Conditions: Cold Agglutinin Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 42
Healthy volunteers: no

Brief summary:
The purpose of Part A was to determine whether sutimlimab administration resulted in a greater than or equal to (\>=)1.5 grams per deciliter (g/dL) increase in hemoglobin (Hgb) level and avoidance of transfusion in participants with primary cold agglutinin disease (CAD) without a recent history of blood transfusion. The purpose of Part B was to evaluate the long-term safety and tolerability of sutimlimab in participants with primary CAD.

Detailed description:
The planned total study duration per participant was approximately 1.5 to 2.5 years.

Arms:
arm 1: Participants with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an intravenous (IV) infusion of BIVV009 6.5 g (for participants less than \[\<\]75 kilograms \[kg\]) or 7.5 g dose (for participants greater than or equal to \[\>=\]75 kg) on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25. Participants who completed Part A per protocol through the end of treatment visit (Week 26), received placebo on Week 26 and continued to receive BIVV009 6.5 or 7.5 g in Part B, every 2 weeks starting at Week 27 for up to an additional 149 weeks (for 6.5 g) or 121 weeks (for 7.5 g). All participants who completed Part A elected to continue in Part B. arm 2: Participants with primary CAD and without a recent history of blood transfusion during the last 6 months prior to enrollment in this study, received an IV infusion of placebo matched to BIVV009 on Day 0 and Day 7 and every 14 days thereafter in Part A up to Week 25. Participants who completed Part A per protocol through the end of treatment visit (Week 26) received BIVV009 6.5 (if \<75 kg) or 7.5 g (if \>=75 kg) in Part B, on Week 26 and Week 27 and every 2 weeks thereafter for up to an additional 123 weeks (for 6.5 g) or 137 weeks (for 7.5 g). All participants who completed Part A elected to continue in Part B.

Interventions: intervention 1: sutimlimab (BIVV009) intervention 2: placebo
Intervention descriptions: intervention 1: Pharmaceutical form: solution for injection Route of administration: intravenous (i.v.) intervention 2: Pharmaceutical form: solution for injection Route of administration: intravenous (i.v.)

Protocol document:
Prot_000.pdf: 
PROTOCOL BIVV009-04 (EFC16216) 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to 
Assess the Efficacy and Safety of BIVV009 in Patients with 
Primary Cold Agglutinin Disease Without a Recent  
History of Blood Transfusion 
IND #128190  
EudraCT #2017-003539-12 
Version 1: 24 August 2017  
Version 1.1: 09 September 2017 
Version 3: 21 March 2018  
Version 4: 29 June 2018  
Version 5: 19 July 2018  
Version 6: 15 October 2019  
Version 7: 07 July 2020 
Version 8: 04 November 2020 
Bioverativ USA, Inc. 
225 Second Avenue 
Waltham, MA 02451 
This study will be performed in compliance with Good Clinical Practice. 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ USA Inc. 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
Document 
Country/countries 
impacted by amendment 
Date 
Protocol Version 8 
All 
04 November 2020 
Protocol Version 7 
All 
07 July 2020 
Protocol Version 6 
All 
15 October 2019 
Protocol Version 5 
All 
19 July 2018 
Protocol Version 4 
Not implemented 
29 June 2018 
Protocol Version 3.1 
Japan 
27 March 2018 
Protocol Version 3 
All, except Japan 
21 March 2018 
Protocol Version 2 
Not implemented 
NA 
Protocol Version 1.6 
Italy 
29 January 2018 
Protocol Version 1.5 
Belgium 
10 January 2018 
Protocol Version 1.4 
France 
15 December 2017 
Protocol Version 1.3 
Norway 
06 December 2017 
Protocol Version 1.2 
UK 
29 November 2017 
Protocol Version 1.1 
All 
09 September 2017 
Protocol Version 1 (original) 
All 
24 August 2017 
Present amendment (Version 8) to the protocol 04 November 2020 
This is a global amendment to protocol Version 7 and is regarded as a substantial amendment 
based on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European 
Parliament and the Council of the European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
The primary reasons for this amendment to Protocol BIVV009-04 (Cadenza), Version 8 are: 
• To include post-infusion vital signs assessment for patients who will receive undiluted 
infusions, 
• To clarify that the hematology panel and Direct Antiglobulin Test (DAT) are performed 
at the site local laboratory and not at the central laboratory, 
• To change for Part A the statistical method for the primary efficacy endpoint (responder 
status) in using the Cochran-Mantel-Haenszel (CMH) test instead of the Fisher’s Exact 
test, 
• To remove reference to the study procedural manual and replace it with the specific 
manuals. 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Section # and name Description of change 
Brief rationale 
Title Page, Approval of 
the Protocol, Protocol 
Amendment Summary of 
Changes Table 
Document formatting revisions. 
The change was made to reflect the update 
of the amended protocol version 8 and 
include a previous protocol version.  
Section 1 Synopsis: 
Safety Outcome 
Measures 
“Post-infusion vital signs and” were added to the 
list of endpoints for the patients receiving 
undiluted infusions. 
The changes were made in relation to the 
inclusion of post-infusion vital signs 
assessment for the subset of patients 
receiving undiluted infusions of the IMP. 
Section 1 Synopsis: 
Statistical Methods 
Regarding the primary endpoint (responder 
status) analysis for Part A, the Fisher’s Exact test 
was replaced by “Cochran-Mantel-Haenszel 
(CMH) test”. 
The primary efficacy analysis method was 
changed and will use the Cochran–Mantel–
Haenszel (CMH) test instead of the 
Fisher’s exact test to apply a statistically 
more powerful method with regard to the 
small sample size setting, and to ensure 
consistency in primary analysis and 
sensitivity analyses for the primary 
endpoints. 
Section 4.3.5 Safety 
Endpoints 
“Post infusion vital signs and” were added to the 
list of endpoints for the patients receiving 
undiluted infusions. 
The changes were made in relation to the 
inclusion of post-infusion vital signs 
assessment for the subset of patients 
receiving undiluted infusions of the IMP. 
Section 6.1 Schedule of 
Study Procedures: Table 
3, footnote “l” 
The following text was added: 
“or for post-infusion vital signs in case of undiluted 
administration, after each undiluted infusion”.  
The changes were made in relation to the 
inclusion of post-infusion vital signs for 
patients receiving undiluted infusions of the 
IMP for a subset of patients. 
Section 6.1.1.1 Screening 
assessments (initiating at 
Day -42) 
The following text in the Bone Marrow Biopsy was 
removed:  
“in the study procedural manual” and replaced by: 
“in Appendix A (Bone Marrow Biopsy Report 
Review Process) to the ‘Subject Eligibility Review 
Process Overview’”. 
As study procedural manual was not 
created, references to this document 
across the protocol were either removed or 
replaced by references to the applicable 
study manuals.  
Section 6.1.1.3 
Confirmatory review of 
patient eligibility 
The following text was removed: “forms and the 
adjudication process may be found in the study 
procedural manual” and replaced by “process may 
be found in the ‘Subject Eligibility Process 
Overview’”. 
As study procedural manual was not 
created, references to this document 
across the protocol were either removed or 
replaced by references to the applicable 
study manuals. 
Section 6.1.5.6 Infusion 
of the Undiluted Study 
Drug 
This following text was added: “Post-infusion vital 
signs will be collected for these patients”.  
The changes were made in relation to the 
inclusion of post-infusion vital signs 
assessment for the subset of patients 
receiving undiluted infusions of the IMP. 
Section 6.2.2 Patient 
number and identification 
The following text was removed: “Details on 
patient number assignments will be available in 
the study procedural manual.” 
As study procedural manual was not 
created, references to this document 
across the protocol were either removed or 
replaced by references to the applicable 
study manuals. 
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Section # and name Description of change 
Brief rationale 
Section 6.2.3 
Randomization 
The following text was modified:  
Details on the randomization process are will be 
available in the study procedural manual eCRF 
Completion Guidelines. 
As study procedural manual was not 
created, references to this document 
across the protocol were either removed or 
replaced by references to the applicable 
study manuals. 
Section 6.2.5 Blinding 
The following text was removed:  
“Further details on blinding procedures will be 
provided in the study procedural manual”.   
As study procedural manual was not 
created, references to this document 
across the protocol were either removed or 
replaced by references to the applicable 
study manuals. 
Section 6.3.7 Clinical 
Laboratory Evaluations  
The following text was removed:  
“For efficacy evaluations results from the central 
laboratory (when collected and available) will be 
recorded in the eCRF and utilized for analyses.” 
As the hematology panel tests are 
performed at the site local laboratory, the 
reference to the central laboratory was 
removed from this section.  
Section 7.1 Description of 
Objectives and Endpoints  
The following text was modified:  
“For endpoints involving laboratory parameters, 
except for hematology panel, results from the 
central laboratory will be used. Local laboratory 
values were utilized for Direct Antiglobulin Test 
(DAT) for, among others, eligibility purposes and 
hematology panel that allows both determination 
of eligibility and the medical management of the 
patient, with assessment of the hemoglobin 
criteria necessitating blood transfusions.” 
As the hematology panel tests and Direct 
Antiglobulin Test (DAT) are performed at 
the site local laboratory, this section was 
modified to be consistent with what is done 
in the study.  
Section 7.3.2 Methods of 
analysis  
The following text was removed: “Fisher’s Exact 
test” and replaced with: “Cochran-Mantel-
Haenszel test”. 
The primary efficacy analysis method was 
changed from Fisher’s exact test to a 
stratified Cochran–Mantel–Haenszel test, 
to apply a statistically more powerful 
method in the small sample size setting, 
and to ensure result consistency between 
primary analysis and sensitivity analyses 
for the primary endpoints. 
Investigator Agreement 
Document formatting revisions. 
The change was made to reflect the update 
of the amended protocol version 8.  
Appendix A Clinical 
Laboratory Evaluations 
The following text was added to Appendix A: 
“Detailed information on the allocation of samples 
for central or local laboratory processing is 
available in the Laboratory Manual.” 
As the hematology panel tests are 
performed at the site local laboratory, this 
section was modified to be consistent with 
what is done in the study. 
Appendix B CI-CTC 
Version 4.03 (CTCAE 
V4.03) 
Hyperlink replacement.  
The change was made to replace obsolete 
hyperlink with active hyperlink to CTCAE 
web page. 
Appendix J Protocol 
Amendment History 
Document formatting revisions. 
The change was made to include the 
summary of changes introduced with the 
previous amendment. 
 
 
 
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TABLE OF CONTENTS 
PROTOCOL BIVV009-04 (EFC16216) ........................................................................................................ 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................ 2 
TABLE OF CONTENTS ............................................................................................................................... 5 
LIST OF TABLES ......................................................................................................................................... 9 
LIST OF ABBREVIATIONS........................................................................................................................ 10 
1 
SYNOPSIS .................................................................................................................................. 12 
2 
INTRODUCTION ......................................................................................................................... 20 
2.1 
PHARMACOLOGY OF BIVV009 ................................................................................................. 20 
2.2 
BACKGROUND AND STUDY RATIONALE ................................................................................ 20 
2.2.1 
Non-clinical experience................................................................................................................ 22 
2.2.2 
Clinical experience ....................................................................................................................... 23 
2.2.3 
Pharmacokinetic experience and dose justification ..................................................................... 24 
2.2.4 
Potential risks and benefits .......................................................................................................... 24 
3 
STUDY OBJECTIVES ................................................................................................................. 27 
3.1 
PRIMARY OBJECTIVE (PART A) ............................................................................................... 27 
3.2 
SECONDARY OBJECTIVES (PART A) ...................................................................................... 27 
3.3 
PRIMARY OBJECTIVE (PART B) ............................................................................................... 27 
3.4 
SECONDARY OBJECTIVE (PART B) ........................................................................................ 27 
3.5 
EXPLORATORY OBJECTIVE (PART B) .................................................................................... 28 
4 
INVESTIGATIONAL PLAN ......................................................................................................... 29 
4.1 
STUDY DESIGN .......................................................................................................................... 29 
4.2 
DISCUSSION OF STUDY DESIGN ............................................................................................ 31 
4.3 
STUDY ENDPOINTS ................................................................................................................... 32 
4.3.1 
Primary endpoint (Part A) ............................................................................................................ 32 
4.3.2 
Secondary efficacy endpoints (Part A) ........................................................................................ 32 
4.3.3 
Exploratory efficacy endpoints (Part A) ....................................................................................... 32 
4.3.4 
Efficacy endpoints (Part B) .......................................................................................................... 33 
4.3.5 
Safety endpoints .......................................................................................................................... 33 
4.3.6 
Pharmacokinetic endpoints ......................................................................................................... 34 
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4.3.7 
Pharmacodynamic endpoints ...................................................................................................... 34 
4.3.8 
Immunogenicity endpoints ........................................................................................................... 35 
4.4 
DURATION OF THE STUDY ...................................................................................................... 35 
4.5 
END OF STUDY .......................................................................................................................... 35 
5 
PATIENT SELECTION ................................................................................................................ 36 
5.1 
INCLUSION CRITERIA ............................................................................................................... 36 
5.2 
EXCLUSION CRITERIA .............................................................................................................. 37 
5.3 
REMOVAL OF PATIENTS FROM STUDY PARTICIPATION, AND STUDY SUSPENSION AND 
STOPPING RULES ..................................................................................................................... 38 
6 
STUDY PROCEDURES .............................................................................................................. 40 
6.1 
SCHEDULE OF STUDY PROCEDURES ................................................................................... 40 
6.1.1 
Screening/observation period (Days -42 to Day -1) .................................................................... 45 
6.1.1.1 
Screening assessments (initiating at Day -42) ............................................................................ 45 
6.1.1.2 
Interim visits during screening/observation period ...................................................................... 47 
6.1.1.3 
Confirmatory review of patient eligibility ...................................................................................... 47 
6.1.2 
Day 0 visit (first dose) .................................................................................................................. 47 
6.1.3 
Weeks 1-25 Part-A ...................................................................................................................... 49 
6.1.4 
End-of-treatment visit in Part A (Week 26) .................................................................................. 50 
6.1.5 
Part B extension phase................................................................................................................ 50 
6.1.5.1 
Procedures to be performed every 2 weeks ................................................................................ 50 
6.1.5.2 
Procedure to be performed every 4 weeks.................................................................................. 51 
6.1.5.3 
Procedures to be performed every 3 months .............................................................................. 51 
6.1.5.4 
Additional PK, PD, and ADA sampling ........................................................................................ 52 
6.1.5.5 
Infusion of the study drug at patient’s home ................................................................................ 52 
6.1.5.6 
Infusion of the undiluted study drug ............................................................................................. 52 
6.1.5.7 
Early termination/end of study/safety follow-up visit .................................................................... 52 
6.2 
STUDY TREATMENT .................................................................................................................. 53 
6.2.1 
Drug supplies and accountability ................................................................................................. 53 
6.2.2 
Patient number and identification ................................................................................................ 54 
6.2.3 
Randomization ............................................................................................................................. 54 
6.2.4 
Dose preparation and administration ........................................................................................... 54 
6.2.5 
Blinding ........................................................................................................................................ 55 
6.2.6 
Concomitant medications ............................................................................................................ 55 
6.2.7 
Contraception .............................................................................................................................. 56 
6.3 
STUDY ASSESSMENTS............................................................................................................. 57 
6.3.1 
Demographic data ....................................................................................................................... 57 
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6.3.2 
Medical history ............................................................................................................................. 57 
6.3.3 
Height, body weight, and vital signs ............................................................................................ 57 
6.3.4 
Electrocardiograms ...................................................................................................................... 57 
6.3.5 
Physical examinations ................................................................................................................. 58 
6.3.6 
Immunization review .................................................................................................................... 58 
6.3.7 
Clinical laboratory evaluations ..................................................................................................... 58 
6.3.8 
Additional testing in case of hypersensitivity/allergic reaction ..................................................... 58 
6.4 
PHARMACOKINETIC PROCEDURES ....................................................................................... 59 
6.4.1 
Pharmacokinetic blood sample collection and processing .......................................................... 59 
6.4.2 
Analytical methodology ................................................................................................................ 59 
6.5 
PHARMACODYNAMIC PROCEDURES ..................................................................................... 59 
6.5.1 
Pharmacodynamic and ADA blood sample collection and processing ....................................... 59 
6.5.2 
Analytical methodology ................................................................................................................ 59 
6.6 
SAFETY PROCEDURES ............................................................................................................ 59 
6.7 
ADVERSE EVENTS AND LABORATORY ABNORMALITIES ................................................... 60 
6.7.1 
Definition of adverse events ........................................................................................................ 60 
6.7.1.1 
Definition of adverse drug reactions ............................................................................................ 60 
6.7.1.2 
Definition of serious adverse events ............................................................................................ 61 
6.7.1.3 
Definition of unexpected adverse event/SUSAR ......................................................................... 62 
6.7.2 
Clinical adverse events ................................................................................................................ 62 
6.7.3 
Laboratory test abnormalities ...................................................................................................... 64 
6.7.4 
Serious adverse event reporting - procedures for investigators .................................................. 64 
6.7.5 
Follow-up of adverse events ........................................................................................................ 64 
6.7.6 
Follow-up of abnormal laboratory results .................................................................................... 65 
6.7.7 
Pregnancy .................................................................................................................................... 65 
6.7.8 
Overdose ..................................................................................................................................... 65 
7 
DATA ANALYSES AND SAMPLE SIZE .................................................................................... 66 
7.1 
DESCRIPTION OF OBJECTIVES AND ENDPOINTS ................................................................ 66 
7.2 
DEMOGRAPHICS AND BASELINE DISEASE CHARACTERISTICS ........................................ 66 
7.3 
EFFICACY - PART A ................................................................................................................... 66 
7.3.1 
Analysis populations .................................................................................................................... 66 
7.3.2 
Methods of analysis ..................................................................................................................... 67 
7.4 
EFFICACY - PART B ................................................................................................................... 68 
7.4.1 
Analysis populations .................................................................................................................... 68 
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7.4.2 
Methods of analysis ..................................................................................................................... 68 
7.5 
PHARMACOKINETICS ............................................................................................................... 68 
7.5.1 
Analysis population ...................................................................................................................... 68 
7.5.2 
Methods of analysis ..................................................................................................................... 68 
7.6 
PHARMACODYNAMICS ............................................................................................................. 69 
7.6.1 
Analysis population ...................................................................................................................... 69 
7.6.2 
Methods of analysis ..................................................................................................................... 69 
7.7 
IMMUNOGENICITY ..................................................................................................................... 69 
7.7.1 
Analysis population ...................................................................................................................... 69 
7.7.2 
Methods of analysis ..................................................................................................................... 69 
7.8 
SAFETY ....................................................................................................................................... 69 
7.8.1 
Analysis population ...................................................................................................................... 69 
7.8.2 
Methods of analysis ..................................................................................................................... 70 
7.9 
INTERIM ANALYSES .................................................................................................................. 70 
7.10 
SAMPLE SIZE CONSIDERATIONS ............................................................................................ 70 
7.11 
DATA HANDLING AND RECORD KEEPING ............................................................................. 70 
7.12 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................. 71 
8 
ADMINISTRATIVE ASPECTS .................................................................................................... 72 
8.1 
CHANGE IN PROTOCOL............................................................................................................ 72 
8.2 
SITE INITIATION VISIT/INVESTIGATOR MEETING ................................................................. 72 
8.3 
DISCLOSURE ............................................................................................................................. 72 
8.4 
MONITORING ............................................................................................................................. 72 
8.5 
ETHICAL ASPECTS .................................................................................................................... 73 
8.5.1 
Declaration of helsinki/good clinical practice ............................................................................... 73 
8.5.2 
Patient information and informed consent ................................................................................... 73 
8.6 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD AND 
REGULATORY AUTHORITIES ................................................................................................... 74 
8.7 
RECORDS ................................................................................................................................... 74 
9 
REFERENCES ............................................................................................................................ 76 
INVESTIGATOR AGREEMENT ................................................................................................................. 78 
10 
APPENDICES ............................................................................................................................. 79 
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APPENDIX A 
CLINICAL LABORATORY EVALUATIONS ...................................................................... 80 
APPENDIX B 
CI-CTC VERSION 4.03 (CTCAE V4.03) ........................................................................... 81 
APPENDIX C 
FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY (FACIT)-FATIGUE 
SCALE ......................................................................................................................................... 82 
APPENDIX D 
EQ-5D-5L .......................................................................................................................... 83 
APPENDIX E 
12-ITEM SHORT FORM SURVEY (SF-12) ...................................................................... 86 
APPENDIX F 
PATIENT’S GLOBAL IMPRESSION OF CHANGE (PGIC) .............................................. 90 
APPENDIX G 
HEALTHCARE RESOURCE UTILIZATION ..................................................................... 91 
APPENDIX H 
PATIENT’S GLOBAL IMPRESSION OF [FATIGUE] SEVERITY ..................................... 92 
APPENDIX I 
VACCINE SCHEDULE FOR PATIENTS IN JAPAN ONLY ................................................ 93 
APPENDIX J 
PROTOCOL AMENDMENT HISTORY .............................................................................. 94 
APPENDIX K 
COUNTRY SPECIFIC REQUIREMENT – HOME INFUSIONS WITH BIVV009 ............ 103 
APPENDIX L 
HOME INFUSION PATIENT SATISFACTION SURVEY ................................................ 110 
 
LIST OF TABLES  
Table 1 - Transfusion criteria ...................................................................................................................... 29 
Table 2 - Responder definition .................................................................................................................... 30 
Table 3 - Study schedule of events ............................................................................................................. 41 
Table 4 - Study schedule of events (Part B) for patients with home infusions after Day 273 ................... 104 
 
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LIST OF ABBREVIATIONS  
 
ADA 
antidrug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AMR 
antibody-mediated rejection 
ANCOVA 
analysis of covariance  
AUC 
area under the concentration-time curve 
BLA 
Biologics License Application 
BP 
bullous pemphigoid 
CAgD 
cold agglutinin disease 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CIC 
circulating immune complex 
Cmax 
maximum observed concentration 
CP 
complement classical pathway 
CRO 
Clinical Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAT 
direct antiglobulin test 
DNA 
deoxyribonucleic acid 
dsDNA 
double-stranded DNA 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
EOS 
end of study 
EOT 
end of treatment 
EQ-5D-5L 
five level EuroQol – five dimensions questionnaire 
ET 
early termination 
FACIT 
Functional Assessment of Chronic Illness Therapy 
FAS 
Full Analysis Set 
FAX 
facsimile  
FDA 
Food and Drug Administration 
FIH 
first in human 
GCP 
Good Clinical Practice 
Hgb 
Hemoglobin 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IM 
Intramuscularly 
IRB 
Institutional Review Board  
ITT 
Intent-to-Treat 
IUD 
intrauterine device 
IV 
intravenous  
IWRS 
Interactive Web-based System  
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LDH 
lactate dehydrogenase  
LPO 
last patient out 
MAA 
Market Authorization Application 
mAb 
monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
NHP 
non-human primate 
NHV 
normal healthy volunteer 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PGIC 
Patient’s Global Impression of Change 
PGIS 
Patient’s Global Impression of [Fatigue] Severity  
PI 
Principal Investigator 
PK 
pharmacokinetic(s) 
PP 
per-protocol  
QOL 
quality of life 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SF-12 
12-Item Short Form Survey 
SLE 
systemic lupus erythematosus 
SOP 
Standard Operating Procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
USA 
United States of America 
WAIHA 
warm autoimmune hemolytic anemia 
 
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1 
SYNOPSIS  
Title of Study: 
Cadenza Study: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Assess the 
Efficacy and Safety of BIVV009 in Patients with Primary Cold Agglutinin Disease Without a 
Recent History of Blood Transfusion 
Overview of Study 
Design: 
This is a randomized, double-blind, placebo-controlled, multicenter study in patients with primary 
cold agglutinin disease (CAgD) without a recent history of blood transfusion.  Eligible patients will 
receive study drug (BIVV009 or placebo) and undergo safety and efficacy assessments for 
6 months (26 weeks) during Part A.  
Following completion of the initial 6-month treatment period (Part A), patients will roll into the 
open-label long-term safety and durability of response extension phase (Part B) during which they 
will receive BIVV009.  
For the purpose of marketing authorization application, an interim analysis of safety and efficacy 
data will be performed after all patients have completed the double-blind treatment period 
(Part A).  The Part B open-label extension study will run for 1 year following last patient out (LPO) 
under Part A. 
Objectives: 
Part A 
Primary Objective: 
• 
The primary objective of Part A is to determine whether BIVV009 administration results 
in a ≥1.5 g/dL increase in hemoglobin (Hgb) level and avoidance of transfusion in 
patients with primary CAgD without a recent history of blood transfusion  
Secondary Objectives: 
Efficacy: 
• 
To assess the effect of BIVV009 on clinical events and laboratory parameters related to 
hemolysis and anemia in patients with primary CAgD  
• 
To assess the effect of BIVV009 on specific complications of CAgD (acrocyanosis, 
Raynaud’s syndrome, hemoglobinuria, and thromboembolism) 
• 
To assess the effect of BIVV009 on quality of life (QOL) in patients with primary CAgD 
Safety: 
• 
To evaluate the overall safety and tolerability of BIVV009 in patients with primary CAgD 
Exploratory: 
• 
To evaluate the effect of BIVV009 on certain disease-related biomarkers in patients 
with primary CAgD 
• 
To evaluate the pharmacokinetics of BIVV009 
• 
To evaluate the immunogenicity of BIVV009  
Part B 
Primary Objective: 
• 
The primary objective of Part B is to evaluate the long-term safety and tolerability of 
BIVV009 in patients with primary CAgD. 
Secondary Objective: 
• 
The secondary objective of Part B is to investigate the durability of response during 
long-term treatment with BIVV009 in patients with primary CAgD. 
Exploratory Objective: 
• 
To describe the safety and patient satisfaction with the convenience of home infusions 
with BIVV009 in a subset of patients 
• 
To describe the safety of undiluted infusions with BIVV009 
• 
To evaluate the immunogenicity of BIVV009  
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Methodology/Study 
Design: 
This randomized, double-blind, placebo-controlled study is designed to evaluate the efficacy, 
safety, and tolerability of BIVV009 in symptomatic patients with the complement-mediated 
disorder primary CAgD who do not have a recent history of blood transfusion. 
During the 6-week Screening/Observation Period, prospective patients will have a detailed 
medical history documented (including all available transfusion history), physical evaluations, and 
blood samples collected for characterization of CAgD biomarkers, including Hgb levels on 
3 occasions approximately every 2 weeks.  
Patients under screening for Cadenza who require a transfusion(s) during the Screening/ 
Observation Period prior to the first study drug infusion (if medically indicated per the 
Investigator’s discretion and within the parameters of the protocol specified transfusion criteria, 
see Table 1) will remain eligible.  If a patient receives a transfusion(s) during the 
Screening/Observation Period prior to the first study drug infusion, the baseline visit (and first 
infusion of study drug) must occur at least 7 days following the transfusion. 
Part A 
The study will enroll approximately 40 primary CAgD patients who do not have a recent history of 
blood transfusion (ie, ≤1 transfusion during the last year and no transfusion during the last 
6 months prior to enrollment).  Eligible patients should have been diagnosed with primary CAgD 
at least 6 months prior to enrollment and should have had no history of transfusion during this 
period. 
Eligible patients will be randomized 1:1 to receive an intravenous (IV) infusion of BIVV009 or 
placebo over approximately 60 minutes on Day 0, Day 7, and every 14 days thereafter through 
Week 25 (ie, Days 21, 35, 49, 63, 77, 91, 105, 119, 133, 147, 161, and 175). Patients who miss a 
dose (ie, outside the dosing window or >17 days since last dose) should return to the site for an 
unscheduled visit to receive another loading dose prior to their next scheduled visit.  Patients will 
have an End-of-Treatment (EOT) visit in Part A on Day 182 (Week 26). 
Patients who meet the transfusion criteria in Table 1 during the 6-month double-blind treatment 
period will receive a transfusion.  Patients who receive a transfusion during Part A will not be 
withdrawn from the study and will be eligible to participate in Part B. 
Table 1: Transfusion criteria 
A patient will receive a transfusion during Part A or Part B if his or her Hgb level meets either 
of the following criteria: 
• 
Hgb is <9 g/dL and the patient is symptomatic, or 
• 
Hgb is <7 g/dL and the patient is asymptomatic 
A responder analysis will be conducted following completion of the EOT visit at Week 26. The 
responder definition is provided in Table 2.  
Table 2: Responder definition 
A patient will be considered a responder in Part A if: 
• 
Hgb increases ≥1.5 g/dL from baseline (defined as the last Hgb value before 
administration of the first dose of study drug) at treatment assessment endpoint 
(defined as mean value from Weeks 23, 25, and 26) and 
• 
The patient did not receive a blood transfusion from Week 5 through Week 26 (EOT), 
and 
• 
The patient did not receive treatment for CAgD beyond what is permitted per protocol 
from Week 5 through Week 26 (EOT) 
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A list of excluded concomitant medications, as well as allowed concomitant medications with 
restrictions, is provided in the protocol.  Beyond the permitted concomitant medications, study 
drug, and transfusions, patients may receive no other therapies for the treatment of CAgD while 
enrolled in Part A of this study; patients requiring other treatment for their CAgD in Part A will be 
withdrawn from the study and counted as non-responders.  These patients will not be eligible to 
participate in Part B. 
Part B 
Following completion of dosing in the initial 6-month treatment period, patients will roll into the 
long-term safety and durability of response extension phase and receive BIVV009 in an open-
label manner.  Part B will run for 1 year following LPO under Part A.  Patients requiring treatment 
with permitted concomitant medications and/or transfusions will not be discontinued from the 
study.  Patients in Part B will be transfused per the transfusion criteria in Table 1.  Patients who 
receive a transfusion in Part B will not be withdrawn from the study.   
Blinding will be maintained when rolling patients into the extension period by providing a 
crossover dose at Week 26 to allow placebo patients to receive the BIVV009 loading dose at start 
of BIVV009 dosing.  Patients who were randomized to BIVV009 during the 6-month treatment 
period will receive a placebo dose at Week 26 to maintain blinding.  
All patients will then continue to receive BIVV009 dosing every 2 weeks starting at Week 27.  
Should patients deviate from their scheduled dosing, a repeat loading dose may be required.  
On-site visits will be completed ~ every 3 months (at a minimum) for collection of 
pharmacodynamic (PD) and pharmacokinetic (PK) samples, ADA samples and additional safety 
and efficacy measures. PK, PD and anti-drug antibodies (ADAs) samples will be collected 
9 weeks after administration of the last dose of study drug in patients who discontinue early, as 
well as in patients who experience a hematological breakthrough event. 
The study will be complete 12 months following LPO for Part A at which time all patients receiving 
on-going treatment will proceed to an End-of-Study (EOS) visit. 
Number of 
Patients: 
Approximately 40 male and/or female patients ≥18 years of age who have a confirmed diagnosis 
of primary CAgD and who do not have a recent history of blood transfusion will be randomized. 
Number of Study 
Sites: 
Approximately 55 sites worldwide will be targeted for participation to identify approximately 
40 eligible primary CAgD patients. 
Main Criteria for 
Inclusion: 
All patients must meet all the following inclusion criteria to be enrolled: 
I 01. 
Adult male and female patients ≥18 years of age at Screening  
I 02. 
Body weight of ≥39 kg at Screening 
I 03. 
Confirmed diagnosis of primary CAgD based on the following criteria:  
a) 
Chronic hemolysis 
b) 
Polyspecific direct antiglobulin test (DAT) positive 
c) 
Monospecific DAT strongly positive for C3d 
d) 
Cold agglutinin titer ≥64 at 4○C 
e) 
IgG DAT ≤1+, and 
f) 
No overt malignant disease  
I 04. 
Hemoglobin level ≤10.0 g/dL  
I 05. 
Bilirubin level above the normal reference range, including patients with Gilbert’s 
Syndrome 
I 06. 
Ferritin levels above the lower limit of normal.  Concurrent treatment with iron 
supplementation is permitted if the patient has been on a stable dose during the 
previous 4 weeks. 
I 07. 
Presence of one or more of the following CAgD-related signs or symptoms within 
3 months of Screening:  
a) 
Symptomatic anemia defined as: 
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i. Fatigue 
ii. Weakness 
iii. Shortness of breath 
iv. Palpitations, fast heart beat 
v. Light headedness, and/or 
vi. Chest pain 
b) 
Acrocyanosis 
c) 
Raynaud’s syndrome 
d) 
Hemoglobinuria 
e) 
Disabling circulatory symptoms, and/or 
f) 
Major adverse vascular event (including thrombosis)  
I 08. 
Bone marrow biopsy within 6 months of Screening with no overt evidence of 
lymphoproliferative disease or other hematological malignancy.  An additional bone 
marrow biopsy will be required if the prior bone marrow is deemed unsuitable for 
analysis by the Sponsor. 
I 09. 
Documented vaccinations against encapsulated bacterial pathogens (Neisseria 
meningitis, including serogroup B meningococcus, where available, Haemophilus 
influenzae, and Streptococcus pneumoniae) within 5 years of enrollment or as specified 
in Section 6.1.1.1. 
I 10. 
Patients must be willing to receive transfusions if they meet the eligibility criteria during 
the study treatment period.  Patients who do not have a recent history of transfusion 
due to patient refusal or patient decision should not be enrolled if they do not agree to 
receive blood transfusions as needed. 
I 11. 
Adequate IV access 
I 12. 
If female, must be post-menopausal, surgically sterile, or be established on (≥3 months 
prior to Screening) and agree to continue to use the same highly effective methods of 
birth control throughout the study and for 9 weeks following administration of the last 
dose of study drug 
I 13. 
Males must be surgically sterile for at least 90 days or when sexually active with female 
partners of child-bearing potential will agree to use highly effective contraception from 
Day 0 until 9 weeks following administration of the last dose of study drug. 
I 14. 
Able to comprehend and give informed consent 
I 15. 
Able to comply with the requirements of the study and to complete the full sequence of 
protocol-related procedures 
Exclusion Criteria: 
Patients who meet any of the following criteria will be excluded from the study: 
E 01. 
Cold agglutinin syndrome secondary to infection, rheumatologic disease, or active 
hematologic malignancy  
E 02. 
History of blood transfusion within 6 months of screening or history of more than one 
blood transfusion within 12 months of screening 
E 03. 
Clinically relevant infection of any kind within the month preceding enrollment (eg, active 
hepatitis C, pneumonia) 
E 04. 
Clinical diagnosis of systemic lupus erythematosus (SLE); or other autoimmune 
disorders with anti-nuclear antibodies at Screening.  Anti-nuclear antibodies of 
long-standing duration without associated clinical symptoms will be adjudicated 
on a case-by-case basis during the Confirmatory Review of Patient Eligibility 
(Section 6.1.1.3). 
E 05. 
Positive hepatitis panel (including hepatitis B surface antigen and/or hepatitis C virus 
antibody) prior to or at Screening 
E 06. 
Positive human immunodeficiency virus (HIV) antibody at Screening 
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E 07. 
Treatment with rituximab monotherapy within 3 months or rituximab combination 
therapies (eg, with bendamustine, fludarabine, ibrutinib, or cytotoxic drugs) within 
6 months prior to enrollment 
E 08. 
Concurrent treatment with corticosteroids other than a stable daily dose equivalent to 
≤10 mg/day prednisone for previous 3 months 
E 09. 
Erythropoietin deficiency. Concurrent treatment with erythropoietin is permitted if the 
patient has been on a stable dose for the previous 3 months. 
E 10. 
Concurrent usage of iron supplementation unless the patient has been on a stable dose 
for at least 4 weeks.  
E 11. 
Clinically significant medical history or ongoing chronic illness that would jeopardize the 
safety of the patient or compromise the quality of the data derived from his/her 
participation in this study (as determined by the Investigator [or designee]) at Screening 
E 12. 
Concurrent treatment with other experimental drugs or participation in another clinical 
trial with any investigational drug within 30 days or 5 half-lives, whichever is greater, 
prior to treatment start 
E 13. 
Females who are pregnant, lactating, or, if having reproductive potential, are considered 
potentially unreliable with respect to contraceptive practice 
E 14. 
History of hypersensitivity to BIVV009 or any of its components. 
Test Product(s), 
Dose, and Mode of 
Administration: 
Study drug will be administered over approximately 60 minutes by IV infusion in accordance with 
the Pharmacy Manual.  Patients with underlying cardiopulmonary disease may receive a 2-hour 
infusion with Sponsor approval. At pre-selected countries/sites and at certain visits during Part B 
administration of the study drug may be provided in the form of home infusions (Appendix K). In 
Part B, administration of the study drug may be provided in the form of undiluted solution to a 
subset of patients. 
Patients will be randomized to receive 1 of the following treatments: 
Test Product: Patients who weigh less than 75 kg will receive fixed doses of 6.5 g of BIVV009.  
Patients who weigh 75 kg or more will receive fixed doses of 7.5 g of BIVV009. 
Placebo Control: Sterile saline solution for IV infusion-based formulation buffer. 
Duration of 
Treatment: 
 
Part A 
Screening/Observation Period:  
6 weeks (Days -42 through Day -1) 
Treatment Period:  
25 weeks (Day 0 through Day 175) 
End-of-Treatment (EOT) visit:  
Week 26: 1 week after administration of 
the last dose of study drug in Part A 
(Day 182) 
Part B 
Safety and Durability of Response 
Extension Phase: 
Crossover loading dose at Week 26; 
bi-weekly dosing starting at Week 27 
and continuing for 1 year after LPO in 
Part A  
Part A/B 
Early Termination (ET) visit/ Safety 
Follow-up visit/EOS visit:  
9 weeks after last dose of study drug 
administration 
Patients who complete Part A per protocol through the EOT visit will participate in Part B, the 
long-term safety and durability of response extension phase of the study. 
Efficacy Endpoints 
and Outcome 
Measures: 
Part A 
Primary efficacy endpoint: 
The primary efficacy endpoint is the responder rate as defined in Table 2. 
Secondary efficacy endpoints:  
• 
Mean change from baseline in Hgb at treatment assessment endpoint (mean of values 
at Week 23, 25, and 26)  
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• 
Mean change from baseline in bilirubin (excluding patients with Gilbert’s Syndrome) at 
treatment assessment endpoint 
• 
Mean change from baseline in QOL, as assessed by the change in Functional 
Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale scores at treatment 
assessment endpoint 
• 
Mean change from baseline in lactate dehydrogenase (LDH) at treatment assessment 
endpoint  
• 
Incidence of solicited symptomatic anemia at EOT 
Exploratory efficacy endpoints: 
• 
Mean change from baseline in QOL, as assessed by the change in the five level 
EuroQol – five dimensions questionnaire (EQ-5D-5L) scores at treatment assessment 
endpoint 
• 
Mean change from baseline in QOL, as assessed by the change in the 12-Item Short 
Form Survey (SF-12®) at the end of treatment assessment endpoint 
• 
Proportion of patients with ≥12 g/dL Hgb at treatment assessment endpoint 
• 
Incidence of thromboembolic events after the first 5 weeks of study drug administration 
• 
Median time to normalization of bilirubin  
• 
Median time to normalization of LDH  
• 
Median time to normalization of haptoglobin  
• 
Median time to Hgb of ≥12 g/dL  
• 
Proportion of patients normalizing haptoglobin at treatment assessment endpoint 
• 
Proportion of patients normalizing bilirubin at treatment assessment endpoint 
• 
Proportion of patients with abnormal LDH at baseline who normalize LDH at treatment 
assessment endpoint  
• 
Patient’s Global Impression of Change (PGIC) to assess patient’s perception of 
changes in CAgD disease burden at EOT  
• 
Patient’s Global Impression of [Fatigue] Severity (PGIS) to assess patient’s perception 
of changes in fatigue at EOT  
• 
Incidence of disabling circulatory symptoms at treatment assessment endpoint 
• 
Total healthcare resource utilization at EOT (Part A) 
Part B 
The following parameters of disease activity will be assessed:  
• 
Hemoglobin 
• 
Bilirubin (total) 
• 
QOL assessments (FACIT-fatigue, EQ-5D-5L, SF-12, PGIS, and PGIC) 
• 
LDH 
• 
Transfusion requirements 
• 
Haptoglobin 
• 
Total healthcare resource utilization at EOT  
• 
Satisfaction with home infusion after first home infusion and after fourth home infusion 
will be assessed in patients with home infusions (Appendix K, Appendix L) 
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Safety Outcome 
Measures: 
Safety assessments for this study include adverse events (AEs), serious AEs (SAEs), clinical 
laboratory evaluations, SLE panel, vital sign measurements, electrocardiograms (ECGs), physical 
examination findings, and serum disease-related biomarkers. 
In addition, the following will be assessed for safety evaluation: 
• 
Hemolytic breakthrough (rapid fall in Hgb ≥2 g/dL associated with an increase in 
LDH/bilirubin and/or decrease in haptoglobin since the last scheduled visit) through the 
EOT at Week 26 
• 
Infections of ≥ Grade 3 severity (ie, requiring IV antibiotics)  
• 
Thromboembolic events  
• 
For patients with home infusions, safety assessments will additionally include AEs with 
onset within 24 hours of the infusion 
• 
For patients receiving undiluted infusions, safety assessments will additionally include 
post-infusion vital signs and AEs with onset within 24 hours of the infusion 
Pharmacokinetic 
Outcome 
Measures: 
Pharmacokinetic endpoints will include: 
• 
Plasma concentrations of BIVV009 
• 
PK parameters.  Appropriate exposure parameters (Cmax, AUC) will be derived using a 
population PK approach.  
During Part A, PK blood samples will be collected at predose and 1 hour postdose (ie, 1 hour 
after completion of study drug infusion) from all patients on Days 0, 7, 21, 35, 49, 63, 77, 91, 105, 
119, 133, 147, 161, and 175.  An additional blood sample for PK analysis will be collected during 
the EOT visit on Day 182 or at ET if a patient withdraws early.  
During Part B, PK samples will continue to be collected at predose and 1 hour  
(±15 minutes) postdose on Days 189, 217, and 245, then routinely at 3-month intervals starting at 
Day 273 through the remainder of the study.  Samples will also be collected if a patient 
experiences a hematologic breakthrough event or withdraws from the study. 
Pharmacodynamic 
Outcome 
Measures: 
PD Primary Outcome Measure: 
• 
Wieslab-CP 
Exploratory Complement System Measures: 
• 
CH50 
• 
Total C4 
• 
C1q 
• 
C1s 
During Part A, PD blood samples will be collected at predose and 1 hour postdose (ie, 1 hour 
after completion of study drug infusion) from all patients on Days 0, 7, 21, 35, 49, 63, 77, 91, 105, 
119, 133, 147, 161, and 175.  An additional blood sample for PD analysis will be collected during 
the EOT visit on Day 182 or at ET if a patient withdraws early. 
During Part B, PD samples will continue to be collected at predose and 1 hour  
(±15 minutes) postdose on Days 189, 217, and 245, then routinely at 3-month intervals starting at 
Day 273 through the remainder of the study.  Samples will also be collected if a patient 
experiences a hematologic breakthrough event or withdraws from the study. 
Immunogenicity 
Outcome 
Measures: 
Immunogenicity Outcome Measures will include pre-existing ADA and treatment-emergent ADA. 
During Part A, samples will be collected at predose, on Day 0, 7, 35, 77, 133, 175 and on Day 182 
(EOT) or at ET if a patient withdraws early. During Part B, ADA samples will continue to be 
collected at predose, on Days 189, 217, and 245, then routinely at 3-month intervals starting at 
Day 273 through the remainder of the study and at Safety Follow up visit 9 weeks after last dose. 
Samples will also be collected if a patient experiences a hematologic breakthrough or withdraws 
from the study. 
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Sample Size: 
With 40 patients (20 per group), there is 87% power to detect a statistically significant difference 
of 50% between the BIVV009 group and placebo group if the true response rates are 85% and 
35% for the BIVV009 and placebo groups, respectively.  This calculation assumes a 2-sided 5%-
level test comparing the response rates between the BIVV009 and placebo groups.  A 50% 
improvement over placebo is considered clinically relevant. 
Statistical 
Methods: 
Interim analysis:  
For the purpose of regulatory submission, an interim analysis of safety and efficacy data will be 
performed after all patients have completed Part A. 
Analyses:  
The efficacy endpoints will be presented for both the ITT and PP populations.  All the per-protocol 
analyses will be considered supportive analyses.  All hypothesis tests will be performed at a two-
sided 0.05 significance level. 
For Part A, the primary efficacy endpoint (responder status) will be compared between treatment 
groups using Cochran-Mantel-Haenszel (CMH) test for the ITT population, consisting of all 
patients who received at least 1 dose of study drug.  
Secondary endpoints, defined as follows, will be tested only when the primary endpoint is 
statistically significant: 
1. 
Mean change from baseline in Hgb at the treatment assessment endpoint (mean of values 
at Week 23, 25, and 26) 
2. 
Mean change from baseline in bilirubin (excluding patients with Gilbert’s Syndrome) at the 
treatment assessment endpoint 
3. 
Mean change from baseline in QOL, as assessed by the change in FACIT-fatigue scale 
scores at the treatment assessment endpoint 
4. 
Mean change from baseline in LDH at the treatment assessment endpoint 
5. 
Incidence of solicited symptomatic anemia at EOT 
The change from baseline variables will be analyzed using analysis of covariance (ANCOVA) with 
baseline as covariate.  A multiple testing procedure will be specified in the statistical analysis plan 
to control the overall Type I error rate among the secondary endpoints. 
For Part B, the analyses will be performed for all patients who received at least 1 dose of study 
drug in the extension period.  All efficacy endpoints will be summarized by descriptive statistics 
and graphically (where appropriate) by prior treatment group in Part A.  All safety endpoints will 
be summarized for all patients. 
Further details regarding other endpoints and proposed analyses will be described in full in the 
Statistical Analysis Plans (SAP) for Part A and Part B. 
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2 
INTRODUCTION  
2.1 
PHARMACOLOGY OF BIVV009  
BIVV009 is a humanized monoclonal antibody (mAb) directed against human complement 
factor C1s, which along with C1r and C1q is a part of the C1 complex that sits at the apex of the 
complement classical pathway (CP).  By binding C1s BIVV009 prevents the enzymatic action of 
the C1 complex on its substrates, complement factors C4 and C2, and thereby blocks formation 
of the C3 convertase.  Note that this site of action of BIVV009 lies above the level of C3, which 
is the junction of all three pathways of complement activation.  This is important to the 
specificity of the mechanism of action of BIVV009 because it means that the two other 
complement pathways, the alternative pathway and the lectin pathway, remain functionally intact 
for the purpose of host defense in the presence of BIVV009.  Note, too, that the non-enzymatic 
role of C1q is left intact by BIVV009; this may be particularly relevant because of the 
importance of the pro-phagocytic “housekeeping” functions of the complement system including 
removal of apoptotic cells. 
BIVV009 binds with high affinity and specificity to C1s of humans and non-human primates 
(NHPs).  It has no affinity for the related proteases of the lectin pathway, MASP-1, and MASP-2. 
As discussed above, BIVV009 has disease-relevant inhibitory activity against CP in a variety of 
human in vitro models of human disease (including cold agglutinin disease [CAgD], bullous 
pemphigoid [BP], and warm autoimmune hemolytic anemia [WAIHA]).  BIVV009 exerts its 
effect on the CP in a characteristic two-state behavior: complete inhibition at concentrations 
≥20 g/mL, and no inhibition at concentrations <20 g/mL, with an abrupt transition between 
the two.  This behavior means that graded degrees of inhibition are not readily measurable and 
that increasing BIVV009 concentration to ≥20 g /mL results not in greater degrees of 
inhibition, but only in longer duration of inhibition (ie, longer dwell time in the “off” state of the 
CP).  In turn, this means that the dose-effect relationship is demonstrated in the duration of 
action, such that higher doses lead to longer possible inter-dose intervals while maintaining full 
pathway inhibition. 
2.2 
BACKGROUND AND STUDY RATIONALE  
The CP has been implicated in many diseases that are driven by the presence of a pathogenic 
antibody; CAgD is one such example.  Complement inhibition has proven to be a safe and 
effective treatment for another form of hemolytic anemia, paroxysmal nocturnal hemoglobinuria.  
Currently, there are approved complement inhibitors being used therapeutically for various 
indications, including Soliris® (eculizumab), a mAb targeting C5; Berinert® and Cinryze®, both 
C1 esterase inhibitors purified from human plasma; and Ruconest®, a recombinant form of 
human C1 esterase inhibitor.  Unlike Soliris and the C1 esterase inhibitors, by specifically 
targeting C1s, BIVV009 inhibits only the CP, leaving the alternative complement pathway and 
the lectin complement pathway available for immune surveillance.  Furthermore, by blocking at 
the level of the C1 complex, BIVV009 is expected to prevent generation of all anaphylatoxins 
and opsonins (eg, C3 fragments) that produce pathologic lesions in CP-mediated disorders. 
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CAgD is an autoimmune hemolytic anemia caused by IgM-induced CP activation.  The IgM 
autoantibodies in CAgD are referred to as “cold agglutinins” given their inherent property of 
increased binding as a function of decreased temperature.  The cold agglutinin thermal 
amplitude, which is the highest temperature at which the cold agglutinin can be detected to react 
with the red blood cell antigen approaches core body temperature in many patients (1).  CAgD 
symptoms are typically triggered by exposure to cold environmental temperatures  
(ie, temperatures at or below core body temperature), viral infections, or inflammation (2, 3, 4, 5, 
6, 7).  All patients with CAgD have active disease with varying levels of chronic, ongoing 
hemolysis resulting in anemia (8).  CAgD patients without recent transfusion remain 
significantly compromised with symptoms associated with hemolytic anemia including shortness 
of breath, fatigue, lightheadedness, and general weakness, in addition to vascular symptoms such 
as Raynaud’s and acrocyanosis.  The symptomatic impact of anemia is increased in CAgD 
patients due to the advanced age of the population (1, 9) who tolerate anemia symptoms poorly.  
CAgD patients who have not recently been transfused often have similar Hgb levels as 
recently-transfused patients and can have significant symptoms (9). These complications have a 
significant adverse impact on quality of life.  Patients with CAgD are also at increased risk of 
arterial and venous thromboembolic events, including potentially life-threatening events such as 
stroke, myocardial infarction, and pulmonary embolism (10, 11, 12).  This increased risk of 
thromboembolic events occurs in CAgD patients with even mild anemia and is related to the 
ongoing hemolysis (10, 12).  Thus, CAgD patients who are not recently transfused remain at risk 
for severe complications of the disease.  
There are no currently approved therapies for CAgD.  CAgD is typically not responsive to 
treatment with steroids or splenectomy and can only be managed by supportive measures 
(avoidance of cold, blood transfusions as needed), and/or immunosuppressive, cytotoxic 
therapies (eg, rituximab with or without fludarabine or bendamustine) (8).  Because all red blood 
cells express the antigen targets of the IgM autoantibody (13), transfused blood in CAgD patients 
is subject to the same IgM-induced CP-mediated destruction as the patients’ own red blood cells 
and is of limited efficacy beyond short-term alleviation of acute anemia symptoms.  Chronic 
transfusion support can lead to iron overload and the need for additional chelation therapy.  
Immunomodulatory and cytotoxic therapies are used based on the association of CAgD with a 
clonal lymphoproliferative disorder found in most patients (8, 14).  Targeting an underlying 
clonal disorder with immuno- and/or cytotoxic therapy can have significant toxicity risks with 
variable treatment responses that are often delayed and/or non-durable (8).   
Patients with CAgD have disease activity that fluctuates over time.  In population-based natural 
history studies on CAgD, approximately 35-49% of patients did not receive transfusion support 
despite being anemic (9, 15).  However, approximately 21% of patients convert from transfusion 
independence to transfusion dependence (15) and almost all patients undergo recurrent episodes 
of more severe anemia exacerbations over time that require periodic transfusion support (9).  
Thus, the BIVV009-04 study patient population is a distinct population from CAgD patients who 
have been recently transfused, representing patients in a different phase of their disease with 
respect to transfusion usage.  
CAgD patients without recent transfusion suffer from significant symptoms due both to anemia 
and hemolysis as described above and are at risk for thromboembolic events as well as severe 
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exacerbations of their disease.  Patients without recent transfusion remain symptomatic and at 
risk of disease complications, particularly those patients with significant anemia (Hgb ≤10 g/dL). 
The Phase 1b clinical trial of BIVV009 in patients with CAgD showed that it can rapidly block 
hemolytic activity, induce complete remission of anemia, and prevent the need for blood 
transfusion (16, 17).  In this Phase 1b study, as well as in the completed healthy volunteer 
Phase 1 studies, BIVV009 was well tolerated.  Based on the lack of available therapies, the 
eligibility criteria requiring symptomatic CAgD with anemia, the known complications including 
thromboembolic event risk faced by the patient population, and that most patients experience 
episodic worsening of their disease requiring initiation of transfusion, there is a high unmet need 
for this patient population.  The ultimate goal in the treatment of CAgD is to control the 
underlying hemolysis, thus alleviating anemia and addressing the symptomatology that can have 
a significant impact on quality of life, as well as other complications such as hemolytic 
breakthrough and thromboembolic events.  The absence of approved therapy and the clinical data 
available from prior study of BIVV009 in CAgD supports the benefit:risk in this population. 
Patients with CAgD are often elderly and/or have numerous co-morbidities affecting their 
mobility. Moreover, clinical centers specialized in the management of CAgD are infrequent and 
may be located far from patients’ home. Consequently, some patients may find the option of 
home infusions with drug against CAgD beneficial. To this end a group of patients at preselected 
sites/countries will be offered the possibility of home infusions during Part B, assisted by trained 
health care professional. For the US, the Netherlands, Norway, France, Italy, Austria, Germany, 
and Spain specific amendments (Appendix K). 
In addition, in Part B, a subset of at least 15 patients will be administered the study drug 
undiluted with saline solution. An undiluted infusion gives the opportunity to administer study 
drug without diluting with normal saline. The volume of injection can be reduced from 500 mL 
to 150 mL or 130 mL, depending on body weight. Consequently, administration of undiluted 
study drug may be found beneficial by patients and pharmacy staff. 
2.2.1 Non-clinical experience  
The non-clinical safety foundation for this study includes a completed 6-month toxicology study 
in which NHPs were treated with weekly doses of BIVV009 as high as 180 mg/kg for 26 weeks. 
Non-clinical safety studies of BIVV009 have demonstrated no toxicologically adverse findings 
related to BIVV009 in cynomolgus monkey studies of up to 6-months treatment duration; 
furthermore, no adverse effects from exaggerated pharmacology (ie, autoimmune diseases, 
bacterial infections) were observed in those studies.  As a result, the no observed adverse effect 
(dose) level (NOAEL) established for BIVV009 is 180 mg/kg by weekly intravenous (IV) 
administration for 26 weeks; this translates to a safety margin that more than adequately covers 
the BIVV009 dose regimen for use in Study BIVV009 -04.  Hence the NOAEL in cynomolgus 
monkeys is more than twice the intended fixed doses of 6.5 grams or 7.5 grams, based on adults 
weighing approximately 75 kg. 
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2.2.2 Clinical experience  
The clinical safety foundation for this study includes an ongoing prospective, double-blind, 
randomized, placebo-controlled, First In Human (FIH) Phase 1a/b study (BIVV009-01). 
Phase 1a included Part A, a single-ascending dose study in normal healthy volunteers (NHV), 
and Part B, a multiple-ascending dose study in NHVs.  Phase 1b included Part C, a multi-dose 
study in patients with complement-mediated disorders including CAgD, WAIHA, BP, and 
antibody-mediated rejection (AMR) in kidney transplant recipients, and Part E, which was added 
to both allow continued access to study drug in a subset of study patients with CAgD, and to 
further characterize the safety and efficacy to BIVV009.  Part D was not implemented. 
Part A was conducted according to an ascending dose cohort paradigm in which a unique cohort 
of NHVs was treated at each single dose level.  There were 7 cohorts of NHVs. The first 2 cohorts 
consisted of 4 healthy volunteers each, 3 given BIVV009 (0.3 or 1 mg/kg) by IV infusion and 
1 given placebo.  The remaining 5 cohorts consisted of 8 healthy volunteers each, 6 given 
BIVV009 by IV infusion (3, 10, 30, 60, or 100 mg/kg) and 2 given placebo. 
Part B was conducted according to an ascending dose cohort paradigm in which a unique cohort 
of NHVs was treated at each dose level.  There were 2 cohorts of NHVs, each consisting of 
8 healthy volunteers, in this part of the study.  These cohorts were given 4 weekly IV doses of 
BIVV009 or placebo (6:2 for active:placebo) at a dose level previously administered to NHVs in 
Part A of the study (30 or 60 mg/kg). 
Part C was conducted in a single cohort of patients enrolled in 4 strata, representing four 
complement-mediated disorders (CAgD, WAIHA, BP, and AMR).  Patients in Part C received a 
single IV test dose of 10 mg/kg followed by 4 weekly doses of 60 mg/kg. 
Clinical proof of concept for BIVV009 was achieved in Phase 1b based upon the demonstration 
of immediate cessation of hemolysis and rapid correction of anemia during short-term treatment 
of patients with CAgD (a complement-mediated hemolytic anemia).  These results confirm that 
continuous C1s inhibition is sufficient to observe a treatment effect, while the observation of 
relapse of hemolytic anemia upon washout of BIVV009 and restoration of C1s activity confirms 
that continuous C1s inhibition is necessary for treatment of CAgD. 
The clinical safety profile of single- or multiple-dose administration of BIVV009 to healthy 
volunteers was similar to placebo with respect to type, frequency, or severity of adverse events 
(AEs) and there have been no clinically meaningful AEs seen in healthy volunteers exposed to 
BIVV009 at doses up to 60 mg/kg weekly for 4 doses.  The clinical safety profile of multiple-
dose administration of BIVV009 to patients with a variety of complement-mediated disorders 
has not revealed any new safety concerns in this older-aged, medically complex population.  
With respect to the hypothetical, mechanism-related risks from C1s inhibition (ie, autoimmune 
diseases, bacterial infections), prophylactic vaccination against encapsulated bacterial pathogens 
per regional guidelines and routine surveillance with systemic lupus erythematosus (SLE) 
serologic testing are available to mitigate these risks. 
A second prospective, double-blind, randomized, placebo-controlled study of multi-dose 
BIVV009 in healthy volunteers was recently completed under Protocol TNT009-02.  A single 
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cohort of 24 NHVs was randomized to BIVV009 (75 mg/kg) or placebo at a ratio of 3:1. 
Volunteers were dosed on Days 1, 8, 22, and 36.  Intensive PK/PD/exploratory complement 
sampling was performed during the study.  This study added an additional dose level, which was 
combined with data from the BIVV009-01 study to augment PK modeling and simulations.  
The results of this study, in conjunction with existing PK data, were used to propose dose 
regimens for the current protocol. 
2.2.3 Pharmacokinetic experience and dose justification  
The pharmacokinetic/pharmacodynamic (PK/PD) profile of BIVV009 in healthy volunteers and 
in patients has been established based on the data collected from the first-in-human clinical trial. 
A human PK model was constructed from the complete and final Phase 1a data. This model was 
then augmented with the available PK data emerging from the Phase 1b component of this trial, 
and the combined model was used to simulate a variety of possible dose regimens for use in 
patients.  The dose regimen proposed for use in current and future clinical trials with BIVV009, 
including Study BIVV009-04, differs from that used in the Phase 1a and 1b program because 
weekly IV administration was deemed to be logistically challenging for patients when the period 
of treatment is increased from weeks to months.  A regimen based upon a single priming dose on 
Day 0, followed by bi-weekly dosing on Days 7, 21, 35, 49, etc, can provide continuous, 
complete C1s inhibition while better accommodating to the needs of patients.  Human PK 
modeling suggests that a dose level of 6.5 grams or 7.5 grams (based on body weight of <75 kg 
or ≥75 kg, respectively) is necessary to protect patients better from potential restoration of CP 
activity at the end of the inter-dose interval.  The weight cut-off of 75 kg was chosen based on 
the expected weight distribution in CAgD patients with a median weight of 74.8 kg. 
The in vitro and in vivo pharmacologic profile of BIVV009 has two especially important features 
that help to define the optimal dose regimen for clinical use.  First, BIVV009 has very high 
affinity and selectivity for C1s, with negligible off-target activity.  Second, it is a potent CP 
inhibitor with such a steep concentration-effect relationship that it behaves as a switch-like 
inhibitor of C1s: at concentrations of BIVV009 ≥20 µg/mL, CP activity is virtually undetectable; 
at BIVV009 concentrations below this threshold the CP is fully active.  This property results in 
the requirement to maintain a blood concentration of BIVV009 that is always at least 
≥20 µg/mL, even at trough, lest CP activity be fully restored. 
2.2.4 Potential risks and benefits  
As previously noted, clinical proof of concept for BIVV009 was achieved in a Phase 1b study, 
which demonstrated immediate cessation of hemolysis and rapid correction of anemia during 
short-term treatment of patients with CAgD.  
The human safety risk from off-target effects of mAb therapeutics is generally considered to be 
low, and in this regard BIVV009 is no exception.  The human safety risk from short-term 
inhibition of the complement system also appears to be low, based upon the experience with 
five approved products in this therapeutic class.  Long-term, complement inhibition may increase 
the risk of infection with encapsulated bacteria, as reflected in the product label for eculizumab 
(Soliris), an inhibitor of the terminal portion of the complement system.  However, to provide 
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optimal protection against infections with encapsulated bacteria, the design of this study includes 
an appropriate program of prophylactic vaccinations. 
The risks associated with long-term inhibition of the proximal portion of the CP are presently 
unknown.  Theoretically, it could increase the risk of SLE or circulating immune complexes 
(CIC) disease due to the role of the C1 complex in immune complex clearance, as observed in 
patients with congenital deficiencies of C1 complex components (C1q, C1s, and C1r).  However, 
pharmacologic inhibition of C1s differs from congenital deficiency of the C1 complex because: 
1) congenital C1 complex component deficiency are commonly not single gene mutations but 
typically are associated with second mutations in other immune system genes; 2) pharmacologic 
inhibition of C1s enzymatic function in the C1 complex leaves intact the non-enzymatic function 
of C1q, which is important for the opsonization and phagocytic removal of apoptotic cells which 
protects against autoimmunity; and 3) the phenotype associated with life-long, often total 
absence of C1 complex structure and function is unlikely to be reproduced by pharmacologic 
antagonism of C1 enzymatic function in fully developed adults.  Nevertheless, standard clinical 
biomarkers related to SLE (eg, antibodies to double-stranded DNA [dsDNA]) have been 
incorporated into the study design as safety surveillance measures. 
Home infusions with the study drug will be proposed to a number of patients in countries pre-
selected to participate in home infusion. Home infusions will be assisted by a trained healthcare 
professional, and will concern patients who express such wish, after having been qualified by the 
Investigator and no sooner than after Week 39 (Day 273) and without evidence of intolerance of 
the study drug as determined by the Investigator based on the criteria outlined in Appendix K. 
The potential risks associated with home BIVV009 administrations are the same as the risks with 
BIVV009 administration in a clinical setting. Only patients treated with BIVV009 for a 
minimum of 3 months and who do not have a history of hypersensitivity to BIVV009 are eligible 
for the home infusion. Additionally, patients who are participating in or have ever participated in 
undiluted infusions of BIVV009 are not eligible for home infusions. Rescue medications to treat 
hypersensitivity/allergic reactions as per the PI’s guidance will be available during home 
infusion visits. The home infusion personnel will be trained in basic life support 
(cardiopulmonary resuscitation [CPR]) but will not be required to have equipment to perform 
advanced life support (eg, defibrillators). 
At least 15 patients in Part B will be proposed to receive infusions of the study drug undiluted 
with saline solution. An undiluted infusion gives the opportunity to administer study drug without 
diluting with normal saline. Undiluted infusions may begin no sooner than after Week 39 
(Day 273) in patients who provide their consent and are without evidence of intolerance to the 
study drug as determined by the Investigator based on the criteria outlined in Section 4.1, Part B. 
Patients who are participating in or have ever participated in home infusions are not eligible for 
undiluted infusion.  Safety concerns associated with undiluted BIVV009 are not anticipated; 
however, an increase in infusion-related reactions may be possible due to the altered 
concentration of the protein/active compound. Therefore, patients treated with BIVV009 for a 
minimum of 3 months and who do not have a history of hypersensitivity to BIVV009 may be 
eligible for undiluted infusions with BIVV009. Decreased fluid load associated with BIVV009 
administration may be found clinically advantageous, particularly in this population of CAgD 
patients who often have numerous co-morbidities which may include cardio-pulmonary 
conditions. Moreover, the preparation of BIVV009 infusion without the need for dilution in 
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normal saline is associated with reduced complexity. There is no impact anticipated on PK 
between undiluted solution and diluted solution. 
The overall risk/benefit balance for participants in Study BIVV009-04 is favorable based on 
available data to date. 
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3 
STUDY OBJECTIVES  
3.1 
PRIMARY OBJECTIVE (PART A)  
The primary objective of Part A is to determine whether BIVV009 administration results in a 
≥1.5 g/dL increase in hemoglobin (Hgb) level and avoidance of transfusion in patients with 
primary CAgD without a recent history of blood transfusion. 
3.2 
SECONDARY OBJECTIVES (PART A)  
The secondary efficacy objectives of Part A are: 
• To assess the effect of BIVV009 on clinical events and laboratory parameters related to 
hemolysis and anemia in patients with primary CAgD  
• To assess the effect of BIVV009 on specific complications of CAgD (acrocyanosis, 
Raynaud’s syndrome, hemoglobinuria, and thromboembolism) 
• To assess the effect of BIVV009 on quality of life (QOL) in patients with primary CAgD. 
The safety objective of Part A is: 
• To evaluate the overall safety and tolerability of BIVV009 in patients with primary 
CAgD 
The exploratory objectives of Part A are: 
• To evaluate the effect of BIVV009 on certain disease-related biomarkers in patients with 
primary CAgD 
• To evaluate the pharmacokinetics of BIVV009  
• To evaluate the immunogenicity of BIVV009 
3.3 
PRIMARY OBJECTIVE (PART B)  
The primary objective of Part B is to evaluate the long-term safety and tolerability of BIVV009 
in patients with primary CAgD. 
3.4 
SECONDARY OBJECTIVE (PART B)  
The secondary objective of Part B is   
• To investigate the durability of response during long-term treatment with BIVV009 in 
patients with primary CAgD 
• To evaluate the immunogenicity of BIVV009 
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3.5 
EXPLORATORY OBJECTIVE (PART B)  
• To describe the safety and patient satisfaction with the convenience of home infusions 
with BIVV009 in a subset of patients (for the US, the Netherlands, Norway, France, Italy, 
Austria, Germany, and Spain specific amendments (Appendix K) 
• To describe the safety of undiluted infusions with BIVV009 
• To evaluate the immunogenicity of BIVV009 
 
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4 
INVESTIGATIONAL PLAN  
4.1 
STUDY DESIGN  
This randomized, double-blind, placebo-controlled study is designed to evaluate the efficacy and 
safety of BIVV009 in symptomatic patients with the complement-mediated disorder primary 
CAgD who do not have a recent history of blood transfusion. 
During the 6-week Screening/Observation Period, prospective patients will have a detailed 
medical history documented (including all available transfusion history), physical evaluations, 
and blood samples collected on 3 occasions approximately every 2 weeks.  
Patients may receive a transfusion(s) during the Screening/Observation Period prior to the 
first study drug infusion if medically indicated per the Investigator’s discretion.  However, the 
baseline visit (and first infusion of study drug) must occur at least 7 days following the 
transfusion. 
Part A 
The study will enroll approximately 40 primary CAgD patients who do not have a recent history 
of blood transfusion (ie, ≤1 transfusion during the last year and no transfusion during the last 
6 months prior to enrollment).  Eligible patients should have been diagnosed with primary CAgD 
at least 6 months prior to enrollment and should have had no history of transfusion during this 
period.  
Eligible patients will be randomized 1:1 to receive an IV infusion of BIVV009 or placebo over 
approximately 60 minutes on Day 0, Day 7, and every 14 days thereafter through Week 25 
(ie, Days 21, 35, 49, 63, 77, 91, 105, 119, 133, 147, 161, and 175).  Patients who miss a dose 
(ie, outside the dosing window or >17 days since last dose) should return to the site for an 
unscheduled visit 1 week prior to the next scheduled dose in order to receive an additional 
loading dose.  Patients will have an End-of-Treatment (EOT) visit in Part A on Day 182 
(Week 26). 
Patients who meet the transfusion criteria in Table 1 during the 6-month double-blind treatment 
period will receive a transfusion.  Patients who receive a transfusion during Part A will not be 
withdrawn from the study and will be eligible to participate in Part B. 
Table 1 - Transfusion criteria  
A patient will receive a transfusion during Part A or Part B if his or her Hgb level meets either 
of the following criteria: 
• Hgb is <9 g/dL and the patient is symptomatic, or 
• Hgb is <7 g/dL and the patient is asymptomatic 
A responder analysis will be conducted following completion of the EOT visit at Week 26. 
The responder definition is provided in Table 2.  
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Table 2 - Responder definition  
A patient will be considered a responder in Part A if: 
• Hgb increases ≥1.5 g/dL from baseline (defined as the last Hgb value before 
administration of the first dose of study drug) at treatment assessment endpoint 
(defined as mean value from Weeks 23, 25, and 26) and 
• The patient did not receive a blood transfusion from Week 5 through Week 26 (EOT), 
and 
• The patient did not receive treatment for CAgD beyond what is permitted per protocol 
from Week 5 through Week 26 (EOT) 
A list of excluded concomitant medications, as well as allowed concomitant medications with 
restrictions, is provided in Section 6.2.6. Beyond the permitted concomitant medications, study 
drug, and transfusions, patients may receive no other therapies for the treatment of CAgD while 
enrolled in this study; patients requiring other treatment for their CAgD in Part A will be 
withdrawn from the study and counted as non-responders.  These patients will not be eligible to 
participate in Part B. 
Part B 
Following completion of dosing in the initial 6-month treatment period, patients will roll into 
the long-term safety and durability of response extension phase and receive BIVV009 in an 
open-label manner.  Part B will run for 1 year following last patient out (LPO) under Part A.  
Patients requiring treatment with permitted concomitant medications and/or transfusions will not 
be discontinued from the study.  Patients in Part B will be transfused per the transfusion criteria 
in Table 1.  Patients who receive a transfusion in Part B will not be withdrawn from the study.   
Blinding will be maintained when rolling patients into the extension period by providing a 
crossover dose at Week 26 to allow placebo patients to receive the BIVV009 loading dose at 
start of BIVV009 dosing.  Patients who were randomized to BIVV009 during the 6-month 
treatment period will receive a placebo dose at Week 26 to maintain blinding.  All patients will 
then continue to receive bi-weekly BIVV009 dosing starting at Week 27. 
Patients will be dosed with BIVV009 every 2 weeks, as in Part A.  Should patients deviate from 
their scheduled dosing, a repeat loading dose may be required.  On-site visits will be completed 
~ every 3 months (at a minimum) for collection of PK, PD and ADA samples, and additional 
safety and efficacy measures. 
Home infusion will be performed by a healthcare professional caregiver contingent upon 
completion of training delivered by the Investigator or delegated site staff member only in 
patients willing to be administered study drug in home, who have been treated with at least  
3 months with BIVV009 in Part B and who satisfy the criteria mention in the appendix K 
(Appendix K). 
A subset of patients from countries pre-selected to participate in home infusion, who have been 
treated for a minimum 3 months (completed visit Day 273) in Part B and who were determined 
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to have tolerated BIVV009 well, will be invited to have infusions with BIVV009 performed at 
their homes, after having been qualified by the Investigator. Home infusion will be performed by 
a healthcare professional caregiver contingent upon completion of training delivered by the 
Investigator or delegated site staff member. Patients will follow the alternate home infusion 
scheme, ie, home infusion at the patient’s home will be alternating with office visits, so that 
patients will attend office visit every 4 weeks alternating with home infusions every 4 weeks 
(±2 days) (Appendix K). 
At least 15 patients in Part B will be proposed to receive infusions with study drug undiluted 
with saline solution. Undiluted infusions may begin in patients who consent to and without 
evidence of intolerance of the study drug and who satisfy the following criteria:  
1. Able to comprehend and give informed consent for receiving undiluted infusions of 
BIVV009 and willing to be infused for at least 1 dose 
2. Treated for at least 3 months in Part B (completed visit Day 273) 
3. No history of hypersensitivity reaction to BIVV009 
4. Not selected to participate in home infusion administration  
5. Considered by Investigator as suitable for undiluted infusion of BIVV009 
Each qualified patient is supposed to receive at least one undiluted infusion of BIVV009, 
however, patients are free to continue with undiluted infusion of BIVV009 until the end of study. 
Undiluted infusions with BIVV009 versus infusions of BIVV009 diluted in saline will be 
captured through the case report form (CRF) for drug administration.  
A safety follow-up visit for collection of AE data, PK, PD, and anti-drug antibody (ADA) 
samples will be performed 9 weeks after administration of the last dose of study drug in patients 
who discontinue early or following the end of dosing in the long-term extension period.  Samples 
for PK, PD, and ADA will also be collected from patients who experience a hematological 
breakthrough event.  The study will be complete 12 months following LPO for Part A at which 
time all patients receiving on-going treatment will proceed to an End-of-Study (EOS) visit. 
4.2 
DISCUSSION OF STUDY DESIGN  
The route of administration, dose, and dosing interval for BIVV009 planned for use in this study 
are based on the initial Phase 1a/1b clinical experience (BIVV009-01) and corresponding 
non-clinical data for safety, PK, and PD observations.  BIVV009 has thus far been administered 
to healthy human volunteers and patients with complement-mediated disease entities including 
CAgD, BP, WAIHA, and AMR. 
During Part A, randomized patients will receive fixed doses via IV infusion of either 6.5 grams 
(if <75 kg) or 7.5 grams (if ≥75 kg) of BIVV009 or placebo based on their baseline body weight.  
During Part B, all patients will receive BIVV009 in an open-label manner based on their body 
weight as described above. 
The repeated dose regimen is predicted to provide continuous C1s inhibition throughout the 
dosing interval, with an adequate safety margin based on comparative drug exposures in NHPs 
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(Section 2.2.1) and in healthy volunteers given a single dose of 100 mg/kg in Phase 1a 
(Section 2.2.2).  
Safety, tolerability, PK, PD and immunogenicity assessments will be evaluated at the time points 
indicated in the study schedule of events (Table 3). In patients having consented to the use of 
their blood samples for future research, ADA may be tested using available predose PD back-up 
samples.  
4.3 
STUDY ENDPOINTS  
4.3.1 Primary endpoint (Part A)  
The primary efficacy endpoint is the responder rate as defined in Table 2. 
4.3.2 Secondary efficacy endpoints (Part A)  
• Mean change from baseline in Hgb at treatment assessment endpoint (mean of values at 
Week 23, 25, and 26)  
• Mean change from baseline in bilirubin (excluding patients with Gilbert’s Syndrome) at 
treatment assessment endpoint 
• Mean change from baseline in QOL, as assessed by the change in Functional Assessment 
of Chronic Illness Therapy (FACIT)-Fatigue scale (Appendix C) scores at the treatment 
assessment endpoint 
• Mean change from baseline in lactate dehydrogenase (LDH) at the treatment assessment 
endpoint 
• Incidence of solicited symptomatic anemia at EOT 
4.3.3 Exploratory efficacy endpoints (Part A)  
• Mean change from baseline in QOL, as assessed by the change in the five level EuroQol 
– five dimensions questionnaire (EQ-5D-5L) scores at the treatment assessment endpoint 
• Mean change from baseline in QOL, as assessed by the change in the 12-Item Short Form 
Survey (SF-12®) at the end of treatment assessment endpoint 
• Proportion of patients with ≥12 g/dL Hgb at treatment assessment endpoint 
• Incidence of thromboembolic events after the first 5 weeks of study drug administration 
• Median time to normalization of bilirubin  
• Median time to normalization of LDH  
• Median time to normalization of haptoglobin  
• Median time to Hgb of ≥12 g/dL  
• Proportion of patients normalizing haptoglobin at treatment assessment endpoint 
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• Proportion of patients normalizing bilirubin at treatment assessment endpoint 
• Proportion of patients with abnormal LDH at baseline who normalize LDH at treatment 
assessment endpoint  
• Patient’s Global Impression of Change (PGIC) to assess the patient’s perception of 
changes in CAgD disease burden at EOT  
• Patient’s Global Impression of [Fatigue] Severity (PGIS) to assess the patient’s 
perception of changes in fatigue at EOT  
• Incidence of disabling circulatory symptoms at treatment assessment endpoint 
• Total healthcare resource utilization at EOT  
4.3.4 Efficacy endpoints (Part B)  
The following parameters of disease activity will be assessed:  
• Hemoglobin 
• Bilirubin (total) 
• QOL assessments (FACIT-fatigue, EQ-5D-5L, SF-12, PGIS, and PGIC) 
• LDH 
• Transfusion requirements  
• Haptoglobin 
• Total healthcare resource utilization at EOT  
• Satisfaction with home infusion after first home infusion and after fourth home infusion 
will be assessed in patients with home infusions (Appendix K, Appendix L) 
4.3.5 Safety endpoints  
• Incidence of treatment-emergent AEs (TEAEs) and serious AEs (SAEs)  
• Change from baseline in clinical laboratory evaluations 
• Change from baseline in SLE panel 
• Change from baseline in vital signs 
• Change from baseline in electrocardiogram (ECG) data  
• Physical examination findings  
• Serum disease-related biomarkers 
• Incidence of hemolytic breakthrough (rapid fall in Hgb ≥2 g/dL associated with an 
increase in LDH/bilirubin and/or decrease in haptoglobin since the last scheduled visit) 
through the EOT at Week 26 
• Incidence of infections of ≥ Grade 3 severity (ie, requiring IV antibiotics)  
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• Incidence of thromboembolic events  
• For patients with home infusions, safety assessments will additionally include AEs with 
onset within 24 hours of the of infusion 
• For patients receiving undiluted infusions, safety assessments will additionally include 
post-infusion vital signs and AEs with onset within 24 hours of the infusion  
4.3.6 Pharmacokinetic endpoints  
• Plasma concentrations of BIVV009  
• PK parameters. Appropriate exposure parameters (Cmax, AUC) will be derived using a 
population PK approach.  
During Part A, PK blood samples will be collected at predose and 1 hour postdose (ie, 1 hour 
after completion of study drug infusion) from all patients on Days 0, 7, 21, 35, 49, 63, 77, 91, 
105, 119, 133, 147, 161, and 175.  An additional blood sample for PK analysis will be collected 
during the EOT visit on Day 182 or at early termination (ET) if a patient withdraws early.  
During Part B, PK samples will continue to be collected at predose and 1 hour (±15 minutes) 
postdose on Days 189, 217, and 245, then routinely at 3-month intervals starting at Day 273 
through the remainder of the study.  Samples will also be collected if a patient experiences a 
hematologic breakthrough event or withdraws from the study. 
4.3.7 Pharmacodynamic endpoints  
PD Primary Outcome Measure: 
• Wieslab-CP 
Exploratory Complement System Measures: 
• CH50 
• Total C4 
• C1q 
• C1s 
During Part A, PD blood samples will be collected at predose and 1 hour postdose (ie, 1 hour 
after completion of study drug infusion) from all patients on Days 0, 7, 21, 35, 49, 63, 77, 91, 
105, 119, 133, 147, 161, and 175.  An additional blood sample for PD analysis will be collected 
during the EOT visit on Day 182 or at ET if a patient withdraws early. 
During Part B, PD samples will continue to be collected at predose and 1 hour postdose  
(±15 minutes) on Days 189, 217, and 245, then routinely at 3-month intervals starting at  
Day 273 through the remainder of the study.  Samples will also be collected if a patient 
experiences a hematologic breakthrough event or withdraws from the study. 
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4.3.8 Immunogenicity endpoints  
During Part A, ADA samples will be collected at predose on Day 0, 7, 35, 77, 133, 175 and on 
Day 182 (EOT) or at ET if a patient withdraws early. During Part B, ADA samples will continue 
to be collected at predose, on Days 189, 217, and 245, then routinely at 3-month intervals 
starting at Day 273 through the remainder of the study and at Safety Follow up visit 9 weeks 
after last dose. Samples will also be collected if a patient experiences a hematologic 
breakthrough or withdraws from the study.  
In patients enrolled prior protocol v6.0 and having consented to the use of their blood samples 
for future research, ADA may be tested using available predose PD back-up samples.  
4.4 
DURATION OF THE STUDY  
The planned total study duration per patient is approximately 1.5 to 2.5 years: 
• Screening/Observation Period: 6 weeks (Day -42 through Day -1) 
• Part A treatment period: 25 weeks (Day 0 through Day 175) 
• Part A EOT visit: 1 week after administration of the last dose of study drug during Part A 
(Week 26/Day 182) 
Patients who complete Part A per protocol through the EOT visit will participate in Part B, the 
long-term safety and durability of response extension phase of the study. 
• Part B safety and durability of response extension phase: blinding will be maintained 
when rolling patients into the extension period by providing a crossover dose at Week 26 
to allow placebo patients to receive the BIVV009 loading dose at start of BIVV009 
dosing.  Patients who were randomized to BIVV009 during the 6-month treatment period 
will receive a placebo dose at Week 26 to maintain blinding.  All patients will then 
continue to receive bi-weekly BIVV009 dosing starting at Week 27.  For individual 
patients, dosing in Part B may last from 1 to 2 years, depending on when the patient 
enters Part B.  Part B will to run for 1 year following completion of LPO in Part A. 
• Part A/B ET/Safety Follow-up visit: 9 weeks after administration of the last dose of study 
drug. 
4.5 
END OF STUDY  
The study will be considered complete 12 months following LPO from Part A. When this occurs, 
all ongoing patients in Part B will return to the clinic for EOS assessments (see Section 6.1.5.7 
and Table 3). The EOS will occur when the last patient has had his or her last visit (Last Patient 
Last Visit). 
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5 
PATIENT SELECTION  
This study will enroll approximately 40 adult patients with primary CAgD who do not have a 
recent history of blood transfusion.  Patients who meet all the inclusion criteria and for whom 
none of the exclusion criteria apply will be eligible for enrollment.  
5.1 
INCLUSION CRITERIA  
All patients must meet all the following inclusion criteria to be enrolled: 
I 01. Adult male and female patients ≥18 years of age at Screening.  
I 02. Body weight of ≥39 kg at Screening. 
I 03. Confirmed diagnosis of primary CAgD based on the following criteria:  
a) Chronic hemolysis 
b) Polyspecific direct antiglobulin test (DAT) positive 
c) Monospecific DAT strongly positive for C3d 
d) Cold agglutinin titer ≥64 at 4˚C 
e) IgG DAT ≤1+, and 
f) No overt malignant disease  
I 04. Hemoglobin level ≤10.0 g/dL.  
I 05. Bilirubin level above the normal reference range, including patients with Gilbert’s 
Syndrome.  
I 06. Ferritin levels above the lower limit of normal. Concurrent treatment with iron 
supplementation is permitted if the patient has been on a stable dose during the previous 
4 weeks.  
I 07. Presence of one or more of the following CAgD-related signs or symptoms within 
3 months of Screening:  
a) Symptomatic anemia defined as: 
i. Fatigue 
ii. Weakness 
iii. Shortness of breath 
iv. Palpitations, fast heart beat 
v. Light headedness and/or 
vi. Chest pain 
b) Acrocyanosis 
c) Raynaud’s syndrome 
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d) Hemoglobinuria 
e) Disabling circulatory symptoms, and/or 
f) Major adverse vascular event (including thrombosis)  
I 08. Bone marrow biopsy within 6 months of Screening with no overt evidence of 
lymphoproliferative disease or other hematological malignancy.  An additional bone 
marrow biopsy will be required if the prior bone marrow is deemed unsuitable for 
analysis by the Sponsor. 
I 09. Documented vaccinations against encapsulated bacterial pathogens (Neisseria meningitis, 
including serogroup B meningococcus, Haemophilus influenzae, where available, and 
Streptococcus pneumoniae) within 5 years of enrollment or as specified in Section 6.1.1.1. 
I 10. Patients must be willing to receive transfusions if they meet the eligibility criteria during 
the study treatment period.  Patients who do not have a recent history of transfusion due 
to patient refusal or patient decision should not be enrolled if they do not agree to receive 
blood transfusions as needed. 
I 11. Adequate IV access. 
I 12. If female, must be post-menopausal, surgically sterile, or be established on (≥3 months 
prior to Screening) and agree to continue to use the same highly effective methods of 
birth control throughout the study and for 9 weeks following administration of the last 
dose of study drug.  
I 13. Males must be surgically sterile for at least 90 days or when sexually-active with female 
partners of child-bearing potential will agree to use highly effective contraception from 
Day 0 until 9 weeks following administration of the last dose of study drug.  
I 14. Able to comprehend and give informed consent. 
I 15. Able to comply with the requirements of the study and to complete the full sequence of 
protocol-related procedures. 
5.2 
EXCLUSION CRITERIA  
Patients who meet any of the following criteria will be excluded from the study: 
E 01. Cold agglutinin syndrome secondary to infection, rheumatologic disease, or active 
hematologic malignancy. 
E 02. History of blood transfusion within 6 months of screening, or history of more than one 
blood transfusion within 12 months of screening. 
E 03. Clinically relevant infection of any kind within the month preceding enrollment 
(eg, active hepatitis C, pneumonia). 
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E 04. Clinical diagnosis of SLE; or other autoimmune disorders with anti-nuclear antibodies at 
Screening.  Anti-nuclear antibodies of long-standing duration without associated clinical 
symptoms will be adjudicated on a case-by-case basis during the Confirmatory Review of 
Patient Eligibility (Section 6.1.1.3). 
E 05. Positive hepatitis panel (including hepatitis B surface antigen and/or hepatitis C virus 
antibody) prior to or at Screening. 
E 06. Positive human immunodeficiency virus (HIV) antibody at Screening. 
E 07. Treatment with rituximab monotherapy within 3 months or rituximab combination 
therapies (eg, with bendamustine, fludarabine, ibrutinib, or cytotoxic drugs) within 
6 months prior to enrollment. 
E 08. Concurrent treatment with corticosteroids other than a stable daily dose equivalent to 
≤10 mg/day prednisone for previous 3 months. 
E 09. Erythropoietin deficiency.  Concurrent treatment with erythropoietin is permitted if the 
patient has been on a stable dose for the previous 3 months. 
E 10. Concurrent usage of iron supplementation unless the patient has been on a stable dose for 
at least 4 weeks. 
E 11. Clinically significant medical history or ongoing chronic illness that would jeopardize the 
safety of the patient or compromise the quality of the data derived from his/her 
participation in this study (as determined by the Investigator [or designee]) at Screening. 
E 12. Concurrent treatment with other experimental drugs or participation in another clinical 
trial with any investigational drug within 30 days or 5 half-lives, whichever is greater, 
prior to treatment start. 
E 13. Females who are pregnant, lactating, or, if having reproductive potential, are considered 
potentially unreliable with respect to contraceptive practice. 
E 14. History of hypersensitivity to BIVV009 or any of its components. 
For home infusion in/exclusion criteria see (Appendix K). 
For undiluted infusion eligibility criteria see Section 4.1. 
5.3 
REMOVAL OF PATIENTS FROM STUDY PARTICIPATION, AND STUDY 
SUSPENSION AND STOPPING RULES  
Patients will be informed that they are free to withdraw from the study at any time and for any 
reason.  Patients should inform the site of withdrawal in writing.  The Investigator (or designee) 
may remove a patient from the study if, in the Investigator’s (or designee’s) opinion, it is not in 
the best interest of the patient to continue the study.  Patients may be withdrawn due to the 
following:  
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• Change in compliance with inclusion/exclusion criteria that is clinically relevant and 
affects patient safety 
• Occurrence of AEs that, in the opinion of the Investigator, may jeopardize patient safety 
or data integrity.  This includes clinically significant hematologic breakthrough events 
attributable to the development of ADA and/or the development of positive SLE auto-
antibody titers 
• Occurrence of pregnancy in patient while receiving study drug 
• Intake of non-permitted concomitant medication that might affect patient safety or study 
assessments/objectives  
• Clinical signs of SLE or any other immune complex disease 
• Hypersensitivity or allergic reaction, including anaphylaxis, to study drug 
The Investigator will immediately notify the Sponsor’s Study Monitor of all patients who withdraw 
from treatment. In case of withdrawal, all ET assessments should be performed as applicable 
(Section 6.1.4). The date the patient is withdrawn from the study and the reason for withdrawal 
will be recorded on the patient’s electronic Case Report Form (eCRF). All withdrawn patients 
will be followed until resolution of all their AEs or until the unresolved AEs are judged by the 
Investigator (or designee) to have stabilized.  Patients who withdraw from study early (prior to 
Week 5) may be replaced at the discretion of the Sponsor.  Patients who withdraw from the after 
Week 5 and prior to Week 23 will not be eligible to participate in Part B. 
The entire study may be discontinued at the discretion of the Sponsor based on the occurrence of 
the following: 
• Adverse events unknown to date or increased frequency, and/or severity, and/or duration 
of known AEs, 
• Results of the interim analysis (Section 7.9) demonstrating absence of clinically 
significant increases in Hgb,  
• Medical or ethical reasons affecting the continued performance of the study, 
• Difficulties in the recruitment of patients, 
• Cancellation of or change in drug development program per the discretion of the Sponsor. 
 
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6 
STUDY PROCEDURES  
6.1 
SCHEDULE OF STUDY PROCEDURES  
A schedule of events is presented in Table 3.  Laboratory tests, including PD assays, are 
specified in Appendix A. 
 
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Table 3 - Study schedule of events  
Study Visit (Week/Day) 
Screening/ 
Observation 
Perioda 
Baseline 
Part A Dosing 
(Weeks 1–25) 
Part A EOT: 
Part B 
Crossover 
Loading Dose 
(Week 26) 
Part B 
Open-
Label 
Extension 
Phase 
ET/EOS/ 
Safety 
Follow-
upb  
Days -42 to -1 
Day 0 
Days 7, 21, 35, 49, 63, 77, 
91, 105, 119, 133, 147, 
161, 175 
Day 182 
Every 2 
Weeks 
after 
Week 25 
9 Weeks 
after Last 
Dose 
Visit Windows 
 3 days 
N/A 
 2 days 
 2 days 
 2 days 
 2 days 
Written informed consent 
X 
 
 
 
 
 
Demographic & baseline characteristics 
X 
 
 
 
 
 
Detailed medical history 
X 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
Immunization review/vaccinationc 
When applicable, vaccinations should be initiated on Day -42 or as 
soon as possible during Screening.  The primary vaccine series 
should be completed during Screening when possible and otherwise 
prior to Week 5 of Part A. See Appendix I for the vaccination 
schedule for Japan. 
 
 
 
Bone marrow biopsy report reviewd 
X 
 
 
 
 
 
Optional bone marrow testing for MYD88 status 
for consenting patients 
X 
 
 
 
 
 
Pregnancy test (if applicable)e 
X 
X 
X (Prior to study drug infusion on 
Days 21, 49, 77, 105, 133, and 
161)e 
X  
Xe 
X 
Body weight and heightf 
X 
X 
 
X 
Xl  
X 
Physical examination, full 
X 
 
 
X 
 
X 
Physical examination, brief 
 
X 
X 
 
Xl 
 
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Study Visit (Week/Day) 
Screening/ 
Observation 
Perioda 
Baseline 
Part A Dosing 
(Weeks 1–25) 
Part A EOT: 
Part B 
Crossover 
Loading Dose 
(Week 26) 
Part B 
Open-
Label 
Extension 
Phase 
ET/EOS/ 
Safety 
Follow-
upb  
Days -42 to -1 
Day 0 
Days 7, 21, 35, 49, 63, 77, 
91, 105, 119, 133, 147, 
161, 175 
Day 182 
Every 2 
Weeks 
after 
Week 25 
9 Weeks 
after Last 
Dose 
Visit Windows 
 3 days 
N/A 
 2 days 
 2 days 
 2 days 
 2 days 
Vital signs (BP, PR, RR, body temperature)g 
X 
X 
X 
X 
Xl 
X 
12-lead electrocardiogram (predose and  
1 hour after infusion on dosing days) 
X 
X 
X (Day 91 only) 
 
Xp  
 
Virology/serology panelh  
X 
 
 
 
 
 
Gilbert’s Syndrome test (UGT1A1 gene) 
X 
 
 
 
 
 
SLE panelh 
X 
 
 
X 
Xt 
X 
Iron panel and erythropoietinh 
X 
 
 
 
 
 
Hematology panelh 
X 
X 
X 
X 
X 
X 
Coagulation panelh  
X 
X 
 
X 
 
X 
Clinical chemistry panelh 
X 
X 
X 
X 
X 
X 
Urinalysish 
X 
X 
 
X 
Xl 
X 
FACIT-Fatiguer  
 
X 
X 
X 
Xl 
X 
PGISr 
 
X 
X (Days 35, 77, and 119 only) 
X 
Xl 
X 
PGICr 
 
X 
X (Days 35, 77, and 119 only) 
X 
Xl 
X 
SF-12r 
 
X 
X (Days 35, 77, and 119 only) 
X 
Xl 
X 
EQ-5D-5Lr 
 
X 
X (Days 49, 91, 133 only)  
X 
Xl 
X 
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Study Visit (Week/Day) 
Screening/ 
Observation 
Perioda 
Baseline 
Part A Dosing 
(Weeks 1–25) 
Part A EOT: 
Part B 
Crossover 
Loading Dose 
(Week 26) 
Part B 
Open-
Label 
Extension 
Phase 
ET/EOS/ 
Safety 
Follow-
upb  
Days -42 to -1 
Day 0 
Days 7, 21, 35, 49, 63, 77, 
91, 105, 119, 133, 147, 
161, 175 
Day 182 
Every 2 
Weeks 
after 
Week 25 
9 Weeks 
after Last 
Dose 
Visit Windows 
 3 days 
N/A 
 2 days 
 2 days 
 2 days 
 2 days 
Solicited symptomatic anemia 
X (Day -42 
only) 
X 
X 
X 
X 
X 
Study drug administrationi  
 
X 
X 
Xm  
X 
 
ADAs against BIVV009 
 
X 
Xs  
Xs 
Xs 
X 
PK Samplesj  
 
X 
X  
X 
Xl 
X 
PD Samplesh, j  
Xn  
X 
X 
X 
Xl 
X 
Disease-related biomarkersh 
X 
X 
Xo (Day 91 only) 
X 
 
 
Prior & concomitant medications including 
transfusions 
X 
X 
X 
X 
X 
X 
Healthcare resource utilization 
X 
X 
X (Days 21, 49, 77, 105, 133, 
and 161) 
X 
Xq  
X 
Adverse eventsk  
X 
X 
X 
X 
X 
X 
ADA = anti-drug antibodies; BP = blood pressure; EOS = End of Study; EOT = End of Treatment; EQ-5D-5L = five level EuroQol five dimensions questionnaire; ET = Early Termination Visit; 
FACIT-Fatigue = functional assessment of chronic illness therapy - fatigue; N/A = not applicable; PD = pharmacodynamic; PGIC = Patient’s Global Impression of Change; PGIS = Patient’s Global 
Impression of [Fatigue] Severity; PK = pharmacokinetic; PR = pulse rate; QOL = quality of life; RR = respiratory rate; SF-12 = 12-Item Short Form Survey; SLE = systemic lupus erythematosus. 
a The 6-week Screening/Observation Period may be extended by 1 week for patients requiring a blood transfusion during Screening/Observation prior to study drug administration.   
b Patients should return to site 9 weeks after last dose for ET procedures, EOS assessment, or Safety Follow-up procedures upon completion of dosing in the study.  If patient experiences a 
hematological breakthrough event, a PK, PD, and ADA sample should be collected at the time of the event. 
c Applicable to patients who do not have documented vaccination against encapsulated bacterial pathogens within 5 years of enrollment.  Refer to immunization recommendations per  
Section 6.1.1.1 for patients requiring vaccination.  A blood sample for vaccine titers will be collected on Day 0 prior to study drug infusion to be used to determine serum relevant antibody titers 
should the patient be diagnosed with an infection associated with an encapsulated organism during the study.  A second sample will be collected during the study period if a patient presents with 
symptoms of infection. 
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d Prior bone marrow biopsy report review, prior tissue assessment, or new bone marrow biopsy (as applicable).  Sites will submit de-identified biopsy reports to independent central reader for 
eligibility adjudication.  If biopsy is deemed unsuitable or insufficient to determine eligibility, either prior tissue may be submitted for additional hematopathology assessment or a new bone marrow 
biopsy will be performed during the screening period. 
e Females of child-bearing potential only.  Serum pregnancy test to be performed at Screening.  Serum or urine pregnancy test in WOCBP (ie, women of child bearing potential) to be performed on 
Days 0, 21, 49, 77, 105, 133, and 161, and at Week 26/EOT or at the ET visit.  Repeat serum or urine pregnancy test every 4 weeks (±2 days) during Part B. 
f 
Height measured at Screening only.  Body weight measured every 3 months during Part B. 
g Vital signs measurements (supine BP, PR, RR, and oral temperature) are to be obtained at Screening and at each subsequent visit, with measurements performed predose and 1 hour 
(±5 minutes) after completion of administration of each dose of study drug. 
h For a complete list of analytes, see protocol Appendix A. 
i 
Study drug doses of 6.5 grams (if <75 kg) or 7.5 grams (if ≥75 kg) based on patient’s baseline body weight will be administered via IV infusion over ~ 60±5 minutes on Days 0, 7, and every  
14 days thereafter during Part A and every 2 weeks starting at Week 27 during Part B.  Patients with underlying cardiopulmonary disease may receive a 2-hour infusion with Sponsor approval.  If 
a patient misses a scheduled dose (outside of the 2-day window or >17 days since last dose), they must return to site (unscheduled visit) to receive another loading dose 1 week prior to the next 
scheduled dose. Qualifying patients at participating sites may have study drug dosed at home during certain visits in Part B, according to the rules specified in Appendix K (for  the US, the 
Netherlands, Norway, France, Italy, Austria, Germany, and Spain specific amendments (Appendix K). 
j 
During Part A, PK and PD blood samples will be collected at predose and 1 hour (±15 minutes) post-dose (ie, 1 hour after completion of study drug infusion) from all patients on Days 0, 7, 21, 35, 
49, 63, 77, 91, 105, 119, 133, 147, 161, and 175.  An additional blood sample for PK and PD analysis will be collected during the EOT visit on Day 182 or at ET if a patient withdraws early.  
During Part B, PK and PD samples will continue to be collected at predose and 1 hour (±15 minutes) postdose on Days 189, 217, and 245, then routinely at 3-month intervals starting at Day 273 
through the remainder of the study.  PK and PD samples will also be collected if a patient experiences a hematologic breakthrough event at any point during the study. 
k AEs will be recorded from the time the patient signs the informed consent form until 9 weeks after administration of the last dose of study drug. 
l 
To be performed every 3 months during the on-site visits, or for post-infusion vital signs in case of undiluted administration, after each undiluted infusion. 
m After completion of all Part A EOT assessments, a cross-over loading dose will be administered to patients in a blinded manner at the Week 26 visit to initiate dosing in Part B. 
n Refer to the Laboratory Manual for details of sample collection during Screening. 
o Samples will be collected for a subset of the disease-related biomarkers at Day 91.  Refer to the Laboratory Manual for details. 
p During Part B, a 12-lead ECG will be conducting pre- and postdose at 3 months (Day 273). 
q During Part B, the healthcare resource utilization data will be recorded every 4 weeks. 
r 
To be performed in the following order: FACIT-Fatigue first, PGIS second, PGIC third, SF-12 fourth, and EQ-5D-5L fifth. 
s During Part A, ADA samples will be collected at predose on Day 0, Day 7, 35, 77, 133, 175 and on Day 182 (EOT) or at ET if a patient withdraws early. During Part B, ADA samples will continue 
to be collected at predose, on Days 189, 217, and 245, then routinely at 3-month intervals starting at Day 273 through the remainder of the study and at safety follow up visit 9 weeks after last 
dose. Samples will also be collected if a patient experiences a hematologic breakthrough event or withdraws from the study early. 
t 
 SLE panel will be performed every 6 months in Part-B of the study. 
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6.1.1 Screening/observation period (Days -42 to Day -1)  
Patients (or their legally authorized representative) must provide informed consent before any 
study-specific screening tests are performed.  Participating study sites are required to document 
all screened candidates initially considered for inclusion in the study.  Patients will be designated 
as screened following completion of all screening assessments. 
Screen failures are defined as patients who sign the informed consent form (ICF) but are not 
subsequently dosed with BIVV009 or placebo.  If a patient is considered a screen failure, the 
reason(s) will be documented on the screening log and in source records. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities.  Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAEs. 
6.1.1.1 Screening assessments (initiating at Day -42)  
The following assessments and procedures will be initiated following collection of written 
informed consent at Day -42 and completed during the 6-week Screening/Observation Period: 
• Written informed consent 
• Demographic and baseline characteristics including height and body weight 
• Detailed medical history 
• Immunization review and vaccination, if applicable  
• Serum pregnancy test (if applicable) 
• Physical examination (full) 
• Vital signs  
• Virology/serology panel 
• Gilbert’s Syndrome testing (UGT1A1 gene) 
• SLE panel  
• Hematology panel 
• Coagulation panel 
• Clinical chemistry panel 
• Urinalysis  
• PD samples (refer to Laboratory Manual) 
• Iron panel and erythropoietin assays 
• Disease-related biomarkers 
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• 12-lead ECG 
• Prior bone marrow biopsy report review, prior tissue assessment, or new bone marrow 
biopsy (as applicable) 
• Optional bone marrow testing for MYD88 status 
• Inclusion/exclusion criteria review for determination of eligibility 
• Solicited symptomatic anemia assessment 
• Record healthcare resource utilization data from previous 6 months 
• Record prior and concomitant medications/procedures including transfusions 
• Adverse event monitoring 
Bone Marrow Biopsy 
A bone marrow biopsy is required to have been performed within 6 months of Screening to rule 
out overt evidence of lymphoproliferative disease or other hematological malignancy prior to 
enrollment.  Sites will submit de-identified biopsy reports to an independent central reader for 
eligibility adjudication.  If biopsy is deemed unsuitable or insufficient to determine eligibility, 
then either the prior tissue may be submitted for additional hematopathology assessment or a 
new bone marrow biopsy will be performed during the screening period.  Patients will have the 
option to consent to additional testing of bone marrow for MYD88 status. Further instructions 
for bone marrow biopsy assessment will be available in Appendix A (Bone Marrow Biopsy 
Report Review Process) to the ‘Subject Eligibility Review Process Overview’. 
Vaccination Against Encapsulated Bacterial Pathogens 
In the event a patient does not have documented vaccination against encapsulated bacterial 
pathogens (Neisseria meningitis, including serogroup B meningococcus, where available, 
Haemophilus influenzae, and Streptococcus pneumoniae) within 5 years prior to enrollment, 
vaccination should be initiated during the Screening/Observation Period prior to enrollment 
(see Table 3).  Vaccination series for these pathogens should be completed as per current 
regional guidelines specified for patients with persistent complement deficiency and in 
accordance with their respective labels, as applicable.  Where no regional guidelines are 
available for patients with persistent complement deficiency, it is recommended that vaccinations 
include meningococcal conjugate, meningococcal serogroup B, 13-valent pneumococcal, 23-valent 
pneumococcal, and Haemophilus influenza Type b vaccines where commercially available. 
Vaccinations should be initiated on Day -42 or as early as possible during the 
Screening/Observation period. The primary vaccine series should be completed during Screening 
when possible and otherwise prior to Week 5 of Part A.  Patients must be advised that 
vaccination may not prevent meningococcal infections and that they should immediately report 
fevers or other symptoms consistent with acute infection to the Investigator. 
Patients who develop symptoms consistent with an infection due to encapsulated bacterial 
pathogens during the study period will have a blood sample collected to test for confirmation of 
infection and vaccination status. 
A separate vaccination schedule for Japan is provided in Appendix I. 
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Laboratory Tests 
The first set of laboratory test results collected during the Screening Period will be utilized to 
assess patient eligibility for the study.  Screening assessments may be repeated once at the 
discretion of the Principal Investigator (PI).  Additional repeat screening tests may not be 
performed without Sponsor (or designee) approval. 
6.1.1.2 Interim visits during screening/observation period  
During the 6-week Screening/Observation Period, the patient will return to the clinical site 
approximately every 2 weeks (Day -28 and Day -14) after the initial visit for collection of 
laboratory samples to assess and characterize their CAgD.  During these visits, the following 
assessments and procedures will be performed: 
• Vital signs 
• Collection of blood samples for assessment of the following indicators of CAgD: 
- 
Hemoglobin 
- 
Bilirubin 
- 
LDH 
- 
Haptoglobin 
- 
Reticulocytes 
- 
CH50 
• Record prior and concomitant medications/procedures including transfusions 
• Adverse event monitoring 
Detailed information on sample collection and a list of analytes to be tested may be found in the 
Study Schedule of Events (Table 3) in Section 6.1, Appendix A, and the Laboratory Manual.  
6.1.1.3 Confirmatory review of patient eligibility  
Upon completion of screening assessments, the site will compile de-identified, key eligibility 
data for each patient and forward to the Study Medical Monitor for review and confirmation of 
eligibility prior to study enrollment/randomization. Details on the eligibility data review process 
may be found in the ‘Subject Eligibility Process Overview’.  
6.1.2 Day 0 visit (first dose)  
On Day 0, patients will undergo the following procedures before administration of the study 
drug: 
• Inclusion/exclusion criteria review for confirmation of continued eligibility 
• Serum or urine pregnancy test (if applicable) 
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• Vaccine titers 
• Body weight 
• Physical examination (brief) 
• Vital signs 
• Hematology panel 
• Coagulation panel 
• Clinical chemistry panel  
• Urinalysis  
• Solicited symptomatic anemia assessment 
• QOL assessments 
- 
FACIT-Fatigue (Appendix C) 
- 
EQ-5D-5L (Appendix D) 
- 
SF-12 (Appendix E) 
- 
PGIS (see Appendix H) 
- 
PGIC (see Appendix F) 
• ADAs against BIVV009  
• PK and PD sampling 
• Disease-related biomarkers 
• Record healthcare resource utilization data (see Appendix G) since previous assessment 
• 12-lead ECG 
• Record prior and concomitant medications/procedures including transfusions 
• Adverse event monitoring 
At 0 hour, study drug will be infused via an indwelling IV catheter over a period of 60±5 minutes. 
Patients with underlying cardiopulmonary disease may receive a 2-hour infusion with Sponsor 
approval. Additionally, study drug infusion may be interrupted or slowed in the event of 
suspicion of an allergic reaction or anaphylaxis. 
After completion of the infusion, patients will undergo the following procedures: 
• Vital signs at 1 hour (±5 minutes) postdose 
• 12-lead ECG at 1 hour (±15 minutes) postdose 
• PK and PD sampling at 1 hour (±15 minutes) postdose 
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6.1.3 Weeks 1-25 Part-A  
On Days 7, 21, 35, 49, 63, 77, 91, 105, 119, 133, 147, 161, and 175, patients will undergo the 
following procedures before administration of the study drug: 
• Serum or urine pregnancy test in WOCBP (ie, women of child bearing potential), if 
applicable, on Days 21, 49, 77, 105, 133, and 161 
• Physical examination (brief) 
• Vital signs 
• Hematology panel 
• Clinical chemistry panel  
• Solicited symptomatic anemia assessment 
• QOL assessments: 
- 
FACIT-Fatigue: all scheduled visits 
- 
PGIS: Days 35, 77, and 119 only  
- 
PGIC: Days 35, 77, and 119 only  
- 
SF-12: Days 35, 77, and 119 only   
- 
EQ-5D-5L: Days 49, 91, and 133 only  
• 12-lead ECG (Day 91 only) 
• During Part A, ADA samples will be collected at predose on Day 0, 7, 35, 77, 133, 175 
on Day 182 (EOT) 
• PK and PD sampling 
• Disease-related biomarkers (subset at Day 91 only); refer to the Laboratory Manual for 
details 
• Record healthcare resource utilization data since previous assessment on Days 21, 49, 77, 
105, 133, and 161 
• Record concomitant medications/procedures including transfusions  
• Adverse event monitoring 
At 0 hour, study drug will be infused via an indwelling IV catheter over a period of 
60 ±5 minutes.  Patients with underlying cardiopulmonary disease may receive a 2-hour infusion 
with Sponsor approval.  Additionally, study drug infusion may be interrupted or slowed in the 
event of suspicion of an allergic reaction or anaphylaxis. 
After completion of the infusion, patients will undergo the following procedures: 
• Vital signs at 1 hour (±5 minutes) postdose 
• 12-lead ECG (Day 91 only) at 1 hour (±15 minutes) postdose 
• PK and PD sampling at 1 hour (±15 minutes) postdose 
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Vaccinations should be administered according to Section 6.1.1.1, if applicable, or Appendix I 
for Japan. 
Note: Patients who miss a dose (ie, outside the dosing window or >17 days since last dose) 
should return to the site for an unscheduled visit 1 week prior to the next scheduled dose in order 
to receive an additional loading dose.  The patient should then resume subsequent dosing visits 
every 14 days after the loading dose. 
6.1.4 End-of-treatment visit in Part A (Week 26)  
On Day 182, patients will undergo the following procedures: 
• Serum or urine pregnancy test (if applicable) 
• Body weight 
• Physical examination (full) 
• Vital signs 
• SLE panel 
• Hematology panel 
• Coagulation panel 
• Clinical chemistry panel  
• Urinalysis  
• Solicited symptomatic anemia assessment 
• QOL assessment (FACIT-Fatigue, EQ-5D-5L, SF-12, PGIS, and PGIC) 
• ADAs against BIVV009 (predose) or at ET if patient withdraws early. 
• PK and PD sampling 
• Disease-related biomarkers 
• Record healthcare resource utilization data since previous assessment 
• Record concomitant medications/procedures including transfusions  
• Adverse event monitoring 
After completion of all Part A EOT assessments, a cross-over loading dose will be administered 
to patients in a blinded manner at the Week 26 visit to initiate dosing in Part B. 
6.1.5 Part B extension phase  
6.1.5.1 Procedures to be performed every 2 weeks  
For patients completing Part A, the following procedures will be performed every 2 weeks 
(beginning at Week 27) during Part B prior to administration of study drug: 
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• Hematology panel 
• Clinical chemistry panel  
• Solicited symptomatic anemia assessment 
• Record concomitant medications/procedures including transfusions  
• Adverse event monitoring 
6.1.5.2 Procedure to be performed every 4 weeks  
• Women of childbearing potential will undergo serum or urine pregnancy testing every 
4 weeks (beginning at Week 27) during Part B prior to administration of study drug. 
• Record healthcare resource utilization data.  
6.1.5.3 Procedures to be performed every 3 months  
In addition, the following procedures will be performed every 3 months beginning after Week 27 
(or as otherwise noted) during Part B prior to administration of study drug: 
• Body weight 
• Physical examination (brief) 
• Vital signs 
• Urinalysis  
• QOL assessments: 
- 
FACIT-Fatigue  
- 
EQ-5D-5L 
- 
SF-12 
- 
PGIS 
- 
PGIC  
• 12-lead ECG (once at 3 months [Day 273]) 
• SLE panel (every 6 months) 
• PK, PD, and ADA sampling 
At 0 hour, study drug will be infused via an indwelling IV catheter over a period of 
60±5 minutes.  Patients with underlying cardiopulmonary disease may receive a 2-hour infusion 
with Sponsor approval.  Additionally, study drug infusion may be interrupted or slowed in the 
event of suspicion of an allergic or anaphylactic reaction. 
After completion of the infusion, patients will undergo the following procedures: 
• Vital signs at 1 hour (±5 minutes) postdose 
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• 12-lead ECG (once at 3 months [Day 273]) at 1 hour (±15 minutes) postdose 
• PK and PD sampling (every 3 months) at 1 hour (±15 minutes) postdose  
6.1.5.4 Additional PK, PD, and ADA sampling  
PK and PD samples will continue to be collected at predose and 1 hour (+/- 15 minutes) post-
dose on Days 189, 217, and 245. 
ADA samples will be collected at predose, on Day 189, 217, and 245. 
PK, PD, and ADA samples will be collected if a patient experiences a hematologic breakthrough 
event (rapid fall in Hgb ≥2 g/dL associated with an increase in LDH/bilirubin and/or decrease in 
haptoglobin since the last scheduled visit). 
6.1.5.5 Infusion of the study drug at patient’s home  
Home infusions will be performed at pre-selected countries/sites by a healthcare professional 
caregiver contingent upon completion of training delivered by the Investigator or delegated site 
staff member only in patients willing to be administered study drug at home, who have been 
treated for at least 3 months (completed visit Day 273) in Part B and in whom previous on-site 
infusions were uncomplicated (for the US, the Netherlands, Norway, France, Italy, Austria, 
Germany, and Spain, specific amendments) (Appendix K). Only patients who do not participate 
in, or have never participated in undiluted infusions can be considered for home infusion. 
6.1.5.6 Infusion of the undiluted study drug  
A subset of patients in Part B will be proposed to receive infusions with study drug undiluted 
with saline solution. Undiluted infusions may begin no sooner than after Week 39 (Day 273) in 
patients who consent to and without evidence of intolerance to the study drug  and who satisfy 
criteria outlined in Section 4.1. Only patients who do not participate in, or have never 
participated in home infusion can be considered for undiluted infusions. Each qualified patient is 
supposed to receive at least one undiluted infusion of BIVV009, however patients are free to 
continue with undiluted BIVV009 until the end of study. Post-infusion vital signs will be 
collected for these patients. Patients receiving undiluted infusions of BIVV009 may return to 
diluted infusions any time, or this may be the Investigator’s decision. Patients receiving 
undiluted BIVV009 will return to diluted infusions if they experience adverse event that in the 
opinion of the Investigator, may jeopardize patient safety if undiluted infusions are continued. 
Patients may return to diluted infusions if this AE is considered by the Investigator to be 
unrelated to BIVV009 and once resolved or stabilized. Hypersensitivity or allergic reactions to 
study drug will always result in study drug discontinuation and withdrawal from the study.  
6.1.5.7 Early termination/end of study/safety follow-up visit  
Upon completion of dosing in the study, or if a patient terminates the study early, the following 
assessments should be completed 9 weeks after administration of the last dose of study drug: 
• Serum or urine pregnancy test (if applicable) 
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• Body weight 
• Physical examination (full) 
• Vital signs 
• SLE panel 
• Hematology panel 
• Coagulation panel 
• Clinical chemistry panel  
• Urinalysis  
• Solicited symptomatic anemia assessment 
• QOL assessments (FACIT-Fatigue, EQ-5D-5L, SF-12, PGIS, and PGIC) 
• ADAs against BIVV009  
• PK and PD sampling 
• Record healthcare resource utilization data since previous assessment 
• Record concomitant medications/procedures including transfusions  
• Adverse event monitoring 
If a patient experiences a hematological breakthrough event during the safety follow-up period, 
a PK, PD, and ADA sample should be collected at the time of the event. 
6.2 
STUDY TREATMENT  
6.2.1 Drug supplies and accountability  
Patients will receive doses of either 6.5 grams or 7.5 grams of BIVV009, depending on their 
body weight.  BIVV009 is supplied to the pharmacy for preparation for infusion in either 10 mL 
glass vials (18 mg/mL) or 25 mL glass vials (50 mg/mL); for subjects receiving undiluted 
infusions, BIVV009 is supplied in 25 mL glass vials (50 mg/mL). The Sponsor (or designee) will 
provide the Investigators (or designees) with adequate quantities of BIVV009 and placebo.  
BIVV009 drug product will be provided as a sterile, nonpyrogenic, isotonic aqueous solution 
containing 18 mg/mL or 50 mg/mL BIVV009 with 10 mM sodium phosphate buffer, 140 mM 
NaCl, 0.02% polysorbate 80 (Tween-80), and water for injection; the pH is 6.1.  Each Type 1 
glass vial, which has a bromobutyl rubber stopper and an aluminum seal, contains sufficient 
overfill to account for vial, needle, and syringe loss.  Drug product can be used for IV 
administration only. 
BIVV009 placebo is manufactured and packaged in the same configuration as the BIVV009 drug 
product, but without BIVV009.  BIVV009 placebo will be provided as a sterile, nonpyrogenic, 
isotonic aqueous solution containing 10 mM sodium phosphate buffer, 140 mM NaCl, 0.02% 
polysorbate 80 (Tween-80), and water for injection; the pH is 6.1.  Each Type 1 glass vial, which 
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has a bromobutyl rubber stopper and an aluminum seal, contains sufficient overfill to account for 
vial, needle, and syringe loss.  BIVV009 placebo can be used for IV administration only.  
BIVV009 and BIVV009 placebo should be stored at 2°C to 8°C, protected from light, and kept 
under secure conditions until immediately before use.  It is to be administered via IV infusion 
according to the instructions given in the Pharmacy Manual for this study. 
Preparation and accountability procedures for the investigational product including those 
associated with home infusions (for the US, the Netherlands, Norway, France, Italy, Austria, 
Germany, and Spain) specific amendments (Appendix K), whenever applicable, are described in 
further detail in the Pharmacy Manual.  
6.2.2 Patient number and identification  
Patients will be assigned unique study numbers that will be used on all study documentation 
during the course of the trial.  For patients who are withdrawn by an Investigator (or designee) or 
who voluntarily withdraw prematurely from the study, replacement patients will be enrolled only 
if deemed necessary by the Sponsor. Numbers will not be reused. 
6.2.3 Randomization  
On Day 0, eligible patients will be randomized in a 1:1 ratio to treatment with either BIVV009 or 
placebo using an Interactive Web-based System (IWRS).  Details on the randomization process 
are available in the eCRF Completion Guidelines. 
6.2.4 Dose preparation and administration  
Qualified pharmacy or clinical staff will prepare each unit dose of study drug for IV infusion.  
Dose preparation shall proceed as detailed in the Pharmacy Manual for this study.  Briefly, 
placebo or an appropriate number of 10 mL drug product glass vials (each containing 180 mg of 
BIVV009) or 25 mL drug product glass vials (each containing 1.1 grams of BIVV009) will be 
pooled and diluted with saline solution to a total volume of 500 mL to administer either a 
6.5 gram dose (for patients <75 kg) or a 7.5 gram dose (for patients ≥75 kg), depending on the 
patient’s baseline (Day 0) body weight.   
For subjects receiving undiluted infusions, appropriate number of 25 mL drug product glass vials 
(each containing 1.1 grams of BIVV009) will be pooled to administer either a 6.5 gram 
dose/130 mL (for patients <75 kg) or a 7.5 gram dose/150 mL (for patients ≥75 kg), depending 
on the patient’s baseline (Day 0) body weight. Details are provided in the Pharmacy Manual. 
Study drug or placebo will be infused IV by a suitable infusion pump over a period of 
approximately 60 minutes.  (Patients with underlying cardiopulmonary disease may receive a 
2-hour infusion with Sponsor approval.)  The infusion catheter and tubing will be flushed both 
immediately before and immediately following completion of the infusion with a sufficient 
quantity of sterile saline for injection.  For each dose, the patient’s actual dose, time of dosing, if 
the administration is being performed at the patient’s home (Appendix K), or if study drug is 
administered in the form of undiluted infusions will be recorded in the source documents and 
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transcribed onto the eCRFs.  The administration location, rate, start time, stop time, any infusion 
interruptions, and total volume of investigational product actually administered will be recorded 
in the eCRFs.  If an AE occurs during the administration of study drug, the rest of the infusion 
during which the AE occurred may be slowed or stopped at the discretion of the Investigator or 
the professional healthcare caregiver in case of home infusions (Appendix K). 
Patients must be monitored for acute allergic reactions during infusion and for at least 2 hours 
after the completion of the first administration of study drug or 1 hour after the completion of 
each administration of study drug thereafter. Additionally, patients undergoing home infusions 
will be monitored by the professional healthcare caregiver for 2 hours after the completion of the 
first home infusion or 1 hour after the completion of each subsequent home infusion (Appendix K). 
Epinephrine, parenteral diphenhydramine and, for infusions carried at the study site, cardiac 
resuscitation equipment, must be immediately available in case an allergic reaction or 
anaphylaxis occurs. Site personnel or professional healthcare caregiver in case of home infusions 
(Appendix K), must be qualified to detect allergic reactions and anaphylaxis and treat those 
reactions under the guidance of the PI. The home infusion personnel will be trained in basic life 
support (cardiopulmonary resuscitation [CPR]) but will not be required to have equipment to 
perform advanced life support (eg, defibrillators). See Section 6.3.8 for further details regarding 
additional testing. 
Patients should be instructed to report the development of rash, hives, pruritus, flushing, 
urticaria, etc, that may represent an allergic or hypersensitivity reaction to study drug.  If any 
signs or symptoms of an allergic or anaphylactic reaction are observed during the infusion, 
administration of study drug must be immediately discontinued and the patient treated as 
appropriate. In case of home infusion, the investigator has to be notified immediately to guide 
treatment (Appendix K). 
6.2.5 Blinding  
Patients and all study staff will be blinded to treatment assignment.  Study drug or placebo doses 
for infusion will be prepared by the pharmacist or qualified site staff in a blinded manner. 
Investigators will have direct access to unblinding of treatment through the IWRS in the event of 
an emergency in which knowledge of treatment assignment would aid in immediate patient care. 
Should a patient’s treatment be unblinded, every effort will be undertaken to protect the blind 
within the study team. Only a pre-specified group of unblinded team members (safety associate, 
data manager, biostatistician) will have access to the patient’s unblinded data while the study is 
ongoing. 
6.2.6 Concomitant medications  
Patients will refrain from participation in any other investigational study drug trial in which 
receipt of any investigational drug occurred within 5 half-lives or 30 days, whichever is longer, 
prior to Day 0 and during the entire study. 
Treatment with rituximab monotherapy or rituximab combination therapies (eg, with 
bendamustine, fludarabine, ibrutinib, or cytotoxic drugs) is prohibited. 
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During Part A, patients will not take any prescription or over-the-counter medications/products 
until completion of the follow-up assessments, unless prescribed by the Investigator or another 
physician for the treatment of an AE.  
As noted in Section 5.2, concurrent administration of erythropoietin and/or a daily dose of 
corticosteroids (equivalent to ≤10 mg/day of prednisone) is acceptable provided the patient has 
been on a stable dose during the previous 3 months; concurrent use of B12, folate and iron 
supplementation is acceptable provided the patient has been on a stable dose during the previous 
4 weeks. 
Topical therapies without risk of systemic absorption may be allowed, and non-prescription 
medications for treatment of minor intercurrent illnesses (headache, viral upper respiratory tract 
infections, etc) are permitted at the discretion of the PI.  Hormonal contraception in female 
patients is allowed provided patients are receiving stable treatment ≥3 months prior to Screening.  
Any medication taken by the patient during the study, along with its strength, frequency of 
dosing, and reason for its use, will be documented in the patient’s source data and the eCRF.  
6.2.7 Contraception  
Women of non-childbearing potential are defined as permanently sterile (ie, due to hysterectomy, 
bilateral salpingectomy, bilateral oophorectomy) or postmenopausal (defined as at least 
12 months post-cessation of menses without an alternative medical cause).  Women who are of 
non-childbearing potential will not be required to use contraception. 
Female patients of childbearing potential must be established on (≥3 months prior to Screening) 
and agree to continue to use the same highly effective methods of birth control (ie, contraceptive 
measure with a failure rate of <1% per year) in conjunction with male barrier contraception 
(ie, male condom with spermicide) throughout the study and for 9 weeks after the administration 
of the last dose of study drug.  Highly effective methods of contraception include: 
• Intrauterine device (IUD; Mirena®) 
• Established use of oral (PO), implanted, transdermal, or hormonal method of 
contraception associated with inhibition of ovulation 
• Bilateral tubal ligation 
• Permanent birth control via the Essure procedure 
Male patients will be surgically sterile for at least 90 days or when sexually active with female 
partners of childbearing potential will be required to use a male condom with spermicide 
(if locally approved for use) throughout the study and for 9 weeks after the last dose of study 
drug. 
Patients who practice true abstinence, because of the patient’s lifestyle choice (ie, the patient 
should not become abstinent just for the purpose of study participation) are exempt from 
contraceptive requirements.  Periodic abstinence (eg, calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception.  If a patient 
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who is abstinent at the time of signing the ICF becomes sexually active they must agree to use 
contraception as described above.  
For male patients, sexual intercourse with female partners who are pregnant or breastfeeding 
should be avoided unless condoms are used from the time of administration of the first dose until 
9 weeks after administration of the last dose of study drug.  Male patients are required to refrain 
from donation of sperm from Day 0 until 9 weeks after administration of the last dose of study 
drug. 
6.3 
STUDY ASSESSMENTS  
Please refer to Table 3 and Section 6 (Study Procedures) for an overview of the study procedures 
and schedule of events.  Data will be collected via an eCRF for each randomized patient.  
All patients will provide written informed consent before any study-specific assessment is 
performed.  A study-specific assessment is defined as a procedure that is not part of the routine 
assessments performed for diagnostic purposes or standard care.  Screening assessments should 
occur within 6 weeks prior to administration of the study treatment (ie, on Days -42 to -1).  
The immunization status should be confirmed at least 14 days prior to the planned administration 
of study drug (ie, on or before Day -14). 
6.3.1 Demographic data  
The date of birth, sex, race, and ethnicity will be documented, as permitted by local regulations. 
6.3.2 Medical history  
A detailed general medical history of clinically significant diseases and surgeries will be 
collected during Screening.  Additionally, a detailed medical history of the patient’s primary 
CAgD as well as history of all blood transfusions will be reviewed and recorded.  
6.3.3 Height, body weight, and vital signs  
Height, body weight, and vital signs will be documented.  Vital sign measurements (including 
oral temperature, respiratory rate, supine blood pressure, and pulse rate) will be obtained at the 
time points specified in Table 3.  Vital signs will be measured after the patient has been supine 
for at least 5 minutes. Vital signs should be measured before any other procedures that may 
affect pulse rate or blood pressure (eg, blood draws). 
6.3.4 Electrocardiograms  
A 12-lead ECG will be obtained at the time points specified in Table 3.  Patients will be supine 
for at least 5 minutes prior to obtaining an ECG measurement.  The ECG should be performed 
before any other procedures that may affect heart rate (eg, blood draws). 
The Investigator’s overall interpretation of the ECG will be recorded and any abnormalities 
reported. 
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6.3.5 Physical examinations  
Full and brief physical examinations will be performed at the time points specified in Table 3.  
The time and date of the physical examinations will be recorded in the source document and 
eCRF, and any clinically significant changes from baseline will be recorded as AEs. 
Full physical examinations will consist of the following: general appearance, head and neck, 
eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and joints, lymph nodes, 
skin, and neurology. 
Brief physical examinations will consist of the following: general appearance, chest, lungs, heart, 
abdomen, and skin. 
6.3.6 Immunization review  
The patient’s medical and vaccination history will be reviewed to ensure that each patient is 
up-to-date with all required immunizations; if not already vaccinated against Neisseria 
meningitidis, including serogroup B meningococcus, where available, Haemophilus influenzae, 
and Streptococcus pneumoniae within 5 years of enrollment, these will be administered 
following informed consent, as applicable, per Table 3 and as described in Section 6.1.1.1 
(Screening procedures) or Appendix I for Japan.  
6.3.7 Clinical laboratory evaluations  
Clinical laboratory evaluations (including hematology panel, clinical chemistry panel, iron panel, 
erythropoietin assay, coagulation safety panel, SLE panel, virology/serology panel, disease-
related biomarkers, and urinalysis) as outlined in Appendix A will be performed at the time 
points specified in Table 3.  Clinical laboratory results will be reviewed by the Investigator and 
results outside of the reference ranges will be documented and clinical significance noted.  
Local laboratory values may be utilized for eligibility evaluation and medical management of the 
patient, including assessing the hemoglobin criteria necessitating blood transfusions. Detailed 
information on the allocation of samples for central or local laboratory processing will be 
available in the Laboratory Manual. 
6.3.8 Additional testing in case of hypersensitivity/allergic reaction  
If a patient exhibits signs of a hypersensitivity/allergic reaction during study drug administration, 
the study drug infusion should be stopped immediately, and medical treatment provided, as 
appropriate. 
If a suspected anaphylactic reaction occurs (18), the following labs may be obtained per the 
discretion of the Investigator, after discussion with the Sponsor Medical Monitor: 
• Approximately 30 to 120 minutes after the start of symptoms: blood draw for ADAs 
(including isotyping), tryptase, IL-6, IL-33, plasma histamine, CICs, and complement 
levels (CH50).  A follow-up tryptase level should be obtained 8 days following the 
reaction. 
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• 24-hour urine collection for methylhistamine analysis (ideally collection should be started 
within 6 hours of onset of symptoms and collected even if the patient is sent to the 
emergency room; patient can be provided with a container for the collection. 
6.4 
PHARMACOKINETIC PROCEDURES  
6.4.1 Pharmacokinetic blood sample collection and processing  
Blood samples for PK analysis of BIVV009 levels and ADAs against BIVV009 will be collected 
via an indwelling catheter and/or via direct venipuncture from the arm opposite from the site of 
infusion.  Blood samples will be collected at the time points specified in Table 3.  If an 
indwelling catheter is used, saline flushes will be used. 
6.4.2 Analytical methodology  
Plasma concentrations of BIVV009 will be determined using a validated analytical procedure.  
Specifics of the analytical methods will be provided in a separate document. 
6.5 
PHARMACODYNAMIC PROCEDURES  
6.5.1 Pharmacodynamic and ADA blood sample collection and processing  
Blood samples for ADA and PD analysis of the Complement System Classical Pathway levels 
(Wieslab assay) will be obtained via an indwelling catheter and/or via direct venipuncture. Blood 
samples for PD analysis will be collected at the time points specified in Table 3. Complement 
assays will also be performed on samples, including: 
• Total complement (CH50)  
• Total C4 
• C1q  
• C1s 
If an indwelling catheter is used, saline flushes will be used. 
6.5.2 Analytical methodology  
PK, PD, and ADA parameters will be determined using a validated analytical procedure.  
Specifics of the analytical methods and appropriate matrices for the different parameters will be 
provided in a separate document. 
6.6 
SAFETY PROCEDURES  
Safety evaluations as needed for medical management of the patient may be repeated at the 
Investigator’s (or designee’s) discretion. 
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Every effort will be made to schedule and perform the procedures in accordance with the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, and 
the other procedures to be performed at the same time point.  
The order of priority for scheduling procedures around a time point is (in descending order of 
priority): 
• PK and PD blood sampling 
• ADAs against BIVV009   
• Vital sign measurements 
• ECGs 
• Blood and urine samples for clinical laboratory testing 
• Physical examinations 
6.7 
ADVERSE EVENTS AND LABORATORY ABNORMALITIES  
It is the responsibility of the Investigator to report all AEs in the eCRF.  The AE and SAE 
reporting period will begin from the time the patient signs the ICF and continue through 9 weeks 
after administration of the last dose of study drug.  Any SAE must be reported within 24 hours of 
the knowledge of the occurrence to the Study Medical Monitor and the designated Clinical 
Research Organization’s (CRO) Clinical Safety Group.  Refer to Section 6.7.4 for further details 
regarding SAE reporting procedures.  
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the study reference manual’s Official Study Contact List for complete contact 
information. 
6.7.1 Definition of adverse events  
An AE is defined in the International Council for Harmonisation (ICH) Guideline for Good 
Clinical Practice (GCP) as “any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
a causal relationship with this treatment” (ICH E6: Section 1.2).  An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product. 
6.7.1.1 Definition of adverse drug reactions  
Adverse drug reactions are defined as all noxious and unintended responses to a medicinal 
product related to any dose administered.  The phrase “responses to a medicinal product” means 
that a causal relationship between a medicinal product and an AE is at least a reasonable 
possibility (ie, the relationship cannot be ruled out). 
The following categories for determining the causal relationship to the investigational medicinal 
product are to be used: 
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Probable (must have first three): 
• It follows a reasonable temporal sequence from administration of study drug. 
• It cannot be reasonably explained by the known characteristics of the patient’s clinical 
state, environmental or toxic factors, or other modes of therapy administered to the patient. 
• It disappears or decreases on cessation or reduction in dose. 
• It follows a known pattern of response to the suspected drug. 
• It reappears upon re-challenge. 
Possible (must have first two): 
• It does not follow a reasonable temporal sequence from administration of the drug. 
• It may readily have been produced by the patient’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to the patient. 
• It does not reappear or worsen when the drug is re-administered. 
Unrelated: 
An AE will be considered “Unrelated” to the use of the investigational drug if there is not a 
reasonable possibility that the event has been caused by the product under investigation and does 
not meet the criteria for drug relationship listed under possible or probable.  Factors pointing 
toward this assessment include, but are not limited to, the lack of reasonable temporal 
relationship between administration of the drug and the event, the presence of a biologically 
implausible relationship between the product and the AE (eg, the event occurred before 
administration of drug), or the presence of a more likely alternative explanation for the AE.  
In case of missing causality assessment in the eCRF or SAE reporting form, the event will be 
regarded as possibly related unless further specified.  Any SAE recorded as probably or possibly 
related will be categorized as “related” for regulatory reporting purposes. 
A serious drug reaction is an adverse drug reaction that meets the definition of a serious event 
(provided below). 
6.7.1.2 Definition of serious adverse events  
An SAE is defined as any untoward medical occurrence (AE) that at any dose: 
• Results in death 
• Is life-threatening (patient was at immediate risk of death at the time of the event) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect  
• Any other significant medical condition 
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A hospitalization meeting the regulatory definition for “serious” is any inpatient hospital 
admission.  Any AE that does not meet one of the definitions of serious (ie, important medical 
events that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require interventions to prevent one of the other outcomes listed 
above [eg, emergency room visit, outpatient surgery, or requires urgent investigation]) may be 
considered by the Investigator to meet the “other significant medical condition” criterion for 
classification as an SAE.  Examples include allergic bronchospasm, convulsions, and blood 
dyscrasias. 
If a subject develops a Grade 3 or higher allergic reaction per Common Terminology Criteria for 
Adverse Events (CTCAE) grading or an anaphylactic reaction (see Section 6.3.8) in association 
with BIVV009 administration, the event should be reported as an SAE. 
Exceptions from SAE reporting: 
Hospitalization for performing protocol-required procedures or administration of study treatment 
is not classified as an SAE. 
6.7.1.3 Definition of unexpected adverse event/SUSAR  
An unexpected AE is any adverse drug event, the specificity or severity of which is not 
consistent with the current Investigator’s Brochure (IB) of BIVV009.  Also, reports that add 
significant information on specificity or severity of a known, already documented AE constitute 
unexpected AEs.  An event more specific or more severe than described in the IB would be 
considered “unexpected.” 
A suspected unexpected serious adverse reaction (SUSAR) is a serious adverse reaction, the 
nature or severity of which is not consistent with the IB.  All suspected adverse reactions related 
to BIVV009 that occur in the concerned clinical trial and that are both unexpected and serious 
(SUSARs) are subject to expedited reporting as per national regulatory requirements in 
participating countries. 
6.7.2 Clinical adverse events  
The Investigator is responsible for ensuring that all AEs observed by the Investigator or reported 
by the patient are properly captured in the patient’s medical records. 
The following AE attributes must be assigned by the Investigator: 
• Adverse event term 
• Dates of onset and resolution 
• Seriousness (yes/no)/seriousness criterion 
• Severity 
• Assessment of relatedness to study drug 
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• Outcome 
- 
Recovered/resolved 
- 
Recovered/resolved with sequelae 
- 
Not recovered/not resolved 
- 
Fatal 
- 
Unknown (only applicable if patient is lost to follow-up) 
• Action taken: 
- 
None 
- 
Study drug temporarily interrupted 
- 
Study drug permanently discontinued 
During the study, serious and non-serious AEs will be followed until resolved or clinically 
stable.  At the end of the study, all ongoing SAEs will be followed until resolved, stabilized, or 
returned to baseline. 
It will be left to the Investigator’s clinical judgment to determine whether an AE is related and of 
sufficient severity to require the patient’s removal from treatment or from the study.  A patient 
may also voluntarily withdraw from treatment due to what he or she perceives as an intolerable 
AE.  If either of these situations arises, the patient should be strongly encouraged to undergo an 
ET visit assessment and be under medical supervision until symptoms cease or the condition 
becomes stable. 
All clinical AEs encountered during the clinical study will be reported on the AE page of the 
eCRF, regardless of causality.  Severity of AEs will be graded using the CTCAE, version 4.03  
(see Appendix B). 
If an AE occurs that is not contained in the CTCAE version 4.03, the five-point scale below will 
be used. 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2:  
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL) 
Grade 3:  
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limited 
self-care ADL 
Grade 4:  
Life-threatening consequences; urgent intervention indicated 
Grade 5: 
Death related to AE 
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6.7.3 Laboratory test abnormalities  
Laboratory test value abnormalities that have worsened from baseline should not be reported on 
the AE page of the eCRF as AEs unless they satisfy one or more of the following conditions for 
clinical significance: 
• Accompanied by clinical symptoms 
• Leading to a change in study medication (eg, dose modification, interruption, or 
permanent discontinuation) 
• Requiring a change in concomitant therapy (eg, addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy, or 
treatment 
Any laboratory result abnormality fulfilling the criteria for an SAE should be reported as such, in 
addition to being recorded as an AE in the eCRF. 
6.7.4 Serious adverse event reporting - procedures for investigators  
All SAEs occurring from the time of informed consent through the final study visit, or 9 weeks 
after administration of the last dose of study drug, whichever occurs later, must be reported to the 
Sponsor’s designated CRO’s Clinical Safety Group within 24 hours of the knowledge of the 
occurrence.  All SAEs that the Investigator considers related to study drug occurring after the 
follow-up period must be reported directly to the Sponsor. 
To report the SAE, the SAE form for the study should be completed and submitted within 
24 hours of the site becoming aware of the event to the designated CRO’s Clinical Safety Group 
via email or facsimile (FAX) per the instructions provided on the SAE report form. 
The Sponsor (or designee) will report SUSARs to the appropriate regulatory authorities and 
Investigators according to local law. 
6.7.5 Follow-up of adverse events  
All serious and non-serious AEs, regardless of whether or not they are assessed as related to 
study drug, should be followed up during the study until they have resolved, returned to baseline 
status, or stabilized.  If a clear explanation is established, it should be recorded on the eCRF. 
If there is a unifying diagnosis, the diagnosis should be reported rather than a collection of signs 
and symptoms.  
Ongoing SAEs at the end of study should continue to be followed until the event has resolved, 
returns to baseline, the condition becomes chronic in nature, stabilizes (in the case of persistent 
impairment), or the patient dies.  Within 24 hours of receipt of any follow-up information, the 
Investigator must update the eCRF, complete and submit an SAE follow-up form along with any 
supporting documentation (eg, patient discharge summary or autopsy reports) to the designated 
CRO’s Clinical Safety Group via email or FAX per the instructions provided on the SAE report 
form.  
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6.7.6 Follow-up of abnormal laboratory results  
In the event of unexplained abnormal laboratory test values, the tests should be repeated 
immediately and follow-up until they have returned to the normal range and/or an adequate 
explanation of the abnormality is found.  If a clear explanation is established, it should be 
recorded on the eCRF.  Regarding the documentation of abnormal laboratory tests, please refer 
to Section 6.7.3. 
6.7.7 Pregnancy  
If a patient becomes pregnant during the study or within 9 weeks of receiving study drug, or if 
the partner of a patient participating in the study conceives after the patient has received the first 
dose of study drug and up to 9 weeks after receiving the last dose of study drug, the Investigator 
should report the pregnancy to the designated CRO’s Clinical Safety Group by completing and 
forwarding a Pregnancy Report Form within 24 hours of being notified. 
A patient becoming pregnant while on study drug will immediately be withdrawn from the study, 
study treatment will be stopped, and early study termination procedures will be performed. 
The patient or patient’s partner should be followed by the Investigator until the end of the 
pregnancy.  If the pregnancy ends for any reason before the anticipated date, the Investigator 
should notify the designated CRO’s Clinical Safety group by completing and forwarding an 
updated Pregnancy Report Form.  At the end of the pregnancy, the Investigator should document 
the outcome of the pregnancy and provide a final update via an updated Pregnancy Report Form.  
If outcome of the pregnancy meets the criteria for immediate classification as an SAE 
(ie, postpartum complication, spontaneous abortion, stillbirth, neonatal death, or congenital 
anomaly), the Investigator should follow the procedures for reporting an SAE. 
6.7.8 Overdose  
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol.  Overdoses are not considered 
AEs and should not be recorded as an AE on the CRF; however, all overdoses must be recorded 
on an Overdose form and faxed or emailed to the designated CRO’s Clinical Safety Group within 
24 hours of the site becoming aware of the overdose.  An overdose must be reported to the 
designated CRO’s Clinical Safety Group even if the overdose does not result in an AE.  If an 
overdose results in an AE, the AE must be recorded.  If an overdose results in an SAE, both the 
SAE and Overdose forms must be completed and faxed or emailed to the designated CRO’s 
Clinical Safety Group.  All study treatment-related dosing information must be recorded on the 
dosing CRF. 
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7 
DATA ANALYSES AND SAMPLE SIZE  
Data from Part A and Part B of this study will be analyzed and reported separately.  A separate 
Statistical Analysis Plan (SAP) for each part of the study will be produced providing full details 
of all analyses to be performed for Part A and Part B.  Should there be any differences between 
the analyses plan and methodology described within the SAP versus the clinical protocol, the 
SAP will take precedence. 
For the purposes of regulatory submission, an interim analysis of the Part A data will be 
performed after all patients have completed Part A. 
7.1 
DESCRIPTION OF OBJECTIVES AND ENDPOINTS  
The objectives of the study and the endpoints to be analyzed are described in Section 4.3. 
In general, continuous variables will be summarized by descriptive statistics, including: number, 
mean, median, standard deviation (SD), minimum, and maximum.  Categorical variables and 
response variables will be presented with the number and percentage in each category. Any 
hypothesis tests will be performed at a two-sided 0.05 significance level.  Unless otherwise 
specified, all data will be presented in patient data listings.  
For analyses purposes in Part A, baseline is defined as the last value obtained during Screening 
immediately prior to administration of the first dose of study drug. 
For endpoints involving laboratory parameters, except for hematology panel, results from the 
central laboratory will be used. Local laboratory values were utilized for Direct Antiglobulin 
Test (DAT) for, among others, eligibility purposes and hematology panel that allows both 
determination of eligibility and the medical management of the patient, with assessment of the 
hemoglobin criteria necessitating blood transfusions.  
7.2 
DEMOGRAPHICS AND BASELINE DISEASE CHARACTERISTICS  
Demographic and other baseline disease characteristics will be summarized using descriptive 
statistics for the overall population.  Data to be tabulated will include, but not be limited to, age, 
race, medical history, and other disease-specific measures. 
7.3 
EFFICACY - PART A  
7.3.1 Analysis populations  
Full Analysis Set Population: The Intent-to-Treat (ITT) Population consists of all randomized 
subjects who received at least 1 dose (including partial dose) of study drug. All subjects in the 
ITT population will be included in the Full Analysis Set (FAS). For analysis, FAS and the ITT 
Population are considered exchangeable, but the term FAS will be used in subsequent sections. 
Per-Protocol (PP) Population: The PP Population is defined as a subset of FAS who do not have 
any important protocol deviations impacting their efficacy assessments. 
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The FAS analyses will be the primary analyses and the PP analyses will be considered as 
supportive. 
The patients in the FAS that are excluded from the PP Population will be listed, together with the 
reason for exclusion from the PP Population. 
7.3.2 Methods of analysis  
Each patient in the FAS will be classified as a responder or non-responder per the response 
criteria, and will be compared between treatment groups using Cochran-Mantel-Haenszel test at 
the significance level of 0.05.  The difference in the proportion of responders between groups 
will be calculated with a 95% exact confidence interval (CI). To assess the hematology 
component of response, the mean of the non-missing Hgb assessments at the Week 23, Week 25, 
and Week 26 analysis visits (treatment assessment endpoint) will be used.  Visit windows will be 
used to assign analysis visits, as detailed in the SAP.  Patients missing all three analysis visits 
will be counted as non-responders.  Sensitivity analyses will be performed to evaluate the impact 
by the missing data, when appropriate.  Details will be specified in the SAP.  
Secondary endpoints, defined as follows, will be tested only when the primary endpoint is 
statistically significant: 
1. Mean change from baseline in Hgb at the treatment assessment endpoint (mean of values 
at Week 23, 25, and 26) 
2. Mean change from baseline in bilirubin (excluding patients with Gilbert’s Syndrome) at 
the treatment assessment endpoint 
3. Mean change from baseline in QOL, as assessed by the change in FACIT-fatigue scale 
scores at the treatment assessment endpoint 
4. Mean change from baseline in LDH at the treatment assessment endpoint 
5. Incidence of solicited symptomatic anemia at EOT 
The change from baseline variables will be analyzed using analysis of covariance (ANCOVA) 
with baseline as covariate.  A multiple testing procedure will be specified in the SAP to control 
the overall Type I error rate among the secondary endpoints. 
As a sensitivity analysis, the efficacy analysis will be repeated with patients stratified by 
previous rituximab therapy and/or cytotoxic therapy versus patients who are naïve to rituximab 
therapy and/or cytotoxic therapy using the FAS. 
Other efficacy assessments will be summarized by overall population using descriptive statistics, 
proportions and graphically where applicable.  
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7.4 
EFFICACY - PART B  
7.4.1 Analysis populations  
Intent-to-Treat Population: The ITT Population is defined as all patients who received at least 
1 dose of study drug in Part B.  
Per-Protocol Population: The PP Population is defined as a subset of ITT Population who do not 
have any important protocol deviations impacting their efficacy assessments.  
7.4.2 Methods of analysis  
All endpoints will be analyzed using descriptive statistics, frequency, percentage, 95% CIs, and 
graphically, as appropriate. 
7.5 
PHARMACOKINETICS  
7.5.1 Analysis population  
Part A – All patients who receive at least 1 dose of study drug and have at least 1 evaluable PK 
sample will be included in the PK analysis population. 
Part B – all patients who receive at least 1 dose of study drug and have at least 1 evaluable PK 
sample during the extension phase will be included in the PK analysis population. 
For the purposes of PK parameter analysis, an evaluable patient is defined as a patient who has 
received at least 1 dose of BIVV009 and has completed the relevant blood sample collections 
enabling acceptable determination of PK parameters. 
7.5.2 Methods of analysis  
In general, descriptive statistics including number of observations, mean, SD, median, minimum, 
and maximum will be presented for continuous parameters.  Summary descriptive statistics and 
individual patient listings will be presented for all PK parameters by time point and study day. 
BIVV009 concentrations and individual PK parameter estimates will be listed for each patient 
and summarized descriptively by time point and study day.  Summary descriptive statistics will 
include the number of observations, arithmetic and geometric means, and their associated CIs, 
SD, coefficient of variation, median, minimum, and maximum.  Mean BIVV009 concentration-
versus-time profiles will be plotted. 
PK parameters will be log-transformed for these analyses and estimated means, mean 
differences, and CIs on the log scale will be exponentiated to obtain estimates for geometric 
means, geometric mean ratios, and CIs, respectively, on the original scale.  In addition, 
untransformed PK parameters will be used to calculate arithmetic means and arithmetic mean 
ratios. 
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7.6 
PHARMACODYNAMICS  
7.6.1 Analysis population  
Part A – All patients who receive at least 1 dose of study drug and have at least 1 evaluable PD 
sample during Part A will be included in the PD analysis population. 
Part B – all patients who receive at least 1 dose of study drug and have at least 1 evaluable PD 
sample during the extension period will be included in the PD analysis population. 
7.6.2 Methods of analysis  
In general, descriptive statistics including number of observations, mean, SD, median, minimum, 
and maximum will be presented for continuous parameters.  Categorical variables will be 
presented with the number and percentage in each category.  Summary descriptive statistics 
(absolute values and changes from baseline) and individual patient listings will be presented for 
all PD parameters by time point and study day. 
7.7 
IMMUNOGENICITY  
7.7.1 Analysis population  
Part A – All patients who receive at least 1 dose of study drug and have at least 1 evaluable ADA 
sample during Part A will be included in the ADA analysis population. 
Part B – All patients who receive at least 1 dose of study drug and have at least 1 evaluable ADA 
sample during the extension period will be included in the ADA analysis population. 
7.7.2 Methods of analysis  
Methods of analysis will be described in the statistical analysis plan (SAP). 
7.8 
SAFETY  
7.8.1 Analysis population  
Part A – all patients who receive at least 1 dose of study drug will be evaluable for the analysis 
of safety.  
Part B – all patients who received at least 1 dose of study drug during the extension period will 
be evaluable for the analysis of safety. 
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7.8.2 Methods of analysis  
Adverse events will be classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term.  Tabulations of TEAEs and serious TEAEs 
by frequency, relatedness, and severity will be presented.  Patient listings will be provided for 
SAEs, AEs resulting in discontinuation of the study or study treatment, and all deaths.  In 
addition, specific summary tables will be presented for hemolytic breakthrough, infections 
(Grade 3 or above), and thrombolytic events. 
Changes from baseline in clinical laboratory parameters (except those considered efficacy and 
PD endpoints), vital signs, and ECG parameters will be summarized over time using descriptive 
statistics.  The number and percentage of patients who have positive ADAs will be presented. 
Concomitant medications and physical exam data will be displayed in listings only. 
7.9 
INTERIM ANALYSES  
For the purposes of regulatory submission, an interim analysis of safety and efficacy data will be 
performed for Part A after all patients have completed Part A.  Parts A and B will have separate 
database locks to enable submission of the BLA/MAA following completion of Part A.  
Additional interim analyses of Part B data may be performed at the Sponsor’s discretion for 
purposes of regulatory filings, publications, or future planning.  
7.10 
SAMPLE SIZE CONSIDERATIONS  
Approximately 40 patients with primary CAgD who do not have a recent history of transfusion 
will be randomized.  
With 40 patients (20 per group), there is 87% power to detect a statistically significant difference 
of 50% between the BIVV009 group and placebo group if the true response rates are 85% and 
35% for the BIVV009 and placebo groups, respectively.  This calculation assumes a 2-sided 
5%-level test comparing the response rates between the BIVV009 and placebo groups.  A 50% 
improvement over placebo is considered clinically relevant. 
7.11 
DATA HANDLING AND RECORD KEEPING  
Any changes to information in the study progress notes and other source documents will be 
initialed and dated on the day the change is made by a clinical site staff member authorized to 
make the change.  Changes will be made by striking a single line through erroneous data and 
clearly entering the correct data (eg, wrong data right data). If the reason for the change is not 
apparent, a brief explanation for the change will be written adjacent to the change by the 
clinician. 
Patient information will be captured and managed by study sites on eCRFs by a web-based 
electronic data capture (EDC) tool developed and supported by CRO and approved by the 
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Sponsor.  Data should be entered into the EDC system in a timely manner as outlined within the 
CRF Completion Guidelines. 
Data management will be performed by CRO according to their Standard Operating Procedures 
(SOPs).  The Data Management Plan will be approved by the Sponsor. 
7.12 
QUALITY CONTROL AND QUALITY ASSURANCE  
Quality control procedures will be implemented at each stage of data handling to ensure that all 
data are reliable and have been processed correctly.  Data anomalies will be communicated to the 
sites for clarification and resolution, as appropriate. 
During and/or after completion of the study, quality assurance officers assigned by the Sponsor 
or the regulatory authorities may wish to perform onsite audits or inspections.  The Investigator 
will be expected to cooperate with any audit or inspection and to provide assistance and 
documentation (including source data) as requested.  
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8 
ADMINISTRATIVE ASPECTS  
8.1 
CHANGE IN PROTOCOL  
There will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator. 
There will be no alterations in the protocol affecting patient safety without the express written 
approval of the Sponsor, Investigator, and the Institutional Review Boards/Ethics Committees 
(IRBs/ECs) (see form FDA 1572). 
All protocol amendments must be submitted to the IRBs/ECs and regulatory authorities if 
required by local law.  Protocol modifications that affect patient safety, the investigational scope, 
or the scientific quality of the study must be approved by the IRB/EC before implementation of 
such modifications to the conduct of the study.  If required by local law, such modifications must 
also be approved by the appropriate regulatory agency before implementation.  However, the 
Sponsor may, at any time, amend this protocol to eliminate an apparent immediate hazard to a 
patient.  In this case, the appropriate regulatory authorities will be notified subsequent to the 
modification. 
8.2 
SITE INITIATION VISIT/INVESTIGATOR MEETING  
Prior to the start of the clinical study, the representative(s) of the Sponsor will meet with the 
Investigator and appropriate clinical staff to familiarize the Investigator and clinical staff with 
the clinical protocol and the materials necessary for conducting the clinical study. 
8.3 
DISCLOSURE  
All information provided regarding the study, as well as all information collected/documented 
during the study will be regarded as confidential.  The Investigator (or designee) agrees not to 
disclose such information in any way without prior written permission from the Sponsor. 
Any publication of the results, either in part or in total (eg, articles in journals or newspapers, 
oral presentations, abstracts) by the Investigator or their representative(s), shall require prior 
notification and review, within a reasonable time frame, by the Sponsor, and cannot be made in 
violation of the Sponsor’s confidentiality restrictions or to the detriment of the Sponsor’s 
intellectual property rights.  
Sponsor will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 
8.4 
MONITORING  
The Monitor has the responsibility to familiarize the Investigator(s) and the entire center staff 
involved in the study with all study procedures including the administration of study drug.  The 
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Monitor will monitor the study conduct, proper eCRF and source documentation completion and 
retention, and accurate study drug accountability.  To this end, the Monitor will visit the clinical 
site at suitable intervals and be in frequent contact through verbal and written communication.  It 
is essential that the Study Monitor has access to all documents (related to the study and the 
individual participants) at any time these are requested.  In turn, the Monitor will adhere to all 
requirements for patient confidentiality as outlined in the ICF.  The Investigator and 
Investigator’s staff will be expected to cooperate with the Study Monitor, to be available during a 
portion of the monitoring visit to answer questions, and to provide any missing information. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such as 
Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in separate study documents. 
8.5 
ETHICAL ASPECTS  
The Sponsor, CRO, and the Investigator must comply with all instructions, regulations, and 
agreements in this protocol and applicable ICH and GCP guidelines, and conduct the study 
according to local regulations.  The Investigator may delegate responsibilities for study-related 
tasks where appropriate to individuals sufficiently qualified by education, training, and 
experience, in accordance with applicable ICH and GCP guidelines.  The Investigator should 
maintain a list of the appropriately qualified persons to whom significant study-related duties 
have been delegated.  The Investigator is responsible for supervising those individuals and for 
implementing procedures to ensure the integrity of the tasks performed and any data generated. 
8.5.1 Declaration of helsinki/good clinical practice  
The Declaration of Helsinki is the accepted basis for clinical study ethics, and must be fully 
followed and respected by all engaged in research on human beings.  Any exceptions must be 
justified and stated in the protocol.  The latest version of the Declaration of Helsinki is available 
under www.wma.net/en/30publications/10policies/b3/index.html.pdf.  Additionally, it is the 
responsibility of all engaged in research on human beings to ensure that the study is performed in 
accordance with the international GCP standards and according to all local laws and regulations 
concerning clinical studies. 
8.5.2 Patient information and informed consent  
It is the responsibility of the Investigator to obtain written informed consent from each patient 
participating in this study, after adequate explanation of aim, importance, anticipated benefits, 
and potential hazards and consequences of the study according to applicable local laws.  Written 
informed consent must be obtained before any study-specific procedures are performed.  It must 
be also explained to the patient that he/she is completely free to refuse to enter the study or to 
withdraw from it at any time for any reason without incurring any penalty or withholding of 
treatment on the part of the Investigator. 
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With the declaration of consent the patient agrees that data on his/her medical history are 
recorded within the framework of the clinical study and that they are transferred to the Sponsor 
in a pseudo-anonymized manner.  Patients will be informed that their race and ethnicity will be 
collected and will be used during analysis of study results. 
The patient also agrees to allow the monitor/auditor/health authorities to verify the collected 
patient data against the patient's original medical records for the purpose of source data 
verification. 
The ICF – personally signed and dated by the patient and the Investigator – must be kept on file 
by the Investigator(s) and documented in the eCRF and the patient’s medical records.  The 
Investigator confirms to the Sponsor to obtain the written informed consent from any patient 
before participating in the study. 
If new safety information results in significant changes in the risk/benefit assessment, the 
consent form should be reviewed and updated if necessary.  All patients (including those already 
being treated) should be informed of the new information and must give their written informed 
consent to continue in the study. 
If the family doctors are informed of their patients’ participation in the clinical study, this should 
be mentioned in the consent form. 
8.6 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD AND 
REGULATORY AUTHORITIES  
It is the responsibility of the Sponsor to obtain and maintain independent approval from the 
applicable Regulatory Authorities to conduct the study in accordance with applicable regulatory 
requirements.  It is the responsibility of the Sponsor to ensure that a positive opinion from the 
ECs/IRBs to conduct the study in accordance with applicable regulatory requirements is in place. 
8.7 
RECORDS  
Data collected at Screening and during the study will be recorded in the patient’s source 
documents and retained at the study site for all patients who sign the ICF.  Patients who are 
enrolled in the study will have their data retained in the source documents at the site and also 
have their data entered into the eCRF.  To maintain confidentiality, the patients will be identified 
only by screening and patient numbers. 
The completed eCRFs will be transferred to the Sponsor (or designee).  Copies of each source 
document will be retained by the Investigator (or designee).  A compact disk containing the site 
eCRF data will be provided to the site at the completion of the study.  All source documents, 
records, and reports will be retained by the clinical site in accordance with 21 CFR 312.62(c).  
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local, national, or regional laws or 
regulations.  Prior to proceeding with destruction of records, the Investigator must notify the 
Sponsor in writing and receive written authorization from the Sponsor to destroy study records. 
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In addition, the Investigator must notify the Sponsor of any changes in the archival arrangements 
including but not limited to archival at an offsite facility or transfer of ownership if the 
Investigator leaves the site. 
All primary data, or copies thereof (eg, laboratory records, eCRFs, data sheets, correspondence, 
photographs, and computer records), which are a result of the original observations and activities 
of the study and are necessary for the reconstruction and evaluation of any study report, will be 
retained in the clinical site archives. 
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9 
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3. Petz LD. Cold antibody autoimmune hemolytic anemias. Blood Rev. 2008;22(1):1-15. 
4. Berentsen S. How I manage cold agglutinin disease. Br J Haematol. 2011;153(3):309-17. 
5. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013;122(7):1114-
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6. Arthold C, Skrabs C, Mitterbauer-Hohendanner G, Thalhammer R, Simonitsch-Klupp I, 
Panzer S, et al. Cold antibody autoimmune hemolytic anemia and lymphoproliferative 
disorders: a retrospective study of 20 patients including clinical, hematological, and 
molecular findings. Wien Klin Wochenschr. 2014;126(11-12):376-82. 
7. Berentsen S. Complement, cold agglutinins, and therapy. Blood. 2014;123(26):4010-2. 
8. Berentsen S.  How I manage patients with cold agglutinin disease. Br J Haematol. 
2018;181(3):320-30. 
9. Mullins M, Jiang X, Bylsma LC, Fryzek JP, Reichert H, Chen EC, et al. Cold agglutinin 
disease burden: a longitudinal analysis of anemia, medications, transfusions, and health care 
utilization. Blood Adv. 2017;1(13):839-48. 
10. Barcellini W, Fattizzo B, Zaninoni A, Radice T, Nichele I, Di Bona E, er al.  Clinical 
heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a 
GIMEMA study of 308 patients. Blood. 2014;124(19):2930-6. 
11. Röth A, Bommer M, Hüttmann A, Herich-Terhürne D, Kuklik N, Veronika L, et al. 
Complement inhibition with eculizumab in patients with cold agglutinin disease (CAD): 
Results from a prospective Phase II trial (DECADE Trial). Blood. 2015;128(23):274. 
12. Broome C, Cunningham JM, Mullins M, Jiang X, Bylsma L, Fryzek J, et al. Incidence of 
thromboembolic events is increased in a retrospective analysis of a large cold agglutinin 
disease (CAD) cohort. Blood. 2017;130(Suppl 1):928. 
13. Berentsen S. Cold agglutinin disease. Hematology Am Soc Hematol Educ Program. 
2016(1):226-31. 
14. Randen U, Troen G, Tierens A, Steen C, Warsame A, Beiske K, et al. Primary cold 
agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow 
distinct from lymphoplasmacytic lymphoma. Haematologica. 2014; 99(3):497-504. 
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15. Berentsen S, Ulvestad E, Langholm R, Beiske K, Hjorth-Hansen H, Ghanima W, et al. 
Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. 
Haematologica. 2006;91(4):460-6. 
16. Jäger U, Gilbert JC, Panicker S, Parry GC, Fillitz M, Schenk T, et al. The anti C1s 
complement antibody TNT009 induces rapid complete remissions of anaemia in patients 
with primary cold agglutinin disease. 21st European Haematology Association (EHA) 
Conference. 2016;Abstract LB2237, 341. 
17. Jaeger U, D'Sa S, Schoergenhofer C, Bartko J, Sillaber C, Jilma-Stohlawetz P, et al. Long 
term efficacy, safety and PK/PD profile of the anti-C1s antibody (BIVV009) in primary cold 
agglutinin disease patients. Blood. 2017;130(Suppl 1):703. 
18. Simons FE. Anaphylaxis. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S161-81.  
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INVESTIGATOR AGREEMENT  
 
 
 
Study Drug: BIVV009  
Protocol: BIVV009-04  
 
 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO 
ASSESS THE EFFICACY AND SAFETY OF BIVV009 IN PATIENTS WITH PRIMARY COLD 
AGGLUTININ DISEASE WITHOUT A RECENT HISTORY OF BLOOD TRANSFUSION  
 
Version 8  
04 November 2020 
 
 
 
 
I have read the foregoing protocol and agree to conduct the study as described herein. 
 
 
 
 
 
Principal Investigator (signature) 
 
Date 
 
 
 
 
Principal Investigator (print) 
 
 
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10 
APPENDICES  
 
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Appendix A 
CLINICAL LABORATORY EVALUATIONS  
Clinical Chemistry Panel: 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
Creatinine 
Glucose 
Haptoglobin 
Lactate dehydrogenase (LDH) 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin 
Indirect bilirubin 
Total protein 
Uric acid 
Hematology Panel: 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width 
Reticulocyte count 
White blood cell (WBC) count 
WBC differential (absolute): 
Basophils 
Eosinophils 
Lymphocytes 
Monocytes 
Neutrophils 
Urinalysis: 
Bilirubin 
Color and appearance 
Glucose 
Ketones 
Leukocyte esterase 
Nitrite 
Occult blood 
pH and specific gravity 
Protein 
Urobilinogen 
Microscopic exam including  
bacteria, casts, crystals, 
epithelial cells, RBCs, and 
WBCs (if protein, leukocyte 
esterase, nitrite, or blood is 
positive) 
Pregnancy Test  
(for women of childbearing 
potential): serum test during 
Screening, serum or urine test at all 
other time points 
Hepatic Panel/HIV: 
Hepatitis B surface antigen 
Hepatitis C virus antibody 
Human immunodeficiency virus 
antibody 
Pharmacodynamic (PD) Assays: 
Complement System Classical 
Pathway (Wieslab-CP) 
CH50 
Total C4 
C1q 
C1s 
Systemic Lupus Erythematosus 
Panel: 
Antinuclear antibodies (ANA)  
multiplex with double stranded DNA  
Anti-La/SSB antibody (SS-B) 
Anti-ribonucleoprotein antibody 
(RNP) 
Anti-Smith antibody (Sm) 
Anti-Ro/SSA antibody (SS-A) 
Anti-scleroderma antibody (Scl-70)  
Anti-Chromatin antibody 
Anti-Jo-1 antibody 
Anti-Centromere B antibody 
Circulating immune complexes (CIC) 
Coagulation Panel: 
Prothrombin time or the 
international ratio of PT (PT-INR) 
Activated partial thromboplastin 
time (aPTT) 
D-dimer 
Thrombin-antithrombin assay 
 
Iron Panel and Erythropoietin 
Erythropoietin 
Serum iron 
Total iron binding capacity (TIBC) 
Transferrin saturation 
Ferritin 
Gilbert’s Syndrome Test  
UGT1A1 gene  
 
Disease-Related Biomarkers  
DAT (polyspecific, anti-IgG & 
anti-C3d) 
LDH isoforms 
Cold agglutinin (CAg) titer 
Ig subsets (IgA, IgD, IgG, IgM) 
Vaccine titers 
CAg thermal amplitude 
For information on the anti-drug antibody (ADA) and PK evaluations please refer to the Laboratory Manual. 
Detailed information on the allocation of samples for central or local laboratory processing is 
available in the Laboratory Manual.  
 
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Appendix B 
CI-CTC VERSION 4.03 (CTCAE V4.03)  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf  
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Appendix C 
FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY 
(FACIT)-FATIGUE SCALE  
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Appendix D 
EQ-5D-5L  
 
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Appendix E 
12-ITEM SHORT FORM SURVEY (SF-12)  
 
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Appendix G 
HEALTHCARE RESOURCE UTILIZATION  
Healthcare resource utilization data will be collected during the Screening/Observation Period; 
on Day 0; on Days 21, 49, 77, 105, 133, and 161; at EOT for Part A; every 4 weeks during 
Part B; and at the ET/EOS visit. 
For screening, please provide the healthcare resource utilization data for the past 6 months prior 
to the start of the Screening/Observation period. 
____________________________________________________________________________ 
Has the patient had any additional non-study outpatient visits, emergency room visits, or 
inpatient hospitalizations related to their cold agglutinin disease during the last 4 weeks? 
Yes or No 
If yes, please provide the information below including the number of visits. 
 
 
Yes/No 
 
How 
Many 
A. Extra or unscheduled (non-study) visit to the office of the study doctor 
 
 
 
B. Visit to a generalist doctor 
 
 
 
C. Visit to a specialist doctor 
 
 
 
D. Visit to another healthcare professional (eg, nurse, therapist) 
 
 
 
E. Complementary/alternative visit (eg, homeopathic, herbalist) 
 
 
 
F. Visit to an urgent care or walk-in clinic (excluding a hospital 
emergency room) 
 
 
 
G. Visit to a hospital emergency room 
Reason(s) for the visit (diagnosis): ___________________________  
 
 
 
H. Use of an ambulance service 
 
 
 
I. 
Hospitalization 
Date of hospital admission ___________________ and date of discharge _______________ 
Discharge diagnosis: ____________________________ 
 
Was the patient admitted to the intensive care unit (ICU)?  Yes or No   
If yes, please provide dates or duration in the ICU. 
Date of ICU admission: __________________ and date of ICU discharge: _________________ 
OR  
Duration of ICU stay: _________________ 
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Appendix H 
PATIENT’S GLOBAL IMPRESSION OF [FATIGUE] SEVERITY  
See below for an example. 
 
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Appendix I 
VACCINE SCHEDULE FOR PATIENTS IN JAPAN ONLY  
The vaccine schedule for patients in Japan who do not have documented vaccination in the 
5 years prior to enrollment is provided below. 
1. Meningococcal conjugate vaccine (MenACWY) (2-dose series 8 weeks apart) 
a) The first dose should be given on Day -42 when possible and no later than Day -28 
during the Screening/Observation Period. 
b) The second dose should be given 8 weeks after the first dose, between Day 14 and 
Day 32 in Part A.  
2. Pneumococcal vaccine (PPSV23) 
a) Single dose should be given on Day -42 when possible and no later than Day -28 
during the Screening/Observation Period. 
Notes: If necessary, vaccinations may be administered at an unscheduled visit per patient and 
vaccine availability. 
For vaccination requirements in countries other than Japan, please vaccinate per local vaccine 
availability and vaccination guidelines for patients with complement deficiency as discussed in 
Section 6.1.1.1. 
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Appendix J 
PROTOCOL AMENDMENT HISTORY  
The “Protocol Amendment Summary of Changes Table” for the current amendment is located at 
the start of this document (after title page). 
History of previous protocol amendments is as follows: 
 
Document 
Country/countries 
impacted by amendment 
Date 
Protocol Version 7 
All 
07 JULY 2020 
Protocol Version 6 
All 
15 OCTOBER 2019 
Protocol Version 5 
All 
19 JULY 2018 
Protocol Version 4 
Not implemented 
29 JUNE 2018 
Protocol Version 3.1 
Japan 
27 MARCH 2018 
Protocol Version 3 
All, except Japan 
21 MARCH 2018 
Protocol Version 2 
Not implemented 
NA 
Protocol Version 1.6 
Italy 
29 JANUARY 2018 
Protocol Version 1.5 
Belgium 
10 JANUARY 2018 
Protocol Version 1.4 
France 
15 DECEMBER 2017 
Protocol Version 1.3 
Norway 
06 DECEMBER 2017 
Protocol Version 1.2 
UK 
29 NOVEMBER 2017 
Protocol Version 1.1 
All 
09 SEPTEMBER 2017 
Protocol Version 1 (original) 
All 
24 AUGUST 2017 
Protocol Version 7: 
This is a global amendment to protocol Version 6 and is regarded as substantial amendment 
based on the criteria set forth in Article 10(a) of Directive 2001/20/EC of the European 
Parliament and the Council of the European Union. 
The primary reasons for this amendment to Protocol BIVV009-04 (Cadenza), Version 7 are: 
• To remove requirements for cardiac resuscitation equipment during home infusion visits 
in countries already identified for the home infusion sub-study (the US, the Netherlands, 
Norway, France, Italy, Austria, Germany, and Spain) as the risk of occurrence of 
emergency situations during infusions at home has been minimized by authorizing 
enrollment of patients without history of hypersensitivity reactions to study drug, and 
assistance by personnel trained in basic life support will be implemented, 
• To introduce the option of infusion with undiluted solution of BIVV009 in a subset of 
patients in Part B of the study,  
• To clarify the order of assessments post dose of IMP,  
• To add clarification regarding action taken with the IMP in case of allergic or 
hypersensitivity reactions. 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Section # and name Description of change 
Brief rationale 
Title Page, Approval of 
the Protocol, Protocol 
Amendment Summary of 
Changes Table 
Document formatting revisions. 
The change was made to reflect the update 
of the amended protocol version 7.  
Synopsis: Objectives 
Exploratory Objective in Part B to describe the 
safety of undiluted infusions with BIVV009 was 
added. 
The changes were made in relation to the 
introduction of undiluted infusion of the IMP 
for a subset of patients. 
Synopsis: Test 
Product(s), Dose, and 
Mode of Administration 
At certain visits during Part B administration of the 
study drug may be provided in the form of 
undiluted solution to a subset of patients was 
added.  
Synopsis: Safety 
Outcome Measures 
For patients receiving undiluted infusions, safety 
assessments will additionally include AEs with 
onset within 24 hours of the infusion was added.  
Section 2.2 Background 
and Study Rationale 
Information about undiluted solution and its 
benefits to patients and pharmacy staff was 
added.  
Section 2.2.4 Potential 
Risks and Benefits and  
Appendix K 
Potential risks associated with dosing at home 
were further detailed. 
Section 2.2.4 Potential 
Risks and Benefits 
Benefit and risk information for the inclusion of 
undiluted infusions was added.  
Section 3.5 Exploratory 
Objective (Part B) 
Exploratory objective to describe the safety of 
undiluted infusions with BIVV009 was added.  
Section 4.1 Study Design 
Criteria for qualifying patients in Part B to receive 
infusions with study drug undiluted with saline 
solution were added. 
Section 4.1 Study Design 
Updated the responder definition in Table 2 for 
Part A. 
The responder definition was not changed, 
rather the update to the language was 
made to make the definition clearer for 
each individual component. 
4.3.5 Safety Endpoints 
For patients receiving undiluted infusions, safety 
assessments will additionally include AEs with 
onset within 24 hours of the infusion was added.  
The change was made in relation to the 
introduction of undiluted infusion of the IMP 
for a subset of patients. 
Section 5.2 Exclusion 
Criteria 
Reference to Section 4.1 eligibility criteria for 
undiluted infusion was added.  
The change was made in relation to the 
introduction of undiluted infusion of the IMP 
for a subset of patients. 
Section 5.3 Removal of 
Patients from Study 
Participation, and Study 
Suspension and Stopping 
Rules 
Hypersensitivity or allergic reactions including 
anaphylaxis to study drug were added to the list of 
withdrawal criteria. The last point in the list of 
reasons for study discontinuation regarding 
hypersensitivity reactions during home infusions 
was removed. 
The change was not due to new safety 
concern but rather to clarify that any new 
hypersensitivity/allergic and/or anaphylactic 
reactions to study drug should lead to study 
drug discontinuation as hypersensitivity is a 
contraindication to BIVV009 administration.  
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Section # and name Description of change 
Brief rationale 
Section 6.1.5.3 
Procedures to be 
Performed Every 3 Months 
Day of ECG postdose in Part B changed from 217 
to 273. 
Correction of a typo.  
Section 6.1.5.5. Infusion 
of Study Drug at Patient’s 
Home and Appendix K 
Participation in undiluted infusions was added as 
a non-eligibility criteria for home infusion. 
The change was made to precise home 
infusion eligibility criteria. 
Section 6.1.5.6 Infusion 
of the Undiluted Study 
Drug 
This is a new section that was added to amended 
protocol version 7.  
The change was made in relation to the 
introduction of undiluted infusion of the IMP 
for a subset of patients. 
Section 6.1.5.7 Early 
Termination/End of 
Study/Safety Follow-up 
Visit 
The title and content in this section were 
previously found in Section 6.1.5.6 in amended 
protocol version 6 and the title and content in this 
section has been moved its current location in 
amended protocol version 7.  
The change was made to reflect the update 
in formatting of sections the amended 
protocol version 7. 
Section 6.2.1 Drug 
Supplies and 
Accountability 
Information about the IMP BIVV009 kit 
configuration supplied for subjects receiving 
undiluted infusions was added.  
The change was made in relation to the 
introduction of undiluted infusion of the IMP 
for a subset of patients. 
Section 6.2.4 Dose 
Preparation and 
Administration and 
Appendix K 
Removal of the requirement for cardiac 
resuscitation equipment during home infusion 
visits (for the countries identified as per protocol 
version 6 eg, US, the Netherlands, Norway, 
France, Italy, Austria, Germany, and Spain). 
Only patients treated for the minimum of 
3 months with BIVV009 and who did not 
exhibit hypersensitivity reaction to study 
drug are eligible for home infusions. 
Rescue medications will be immediately 
available for use as per the PI’s guidance 
during home infusion visits and the home 
infusion personnel will be trained in basic 
life support (cardiopulmonary resuscitation 
[CPR]). As a result, the requirement for 
cardiac resuscitation equipment during 
home infusion was removed. 
Section 6.2.4 Dose 
Preparation and 
Administration  
Information for dose preparation and 
administration for subjects receiving undiluted 
infusions was added. 
The change was made in relation to the 
introduction of undiluted infusion of the IMP 
for a subset of patients. 
Section 6.3.3 Height, 
Body Weight, and Vital 
Signs 
It was specified that 1-hour post-infusion vital 
signs should be measured before blood draws. 
The order of post-infusion assessments 
was clarified to make sure that procedures 
that may impact vital signs, ie, blood draws 
are done at the end of the office visit. 
Section 7.3.1 Analysis 
Populations 
Regarding ITT population description addition of 
the term “Full Analysis Set” has been added and 
will be used instead of “ITT Population”. 
The change was made to align with the 
language in the SAP. 
Section 7.3.2 Methods of 
Analysis 
Regarding ITT population description addition of 
the term “Full Analysis Set” has been added and 
will be used instead of “ITT Population”. 
The change was made to align with the 
language in the SAP. 
Appendix K 
Editorial changes to the Appendix K. 
This change was made to remove 
redundant text and correct existing 
inconsistencies. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical error corrections) were 
implemented throughout the protocol, as well as an administrative change in (Section 8.4).  
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Protocol Version 6: 
 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Section 2.2, 
Section 2.2.4, Section 3.5, 
Section 4.1 (Part-B), 
Section 4.3.4, Section 4.3.5, 
Section 5.2, Section 5.3, 
Section 6.1 Table-3, 
Section 6.1.5.5, 
Section 6.2.1, Section 6.2.4, 
Appendix K (Appendix K) 
and Appendix L  
(Appendix L). 
Home infusion will be performed by a healthcare 
professional caregiver, applicable to pre specified 
countries (the US, the Netherlands, Norway, France, 
Italy, Austria, Germany, Spain), and sites only. 
Qualifying patients who consent for home infusions will 
have study drug infused at their homes at selected 
visits, supported by a healthcare professional 
caregiver. 
The primary reasons for this 
amendment to Protocol BIVV009-
04 (Cadenza) are  
- to provide home infusion facilities 
to the patients (the option of home 
infusions may be beneficial for 
CAgD patients who often are an 
elderly population with other 
comorbidities. This procedure is 
intended to characterize the 
safety and patient satisfaction 
with the convenience of home 
infusions).  
- to add new exploratory objective 
of immunogenicity,  
- to introduce additional time points 
when samples for ADAs against 
BIVV009 are collected (additional 
ADA samplings will help 
characterize immunogenicity of 
BIVV0009),  
- to specify that predose PD back-
up samples will be used to assess 
immunogenicity in patients who 
consented to future use of 
samples, - to introduce additional 
time points for SLE panel in Part 
B (As duration of participation in 
Part B is patient-specific, it has 
been specified that surveillance 
with systemic lupus 
erythematosus (SLE) serologic 
testing will be done every 
6 months),  
- to clarify PK/PD sampling 
schedules for Part-B of the study 
(to fix the inconsistency 
concerning PK and PK sampling 
schedule during Part B between 
Schedule of Study Procedures 
table and body of the protocol) 
- to introduce a correction in  
Appendix A. 
Synopsis, Section 3.2, 
Section 3.4, Section 4.1 
(Part-B), Section 4.2, 
Section 4.3.8, Section 6.1 
Table-3, Section 6.1.3, 
Section 6.1.4, Section 
6.1.5.3, Section 6.1.5.4, 
Section 6.5.1, Section 6.5.2, 
Section 6.6, Section 7.7 and 
Table 4 Appendix K 
(Appendix K) 
Additional time points for ADAs sample collection 
against BIVV009 have been added. New exploratory 
objective of immunogenicity has also been added. 
Synopsis, Section 4.2, 
Section 4.3.6, Section 4.3.7, 
Section 6.1 Table -3, 
section 6.1.5.3, Section 
6.1.5.4, Section 6.5.1, 
Section 6.5.2 and Table 4 
Appendix K (Appendix K). 
Time points when PK and PD samples are to be 
collected during Part B has been clarified. 
 
Section 6.1 Table-3, Section 
6.1.5.3, and Table 4 
Appendix K (Appendix K). 
New time points for SLE panel in Part B have been 
added 
Section 4.2, Section 4.3.8 
Mentioned that ADA against BIVV009 may be 
assessed using available predose PD back-up samples 
for patients having consented to the use of their blood 
samples for future research. 
Appendix A 
“Iron” was deleted from the clinical chemistry panel list. 
Three new appendix sections have also been created to add “Home Infusion Patient Satisfaction Questionnaire” (Appendix L), 
to display “Protocol Amendments History” (Appendix J), and to add “Country Specific Requirements- home infusions with 
BIVV009” (Appendix K). 
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Protocol Version 5: 
 
Protocol Version 
Description of Change 
Brief Rationale 
Protocol Version 5 (from 
Version 3)  
Synopsis, Section 2.2.2, Section 4, Section 5.1, 
Section 6, Table -3 and appendices have been 
updated. 
 
The primary reason for this 
amendment to Protocol BIVV009-
04 was to incorporate the following 
changes: 
- The study number was revised. 
- The PGIS was added per FDA 
request. 
- “Documented” was added to 
clarify that previous vaccinations 
must be confirmed with 
vaccination records rather than 
just patient report. “Where 
available” was added because 
vaccination against serogroup B 
meningococcus isn’t available in 
all of the participating countries. 
- The start date for the collection of 
PK & PD samples during Part B 
was corrected. 
- BIVV009-01 study information 
was revised for clarity and 
updated to include Part E. 
- To reduce the number of patients 
in the Cardinal study who are 
minimally transfused. 
- The vaccination schedule from the 
country-specific protocol for 
Japan (Version 3.1) was added to 
the vaccination schedule for the 
other participation countries in this 
version of the protocol for 
completeness. 
- Windows were added for the post-
dose vital signs, ECGs, and 
PK/PD sampling time points for 
completeness. 
- BIVV009 to be supplied in larger 
volume and concentration. 
Protocol Version 4 (not 
implemented) 
Synopsis, Section 2.2.2, Section 4, Section 5.1, 
Section 6, Table -3, appendices have been updated. 
 
The primary reason for this 
amendment to Protocol BIVV009-
04 was to incorporate the following 
changes: 
- The study number was revised. 
- The PGIS was added per FDA 
request. 
- The start date for the collection of 
PK & PD samples during Part B 
was corrected. 
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Protocol Version 
Description of Change 
Brief Rationale 
- BIVV009-01 study information 
was revised for clarity and 
updated to include Part E. 
- To reduce the number of patients 
in the Cardinal study who are 
minimally transfused. 
- The vaccination schedule from the 
country-specific protocol for 
Japan (Version 3.1) was added to 
the vaccination schedule for the 
other participation countries in this 
version of the protocol for 
completeness. 
- Windows were added for the post-
dose vital signs, ECGs, and 
PK/PD sampling time points for 
completeness. 
- BIVV009 to be supplied in larger 
volume and concentration. 
- The frequency of PGIC 
assessment time points was 
updated to every 3 months 
-  Footnote "r" was added to show 
the order the assessments are to 
be conducted  
- The PGIS and PGIC assessments 
were added at the same time 
points as the SF-12 
Protocol Version 3.1 (from 
Version 3) 
Synopsis, Section 5.1, Section 6.1.1.1, Section 6.1.1.2, 
and Table-3 were updated and Appendix-H was added. 
The primary reason for this 
amendment to Protocol BIVV009-
04 was to incorporate the following 
changes: 
- The inclusion criterion on 
vaccinations was changed. 
- Instructions on vaccination were 
updated. 
Protocol Version 3 (from 
Version 1.1) 
Synopsis, Section 2.2, Section 2.2.2, Section 2.2.3, 
Section 2.2.4, Section 4.1, Section 4.3.3, Section 4.3.4, 
Section 4.4, Section 4.5, Section 5.1, Section 5.2, 
Section 5.3, Table -3, Section 6.1.1.1, Section 6.1.2, 
Section 6.1.3, Section 6.1.4, and Section 6.1.5, 
Section 6.1.6, Section 6.2.4, Section 6.2.5, and 
Section 6.2.7, Section 6.3.6, Section 6.3.8, Section 6.7, 
Section 6.7.1.1, Section 6.7.1.2, Section 6.7.1.3, 
Section 6.7.2,  Section 6.7.4, Section 6.7.5, 
Section 6.7.7, and Section 9  have been updated. 
 
The primary reason for this 
amendment to Protocol BIVV009-
04 was to incorporate the following 
changes: 
- The original Appendix B 
(Vaccination Schedule – 
Encapsulated Bacterial 
Pathogens) was removed and 
additional instructions were added 
to Section 6.1.1.1 (reference to 
the vaccination schedule was 
changed from Appendix B to 
Section 6.1.1.1). 
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Protocol Version 
Description of Change 
Brief Rationale 
- The original Appendix C 
(Guidelines for the Diagnosis and 
Treatment of Hypersensitivity 
Reactions and Anaphylaxis) also 
was removed. 
- A healthcare resource utilization 
appendix was added. 
- The current appendices are 
labeled per below: 
Appendix A: Clinical Laboratory 
Evaluations 
Appendix B: NCI-CTC Version 
4.03 (CTCAE V4.03) 
Appendix C: Functional 
Assessment of Chronic Illness 
Therapy (FACIT) – Fatigue Scale 
Appendix D: EQ-5D-5L 
Appendix E: 12-Item Short Form 
Survey (SF-12) 
Appendix F: Patient’s Global 
Impression of Change (PGIC) 
Appendix G: Healthcare Resource 
Utilization 
- The number of patients was 
changed from 40 to approximately 
40 patients. 
- Hemolytic “flare” was changed to 
hemolytic breakthrough. 
- Beginning on Day 0, urine 
pregnancy testing was changed to 
serum or urine pregnancy testing. 
- Phase 3 was added to the study 
title. 
Protocol Version 1.6 (from 
Version 1.1) 
Section 6.2.5 has been updated. 
The primary reason for this 
amendment to Protocol BIVV009-
04 was to incorporate the following 
changes: 
- New instructions on 
blinding/unblinding procedure in 
Section 6.2.5 have been added. 
Protocol Version 1.5 (from 
Version 1.1) 
Table 3 (Study schedule of events), Section 6.1.3, and 
Section 6.1.5 have been updated. 
The primary reason for this 
amendment to Protocol BIVV009-
04 was to incorporate the following 
changes: 
- Pregnancy test instructions were 
modified. 
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Protocol Version 
Description of Change 
Brief Rationale 
Protocol Version 1.4 (from 
Version 1.1) 
Synopsis, Section 4.1, Section 4.4, Section 4.5, 
Section 5.1, Section 5.2, Section 5.3, Table-3, 
Section 6.1.5, Section 6.1.6, Section 6.2.5, 
Section 6.2.7, Section 6.7, Section 6.7.4, and 
Section 6.7.7 have been updated. 
The primary reason for this 
amendment to Protocol BIVV009-
04 was to incorporate the following 
changes: 
- Global: For clarity, hemolytic 
“flare” was changed to hemolytic 
breakthrough.  
- Blinding/unblinding instructions 
were added 
- Inclusion criteria (bilirubin level, 
use of contraception) and one 
exclusion criterion (other 
autoimmune disorders) were 
modified. 
- Part A/B duration of treatment 
was changed from every 6 weeks 
to 9 weeks. 
Protocol Version 1.3 (from 
Version 1.1) 
Synopsis, Section 4.1, Section 4.5, Section 5.1, 
Section 5.2, Table-3, Section 6.1.3, Section 6.1.5, and 
Section 6.1.6, Section 6.2.5, and Section 6.7.1.3 have 
been updated. 
The primary reason for this 
amendment to Protocol BIVV009-
04 was to incorporate the following 
changes: 
- The Part B study duration was 
changed from approximately 
1 year to 1 year. 
- Ferritin level at baseline was 
adjusted in inclusion criteria and 
exclusion criteria. 
- Urine pregnancy testing frequency 
was changed from every 3 months 
to every 4 weeks. 
- Blinding/unblinding instructions 
were added. 
- Unexpected adverse 
event/SUSAR data collection 
instruction was modified. 
Protocol Version 1.2 (from 
Version 1.1) 
Synopsis, Section 2.2.2, Section 4.1, Section 4.5, 
Section 5.1, Table -3, Section 6.1.1.1, Section 6.1.6, 
Section 6.2.5, and Section 6.3.6 have been updated. 
The primary reason for this 
amendment to Protocol BIVV009-
04 was to incorporate the following 
changes: 
- The original Appendix B 
(Vaccination Schedule – 
Encapsulated Bacterial 
Pathogens) was removed and 
additional instructions were added 
to Section 6.1.1.1 (reference to 
the vaccination schedule was 
changed from Appendix B to 
Section 6.1.1.1). 
- The appendices were relabeled 
as shown below. 
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Protocol Version 
Description of Change 
Brief Rationale 
Appendix A: Clinical Laboratory 
Evaluations 
Appendix B: Guidelines for the 
Diagnosis and Treatment of 
Hypersensitivity Reactions and 
Anaphylaxis 
Appendix C: NCI-CTC Version 
4.03 (CTCAE V4.03) 
Appendix D: Functional 
Assessment of Chronic Illness 
Therapy (FACIT) – Fatigue Scale 
Appendix E: EQ-5D-5L 
Appendix F: 12-Item Short Form 
Survey (SF-12) 
Appendix G: Patient’s Global 
Impression of Change (PGIC) 
Protocol Version 1.1 
The company name, True North Therapeutics, Inc. was 
replaced by Bioverativ USA throughout the document. 
Exploratory efficacy end-point, “Patients Global 
Impression of Severity (PGIS)” was deleted throughout 
the document. 
 
The primary reason for this 
amendment to Protocol BIVV009-
04 was to incorporate a change in 
responsibility and obligations of the 
study sponsor and to delete 
Exploratory efficacy end-point, 
PGIS and changes in time point of 
12 lead ECG. 
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Appendix K 
COUNTRY SPECIFIC REQUIREMENT – HOME INFUSIONS WITH 
BIVV009  
Compared to the global protocol, the following country specific changes are applicable to the 
US, the Netherlands, Norway, France, Italy, Austria, Germany, and Spain: 
Synopsis (Objectives) 
Part B 
Exploratory objective: 
• To describe the safety and patient satisfaction with the convenience of home infusions 
with BIVV009 in a subset of patients. 
Synopsis (Test Product(s), Dose, and Mode of Administration) 
Home infusion will be performed at pre-selected countries/sites by a healthcare professional 
caregiver contingent upon completion of training delivered by the investigator or delegated site 
staff member only in patients willing to be administered study drug in home, who have been 
treated for at least 3 months (completed visit Day 273) with the study drug BIVV009 in Part B, 
in whom previous on-site infusions were uncomplicated, and who satisfy the following criteria: 
1. Able to comprehend and give informed consent for participation in the alternate home 
infusion scheme and willing to be infused at home for at least 4 doses, alternating with 
regular office visits. 
2. Treated for at least 3 months in Part B (completed visit Day 273) 
3. No history of hypersensitivity reaction to BIVV009 
4. Considered by the investigator to be a good candidate for home infusions 
5. Not participating in, or have never participated in undiluted infusion administration  
Qualifying patients who consent for home infusions will have study drug administered in home 
every other bi-weekly visit alternating with regular office visit with drug infusion. Qualification 
for home infusions and informed consent will be collected no later than at office visit two weeks 
before first planned home infusion.  
For subjects receiving drug injections in home as administered by a healthcare professional 
during the Part B open-label phase, the healthcare professional will collect during home visits 
specific information (AEs, concomitant medications, solicited anemia assessment, as well as, 
after the 1st and 4th home infusions, the patient will answer (by filling up the form) the Home 
Infusion Patient Satisfaction Survey) (Appendix L). The data collected on dedicated paper forms 
will be provided to the Investigator within 24 hours for entry in EDC. The healthcare 
professional will monitor the subject during infusion lasting 1-hour or, in certain patients 2-hour 
(eg, patients with underlying cardiopulmonary disease, with sponsor's approval) and for 2 hours 
after the first home infusion dose and 1 hour after the completion of each subsequent home 
infusion. Any adverse events occurring during home visits will be immediately reported by the 
healthcare professional caregiver to the Investigator.  
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First office visit 2 weeks after first home infusion will include assessments normally planned to 
be performed every 3 months. Neither blood samples nor urine or serum pregnancy tests will be 
performed during home infusion visits; blood tests scheduled to be performed at 2, or 4 weeks 
intervals as well urine or serum pregnancy tests in WOCBP (ie, women of child bearing 
potential) will be performed during office visits every four weeks while the patient is within the 
home infusion scheme.  
In case a scheduled home infusion visit happens to coincide with an every 3 month office visit, 
rather than this visit occurring at home, the patient should attend the office visit with study drug 
infused at the office site. The next home infusion visit will then occur 2 weeks later. 
Subsequently, the bi-weekly alternating office visit and home visits with drug infusions will then  
resume as previously planned.  
Patients who miss a dose (ie, outside the dosing window or >17 days since last dose, regardless if 
last dose was given at home or at the site) should return to the site for an unscheduled visit to 
receive another loading dose prior to their next scheduled visit which will also take place at the 
office. Such patient may return to the schedule of home visits alternating with regular office 
visits if eligibility criteria for home infusions are still met.  
Patients undergoing home infusions with BIVV009 will return to bi-weekly dosing at the study 
site if they experience adverse event that in the opinion of the Investigator, may jeopardize 
patient safety if home infusions are continued. Patients may return to home infusions if this AE 
is considered by the Investigator to be unrelated to BIVV0009 and once resolved or stabilized. 
Hypersensitivity or allergic reactions to study drug will always result in study drug 
discontinuation and withdrawal from the study. 
Infusions given in the home setting versus at the investigational site will be captured through the 
case report form (CRF) for drug administration.   
Table 4 - Study schedule of events (Part B) for patients with home infusions after Day 273  
Study Visit (Week/Day) 
Part B post Day 273 
Open-Label Extension 
Phase 
Part B post Day 273 
Open-Label 
Extension 
Phase m 
ET/EOS/Safety 
Follow-up a 
On site visit 
Home visit 
9 Weeks after 
Last Dose 
On site visit 
Visit Windows 
 2 days 
 2 days 
 2 days 
Pregnancy test (if applicable) b 
X  
 
X 
Body weight  
Xh 
 
X 
Physical examination, full 
 
 
X 
Physical examination, brief 
Xh 
 
 
Vital signs (BP, PR, RR, body 
temperature) c 
Xh 
 
X 
SLE panel d 
Xd 
 
X 
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Study Visit (Week/Day) 
Part B post Day 273 
Open-Label Extension 
Phase 
Part B post Day 273 
Open-Label 
Extension 
Phase m 
ET/EOS/Safety 
Follow-up a 
On site visit 
Home visit 
9 Weeks after 
Last Dose 
On site visit 
Visit Windows 
 2 days 
 2 days 
 2 days 
Hematology panel d 
X 
 
X 
Coagulation panel d 
 
 
X 
Clinical chemistry panel d 
X 
 
X 
Urinalysis d 
Xh 
 
X 
FACIT-Fatigue j 
Xh 
 
X 
PGIS j 
Xh 
 
X 
PGIC j 
Xh 
 
X 
SF-12 j 
Xh 
 
X 
EQ-5D-5L j 
Xh 
 
X 
Solicited symptomatic anemia 
X 
X 
X 
Study drug administration e 
X 
X 
 
ADAs against BIVV009 and 
neutralizing anti bodies 
Xk 
 
X 
PK Samples f 
Xh 
 
X 
PD Samples d, f 
Xh 
 
X 
Concomitant medications including 
transfusions 
X 
X 
X 
Healthcare resource utilization 
Xi 
 
X 
Adverse events g 
X 
Xn 
X 
Home infusion satisfaction survey 
 
Xl 
 
ADA = anti-drug antibodies; BP = blood pressure; EOS = End of Study; EQ-5D-5L = five level EuroQol five dimensions questionnaire; ET = 
Early Termination Visit; FACIT-Fatigue = functional assessment of chronic illness therapy - fatigue; N/A = not applicable; 
PD = pharmacodynamic; PGIC = Patient’s Global Impression of Change; PGIS = Patient’s Global Impression of [Fatigue] Severity; PK = 
pharmacokinetic; PR = pulse rate; QOL = quality of life; RR = respiratory rate; SF-12 = 12-Item Short Form Survey;  
a Patients should return to site 9 weeks after last dose for ET procedures, EOS assessment, or Safety Follow-up procedures upon completion 
of dosing in the study.  If patient experiences a hematological breakthrough event, a PK, PD, and ADA sample should be collected at the 
time of the event. 
b Females of child-bearing potential only.  Serum or urine pregnancy test every 4 weeks (+/- 2 days) during Part B at on-site visit and at 
ET/EOS safety follow-up visit 
c Vital signs measurements (supine BP, PR, RR, and oral temperature) are to be obtained with measurements performed predose and 1 hour 
(±5 minutes) after completion of administration of each dose of study drug (on site visits only). 
d For a complete list of analytes, see protocol Appendix A. SLE panel testing should occur every 6 months at on site visits in Part B. 
e Study drug doses of 6.5 grams (if <75 kg) or 7.5 grams (if ≥75 kg) based on patient’s baseline body weight will be administered via IV 
infusion over ~ 60±5 minutes, every 2 weeks during Part B.  Patients with underlying cardiopulmonary disease may receive a 2-hour infusion 
with Sponsor approval.  If a patient misses a scheduled dose (outside of the 2-day window or >17 days since last dose), they must return to 
site (unscheduled visit) to receive another loading dose 1 week prior to the next scheduled dose.  
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f During Part B, PK and PD samples will continue to be collected routinely at predose and 1 hour (±15 minutes) postdose at 3-month intervals 
starting at Day 273 through the remainder of the study. PK and PD samples will also be collected if a patient experiences a hematologic 
breakthrough event at any point during the study. 
g AEs will be recorded from the time the patient signs the informed consent form until 9 weeks after administration of the last dose of study 
drug. For patients with home infusions, safety assessments will additionally include AEs with onset within 24 hours of the of infusion. 
h   To be performed every 3 months during the on-site visits. 
i During Part B, the healthcare resource utilization data will be recorded every 4 weeks, at on site visit; 
j   To be performed in the following order: FACIT-Fatigue first, PGIS second, PGIC third, SF-12 fourth, and EQ-5D-5L fifth. 
k During Part B post Day 273, ADA samples will be collected every 3 months predose, and at Safety Follow up visit 9 weeks after last dose. 
Samples will also be collected if a patient experiences a hematologic breakthrough event or withdraws from the study early.  
l   After the 1st and 4th home infusions 
m Post-Day 273 extension phase home visit is alternating with every 4 weeks with site visit and if needed, a loading dose can be infused at the 
site visit. 
n  HCP records and AEs will be collected on paper forms and will be forwarded to PI within 24h; site will be informed of any AEs immediately; 
All SAE reporting timelines still apply (ie need to be reported to sponsor safety database within 24 hours of awareness by the home infusion 
healthcare professional). 
Section 2.2 (Background and Study Rationale) 
Patients with CAgD are often elderly and/or have numerous co-morbidities affecting their 
mobility. Moreover, clinical centers specialized in the management of CAgD are infrequent and 
may be located far from patients’ home. Consequently, some patients may find the option of 
home infusions with drug against CAgD, beneficial. To this end a group of patients at 
preselected sites/countries will be offered the possibility of home infusions during Part B, 
assisted by trained health care professional. 
Section 2.2.4 (Potential Risks and Benefits) 
Home infusions with the study drug will be proposed to a number of patients in countries pre-
selected to participate in home infusion. Home infusions will be assisted by a trained healthcare 
professional, and will concern patients who express such wish, after having been qualified by the 
Investigator and no sooner than after Week 39 (Day 273) and without evidence of 
hypersensitivity to study drug. Only patients treated with BIVV009 for the minimum of 
3 months and in whom previous infusions with BIVV009 were not associated with a 
hypersensitivity reaction are eligible for the home infusion. Additionally, patients who are 
participating in or have ever participated in undiluted infusions are not eligible for home 
infusions. Rescue medications to treat hypersensitivity/allergic reactions as per the PI’s guidance 
will be immediately available during home infusion visits. The home infusion personnel will be 
trained in basic life support (cardiopulmonary resuscitation [CPR]) but will not be required to 
have equipment to perform advanced life support (eg, defibrillators). 
Section 3.5 (Exploratory objective [Part B]) 
• To describe the safety and patient satisfaction with the convenience of home infusions 
with BIVV009 in a subset of patients in the US, the Netherlands, Norway, France, Italy, 
Austria, Germany, and Spain.  
Section 4.1 (Study Design: Part-B) 
A subset of patients from selected sites/countries, who have been treated for a minimum 
3 months (completed visit Day 273) in Part B, and who were determined to have tolerated 
BIVV009 well, will be invited to have infusions with BIVV009 performed at their homes, after 
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having been qualified by the Investigator. Home infusions will be carried out by a trained nurse. 
Patients will follow the alternate home infusion scheme, ie, home infusion at the patient’s home 
will be alternating with office visits, so that patients will attend office visit every 4 weeks 
alternating with home infusions every 4 weeks (+/- 2 days). 
Section 6.1, Table -3 (Footnote “i”) 
Study drug doses of 6.5 grams (if <75 kg) or 7.5 grams (if ≥75 kg) based on patient’s baseline 
body weight will be administered via IV infusion over ~ 60±5 minutes on Days 0, 7, and every 
14 days thereafter during Part A and every 2 weeks starting at Week 27 during Part B.  Patients 
with underlying cardiopulmonary disease may receive a 2-hour infusion with Sponsor approval.  
If a patient misses a scheduled dose (outside of the 2-day window or >17 days since last dose), 
they must return to site (unscheduled visit) to receive another loading dose 1 week prior to the 
next scheduled dose. Qualifying patients at participating sites may have study drug dosed at 
home, alternating with study drug dosed during office visits in Part B. 
Section 6.1.5.5 (Infusion of the study drug at patient’s home) 
Home infusions will be performed at pre-selected countries/sites by a healthcare professional 
caregiver contingent upon completion of training delivered by the Investigator or delegated site 
staff member only in patients willing to be administered study drug at home, who have been 
treated for at least 3 months (completed visit Day 273) with the study drug BIVV009 in Part B, 
and in whom previous on-site infusions were uncomplicated, who satisfy the following criteria: 
1. Able to comprehend and give informed consent for participation in the alternate home 
infusion scheme and willing to be infused at home for at least 4 doses, alternating with 
regular office visits. 
2. Treated for at least 3 months in Part B (completed visit Day 273) 
3. No history of hypersensitivity reaction to BIVV009 
4. Considered by the investigator to be a good candidate for home infusions 
5. Not participating in, or have never participated in undiluted infusion administration  
Qualifying patients who consent for home infusions will have study drug administered in home 
every other bi-weekly visit alternating with regular office visit with drug infusion. Qualification 
for home infusions and informed consent will be collected no later than at office visit two weeks 
before first planned home infusion.  
For subjects receiving drug injections in home as administered by a healthcare professional 
during the Part B open-label phase, the healthcare professional will collect specific information 
(AEs, concomitant medications, solicited anemia assessment as well as, after the 1st and 4th 
home infusions, the patient will answer the Home Infusion Patient Satisfaction Survey). The data 
collected on dedicated paper forms will be provided to the Investigator within 24 hours for entry 
in EDC. The healthcare professional will monitor the subject during 1-hour or, in certain patients 
2-hour infusion (eg, patients with underlying cardiopulmonary disease, with sponsor's approval) 
and for at least 1 hour after the completion of the first home infusion or 2 hours after the 
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completion of each subsequent home infusion. Any adverse events occurring during home visits 
will be immediately reported by the healthcare professional caregiver to the Investigator.  
First office visit 2 weeks after first home infusion will include assessments normally planned to 
be performed every 3 months. Neither blood samples nor urine pregnancy tests will be 
collected/performed during home infusion visits; blood tests scheduled to be performed at 2, or 
4 weeks intervals as well urine pregnancy tests in WOCBP (ie, women of child bearing potential) 
will be performed during office visits every four weeks while the patient is within the home 
infusion scheme.  
In case a scheduled home infusion visit happens to coincide with an every 3 month office visit, 
rather than this visit occurring at home, the patient should attend the office visit with study drug 
infused at the office site. The next home infusion visit will then occur 2 weeks later. 
Subsequently, the bi-weekly alternating office and home visits with drug infusions will then 
resume as previously planned. 
Patients who miss a dose (ie, outside the dosing window or >17 days since last dose, regardless if 
last dose was given at home or at the site) should return to the site for an unscheduled visit to 
receive another loading dose prior to their next scheduled visit which will also take place at the 
office. Such patient may return to the schedule of home visits alternating with regular office 
visits if eligibility criteria for home infusions are still met. 
Patients undergoing home infusions with BIVV009 will return to bi-weekly dosing at the study 
site if they experience adverse event that in the opinion of the Investigator, may jeopardize 
patient safety if home infusions are continued. Patients may return to home infusions if this AE 
is considered by the Investigator to be unrelated to BIVV0009 and once resolved or stabilized. 
Hypersensitivity or allergic reactions to study drug will always result in study drug 
discontinuation and withdrawal from the study. 
Infusions given in the home setting versus at the investigational site will be captured through the 
case report form (CRF) for drug administration.   
Section 6.2.1 (Drug Supplies and Accountability) 
Preparation and accountability procedures for the investigational product, including those 
associated with home infusions whenever applicable, are described in further detail in the 
Pharmacy Manual. 
Section 6.2.4 (Dose Preparation and Administration) 
Patients must be monitored for acute allergic reactions during infusion and for at least 2 hours 
after the completion of the first administration of study drug at a home infusion visit or 1 hour 
after the completion of each administration of study drug thereafter at subsequent home infusion 
visits.   
Epinephrine, parenteral diphenhydramine and, for infusions carried at the study site, cardiac 
resuscitation equipment, must be immediately available in case an allergic reaction or 
anaphylaxis occurs. Site personnel or professional healthcare caregiver in case of home infusions 
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(Appendix K), must be qualified to detect allergic reactions and anaphylaxis and treat those 
reactions under the guidance of the PI. The home infusion personnel will be trained in basic life 
support (cardiopulmonary resuscitation [CPR]) but will not be required to have equipment to 
pTerform advanced life support (eg, defibrillators). See Section 6.3.8 for further details regarding 
additional testing. 
Patients should be instructed to report the development of rash, hives, pruritus, flushing, 
urticaria, etc, that may represent an allergic or hypersensitivity reaction to study drug.  If any 
signs or symptoms of an allergic or anaphylactic reaction are observed during the infusion, 
administration of study drug must be immediately discontinued and the patient treated as 
appropriate. In case of home infusion, the investigator has to be notified immediately to guide 
treatment. 
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Appendix L 
HOME INFUSION PATIENT SATISFACTION SURVEY  
 
 
How satisfied or dissatisfied are you with the overall convenience of being infused at home? 
 
Very satisfied 
Satisfied 
 
Dissatisfied 
Very dissatisfied 





  
 1 
  
 2 
 
  
 3 
  
 4 
 
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SAP_001.pdf: 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive 
property of Sanofi (or any of its affiliated companies). The use of such confidential information must be restricted to the 
recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized 
persons, for any reason, in any form whatsoever without the prior written consent of Sanofi (or the concerned affiliated 
company); ‘affiliated company’ means any corporation, partnership or other entity which at the date of communication 
or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ 
meaning direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, 
partnership or other entity 
According to template: QSD-002643 VERSION 8.0 (17-JUN-2020) 
Page 1 
STATISTICAL ANALYSIS PLAN 
Protocol title: 
A Phase 3, randomized, double-blind, placebo-
controlled study to assess the efficacy and safety of 
BIVV009 in patients with primary Cold Agglutinin 
Disease without a recent history of blood transfusion 
Protocol number: 
BIVV009-04 Part A 
Compound number 
(INN/Trademark): 
BIVV009 
Study phase: 
Phase III 
Short title: 
Cadenza 
Statistician: 
 
Statistical project leader: 
 
Date of issue: 
02-Oct-2020
Regulatory agency identifier number(s): 
Registry: 
NA 
Enter Registry Name: 
NA 
Total number of pages: 52 
VV-CLIN-0586110 2.0
NCT03347422


Statistical Analysis Plan  
02-Oct-2020 
BIVV009-04 Part A - sutimlimab 
Version number: 2 
 
Property of the Sanofi group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
LIST OF FIGURES .......................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 7 
1.2.1 
Estimands ........................................................................................................................................ 9 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 13 
3 
ANALYSIS POPULATIONS .......................................................................................................... 14 
4 
STATISTICAL ANALYSES ........................................................................................................... 15 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 15 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 18 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 19 
4.3.1 
Definition of endpoint(s) ................................................................................................................. 19 
4.3.2 
Main analytical approach ............................................................................................................... 19 
4.3.3 
Sensitivity analysis ......................................................................................................................... 20 
4.3.3.1 
Sensitivity Analysis I - Composite estimand .................................................................................. 20 
4.3.3.2 
Sensitivity Analysis II - Modified composite estimand ................................................................... 21 
4.3.3.3 
Sensitivity Analysis III - Completer estimand ................................................................................. 21 
4.3.3.4 
Sensitivity Analysis IV - Per protocol estimand .............................................................................. 22 
4.3.4 
Subgroup analyses ........................................................................................................................ 22 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 23 
4.4.1 
Key/Confirmatory secondary endpoint(s) ...................................................................................... 23 
4.4.1.1 
Definition of endpoint(s) ................................................................................................................. 23 
4.4.1.2 
Main analytical approach ............................................................................................................... 23 
4.4.2 
Supportive secondary endpoint(s) ................................................................................................. 25 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 26 
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4.5.1 
Definition of endpoint(s) ................................................................................................................. 26 
4.5.2 
Main analytical approach ............................................................................................................... 27 
4.5.3 
Details on endpoints based on patient-reported outcomes (PROs) .............................................. 28 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 30 
4.7 
SAFETY ANALYSES ..................................................................................................................... 31 
4.7.1 
Extent of exposure ......................................................................................................................... 31 
4.7.1.1 
Overall exposure ............................................................................................................................ 32 
4.7.2 
Adverse events .............................................................................................................................. 32 
4.7.3 
Additional safety assessments ....................................................................................................... 34 
4.7.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 34 
4.8 
OTHER ANALYSES....................................................................................................................... 38 
4.8.1 
PK Analyses ................................................................................................................................... 38 
4.8.2 
PD Analyses ................................................................................................................................... 38 
4.9 
INTERIM ANALYSES .................................................................................................................... 38 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 40 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 40 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 41 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 41 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 43 
5.5 
APPENDIX 5 PATIENT-REPORTED OUTCOMES ...................................................................... 44 
5.5.1 
Scoring algorithm for FACIT-F ....................................................................................................... 44 
5.5.2 
EQ-5D-5L questionnaire score definitions ..................................................................................... 46 
5.5.3 
12-item short form survey (SF-12) ................................................................................................. 48 
5.5.4 
Patient’s global impression of change (PGIC) ............................................................................... 51 
5.5.5 
Patient’s global impression of [fatigue] severity ............................................................................. 51 
6 
REFERENCES ............................................................................................................................... 52 
 
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LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 5 
Table 2 - Objectives and endpoints ................................................................................................................. 7 
Table 3 - Summary of primary estimand for main endpoints .......................................................................... 9 
Table 4 - Populations for analyses ................................................................................................................ 14 
Table 5 - Severity grade for symptomatic anemia related CAD .................................................................... 16 
Table 6 - COVID-adjusted composite estimand for primary analysis ........................................................... 19 
Table 7 - Composite estimand for primary analysis ...................................................................................... 21 
Table 8 - Completer estimand for primary analysis ....................................................................................... 22 
Table 9 - Estimands for change from baseline in Hgb .................................................................................. 24 
Table 10 - Direction of change indicating clinical concern for laboratory tests ............................................. 35 
Table 11 - Thresholds for potentially clinically significant laboratory abnormalities ...................................... 36 
Table 12 - Criteria to determine clinically relevant abnormalities in vital signs ............................................. 38 
Table 13 - Major statistical changes in protocol amendment(s) .................................................................... 41 
Table 14 - Analyses window definition .......................................................................................................... 43 
 
LIST OF FIGURES  
Figure 1 - FACIT-Fatigue Scale .................................................................................................................... 44 
Figure 2 - EQ-5D-5L Questionnaire .............................................................................................................. 46 
Figure 3 - SF-12 Survey ................................................................................................................................ 48 
Figure 4 - PGIC ............................................................................................................................................. 51 
Figure 5 - PGIS .............................................................................................................................................. 51 
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VERSION HISTORY  
This Statistical Analysis Plan (SAP) for study BIVV-009-04 (Cadenza) is based on the protocol 
dated [15-Oct-2019]. There are no major changes to the statistical analysis features in this SAP. 
The first participant was randomized on 16 Apr 2018. This SAP is approved before the first interim 
analysis is conducted. 
 Table 1 - Major changes in statistical analysis plan  
SAP Version 
Approval Date 
Changes 
Rationale 
Version 1 
(electronic 1.0) 
07-Jul-2020 
Not Applicable 
Original version 
Version 2 
(electronic 2.0) 
02-Oct-2020 
Updated primary endpoint to CMH test (previously Fisher’s 
Exact test) per feedback from FDA. 
Feedback from 
FDA 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the 
efficacy and safety of BIVV009 in symptomatic patients with the complement-mediated disorder, 
primary CAD, who do not have a recent history of blood transfusion. 
During the 6-week Screening/Observation Period, prospective patients will have a detailed 
medical history documented (including all available transfusion history), physical evaluations, and 
blood samples collected on 3 occasions approximately every 2 weeks. 
The study will enroll approximately 40 primary CAD patients who do not have a recent history of 
blood transfusion (ie, ≤1 transfusion during the last year and no transfusion during the last 6 months 
prior to enrollment). Eligible patients should have been diagnosed with primary CAD at least 
6 months prior to enrollment and should have had no history of transfusion during this period. 
Eligible patients are randomized with a ratio of 1:1 to BIVV009 or Placebo by a permuted block 
randomization. The block size is fixed at 4. The randomization is performed by Pharm-Olam’s 
Interactive Web Response System (IWRS). Sponsor personnel (except for those who provide drug 
supply) are blinded to the treatment assignment until the interim analysis (defined below). 
Eligible patients will be randomized 1:1 to receive an IV infusion of BIVV009 or placebo over 
approximately 60 minutes on Day 0, Day 7, and every 14 days thereafter through Week 25 
(ie, Days 21, 35, 49, 63, 77, 91, 105, 119, 133, 147, 161, and 175). Patients who weigh less than 
75 kg will receive fixed doses of 6.5 g of BIVV009 or placebo. Patients who weigh 75 kg or more 
will receive fixed doses of 7.5 g of BIVV009 or placebo. Patients who miss a dose (ie, outside the 
dosing window or >17 days since last dose) should return to the site for an unscheduled visit 
1 week prior to the next scheduled dose in order to receive an additional loading dose. Patients 
will have an EOT visit on Day 182 (Week 26). 
During the 6-month treatment period, patients will receive a transfusion, if his or her Hgb level 
meets either of the following criteria: 
• Hgb is <9 g/dL and the patient is symptomatic, or 
• Hgb is <7 g/dL and the patient is asymptomatic.  
Following completion of dosing in the 6-month treatment period, patients will continue to receive 
BIVV009 dosing during Part B, the long-term safety and durability of response extension phase. 
Part B will run for approximately one year following last patient out (LPO) under Part A. 
Study primary analysis will be conducted for Part A after all patients have completed Part A and 
the data are cleaned. Parts A and B will have separate database locks to enable submission of the 
MAA following completion of Part A. Additional analyses of Part B data will be defined in a 
separate Part B SAP. 
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This statistical analysis plan contains information pertaining definitions of analysis sets and 
derived variables, and statistical methods for the analysis of efficacy, safety, pharmacokinetics 
(PK), and pharmacodynamics (PD) for Part A of the referenced study. 
1.2 
OBJECTIVE AND ENDPOINTS  
 Table 2 - Objectives and endpoints  
 
Objectives 
Endpoints 
Primary 
• 
to determine whether 
BIVV009 administration 
results in a ≥1.5 g/dL 
increase in hemoglobin (Hgb) 
level and avoidance of 
transfusion in patients with 
primary CAD without a recent 
history of blood transfusion. 
• 
responder rate: A patient is considered a 
responder if he or she did not receive a blood 
transfusion from Week 5 through Week 26 (end 
of treatment [EOT]) and did not receive 
treatment for CAD beyond what is permitted per 
protocol. Additionally, the patient’s Hgb level 
must meet the following criterion: Hgb increased 
≥1.5 g/dL from baseline (defined as the last Hgb 
value before administration of the first dose of 
study drug) at treatment assessment timepoint 
(defined as mean value from Weeks 23, 25, and 
26) 
Secondary 
• 
To assess the effect of 
BIVV009 on clinical events 
and laboratory parameters 
related to hemolysis and 
anemia in patients with 
primary CAD 
• 
To assess the effect of 
BIVV009 on specific 
complications of CAD 
(acrocyanosis, Raynaud’s 
syndrome, hemoglobinuria, 
and thromboembolism) 
• 
To assess the effect of 
BIVV009 on quality of life 
(QOL) in patients with primary 
CAD 
• 
To evaluate the overall safety 
and tolerability of BIVV009 in 
patients with primary CAD 
• 
Mean change from baseline in Hgb at treatment 
assessment timepoint (mean of values at 
Week 23, 25, and 26) 
• 
Mean change from baseline in bilirubin 
(excluding patients with Gilbert’s Syndrome) at 
treatment assessment timepoint 
• 
Mean change from baseline in QOL, as 
assessed by the change in Functional 
Assessment of Chronic Illness Therapy (FACIT)-
Fatigue scale scores at the treatment 
assessment timepoint 
• 
Mean change from baseline in lactate 
dehydrogenase (LDH) at the treatment 
assessment timepoint 
• 
Incidence of solicited symptomatic anemia at 
EOT 
• 
Incidence of treatment-emergent AEs (TEAEs) 
and serious AEs (SAEs) 
• 
Change from baseline in clinical laboratory 
evaluations 
• 
Change from baseline in SLE panel 
• 
Change from baseline in vital signs 
• 
Change from baseline in electrocardiogram 
(ECG) data 
• 
Physical examination findings 
• 
Serum disease-related biomarkers 
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Objectives 
Endpoints 
• 
Incidence of hemolytic breakthrough (rapid fall in 
Hgb ≥2 g/dL associated with an increase in 
LDH/bilirubin and/or decrease in haptoglobin 
since the last scheduled visit) through the EOT 
at Week 26 
• 
Incidence of infections of ≥ Grade 3 severity 
(ie, requiring intravenous [IV] antibiotics) 
• 
Incidence of thromboembolic events 
Tertiary/exploratory 
• 
To assess the effect of 
BIVV009 on other quality of 
life (QOL) measures in 
patients with primary CAD 
• 
To assess the effect of 
BIVV009 on other laboratory 
parameters in patients with 
primary CAD 
• 
Pharmacokinetics of BIVV009 
• 
Pharmacodynamics of 
BIVV009 
• 
Mean change from baseline in QOL, as 
assessed by the change in the five level EuroQol 
– five dimensions questionnaire (EQ-5D-5L) 
scores at the treatment assessment timepoint 
• 
Mean change from baseline in QOL, as 
assessed by the change in the 12-item short 
form survey (SF-12®) at the end of treatment 
assessment timepoint 
• 
Proportion of patients with Hgb level of ≥12 g/dL 
at the treatment assessment timepoint 
• 
Incidence of thromboembolic events after the 
first 5 weeks of study drug administration 
• 
Median time to normalization of bilirubin 
• 
Median time to normalization of LDH 
• 
Median time to normalization of haptoglobin 
• 
Median time to obtain Hgb level of ≥12 g/dL 
• 
Proportion of patients normalizing haptoglobin at 
the treatment assessment timepoint 
• 
Proportion of patients normalizing bilirubin at the 
treatment assessment timepoint 
• 
Proportion of patients with abnormal LDH at 
baseline who normalize LDH at treatment 
assessment timepoint 
• 
Patient’s Global Impression of Change (PGIC) to 
assess patient’s perception of changes in CAgD 
disease burden at EOT 
• 
Patient’s Global Impression of [Fatigue] severity 
(PGIS) to assess the patient’s perception of 
changes in fatigue at EOT 
• 
Incidence of disabling circulatory symptoms at 
treatment assessment timepoint 
• 
Total healthcare resource utilization at EOT 
• 
Plasma concentrations of BIVV009 
• 
PK parameters: Appropriate exposure 
parameters (Cmax, AUC) will be derived using a 
population PK approach  
• 
Plasma concentrations of BIVV009  
• 
PK parameters: Appropriate exposure 
parameters (Cmax, AUC) will be derived using a 
population PK approach  
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1.2.1 Estimands  
Following International Conference of Harmonisation (ICH) (1) and National Research Counsel 
(NRC) (2) guidelines, the following estimands are considered for efficacy endpoints to provide 
clarity of what to be estimated and its connection to the trial objectives. Akacha, et al. (3) 
proposed a framework for defining an estimand using three attributes: 
• The population of interest; 
• The variable to be used for the clinical question, which consists of measurements at a 
specific timepoint. It could be a composite endpoint that incorporates post-randomization 
events. 
• The measure of intervention effect, which accounts for potential effects of post-
randomization events. 
A composite estimand will be used for the primary endpoint and a hypothetical estimand will be 
used for lab parameter defined secondary endpoints.  Alternative estimands are also proposed to 
either assist the interpretation of primary estimand or used for exploratory endpoints. 
Primary estimand defined for main endpoints are summarized in below Table 3. More details are 
provided in Section 4. 
For all these estimands, the comparison of interest will be the comparison of BIVV009 vs. 
Placebo control. 
 Table 3 - Summary of primary estimand for main endpoints  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) 
handling strategy 
Population-level 
summary 
(Analysis and 
missing data 
handling) 
Primary objective: to determine whether BIVV009 administration results in a ≥1.5 g/dL increase in hemoglobin (Hgb) level and 
avoidance of transfusion in patients with primary CAD without a recent history of blood transfusion 
Primary 
endpoint 
(COVID-
adjusted 
Composite 
estimand) 
Responder if: 
• 
Free of post-baseline 
transfusion within the 
range of Week 5 and 
Week 26 visit dates, and 
• 
The change from 
baseline in Hgb at 
treatment assessment 
timepoint >= 1.5 g/dL, 
and 
• 
Receive no protocol 
prohibited medications 
defined in Section 5.1.1 
within the range of Week 
FAS 
• 
Subjects who early 
discontinue study prior 
to Week 23, for 
reasons other than 
COVID-19, are 
considered non-
responders 
• 
Subjects with no Hgb 
data from Week 23, 
25, and 26, for 
reasons other than 
COVID-19, are 
considered as non-
responders 
• 
odds ratio of the 
proportion of 
responders in 
BIVV009 and 
placebo, using  
stratified Cochran-
Mantel-Haenszel test 
• 
Multiple imputation 
will be performed to 
fill in Hgb data at TAT 
using an MMRM 
approach, for 
subjects missing 
infusions at Week 23 
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Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) 
handling strategy 
Population-level 
summary 
(Analysis and 
missing data 
handling) 
5 and Week 26 visit 
dates (excluding 
medications taken during 
a COVID-related infusion 
gap or within the 
following 5 weeks) 
• 
If a subject has a 
COVID-related 
infusion gap (defined 
as 2 consecutive 
missed infusions due 
to COVID-19), 
transfusions received 
and protocol-
prohibited CAD 
medications taken 
during the infusion 
gap and within the 
5 weeks following the 
infusion gap will not 
be included in the 
responder derivation. 
and 25 due to 
COVID-19 
Primary 
endpoint 
(Composite 
estimand) 
Responder if: 
• 
Free of post-baseline 
transfusion within the 
range of Week 5 and 
Week 26 visit dates, and 
• 
The change from 
baseline in Hgb at 
treatment assessment 
timepoint >= 1.5 g/dL, 
and 
• 
Receive no protocol 
prohibited medications 
defined in Section 5.1.1 
within the range of Week 
5 and Week 26 visit 
dates  
FAS 
• 
Subjects who early 
discontinue study prior 
to Week 23 are 
considered as non-
responders 
• 
Subjects with no Hgb 
data from Week 23, 
25 and 26 are 
considered as non-
responders 
odds ratio of the 
proportion of responders 
in BIVV009 and placebo, 
using stratified Cochran-
Mantel-Haenszel test 
 
Primary 
endpoint 
(Modified 
Composite 
estimand) 
Responder if: 
• 
Free of post-baseline 
transfusion within the 
range of Week 5 and 
Week 26 visit dates, and 
• 
The change from 
baseline in Hgb at 
treatment assessment 
timepoint >= 1.5 g/dL, 
and 
• 
Receive no protocol 
prohibited medications 
defined in Section 5.1.1 
mFAS 
• 
Subjects who early 
discontinue study prior 
to Week 23 are 
considered as non-
responders 
• 
Subjects with no Hgb 
data from Week 23, 
25 and 26 are 
considered as non-
responders 
Odds ratio of i the 
proportion of responders 
in BIVV009 and placebo, 
using stratified Cochran-
Mantel-Haenszel test 
 
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Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) 
handling strategy 
Population-level 
summary 
(Analysis and 
missing data 
handling) 
within the range of Week 
5 and Week 26 visit 
dates  
Primary 
endpoint 
(Completer 
estimand) 
Responder if: 
• 
Free of post-baseline 
transfusion within the 
range of Week 5 and 
Week 26 visit dates, and 
• 
The change from 
baseline in Hgb at 
treatment assessment 
timepoint >= 1.5 g/dL, 
and 
• 
Receive no protocol 
prohibited medications 
defined in Section 5.1.1 
within the range of Week 
5 and Week 26 visit  
A subset of FAS 
with those who 
complete 
treatment at 
least through 
Week 23 and 
have at least 1 
evaluable Hgb 
from Week 23, 
25, and 26 
N/A 
Odds ratio of the 
proportion of responders 
in BIVV009 and placebo, 
using stratified Cochran-
Mantel-Haenszel test 
 
Primary 
endpoint 
(Per-Protocol 
estimand) 
Responder if: 
• 
Free of post-baseline 
transfusion within the 
range of Week 5 and 
Week 26 visit, and 
• 
The change from 
baseline in Hgb at 
treatment assessment 
timepoint >= 1.5 g/dL, 
and 
• 
Receive no protocol 
prohibited medications 
defined in Section 5.1.1 
within the range of Week 
5 and Week 26 visit 
dates  
PP set 
N/A 
Odds ratio of the 
proportion of responders 
in BIVV009 and placebo, 
using stratified Cochran-
Mantel-Haenszel test 
 
Secondary objective: To assess the effect of BIVV009 on clinical events and laboratory parameters related to hemolysis and 
anemia in patients with primary CAD 
Secondary 
endpoint 
(Hypothetical 
estimand) 
Mean change from baseline in 
Hgb and FACIT-F Score at 
treatment assessment 
timepoint (mean of values at 
Week 23, 25, and 26) 
FAS 
• 
Any value after 
transfusion and 
prohibited medication 
is considered missing 
Difference in mean 
change from baseline at 
TAT between BIVV009 
and Placebo 
Secondary 
endpoint 
Mean change from baseline in 
Hgb and FACIT-F Score at 
treatment assessment 
mFAS 
• 
Any value after 
transfusion and 
Difference in mean 
change from baseline at 
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Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) 
handling strategy 
Population-level 
summary 
(Analysis and 
missing data 
handling) 
(modified 
hypothetical 
estimand) 
timepoint (mean of values at 
Week 23, 25, and 26) 
prohibited medication 
is considered missing 
TAT between BIVV009 
and Placebo 
Secondary 
endpoint 
(De-facto 
estimand) 
Mean change from baseline in 
Hgb and FACIT-F Score at 
treatment assessment 
timepoint (mean of values at 
Week 23, 25, and 26) 
FAS 
N/A 
Difference in mean 
change from baseline at 
TAT between BIVV009 
and Placebo 
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2 
SAMPLE SIZE DETERMINATION  
Approximately 40 patients with primary CAD who do not have a recent history of transfusion will 
be randomized. There are limited data from the published literature or available natural history 
data to estimate the placebo response for the transfusion-independent study population. Since 
patients with evidence of ongoing hemolysis, hemoglobin <10 g/dL, and symptomatic are 
included in the study, it is expected that few patients would meet the responder definition for the 
primary endpoint without treatment intervention. The proposed sample size was chosen to provide 
sufficient power to detect a 50% improvement for BIVV009 over a range of possible placebo 
responder rates with a significance level of 0.05. A total of 40 patients (20 patients per group) 
provides a statistical power of greater than 85% to detect a treatment difference of 50% for 
placebo response rates between the range of 15% to 40%.  This calculation assumes a 2-sided 
5%-level test comparing the response rates between the BIVV009 and placebo groups. A 50% 
improvement over placebo is considered clinically relevant. 
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3 
ANALYSIS POPULATIONS  
The following analysis populations are defined for Part A of the study. For the remainder of the 
SAP, the term “subjects” will be used to refer to patients in the study to keep consistent with the 
term used within table, figure, and listing (TFL) displays. 
The following populations for analyses are defined:  
 Table 4 - Populations for analyses  
Population 
Description 
Full Analysis Set (FAS) 
The ITT population consists of all randomized subjects who received at least 1 dose 
(including partial dose) of study drug. All subjects in the ITT population will be 
included in the Full Analysis Set. Analyses of efficacy will be performed on the FAS. 
For analysis, FAS and the ITT population are considered exchangeable in the SAP, 
but the term FAS will be used in subsequent sections of the SAP and TFLs. 
Modified Full Analysis Set (mFAS) 
The COVID-19 pandemic occurred during the conduct of Part A study. Following 
the guidelines from FDA and EMA to assess any potential impact of COVID-19 on 
efficacy evaluation, we propose a modified full analysis (mFAS) set. The mFAS 
population consists of a subset of FAS who did not miss any visits or discontinue 
early due to the COVID-19 pandemic. 
Per-protocol Set 
The per-protocol (PP) population is defined as a subset of FAS who do not have 
any important protocol deviations impacting their efficacy assessments (defined in 
Section 6.3). Selected efficacy endpoints will be analyzed for the PP Population. 
Safety Analysis Set 
Subjects who received at least 1 dose (including partial dose) of study drug will be 
included in the Safety Analysis Set.  Note that Safety Analysis Set is the same as 
FAS in this study. 
PK Analysis Set 
Subjects who received at least 1 dose of study drug and have evaluable PK 
concentrations will be included in PK analysis set. 
PD Analysis Set 
All subjects who receive at least 1 dose of study drug and have at least 1 evaluable 
PD sample during Part A will be included in the PD analysis population. 
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4 
STATISTICAL ANALYSES  
Statistical analysis will be performed by Sanofi, using SAS® version 9.3 or higher and, where 
appropriate, additional validated software.  This SAP is based on protocol Version 6, dated 
15 October, 2019. 
4.1 
GENERAL CONSIDERATIONS  
Safety, efficacy, and PK/PD data will be summarized using standard summary statistics for 
continuous, categorical, and event-time data.  Data will be summarized for the populations 
defined. All statistical hypothesis testing will be performed at the 2-sided, 5% significance level, 
unless specified otherwise.  All p-values will be presented to 3 decimal places; p-values less than 
0.001 will be presented as “<0.001,” and p-values greater the 0.999 will be presented as “>0.999.” 
Unless otherwise specified, analyses will be performed by intervention group (and overall for 
baseline and demographics characteristics).  
Continuous variables will be summarized using descriptive statistics including the number of non-
missing values (n), mean, standard deviation (SD), median, minimum, and maximum. Where 
specified in the table shells, the 25th and 75th percentiles will also be provided. Means, medians, 
and the 25th and 75th percentiles will be presented to one decimal place beyond that with which the 
data were captured.  SDs will be presented to two decimal places beyond that with which the data 
were captured.  Minimum and maximum will be displayed to the same number of decimal places 
as that with which the data were captured. 
Categorical variables will be summarized by counts and percentages. All percentages will be 
rounded to one decimal place.  The percentage will be suppressed when the count is zero.  Unless 
specified otherwise, the denominator for all percentages will be the number of non-missing data 
for a given summarization. 
Time-to-event variables will be summarized using Kaplan-Meier estimate over time, along with 
median time to event and probability of an event at specific time points.  Partial dates will not be 
imputed, hence considered unknown.  In general, for subjects who do not experience the event, 
they will be censored at the study day of last assessment within Part A. 
Part A Study Treatment Period 
The Part A study treatment period starts at the date of first dose of study drug and ends at the date 
of Week 26 Visit if the subject completes Part A study treatment, or at the date of Early 
Termination (ET)/Safety Follow-up Visit if the subject discontinues the study treatment prior to 
Week 25. 
Treatment Assessment Timepoint (TAT) 
The value of an assessment (eg, Hgb) at the treatment assessment timepoint is defined as the 
average of the values from Week 23, 25, and 26 visits.  In the case of any missing value at any of 
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these visits, it will be calculated as the average of the available values, unless no value is available 
from all three visits.  
COVID-related infusion gap 
COVID-related infusion gap is defined as 2 or more consecutive missed scheduled infusions due 
to COVID-19. For the primary endpoint analysis, transfusions and protocol-prohibited CAD 
medications received during a COVID-related infusion gap and within the first 5 weeks of 
infusion resumption will not preclude a subject from being a responder. 
Solicited Symptomatic Anemia 
The severity of CAD symptomatic anemia is defined in Table 5. The severity grading for 
symptomatic anemia is adopted based on Common Toxicity Criteria for Adverse Events 
(CTCAE) grades and is collected in eCRFs at every visit.  
 Table 5 - Severity grade for symptomatic anemia related CAD  
CAgD Symptomatic 
Anemia Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Fatigue 
Fatigue relieved by 
rest 
Fatigue not relieved by 
rest; limiting 
instrumental ADL 
Fatigue not relieved 
by rest, limiting self 
care ADL 
Not defined 
Weakness 
Uneasiness or lack 
of well being 
Uneasiness or lack of 
well being; limiting 
instrumental ADL 
Not defined 
Not defined 
Shortness of Breath 
Shortness of breath 
with moderate 
exertion 
Shortness of breath 
with minimal exertion; 
limiting instrumental 
ADL 
Shortness of breath 
at rest; limiting self 
care ADL 
Life-threatening 
consequences; urgent 
intervention indicated 
Palpitations, fast heart 
beat 
Mild symptoms; 
intervention not 
indicated 
Intervention indicated 
Not defined 
Not defined 
Lightheadedness 
Not defined 
Present (eg, near 
fainting) 
Not defined 
Not defined 
Chest Pain 
Mild pain 
Moderate pain; limiting 
instrumental ADL 
Pain at rest; limiting 
self care ADL 
Not defined 
ADL = activities of daily living 
Thromboembolic Events  
The thromboembolic events prior to study entry are recorded as medical history in the eCRFs, 
notably pre-specified categories of TE events occurring within 1 year prior to screening are 
captured, while thromboembolic events on study are captured as adverse events.  Both medical 
history and adverse events will be coded according to Medical Dictionary for Regulatory 
Activities (MedDRA) v20.1 (or higher).  
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In general, thromboembolic events may include but are not limited to: 
• Any venous events 
- 
Portal vein obstruction 
- 
Deep vein thrombosis 
- 
Pulmonary embolism 
- 
Mesenteric (abdominal) venous thrombosis 
• Any cerebral events 
- 
Cerebral infarction, occlusion, and stenosis of cerebral and precerebral arteries 
- 
Vascular syndromes of brain in cerebrovascular diseases, transient cerebral ischemic 
attacks, and related syndromes 
• Any arterial events 
- 
Myocardial infarction 
- 
Mesenteric arterial thrombosis 
- 
Other arterial embolism and thrombosis 
Medical review of medical history and AEs will ascertain thromboembolic events for analysis. 
Normalization of Bilirubin 
The normalization of bilirubin is defined as total bilirubin ≤ upper limit of normal (ULN) 
(specified by the central lab).  
Normalization of LDH 
The normalization of LDH is defined as LDH value ≤ ULN (specified by the central lab).  
Normalization of Haptoglobin 
The normalization of haptoglobin is defined as haptoglobin above the level of detection.  
Normalization of Hemoglobin 
The normalization of hemoglobin is defined as hemoglobin ≥12 g/dL. Hemoglobin ≥11 g/dL will 
also be investigated.  
Hemolytic Breakthrough 
Hemolytic breakthrough at any visit is defined as  
• A decrease of 2 g/dL or more in Hgb from the last scheduled visit, and 
• One of the followings: 
- 
An increase of LDH from the last scheduled visit, 
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- 
An increase of bilirubin from the last scheduled visit,  
- 
A decrease in haptoglobin from the last scheduled visit. 
Protocol Prohibited CAD Medications 
The following concomitant medications are prohibited during the study treatment period in 
Part A: 
• Rituximab alone or as part of combination therapy 
• Cytotoxic drugs (such as fludarabine, bendamustine, ibrutinib, cyclophosphamide) 
• Other investigational drugs 
The efficacy endpoint (estimand) accounting for protocol prohibited CAD medication(s) use will 
be based on the eCRF questionnaire “Did the subject receive any prohibited medications since the 
last visit?” at post-baseline visits.  The medical review for the list of prohibited medications will 
be reconciled with the eCRF questionnaire. 
Pooling Sites for Analysis 
Data from all investigational sites will be pooled for the analysis, unless specified otherwise.  
4.2 
PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 4 will 
be summarized. 
The number of subjects with the status of completed, and discontinued study treatment early, 
including the primary reason for those who discontinued, will be tabulated for the FAS in Part A. 
In particular, the number of subjects who early discontinue study and the number of subjects with 
a missing dose due to COVID-19 will be presented. Subject disposition, including the date of the 
last visit and the reason for early termination for subjects who did not complete the study 
treatment, will be provided in a data listing. 
Additionally, subject enrollment by country and site as well as the number and percentage of 
subjects attending each planned visit will be summarized for the FAS. 
Protocol deviations 
All protocol deviations will be recorded throughout the study and will be medically adjudicated 
and categorized into major and minor. Deviations due to COVID-19 will be adjudicated and 
identified as such. Major and minor protocol deviations/violations are to be pre-specified prior to 
database lock. All major protocol deviations will be summarized for the FAS.  
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Important protocol deviations (within Part A study treatment period) impacting efficacy 
assessment are defined as any of the following: 
• Not meeting eligibility inclusion criterion #3 as in the protocol,  
• Missing at least 2 consecutive doses or 3 intermittent doses,  
• Received protocol prohibited CAD treatment (Section 4.1), 
• Free of transfusion after Week 5 but missing hemoglobin assessments at all three visits of 
Weeks 23, 25, and 26.  
Important protocol deviations will be summarized for the FAS. Subjects who have had any of the 
important protocol deviations will be excluded from the PP population. 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS  
4.3.1 Definition of endpoint(s)  
The primary endpoint is the responder rate, defined in Section 1.2, and is a composite endpoint of 
the following components: 
1. Free of post-baseline transfusion within the range of Week 5 and Week 26 visit dates; 
2. Change from baseline in Hgb at treatment assessment timepoint is >= 1.5 g/dL,  
3. Receive no protocol prohibited medications (defined in Section 4.1) within the range of 
Week 5 and Week 26 visit dates  
Components 1 and 3 will be determined by the corresponding questions in eCRF at all visits (from 
Week 5 through Week 26) in Part A. 
4.3.2 Main analytical approach  
The primary analysis of the primary endpoint is to compare the responder rate of the BIVV009 
treatment arm with the placebo treatment arm via the COVID-adjusted Composite estimand as 
defined in Table 6 below. 
To reject the null hypothesis of no treatment difference, the two-sided p-value based on a 
stratified Cochran-Mantel-Haenszel (CMH) test must be <0.05. The test will be stratified by 
baseline hemoglobin (< median baseline Hgb vs ≥ median baseline Hgb) and geographic region 
(Japan/Australia, United States, Europe). In the case of completely unbalanced strata (all records 
within any strata fall within a single treatment arm), the CMH test will be stratified only by 
baseline hemoglobin. 
 Table 6 - COVID-adjusted composite estimand for primary analysis  
 
COVID-adjusted Composite Estimand 
Population 
FAS 
Response variable  
Responder if 
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COVID-adjusted Composite Estimand 
• 
Free of post-baseline transfusion within the range of Week 5 and Week 26 visit dates, and 
• 
The change from baseline in Hgb at treatment assessment timepoint >= 1.5 g/dL, and 
• 
Receive no protocol prohibited medications defined in Section 4.1 within the range of Week 5 
and Week 26 visit dates 
ICEs handling 
• 
Subjects who early discontinue study prior to Week 23, for reasons other than COVID, are 
considered non-responders 
• 
Subjects with no Hgb data from Week 23, 25, and 26, for reasons other than COVID, are 
considered as non-responders 
• 
If a subject has a COVID-related infusion gap (defined as 2 consecutive missed infusions due to 
COVID-19), transfusions received and protocol-prohibited CAD medications taken during the 
infusion gap and within the 5 weeks following the infusion gap will not be included in the 
responder derivation. 
Measure of treatment 
effect 
• 
Odds ratio of the proportion of responders in BIVV009 and Placebo using the Cochran-Mantel-
Haenszel test 
• 
Subjects missing infusions at Week 23 and 25 due to COVID will have their Hgb at TAT imputed 
using multiple imputation with an MMRM approach. 
Multiple imputation (n=100 imputations) will first be run on subjects who missed both the 
Week 23 and 25 study visits due to COVID-19 to fill in their missing Hgb data at TAT. A CMH 
test will be conducted on each imputation and the chi-square statistics will be pooled using 
Rubin’s Rules, together with the pooled CMH odds ratio and a 95% confidence interval for the 
odds ratio will be computed. 
In addition, the proportion of subjects who meet each of the three response criteria will be 
summarized by treatment group. A separate table for the number of transfusions by study period 
(before Week5 and between Week 5 and Week 26) and by treatment arm will be generated.  
If there are no patients who missed both the Week 23 and 25 study visits due to COVID-19, the 
primary efficacy analysis would be completed using the Composite estimand (Section 4.3.3.1). 
4.3.3 Sensitivity analysis  
All sensitivity analyses are designed to evaluate the robustness of the primary efficacy results in 
different aspects, aiming to provide additive evidence of the treatment effect of BIVV009. 
4.3.3.1 Sensitivity Analysis I - Composite estimand  
The purpose of this sensitivity analysis is to assess the primary endpoint without adjusting for 
COVID-related ICEs. This analysis will compare the responder rate of the BIVV009 treatment 
arm with the placebo treatment arm via the Composite estimand as defined in Table 7 below. 
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 Table 7 - Composite estimand for primary analysis  
 
Composite Estimand 
Population 
FAS 
Response variable  
Responder if 
• 
Free of post-baseline transfusion within the range of Week 5 and Week 26 visit dates, and 
• 
The change from baseline in Hgb at treatment assessment timepoint >= 1.5 g/dL, and 
• 
Receive no protocol prohibited medications defined in Section 4.1 within the range of Week 5 
and Week 26 visit dates  
ICEs handling 
• 
Subjects who early discontinue study prior to Week 23 are considered as non-responders 
• 
Subjects with no Hgb data from Week 23, 25 and 26 are considered as non-responders 
Measure of treatment 
effect 
Odds ratio of the proportion of responders in BIVV009 and Placebo using the Cochran-Mantel-
Haenszel test 
A stratified CMH test will be used to estimate the treatment effect; the p-value for the 
comparison, together with the CMH odds ratio and a 95% confidence interval for the odds ratio 
will be reported. As with the primary endpoint, the test will be stratified by baseline hemoglobin 
(< median baseline Hgb vs ≥ median baseline Hgb) and geographic region (Japan/Australia, 
United States, Europe). In the case of completely unbalanced strata (all records within any strata 
fall within a single treatment arm), the CMH test will be stratified only by baseline hemoglobin. 
4.3.3.2 Sensitivity Analysis II - Modified composite estimand  
The purpose of this sensitivity analysis is to assess the potential impact of the COVID-19 
pandemic to this study by analyzing the primary efficacy endpoint with subjects did not miss any 
visits or discontinue early due to the COVID-19 pandemic. 
This sensitivity analysis will be carried out via a modified composite estimand, which is the same 
as the composite estimand except with the mFAS population. A stratified CMH test will be used 
to estimate the treatment effect; the p-value for the comparison, together with the CMH odds ratio 
and a 95% confidence interval for the odds ratio will be reported. As with the primary endpoint, 
the test will be stratified by baseline hemoglobin (< median baseline Hgb vs ≥ median baseline 
Hgb) and geographic region (Japan/Australia, United States, Europe). In the case of completely 
unbalanced strata (all records within any strata fall within a single treatment arm), the CMH test 
will be stratified only by baseline hemoglobin. 
4.3.3.3 Sensitivity Analysis III - Completer estimand  
The purpose of this sensitivity analysis is to evaluate the primary endpoint with subjects with 
evaluable hemoglobin data at treatment assessment timepoint, in other words, eliminating 
potential bias introduced by early discontinued subjects. This analysis is performed via the 
completer estimand as defined in Table 8.  
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 Table 8 - Completer estimand for primary analysis  
 
Completer Estimand 
Population 
A subset of FAS with those who complete treatment at least through Week 23 and have at least 1 evaluable 
Hgb from Week 23, 25, and 26 
Response 
Variable  
Responder if 
• 
Free of post-baseline transfusion within the range of Week 5 and Week 26 visit dates and 
• 
The change from baseline in Hgb at treatment assessment >= 1.5 g/dL, and 
• 
Receive no protocol prohibited medications defined in Section 4.1 within the range of Week 5 and 
Week 26 visit dates  
Treatment effect 
Odds ratio of the proportion of responders in BIVV009 and Placebo using the Cochran-Mantel-Haenszel 
test  
A stratified CMH test will be used to estimate the treatment effect; the p-value for the 
comparison, together with the CMH odds ratio and a 95% confidence interval for the odds ratio 
will be reported. As with the primary endpoint, the test will be stratified by baseline hemoglobin 
(< median baseline Hgb vs ≥ median baseline Hgb) and geographic region (Japan/Australia, 
United States, Europe). In the case of completely unbalanced strata (all records within any strata 
fall within a single treatment arm), the CMH test will be stratified only by baseline hemoglobin. 
4.3.3.4 Sensitivity Analysis IV - Per protocol estimand  
The purpose of this sensitivity analysis is to evaluate the primary endpoint with subjects who have 
no important protocol-deviations which potential impact efficacy assessment (the per protocol 
set). Subjects with protocol-prohibited medication use are excluded from the PP set. Subjects with 
at least 2 consecutive, or at least 3 intermittent missing dose for any reason including COVID-19, 
are also excluded.  
This sensitivity analysis will be carried out via a per protocol estimand, which is the same as the 
composite estimand except with the PP set. A stratified CMH test will be used to estimate the 
treatment effect; the p-value for the comparison, together with the CMH odds ratio and a 95% 
confidence interval for the odds ratio will be reported. As with the primary endpoint, the test will 
be stratified by baseline hemoglobin (< median baseline Hgb vs ≥ median baseline Hgb) and 
geographic region (Japan/Australia, United States, Europe). In the case of completely unbalanced 
strata (all records within any strata fall within a single treatment arm), the CMH test will be 
stratified only by baseline hemoglobin. 
4.3.4 Subgroup analyses  
Definitions of subgroups 
The following subgroups will be considered for the selected analyses: 
• Age (<65, >= 65) 
• Gender (Female, Male) 
• Baseline weight (<75 kg, >= 75 kg) 
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• Baseline Hgb level (<median, >= median g/dL) 
• Previous rituximab monotherapy use (Yes, No)  
• Previous rituximab monotherapy or rituximab and other cytotoxic therapy use (Yes, No) 
• Prior thromboembolic events within the last 1 year (Yes, No) 
• Previous reculizumab use (Yes, No) 
In case of very few subjects (eg, <5) in a category, the cutoff value may be changed to suit the 
distribution of these factors. 
Analysis Methods 
The CMH odds ratio and 95% CI will be summarized for the subgroups defined above. As with 
the primary endpoint, the odds ratios for each subgroup will be stratified by baseline hemoglobin 
(< median baseline Hgb vs ≥ median baseline Hgb) and geographic region (Japan/Australia, 
United States, Europe).  The CMH test may not be stratified in the case of completely unbalanced 
strata. . The consistency of the odds ratio among these sub-populations will be examined by forest 
plots. 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS  
4.4.1 Key/Confirmatory secondary endpoint(s)  
4.4.1.1 Definition of endpoint(s)  
Key secondary endpoints are rank ordered by their clinical importance in order to perform a 
sequential closed testing procedure to protect the type I error. The key secondary endpoints will 
be tested only when the primary analysis reaches significance. In this case, the key secondary 
endpoints will be tested using a sequential closed procedure with alpha of 0.05 for each test in the 
order indicated below: 
1. Mean change from baseline in Hgb at the treatment assessment timepoint in BIVV009 arm 
vs in placebo arm (using Hypothetical estimand) 
2. Mean change from baseline in FACIT-F Score at treatment assessment timepoint in 
BIVV009 arm vs in placebo arm (using Hypothetical estimand) 
4.4.1.2 Main analytical approach  
1. Mean Change from Baseline in Hgb at the Treatment Assessment Timepoint 
The change from baseline in Hgb at the treatment assessment timepoint will be analyzed for the 
FAS. The primary analysis will be performed according to the Hypothetical Estimand based on 
the MMRM model, while a sensitivity analysis will be done via De-facto Estimand. Similarly, 
COVID-specific sensitivity analyses will be performed according to the Modified Hypothetical 
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Estimand and Modified De-facto Estimand in order to ascertain the results for subjects unaffected 
by the COVID pandemic. Additional details for these estimands are found below, in Table 9. 
 Table 9 - Estimands for change from baseline in Hgb  
 
Hypothetical Estimand 
Modified Hypothetical 
Estimand 
De-facto Estimand 
Population 
FAS  
mFAS 
FAS  
Variable 
Change from baseline at treatment assessment time point 
ICE handling 
any value after transfusion and 
prohibited medication is 
considered missing 
any value after transfusion and 
prohibited medication is 
considered missing 
None  
Treatment 
effect 
Difference in mean change from baseline at TAT between BIVV009 and Placebo 
Mixed Model with Repeated Measures (MMRM) will be used for the analysis of such endpoints 
at study visits (including the treatment assessment time points). The MMRM model will include 
the baseline value of the endpoint, visit, treatment, and treatment and visit interaction.  A 
heterogeneous Toeplitz (TOEPH) covariance matrix within a subject will be used.  For the 
endpoint at the treatment assessment timepoint (average of Week 23, 25, and 26), the estimate 
will be calculated as the mean of MMRM estimates at Week 23, 25, and 26 visits. 
The pseudo SAS code for MMRM is as follows: 
Proc mixed data=(ADaM dataset) method=reml; 
class usubjid visit; 
model chg = base visit trt trt*visit/ ddfm = kenwardroger 
solution; 
repeated visit / type=TOEPH subject=usubjid; 
estimate ‘BIV009 vs. Placebo at treatment assessment 
timepoint’ trt 1 -1 trt*visit 0 0 0 0 0 0 0 0 0 0 0 0 0.333 
0.333 0.333 0 0 0 0 0 0 0 0 0 0 0 0 -0.333 -0.333 -0.333 
/cl; 
run; 
For either estimand, the mean change from baseline in Hgb at treatment assessment timepoint for 
both treatment arms, the estimated difference in change from baseline at TAT between BIVV009 
and placebo, along with its 95% CI, will be estimated by the MMRM model. The significance test 
for the treatment difference in Hgb at the treatment assessment timepoint will be based on 
appropriate treatment contrast. 
Additional sensitivity analysis based on multiple imputation will be carried out for the 
Hypothetical Estimand to evaluate the appropriateness of the assumption of MAR.  Specifically, 
multiple imputation will be performed using a pattern-mixture model and the above MMRM 
model will be run on the imputed data. Non-monotone missing data will first be transformed to a 
monotone missing data structure. The control-based imputation method assumes subjects in the 
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BIVV009 treatment arm who discontinued from the study or are missing Hgb values at the TAT 
will exhibit similar Hgb values to those subjects in the placebo arm (and subjects in the placebo 
arm will continue to exhibit those Hgb values). Thus, multiple imputation is performed using only 
information from the placebo arm. 
2. Mean Change from Baseline in FACIT-F Score at Treatment Assessment Timepoint  
The derivation of FACIT-F score is detailed in Section 4.5.1. The analyses for hemoglobin 
described above will be performed for the FACIT-F score and is therefore not repeated here. 
Additional sensitivity analysis based on multiple imputation will be carried out for the 
Hypothetical Estimand to evaluate the appropriateness of the assumption of MAR.  Specifically, 
multiple imputation will be performed using a pattern-mixture model and the above MMRM 
model will be run on the imputed data. Non-monotone missing data will first be transformed to a 
monotone missing data structure. The control-based imputation method assumes subjects in the 
BIVV009 treatment arm who discontinued from the study or are missing FACIT-F values at the 
TAT will exhibit similar FACIT-F values to those subjects in the placebo arm (and subjects in the 
placebo arm will continue to exhibit those FACIT-F values). Thus, multiple imputation is 
performed using only information from the placebo arm. 
4.4.2 Supportive secondary endpoint(s)  
Additional analyses for hemoglobin and bilirubin 
To further understand the clinical effect of BIVV009 in increasing hemoglobin level compared 
with placebo, the number of subjects with an increase of hemoglobin level from baseline ≥1 g/dL, 
≥1.5 g/dL, ≥2 g/dL and ≥3 g/dL at TAT will be reported for BIVV009 and for placebo.  
Mean Change from Baseline in Bilirubin by visit (including TAT) 
Total bilirubin will be summarized by-visit, including change from baseline, using the Full 
Analysis Set, with subjects with Gilbert’s syndrome or unknown Gilbert’s test result excluded.  
If the number of subjects with unknown Gilbert’s syndrome status is greater than 2, additional 
sensitivity analysis will be performed to include such subjects (unknown Gilbert’s syndrome). 
Mean Change from Baseline in Lactate Dehydrogenase (LDH) by visit (including TAT) 
LDH will be summarized by-visit, including change from baseline, using the Full Analysis Set. 
Additional descriptive analyses will be performed for LDH isoforms. 
Incidence of Solicited Symptomatic Anemia 
• Incidence of solicited symptomatic anemia will be summarized by visit descriptively using 
the FAS. The summaries will be based on observed data only and missing grades will not 
be imputed. 
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• An improvement in each anemia symptom is defined as at least 1 grade reduction from 
baseline; whereas worsening is defined as at least 1 grade increase from baseline. The 
percentage of improved and worsened subjects for each symptom will be presented by 
visit; this percentage is calculated based on the number of subjects with no missing grade 
at both baseline and each post-baseline visit.  
• The improvement (worsening) in all anemia symptoms is defined as at least 1 grade 
reduction (increase) in at least 1 symptom, and no worsening (improvement) in other 
remaining symptoms. The proportion of subjects improved and worsened in all anemia 
symptoms will be summarized by visit.   
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
The analysis of exploratory endpoints will be based on the Observed Estimand defined in 
Section 1.2.1. Additionally, summary of hemolytic parameters (Hgb, bilirubin, LDH, haptoglobin, 
and reticulocyte) over time (by visit) is included to examine the improvement trend over time. 
Unless specified otherwise, the endpoints will be summarized by visit for continuous and 
categorical variables, and for time to event variables (eg, time to obtain Hgb level of ≥12 g/dL) for 
the entire Part A. The analyses for exploratory endpoints will be outlined by the type of endpoints 
in the following subsection. Details of patient-reported outcomes can be found in Section 4.5.3.  
4.5.1 Definition of endpoint(s)  
Continuous Endpoints 
The continuous endpoints include: 
• Mean change from baseline in QOL, as assessed by the change in the five level EQ-5D-5L 
scores at the treatment assessment timepoint (TAT) and by visit 
• Mean change from baseline in QOL, as assessed by the change in the 12-item short form 
survey (SF-12®) at the end of treatment assessment endpoint and by visit 
• Mean change from baseline in hemolytic parameters (Hgb, total bilirubin, LDH, 
haptoglobin, and absolute reticulocyte) by visit 
• Mean change from baseline in FACIT-F by visit  
Response (Categorical) Endpoints 
The response endpoints include (order different from protocol and not reflecting importance): 
• Incidence of thromboembolic events after the first 5 weeks of study drug administration 
• Incidence of CAD-related symptoms at last scheduled visit of Part A 
• Total healthcare resource utilization at EOT (Part A) 
• Proportion of subjects normalizing Hgb (>= 12 g/dL) at TAT and by visit 
• Proportion of subjects achieving 1.5 g/dL increase in Hgb at TAT and by visit 
• Proportion of subjects normalizing bilirubin at TAT and by visit 
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• Proportion of subjects normalizing LDH at TAT and by visit (Proportion of subjects with 
LDH ≤1.5 x ULN at TAT will also be reported) 
• Proportion of subjects normalizing haptoglobin at TAT and by visit 
• PGIC and change from baseline in PGIS to assess subject’s perception of changes in 
CAgD disease burden at last scheduled visit of Part A 
Time-to-Event Endpoints 
Time-to-event endpoints include: 
• Time to first transfusion after the first 5 weeks of study drug administration from the first 
dose of study drug 
• Time to first transfusion (including the first 5 weeks of study drug administration) from 
the first dose of study drug 
• For subjects who do not receive any transfusion, their time-to-event will be censored at the 
study day of the last scheduled visit in Part A. 
• Time to first normalization of bilirubin from the first dose of study drug 
• Time to first normalization of LDH from the first dose of study drug 
• Time to first normalization of haptoglobin from the first dose of study drug 
• Time to first normalization of Hgb level (≥12 g/dL) 
• Time to first achieving 1.5 g/dL increase in Hgb level 
4.5.2 Main analytical approach  
Continuous Endpoints 
The continuous endpoints will be summarized by visit and treatment arm using descriptive 
statistics for the FAS according to Section 4.1. 
For EQ-5D index score and SF-12 component scores (physical component score and mental 
component score), an ANCOVA (Analysis of Covariance) model will be implemented, where 
treatment arm is the fixed effect, and the baseline score is the covariate; a 95% confidence interval 
for the treatment effect difference and the corresponding p-value will be generated. The treatment 
difference and 95% CI will be estimated by ANOVA with treatment and baseline value as 
independent variables.  
Response (Categorical) Endpoints 
The categorical endpoints will be summarized descriptively by visit for the FAS according to 
Section 4.1 with the exception of total healthcare resource utilization at EOT (Part A), which will 
be presented in a listing. 
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All thromboembolic events reported (in Adverse Events) will be reviewed and determined by 
internal medical staff along with investigators.  In case that there are discrepancies between the 
medical review and investigators’ assessment, separate analyses will be carried out for both sets 
of events. Date of event occurrences will be verified.  The detailed listing for all events will be 
provided including date (study day) of onset, verbatim terms of the event, and the flag for whether 
the event occurred after the first 5 weeks of study drug administration. Incidence of 
thromboembolic events will be calculated as the total number of thromboembolic events after the 
first 5 weeks of study drug administration divided by the total subject-years of time for 
observation (ie, time from Week 5 through Week 26 or EOT visit for subjects who discontinue 
early).  All events from Week 5 through Week 26 or EOT visit for subjects who discontinue early 
will be included.  A 95% exact CI will be provided. 
Time-to-Event Endpoints 
All time-to-event endpoints will be analyzed by treatment group for the FAS using the Kaplan-
Meier method outlined in Section 4.1. For subjects who receive transfusions after Week 5 
infusion, the time to normalization will be censored at the study day of the transfusion visit. For 
subjects who do not experience normalization, the data will be censored at the study day of the 
last assessment in Part A.  
4.5.3 Details on endpoints based on patient-reported outcomes (PROs)  
The FACIT-Fatigue, the EQ-5D-5L, the SF-12, the PGIC and PGIS will be utilized in this study.  
For continuous variables, the overall score and its change from baseline will be analyzed 
descriptively for each time point.   
When applicable missing items will be handled based on the specific patient-reported outcome 
(PRO) instrument.  Subjects missing baseline evaluations would not be included in the PRO 
analyses. 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale 
The questionnaires will be analyzed according to the recommendations of the questionnaire 
authors (see http://www.ser.es/wp-content/uploads/2015/03/FACIT-F_INDICE.pdf).  Details of 
the questionnaire and its algorithm for deriving the score are provided in Section 5.5.1. The 
questionnaires are considered complete, and the subscale total score can be calculated, if at least 
7 of the 13 items were answered by the subject. For each time point, the number and percentage of 
subjects who complete the questionnaires will be summarized. 
The change from baseline in FACIT-F score will be summarized by visit for the FAS. 
EQ-5D-5L 
The questionnaire will be analyzed based on the EQ-5D-5L scoring manual (see 
www.euroqol.org).  EQ-5D consists of 2 parts – a 5 dimension descriptive system and the EQ 
visual analogue scale.  A copy of the questionnaire is provided in Section 5.5.2.  
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The descriptive system contains 5 domains: mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression.  The number and percentage of subjects in each response category were 
tabulated for the FAS.  Percentages are based on the number of subjects for whom an assessment is 
provided at the respective visit.  
The EQ visual analogue scale is a visual scale from 0–100 to record a respondent’s overall self-
rated health state.  The respondent is asked to mark an “X” on the scale then record the 
corresponding number; 0 refers to the worst possible health state, 100 refers to the best possible 
health state.  This will also be presented alongside the 5 dimension descriptive system scores.  
The EQ visual analogue scale will be summarized for the observed response and change from 
baseline for the FAS. 
EQ-5D Index Score 
The EQ-5D-5L descriptive system can be converted into a single index value, the EQ-5D index 
score, by using the “EQ-5D-5L Crosswalk Index Value Calculator” provided by the scoring 
manual (documents and calculation tools will be downloaded from the EuroQol website). The 
index scores, derived as country specific, are a major feature of the EQ-5D instrument, facilitating 
the calculation of quality-adjusted life years (QALYs) that are used to inform economic 
evaluations of health care interventions. 
The derived EQ-5D index scores and change from baseline will be summarized by visit for the 
FAS. 
Additionally, the EQ-5D index score, will be summarized using an ANCOVA (Analysis of 
Covariance) model, where treatment arm is the fixed effect, and the baseline score is the 
covariate; a 95% confidence interval for the treatment effect difference and the corresponding p-
value will be generated. The treatment difference and 95% CI will be estimated by ANOVA with 
treatment and baseline value as independent variables.  
12-Item Short Form Survey (SF-12) 
The questionnaire will be analyzed according to the recommendations of the authors (see 
http://campaign.optum.com/optum-outcomes/what-we-do/health-surveys/sf-12v2-health-
survey.html).  The SF-12 v2 is a 12-item measure, derived from the original 36-item SF-36, which 
includes eight (8) health domains which are used to generate a physical component score as well 
as a mental component score.  Each score ranges from 0–100 on a normative scale and may be 
used to derive a health utility index (SF-6D).  A copy of the questionnaire is provided in  
Section 5.5.3. 
The derived scores and change from baseline for the eight health domains, the physical 
component score, and the mental component score, will be summarized by visit for the FAS. 
Additionally, the SF-12 component scores (physical component score and mental component 
score), will be summarized using an ANCOVA (Analysis of Covariance) model, where treatment 
arm is the fixed effect, and the baseline score is the covariate; a 95% confidence interval for the 
treatment effect difference and the corresponding p-value will be generated. The treatment 
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difference and 95% CI will be estimated by ANOVA with treatment and baseline value as 
independent variables.  
Patient Global Impression of Change (PGIC) 
The questionnaire (listed in Section 5.5.4) will be summarized as an ordinal variable by visit for 
FAS at the end of the study only.  
Patient’s Global Impression Of [Fatigue] Severity (PGIS) 
The change from baseline in questionnaire (listed in Section 5.5.5) will be summarized as an 
ordinal variable by visit for FAS.  
Healthcare Resource Utilization  
The number of healthcare visits by type (office visit, hospital ER visit, hospitalization, and ICU 
stay) will be collected and presented in a listing.  
4.6 
MULTIPLICITY ISSUES  
Primary Endpoint 
The study primary objective is to compare the treatment effect of BIV009 with placebo in 
responder rate (responder definition in Section 7.2).  
The study is designed to test the primary hypothesis whether patients treated with BIVV009 will 
achieve a response rate greater than those treated with Placebo.  The primary statistical hypothesis 
is written as: 
H0: response rate (BIVV009) ≤ response rate (Placebo) 
H1: response rate (BIVV009) > response rate (Placebo), 
where the response rate of a treatment group is the proportion of patients in the intent-to-treat 
(ITT) population who meet the response criteria defined in of the protocol. This will be tested 
using a 1-sided test at the 0.025 significance level. 
Key Secondary Endpoints 
Secondary hypotheses, corresponding to the treatment difference for the key secondary endpoints, 
will be tested only if the primary null hypothesis is rejected at a 1-sided significance level of 
0.025. 
The key secondary endpoints will be tested using a sequential closed procedure with alpha of 0.05 
for each test in the order indicated below: 
1. Mean change from baseline in Hgb at the treatment assessment timepoint in BIVV009 arm 
vs in placebo arm 
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2. Mean change from baseline in FACIT-F Score at treatment assessment timepoint in 
BIVV009 arm vs in placebo arm 
The following secondary endpoints will be analyzed descriptively:  
• Mean change from baseline in bilirubin at the treatment assessment timepoint in BIVV009 
arm vs in placebo arm 
• Mean change from baseline in Lactate Dehydrogenase (LDH) at the treatment assessment 
timepoint 
• Incidence of Solicited Symptomatic Anemia 
4.7 
 SAFETY ANALYSES   
All safety analyses will be performed on the Safety Analysis Set as defined in Section 3, stratified 
by treatment arm, unless otherwise specified, using the following common rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is 
planned.  
• Safety data in participants who do not belong to the safety population (eg, exposed but not 
randomized) will be provided. 
4.7.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and treatment 
compliance and summarized for the Safety Analysis Set. Per the protocol, all subjects rolling over 
to Part B are to receive a loading dose (in a blinded manner). For analysis of Part A exposure, this 
loading dose will not be included in the Part A database. Thus, Part A exposure will end 1 minute 
prior to the date/time of the Week 26 loading dose, and Part B exposure will start on the date/time 
of the Week 26 loading dose. 
Duration of IMP exposure 
Study drug exposure, measured by the duration of study treatment, number of administrations, and 
total actual BIVV009 dose will be summarized for the Safety Analysis Set.  
The duration of the study treatment (in weeks) in Part A is defined as: 
• (Date of Week 26 visit – Date of first dose + 1)/7, if a subject enrolls into Part B; 
• (Date of last dose – Date of first dose + 15)/7, if a subject discontinues study treatment 
early in Part A or does not enroll into Part B. 
Treatment compliance 
Study drug compliance for a subject is measured by the percent of number of doses received out 
of the number of protocol-specified doses.  For example, for a subject who completes Part A 
treatment, the number of protocol-specified doses is 14.  The compliance of the subject will be the 
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number of doses received divided by 14 expressed in percentage.  For a subject who discontinues 
early in Part A, the number of protocol specified doses is the number of scheduled doses prior to 
the date of discontinuation.  The proportion of subjects whose compliance is less than 80%, 80% – 
<100%, and ≥100% will also be summarized.  In addition, the number of subjects and number of 
doses administered out of study windows and number of partial infusion doses will also be 
summarized. 
4.7.1.1 Overall exposure  
The actual dose administered at each visit is calculated as: 
(Total volume administered/Total volume prepared) * assigned dose. 
The total BIVV009 dose is the summation of all actual doses administered in Part A.  
The number of subjects with missing infusion due to COVID-19 will be presented.  
4.7.2 Adverse events  
General common rules for adverse events 
AEs will be classified using the MedDRA system organ classes and preferred terms.  MedDRA 
version 20.1 or higher will be used throughout the study. 
In general, AEs will be analyzed based on incidence, defined as the proportion of subjects who 
had at least one occurrence of an event out of the number of subjects in the Safety Analysis Set.  
An adverse event listing will be provided and will include all adverse events reported with the 
onset and resolution study days relative to Day 0 (Study Day 1). 
All summary table analyses will only include treatment-emergent adverse events unless noted 
otherwise.  
Unless specified otherwise, system organ classes (SOCs) and preferred terms (PTs) within each 
SOC will be presented alphabetically.  For the purpose of summarization, a subject is counted 
once in a SOC or preferred term if the subject reported one or more events in that SOC or 
preferred term.  Unless specified otherwise, percentages will be based on the number of subjects 
in the Safety Analysis Set. 
Overall Summary of Adverse Events 
An overall summary of TEAEs will be provided which tabulates the number and percentage of 
subjects who experienced a TEAE, related TEAE, TEAE grade 3 or higher, TEAE infection of 
grade 3 or higher, TEAE thromboembolic event, TEAE within 24 hours of the start of infusion, 
TESAE, related TESAE, and TESAE infection; the number and percentage of subjects who 
discontinued treatment and/or the study due to a TEAE and the number and percentage of subjects 
who died on-study. 
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Treatment-emergent Adverse Events 
The incidence of TEAEs will be summarized by SOC and preferred term. 
Adverse Events in Descending Order of Incidence 
A table will be provided which displays TEAE preferred terms in descending order of incidence.  
Only preferred terms will be included in this table (ie, the display will not include SOCs). 
A similar table will be provided for Grade 3 or higher TEAEs.  AEs for which the assessment of 
severity is missing will be included in this table in the TEAE Grade 3 or higher category. 
Severity of Adverse Events 
AEs are classified by the Investigator for CTCAE grades v4.03.  A summary of TEAEs by system 
organ class, preferred term, and CTCAE grade will be presented.  AEs with missing severity will 
be excluded from this table and listed separately to supplement the summary table.  A subject will 
be counted once for each SOC and preferred term based on the greatest severity within that SOC 
and preferred term, respectively. 
Relationship of Adverse Events to Study Drug 
AEs are classified by the Investigator for relationship to study drug (“Not related,” “Possible,” 
and “Probable”).  For summary tables, an AE with relationship of “Possible” or “Probable” will 
be considered “Related.”  A summary of TEAEs by SOC, preferred term, and relationship 
(“Related” or “Not related”) will be presented.  AEs with a missing relationship will be counted as 
“Related” in the summary table.  A subject will be counted once for each SOC and preferred term 
based on the highest relationship within that SOC and preferred term, respectively. 
Serious Adverse Events 
Any AE reported as resulting in death, immediate risk of death (life threatening), inpatient 
hospitalization or prolongation of existing hospitalization, persistent or significant 
disability/incapacity, or a congenital/anomaly/birth defect will be classified as an SAE by the 
Investigator.  An SAE may also be any other medically important event that, in the opinion of the 
Investigator, may jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed above.  
Treatment-emergent SAEs and treatment-emergent related SAEs will be summarized by system 
organ class and preferred term. Treatment-emergent SAEs will also be summarized by preferred 
term in descending order of incidence. 
Adverse Events Leading to Treatment Discontinuation and/or Study Withdrawal 
AEs leading to treatment discontinuation and/or study withdrawal will be listed.  All AEs reported 
on the AE log for the item “Action Taken with Study Drug” with a response of “Study drug 
permanently discontinued” or for the item “Was the subject terminated from this study due to this 
AE?” with a response of “Yes” will be included. 
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Deaths on Study 
A listing of deaths occurring on study will be provided. 
Analysis of adverse events of special interest (AESIs)  
AEs within 24 Hours after the Start of Infusion 
All AEs within 24 hours after the start of infusion are captured in the eCRF.  Incidence of AEs 
within 24 hours after the start of infusion will be summarized by SOC and preferred term. 
Infections and Infections of ≥ Grade 3 Severity 
Infections will be captured based on MedDRA SOC of “infections and infestations.”  Incidence of 
all infections of Grade 3 or higher will be summarized by preferred term. 
Hemolytic Breakthrough 
Proportion of subjects with hemolytic breakthrough (defined in Section 4.1) at any visit will be 
summarized.  The date (visit) of onset and hemolytic lab parameters (ie, Hgb, bilirubin, LDH, and 
haptoglobin) over time will be listed for subjects with haemolytic breakthrough.  
Anti-drug Antibody 
Subjects who discontinue treatment early in Part A will be evaluated for anti-drug antibodies.  
Subjects with a positive anti-drug antibody will be listed along with the associated titer, if 
available. 
4.7.3 Additional safety assessments  
4.7.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
Hematology and Chemistry 
All summaries will be structured such that the hematology and chemistry tests are presented in the 
order shown in the tables below.  
Hematology measurements that will be summarized and listed include white blood cell count 
(WBC), red blood cell count (RBC), differentials (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils, reticulocytes), hemoglobin, hematocrit, and platelet count. 
Chemistry measurements that will be summarized and listed include electrolytes (sodium, 
potassium, chloride), glucose, total protein, total bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN), and 
serum creatinine.  
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Change from Baseline 
Hematology and chemistry results at baseline and post baseline visits, along with change from 
baseline, will be summarized for the Safety Analysis Set. 
Shifts from Baseline 
Each subject’s laboratory values will be classified according to whether the test result is “low” 
(below the LLN), “normal” (within the normal range), or “high” (above the ULN).  Shift tables 
will be constructed based on both the minimum and maximum post-baseline values for each 
subject.  Data collected from unscheduled visits will be included in the determination of the per 
subject minimum and maximum values.  A separate table will be provided which summarizes the 
results of the shift tables in which the number and percentage of subjects with a shift to low (from 
normal, high, or unknown) and the number and percentage of subjects with a shift to high (from 
normal, low, or unknown) will be tabulated; percentages will be based on the number of subjects 
at risk.  The number at risk for a shift to low (high) is the number of subjects who have a baseline 
value that isn’t low (isn’t high) including unknown, and have at least one post-baseline value. 
Only directions of change indicating a clinical concern will be included in this table summarizing 
the shifts.  The direction of concern is provided in Table 10. 
 Table 10 - Direction of change indicating clinical concern for laboratory tests  
Laboratory Test  
Direction 
Laboratory Test  
Direction 
Chemistry 
Hematology 
Liver 
 
White blood cells 
Low and High 
ALT/SGPT 
High 
Lymphocytes 
Low and High 
AST/SGOT 
High 
Neutrophils 
Low and High 
Total bilirubin 
High 
Monocytes 
Low and High 
GGT 
High 
Eosinophils 
Low and High 
Renal 
 
Basophils 
Low and High 
Blood urea nitrogen 
High 
Red blood cells 
Low and High 
Creatinine 
High 
Hemoglobin 
Low and High 
Electrolytes 
 
Hematocrit 
Low and High 
Sodium 
Low and High 
Platelets 
Low and High 
Potassium 
Low and High 
 
 
Chloride 
Low and High 
 
 
Other 
 
 
 
Glucose 
Low and High 
 
 
Total protein 
Low and High 
 
 
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Potentially Clinically Significant Laboratory Abnormalities 
Abnormal laboratory values (excluding Hgb, reticulocytes, haptoglobin, bilirubin, and LDH) will 
also be evaluated by determining the number and percentage of subjects with at least one 
potentially clinically significant laboratory abnormality over the course of the study that also 
represents a worsening from baseline.  The potentially clinically significant levels are based on 
Grade 2 or higher thresholds from the CTCAE v4.03 where possible or are defined by the 
Sponsor’s safety group.  Subjects who have a post baseline laboratory value that meets the criteria 
for being potentially clinically significant but do not have a baseline value will be included in the 
numerator for determining the percentage of subjects with an abnormality.  Data collected from 
unscheduled visits will be included in this analysis. The laboratory tests and thresholds for 
determining PCSAs are provided in Table 11. 
 Table 11 - Thresholds for potentially clinically significant laboratory abnormalities   
T 
Threshold 
Laboratory Test  
Threshold 
Chemistry 
Hematology 
ALT (U/L) 
>= 3 x ULN 
Hematocrit (%) 
<= 30% 
>= 60% 
Albumin (g/dL) 
<= 2.5 g/dL 
Hemoglobin (g/L) 
<= 100 g/L 
>= 190 g/L 
Alkaline Phosphatase (U/L) 
>2.5 x ULN 
MCV (fL) 
>= 1.2 x ULN 
<= 0.8 x LLN 
AST (U/L) 
>= 3 x ULN 
Platelet count (10^9/L) 
<= 75 x 10^9/L 
>= 700 x 10^9/L 
Blood urea nitrogen (mmol/L) 
>= 10.7 mmol/L 
WBC (10^9/L) 
<3 x 10^9/L 
>= 16 x 10^9/L 
Chloride (mmol/L) 
<= 90 mmol/L 
>= 118 mmol/L 
Basophils (10^9/L) 
>1.6 x 10^9/L 
Creatinine (umol/L) 
>1.5 x ULN 
Eosinophils (10^9/L) 
>1.6 x 10^9/L 
GGT (U/L) 
>2.5 x ULN 
Lymphocytes (10^9/L) 
>0.8 x 10^9/L 
Glucose (mmol/L) 
<3 mmol/L 
>8.9 mmol/L 
Monocytes (10^9/L) 
<2.5 x 10^9/L 
Potassium (mmol/L) 
<= 3 mmol/L 
>= 6 mmol/L 
Neutrophils (10^9/L) 
>1.5 x 10^9/L 
Sodium (mmol/L) 
<= 126 mmol/L 
>= 156 mmol/L 
 
 
Total bilirubin (umol/L) 
>1.5 x ULN 
 
 
Direct bilirubin (umol/L) 
>1.5 x ULN 
 
 
Total protein (g/L) 
<= 45 g/L 
>= 100 g/L 
 
 
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Systemic Lupus Erythematosus (SLE) Panel 
SLE panel will be summarized with descriptive statistics. The number of subjects with all 
negative or all missing values for all SLE panel parameters prior to receiving study drug and the 
number of subjects with at least one positive value for at least one SLE panel parameter prior to 
receiving study drug will be summarized. Further, among subjects who have all negative or all 
missing values for all SLE parameters prior to receiving study drug and have at least one post-
baseline value for at least one parameter, the number of subjects who test negative at all post-
baseline assessments for all SLE parameters, and the number of subjects who test positive at any 
post-baseline assessment for at least one SLE parameter will be summarized.  
Similar summaries will be generated for individual SLE parameters. In addition, for a given SLE 
parameter, among subjects who have at least one positive or all missing values prior to receiving 
study drug and have at least one post-baseline for this parameter, the number of subjects who test 
positive at all post-baseline assessments, and the number of subjects who test negative at any post-
baseline assessment will be summarized. 
Parameters in the SLE Panel are Antinuclear antibody (ANA), multiplex with dsDNA, Anti-
La/SSB antibody (SS-B), Anti-riboucleoprotein antibody (RNP), Anti-Smith antibody (Sm), Anti-
Ro/SSA antibody (SS A), Anti-scleroderma antibody (Scl-70), Anti-Chromatin antibody, Anti-Jo-
1 antibody, Anti-Centromere B antibody, Circulating immune complexes (CIC).  
Disease-Related Biomarkers  
Disease-related biomarkers include DAT (polyspecific, anti-IgG & anti-C3d), LDH 
isoforms, cold agglutinin (CAg) titre, IgG subsets (IgA, IgD, IgG, IgM), vaccine titres, CAg 
thermal amplitude. Actual values and change from baseline for all biomarkers will be summarized 
by visit by treatment arm.  
Electrocardiogram (ECG)  
The proportion of subjects with clinically significant change from baseline in ECG findings will 
be summarized by visit. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, pulse, respiratory rate, and temperature) will be 
summarized for the observed values and change from baseline using descriptive statistics for the 
Safety Analysis Set. 
The number and percentage of subjects with potentially clinically relevant post-baseline 
abnormalities will be presented.  The criteria for clinically relevant post-baseline abnormalities 
are shown below in Table 12.   
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 Table 12 - Criteria to determine clinically relevant abnormalities in vital signs  
Vital Sign 
Criteria for Abnormalities 
Temperature 
>38oC and an increase from pre-dosing of at least 1oC 
Pulse  
120 beats per minute post-baseline, or 
an increase from pre-dosing of more than 20 beats per minute, or 
<50 beats per minute post-baseline, or 
a decrease from pre-dosing of more than 20 beats per minute 
Systolic Blood Pressure 
>180 mmHg post-baseline, or  
an increase from pre-dosing of more than 40 mmHg, or  
<90 mmHg post-baseline, or  
a decrease from pre-dosing of more than 30 mmHg 
Diastolic Blood Pressure 
>105 mmHg post-baseline, or  
an increase from pre-dosing of more than 30 mmHg, or 
<50 mmHg post-baseline, or  
a decrease from pre-dosing of more than 20 mmHg 
Respiratory Rate 
>35 breaths per minute post-baseline, or  
<10 breaths per minute post-baseline 
4.8 
OTHER ANALYSES  
4.8.1  PK Analyses   
Plasma BIVV009 concentrations will be listed by subject, nominal visit, date and time of 
collection and study day.  Summary statistics of plasma BIVV009 concentrations will be 
presented by nominal visit and study day including n, mean, standard deviation, coefficient of 
variation, geometric mean, median and range stratified by dose cohort (6.5 g vs 7.5 g) for the 
BIVV009 treatment arm. Individual and mean plasma BIVV009 concentration-versus-time 
profiles will be plotted. 
4.8.2 PD Analyses  
Descriptive statistics including number of observations, mean, SD, median, minimum, and 
maximum will be presented for continuous parameters.  Categorical variables will be presented 
with the number and percentage in each category. Summary descriptive statistics (absolute values 
and changes from baseline) and individual subject listings will be presented for all PD parameters 
by time point and study day for both the BIVV009 and Placebo treatment arms.  
4.9 
INTERIM ANALYSES  
For the purposes of regulatory submission, an interim analysis of safety and efficacy data (Part A 
analysis) will be performed for Part A after all patients have completed Part A and the data are 
cleaned.  Parts A and B will have separate database locks to enable submission of the MAA 
following completion of Part A. Additional analyses of Part B data will be defined in a separate 
Part B SAP. 
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Since Part A analysis constitutes the primary analysis of the study hypotheses, no Type I error 
adjustment is necessary. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
AE 
adverse event 
ADL 
activities to daily living 
ALP 
alkaline phosphatase 
ALT  
alanine aminotransferase 
ANA 
antinuclear antibodies 
AST  
aspartate aminotransferase 
AUC 
area under the curve 
BLA 
Biologics License Applications 
BUN  
blood urea nitrogen 
CAgD 
cold agglutinin disease 
CI 
confidence interval 
CIC 
circulating immune complexes 
Cmax 
maximum concentration 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DBL 
database lock 
ECG 
electrocardiogram 
eCRF  
electronic Case Report Form 
EOT 
end of treatment 
EQ-5D-5L 
EuroQol – five dimensions questionnaire 
ET 
early termination 
FACIT 
functional assessment of chronic illness therapy 
FAS 
full analysis set 
GGT 
gamma-glutamyl transferase 
Hgb 
hemoglobin 
HUI 
health utility index 
ICE 
intercurrent events 
ICH 
International Conference of Harmonisation 
ITT 
intent-to-treat 
IV  
intravenous 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LPO 
last patient out 
MAA 
Marketing Authorization Application 
MAR 
missing at random 
MCMC 
Markov chain Monte-Carlo 
MedDRA  
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not At Random 
NRC 
National Research Counsel 
PD 
pharmacodynamics 
PGIC 
Patient’s Global Impression of Change 
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PGIS 
Patient’s Global Impression of Severity 
PK  
pharmacokinetics 
PP 
per-protocol 
PRO 
patient-reported outcome 
QOL 
quality of life 
RBC  
red blood cell count 
SAE  
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SF-12 
12-Item Short Form Survey 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic-pyruvate transaminase 
SLE 
systemic lupus erythematosus 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TLF 
tables, figures, and listings 
TOEPH 
heterogeneous Toeplitz 
ULN 
upper limit of normal 
WBC  
white blood cell count 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
This section summarizes major statistical changes in the protocol amendment(s). 
 Table 13 - Major statistical changes in protocol amendment(s)  
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
Version 1 (original) 
24-Aug-2017 
Not applicable 
Not applicable 
 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics and baseline disease characteristics will be summarized for the FAS. 
Demography 
Demographic characteristics including age (years), age category (<65, >=65), gender, race, 
ethnicity, country, geographic location, height (cm), weight (kg), weight category (<75 kg,  
>=75 kg), and body mass index (kg/m2) will be summarized.  Geographic locations are defined as 
Europe, North America, Asia/Japan, and other. 
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General Medical History 
Medical history by system organ class (SOC) and preferred term (PT) will be summarized. A 
subject will be counted only once if they reported one or more occurrences in the same SOC or PT.  
A summary of prior hospitalizations related to CAD within the last 2 years, prior hematological 
malignancies within the last 5 years, prior non-malignant hematologic diseases within the last 
5 years, and prior thromboembolic events within the last 1 year will be presented based off the 
“Targeted Medical History” eCRF form. 
Baseline Disease Characteristics  
Screening and baseline lab parameters, including hematology (such as Hgb, bilirubin, LDH), 
Gilbert’s Syndrome testing, and bone marrow biopsy results will be summarized. Prior transfusion 
history (eg, number of transfusions within 12 months of study entry) will also be summarized.  
Severity of anemia symptoms and other CAD-related disease characteristics (eg, presence of 
acrocyanosis, Raynaud’s syndrome, hemoglobinuria, disabling circulatory symptoms, and major 
adverse vascular events) within 3 months of screening will be summarized. 
The proportion of subjects who had documented vaccines within 5 years and who have received 
vaccination during the study will be summarized. The vaccines include meningococcal vaccine, S. 
pneumoniae vaccine, and H. influenza vaccine. 
Prior or concomitant medications 
Prior medications are those taken before the first dose of study drug in Part A. Concomitant 
medications are those administered on or after the first dose of study drug, or those administered 
before the first dose that are ongoing when study treatment begins. Prior and concomitant 
medications will be coded using World Health Organization drug enhanced dictionary (March 
2020 version or higher). 
Separate tables will be generated to summarize concomitant medications and concomitant 
protocol-prohibited medications by ATC level 2 and WHODrug standardized medication text. 
Additionally, a summary of targeted prior therapies will be generated based off the responses 
provided in the “Targeted Prior Therapy” eCRF form. 
Concomitant non-drug treatments and procedures 
Concomitant non-drug treatments and procedures will be summarized for the FAS. 
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5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
Study Day 
Study Day is defined as days relative to the date of first dose of study drug (BIVV009 or placebo) 
in Part A (Day 0 as in the protocol). The Study Day of an event is calculated as  
• (date of event – date of first dose of study drug in Part A + 1), if the event is on or after the 
first dose date; 
• (date of event – date of first dose of study drug in Part A), if the event is prior to the first 
dose date. 
The date of the first dose of study drug in Part A is Study Day 1.  
Baseline 
Baseline measures are defined as the last value prior to the first dose of study drug. If a subject 
receives a transfusion during the screening period, the baseline measure must be at least 7 days 
after the transfusion. 
Visit Windows 
Analysis by study visit will utilize the data recorded on the corresponding nominal visit from 
electronic Case Report Forms (eCRFs).  In case of missing data/assessments for a visit, data from 
an unscheduled visit, or ET/Safety Follow-up Visit will be used, if the Study Day of such a visit 
fits in the analytic window defined in Table 14, below. If multiple values are identified within the 
analytic window, the one closest to the target study day will be used.  
 Table 14 - Analyses window definition  
Visit 
Target Study Day 
Analytic Visit Window 
Baseline (Day 0) 
1 
≤1 
Week 1 (Day 7) 
8 
2 – 15 
Week 3 (Day 21) 
22 
16 – 29 
Week 5 (Day 35) 
36 
30 – 43 
Week 7 (Day 49) 
50 
44 – 57 
Week 9 (Day 63) 
64 
58 – 71 
Week 11 (Day 77) 
78 
72 – 85 
Week 13 (Day 91) 
92 
86 – 99 
Week 15 (Day 105) 
106 
100 – 113 
Week 17 (Day 119) 
120 
114 – 127 
Week 19 (Day 133) 
134 
128 – 141 
Week 21 (Day 147) 
148 
142 – 155 
Week 23 (Day 161) 
162 
156 – 169 
Week 26 (Day 175 
176 
170 – 179 
Week 26 (Day 182; EOT Visit in Part A) 
183 
180 – 189 
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5.5 
APPENDIX 5 PATIENT-REPORTED OUTCOMES  
5.5.1 Scoring algorithm for FACIT-F  
Figure 1 - FACIT-Fatigue Scale  
 
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5.5.2 EQ-5D-5L questionnaire score definitions  
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5.5.3 12-item short form survey (SF-12)  
 
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5.5.4 Patient’s global impression of change (PGIC)  
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6 
REFERENCES  
1. International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use. Final Concept Paper: E9(R1): Addendum to Statistical 
Principles for Clinical Trials on Choosing Appropriate Estimands and Defining Sensitivity 
Analyses in Clinical Trials. 2014. 
2. National Research Council. The Prevention and Treatment of Missing Data in Clinical Trials. 
Washington DC: National Academies Press. 2010. 
3. Akacha M, Bretz F, Ohlssen D, Rosenkranz G, Schmidli H. Estimands and Their Role in 
Clinical Trials. Stat Biopharm Res. 2017;9(3):268-71.  
 
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persons, for any reason, in any form whatsoever without the prior written consent of Sanofi (or the concerned affiliated 
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partnership or other entity 
According to template: QSD-002643 VERSION 8.0 (17-JUN-2020) 
Page 1 
STATISTICAL ANALYSIS PLAN 
Protocol title: 
A Phase 3, randomized, double-blind, placebo-
controlled study to assess the efficacy and safety of 
BIVV009 in patients with primary Cold Agglutinin 
Disease without a recent history of blood transfusion 
Protocol number: 
BIVV009-04 Part B 
Compound number 
(INN/Trademark): 
BIVV009 
Study phase: 
Phase III Extension 
Short title: 
Cadenza 
Statistician: 
 
Statistical project leader: 
 
Date of issue: 
11-Aug-2020
Regulatory agency identifier number(s): 
Registry: 
Enter Registry Name: 
Total number of pages: 29 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 7 
1.2.1 
Estimands ........................................................................................................................................ 8 
2 
SAMPLE SIZE DETERMINATION .................................................................................................. 9 
3 
ANALYSIS POPULATIONS .......................................................................................................... 10 
4 
STATISTICAL ANALYSES ........................................................................................................... 11 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 11 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 12 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 12 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 13 
4.4.1 
Key/Confirmatory secondary endpoint(s) ...................................................................................... 13 
4.4.1.1 
Definition of endpoint(s) ................................................................................................................. 13 
4.4.1.2 
Main analytical approach ............................................................................................................... 13 
4.4.1.3 
Details on endpoints based on patient-reported outcomes (PROs) .............................................. 14 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 15 
4.5.1 
Definition of endpoint(s) ................................................................................................................. 15 
4.5.2 
Main analytical approach ............................................................................................................... 15 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 15 
4.7 
SAFETY ANALYSES ..................................................................................................................... 15 
4.7.1 
Extent of exposure ......................................................................................................................... 15 
4.7.1.1 
Overall exposure ............................................................................................................................ 16 
4.7.2 
Adverse events .............................................................................................................................. 16 
4.7.3 
Additional safety assessments ....................................................................................................... 19 
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4.7.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 19 
4.8 
OTHER ANALYSES....................................................................................................................... 23 
4.8.1 
Pharmacokinetic analysis .............................................................................................................. 23 
4.8.2 
Pharmacodynamic analysis ........................................................................................................... 23 
4.9 
INTERIM ANALYSES .................................................................................................................... 23 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 24 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 24 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 25 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 25 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 27 
6 
REFERENCES ............................................................................................................................... 29 
 
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LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 5 
Table 2 - Objectives and endpoints ................................................................................................................. 7 
Table 3 - Populations for analyses ................................................................................................................ 10 
Table 4 - Direction of change indicating clinical concern for laboratory tests ............................................... 20 
Table 5 - Thresholds for potentially clinically significant laboratory abnormalities ........................................ 21 
Table 6 - Criteria to determine clinically relevant abnormalities in vital signs ............................................... 22 
Table 7 - Major statistical changes in protocol amendment(s) ...................................................................... 25 
Table 8 - Analytic visit window ...................................................................................................................... 27 
 
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VERSION HISTORY  
This statistical analysis plan (SAP) for study BIVV009-04 (Cadenza) Part B is based on the 
protocol dated 07-Jul-2020. There are no major changes to the statistical analysis features in this 
SAP. 
The first participant was enrolled into Part B on 27-Nov-2018. This SAP is approved before the 
first interim analysis is conducted. 
Table 1 - Major changes in statistical analysis plan  
SAP Version 
Approval Date 
Changes 
Rationale 
1.0 
20-Jul-2020 
Not Applicable 
Original version 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
BIVV009-04 is a Phase 3, randomized, double-blinded, placebo-controlled, multicenter study in 
patients with primary cold agglutinin disease (CAD) without a recent history of blood transfusion. 
Eligible patients received study drug (BIVV009 or placebo) and underwent safety and efficacy 
assessments for 6 months (26 weeks) in Part A of the study. 
Following completion of the initial 6-month treatment period, patients will roll into the long-term 
safety study (Part B) where they will continue to receive the study drug, BIVV009. After 
completion of all Part A EOT assessments, patients who qualify to roll-over into Part B will 
receive a cross-over loading dose, in a blinded manner, at the Week 26 visit. Patients who were 
randomized to placebo during the 6-month treatment period will receive BIVV009; and patients 
who were randomized to BIVV009 during the 6-month treatment period will receive a placebo 
dose in order to maintain the blinding. Part B will run for one year following last patient out 
(LPO) under Part A. In Part B, patients will be dosed with open-label BIVV009 every two weeks, 
as in Part A. On-site visits will be completed every two weeks when samples for safety and 
efficacy measures will be collected; samples for pharmacokinetics (PK) and pharmacodynamics 
(PD) will be collected at visits approximately every three months. Sample for antidrug antibodies 
will be collected every three months (at a minimum). The study will be complete 12 months 
following LPO under Part A at which time all patients receiving on-going treatment will proceed 
to an End-of-Study (EOS) visit 9 weeks after the last administration of study drug. 
After Week 39, a subgroup of patients will have their study drug infused at home, every four 
weeks, alternating with study drug administration during office visits. Additionally, after 
Week 39, another subgroup of patients will have their study drug administered in the form of 
infusions undiluted with normal saline. 
Study primary analysis will be conducted for Part B after all patients have completed Part B and 
the data are cleaned. 
This statistical analysis plan contains information pertaining to definitions of analysis sets and 
derived variables, and statistical methods for the analysis of efficacy, safety, PK, and PD for 
Part B of the referenced study. 
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1.2 
OBJECTIVE AND ENDPOINTS  
Table 2 - Objectives and endpoints  
 
Objectives 
Endpoints 
Primary 
• 
The primary objective of Part B is to 
evaluate the long-term safety and tolerability 
of BIVV009 in patients with primary CAD 
Safety Endpoints: 
• 
Incidence of treatment-emergent 
adverse events (TEAEs) and serious 
adverse events (SAEs) 
• 
Change from baseline in clinical 
laboratory evaluations 
• 
Change from baseline in systemic 
lupus erythematosus (SLE) panel 
• 
Change from baseline in vital signs 
• 
Change from baseline in 
electrocardiograms (ECG) data 
• 
Physical examination findings 
• 
Incidence of infections of ≥ Grade 3 
severity (ie, requiring intravenous 
[IV] antibiotics)  
• 
Serum disease-related biomarkers 
• 
Incidence of hemolytic breakthrough 
through EOT 
• 
Incidence of thromboembolic events 
Secondary 
• 
The secondary objective of Part B is to 
investigate the durability of response during 
long-term treatment with BIVV009 in 
patients with primary CAD. 
The following parameters of disease activity 
will be assessed: 
• 
Hemoglobin 
• 
Bilirubin 
• 
QOL assessments (FACIT-Fatigue, 
EQ-5D-5L, SF-12, PGIS, and PGIC) 
• 
LDH 
• 
Transfusion requirements 
• 
Haptoglobin 
• 
Total healthcare resource utilization at 
EOT 
Tertiary/exploratory 
• 
To describe the safety and patient 
satisfaction with the convenience of home 
infusions with BIVV009 in a subset of 
patients 
For subjects receiving home infusions: 
• 
Satisfaction with home infusion after 
first home infusion and after fourth 
home infusion 
• 
Incidence of AEs with onset within 
24 hours of a home infusion 
• 
To describe the safety of undiluted infusions 
with BIVV009 
For subjects receiving undiluted infusions: 
• 
Incidence of AEs with onset within 
24 hours of an undiluted infusion 
• 
To evaluate the immunogenicity of BIVV009 
• 
Anti-drug antibodies 
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Objectives 
Endpoints 
• 
Pharmacokinetics of BIVV009 
• 
Plasma concentrations of BIVV009 
• 
PK parameters: Appropriate exposure 
parameters (Cmax, AUC) will be 
derived using a population PK 
approach 
• 
Pharmacodynamics of BIVV009 
• 
Weislab-CP 
• 
CH50 
• 
Total C4 
• 
C1q 
• 
C1s 
1.2.1 Estimands  
There are no primary efficacy endpoints in Part B. Thus, estimands will not be utilized in this 
SAP.
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2 
SAMPLE SIZE DETERMINATION  
Patients in Part B will be a subset of the patients enrolled in Part A. All patients who complete 
Part A, including those receiving transfusions, will be eligible for Part B. Patients who withdraw 
from the study in Part A, including those who received prohibited concomitant medications, will 
not be eligible to participate in Part B. Subject inclusion and exclusion criteria for Part A can be 
found in Sections 5.1 and 5.2 of the protocol. 
No power and sample size analysis was conducted for Part B. Patients from Part A were enrolled 
into Part B following Part A EOT. The power and sample size calculation for Part A can be found 
in the Part A SAP. 
 
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3 
ANALYSIS POPULATIONS  
The important protocol deviations defined in Part A do not apply to Part B; and thus, the Per-
Protocol Population described in the protocol was determined to have little utility and has not 
been included in this SAP. 
The following populations for analyses are defined:  
Table 3 - Populations for analyses  
Population 
Description 
Full Analysis Set 
All subjects who enroll into Part B and receive at least 1 dose (including partial 
dose) of study drug. The Full Analysis Set is synonymous with the Intent-to-Treat 
Population described in the protocol. 
Safety Analysis Set 
All subjects who receive at least 1 dose (including partial dose) of study drug in 
Part B. Note that the Safety Analysis Set is the same as the Full Analysis Set in this 
study. 
PK Analysis Set 
All subjects who receive at least 1 dose of study drug in Part B and have evaluable 
PK concentrations. 
PD Analysis Set 
All subjects who receive at least 1 dose of study drug in Part B and have at least 
1 evaluable PD sample. 
 
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4 
STATISTICAL ANALYSES  
Part B is an open-label study with no blinding or randomization. No formal statistical hypotheses 
will be tested. Analyses of efficacy endpoints will be primarily descriptive.  
Statistical analysis will be performed by Sanofi, using SAS 9.4 or higher and, where appropriate, 
additional validated software.  
4.1 
GENERAL CONSIDERATIONS  
Safety, efficacy, and PK/PD data will be summarized using standard summary statistics for 
continuous, categorical, and time-to-event data. Data will be summarized for the populations 
defined. 
No statistical hypothesis testing is planned. 
Continuous Variables 
Continuous variables will be summarized using descriptive statistics including the number of non-
missing values (n), mean, standard deviation (SD), median, minimum and maximum. Where 
specified in the table shells, the 25th and 75th percentiles will also be provided. Means, medians, 
and the 25th and 75th percentiles will be presented to one decimal place beyond that with which the 
data were captured. SDs will be presented to two decimal places beyond that with which the data 
were captured. Minimum and maximum will be displayed to the same number of decimal places 
as that with which the data were captured. 
Unless impractical within a given table, statistics will be aligned by the decimal place (or assumed 
decimal place) in the summary tables. 
Categorical Variables 
Categorical variables will be summarized by counts and percentages. All percentages will be 
rounded to one decimal place. The percentage will be suppressed when the count is zero. Unless 
specified otherwise, the denominator for all percentages will be the number of subjects with non-
missing data for a given summarization. 
Part B Study Treatment Period 
For subjects who enroll into Part B, the Part A study treatment period starts at the date of 
first study drug administration and ends at the date of Week 26 visit. The Part B study treatment 
period starts following completion of Part A (ie, immediately following Week 26 visit) and ends 
at the ET/EOS/Safety follow-up visit, which is 9 weeks after each subject’s last dose. 
Combined Study Period 
The Combined Study Period includes all visits in Part A and Part B and will be utilized for a 
subset of analyses in order to support regulatory submissions and/or publications. 
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Thromboembolic Events 
Thromboembolic events prior to Part A study entry are recorded as medical history in the eCRFs, 
while thromboembolic events on Part A and Part B study are captured as adverse events. Both 
medical history and adverse events will be coded according to Medical Dictionary for Regulatory 
Activities (MedDRA) v23.0 or higher. 
All thromboembolic events reported (as AEs) will be reviewed and determined by internal 
medical staff via medical adjudication. 
Hemolytic Breakthrough 
Hemolytic breakthrough at any visit is defined as 
• A decrease of 2 g/dL or more in Hgb from the last scheduled visit, and 
• One of the followings: 
- 
An increase of LDH from the last scheduled visit, or 
- 
An increase of bilirubin from the last scheduled visit, or 
- 
A decrease in haptoglobin from the last scheduled visit. 
4.2 
PARTICIPANT DISPOSITIONS  
Subject disposition will be summarized for all enrolled subjects in Part B by treatment arm in 
Part A (ie, BIVV009 and Placebo) and Total. Subject disposition will be summarized including 
the number of subjects in FAS, Safety Analysis Set, PK Analysis Set, and PD Analysis Set. The 
number of subjects with the status of completed Part B and discontinued Part B early, including 
the primary reason for those who discontinued, will be tabulated for all subjects enrolled in 
Part B. 
Protocol deviations 
All protocol deviations will be recorded throughout the study. Major and minor protocol 
deviations/violations are to be pre-specified prior to database lock. All major protocol deviations 
will be summarized for FAS by treatment arm in Part A (ie, BIVV009 and Placebo) and Total.  
4.3 
PRIMARY ENDPOINT(S) ANALYSIS  
The primary objective of Part B is to evaluate the long-term safety and tolerability of BIVV009 in 
patients with primary CAD. Thus, all endpoints related to this objective and the analyses for these 
endpoints will be described, in full, in Section 4.7. 
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4.4 
SECONDARY ENDPOINT(S) ANALYSIS  
Unless specified otherwise, all analyses described will be performed using the FAS. All 
summaries of efficacy endpoints will be descriptive and will not test any formal hypotheses. All 
summaries will be tabulated by treatment arm in Part A (ie, BIVV009 and Placebo) and Total. 
4.4.1 Key/Confirmatory secondary endpoint(s)  
4.4.1.1 Definition of endpoint(s)  
Continuous endpoints 
The continuous endpoints are: 
• Mean change from baseline in hemolytic parameters including 
- 
Hemoglobin 
- 
Total bilirubin 
- 
LDH 
- 
Haptoglobin 
• Mean change from baseline in FACIT-Fatigue score 
• Mean change from baseline in QOL, as assessed by the change in the five-level EQ-5D-5L 
scores by visit 
• Mean change from baseline in QOL, as assessed by the change in the 12-item short form 
survey (SF-12 ®) 
• Number of transfusions and total transfusion units 
• Annualized number of transfusions and annualized transfusion units 
Categorical Endpoints 
The categorical endpoints include: 
• Incidence of thromboembolic events 
• Incidence of hemolytic breakthrough 
• PGIC 
• Change from baseline in PGIS 
4.4.1.2 Main analytical approach  
Continuous Endpoints 
The continuous endpoints will be summarized by visit and treatment arm using descriptive 
statistics for the FAS according to Section 4.1. Change from baseline will also be summarized by 
visit. 
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Line plots of hemoglobin, bilirubin, and FACIT-F score over time, starting at Baseline/Day 0, will 
be presented. Additionally, line plots of mean change from baseline in hemoglobin, bilirubin, and 
FACIT-F score over time, starting at Baseline/Day 0, will be presented. 
The endpoints related to transfusions and transfusion units will be summarized by study period 
using the FAS. 
Annualized values will be calculated for each patient using the following formula:  
Annualized value = 
× 365.25 
 
 
Response (Categorical) Endpoints 
The categorical endpoints will be summarized descriptively by visit and treatment arm for the 
using the FAS according to Section 4.1 with the exception of total healthcare resource utilization 
at EOT (Part A), which will be presented in a listing. 
All thromboembolic events reported (in Adverse Events) will be reviewed and determined by 
internal medical staff along with investigators. In case that there are discrepancies between the 
medical review and investigators’ assessment, separate analyses will be carried out for both sets 
of events. Date of event occurrences will be verified. The incidence of thromboembolic events 
and hemolytic breakthrough events will be summarized using all data in Part B (including data 
from the Week 79 visit and beyond). 
4.4.1.3 Details on endpoints based on patient-reported outcomes (PROs)  
The patient-reported outcome (PRO) endpoints are as follows: 
• Continuous Endpoints 
- 
FACIT-Fatigue score 
- 
EQ-5D index score 
- 
EQ-5D-5L visual analogue scale 
- 
SF-12 physical component score (PCS) and mental component score (MCS) 
- 
SF-12 sub-scale scores 
• Categorical Endpoints 
- 
Patient’s Global Impression of Change (PGIC) 
- 
Patient’s Global Impression of [Fatigue] Severity (PGIS) 
- 
EQ-5D-5L Descriptive System 
Details of the above PRO instruments and algorithms for deriving the scores can be found in the 
Part A SAP.  
Number of events during the Study Period 
Total number of days during the Study Period 
 
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When applicable missing items will be handled based on the specific PRO instrument. Subjects 
missing baseline evaluations would not be included in the PRO analyses. 
Healthcare Resource Utilization 
The number of healthcare visits by type (office visit, hospital ER visit, hospitalization, and ICU 
stay) will be collected and presented in a listing.  
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
4.5.1 Definition of endpoint(s)  
Per the protocol, home infusions will be performed at pre-selected countries/sites for a select 
number of subject who meet the criteria specified in Appendix K of the protocol. For these 
subjects, a survey will be conducted after the first and fourth home infusion to assess patient 
satisfaction with the home infusion. 
4.5.2 Main analytical approach  
The patient satisfaction survey will be summarized descriptively for the subset of subjects who 
receive home infusions. 
4.6 
MULTIPLICITY ISSUES  
There are no multiplicity issues for Cadenza Part B. 
4.7 
SAFETY ANALYSES  
All safety analyses will be performed on the Safety Analysis Set, stratified by dose cohort, unless 
otherwise specified, using the following common rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is 
planned. 
• Safety data in participants who do not belong to the safety population (eg, exposed but not 
randomized) will be provided. 
4.7.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and treatment 
compliance and summarized for the Safety Analysis Set. Per the protocol, subjects rolling over to 
Part B are to receive a loading dose (in a blinded manner). For analysis of Part B exposure, this 
loading dose will be included in the Part B database. Thus, Part B exposure will start on the 
date/time of the Week 26 loading dose. 
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Duration of IMP exposure 
Study drug exposure, measured by the duration of study treatment, the number of BIVV009 
administrations and total actual BIVV009 dose, will be summarized by study period for the Safety 
Analysis Set by treatment cohort in Part A (ie, BIVV009 and Placebo) and Total.  
The duration of the study treatment (in weeks) is calculated as follows: 
1. Combined Study Period: (date of last dose – date of first dose in Part A + 15)/7 
2. Part B Study Period: (date of last dose – Part B start date + 15)/7 
Treatment compliance 
Study drug compliance for a subject is measured by the percent of number of doses received out 
of the number of protocol-specified doses. The proportion of subjects whose compliance is less 
than 80%, 80% - <100%, and ≥100% will also be summarized. In addition, the number of subjects 
and number of doses administered out of study windows and number of partial infusion doses will 
be summarized. 
4.7.1.1 Overall exposure  
The actual dose administered at each visit is calculated as: 
 
Total volume administered / Total volume prepared * assigned dose.  
The total BIVV009 dose will be summarized as follows: 
1. Combined Study Period: The summation of all actual doses administered in Parts A and B. 
2. Part B Study Period: The summation of all actual doses administered in Part B, alone. 
The number of subjects with missing infusion due to COVID-19 will be presented. 
4.7.2 Adverse events  
General common rules for adverse events 
AEs will be classified using the MedDRA system organ classes and preferred terms. MedDRA 
version 23.0 or higher will be used throughout the study. 
In general, AEs will be analyzed based on incidence, defined as the proportion of subjects who 
had at least one occurrence of an event out of the number of subjects in the Safety Analysis Set.  
All summary tables and listings will only include treatment-emergent adverse events in Part B 
unless noted otherwise.  
Unless specified otherwise, system organ classes and preferred terms within each SOC will be 
presented alphabetically. For the purpose of summarization, a subject is counted once in a SOC or 
preferred term if the subject reported one or more events in that SOC or preferred term. Unless 
specified otherwise, percentages will be based on the number of subjects in the Safety Analysis Set. 
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Overall Summary of Adverse Events 
An overall summary of TEAEs will be provided which tabulates the number and percentage of 
subjects who experienced a TEAE, related TEAE, treatment-emergent SAE, treatment-emergent 
related SAE, treatment-emergent Grade 3 or higher AE, treatment-emergent infections of Grade 3 
or higher severity, TEAE thromboembolic event, TEAE autoimmune event, TEAE potential 
hypersensitivity event, and TEAEs within 24 hours after the start of infusion; TEAEs within 
24 hours after the start of home infusion of BIVV009 and TEAEs within 24 hours after the start of 
undiluted infusion of BIVV009; the number and percentage of subjects who discontinued 
treatment and/or the study due to an AE; and the number and percentage of subjects who died. In 
addition, the number of TEAEs, TESAEs, TEAE thromboembolic events and TEAEs within 
24 hours after the start of infusion will be presented. 
Treatment-emergent Adverse Events 
The incidence of TEAEs will be summarized by SOC and preferred term. 
Adverse Events in Descending Order of Incidence 
Tables will be provided which display TEAE and TESAE preferred terms in descending order of 
incidence. Only preferred terms will be included in these tables (ie, the display will not include 
SOCs). 
A similar table will be provided for Grade 3 or higher TEAEs. AEs for which the assessment of 
severity is missing will be included in this table. 
Severity of Adverse Events 
AEs are classified by the Investigator for CTCAE grades v4.03. A summary of TEAEs by system 
organ class, preferred term, and CTCAE grade will be presented. AEs with a missing severity will 
be excluded from this table and listed separately to supplement the summary table. A subject will 
be counted once for each SOC and preferred term based on the greatest severity within that SOC 
and preferred term, respectively. 
Relationship of Adverse Events to Study Drug 
AEs are classified by the Investigator for relationship to study drug (“Not related,” “Possible,” 
and “Probable”). For summary tables, an AE with relationship of “Possible” or “Probable” will be 
considered “Related.” A summary of TEAEs by SOC, preferred term, and relationship (“Related” 
or “Not related”) will be presented. AEs with a missing relationship will be counted as “Related” 
in the summary table. A subject will be counted once for each SOC and preferred term based on 
the highest relationship within that SOC and preferred term, respectively. 
Serious Adverse Events 
Any AE reported as resulting in death, immediate risk of death (life threatening), inpatient 
hospitalization or prolongation of existing hospitalization, persistent or significant 
disability/incapacity, or a congenital/anomaly/birth defect will be classified as an SAE by the 
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Investigator. An SAE may also be any other medically important event that, in the opinion of the 
Investigator, may jeopardize the subject or may require intervention to prevent one of the other 
outcomes listed above.  
Treatment-emergent SAEs and treatment-emergent related SAEs will be summarized by system 
organ class and preferred term. Treatment-emergent SAEs will also be summarized by preferred 
term in descending order of incidence. 
Adverse Events Leading to Treatment Discontinuation and/or Study Withdrawal 
AEs leading to treatment discontinuation and/or study withdrawal will be listed. All AEs reported 
on the AE log for the item “Action Taken with Study Drug” with a response of “Study drug 
permanently discontinued” or for the item “Was the subject terminated from this study due to this 
AE?” with a response of “Yes” will be included.  
Death on Study 
A listing of deaths occurring on study will be provided. 
Analysis of adverse events of special interest (AESIs) 
AEs within 24 Hours after the Start of Site Infusion 
All AEs within 24 hours after the start of site infusion are captured in the eCRF. Incidence of AEs 
within 24 hours after the start of site infusion will be summarized by SOC and preferred term. 
AEs within 24 Hours after the Start of Home Infusion 
All AEs within 24 hours after the start of home infusion are captured in the eCRF. Incidence of 
AEs within 24 hours after the start of home infusion will be summarized by SOC and preferred 
term. AEs within 24 hours after the start of home infusion will be flagged on the listing of adverse 
events. 
AEs within 24 Hours after the Start of Undiluted Infusion 
All AEs within 24 hours after the start of undiluted infusion are captured in the eCRF. Incidence 
of AEs within 24 hours after the start of undiluted infusion will be summarized by SOC and 
preferred term. AEs within 24 hours after the start of undiluted infusion will be flagged in the 
listing of adverse events. 
Infections and Infections of ≥ Grade 3 Severity 
Infections will be captured based on MedDRA SOC of “infections and infestations.” Incidence of 
infections of Grade 3 or higher will be summarized by preferred term. Listings of all infections, 
infections of Grade 3 or higher and serious infections will be provided. 
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Autoimmune Events 
Treatment-emergent autoimmune events will be adjudicated and flagged on the Listing of adverse 
events. 
Hypersensitivity Events 
Treatment-emergent hypersensitivity events will be adjudicated and flagged on the Listing of 
adverse events. 
Anti-drug Antibody 
Subjects will be evaluated for anti-drug antibodies at Baseline and at the ET/EOS/Safety Follow-
up visits in Part B. Subjects with negative or positive anti-drug antibodies at baseline and post 
baseline, as well as the incidence and prevalence will be summarized for the Combined Study 
Period by dose cohort in Part B (ie, 6.5 g and 7.5 g) and Total. A listing will be provided for 
subjects with negative or positive anti-drug antibodies along with the associated titer if available. 
If applicable, TEAEs for those subjects will be included in the same listing. 
4.7.3 Additional safety assessments  
4.7.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
Hematology and Chemistry 
All summaries will be structured such that the hematology and chemistry tests are presented in the 
order shown in the tables below. All hematology and chemistry lab summaries will be analyzed 
by dose cohort in Part B (ie, 6.5 g and 7.5 g) and Total using the Safety Analysis Set. 
Hematology measurements that will be collected and listed include white blood cell count (WBC), 
red blood cell count (RBC), differentials (basophils, eosinophils, lymphocytes, monocytes, 
neutrophils, reticulocytes), hemoglobin, hematocrit, and platelet count. 
Chemistry measurements that will be collected and listed include electrolytes (sodium, potassium, 
chloride), glucose, total protein, total bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN), and serum 
creatinine.  
Change from Baseline 
Hematology and chemistry results at baseline and Part B post-baseline visits, along with change 
from baseline, will be summarized with descriptive statistics. These by-visit summaries will be 
presented through the end of Part B. 
Shifts from baseline 
Each subject’s laboratory values will be classified according to whether the test result is “low” 
(below the LLN), “normal” (within the normal range), “high” (above the ULN). Shift tables will 
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be constructed based on both the minimum and maximum post-baseline values for each subject. A 
separate table will be provided which summarizes the results of the shift tables in which the 
number and percentage of subjects with a shift to low (from normal, low, or unknown) and the 
number of subjects with a shift to high (from normal, low, or unknown) will be tabulated; 
percentages will be based on the number of subjects at risk. The number at risk for a shift to low 
(high) is the number of subjects whose baseline value was not low (high), including unknown, 
who had at least one post-baseline value. Only directions of change indicating a clinical concern 
will be included in this table summarizing the shifts. The direction of concern is provided in 
Table 4. 
All data collected during Part B, including data collected from unscheduled visits, will be 
included in the above-mentioned analyses. 
Table 4 - Direction of change indicating clinical concern for laboratory tests  
Laboratory Test 
Direction 
Laboratory Test 
Direction 
Chemistry 
Hematology 
Liver 
 
White blood cells 
Low and High 
ALT/SGPT 
High 
Lymphocytes 
Low and High 
AST/SGOT 
High 
Neutrophils 
Low and High 
Total bilirubin 
High 
Monocytes 
Low and High 
GGT 
High 
Eosinophils 
Low and High 
Renal 
 
Basophils 
Low and High 
Blood urea nitrogen 
High 
Red blood cells 
Low and High 
Creatinine 
High 
Hemoglobin 
Low and High 
Electrolytes 
 
Hematocrit 
Low and High 
Sodium 
Low and High 
Platelets 
Low and High 
Potassium 
Low and High 
 
 
Chloride 
Low and High 
 
 
Other 
 
 
 
Glucose 
Low and High 
 
 
Total protein 
Low and High 
 
 
Potentially Clinically Significant Laboratory Abnormalities 
Abnormal laboratory values (excluding LDH, haptoglobin, and reticulocytes) will also be 
evaluated by determining the number and percentage of subjects with at least one potentially 
clinically significant laboratory abnormality over the course of Part B of the study that also 
represents a worsening from baseline. The potentially clinically significant levels are based on 
Grade 2 or higher thresholds from the CTCAE v4.03 where possible, or are defined by Sanofi’s 
safety group. Subjects who have a post baseline laboratory value that meets the criteria for being 
potentially clinically significant but do not have a baseline value will be included in the numerator 
for determining the percentage of subjects with an abnormality. The laboratory tests and 
thresholds for determining PCSAs are provided in Table 5. 
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Table 5 - Thresholds for potentially clinically significant laboratory abnormalities  
Laboratory Test  
Threshold 
Laboratory Test  
Threshold 
Chemistry 
Hematology 
ALT (U/L) 
>= 3 x ULN 
Hematocrit (%) 
<= 30% 
>= 60% 
Albumin (g/dL) 
<= 2.5 g/dL 
Hemoglobin (g/L) 
<= 100 g/L 
>= 190 g/L 
Alkaline Phosphatase (U/L) 
> 2.5 x ULN 
MCV (fL) 
>= 1.2 x ULN 
<= 0.8 x LLN 
AST (U/L) 
>= 3 x ULN 
Platelet count (10^9/L) 
<= 75 x 10^9/L 
>= 700 x 10^9/L 
Blood urea nitrogen (mmol/L) 
>= 10.7 mmol/L 
WBC (10^9/L) 
<3 x 10^9/L 
>= 16 x 10^9/L 
Chloride (mmol/L) 
<= 90 mmol/L 
>= 118 mmol/L 
Basophils (10^9/L) 
> 1.6 x 10^9/L 
Creatinine (umol/L) 
> 1.5 x ULN 
Eosinophils (10^9/L) 
> 1.6 x 10^9/L 
GGT (U/L) 
> 2.5 x ULN 
Lymphocytes (10^9/L) 
> 0.8 x 10^9/L 
Glucose (mmol/L) 
<3 mmol/L 
> 8.9 mmol/L 
Monocytes (10^9/L) 
< 2.5 x 10^9/L 
Potassium (mmol/L) 
<= 3 mmol/L 
>= 6 mmol/L 
Neutrophils (10^9/L) 
> 1.5 x 10^9/L 
Sodium (mmol/L) 
<= 126 mmol/L 
>= 156 mmol/L 
 
 
Total bilirubin (umol/L) 
> 1.5 x ULN 
 
 
Direct bilirubin (umol/L) 
> 1.5 x ULN 
 
 
Total protein (g/L) 
<= 45 g/L 
>= 100 g/L 
 
 
All data collected during Part B, including data collected from unscheduled visits, will be 
included in this analysis. 
Systemic Lupus Erythematosus (SLE) Panel  
SLE panel will be summarized with descriptive statistics. The number of subjects with all 
negative or all missing values for all SLE panel parameters prior to receiving study drug and the 
number of subjects with at least one positive value for at least one SLE panel parameter prior to 
receiving study drug will be summarized. Further, among subjects who have all negative or all 
missing values for all SLE parameters prior to receiving study drug and have at least one post-
baseline value for at least one parameter, the number of subjects who test negative at all post-
baseline assessments for all SLE parameters, and the number of subjects who test positive at any 
post-baseline assessment for at least one SLE parameter will be summarized.  
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Similar summaries will be generated for individual SLE parameters. In addition, for a given SLE 
parameter, among subjects who have at least one positive or all missing values prior to receiving 
study drug and have at least one post-baseline for this parameter, the number of subjects who test 
positive at all post-baseline assessments, and the number of subjects who test negative at any post-
baseline assessment will be summarized. 
Parameters in the SLE panel include Antinuclear antibody (ANA), multiplex with dsDNA, Anti-
La/SSB antibody (SS-B), Anti-riboucleoprotein antibody (RNP), Anti-Smith antibody (Sm), Anti-
Ro/SSA antibody (SS A), Anti-scleroderma antibody (Scl-70), Anti-Chromatin antibody, Anti-Jo-
1 antibody, Anti-Centromere B antibody, Circulating immune complexes (CIC). 
ECG and Vital Signs 
The proportion of subjects with specific clinical interpretations (Normal; Abnormal, not an AE; 
Abnormal, AE) will be summarized by visit, through the end of Part B. 
The proportion of subjects with a shift in clinical interpretation from baseline will be summarized. 
All data collected during Part B, including data collected from unscheduled visits, will be 
included in this analysis. 
Vital signs 
Vital signs (systolic and diastolic blood pressure, pulse, respiratory rate, and temperature) will be 
summarized by visit, through the end of Part B, for the observed values and change from baseline 
using descriptive statistics for the Safety Analysis Set. 
The number and percentage of subjects with potentially clinically relevant post-baseline 
abnormalities will be presented. All data collected during Part B, including data collected from 
unscheduled visits, will be included in this analysis. The criteria for potentially clinically relevant 
post-baseline abnormalities are shown below in Table 6. 
Table 6 - Criteria to determine clinically relevant abnormalities in vital signs  
Vital Sign 
Criteria for Abnormalities 
Temperature 
>38oC and an increase from pre-dosing of at least 1oC 
Pulse  
120 beats per minute post-baseline or 
an increase from pre-dosing of more than 20 beats per minute; 
<50 beats per minute post-baseline or 
a decrease from pre-dosing of more than 20 beats per minute 
Systolic Blood Pressure 
>180 mmHg post-baseline or  
an increase from pre-dosing of more than 40 mmHg; 
<90 mmHg post-baseline or  
a decrease from pre-dosing of more than 30 mmHg 
Diastolic Blood Pressure 
>105 mmHg post-baseline or  
an increase from pre-dosing of more than 30 mmHg; 
<50 mmHg post-baseline, or  
a decrease from pre-dosing of more than 20 mmHg 
Respiratory Rate 
>35 breaths per minute post-baseline; 
<10 breaths per minute post-baseline 
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4.8 
OTHER ANALYSES  
4.8.1 Pharmacokinetic analysis  
Plasma BIVV009 concentrations will be listed by subject, nominal visit, date and time of 
collection and study day. Summary statistics of plasma BIVV009 concentrations will be presented 
by nominal visit and study day including n, mean, standard deviation, coefficient of variation, 
geometric mean, median and range. All summaries will be tabulated by treatment cohort in Part B 
(ie, 6.5 g and 7.5 g) and Total. Individual and mean plasma BIVV009 concentration-versus-time 
profiles will be plotted. The above analyses will be conducted using the PK Analysis Set for the 
Cumulative Study Period.  
4.8.2 Pharmacodynamic analysis  
Descriptive statistics including number of observations, mean, SD, median, minimum, and 
maximum will be presented for continuous parameters. Categorical variables will be presented 
with the number and percentage in each category. Summary descriptive statistics (absolute values 
and changes from baseline) and individual subject listings will be presented by time point and 
study day. All summaries will be tabulated by treatment cohort in Part A (ie, BIVV009 and 
Placebo) and Total. The above analyses will be conducted using the PD Analysis Set for the 
Cumulative Study Period. 
4.9 
INTERIM ANALYSES  
For purposes of regulatory submission, an interim analysis of safety and efficacy data will be 
performed after all subjects have completed Part A and the data are cleaned. Part B data, up to the 
date of Part A database lock, will be summarized descriptively. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
AE 
adverse event 
ADL 
activities to daily living 
ALP 
alkaline phosphatase 
ALT  
alanine aminotransferase 
ANA 
antinuclear antibodies 
AST  
aspartate aminotransferase 
AUC 
area under the curve 
BLA 
Biologics License Applications 
BUN  
blood urea nitrogen 
CAD 
cold agglutinin disease 
CI 
confidence interval 
CIC 
circulating immune complexes 
Cmax 
maximum concentration 
CTCAE 
Common Toxicity Criteria for Adverse Events 
DBL 
database lock 
ECG 
electrocardiogram 
eCRF  
electronic Case Report Form 
EOT 
end of treatment 
EQ-5D-5L 
EuroQol – five dimensions questionnaire 
ET 
early termination 
FACIT 
functional assessment of chronic illness therapy 
FAS 
full analysis set 
GGT 
gamma-glutamyl transferase 
Hgb 
hemoglobin 
HUI 
health utility index 
ICH 
International Conference of Harmonisation 
ITT 
intent-to-treat 
IV  
intravenous 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LPO 
last patient out 
MAA 
Marketing Authorization Application 
MAR 
missing at random 
MCMC 
Markov chain Monte-Carlo 
MedDRA  
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model for Repeated Measures 
MNAR 
Missing Not At Random  
NCMV 
Neighboring-Case Missing Value  
PD 
pharmacodynamics 
PGIC 
PGIS 
Patient’s Global Impression of Change 
Patient’s Global Impression of Severity 
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PK  
pharmacokinetics 
PP 
per-protocol 
PRO 
patient-reported outcome 
QOL 
quality of life 
RBC  
red blood cell count 
SAE  
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SF-12 
12-Item Short Form Survey 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic-pyruvate transaminase 
SLE 
systemic lupus erythematosus 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TLF 
tables, figures, and listings 
TOEPH 
heterogeneous Toeplitz 
ULN 
upper limit of normal 
WBC  
white blood cell count 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
This section summarizes major statistical changes in the protocol amendment(s). 
Table 7 - Major statistical changes in protocol amendment(s)  
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
Version 1 (original) 
24-Aug-2017 
Not applicable 
Not applicable 
 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics and baseline disease characteristics will be summarized for the FAS. 
Demography 
Demographic characteristics including age (years), age category (<65, >= 65), gender, race, 
ethnicity, country, geographic location, height (cm), weight (kg), weight category (<75 kg, 
 >= 75 kg), and body mass index (kg/m2) will be summarized. Geographic locations are defined as 
Europe, North America, Asia/Japan, and other. 
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General Medical History 
Medical history by system organ class (SOC) and preferred term (PT) will be summarized. A 
subject will be counted only once if they reported one or more occurrences in the same SOC or PT.  
A summary of prior hospitalizations related to CAD within the last 2 years, prior hematological 
malignancies within the last 5 years, prior non-malignant hematologic diseases within the last 
5 years, and prior thromboembolic events within the last 1 year will be presented based off the 
“Targeted Medical History” eCRF form. 
Baseline Disease Characteristics  
Screening and baseline lab parameters, including hematology (such as Hgb, bilirubin, LDH), 
Gilbert’s Syndrome testing, and bone marrow biopsy results will be summarized. Prior transfusion 
history (eg, number of transfusions within 12 months of study entry) will also be summarized.  
Severity of anemia symptoms and other CAD-related disease characteristics (eg, presence of 
acrocyanosis, Raynaud’s syndrome, hemoglobinuria, disabling circulatory symptoms, and major 
adverse vascular events) within 3 months of screening will be summarized. 
The proportion of subjects who had documented vaccines within 5 years and who have received 
vaccination during the study will be summarized. The vaccines include meningococcal vaccine, S. 
pneumoniae vaccine, and H. influenza vaccine. 
Prior or concomitant medications 
Prior medications are those taken before the first dose of study drug in Part A. Concomitant 
medications are those administered on or after the first dose of study drug, or those administered 
before the first dose that are ongoing when study treatment begins. Prior and concomitant 
medications will be coded using World Health Organization drug enhanced dictionary 
(March 2020 version or higher). 
Separate tables will be generated to summarize concomitant medications and concomitant 
protocol-prohibited medications by ATC level 2 and WHODrug standardized medication text. 
Additionally, a summary of targeted prior therapies will be generated based off the responses 
provided in the “Targeted Prior Therapy” eCRF form. 
Concomitant non-drug treatments and procedures 
Concomitant non-drug treatments and procedures will be summarized for the FAS. 
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5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
Study Day 
Study Day is defined as days relative to the date of first dose of BIVV009 or placebo in Part A, 
Day 0. The start/stop day of events will be calculated as (date of event – date of Day 0 +1). 
Incomplete dates will be imputed for the calculation of study days, unless specified otherwise: 
• If missing day only, the start date will be imputed as the first day of the month, while the 
end date will be imputed as the last day of the month; 
• If missing day and month, the start date will be imputed as the first day of the year, while 
the end date will be imputed as the last day of the year; 
Baseline 
For purposes of specified analyses, baseline measures are defined as the last value prior to the 
first dose of study drug in Part A. 
Analysis Windows for time points 
Analysis by study visit will utilize the data recorded on the corresponding nominal visit from 
electronic Case Report Forms (eCRFs). In case of missing data/assessments for a visit, data from 
an unscheduled visit, or ET/Safety Follow-up Visit will be used, if the Study Day of such a visit 
fits in the analytic window defined below. If multiple values are identified within the analytic 
window, the one closest to the target study day will be used. 
Starting at Week 27 and every 2 weeks thereafter, analytic visit windows in Part B will be -6 days 
to +7 days from the Target Study Days of the protocol-defined visits. An example of the first few 
visits in Part B can be seen below . 
Table 8 - Analytic visit window  
Visit 
Target Study Day 
Analytic Visit Window (Study Day) 
Week 27 
189 
183-196 
Week 29 
203 
197-210 
Week 31 
217 
211-224 
Week 33 
231 
225-238 
Etc. 
 
 
Unscheduled visits 
Unscheduled visit measurements of clinical laboratory data, ECG and vital signs will be used for 
computation of baseline, the last on-treatment value, analysis according to PCSAs, and the shift 
summaries for safety. They will also be included in the by-visit summaries if they are re-allocated 
to scheduled visits.  
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Pooling Sites for Analysis 
Data from all investigational sites will be pooled for the analysis, unless specified otherwise. 
Handling of Missing Data 
Best efforts will be utilized to minimize missing values. If a subject discontinues study treatment 
early, the subject will be asked to complete study assessments at ET/safety follow up visit. 
For the analysis of both continuous and categorical data, summary statistics will be computed 
based on observed data. Since the duration of treatment period varies in Part B, efficacy endpoints 
by visit will be summarized through 12 months during Part B. Additional summaries beyond 
12 months may be computed depending on the enrollment pattern, ie, the number of subjects 
attending visits after the Week 77 visit. AE endpoints by visit will be summarized through LPLV 
in Part B. 
For a QOL endpoint, in the event of missing data, the total score will be estimated according to 
the provision for missing domains in the calculation algorithm of the score. For example, if a 
subject has missing data in FACIT-F questionnaire at a visit, the prorated FACIT-F score will be 
calculated if more than 50% of the items (a minimum of 7 out of 13 items) are available. 
Otherwise, the score is missing. 
For the analysis of AEs and concomitant medications/procedures, if the start/stop date of an 
AE/concomitant medication/procedure is missing or partial, the corresponding study day will be 
left blank. However, inferences will be made from the partial and missing dates to classify 
modifications as prior and/or concomitant and AEs as treatment emergent or not treatment 
emergent. 
VV-CLIN-0587710 1.0


Statistical Analysis Plan  
11-Aug-2020 
BIVV009-04 Part B - sutimlimab 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 29 
6 
REFERENCES  
Not applicable. 
VV-CLIN-0587710 1.0


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