................15 
Table 2: 
Disease-Related Symptoms Scoring ................................................................24 
Table 3: 
1-Month Interval Visit Windows (Days) .........................................................32 
Table 4: 
3-Month Interval Visit Windows (Days) .........................................................33 
Table 5: 
Responder Criteria for SF-36v2 Domains and Summary Measures ................52 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic ..................................................................................14 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term 
6MWT 
6-minute walk test 
99mTc 
Radioisotope of Technetium 
A-SAA  
acute phase serum amyloid A 
AE 
adverse event 
AIC 
Akaike’s information criterion 
AL 
amyloid light chain 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
AR (1) 
first-order autoregressive 
AST 
aspartate aminotransferase  
ATC  
Anatomical Therapeutic Chemical 
BMI 
body mass index 
BP 
Bodily Pain (SF-36v2) 
BUN 
blood urea nitrogen 
C 
Celsius 
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 
DOB 
date of birth 
DOIC 
date of informed consent 
dFLC 
difference between involved and uninvolved free light chains 
eCRF 
electronic case report form 
ECG 
Electrocardiogram 


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Abbreviation 
Term 
ECOG 
Eastern Cooperative Oncology Group 
EEOS 
Efficacy End of Study 
eGFR 
Estimated Glomerular Filtration Rate 
EOI 
end of infusion 
EOS 
end of study 
ETD 
early treatment discontinuation 
FDA 
Food and Drug Administration 
FLC 
free light chain 
g/24 hours 
grams per day (24 hours) 
g 
Gram 
GH 
General Health (SF-36v2) 
GGT 
gamma-glutamyl transferase 
HCS 
heterogeneous compound symmetry 
HR 
heart rate 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
ID 
Identification 
IFE 
immunofixation electrophoresis  
in 
Inches 
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 
kg 
kilogram  
KM 
Kaplan-Meier 
L 
Liter 
lb 
Pounds 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LN 
lymph node 


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Abbreviation 
Term 
LS 
least-square 
LVEF 
left ventricular ejection fraction 
LPWd 
left ventricular posterior wall in end-diastole 
LSLV 
last subject last visit 
LVSd 
intraventricular septal at diastole 
m 
Meter 
m2 
meters squared 
mBMI 
modified Body Mass Index 
MCS 
Mental Component Summary (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 
NYHA 
New York Heart Association 
PCS 
Physical Component Summary (SF-36v2) 
PE 
physical examination 
PEP 
protein electrophoresis 
PF 
Physical Functioning (SF-36v2) 
PFS 
progression free survival 


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Abbreviation 
Term 
PK 
Pharmacokinetic 
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 
RBC 
red blood cells 
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 
SI 
standard international unit 
SMC 
Safety Monitoring Committee  
SMQ 
standardized MedDRA query 
SOC 
system organ class 
StdErr 
least squares standard error 
TEAE 
treatment-emergent adverse event 
temp 
Temperature 
TNF 
Tumor Necrosis Factor 


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Abbreviation 
Term 
U/L 
units per liter 
ULN 
upper limit of normal 
VASPI 
Visual Analogue Scale – Pain Intensity 
VGPR 
very good partial response 
vs 
Versus 
VT 
Vitality (SF-36v2) 
WBC 
white blood cells 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 
 


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1. 
INTRODUCTION 
This document outlines the statistical methods to be implemented during the analyses of Study 
NEOD001-201 (PRONTO) 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 this statistical analysis plan will be documented in the clinical study report 
(CSR). 


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2. 
INFORMATION FROM THE STUDY PROTOCOL 
2.1. 
Study Objective 
The objective of this study is to determine the efficacy and safety of NEOD001 versus placebo in 
subjects with AL amyloidosis who have persistent cardiac dysfunction. 
Estimands for the primary and secondary endpoints are detailed in Section 8.7, Section 8.8, and 
Section 8.9. 
2.2. 
Study Design 
2.2.1. 
Overall Study Design 
This is a global, multicenter, Phase 2b, randomized, double-blind, placebo-controlled, two-arm, 
parallel-group efficacy and safety study of NEOD001 as a single agent administered 
intravenously in adults with AL amyloidosis who had a hematologic response (Appendix 1) to 
previous treatment for their amyloidosis (e.g., chemotherapy, ASCT) and have persistent cardiac 
dysfunction. 
Subject screening will occur during the 28 days prior to the first administration of study drug 
(i.e., Month 1 Day 1 Visit). If all eligibility requirements are met, the subject will be enrolled and 
screening assessments will be completed. Screening assessments are listed in Table 1.  
Study visits will occur every 28 days based on scheduling from Month 1 Day 1. A ±5-day 
window is allowed for visits starting after Month 1. Subjects may receive up to 12 infusions of 
study drug. Subjects who discontinue study drug before the End of Study (EOS) Visit should 
have an Early Treatment Discontinuation (ETD) Visit 30 (±5) days after their final 
administration of study drug. If willing, subjects may continue in the study and have monthly 
assessments, through Month 12, per Appendix 12. Subjects who complete the study and meet the 
eligibility criteria will be considered for entry into a separate open-label extension study, during 
which subjects will receive active treatment and may receive concurrent chemotherapy. 
 
 


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2.2.2. 
Study Design Diagram 
Figure 1: 
Study Design Schematic 
 
2.2.3. 
Study Population 
The study population will include men and women with confirmed diagnosis of systemic AL 
amyloidosis, 18 years or older, who had a hematologic response to previous treatment for their 
amyloidosis (e.g., chemotherapy, ASCT) and have persistent cardiac dysfunction. Subjects must 
also provide written informed consent. Please refer to the protocol Sections 4.1 and 4.2 for a 
complete list of the subject selection criteria. 
2.2.4. 
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 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. The volume contained in the administration tubing 
Screening
Treatment (N~130)
Termination
Days -28 to -1
Months 1 through 12
Day 1 (±5 daysd)
30 (±5) Days 
After Last Dose
Population:
Previously
treated AL 
amyloidosis
Response to 
first-line PCD 
therapy,
6-month 
treatment-free 
intervala
Cardiac
involvement
ICF & 
Screening 
Assessments
24 mg/kgb IV NEOD001 every 28 days
EOS/ETD 
Visit
CR = complete response; EOS/ETD = End of Study/Early Treatment Discontinuation; ICF = informed consent form; IV = intravenous; M12 = Month 12; NT-proBNP = N-terminal pro B-type natriuretic peptide; NIS-LL = 
Neuropathy Impairment Score-Lower Limbs; PCD = plasma cell dyscrasia; PCS = Physical Component Score; PR = partial response; SF-36 = Short Form-36; 6MWT = 6 minute walk test; VGPR = very good partial response.
a 6 months chemotherapy or 12 months stem cell transplant treatment-free. 
b Maximum dose not to exceed 2500 mg.
c Eligible subjects will receive active treatment and may receive concurrent chemotherapy.
d ±5-day window applicable to Months 2-12.
e Renal-evaluable subjects, peripheral neuropathy-evaluable subjects, and hepatic-evaluable subjects, respectively.
IV Placebo every 28 days
Randomization 1:1
Randomization Stratification:
• 
Hematologic response; i.e., CR+VGPR vs PR to first-line therapy
• 
NT-proBNP <1800 pg/mL vs ≥1800 pg/mL
Primary Endpoint: 
• 
NT-proBNP best response from baseline through 12 months of treatment
Key Secondary Endpoints:
• 
SF-36 PCS change from baseline to 12 months of treatment
• 
6MWT distance change from baseline to 12 months of treatment
• 
NT-proBNP slope over 12 months of treatment
Secondary Endpoints in Efficacy Subset Populationse:
• 
Renal best response from baseline through 12 months of treatment
• 
NIS-LL Total Score change from baseline to 12 months of treatment
• 
Hepatic best response from baseline through 12 months of treatment
Open-label 
Extension 
Studyc
NEOD001-201 Study Design


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should be completely flushed using approximately 30 mL of 0.9% Sodium Chloride Injection 
after administration of study drug. 
Please refer to the protocol for complete product details. 
2.2.5. 
Randomization Methodology 
A subject number will be assigned via a web-based registration for each subject who has signed 
an informed consent form (ICF). If a subject has completed all Screening requirements and 
meets all of the eligibility criteria, a Subject Registration Form will be submitted for eligibility 
review and approval. If approved, randomization will be implemented through an internet 
connection to an Interactive Web Response System (IWRS) utilizing results from Screening 
assessments. Up to 130 subjects will be enrolled and randomized (1:1) to NEOD001 24 mg/kg or 
placebo. The randomization will be stratified by two factors: 
• Hematologic response; that is, complete response/very good partial response (CR/VGPR) 
vs partial response (PR) to first-line therapy 
• NT-proBNP <1800 ng/L vs ≥1800 ng/L 
Upon successful randomization, the Unblinded Pharmacist or their designee will be provided 
with the treatment assignment. Numbers assigned to subjects who do not receive study drug will 
not be re-used. 
2.2.6. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is presented in Table 1. 
Table 1: 
Schedule of Study Procedures 
  
Screening1 
Treatment 
Termination 
 Assessment or Procedure 
Days -28 
through -1 
Month 1 
Day 1 
Months 2 through 12 
Day 1 (±5 days)2 
EOS/ETD3 
 
Written Informed Consent  
X 
 
 
 
Eligibility Review 
X 
 
 
 
Clinical 
Medical History4 
X 
 
 
 
Historical NT-proBNP/BNP5 Levels 
X 
 
 
 
Prior/Concomitant Medications/Therapy 
X 
X 
X 
X 
Adverse Event Assessment6 
X 
X 
X 
X 
Confirmation of AL Amyloidosis7 
X 
 
 
 
Physical Exam8 
X 
X 
X 
X 
Vital Signs9 
X 
X 
X 
X 
ECOG PS/NYHA Class9 
X 
X 
X 
X 
NIS-LL & VASPI11 
X 
X 
X (Months 3, 6, 9, 12) 
X 
SF-36v212 
X 
 
X (Months 3, 6, 9, 12) 
X 
KCCQ13 
X 
 
X (Months 3, 6, 9, 12) 
X 
6MWT14,15 
X, X16 
 
X (Months 3, 6, 9, 12)17 
X 
Echocardiogram18 
X 
 
X (Month 12) 
X 
ECG (12-lead triplicate) 
X 
X19 
X (Months 3, 6, 9, 12) 19 
X 


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Laboratory Assessments24 
Hematology & Chemistry (including amylase 
and creatine kinase)20 
X 
X 
X 
X 
Coagulation21 
X 
 
X 
X 
Inflammatory Biomarkers22,23 
 
X 
X (Month 3)23 
X 
Troponin T  
X 
 
X 
X 
NT-proBNP14  
X 
X 
X 
X 
Pregnancy (WOCBP)25 
X  
X 
X 
X 
Serum Free Light Chain 
X 
 
X (Months 3, 6, 9, 12) 
X 
Serum IFE & PEP26 
X 
 
X (Months 3, 6, 9, 12) 
X 
Urinalysis – Dipstick27 
X 
X 
X (Months 3, 6, 9, 12) 
X 
Urinalysis - Quantitative/Renal Biomarkers28 
X 
 
X (Months 3, 6, 9, 12) 
 
24-hour Urine Collection: 
 
 
 
 
Urine IFE & PEP26 
X 
 
X (Months 3, 6, 9, 12)  
X 
Urine Protein Excretion 
X 
 
X (Months 3, 6, 9, 12) 
X 
Other 
Serum NEOD001 Sample23,29 
 
X 
X (Months 3, 6, 9, 12)23 
X 
Anti-NEOD001 Serum Sample23,30  
 
X 
X (Months 3, 6, 9, 12)23 
X 
Archive Sample31 
X 
 
X (Months 6, 12) 
 
 Randomization 
 
X 
 
 
 Study Drug Infusion32 
 
X 
X 
 
 Vital Status Phone Call 
 
 
 
X32 
BNP = B-type natriuretic peptide; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group 
performance status; EOI = end of infusion; EOS = End of Study; ETD = Early Treatment Discontinuation; 
IFE = immunofixation electrophoresis; KCCQ = Kansas City Cardiomyopathy Questionnaire; NIS-LL = neuropathy 
impairment score – lower limbs; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart 
Association; PEP = protein electrophoresis; PK = pharmacokinetic; 6MWT = 6-minute walk test; SF-36v2 = Short 
Form-36v2® Health Survey; VASPI = visual analog scale – pain intensity; WOCBP = women of childbearing 
potential. 
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. 
2. 
Study visits will occur every 28 days based on scheduling from Month 1-Day 1. A ±5-day window is allowed 
for visits starting after Month 1. The predose assessments for each visit may be performed within the 3 days 
before the visit unless otherwise specified. 
3. 
Conduct the EOS Visit 30 (±5) days after last administration of study drug. Subjects who discontinue study 
drug before the end of the study should have an ETD Visit 30 (±5) days after their final administration of study 
drug, and if willing, have assessments monthly per Appendix 12. Every effort should be made for the subject to 
return to the clinic and complete the Month 12-Day 1 Visit on schedule. The assessments shown for EOS/ETD 
should also be conducted for any unscheduled visit (i.e., a visit not specified by the protocol) as clinically 
indicated or if deemed necessary.  
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. 
If available, record results of at least 2 prior NT-proBNP or 2 BNP measures from within the previous 6 
months; NT-proBNP is preferred, but BNP may be used if it is the institution’s historical standard. 
6. 
Adverse events will be collected from the time that the informed consent form is signed through 30 days after 
the last dose of study drug or last study visit, whichever is later. 
7. 
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 #3. 
8. 
Screening and EOS/ETD:  conduct a complete physical examination, including height (Screening only), 
weight, and examination of the following:  general appearance; head, ears, eyes, nose, and throat; neck; skin; 


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cardiovascular system; respiratory system; gastrointestinal system; and nervous system. All other visits:  
conduct a directed physical examination, including weight, and the components of the exam will be as clinically 
indicated. All visits:  assess macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, liver/spleen 
size (palpable +/-), ascites (+/-), and edema (which should be quantified on a scale of 0-4). 
9. 
Vital signs include heart rate (HR), respiratory rate (RR), blood pressure (BP), and body temperature; assess 
after subject has been at rest ≥5 minutes; within a visit, assess in the same position for all time points. Month 1:  
Within 30 minutes before dosing, 60 (±10) minutes after the start of the infusion, at EOI (+5 minutes), 30 (±5) 
minutes after EOI, and 60 (±10) minutes after EOI. All Other Months:  Within 30 minutes before dosing, at 
EOI (+5 minutes), and 60 (±10) minutes after EOI. 
10. See Appendix 5 (ECOG) and Appendix 6 (NYHA). 
11. See Appendix 3 (NIS-LL; for all subjects with peripheral neuropathy at Screening) and Appendix 4 (VASPI; for 
subjects with painful peripheral neuropathy at Screening). 
12. See Appendix 7; SF-36v2 should be administered before performing any other study assessments on the same 
calendar day it is administered. 
13. See Appendix 8; administer KCCQ after the SF-36v2, but before conducting any other assessments on the same 
calendar day it is administered. 
14. NT-proBNP should be drawn before conducting 6MWT if being performed on the same calendar day.  
15. Collect blood pressure and heart rate pre- and post-6MWT administration. Subject should plan to be able to 
return to the same clinical site for each 6MWT from first Screening through Month 12. 
16. Two pretreatment 6MWTs are required before the first administration of study drug, with a minimum of 4 days 
in between the two tests. 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). 
17. The postbaseline 6MWTs may be administered on the same calendar day that study drug is administered (i.e., 
Months 3, 6, 9, 12) 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. 
18. Perform echocardiogram locally; Screening:  If an echocardiogram was conducted within 90 days prior to 
Screening Day -28, it does not need to be repeated during Screening and the previous result may be used for 
eligibility; however, to be eligible for the additional cardiac imaging analysis, the subject must have had a 
4-chamber view, 2-dimensional echocardiogram with Doppler. Month 12:  may be conducted within 10 days 
before Day 1; EOS/ETD:  repeat if not performed within 60 days prior to visit.  
19. Months 1, 3, 6, 9, 12:  perform ECGs centrally within 30 minutes before dosing and within 15 minutes after 
EOI.  
20. Hematology and chemistry per Appendix 10. 
21. Collect PT/INR and PTT at each time point. At Screening, EOS/ETD, and 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 11. 
22. Inflammatory biomarkers per Appendix 10. 
23. Collect additional samples as clinically indicated, such as when significant toxicity occurs per protocol Section 
5.4.2. 
24. All laboratory tests to be done centrally, unless otherwise noted. Please refer to Laboratory Manual for details. 
25. Pregnancy tests for WOCBP as follows:  Screening:  serum test (central) within 28 days before Month 1-Day 1; 
Month 1:  serum test (local) within 24 hours before Month 1-Day 1; Months 2-12:  serum test (local) 
preinfusion; EOS/ETD:  serum test (central); 90 (±5) days after the last study drug administration:  serum 
test (local). 
26. The serum and urine PEP must be conducted before the NEOD001 infusion, if being performed on the same 
calendar day. 
27. Per Appendix 10. 
28. Per Appendix 10. It is important that the sample be taken before exercising and at approximately the same time 
for each collection; therefore, the first morning void is recommended. Urine samples will be collected and 
frozen for potential analysis at a later date.  
29. NEOD001 serum samples (for population PK analysis):  collect within 2 hours before infusion and within 
4 hours after EOI. 
30. Anti-NEOD001 serum samples:  collect preinfusion. 
31. Archive samples (only subjects who consented to the collection and archiving of their samples for future 
correlative testing):  collect preinfusion. 


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32. A minimum of 21 days between doses is required. 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. 
Beginning with the third infusion, the Investigator may decrease the monitoring time to no less than 60 minutes, 
if no infusion-related reactions were observed in the previous infusions and allowed per the IRB/IEC. 
33. For randomized subjects who received at least 1 dose of study drug, conduct vital status telephone call 
approximately 3 months after last visit and approximately every 3 months thereafter or until subject enrolls in a 
separate open-label study, death, or for up to 5 years. 
2.2.7. 
Definition of Baseline 
The baseline for the 6MWT distance (meters) will be defined as the longest distance walked 
prior to the first study drug infusion. Baseline for all other efficacy and safety parameters will be 
defined as the last non-missing assessment prior to the first study drug infusion. 
2.2.8. 
Definition of Efficacy End of Study Visit 
The End of Study (EOS) visit occurs 30 (±5) days after last administration of study drug. In 
order to assess efficacy at or through 12 months of treatment, the Efficacy End of Study (EEOS) 
visit is defined as the visit occuring 30 (±5) days after the Month 12 infusion. This may include 
the EOS visit or other unscheduled visits. The visit window algorithm for the EEOS visit is 
specified in Section 4.6.  
For subjects completing all assessments at the EOS visit after 12 months of treatment the EEOS 
visit is the EOS visit. For subjects who do not complete 12 months of treatment or who are 
missing an assessment in the EEOS visit window, EEOS visit efficacy assessments will be 
imputed as specified in Section 8.2.  
2.3. 
Study Endpoints 
2.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is cardiac response as defined by N-terminal pro-brain natriuretic 
peptide (NT-proBNP) best response from baseline through 12 months of treatment. All visits 
after the first infusion of study drug will be included up to and through the EEOS visit.  
NT-proBNP response categories are defined as modified from Table 2 in Comenzo, 2012 
(Appendix 2):   
Response 
Stable  
Progression 
Decrease in NT-proBNP from 
baseline of >30% and >300 
ng/L  
Assessment was 
neither Response 
nor Progression 
Increase in NT-proBNP 
from baseline of >30% and 
from baseline >300 ng/L  
Best response is defined as the most favorable category (response, stable, or progression) across 
all visits. Subjects will be classified as responders or non-responders. Non-response is defined as 
either stable or progression.  
2.3.2. 
Key Secondary Efficacy Endpoints  
The key secondary endpoints, in order of priority are: 


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2.3.2.1. 
Change from Baseline to 12 Months of Treatment 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 7). It allows 
for the scoring of two component summary indices:  the Physical Component Summary (PCS) 
score and the Mental Component Summary (MCS) score. The SF-36v2 is scored as eight 
subscales representing separate domains of functional health and well-being:   
• Physical Functioning (PF:  10 questions, # 3a to 3j)  
• Role-Physical (RP; role limitations due to physical problems:  4 questions, # 4a to 4d)  
• Bodily Pain (BP:  2 questions, # 7 to 8)  
• General Health Perceptions (GH:  5 questions, # 1, 11a to 11d)  
• Vitality (VT:  4 questions,# 9a, 9e, 9g, and 9i)  
• Social Functioning (SF:  2 questions, # 6 and 10)  
• Role-Emotional (RE; role limitations due to emotional problems:  3 questions, # 5a to 5c)  
• 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 score, 
and (3) the MH scale is not missing when calculating the MCS score. 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 EEOS visit to evaluate 12 months of 
treatment. 
2.3.2.2. 
Change from Baseline to 12 Months of Treatment in the 6-Minute Walk Test 
(6MWT) Distance (meters)  
Per guidelines published by the American Thoracic Society (ATS 2002), the 6MWT is a 
practical simple test that requires a minimum walking length of 25 meters (m) but no exercise 


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equipment or advanced training for technicians. The walking track or area should be the same for 
all tests for a subject. 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 EEOS visit to 
evaluate 12 months of treatment. 
2.3.2.3. 
NT-proBNP Slope over 12 Months of Treatment 
The cardiac biomarker NT-proBNP provides important prognostic information in patients with 
AL amyloidosis and it has been demonstrated that decreasing NT-proBNP levels predict lower 
mortality rates (Palladini 2010). All visits after the first infusion of study drug will be included 
up to and through the EEOS visit to evaluate 12 months of treatment. 
2.3.3. 
Additional Secondary Efficacy Endpoints  
2.3.3.1. 
Renal Evaluable Subjects:  Renal Best Response from Baseline through 12 
Months of Treatment  
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 one post-baseline assessment of proteinuria. All visits after the first infusion of study 
drug up and through the EEOS visit will be included to evaluate 12 months of treatment. 
For these subjects, renal response categories (modified from Palladini 2014; Appendix 2) are 
defined as:   
Response 
Stable  
 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, or progression) across 
all visits. Subjects will be classified as responders or non-responders. Non-response is defined as 
either stable or progression. 
2.3.3.2. 
Peripheral Neuropathy Evaluable Subjects:  Change from Baseline to 12 Months 
of Treatment 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 due to AL 
amyloidosis etiologies at screening 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 EEOS visit to evaluate 
12 months of treatment. 
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 3). The 


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scale is 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: 
• Sensory Function (in the great toe) = Sum of (touch pressure, pinprick, vibration, joint 
position) 
• Reflexes = Sum of (knee, ankle) 
• Muscle Strength = Sum of (hip flexion, hip extension, knee flexion, knee extension, ankle 
dorsiflexion, ankle plantar flexion, toe extension, toe flexion) 
• Total score = Sum of (sensory function, reflexes, muscle strength)  
2.3.3.3. 
Hepatic Evaluable Subjects:  Hepatic Best Response from Baseline through 12 
Months of Treatment 
The Hepatic Evaluable Population will include subjects who had hepatic involvement defined as 
>1.5 × ULN alkaline phosphatase (ALP) at baseline and at least one post-baseline assessment of 
ALP. All visits after the first infusion up to and through the EEOS visit will be included to 
evaluate 12 months of treatment. 
For these subjects, hepatic response categories are modified from Table 2 in Comenzo, 2012 
(Appendix 2), where response categories are defined as: 
Response 
Stable  
 Progression 
≥ 50% decrease in alkaline 
phosphatase from baseline 
Assessment was 
neither Response 
nor Progression 
≥ 50% increase in alkaline 
phosphatase from baseline 
Best response is defined as the most favorable category (response, stable, or progression) across 
all visits. Subjects will be classified as responders or non-responders. Non-response is defined as 
either stable or progression. 
2.3.4. 
Exploratory Efficacy Endpoints  
The following exploratory efficacy endpoints will evaluate NEOD001 compared to placebo: 
2.3.4.1. 
Cardiac Endpoints 
2.3.4.1.1. Cardiac Biomarkers (NT-proBNP and Troponin T) 
• Cardiac response (Appendix 2), as assessed by NT-proBNP response criteria, at each visit  
• Cardiac best response (Section 2.3.1), as assessed by NT-proBNP response criteria, 
through 3, 6, and 9 months of treatment 
• Change and percent change from baseline to each visit in NT-proBNP and troponin T  


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2.3.4.1.2. 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  
2.3.4.2. 
Functional Endpoint 
2.3.4.2.1. 6MWT Distance 
• Change and percent change from baseline to each visit in the 6MWT distance (meters) 
(except the key secondary endpoint)  
• Categorical analysis of change from baseline to each visit in the 6MWT distance (meters) 
2.3.4.3. 
Quality of Life Endpoints 
2.3.4.3.1. SF-36v2  
• Change and percent change from baseline to each visit in SF-36v2 PCS score (except the 
key secondary endpoint), MCS score, and the eight subscales  
2.3.4.3.2. KCCQ 
The KCCQ is a self-administered, 15-item questionnaire to assess physical limitation, symptom 
stability, symptom frequency, symptom burden, total symptom score, self-efficacy, quality of 
life, social limitation, overall summary score, and clinical summary score (Appendix 8). Scores 
are transformed to a range of 0-100, in which higher scores reflect better health status. The 
change and percent change from baseline to each visit in the KCCQ subscores and overall 
summary score will be evaluated. 
2.3.4.4. 
Renal Endpoints 
The following endpoints will be evaluated in the Renal Evaluable Population, unless otherwise 
specified.  
2.3.4.4.1. Renal Response  
• Renal response (Appendix 2) at each visit 
• Renal best response through 3, 6, and 9 months of treatment  
2.3.4.4.2. Renal Biomarkers 
• Change and percent change from baseline to each visit in renal biomarkers (urine 
albumin/creatinine ratio, urinary neutrophil gelatinase-associated lipocalin [NGAL] and 
urinary retinol-binding protein [RBP]) in the Renal Evaluable Population and ITT 
Population 


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2.3.4.4.3. Creatinine, Proteinuria, and Estimated Glomerular Filtration Rate (eGFR) 
• Change and percent change from baseline to each visit in creatinine, proteinuria, and 
eGFR in the Renal Evaluable Population and ITT Population 
• Shifts from baseline in Chronic Kidney Stage in the Renal Evaluable Population and ITT 
Population 
2.3.4.5. 
Peripheral Neuropathy Endpoints 
The following endpoints will be evaluated in the Peripheral Neuropathy Evaluable Population.  
2.3.4.5.1. NIS-LL Total Score 
• Change and percent change from baseline to each visit in the NIS-LL total score (except 
the additional secondary endpoint) 
• Peripheral neuropathy response (Appendix 2) at each visit  
2.3.4.5.2. NIS-LL Component Scores 
• Change and percent change from baseline in the three NIS-LL component scores (sensory 
function, reflexes, muscle strength) to each visit  
2.3.4.5.3. Visual Analog Scale – Pain Intensity (VASPI) 
• The VASPI assesses a subject’s level of pain related to peripheral neuropathy on a scale 
from 0 – 100 mm, where 0 is no pain and 100 is the worst imaginable pain (Appendix 4). 
For peripheral neuropathy evaluable subjects with painful neuropathy, defined as a 
baseline VASPI score > 0, change and percent change from baseline in the VASPI score 
to each visit  
2.3.4.6. 
Hepatic Endpoints 
The following endpoints will be evaluated in the Hepatic Evaluable Population.  
• Hepatic response (Appendix 2) at each visit  
• Hepatic best response through 3, 6, and 9 months of treatment  
• Change and percent change from baseline to each visit in ALP  
2.3.4.7. 
Additional Time-to-Event Endpoints 
• Time to All-Cause Mortality (Overall Survival):  Any after the first infusion of study 
drug (i.e. study day 1) through the study’s last subject last visit (LSLV). Time (months) 
to event will be calculated as:  (date of death - the date of first study drug infusion + 1) / 
30.4375. Subjects will be censored at their last assessment known to be alive prior to 
LSLV.  
• Progression free survival:  Time (days) to event will be calculated as the earliest of event 
dates (cardiac disease progression or death) minus the date of first infusion of study drug 
plus 1.  


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• Duration of Cardiac Response:  Time (days) to event will be calculated as the earliest 
date of disease progression subsequent to the first response minus the date of first 
response plus 1. Subjects never achieving response are excluded. 
• Time to derived organ progression for each organ (cardiac, renal) separately 
• Time to cardiac or renal progression  
• Time to first organ response for each organ (cardiac, renal) separately 
• Time to cardiac or renal response 
2.3.4.8. 
Other Efficacy Endpoints 
2.3.4.8.1. Cardiac Hospitalizations 
• Frequency of cardiac hospitalizations over the course of the study 
2.3.4.8.2. ECOG Performance Status, NYHA Class, Renal Stage 
• ECOG Performance Status, NYHA Class, and Renal Stage at each visit including any 
changes from baseline 
2.3.4.8.3. Selected Hematological and Urine Analyte Endpoints 
• Change and percent change from baseline to each visit in serum free light chains (FLCs), 
serum and 24-hour urine PEP, and serum and urine IFE  
2.3.4.8.4. Disease-Related Symptoms 
Disease-related symptoms include macroglossia, submandibular nodes/fullness, adenopathy, 
ecchymoses, edema, ascites, and liver/spleen size. Table 2 defines each symptom’s scoring. 
Table 2: 
Disease-Related Symptoms Scoring  
 Symptom 
Score Definition 
Macroglossia 
0 
Absent 
 
1 
Patient reports that tongue is enlarged and it appears mild to the 
observer. Patient is able to close mouth and swallow without 
difficulty. 
 
2 
Patient reports difficulty in swallowing but is able to close mouth 
fully. 
 
3 
Patient is unable to close mouth fully but able to swallow. 
 
4 
Patient has significant difficulties in swallowing fluid or food. 
 
 
 
Submandibular 
nodes/fullness 
0 
Absent 
 
1 
Fullness but no discrete adenopathy identified by observer 
 
2 
Discrete adenopathy, largest lymph node (LN) ≤ 2 cm  


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 Symptom 
Score Definition 
 
3 
Discrete adenopathy, largest LN >2 cm but ≤ 4 cm 
 
4 
Discrete adenopathy, largest LN >4 cm 
 
 
 
Adenopathy 
0 
Absent 
 
1 
Discrete adenopathy in ≤ 2 LN stations identified by observer 
 
2 
Discrete adenopathy in > 2 LN stations, largest LN ≤ 2 cm 
 
3 
Discrete adenopathy in > 2 LN stations, largest LN >2 cm but ≤ 4 cm 
 
4 
Discrete adenopathy in > 2 LN stations, largest LN >4 cm 
 
 
 
Ecchymoses 
0 
Absent 
 
1 
Discrete ecchymosis in ≤ 2 locations identified by observer 
 
2 
Discrete ecchymosis in > 2 but < 10 locations, largest ecchymosis ≤ 5 
cm 
 
3 
Discrete ecchymosis in > 2 but < 10 locations, largest ecchymosis > 5 
cm 
 
4 
Discrete ecchymosis in > 10 locations 
 
 
 
Edema 
0 
No edema 
 
1 
Slight pitting, normal contour 
 
2 
Moderate deeper pitting, contour preserved 
 
3 
Deeper pitting, contour preserved 
 
4 
Deep persistent pitting, contour not preserved, and appears puffy 
 
 
 
Ascites 
0 
Positive 
 
1 
Negative 
 
 
 
Liver/spleen size 
palpable 
0 
Positive 
 
1 
Negative 
Disease-related symptoms at each visit will be evaluated including any changes from baseline. 


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2.3.4.8.5. Pharmacokinetics (PK) 
Data on serum NEOD001 concentrations from this study will be pooled with data from similar 
samples from other studies in a population PK analysis. Population PK analyses will be reported 
separately from the NEOD001-201 CSR. 
2.3.5. 
Safety Endpoints 
Safety and tolerability of NEOD001 as assessed by vital signs, 12-lead ECGs, routine laboratory 
assessments, AEs, and immunogenicity by measurement of anti-NEOD001 antibodies. 


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3. 
SAMPLE SIZE JUSTIFICATION 
For the primary endpoint, the assumed true rates for NEOD001 vs placebo are 50% and 22.5%, 
respectively. Based on a two-sample comparison of proportions at the alpha=0.05 level of 
significance, a total sample size of 100 subjects (50 in the NEOD001 arm, 50 in the placebo arm) 
will provide >80% power based on a two-sided Cochran-Mantel-Haenszel (CMH) test. Based on 
the actual enrolled sample size (N~130), the final power is 91%. 


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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 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 
(Q1) and 75th (Q3) quartiles, 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 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., 
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 (KM) 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 two-sided 95% CIs comparing groups will be provided. 
4.2. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS software Version 9.4 or higher, 
unless otherwise noted. Medical history and AEs will be coded using Medical Dictionary for 


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Regulatory Activities (MedDRA) version 19.0. Concomitant medications will be coded using 
World Health Organization (WHO) Drug Dictionary, B2 Enhanced December 2015. 
4.3. 
Partial Dates and Unknown Times 
If only a partial date is available and is required for calculation, the following standards will be 
applied: 
• 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). 
• 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 
the same year as the last known alive date, then the partial date will be imputed to 
equal the last known alive date.  
• Diagnosis 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). 
• Start Dates (e.g., event date, adverse event [AE] onset date, or start date of medication) 
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 Imputed start dates must be prior to the stop date. 
• Stop Dates (e.g., AE resolution date or stop date of medication) 


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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: 
• 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. 
• 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. 
• 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  
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. 
4.4. 
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).  
4.5. 
Standard Calculations 
Variables requiring calculation will be derived using the following formulas: 
• 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 


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• Months – A duration expressed in months is calculated as the number of days divided by 
30.4375 
• 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 
• 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. 
• Height – Height entries made in inches (in) are converted to centimeters (cm) using the 
following formula: 
height (cm) = height (in) × 2.54 
• Weight – Weight entries made in pounds (lb) are converted to kilograms (kg) using the 
following formula: 
weight (kg) = weight (lb) / 2.205 
• Temperature – Temperature entries in degrees Fahrenheit are converted to degrees 
Celsius using the following formula: 
temp (degrees Celsius) = 5 / 9 × (temp [degrees Fahrenheit] – 32) 
• 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) 
• Change from baseline – Change from baseline will be calculated as: 
Change = post baseline value – baseline value 
• Percent change from baseline – Change from baseline will be calculated as: 
Percent change from baseline = ([post baseline value – baseline value] / baseline 
value) × 100 
4.6. 
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 every 28 days (±5 days) based 
on the first infusion date. For reporting purposes, the nominal visits will be used for the by-visit 
analyses. Details of the protocol defined visits and visit windows are given in the protocol and 
Table 1. In the event of unscheduled visits, re-test assessments, or ETD assessments, these will 
be reassigned to a scheduled visit for analysis purposes according to Table 3 and Table 4 below. 
If multiple visits occur within a single visit window, after reassignment of unscheduled visits and 
ETD visits, then the visit closest to the target day of the visit window will be used in the analysis. 


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If there is a tie, the later visit will be used in the analysis. Unscheduled assessments that do not 
collect time will not be mapped to any scheduled visit/timepoint. 
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.  
Table 3: 
1-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 
Month 2 
28 
14 
42 
Month 3 
56 
43 
70 
Month 4 
84 
71 
98 
Month 5 
112 
99 
126 
Month 6 
140 
127 
154 
Month 7 
168 
155 
182 
Month 8 
196 
183 
210 
Month 9 
224 
211 
238 
Month 10 
252 
239 
266 
Month 11 
280 
267 
294 
Month 12 
308 
295 
319 [EEOS Low – 1] 
EEOSc 
338 
320 [Month 12 Low + 30 – 5] 
354 [Month 12 High + 30 + 5] 
a Study day will be calculated from first dose date.  
b Baseline is defined in Section 2.2.7. 
c EEOS is defined in Section 2.2.8. 


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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 
14 
98 
Month 6 
140 
99 
182 
Month 9 
224 
183 
266 
Month 12 
308 
267 
319 [EEOS Low – 1] 
EEOSc 
338 
320 [Same definition as table 3] 
354 [Same definition as table 3] 
a Study day will be calculated from first dose date.  
b Baseline is defined in Section 2.2.7. 
c EEOS is defined in Section 2.2.8. 
In data listings, the relative study day from first infusion of all dates will be presented. 


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5. 
ANALYSIS POPULATIONS  
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
• 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. 
• The Efficacy Evaluable (EE) Population will include all subjects in the ITT Population who 
do not have any important protocol deviations (as defined prior to database lock and 
unblinding) and have at least one post baseline efficacy outcome measure of SF-36v2 PCS 
score or 6MWT distance.  
• 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 treatment received. 


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6. 
EXAMINATION OF SUBGROUPS 
Subgroups will be defined based on baseline values, unless otherwise specified, and only if there 
are a sufficient number of subjects in each category of the subgroup (e.g., >5 subjects per 
treatment group). 
General baseline subgroups of interest are as follows: 
• Age categories:  <65 vs ≥65 years 
• Sex:  Male vs Female 
• Race:  White vs All Other Races (Black or African American, Asian, Native Hawaiian or 
Other Pacific Islander, American Indian or Alaska Native) 
• Geographic Region:  North America vs Europe/Rest of World 
• Derived Qualifying Screening NT-proBNP (from central lab):  <1800 ng/L vs ≥1800 
ng/L 
Special baseline population subgroups of interest are as follows: 
• Age categories:  <75 vs ≥75 years 
• Baseline Renal Function:  eGFR < 30 mL/min.1.73m2 vs ≥ 30 to < 60 mL/min.1.73m2 vs 
≥ 60 mL/min.1.73m2 
Efficacy baseline subgroups of interest are as follows: 
• IWRS randomization stratification factor for NT-proBNP:  <1800 ng/L vs ≥1800 ng/L 
• IWRS randomization stratification factor for hematological response to first line therapy:  
CR/VGPR vs PR 
• Derived hematological response to first line therapy as reported on the eCRF:  CR/VGPR 
vs PR 
• NYHA Class (Appendix 6):  I vs II vs III/IV 
• Number of prior regimens for amyloidosis:  1, 2, ≥3  
The primary and key secondary efficacy endpoints will be analyzed for the general and efficacy 
baseline 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 the baseline 
special population subgroups using the Safety population as specified in Section 9. Subgroup 
characteristics will be summarized by treatment group. During the CSR preparation, additional 
subgroup analyses may be performed. Those analyses will be considered as ad-hoc analyses and 
will be presented and discussed in the CSR. 


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7. 
STUDY POPULATION 
7.1. 
Subject Disposition 
Subject disposition will be tabulated 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. 
Time on study in months will be calculated as (last known date of contact minus date of 
randomization plus one)/30.4375. Time on study drug in months will be calculated as (last 
infusion date minus first infusion date plus one)/30.4375. KM estimates of the distribution of the 
time-to-study discontinuation and time-to-treatment discontinuation will be tabulated and 
graphed by treatment group. The tabulation will include the KM estimate of the medians, 25th 
and 75th percentiles, and corresponding 95% CIs, if estimable. The tabular and graphical 
summaries will include the at-risk counts for every visit. In addition, the number and percentage 
of subjects who complete scheduled visits will be presented. Scheduled visit names will be 
footnoted to clarify that nominal visits are spaced every 28 days based on study drug infusion 
occuring every 4 weeks. 
The number and percentage of subjects randomized by geographical region and site will be 
presented by treatment group and overall for the ITT population. The same summary will be 
presented by calendar year and month. 
A summary table will be produced of the IWRS stratification factors and the combined stratum 
groups: 
• Hematologic response; CR/VGPR vs PR to first-line therapy 
• Screening NT-proBNP <1800 ng/L vs ≥1800 ng/L 
• Stratum Group 1:  CR/VGPR, <1800 ng/L 
• Stratum Group 2:  CR/VGPR, ≥1800 ng/L 
• Stratum Group 3:  PR, <1800 ng/L 
• Stratum Group 4:  PR, ≥1800 ng/L 
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 separately. 
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. Also by-subject 
listings of informed consent and eligibility critieria details will be presented. 
7.2. 
Demographics and Baseline Characteristics 
Demographic variables will include the following: 
• Age at informed consent including the subgroups defined in Section 6. 


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• Sex 
• Race 
• Ethnicity 
Other baseline characteristics will include the following: 
• Weight (kg) 
• Height (cm) 
• 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] 
÷ subjects squared height [meters] × serum albumin [g/L]) will be presented. Frequencies of 
categorizations for the above characteristics as defined in Section 6 will also be summarized. 
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: 
• Age at AL amyloidosis diagnosis 
• Duration (months) since AL amyloidosis diagnosis 
• Increase in light chains identified prior to bone marrow biopsy (yes/no) 
• Number of prior regimens for amyloidosis  
• Duration (days) since last reported therapy for amyloidosis  
• Response to last reported therapy for amyloidosis (CR, VGPR, PR, NR) 
• Best response to previously reported therapy (CR, VGPR, PR, NR) 
• Duration (days) since best response to previously reported therapy for amyloidosis  
• Number of derived involved organs (1, 2, 3, or 4 organs:  cardiac, renal, peripheral 
neuropathy, and hepatic) as defined in Section 8.5  
• Number of physician assessed involved organs:  The Investigator also assessed other 
organ involvement including gastrointestinal, autonomic nervous system, lung, soft 
tissue/lymphatic, or other. (1, 2, 3, 4, or 5 organs) 


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• Total number of involved organs (derived plus physician assessed) 
• Screening and Baseline NT-proBNP (ng/L) 
• Renal Stage (Appendix 9):  I, II, III; I/II, III; I, II/III 
• Chronic Kidney Stage:  1, 2, 3, 4, 5 
• NYHA Class (Appendix 6):  I, II, III, IV; I/II vs III/IV 
• Baseline FLC Ratio:  Low (<0.26), Normal (0.26 – 1.65), High (>1.65) 
Historical NT-proBNP or BNP (if NT-proBNP is not available) will be listed including the date 
of assessment, number of days from first dose of study drug since the historical result, result, and 
result unit will be included in a by-subject data listing. Data collected for tissue typing will be 
presented in a listing. 
7.4. 
Disease History Specific AL Symptoms 
Disease history specific AL symptoms verbatim terms as recorded on the Disease History eCRF 
will be mapped to preferred terms (PT) and system organ classes (SOC) using MedDRA version 
19.0. AL symptoms will be summarized by SOC, PT, and treatment group using the Safety 
Population. Summaries will be ordered by descending order of total incidence of SOC and PT 
within each SOC.  
Disease history 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 preferred terms and system organ classes using 
MedDRA version 19.0.  
Medical history will be summarized by SOC, PT, and treatment group using the Safety 
Population. Summaries will be ordered by descending order of total incidence of SOC and PT 
within each SOC.  
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 
prior 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 and separately only important protocol deviations will be summarized by 
deviation category and presented in a by-subject data listing. 


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7.7. 
Pretreatment, Prior, and New Concomitant Medications 
Verbatim terms on the Concomitant Medicaion eCRF will be mapped to 
Anatomical Therapeutic Chemical (ATC) class and Preferred Name using the WHO Drug 
Dictionary, B2 Enhanced December 2015.  
Pretreatment medications are those medications with start and stop 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. If it cannot be determined whether the 
medication was a new concomitant medication due to a partial start or stop date or if the 
medication is taken on the same date as the first infusion of study drug, then it will be counted as 
a new concomitant medication.  
Due to the limited number of infusion-related reactions (IRRs) reported to date, premedication 
was not required, unless the Investigator observed an IRR with a prior infusion of study drug in 
an individual subject or if premedication is required by the Investigator’s institution for the 
administration of monoclonal antibodies. By definition, premedications administered prior to 
each infusion are new concomitant medications. Summaries of premedications are detailed in 
Section 9.1.1. 
Pretreatment medications will only be listed. Prior and new concomitant medications will be 
summarized for each treatment group by WHO ATC level 3, WHO ATC level 4, and preferred 
name using the Safety Population. Prior and new concomitant medications will also be 
summarized separately. These summaries will present the number and percentage of subjects 
using each medication. Subjects may have more than one medication per ATC level and 
preferred name. At each level of subject summarization, a subject is counted once if he/she 
reported one or more medications at that level. Each summary will be ordered by descending 
order of NEOD001 incidence of ATC level and preferred name within each ATC level. 


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8. 
EFFICACY ANALYSES  
All efficacy analyses will use the ITT Population, except where noted for the Efficacy Subset 
Populations (Section 8.5). If the total ITT and EE Population differ by more than 10 subjects, 
efficacy analyses will be repeated for the EE Population for relevant primary, key secondary, 
other secondary efficacy endpoint analyses, and select exploratory efficacy endpoints. All 
efficacy endpoints, recorded and derived, will be presented in by-subject data listings. The 
analyses of primary and key secondary endpoints will be repeated for the general and efficacy 
baseline subject subgroups as specified in Section 6. 
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 is unwilling to continue monthly visits, every effort will be 
made for the subject to return to the clinic and complete the Month 12-Day 1 Visit on schedule. 
Subjects who discontinue study drug before the end of the study should have an ETD Visit 30 
(±5) days after their final administration of study drug, and if willing, have assessments monthly 
per Appendix 12 . For randomized subjects who received any amount of study drug, vital status 
telephone calls will be conducted approximately 3 months after last visit and approximately 
every 3 months thereafter or until subject enrolls in a separate open-label study, death, or for up 
to 5 years. 
For the SF-36v2, missing data conventions for partially completed questionnaires are specified in 
Section 2.3.4.3.1. 
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 8.10.7). 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). These sensitivity analyses will only be performed for 
analyses where death or progression are events and only in cases where at least one subject is 
missing the relevant post-randomization data. Methods for handling missing data for time to 
event endpoints are included in the applicable study endpoint section because the censoring and 
event dates are specific to the events being analyzed. 
8.2.2. 
Responder Endpoints 
The primary analysis for best response analyses will consider a subject as a non-responder until a 
response is achieved. 


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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. To assess the 
effect of missing data as a sensitivity analyses, any subject who does not provide an assessment 
at the specified time point for the response definition will be considered as a non-responder, 
regardless of treatment group. For analyses using a 3-category response (response, stable, 
progression), any subject who does not provide an assessment at the specified time point for the 
defining of response will be considered to have progressed, regardless of treatment group. 
8.2.3. 
Parametric Analyses 
8.2.3.1. 
Missing Not at Random (MNAR):  Imputation for Deaths 
For the primary analysis of the SF-36v2 PCS score and NIS-LL total score, subjects who missed 
the EEOS visit due to death will be imputed as the worst EEOS value in the total population. 
Sensitivity analyses will be conducted imputing subjects who missed the EEOS visit due to death 
as:  Zero, i.e. no quality of life (SF-36); or 88 for NIS-LL, i.e. no neurological function.  
Exploratory analyses at other visits (i.e. not the EEOS visit) will use the same imputation 
methodology for time points at which no value is observed.  
8.2.3.2. 
Missing at Random (MAR):  Multiple Imputation 
For the primary analysis of the SF-36v2 PCS score and NIS-LL total score, subjects who missed 
the EEOS visit 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 nonmonotone 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. Other baseline characteristics that may be explored will be 
documented in the CSR. 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. 
8.2.3.3. 
MNAR:  Multiple Imputation Placebo-Based 
A placebo-based multiple imputation will be performed using a pattern mixture model under the 
assumption of MNAR for the following sensitivity analyses of the SF-36v2 PCS score and NIS-
LL total score: 
1) As a sensitivity analysis for those subjects who missed the EEOS visit for reasons other 
than death. 
2) As a sensitivity analyses for all subjects who missed the EEOS visit, regardless of reason.  


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For these analyses, the imputation model will be estimated using placebo subjects only. The 
imputation models will include randomization stratification factors, and baseline value of the 
endpoint and all previous values of the endpoint at each time point. See Ratitch and O’Kelly 
(2011) for additional details regarding the methodology used to obtain the placebo-based 
imputation datasets. Similar methods as described for the previous multiple imputation method 
will be used to produce a pooled LSM estimate of treatment difference. 
Additional pattern-mixture models may be explored should an unexpected pattern of reason for 
study or treatment discontinuation based on KM distributions or a high percentage (>20%) of 
missing data be observed for reasons other than reaching a primary endpoint. 
Exploratory analyses at other visits (i.e. not EEOS) will use the same imputation methodology 
for time points at which no value is observed. 
8.2.4. 
Non-Parametric Analyses 
8.2.4.1. 
Ranking 
For the primary analysis of 6MWT, subjects will be ranked as follows ordered from worst to 
best: 
1. Subjects who died prior to EEOS where time to death is used to rank earlier deaths worse 
than later deaths, 
2. Subjects who are missing EEOS and vital status is unknown at EEOS will be ranked 
according to time on study drug from worst (shortest time) to best (longest time) 
3. Subjects who are missing EEOS because the subject physically cannot perform the test, 
due to physical incapacity or other reason will be ranked according to time on study drug 
from worst (shortest time) to best (longest time) 
4. Subjects who are missing EEOS and are known to be alive will be ranked according to 
time on study drug from worst (shortest time) to best (longest time) 
5. Completed subject’s values will be ranked from worst (lowest distance) to best (highest 
distance) performance 
Sensitivity analyses of the ranking will be performed by  
a) Only including ranks 1 and 5 above, and for missing reasons besides death, duration 
on study will be used to rank with shorter duration worse than longer duration  
b) Only including ranks 1, 3, and 5 above, and duration on study will be used to rank 
subjects who did not die and who are physically able to perform the test with shorter 
duration worse than longer duration  
c) Imputing subjects who died and who are physically not able to perform the test as 
zero distance in meters first, then imputing ranks for missing data using ranks 2, 4, 
and 5 above 
d) Imputing subjects who died or who are physically not able to perform the test (due to 
physical incapacity, hospitalization, or other reason) as zero distance in meters first, 
then imputing other missing values as the median of the observed placebo subjects at 


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the specified visit, then ranking all values from worst (lowest distance) to best 
(highest distance) performance. 
The ranking paradigm with 5 levels and the ranking paradigms a and c above will also be used as 
sensitivity analyses for the SF-36v2 PCS score key secondary endpoint analyses. 
8.2.5. 
Last Observation Carried Forward (LOCF) 
As sensitivity analyses for changes from baseline in SF-36v2 PCS score, SF-36v2 MCS score, 
SF-36v2 subscales, and NIS-LL total and component scores, subjects who missed a scheduled 
visit will also have their missing visit values imputed using LOCF. For LOCF, each subject’s last 
non-missing observation will be carried forward to the missing visit observation.  
8.2.6. 
Complete Case Analysis 
As sensitivity analyses for changes from baseline in SF-36v2 PCS score, SF-36v2 MCS score, 
SF-36v2 subscales, and NIS-LL total and component scores will be analyzed for subjects with a 
non-missing baseline and specified visit assessment (i.e., complete case analysis). 
8.3. 
Interim Analyses and Data Monitoring 
8.3.1. 
Interim Analysis  
No interim analyses are planned for this study. 
8.3.2. 
Safety Monitoring Committee  
An independent Safety Monitoring Committee (SMC), consisting of at least 2 clinicians and a 
biostatistician not directly involved with the conduct of the trial, will meet to review specified 
blinded subject data during the conduct of the study. The purpose of these independent data 
reviews is to assess the totality of the safety data and provide a recommendation to the Sponsor 
for continuation of dosing or protocol modifications.  
There are 4 planned data review meetings and they are as follows:   
• After the 20th subject reaches Month 3-Day 1 
• After the 60th subject reaches the Month 3-Day 1 visit 
• After the last enrolled subject reaches Month 3-Day 1 
• After the last enrolled subject reaches Month 9-Day 1 
A non-scheduled meeting may be called at the discretion of the Chairperson or the request of the 
Sponsor. The purpose of these independent data review is to assess the totality of the safety data 
and provide recommendations to the Sponsor for continuation of dosing or protocol study 
modifications. Details are provided in the SMC Charter. 
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. 


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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 at screening answered as yes) and had a baseline Neuropathy Impairment 
Score–Lower Limbs (NIS-LL) total score of 2 or greater and at least one post-baseline NIS-LL 
total score. 
The Hepatic Evaluable Population will include subjects who had hepatic involvement defined as 
>1.5 × ULN alkaline phosphatase at baseline and at least one post-baseline assessment of 
alkaline phosphatase. 
8.6. 
Multiple Comparisons/Multiplicity 
For the primary and 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 
2. Placebo and NEOD001 will be compared with respect to change from baseline to 12 months 
of treatment in the SF-36v2 PCS score. 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 12 months 
of treatment 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 NT-proBNP slopes over 12 months of treatment will be compared. 
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 estimand for NT-proBNP (cardiac) best response is the difference in cardiac best response 
rate between treatment groups through 12 months of treatment in all randomized subjects with 
AL amyloidosis who received any amount of drug. 
The primary efficacy analysis will test the following hypothesis: 


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• H0:  The percentage of NT-proBNP best responders through 12 months of treatment is 
equal between placebo and NEOD001. 
• H1:  The percentage of NT-proBNP best responders through 12 months of treatment is 
different between placebo and NEOD001.  
The primary efficacy analyses will compare placebo and NEOD001 on the distribution of 
NT-proBNP (cardiac) best response through 12 months of treatment, at alpha level of 0.05, 
using a CMH test stratified by the randomization stratification factors. All visits after the first 
infusion of study drug will be included up to and through the EEOS visit to evaluate 12 
months of treatment. The number and percentage, with associated two-sided exact (Clopper-
Pearson) 95% CIs, of subjects in each category of best response (response, nonresponse) will 
be presented by treatment group.  
8.7.1. 
Additional Analyses of the Primary Endpoint 
A logistic regression (proportional odds model) 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 95% CI of the odds ratio will be 
presented. An odds ratio greater than 1 favors the NEOD001 treatment group.  
Cardiac response as 3 categories (response, stable, and progression) will be analyzed in the same 
manner described above, except ordinal logistic regression will be used for the analysis of 3 
category response. 
Cardiac response will also be analyzed according to Comenzo 2012 (Appendix 2), where a 
decrease ≥ 2 NYHA class from baseline (must have baseline class of 3 or 4) is also considered a 
response. The same statistical methods described above will be used to evaluate treatment 
differences.  
Cardiac progression will also be analyzed according to Comenzo 2012 (Appendix 2), where 
subject visits that meet renal progression (defined as an eGFR of < 30 mL/min/1.73 m2) will be 
excluded. The same statistical methods described above will be used to evaluate treatment 
differences.  
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 to 12 Months of Treatment 
The estimand for the SF-36v2 PCS score is the mean difference in SF-36v2 PCS score change 
from baseline between treatment groups at EEOS in all randomized subjects with AL 
amyloidosis who received any amount of study drug. 
The key secondary efficacy analysis will test the following hypotheses: 
• H0:  The mean change from baseline in the SF-36v2 PCS score after 12 months of 
treatment is equal between placebo and NEOD001. 


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• H1:  The mean change from baseline in the SF-36v2 PCS score after 12 months of 
treatment is different between placebo and NEOD001.  
For the primary analysis of the SF-36v2 PCS score, subjects who are missing EEOS due to 
death, will be imputed as the worst EEOS value in the total population. Subjects who are 
missing EEOS for reasons other than death, will be imputed using MI methodology using the 
total study sample. Sensitivity analyses to assess the effect of missing data are detailed in 
Section 8.2. 
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 EEOS visit to 
evaluate 12 months of treatment. 
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.  
A plot of the EEOS change from baseline values will be presented. If visual inspection of the 
data finds the normality assumption is violated, a non-parametric rank analysis of covariance 
model (ANCOVA) including fixed effects for randomization strata and treatment group, with the 
ranked baseline value included as a covariate will be used and the Hodges-Lehman estimate of 
the median treatment difference with associated 95% CI will be presented. A plot of the EEOS 
change from baseline ranks will be presented. If visual inspection of the ranks finds the 
normality assumption is violated, the change from baseline at EEOS in SF-36v2 PCS score will 
be analyzed using a van Elteren test with stratification by randomization strata. 
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 each 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. Mean SF-36v2 PCS scores with 
associated standard deviation error bars will be plotted by treatment group over time. LS mean 
change and percent change from baseline in SF-36v2 PCS score with associated StdErr bars will 
be plotted by treatment group over time. In addition, the cumulative distribution of change from 
baseline at the EEOS visit will be plotted. 


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8.8.2. 
6MWT Distance to 12 Months of Treatment 
The estimand for the 6MWT is the median difference in 6MWT distance change from baseline 
between treatment groups after 12 months of treatment in all randomized subjects with AL 
amyloidosis who received any amount of study drug.  
The key secondary efficacy analysis will test the following hypotheses: 
• H0:  The distribution of change from baseline in 6MWT distance (meters) after 12 months 
of treatment is equal between placebo and NEOD001. 
• H1:  The distribution of change from baseline in 6MWT distance (meters) after 12 months 
of treatment 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 EEOS where time to death is used to rank earlier deaths worse 
than later deaths 
2. Subjects who are missing EEOS and vital status is unknown at EEOS where duration on 
study is used to rank shorter duration worse than longer duration will be ranked according 
to time on study drug from worst (shortest time) to best (longest time) 
3. Subjects who are missing EEOS because the subject physically cannot perform the test, 
due to physical incapacity or other reason where duration on study is used to rank shorter 
duration worse than longer duration will be ranked according to time on study drug from 
worst (shortest time) to best (longest time) 
4. Subjects who are missing EEOS and are known to be alive where duration on study is 
used to rank shorter duration worse than longer duration will be ranked according to time 
on study drug from worst (shortest time) to best (longest time) 
5. Completed subject’s values will be ranked from worst (lowest distance) to best (highest 
distance) performance 
Sensitivity analyses to assess the effect of missing data are specified in Section 8.2. 
Descriptive statistics for 6MWT distance, change from baseline, and percent change from 
baseline will be presented by visit for each treatment group. The change from baseline at EEOS 
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. The Hodges-Lehman estimate of the median treatment difference with associated 95% 
CI will be presented.  
The rank ANCOVA assumes the ranked data are normally distributed and homogenous variance. 
A plot of the EEOS change from baseline ranks and the baseline ranks will be presented. If 
visual inspection of the ranks finds the normality assumption is violated, the change from 
baseline at EEOS in 6MWT distance (meters) will be analyzed using a van Elteren test with 
stratification by randomization strata. 
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:   


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• Incorrect course length 
• Use of unapproved course 
• Unapproved administrator of test 
• 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 
In addition, the cumulative distribution of change from baseline at EEOS will be plotted for each 
treatment group. 
The percent change from baseline will be analyzed in the same manner. 
In addition to the planned sensitivity analyses for handling of missing data (Section 8.2), subjects 
who have invalid tests recorded will be used (as if the test was completely correctly) instead of 
being considered as missing. 
8.8.3. 
NT-proBNP Slope Through 12 Months of Treatment  
The estimand for the NT-proBNP is the difference in slopes between treatment groups over 12 
months of treatment in all randomized subjects with AL amyloidosis who received any amount 
of study drug. 
The key secondary efficacy analysis will test the following hypotheses: 
• H0:  The rate of change (i.e., slope) of NT-proBNP over 12 months of treatment is equal 
between placebo and NEOD001. 
• H1:  The rate of change (i.e., slope) of NT-proBNP over 12 months of treatment is 
different between placebo and NEOD001.  
The primary analysis of NT-proBNP will be performed using a general linear mixed effects 
model to compare the rate of change (i.e., slope) of NT-proBNP over 12 months of treatment 
between 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. 


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8.9. 
Additional Secondary Efficacy Analysis 
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 12 months of treatment in all 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: 
• H0:  The percentage of renal best response through 12 months of treatment is equal 
between placebo and NEOD001. 
• H1:  The percentage of renal best response through 12 months of treatment is different 
between placebo and NEOD001.  
All visits after the first infusion of study drug up to and through the EEOS visit will be used to 
evaluate 12 months of treatment. Best renal response will be analyzed in the same manner 
described in Section 8.7 for the primary efficacy endpoint. 
If an assessment qualifies as both response and progression (see Section 2.3.3.1), then 
assessments will be counted as progression for the primary analysis. A sensitivity analysis will 
be conducted counting an assessment that qualifies both as response and progression as a 
response. 
8.9.2. 
Peripheral Neuropathy Evaluable Subjects:  NIS-LL Total Score  
The estimand for peripheral neurological function is the mean difference in NIS-LL total score 
change from baseline between treatment groups after 12 months of treatment in all 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: 
• H0:  The mean change from baseline in NIS-LL total score after 12 months of treatment is 
equal between placebo and NEOD001. 
• H1:  The mean change from baseline in NIS-LL total score after 12 months of treatment is 
different between placebo and NEOD001.  
The change from baseline in NIS-LL total score will be analyzed in the same manner described 
for SF-36v2 PCS score in Section 8.8.1. The EEOS visit will be used to evaluate 12 months of 
treatment. 
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 in 
addition to the other planned sensitivity analyses to support the interpretation of the treatment 
effect. 
8.9.3. 
Hepatic Evaluable Subjects:  Hepatic Best Response 
The estimand for hepatic best response is the difference in hepatic best response rate between 
treatment groups through 12 months of treatment in all randomized subjects with AL 
amyloidosis and hepatic involvement (Section 8.5) who received any amount of drug. 


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The secondary efficacy analysis will test the following hypotheses: 
• H0:  The percentage of hepatic best response through 12 months of treatment is equal 
between placebo and NEOD001. 
• H1:  The percentage of hepatic best response through 12 months of treatment is different 
between placebo and NEOD001.  
All visits after the first infusion of study drug up to and through the EEOS visit will be used to 
evaluate 12 months of treatment. Best hepatic response will be analyzed in the same manner 
described in Section 8.7 for the primary efficacy endpoint.  
8.10. 
Exploratory Efficacy Analyses  
For applicable exploratory efficacy analyses, if the assumptions of the planned parametric 
analyses are violated and inhibit the interpretation of the results, appropriate data transformations 
or parametric analyses will be performed in addition to the other planned sensitivity analyses to 
support the interpretation of the treatment effect. 
8.10.1. 
Cardiac Endpoint Analyses 
8.10.1.1. Cardiac Biomarkers:  NT-proBNP and Troponin T 
NT-proBNP and troponin T results, change from baseline, and percentage change from baseline 
will be analyzed in the same manner described in Section 8.8.1. In addition, the cumulative 
distribution of NT-proBNP change from baseline at EEOS will be plotted. 
Mean NT-proBNP values with associated standard deviation error bars will be plotted by 
treatment group over time, including a reference line at 1800 ng/L. LS mean change and 
percentage change from baseline in NT-proBNP with associated StdErr bars will be presented by 
treatment group over time.  
NT-proBNP best response will be determined for different time intervals, such as through 3, 6, 
and 9 months of treatment. Best response at each of these and response at each visit will be 
analyzed in the same manner described in Section 8.7 and Section 8.7.1.  
If sufficient mortality data are available, NT-proBNP best response will be evaluated as a 
potential predictor for the primary endpoint using a Cox regression model with time to the 
primary endpoint as the outcome, fixed effects for treatment group and NT-proBNP best 
response over different time intervals, and the treatment group × NT-proBNP best response 
interaction. In addition, NT-proBNP change from baseline as a continuous variable may also be 
evaluated as potential predictors of the primary endpoint. Similar analyses may be conducted for 
additional time to event endpoints. 
8.10.1.2. Select Echocardiogram Cardiac Parameters 
Descriptive statistics for Echocardiogram cardiac parameter (see Section 2.3.4.1.2) results, 
change from baseline, and percent change from baseline will be presented by visit for each 
treatment group. Change from baseline and percentage change from baseline will be analyzed 
using an ANCOVA model including fixed effects for randomization strata and treatment group, 
with the baseline value included as a covariate. 


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LVEF is captured in the eCRF as text to allow entry of ranges that may be recorded on the 
source document report. If the eCRF LVEF value contains only numbers, “%”, or “>” the 
numeric portion of the value will be used for LVEF summary. If the eCRF value contains a 
range, the midpoint of the range will be used as the value for LVEF summary.  
The number and percentage of subjects with LVEF (%) change from baseline categorized as 
follows will be summarized:  >20% Reduction, 10-20% Reduction, <10% Increase - <10% 
Reduction, 10-20% Increase, and >20% Increase. The number and percentage of subjects with 
LPWd (mm) change from baseline categorized as follows will be summarized:  ≥ 2 mm Increase 
and < 2 mm Increase. 
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.  
The 6MWT change from baseline will also be categorized as follows: 
• ≥ 30-meter decline (Worsening) 
• < 30-meter decline to < 30-meter improvement (No Change) 
• ≥ 30 -meter improvement (Improvement). 
The categorical change from baseline will be summarized by visit for each scheduled post-
baseline visit. For each post-baseline visit ordinal logistic regression will be performed with 
6MWT categorical change from baseline (Worsening, No Change, Improvement) as the 
dependent variable and factors for treatment group and randomization strata. Estimates of the 
proportional odds ratio comparing NEOD001 to placebo and the 95% CI of the odds ratio will be 
presented. An odds ratio greater than 1 favors the NEOD001 treatment group. 
8.10.3. 
Quality of Life Endpoint Analyses 
8.10.3.1. SF-36v2  
In addition to the key secondary endpoint, the SF-36v2 PCS and MCS scores and the eight 
subscales to all visits will be analyzed in the same manner described in Section 8.8.1. The 
cumulative distribution of change from baseline at the Month 9 visit will also be plotted. 
The rate of change (i.e. slopes) in the SF-36v2 PCS and MCS scores and the eight subscales 
will be analyzed in the same manner described in Section 8.8.3. 
Table 5 below presents the responder definitions recommended by Optum for SF-36v2 domains 
and component summary scores. 


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Table 5: 
Responder Criteria for SF-36v2 Domains and Summary Measures  
 SF-36v2 Domain 
Responder Threshold (≥) 
Physical Functioning (PF) 
4.3 
Role-Physical (RP) 
3.4 
Bodily Pain (BP) 
6.2 
General Health Perceptions (GH) 
7.2 
Vitality (VT) 
6.2 
Social Functioning (SF) 
6.9 
Role-Emotional (RE) 
4.5 
Mental Health (MH) 
6.2 
Physical Component Summary (PCS) 3.4 
Mental Component Summary (MCS) 
4.6 
Response will be defined as greater than or equal to the specified threshold and non-response 
will be less than the specified threshold. Response will be derived for each subject at each 
visit for each subscale, MCS score, and PCS score. NEOD001 and placebo will be compared 
on each response distribution at each visit using a CMH test stratified by the randomization 
stratification factors. The number and percentage, with associated two-sided 95% CIs, of 
subjects in each category of response (response, nonresponse) at each visit will be presented 
by treatment group.  
8.10.3.2. KCCQ 
All KCCQ subscores and overall summary score, changes and percent changes from baseline to 
all visits will be analyzed in the same manner described in Section 8.8.1. 
The rate of change (i.e. slopes) in the KCCQ subscores and overall summary score will be 
analyzed in the same manner described in Section 8.8.3. 
8.10.4. 
Renal Endpoint Analyses 
The following endpoints will be evaluated in the Renal Evaluable Population, unless otherwise 
specified. 
8.10.4.1. Renal Response 
In addition to the secondary endpoint for the Renal Evaluable Population, renal best response 
will be determined for different time intervals, such as through 3, 6, and 9 months of treatment. 
Best response at each of these time intervals and response at each visit will be analyzed in the 
same manner described in Section 8.9.1. 
8.10.4.2. Renal Biomarkers 
Renal biomarkers (urine albumin/creatinine ratio, urinary neutrophil gelatinase-associated 
lipocalin [NGAL] and urinary retinol-binding protein [RBP]) results, change from baseline, and 


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percent change from baseline to all visits will be analyzed in the same manner described in 
Section 8.8.1. Renal biomarkers will be evaluated in the Renal Evaluable Population and 
repeated for the ITT Population. 
8.10.4.3. Creatinine, Proteinuria, and eGFR 
Creatinine, proteinuria (measured by 24-hour urine total protein excretion), and estimated 
glomerular filtration rate (eGFR) to all visits will be analyzed in the same manner described in 
Section 8.8.1. Creatinine, Proteinuria, and eGFR will be evaluated in the Renal Evaluable 
Population and repeated for the ITT Population. 
Shifts in Chronic Kidney Stage from baseline to worst post-baseline value, last post-baseline 
value, best post-baseline value, and at each post-baseline visit will be provided by treatment 
group. Shifts in Chronic Kidney Stage will be evaluated in the Renal Evaluable Population and 
repeated for the ITT Population. 
8.10.5. 
Peripheral Neuropathy Endpoint Analyses 
The following endpoints will be evaluated in the Peripheral Neuropathy Evaluable Population. 
8.10.5.1. NIS-LL Total and Component Scores 
In addition to the secondary endpoint for the Peripheral Neuropathy Evaluable Population, the 
NIS-LL total scores at other visits and the 3 deficit component scores (sensory function, reflexes, 
muscle strength) to all visits will be analyzed in the same manner described in Section 8.9.2. 
Peripheral neuropathy response and progression as defined in Coelho 2012 (Appendix 2), are 
those with an increase from baseline in NIS-LL total score of <2 points and those with an 
increase from baseline in NIS-LL of ≥2 points, respectively. Response at each visit will be 
analyzed in the same manner described in Section 8.7 for the primary efficacy endpoint. 
Peripheral neuropathy response at each visit will be analyzed in the same manner described in 
Section 8.7. 
The rate of change (i.e. slopes) in the NIS-LL component scores and total score will be analyzed 
in the same manner described in Section 8.8.3. 
8.10.5.2. VASPI  
For the Peripheral Neuropathy Evaluable Population with painful neuropathy, defined as a 
baseline VASPI score > 0, the change and percent change from baseline at in VASPI scores will 
be analyzed in the same manner described in Section 8.8.1. 
8.10.6. 
Hepatic Endpoint Analyses 
The following endpoints will be evaluated in the Hepatic Evaluable Population. 
8.10.6.1. Hepatic Response 
In addition to the secondary endpoint, for subjects in the Hepatic Evaluable Population, hepatic 
best response will be determined for different time intervals, such as through 3, 6, and 9 months 
of treatment. Hepatic best response at each of these time intervals and response at each visit will 
be analyzed in the same manner described in Section 8.9.3.  


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Alkaline phosphatase values, change from baseline, and percent change from baseline to all 
visits will be analyzed in the same manner described in Section 8.8.1. 
8.10.7. 
Additional Time-to-Event Endpoints 
8.10.7.1. Time to All-Cause Mortality (Overall Survival) 
Overall survival, time to all-cause mortality, will be calculated in days as the date of death minus 
the date of first study drug infusion plus 1. Subjects will be censored at their last assessment 
known to be alive prior to LSLV.  
NEOD001 will be compared to placebo using the log rank test stratified by the randomization 
stratification factors. Kaplan-Meier (KM) estimates of the distribution 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 estimable. The tabular and 
graphical summaries will include the at-risk counts for every visit. The number and percent of 
subjects censored and with events will be presented. The hazard ratio and 95% CI will be 
determined based on a Cox regression model stratified by randomization strata to estimate the 
magnitude of the effect. 
In addition, the frequency of deaths in NEOD001 and placebo will be analyzed in the same 
manner described in Section 8.7 for the primary efficacy endpoint. 
8.10.7.2. Cardiac Progression-Free Survival 
Cardiac progression is defined as NT-proBNP progression of >30% increase and >300 ng/L 
increase or death. Cardiac progression will not be evaluated in the presence of renal progression, 
defined as an eGFR of < 30 mL/min/1.73 m2, according to Comenzo 2012 (Appendix 2). 
Progression-free survival is defined as the time from first infusion of study drug to the earliest of: 
• first documented date of disease progression (as defined by NT-proBNP 
[Section 2.3.4.1.1]) or  
• withdrawal from treatment or study due to organ (cardiac) progression or  
• death on the study or  
• death following withdrawal from treatment due to any cause.  
Progression-free survival will be calculated in days as the earliest of the above dates (disease 
progression or death) minus the date of first infusion of study drug plus 1.  
Subjects who are alive with no documented progression prior to the end of the study will be 
censored at the earliest of their date of the first assessment that meets renal progression (defined 
as an eGFR of < 30 mL/min/1.73 m2), date of the last NT-proBNP measurement, or date they 
withdraw consent or are lost to follow-up.  
NEOD001 will be compared to placebo using the log rank test stratified by the randomization 
stratification factors. KM estimates of the distribution 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 percentiles, and corresponding 95% CIs, if estimable. The tabular and graphical 
summaries will include the at-risk counts for every visit. The number and percent of subjects 


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censored and with events will be presented overall and for each visit, using last day of the visit 
window. The hazard ratio and 95% CI will be determined based on a Cox regression model 
stratified by randomization strata to estimate the magnitude of the effect.  
In addition, a sensitivity analysis will be performed counting death or progression without 
subsequent response as an event. 
8.10.7.3. Duration of Cardiac Response 
Cardiac response is defined as >30% decrease and >300 ng/L decrease in NT-proBNP from 
baseline.   
Duration of cardiac response is defined for subjects experiencing response as the time from the 
earliest cardiac response to the first documented date of disease progression, as defined by NT-
proBNP progression of >30% increase and >300 ng/L increase. Subjects without response will 
be excluded from this analysis.   
Duration of Cardiac Response will be calculated in days as the date of disease progression minus 
the date of first response plus 1.  
Subjects will be censored at their date of the last NT-proBNP measurement if they complete the 
study or discontinue with no documented progression. 
NEOD001 will be compared to placebo using the log rank test stratified by the randomization 
stratification factors. KM estimates of the distribution of the time-to-event will be tabulated and 
graphed by treatment group. The tabulation will include the summary statistics as described for 
continuous variables in Section 4.1, KM estimate of the medians, 25th and 75th percentiles, and 
corresponding 95% CIs, if estimable. The tabular and graphical summaries will include the at-
risk counts for every visit. The number and percent of subjects censored and with events will be 
presented overall and for each visit, using last day of the visit window. The hazard ratio and 95% 
CI will be determined based on a Cox regression model stratified by randomization strata to 
estimate the magnitude of the effect.  
In addition, a sensitivity analysis will be performed for subjects experiencing response as the 
time from the earliest cardiac response to the first documented date of disease progression 
without subsequent response. 
8.10.7.4. Time to Derived Organ Progression 
The following time-to progression endpoints will be analyzed in the same manner described in 
Section 8.10.7.1. 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. 
• Time (months) to cardiac progression calculated as:  (date first assessed with progression 
(Section 8.7) - the date of first study drug infusion + 1) / 30.4375. Subjects who do not 
experience progression will be censored at the date of last NT-proBNP assessment.  
• For renal evaluable subjects, time (months) to renal progression calculated as:  (date first 
assessed with progression (Section 8.9.1) - the date of first study drug infusion + 1) / 


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30.4375. Subjects who do not progress will be censored at the date of last eGFR 
assessment.  
• Time (months) to cardiac or renal progression calculated as:  (earliest date assessed as a 
NT-proBNP or renal progressor - the date of first study drug infusion + 1) / 30.4375. 
Subjects who do not progress will be censored at the minimum of the last NT-proBNP 
assessment date or last eGFR assessment date.  
8.10.7.5. Time to First Organ Response 
The following time-to response endpoints will be analyzed in the same manner described in 
Section 8.10.7.1.  
• Time (months) to first cardiac response calculated as:  (date first assessed with response 
(Section 8.7) - 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.  
• For renal evaluable subjects, time (months) to first renal response calculated as:  (date 
first assessed with response (Section 8.9.1) - the date of first study drug infusion + 1) / 
30.4375. Subjects who do not respond will be censored at the date of last proteinuria 
(urine total protein) assessment.  
• Time (months) to cardiac or renal response calculated as:  (earliest date assessed as a 
cardiac or renal responder - the date of first study drug infusion + 1) / 30.4375. Subjects 
who do not respond will be censored at the minimum of the last NT-proBNP assessment 
date, last proteinuria (urine total protein) assessment date, or last eGFR assessment date.  
8.10.8. 
Other Efficacy Analyses 
8.10.8.1. Cardiac Hospitalizations  
Hospitalization reason will be coded using MedDRA version 19.0. Any adverse event with a 
preferred term in the broad standardized MedDRA query (SMQ) definition of Cardiac Failure or 
in the SMQ definition of Cardiac Arrhythmias that results in hospitalization will be counted as a 
Cardiac Hospitalization.  
Time to first cardiac hospitalization admission will be calculated in days as the date of first 
cardiac hospitalization admission minus the date of first study drug infusion plus 1. Subjects who 
do not experience an event will be censored at the date of last contact. NEOD001 will be 
compared to placebo using the same methods described in Section 8.10.7.1. In addition, the time 
to recurrent cardiac hospitalization, i.e., time to next cardiac hospitalization after the first, will be 
analyzed in the same manner. 
The number of cardiac hospitalizations per subject over the course of the study will be 
summarized both as a continuous and categorical variable by treatment group. A Poisson 
regression model will be fit using the continuous number of cardiac hospitalizations as the 
dependent variable, the total time in study as the offset variable, and treatment group as a factor. 
The number of cardiac hospitalizations per subject will be categorized as 0, 1, and ≥2. The 
categorical variable will be analyzed using a CMH test stratified by the randomization 
stratification factors. The number and percentage, with associated two-sided 95% CIs, of 
subjects in each category will be presented by treatment group. An ordinal logistic regression 


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will be performed with categorical number of hospitalizations (0, 1, and ≥2) as the dependent 
variable and factors for treatment group and randomization strata.  
8.10.8.2. ECOG Performance Status, NYHA Class, Renal Stage 
The number and percentage of subjects in each ECOG Performance Status (Appendix 5), NYHA 
class (Appendix 6), and Renal Stage (Appendix 9; separately) at each visit will be presented by 
treatment group. Shift tables in a contingency table from baseline to worst post-baseline value, 
last post-baseline value, best post-baseline, and at each post-baseline visit will be provided for by 
treatment group.  
8.10.8.3. Selected Hematological and Urine Analyte Analyses 
Serum FLCs, serum PEP, and serum and urine IFE results will be summarized by treatment 
group using descriptive statistics at baseline, each post-baseline visit, minimum value, and 
maximum value. The change and percentage change from baseline will also be summarized and 
analyzed in the same manner described in Section 8.8.1.  
8.10.8.4. Disease-Related Symptoms  
The number and percentage of subjects in each category of response and best response through 
12 months of treatment will be presented by treatment group.  
In addition, shift tables in a contingency table from baseline to worst post-baseline value, last 
post-baseline value, best post-baseline value, and at each post-baseline visit will be provided by 
treatment group. 
8.10.8.5. 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. Details will be described in a 
separate analysis plan and reported separately from the NEOD001-201 CSR. 
8.10.8.6. PK/PD Analyses 
PK/PD analyses will be described in a separate analysis plan and reported separately from the 
CSR. 


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9. 
SAFETY ANALYSES 
Safety analyses will be conducted using the Safety Population.  
No inferential comparison of safety endpoints will be performed, unless otherwise specified.  
9.1. 
Extent of Exposure 
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 of a treatment group 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 will be summarized by treatment group and will include: 
• The number of subjects exposed to NEOD001, the total PEY, and duration of exposure 
will be summarized using descriptive statistics. This summary will be repeated for all 
general and special baseline subgroups defined in Section 6. 
• 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.  
• Percentage of Expected Infusions will be determined for each subject as the total number 
of infusions received divided by the total number of expected infusions multiplied by 
100. Total number of expected infusions will be defined as the maximum of (the total 
number of infusions received, and the floor of ((EOS/ETD date - first infusion date + 
1)/28), i.e. integer part of the function). 
• Total Number of Dose Interruptions will be determined for each subject by the number of 
times the IV was not completed. 
• Dose Strength (mg/kg) will be calculated for each subject for each visit. Total dose (mg) 
per infusion is not captured on the eCRF. Total dose (mg) is captured in the materials kit 
schedule maintained by IWRS. After unblinding, the total dose in mg will be calculated 
as the number of NEOD001 vials infused at each visit per IWRS, multiplied by 500 mg 
per vial. Total dose (mg) will be divided by the weight used to calculate total dose. If the 
total dose (mg) is missing but the total duration of infusion is 120 +/- 10 minutes for 
Month 1-Day 1 or the total duration of infusion is 60 +/10 minutes for visits after Month 
1-Day1 and IV completed is marked “Yes” then total dose will be imputed to be equal to 
the planned dose strength (described below). Dose strength will only be calculated where 
both the total dose and weight used are available. Once visit/individual specific Dose 
Strengths are determined, subjects will be assigned a single average Dose Strength value 
across all visits to be used for summary statistics in the table. 


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• Percent of Planned Dose Strength will be determined by dividing the actual dose strength 
by the planned dose strength. Calculation of actual dose strength is described above. 
Planned dose strength will be determined in a similar manner except the planned dose 
will be calculated by multiplying the reported NEOD001 dose concentration by the 
weight used.  
• Total Number of Dose Reductions will be determined for each subject by the number of 
times the percent of planned dose was less than 100. 
9.1.1. 
Use of Premedication 
The use of premedications will be summarized for any infusion and by each planned infusion by 
treatment group and will include the following:   
• Total Number of Subjects Infused 
• Total Number of Infusions Administered:  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. 
• Number of Subjects Receiving Premedication 
• For subjects receiving premedication, number of infusions requiring premedication per 
subject:  note that because this value is by definition 1 for by-infusion summaries, this 
should only be presented for the any-infusion summary. 
• For subjects requiring premedication, number of premedications per subject per infusion. 
All recorded and derived exposure data will be presented in a by-subject data listing and any 
dose modifications will be flagged. 
9.2. 
Adverse Events 
Verbatim terms on eCRFs will be mapped to PTs and SOCs 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). 
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 through the 
last study visit or up to 30 days after date of last dose, whichever is later. 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. Summaries of the following types will be presented: 
• Overall summary of AEs including the number and percent of subjects with at least one 
of the following: 
o Any TEAE 


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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 infusion interruption  
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 
- Infusion associated TEAE with premedication concomitant medication for 
infusion related reaction 
- Infusion associated TEAE without premedication concomitant medication for 
infusion related reaction 
o TEAE leading to study drug withdrawal  
• Subject incidence of TEAEs by MedDRA SOC and PT. This summary will be repeated 
for all general and special baseline population subgroups defined in Section 6. 
• Subject incidence of TEAEs by MedDRA SOC and PT occurring in ≥5% of NEOD001 
subjects with greater frequency than placebo. 
• Subject incidence of TEAEs by MedDRA SOC and PT occurring in ≥10% of NEOD001 
subjects with greater frequency than placebo. 
• Subject incidence of TEAEs by MedDRA SOC and PT occurring with greater frequency 
than placebo.  
• Subject incidence of TEAEs by MedDRA SOC and PT occurring in NEOD001 subjects 
at frequencies of Very common (≥10%); Common (≥1 to <10%); Uncommon (≥0.01 to 
<1%); Rare (≥0.001 to <0.01%); Very rare (< 0.001%). 
• Subject incidence of TEAEs by MedDRA SOC, PT, and highest severity (CTCAE 
grade). At each level of subject summarization, a subject is classified according to the 
highest severity if the subject reported 1 or more events. AEs with missing severity 
(CTCAE grade) will be considered grade 3 (severe) for this summary.  
• Subject incidence of CTCAE grade 3 or higher TEAEs by MedDRA SOC and PT. At 
each level of subject summarization, a subject is classified according to the highest 
severity if the subject reported 1 or more events. AEs with missing severity (CTCAE 


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grade) will be considered grade 3 (severe) for this summary. This summary will be 
repeated for the general and special baseline population subgroups defined in Section 6. 
• Subject incidence of TEAEs by MedDRA SOC, PT, and closest relationship to study 
drug (Related/Not Related). At each level of subject summarization, a subject is classified 
according to the closest relationship to study drug if the subject reported 1 or more 
events. AEs with a missing relationship will be considered related for this summary. 
• Subject incidence of related TEAEs by MedDRA SOC and PT. At each level of subject 
summarization, a subject is classified according to the closest relationship to study drug if 
the subject reported 1 or more events. AEs with a missing relationship will be considered 
related for this summary. 
• Subject incidence of related CTCAE grade 3 or higher TEAEs by MedDRA SOC and PT. 
At each level of subject summarization, a subject is classified according to the highest 
severity if the subject reported 1 or more events. AEs with missing severity (CTCAE 
grade) will be considered grade 3 (severe) for this summary. AEs with a missing 
relationship will be considered related for this summary. 
• Subject incidence of serious TEAEs by MedDRA SOC and PT. This summary will be 
repeated for all general and special baseline population subgroups defined in Section 6.  
• Subject incidence of serious related TEAEs by MedDRA SOC and PT. At each level of 
subject summarization, a subject is classified according to the closest relationship to 
study drug if the subject reported 1 or more events. AEs with a missing relationship will 
be considered related for this summary. 
• Subject incidence of TEAEs leading to study drug withdrawal by MedDRA SOC and PT. 
This is a subset of the AEs where Action Taken with Study Treatment is checked as 
“Drug Permanently Withdrawn” is checked. 
• Subject incidence of TEAEs leading to infusion interruption by MedDRA SOC and PT. 
This is a subset of the AEs where Action Taken with Study Treatment is checked as 
“Dose Interrupted” is checked. 
• Subject incidence of TEAEs leading to dose reduction by MedDRA SOC and PT. This is 
a subset of the AEs where Action Taken with Study Treatment is checked as “Dose 
Reduced” is checked. 
• Subject incidence of TEAEs leading to dose held by MedDRA SOC and PT. This is a 
subset of the AEs where Action Taken with Study Treatment is checked as “Dose Held” 
is checked. 
• Subject incidence of TEAEs leading to prolongation of infusion time (>2.5 hours) by 
MedDRA SOC and PT. 
All of the above tables will be repeated only for MedDRA PT, excluding MedDRA SOC. 
The following listings will be presented by treatment group and subject: 
• All AEs 
• SAEs (this is a subset of the AEs where serious is marked as “Yes”) 


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• CTCAE Grade 3 or higher AEs (this is a subset of AEs where severity is marked as 
CTCAE grade 3, 4, or 5) 
• Related AEs (this is a subset of the AEs where relationship marked as “Related”) 
• AEs leading to Study Drug Withdrawal (this is a subset of the AEs where Action Taken 
with Study Treatment is checked as “Drug Permanently Withdrawn”) 
• AEs leading to death (This is a subset of the AEs where outcome is indicated as “Fatal” 
or the CTCAE grade is 5) 
• AEs resulting in any dose change (i.e. interruption, reduction, held, or prolongation)  
• All adverse events for subjects who received the wrong study drug 
9.2.1. 
Other Adverse Events:  Infusion Reactions  
The incidence of infusion associated TEAEs by MedDRA SOC and PT will be summarized by 
treatment group and presented in a listing. This is a subset of the AEs where the question “Was 
the event an infusion-associated adverse event?” is checked “Yes”. Summaries will be repeated 
for all general baseline subgroups indicated in Section 6.  
A separate summary will also be presented by planned infusion number. A TEAE will be 
counted based on AE and infusion start dates. For example, if an AE starts after infusion #2 but 
before infusion #3, the AE will be counted under infusion #2. 
If applicable, the incidence of anaphylactic reaction, defined as the broad algorithmic SMQ of 
“Anaphylactic reaction” given in Appendix 13 will be summarized by treatment group. 
In order to explore the temporal relationship of TEAEs that may be associated with the infusion, 
the incidence of all TEAEs occurring within 24 hours (1 day) of an infusion will be summarized 
by treatment group and presented in a listing. In addition, for this subset of TEAEs, the following 
will be summarized by treatment group for any infusion and at each infusion overall and by PT: 
• the number and percent of subjects infused  
• the number and percent subjects experiencing an event within 24 hours  
• the number of the events  
• descriptive statitstics for the number of events per subject  
• descriptive statistics for the duration (days) of the events  
TEAEs will be counted as occurring within 24 hours (1 day) of an infusion if: 
• the start date/time of the TEAE is not missing and the infusion start date/time ≤ the start 
date/time of the TEAE ≤ the infusion start date/time + 24 hours or 
• the start time of the TEAE is missing and the TEAE start date = the infusion start date or 
the TEAE start date = the infusion start date + 1 day. 
9.3. 
Clinical Laboratory Evaluations 
All laboratory assessments are given in Appendix 10. Laboratory parameters will be summarized 
in standard international (SI) system of units.  


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The following normal ranges will be used where not provided in the central laboratory data: 
• INR Upper Limit of Normal (ULN) = 1.1 
• Creatinine Clearance Lower Limit of Normal (LLN) = 90 mL/sec = 1.5 mL/min 
• eGFR LLN = 90 mL/min/1.73m2 
All clinical laboratory data will be presented in by-subject data listings. In addition, separate 
listings will be presented for any subject with a post-baseline CTCAE grade 3 or 4 laboratory 
value. Normal ranges provided by the central laboratory will be presented in a listing. 
9.3.1. 
Serum Chemistry, Hematology, and Coagulation 
Quantitative serum chemistry, hematology, and coagulation results by treatment group using 
descriptive statistics at baseline and at each post-baseline visit. The change and percentage 
change from baseline will also be summarized.  
9.3.2. 
Inflammatory Biomarkers 
Inflammatory biomarker (Appendix 10) results, change from baseline, and percentage change 
from baseline will be summarized in the same manner described in Section 9.3.1.  
9.3.3. 
Shifts in CTCAE Grade 
Quantitative laboratory tests will be assigned grades based on CTCAE Version 4.03, where 
applicable. Shifts in CTCAE grade of laboratory tests will be presented from baseline to worst 
post-baseline value, last post-baseline value, best post-baseline value, and at each post-baseline 
visit. Summaries will present the number and percentage of subjects with shifts in laboratory 
grade by treatment group. Denominators for percentages will be the number of subjects with 
non-missing data at the specific assessment and baseline. 
These summaries of shifts in CTCAE grade will be repeated for general baseline subgroups as 
described in Section 6. 
In addition, for each laboratory test 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. 
Where applicable, if the quantitative criteria for grading are equivalent for two grades, only 
differentiated by clinical interventions, the clinical intervention will be ignored and the highest 
CTCAE grade will be used. 
For urine protein, values of TRACE or NEGATIVE will be considered normal. 
9.3.4. 
Shifts in Normal Range 
In addition, for laboratory tests that cannot be graded via CTCAE, shift tables (i.e., low-normal-
high at baseline versus low-normal-high at post-baseline visit in a 3-by-3 contingency table) 
from baseline to worst post-baseline value, last post-baseline value, best post-baseline value, and 
at each post-baseline visit will be presented for by treatment group. Denominators for 
percentages will be the number of subjects with non-missing data at the specific assessment and 
baseline. 


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9.3.5. 
Pregnancy Testing and Urinalysis Dipstick 
All pregnancy test results and urinalysis dipstick results will not be summarized but will be 
provided in a by-subject data listing.  
9.4. 
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 summarized by treatment group using 
descriptive statistics at baseline and at each post-baseline visit. In addition, change and percent 
change from baseline will be presented.  
9.5. 
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. Method of 
collection will be provided in the listing, however summaries will be generated without regard to 
the method of collection. Pulse pressure, the difference between diastolic and systolic blood 
pressure, will be calculated. Mean arterial pressure will be calculated as the pulse pressure, 
divided by 3, plus the diastolic blood pressure. 
Summaries of vital sign parameter results, change from baseline, and percentage change from 
baseline will be summarized by treatment group using descriptive statistics at baseline and at 
each post-baseline visit. In addition, change and percent change from baseline will be presented 
from pre-dose to post-dose at each infusion visit.  
9.6. 
Electrocardiograms 
ECGs measurements will be made in triplicate, 5 to 10 minutes apart and assessed by a central 
reader. For summary purposes the mean of the three measurements will be used. 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] will be summarized by treatment group. 
Descriptive statistics will be presented for observed values and changes from baseline at each 
post-baseline time point.  
A categorical summary of the following abnormal maximum mean triplicate QTcF values will be 
presented by treatment group:  >450 msec, >480 msec, and >500 msec. Change from baseline 
summaries will also be presented for measurements that represent a change from baseline of >30 
msec and >60 msec. Three separate listings for those subjects with any QTcF >450 msec or a 
QTcF change from baseline >30 msec, any QTcF >480 msec or a QTcF change from baseline 
>30 msec, and any QTcF >500 msec or a QTcF change from baseline >60 msec will be 
presented. The observation(s) meeting criteria for inclusion will be flagged in the listing.  
QTcF will be assigned grades based on CTCAE Version 4.03, without regard to the clinical 
assessment necessary for Grade 4. Shifts in QTcF CTCAE grade will be presented from baseline 
to worst post-baseline value, last post-baseline value, and at each post-baseline visit. Summaries 
will present the number and percentage of subjects with shifts in grade by treatment group. 
Denominators for percentages will be the number of subjects with non-missing data at the 
specific assessment and baseline. 


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Overall interpretation results for ECGs and the investigator interpretation results are collected as 
normal, abnormal not clinically significant, and abnormal clinically significant. Subjects whose 
interpretation shifts from normal to abnormal clinically significant or not clinically significant 
will be listed separately including description of the abnormality and any associated comments. 
All ECG results will be presented in by-subject data listings. 
9.7. 
Physical Examination 
Analysis of disease-related symptoms collected on the Physical Examination eCRF are detailed 
in Section 8.10.8.4. 
Other physical examination findings based on body systems entered on the eCRF will be 
included in a data listing only. 
9.8. 
Immunogenicity Analyses 
Immunogenicity of NEOD001 will be assessed by anti-NEOD001 antibody levels. Any sample 
found to be confirmed positive for anti-NEOD001 antibodies will be further evaluated by a 
neutralizing antibody assay. Serum anti-NEOD001 antibody levels will be listed and, if sufficient 
data exist, summarized by treatment group. Serum anti-NEOD001 antibody levels may be 
correlated with serum NEOD001 concentrations and select safety endpoints, if sufficient data 
exist.  


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10. 
CHANGES TO PROTOCOL PLANNED ANALYSES 
Per Protocol A3, Section 8.3.4:  “All exploratory quantitative endpoints, except the 6MWT…. 
will be analyzed in the same manner described for the SF-36v2…”. The exploratory analyses of 
LVEF are performed per Section 8.10.1.2 of this SAP.  
Appendix 4 of the protocol, footnotes a and b, state “In addition to the progression criteria listed 
above, the 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.” and 
“Subjects with progressively worsening renal function cannot be scored for NT-proBNP 
progression.”  Repeat assessments were only done using local laboratories and therefore not 
included in the central laboratory data for inclusion in analyses. In addition, per the SAP renal 
progression is not considered for the primary endpoint analyses and is only included as a 
sensitivity analysis. 
Renal endpoints other than renal response will be repeated for the ITT population.  
The Safety Population was updated to use treatment received for all subjects instead of 
randomized treatment. 
The following endpoints were removed: 
• Time to eGFR ≤15 mL/min/1.73 m2 (Chronic Kidney Stage 5)  
• Time to doubling of creatinine 
• Time to peripheral neuropathy organ progression  
• Time to peripheral neuropathy organ response 
• Time to hepatic organ progression 
• Time to hepatic organ response 
• Hematologic response at each visit 
• Hematologic best response through 3, 6, 9, and 12 months of treatment  
• Mayo Clinic Stage including any subgroup analyses 
• Peripheral neuropathy best response through 3, 6, 9, and 12 months of treatment 


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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. 
American Thoracic Society (ATS). ATS statement:  guidelines for the six-minute walk test. Am 
J Respir Crit Care Med. 2002;166:111–117. 
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. 
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. 
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. 
Maruish ME. User’s manual for the SF36v2 health survey (3rd ed.). Lincoln, RI:  QualityMetric, 
Inc.; 2011. 
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. 
Palladini G, Barassi A, Klersy C, et al. The combination of high-sensitivity cardiac troponin T 
(hs-cTnT) at presentation and changes in N-terminal natriuretic peptide type B (NT-proBNP) 
after chemotherapy best predicts survival in AL amyloidosis. Blood. 2010;116(18):3426-30. 
Rubin DB. 1987. Multiple Imputation for Nonresponse in Surveys. New York:  John Wiley and 
Sons. 
Ratitch B, O’Kelly M. Implementation of Pattern-Mixture Models Using Standard SAS/STAT 
Procedures. PharmaSUG 2011. http://www.pharmasug.org/proceedings/2011/SP/PharmaSUG-
2011-SP04.pdf. Accessed 10 December 2017. 


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12. 
APPENDICES 


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APPENDIX 1. 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) 
Abbreviations:  dFLC = difference between involved and uninvolved free light chains. 
*Only applicable for subjects who had dFLC > 50 mg/L (5 mg/dL) prior to treatment. 
Source:  Comenzo 2012. 


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APPENDIX 2. ORGAN RESPONSE AND PROGRESSION CRITERIA 
Organ 
Response 
Progression 
Heart/Cardiaca,b 
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)b 
NT-proBNP progression (>30% 
and >300 ng/L increase)c 
Renald  
≥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 
Nervef 
NIS-LL increase from baseline of <2 points 
NIS-LL increase from baseline of 
≥2 points 
Liver/Hepatica,e  
50% decrease in ALP value from baseline 
OR 
≥2 cm reduction in liver size 
radiographicallye 
≥50% increase in ALP from baseline 
Abbreviations:  ALP = alkaline phosphatase; eGFR = estimated glomerular filtration rate; NIS-LL = Neuropathy Impairment 
Score–Lower Limbs; NT-proBNP = N-terminal pro brain natriuretic peptide; NYHA = New York Heart Association.  
a 
Modified from Table 2 in Comenzo 2012.  
b  
NYHA class not considered for primary efficacy endpoint analyses.  
c 
Subjects with progressively worsening renal function cannot be scored for NT-proBNP progression.  
d 
Palladini 2014. 
e  
Liver size was not collected and is therefore not considered for evaluation of hepatic response. 
f 
Coelho 2012. 
 
 


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APPENDIX 3. NEUROPATHY IMPAIRMENT SCALE – LOWER LIMBS 
 


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APPENDIX 4. VISUAL ANALOG SCALE – PAIN INTENSITY (VASPI)  
 


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APPENDIX 5. EASTERN COOPERATIVE ONCOLOGY GROUP 
(ECOG) PERFORMANCE STATUS 
Grade 
Description 
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. 


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APPENDIX 6. 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. 
Source:  American Heart Association 2015. 


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APPENDIX 7. SF-36V2 HEALTH SURVEY 
 


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APPENDIX 8. KANSAS CITY CARDIOMYOPATHY QUESTIONNAIRE 
(KCCQ) 
 


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APPENDIX 9. RENAL STAGE 
Renal Staging 
Test 
Value 
Score 
Proteinuria [Total Protein] 
≤5 g/24 hours 
0 
 
>5 g/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. 
RCSource: Palladini 2014. 


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APPENDIX 10. LABORATORY TESTS 
Serum Chemistry: 
ALP (E)a 
ALT (E) 
AST (E) 
Bilirubin - total (E) and direct 
GGT 
BUN 
LDH 
Creatinine (E) 
Glucose 
Cholesterol 
Triglycerides 
Calcium 
Phosphate 
Protein - total 
Albumin 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Magnesium 
Amylase 
Creatine kinase  
Uric acid 
Estimated glomerular filtration rate (E)e 
Estimated creatinine clearance 
Cystatin C 
Hematology: 
Hemoglobin (E) 
Hematocrit 
RBC 
WBC 
Neutrophils (absolute [E], %) 
Lymphocytes (absolute, %) 
Monocytes (absolute, %) 
Eosinophils (absolute, %) 
Basophils (absolute, %) 
Platelet count (E) 
Otherb: 
Serum anti-NEOD001 antibodiesc 
Serum NEOD001 concentration 
Serum FLCsd 
24-hr urine protein excretion & total volume 
Serum & 24-hr urine PEP 
Serum & urine IFE 
Inflammatory Biomarkersb: 
IL-6 
IL-8 
TNF-alpha 
INF-gamma 
Complements C3, C4, and CH50 
CRP 
SAA (A-SAA) 
Tryptase 
Urinalysis - Dipstick: 
Color & clarity 
Specific gravity 
pH 
Protein 
Glucose  
Ketones 
Bilirubin 
Urobilinogen 
Blood 
Nitrite 
Leukocyte esterase 
Microscopic 
Urinalysis - Quantitative 
Analysis/Renal 
Biomarkersf: 
Urine albumin/creatinine 
ratio 
Urine NGAL 
Urine RBP  
Cardiac Biomarkers: 
Troponin T 
NT-proBNP  
Coagulation: 
PT/INR 
PTT 
Additional indices - see Appendix 11  
Women of childbearing potential only: 
Serum beta hCG pregnancy tests (E) 


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Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; A-SAA = acute phase serum 
amyloid A; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CRP = C-reactive protein; (E) = 
may be used for eligibility; FLCs = free light chains; GGT = gamma-glutamyl transpeptidase; hCG = human 
chorionic gonadotropin; IFE = immunofixation electrophoresis; IL = interleukin; INF = interferon; 
LDH = lactate dehydrogenase; NGAL = neutrophil gelatinase-associated lipocalin; NT-proBNP = N-terminal 
pro-brain natriuretic peptide; PEP = protein electrophoresis; PT/INR = prothrombin time/international 
normalized ratio; PTT = partial thromboplastin time; RBC = red blood cell; RBP = retinol-binding protein; 
SAA = serum amyloid A; TNF = tumor necrosis factor; WBC = white blood cell. 
a 
Including isozymes for subjects with ALP >5 × upper limit of normal.  
b 
See details in protocol Section 5.4.2 regarding collection of samples in cases of suspected systemic infusion-
related/hypersensitivity reactions. 
c 
Any sample found to be confirmed positive for anti-NEOD001 antibodies may be further evaluated by a 
neutralizing antibody assay. 
d 
Including dFLC (difference between involved and uninvolved FLCs) and FLC ratio. 
e 
GFR = 141 × min (Scr /κ, 1)α × max(Scr /κ, 1)-1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black] where:  
Scr = serum creatinine in mg/dL; κ = 0.7 for females, 0.9 for males; α = -0.329 for females, -0.411 for males; 
min = the minimum of Scr /κ or 1; max = the maximum of Scr /κ or 1. 
f 
It is important that the sample be taken before exercising and at approximately the same time for each 
collection; therefore, the first morning void is recommended. Urine samples to be collected and frozen for 
potential future analysis. 
 


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APPENDIX 11. COAGULATION INDICES 
For each coagulation time point in Table 1, citrated plasma samples will be 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: 
Test Name 
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 
 
 
 
 


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APPENDIX 12. SCHEDULE OF EVENTS FOR SUBJECTS WHO 
DISCONTINUE STUDY DRUG EARLY BUT AGREE TO RETURN 
FOR ASSESSMENTS AFTER THE ETD VISIT  
 Assessment or Procedure 
Monthly 
Day 1 (±5 days)1 
Every 3 Months after 
Last Visit 
Clinical 
Prior/Concomitant Medications/Therapy 
X 
 
Adverse Event Assessment 
X 
 
Physical Exam2 
X 
 
Vital Signs3 
X 
 
ECOG PS/NYHA Class4 
X 
 
NIS-LL & VASPI5 
X 
 
SF-36v26 
X 
 
KCCQ7 
X 
 
6MWT8,9 
X (Months 3, 6, 9, 12) 
 
Echocardiogram10 
X (Month 12) 
 
ECG (12-lead triplicate)11 
X (Months 3, 6, 9, 12) 
 
Laboratory16 
Hematology & Chemistry (including amylase and 
creatine kinase)12 
X 
 
Coagulation13 
X 
 
Inflammatory Biomarkers14 
X (Month 3)15 
 
Troponin T 
X 
 
NT-proBNP8 
X 
 
Pregnancy (WOCBP)  
X17 
 
Serum Free Light Chain 
X (Months 3, 6, 9, 12) 
 
Serum IFE & PEP 
X (Months 3, 6, 9, 12) 
 
Urinalysis – Dipstick18 
X (Months 3, 6, 9, 12) 
 
Urinalysis - Quantitative/Renal Biomarkers19 
X (Months 3, 6, 9, 12) 
 
24-hour Urine Collection: 
 
 
Urine IFE & PEP 
X (Months 3, 6, 9, 12) 
 
Urine Protein Excretion 
X (Months 3, 6, 9, 12) 
 
Other 
Anti-NEOD001 Serum Sample 
X20 
 
Vital Status Phone Call 
 
X21 


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BP = blood pressure; ECG = electrocardiogram; ECOG PS = Eastern Cooperative Oncology Group performance 
status; ETD = Early Treatment Discontinuation; HR = heart rate; IFE = immunofixation electrophoresis; 
KCCQ = Kansas City Cardiomyopathy Questionnaire; NIS-LL = neuropathy impairment score – lower 
limbs; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; 
PEP = protein electrophoresis; RR = respiratory rate; 6MWT = 6-minute walk test; SF-36v2 = Short Form-36v2® 
Health Survey; VASPI = visual analog scale – pain intensity; WOCBP = women of childbearing potential. 
1. 
Study visits will occur every 28 days based on scheduling from Month 1-Day 1. A ±5-day window is allowed 
for visits starting after Month 1. If a subject discontinues study drug rior to the end of the study, but is willing 
to continue to participate in study visits, the subject should have an ETD Visit per Table 1 and then have 
assessments performed monthly, through Month 12, if willing. The most important visit is the Month 12-Day 1 
Visit, so if a subject is unwilling to continue monthly visits, every effort should be made for the subject to 
return and complete the Month 12-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. An 
EOS Visit will not be conducted. 
2. 
Conduct a directed physical examination, including weight, and the components of the exam as clinically 
indicated. Assess macroglossia, submandibular nodes/fullness, adenopathy, ecchymoses, liver/spleen size 
(palpable +/-), ascites (+/-), and edema (which should be quantified on a scale of 0-4). 
3. 
Vital signs include HR, RR, BP, and body temperature; assess any time during visit after subject has been at 
rest ≥5 minutes. 
4. 
See Appendix 5  (ECOG) and Appendix 6  (NYHA). 
5. 
See Appendix 3  (NIS-LL; for all subjects with peripheral neuropathy at Screening) and Appendix 4 (VASPI; 
for subjects with painful peripheral neuropathy at Screening). 
6. 
See Appendix 7; SF-36v2 should be administered before performing any other study assessments on the same 
calendar day it is administered. 
7. 
See Appendix 8; administer KCCQ after the SF-36v2, but before conducting any other assessments on the 
same calendar day it is administered. 
8. 
NT-proBNP should be drawn before conducting 6MWT if being performed on the same calendar day. 
9. 
Collect BP and HR pre- and post-6MWT administration. 
10. Perform echocardiogram locally within 10 days before Day 1.  
11. Perform ECGs centrally any time during visit.  
12. Hematology and chemistry per Appendix 10. 
13. Collect PT/INR and PTT monthly. Collect citrated plasma samples as clinically indicated 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 11 . 
14. Inflammatory biomarkers per Appendix 10  
15. Collect additional samples as clinically indicated, such as when significant toxicity occurs per protocol Section 
5.4.2. 
16. All laboratory tests to be done centrally, unless otherwise noted. Please refer to Laboratory Manual for details. 
17. Obtain local laboratory serum pregnancy test 90 (±5) days after the last study drug administration.  
18. Per Appendix 10 . 
19. Per Appendix 10. t is important that the sample be taken before exercising and at approximately the same time 
for each collection; therefore, the first morning void is recommended. Urine samples will be collected and 
frozen for potential analysis at a later date. 
20. Anti-NEOD001 serum samples:  Collect if an earlier sample established the presence of anti-NEOD001 
antibodies or if a subject discontinued treatment due to a suspected immunologic reaction. 
21. For randomized subjects who received at least 1 dose of study drug, conduct vital status telephone call 
approximately 3 months after last visit and approximately every 3 months thereafter or until subject enrolls in 
a separate open-label study, death, or for up to 5 years. 
 
 


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APPENDIX 13. ANAPHYLACTIC REACTION SMQ 
An Adverse Event or group of Adverse Events starting on the same day should be flagged as 
Anaphylactic Reaction per SMQ if the AE(s) meets one or more of the following criteria: 
• Any term from Group A 
• Any two terms, with one from Group B and one from Group C 
• Any two terms, with one from Group D and one from either Group B or Group C 
 
Group A Terms 
Preferred Term 
Preferred Term Code 
Anaphylactic reaction 
10002198 
Anaphylactic shock 
10002199 
Anaphylactic transfusion reaction 
10067113 
Anaphylactoid reaction 
10002216 
Anaphylactoid shock 
10063119 
Circulatory collapse 
10009192 
Dialysis membrane reaction 
10076665 
Kounis syndrome 
10069167 
Shock 
10040560 
Shock symptom 
10040581 
Type I hypersensitivity 
10045240 
 
Group B Terms 
Preferred Term 
Preferred Term Code 
Acute respiratory failure 
10001053 
Asthma 
10003553 
Bronchial oedema 
10056695 
Bronchospasm 
10006482 
Cardio-respiratory distress 
10049874 
Chest discomfort 
10008469 
Choking 
10008589 
Choking sensation 
10008590 
Circumoral oedema 
10052250 


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Group B Terms 
Cough 
10011224 
Cyanosis 
10011703 
Dyspnoea 
10013968 
Hyperventilation 
10020910 
Irregular breathing 
10076213 
Laryngeal dyspnoea 
10052390 
Laryngeal oedema 
10023845 
Laryngospasm 
10023891 
Laryngotracheal oedema 
10023893 
Mouth swelling 
10075203 
Nasal obstruction 
10028748 
Oedema mouth 
10030110 
Oropharyngeal oedema 
10078783 
Oropharyngeal spasm 
10031111 
Oropharyngeal swelling 
10031118 
Pharyngeal oedema 
10034829 
Respiratory arrest 
10038669 
Respiratory distress 
10038687 
Respiratory failure 
10038695 
Reversible airways obstruction 
10062109 
Sensation of foreign body 
10061549 
Sneezing 
10041232 
Stridor 
10042241 
Swollen tongue 
10042727 
Tachypnoea 
10043089 
Throat tightness 
10043528 
Tongue oedema 
10043967 
Tracheal obstruction 
10044291 
Tracheal oedema 
10044296 
Upper airway obstruction 
10067775 
Wheezing 
10047924 
 


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Group C Terms 
Preferred Term 
Preferred Term Code 
Allergic oedema 
10060934 
Angioedema 
10002424 
Erythema 
10015150 
Eye oedema 
10052139 
Eye pruritus 
10052140 
Eye swelling 
10015967 
Eyelid oedema 
10015993 
Face oedema 
10016029 
Flushing 
10016825 
Generalised erythema 
10051576 
Injection site urticaria 
10022107 
Lip oedema 
10024558 
Lip swelling 
10024570 
Nodular rash 
10075807 
Ocular hyperaemia 
10030041 
Oedema 
10030095 
Periorbital oedema 
10034545 
Pruritus 
10037087 
Pruritus allergic 
10063438 
Pruritus generalised 
10052576 
Rash 
10037844 
Rash erythematous 
10037855 
Rash generalised 
10037858 
Rash pruritic 
10037884 
Skin swelling 
10053262 
Swelling 
10042674 
Swelling face 
10042682 
Urticaria 
10046735 
Urticaria papular 
10046750 
 


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Group D Terms 
Preferred Term 
Preferred Term Code 
Blood pressure decreased 
10005734 
Blood pressure diastolic decreased 
10005737 
Blood pressure systolic decreased 
10005758 
Cardiac arrest 
10007515 
Cardio-respiratory arrest 
10007617 
Cardiovascular insufficiency 
10065929 
Diastolic hypotension 
10066077 
Hypotension 
10021097