Clinical trial NCT03347396
Conditions: Agglutinin Disease, Cold
Sponsor: Bioverativ, a Sanofi company
Start date: 2018-03-05; Completion date: 2021-10-05
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of Part A was to determine whether sutimlimab administration resulted in a greater than or equal to (\>=) 2 grams per deciliter (g/dL) increase in hemoglobin (Hgb) levels or increased Hgb to \>= 12 g/dL and obviated the need for blood transfusion during treatment in participants with primary cold agglutinin disease (CAD) who had 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 CAD.

Detailed description:

Arms: arm 1: Participants with primary CAD who had a recent history of transfusion (defined as at least 1 transfusion during the last 6 months prior to screening) received an intravenous (IV) infusion of BIVV009 6.5 grams (g) (if body weight was less than \[\<\] 75 kilograms \[kg\]) or BIVV009 7.5 g (if body weight was 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) could continue to receive BIVV009 in Part B, every 2 weeks starting at Week 27 for up to an additional 149 weeks. All participants who completed Part A elected to continue in Part B.
Interventions: intervention 1: BIVV009
Intervention descriptions: intervention 1: Sutimlimab was administered as intravenous (IV) infusion.

Protocol documents:
Prot_000.pdf: 
AMENDED CLINICAL TRIAL PROTOCOL 06
BIVV009-03 
IND #128,190 
EudraCT #2017-003538-10 
A PHASE 3, PIVOTAL, OPEN-LABEL, MULTICENTER STUDY TO ASSESS THE 
EFFICACY AND SAFETY OF BIVV009 IN PATIENTS WITH 
PRIMARY COLD AGGLUTININ DISEASE WHO HAVE A RECENT  
HISTORY OF BLOOD TRANSFUSION 
Study Drug: BIVV009 
Bioverativ USA Inc. 
This study will be performed in compliance with Good Clinical Practice. 
CONFIDENTIAL 
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. 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/Countries 
impacted by amendment 
Date 
Amended Clinical Trial Protocol 06 
Global 
19 December 2019 
Clinical Study Protocol Version 5 
Global 
17 July 2018 
Clinical Study Protocol Version 4 
Global 
29 June 2018 
Clinical Study Protocol Version 3.1 
Japan 
21 March 2018 
Clinical Study Protocol Version 3 
Global 
09 March 2018 
Clinical Study Protocol Version 2 
Global 
22 February 2018 
Clinical Study Protocol Version 1.5 
Belgium 
10 January 2018 
Clinical Study Protocol Version 1.4 
France 
15 December 2017 
Clinical Study Protocol Version 1.3 
Norway 
06 December 2017 
Clinical Study Protocol Version 1.2 
United Kingdom 
29 November 2017 
Clinical Study Protocol Version 1.1 
Global 
09 September 2017 
Clinical Study Protocol 
Global 
24 August 2017 
Note: The name and numbering of the protocol is based on a new numbering system followed by the Sponsor.  
AMENDED PROTOCOL 06 (19 December 2019)  
This amended protocol (06) is considered to be substantial 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 BIVV009-03 (Cardinal) are to extend Part B 
duration from 1 to 2 years after Last Patient Out from Part A, to provide home infusion facilities 
to the patients (for US, the Netherlands, Norway, France, Italy, Austria, Germany, and Spain 
specific amendments), to add new exploratory objective of immunogenicity, to introduce 
additional time points when samples for ADAs against BIVV009 are collected, to specify that left 
over PD 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, and to introduce a correction 
in Section 10.1 Appendix A.  
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page 
Title was updated to reflect Amended Clinical 
Trial Protocol 06. 
The change was made to reflect the update 
of the amended clinical trial protocol 06.  
Title Page 
Protocol Date was changed to reflect 19-Dec-
2019. 
The change was made to reflect the 
updated date of approval of the document. 
Approval of the Protocol 
Protocol Date was changed to reflect 19-Dec-
2019. 
The change was made to reflect the update 
of the amended clinical trial protocol 06.  
Section 1: Synopsis: 
Overview of Study Design; 
Methodology/Study Design; 
and throughout the 
document 
The Part B open-label extension study will run 
for 2 years instead of 1 year following last patient 
out (LPO) under Part A.  
The change was made to reflect the 
extension of Part B duration.  
Section 1: Synopsis: 
Objectives 
Secondary Exploratory Objective for Part A was 
added: To evaluate the immunogenicity of 
BIVV009.  
The change was made to help characterize 
immunogenicity of BIVV009. 
Section 1: Synopsis: 
Objectives 
Exploratory Objectives were added for Part B to 
describe the safety and patient satisfaction with 
the convenience of home infusion and to 
evaluate the immunogenicity of BIVV009. 
This change was made to help characterize 
immunogenicity of BIVV009 and evaluate 
the safety and patient satisfaction with the 
convenience of home infusion.  
Section 1: Synopsis: 
Methodology/Study Design: 
Collection of ADA samples during the 1st year of 
treatment in part B, then every 6 months was 
added for Part B. 
This change was made to help characterize 
immunogenicity of BIVV009. 
Section 1: Synopsis: 
Methodology/Study Design; 
Duration of Treatment; and 
Section 4.5 End of Study 
The study will be complete 24 months instead of 
12 months following LPO for Part A. 
The change was made to reflect the 
extension of Part B duration. 
Section 1: Synopsis: Test 
Product(s), Dose, and Mode 
of Administration 
Text specific to Part B for administration of study 
drug provided by home infusions was added. 
This change was made to evaluate the 
safety and patient satisfaction with the 
convenience of home infusion.  
Section 1: Synopsis: 
Efficacy Endpoints and 
Outcome Measures 
Part B Satisfaction with home infusion after first 
home infusion and after four home infusion will 
be assessed in patients with home infusion was 
added. 
This change was made to evaluate patient 
satisfaction with the convenience of home 
infusion.  
Section 1: Synopsis: Safety 
Outcome Measures 
For patients with home infusions, safety 
assessments include AEs with onset within 
24 hours of infusion was added. 
This change was made to evaluate the 
safety of home infusion.  
Section 1: Synopsis: 
Pharmacokinetic Outcome 
Measures 
Collection of PK samples at predose and 1 hour 
(±15 minutes) postdose was added. Samples 
will be collected at 3-month intervals during the 
1st year of treatment in Part B and then at 
6-month intervals for the remainder of the time 
on study. 
This change was made to further define PK 
sampling schedule. 
Section 1: Synopsis: 
Pharmacodynamic 
Outcome Measures 
Collection of PD samples will be collected at 
predose and 1 hour (±15 minutes) postdose was 
added. Samples will be collected at 3-month 
intervals during the 1st year of treatment in 
Part B and then at 6-month intervals for the 
remainder of the time on study. 
This change was made to further define PD 
sampling schedule. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1: Synopsis: 
Immunogenicity Outcome 
Measures 
This entire section was added to the amended 
protocol. 
This change was made to further define the 
exploratory objective of immunogenicity. 
Section 1: Synopsis: 
Statistical Methods, and 
throughout the document 
Intent to treat (ITT) has been replaced with Full 
Analysis Set (FAS) 
This change was made to reflect the 
method used for statistical analysis.  
Section 2.2: Background 
and Study Rationale 
Information regarding CAgD was added and that 
a group of patients at preselected site/countries 
will be offered the possibility of home infusions 
during Part B.  
This change was made to evaluate the 
safety and patient satisfaction with the 
convenience of home infusion.  
Section 2.2.4: Potential 
Risks and Benefits 
Home infusion with the study drug will be 
proposed to a number of patients in countries 
preselected to participate in home infusion and 
information about patient qualification was 
added.  
This change was made to evaluate the 
safety and patient satisfaction with the 
convenience of home infusion.  
Section 3.2: Secondary 
Objectives (Part A) 
Exploratory objective to evaluate the 
immunogenicity of BIVV009 was added.  
This change was made to better 
characterize the immunogenicity of 
BIVV009. 
Section 3.5: Exploratory 
Objective (Part B) 
This entire section was added.  
This change was made to help characterize 
immunogenicity of BIVV009 and evaluate 
the safety and patient satisfaction with the 
convenience of home infusion.  
Section 4.1: Study Design 
Part B 
ADA sampling and text specific to Part B for 
administration of study drug provided by home 
infusions was added. 
This change was made to help characterize 
immunogenicity of BIVV009 and evaluate 
the safety and patient satisfaction with the 
convenience of home infusion. 
Section 4.2: Discussion of 
Study Design 
Immunogenicity assessments evaluation, and 
conditions for ADA testing using available 
predose PD back-up samples was added.  
This change was made to help characterize 
immunogenicity of BIVV009. 
Section 4.3.4: Efficacy 
Endpoints (Part B) 
Part B Satisfaction with home infusion after first 
home infusion and after fourth home infusion will 
be assessed in patients with home infusion was 
added. 
This change was made to evaluate 
satisfaction with the convenience of home 
infusion.  
Section 4.3.5: Safety 
Endpoints 
For patients with home infusions, safety 
assessments include AEs with onset within 
24 hours of infusion was added. 
This change was made to evaluate the 
safety of home infusion. 
Section 4.3.6: 
Pharmacokinetic Endpoints 
PK samples will be collected at predose and 
1 hour (±15 minutes) postdose was added. 
Samples will be collected at 3-month intervals 
during the 1st year of treatment in Part B and 
then at 6-month intervals for the remainder of the 
time on study. 
This change was made to further define PK 
sampling schedule.  
Section 4.3.7: 
Pharmacodynamic 
Endpoints 
PD samples will be collected at predose and 
1 hour (±15 minutes) postdose was added. 
Samples will be collected at 3-month intervals 
during the 1st year of treatment in Part B and 
then at 6-month intervals for the remainder of the 
time on study. 
This change was made to further define PD 
sampling schedule.  
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Section # and Name 
Description of Change 
Brief Rationale 
Section 4.3.8: 
Immunogenicity Endpoints 
This entire section was added. 
This change was made to adhere to 
sponsor standards.  
Section 4.4: Duration of the 
Study 
The planned total study duration per patient is 
increased to reach approximately 2.5 to 
3.5 years. The duration of dosing in Part B will 
last from 2 to 3 years. Part B will run for 2 years 
following completion of LPO in Part A.  
The change was made to gather more 
evidence on long-term safety, tolerability 
and durability of response of BIVV009. 
Section 5.2: Exclusion 
Criteria 
Reference to home infusion inclusion and 
exclusion criteria in Section 10.10 Appendix J 
was added 
This change was made to clarify the specific 
requirements for home infusion.  
Section 5.3: Removal of 
Patients from Study 
Participation, and Study 
Suspension and Stopping 
Rules 
Conditions for which patients undergoing home 
infusions with study drug will return to bi-weekly 
dosing, and which they may return to home 
infusions was added.  
This change was made to specify rules for 
discontinuation and return to the home 
infusion schedule.  
Section 6.1: Schedule of 
Study Procedures, Table 3 
Study Schedule of Events 
SLE panel testing, and ADAs against BIVV009 
was added for Part B Extension Phase. 
Immunization review/vaccination is to be 
assessed during entire study. Footnote “I” was 
edited to include information for qualifying 
patients at participating site to have study drug 
dosed at home. Footnote “c” was edited to 
include information for second sample collection 
criteria.  Footnotes were edited in this section 
and footnotes “r”, “s”, “t”, and “u” were added to 
this table. 
This change was made to reflect changes 
introduced with the amendment in the 
schedule of study procedure. 
Section 6.1.1.1: Screening 
Assessments (initiating at 
Day -42) 
Revaccination with booster doses should be 
given according to regional guidelines for 
patients with persistent complement deficiency 
and in accordance with respective labels. 
This change was made to provide clarity to 
vaccination against encapsulated bacterial 
pathogens.  
Section 6.1.3: Weeks 1-25 
ADA: In patients who consented to the use of 
their blood samples for future research, PD 
back-up samples collected at the following time 
points Day 7, 35, 77, 133 and 175, may be used 
to assay ADA was added. 
This change was made to help characterize 
immunogenicity of BIVV009. 
Section 6.1.4: End-of-
Treatment Visit in Part A 
(Week 26) 
ADA: In patients who consented to the use of 
their blood samples for future research, PD 
back-up samples collected at this visit, may be 
used to assay ADA. 
This change was made to help characterize 
immunogenicity of BIVV009. 
Section 6.1.5.1: Procedures 
to be Performed Every 
2 Weeks 
It was specified that the hematology panel and 
clinical chemistry panel to be performed until 
week 79. 
This change was made to reflect the study 
assessments frequency in the 2nd year of 
Part B. 
Section 6.1.5.2: Procedure 
to be Performed Every 
4 Weeks 
Hematology panel (beginning at Week 79) and 
Clinical chemistry panel (beginning at Week 79) 
were added. 
This change was made to reflect the study 
assessments frequency in the 2nd year of 
Part B. 
Section 6.1.5.3: Procedures 
to be Performed Every 
3 Months 
Information for SLE panel, and ADA sampling 
collection was added.  
This change was made to reflect changes to 
Part B introduced with the amendment in 
the corresponding Study Procedures sub-
section. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 6.1.6: Infusion of 
the study drug at patient’s 
home 
This entire section was added and section on 
early termination/end of study/safety follow-up 
was renumbered as 6.1.7.  
This change was made to evaluate the 
safety and patient satisfaction with the 
convenience of home infusion.  
Section 6.2.1: Drug 
Supplies and Accountability 
Reference to the addition of home infusion 
inclusion in the preparation and accountability 
procedures for the investigational product were 
made. 
This change was made to reflect the option 
of home infusion within the framework of 
preparation and accountability procedures 
for the investigational product.  
Section 6.2.4: Dose 
Preparation and 
Administration 
Information for home administration of study 
drug, slowing or stopping due to AE in the case 
of home infusion, and monitoring of home 
infusion was added.  
This change was made to describe safety 
procedures associated with home infusion. 
Section 6.5.2: Analytical 
Methodology (PD) 
ADA parameter was added to this section. 
This change was made to reflect changes 
with regards to ADA introduced with the 
amendment. 
Section 6.6: Safety 
Procedure 
ADAs against BIVV009 was added.  
This change was made to reflect changes 
with regards to ADA introduced with the 
amendment. 
Section 7.7: 
Immunogenicity 
This entire section was added and subsequent 
sections were renumbered. 
This change was made to help characterize 
immunogenicity of BIVV009. 
Section 10: Supporting 
Documentation and 
Operational Considerations 
Appendices were included under section 10 and 
renamed accordingly throughout the document. 
This change was made to comply with 
Sanofi standards.  
Section 10.1: Appendix A 
Clinical Laboratory 
Evaluations  
"Iron" was removed from the clinical chemistry 
panel 
This change was made to provide 
clarification of clinical laboratory 
evaluations.  
Section 10.10: Appendix J 
Country Specific 
Requirement - Home 
Infusions with BIVV009 
This entire section was added. 
This change was made to evaluate the 
safety and patient satisfaction with the 
convenience of home infusion.  
Section 10.11: Appendix K 
Home Infusion Patient 
Satisfaction Survey 
This entire section was added. 
This change was made to evaluate patient 
satisfaction with the convenience of home 
infusion.  
Section 10.12: Appendix L 
Protocol Amendment 
History 
This entire section was added to comply.  
This change was made to comply with 
Sanofi standards. 
In addition, other minor editorial changes (eg, grammatical, stylistic, and minor typographical error 
corrections) were implemented throughout the protocol. 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 06 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 7 
LIST OF TABLES ......................................................................................................................................... 11 
LIST OF APPENDICES ................................................................................................................................ 11 
LIST OF ABBREVIATIONS .......................................................................................................................... 13 
1 
SYNOPSIS ..................................................................................................................................... 15 
2 
INTRODUCTION ............................................................................................................................ 23 
2.1 
PHARMACOLOGY OF BIVV009 ................................................................................................... 23 
2.2 
BACKGROUND AND STUDY RATIONALE .................................................................................. 23 
2.2.1 
Non-clinical experience .................................................................................................................. 24 
2.2.2 
Clinical experience ......................................................................................................................... 24 
2.2.3 
Pharmacokinetic experience and dose justification ....................................................................... 25 
2.2.4 
Potential risks and benefits ............................................................................................................ 26 
3 
STUDY OBJECTIVES ................................................................................................................... 28 
3.1 
PRIMARY OBJECTIVE (PART A) ................................................................................................. 28 
3.2 
SECONDARY OBJECTIVES (PART A) ........................................................................................ 28 
3.3 
PRIMARY OBJECTIVE (PART B) ................................................................................................. 28 
3.4 
SECONDARY OBJECTIVE (PART B) ........................................................................................... 28 
3.5 
EXPLORATORY OBJECTIVE (PART B)....................................................................................... 29 
4 
INVESTIGATIONAL PLAN ........................................................................................................... 30 
4.1 
STUDY DESIGN ............................................................................................................................ 30 
4.2 
DISCUSSION OF STUDY DESIGN ............................................................................................... 32 
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).......................................................................................... 33 
4.3.4 
Efficacy endpoints (Part B) ............................................................................................................ 33 
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4.3.5 
Safety endpoints ............................................................................................................................ 34 
4.3.6 
Pharmacokinetic endpoints ............................................................................................................ 34 
4.3.7 
Pharmacodynamic endpoints ......................................................................................................... 34 
4.3.8 
Immunogenicity endpoints ............................................................................................................. 35 
4.4 
DURATION OF THE STUDY ......................................................................................................... 35 
4.5 
END OF STUDY ............................................................................................................................ 36 
5 
PATIENT SELECTION .................................................................................................................. 37 
5.1 
INCLUSION CRITERIA .................................................................................................................. 37 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 38 
5.3 
REMOVAL OF PATIENTS FROM STUDY PARTICIPATION, AND STUDY SUSPENSION 
AND STOPPING RULES ............................................................................................................... 39 
6 
STUDY PROCEDURES ................................................................................................................ 41 
6.1 
SCHEDULE OF STUDY PROCEDURES ...................................................................................... 41 
6.1.1 
Screening/observation period (Day -42 to Day -1) ........................................................................ 46 
6.1.1.1 
Screening assessments (initiating at Day -42) .............................................................................. 46 
6.1.1.2 
Interim visits during screening/observation period ......................................................................... 48 
6.1.1.3 
Confirmatory review of patient eligibility......................................................................................... 48 
6.1.2 
Day 0 visit (first dose)..................................................................................................................... 48 
6.1.3 
Weeks 1-25 .................................................................................................................................... 49 
6.1.4 
End-of-treatment visit in Part A (Week 26) .................................................................................... 51 
6.1.5 
Part B extension phase .................................................................................................................. 51 
6.1.5.1 
Procedures to be performed every 2 weeks .................................................................................. 51 
6.1.5.2 
Procedure to be performed every 4 weeks .................................................................................... 51 
6.1.5.3 
Procedures to be performed every 3 months (unless noted otherwise) ........................................ 52 
6.1.6 
Infusion of the study drug at patient’s home .................................................................................. 52 
6.1.7 
Early termination/end of study/safety follow-up visit ...................................................................... 53 
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 ................................................................................................................................. 55 
6.3 
STUDY ASSESSMENTS ............................................................................................................... 56 
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6.3.1 
Demographic data .......................................................................................................................... 56 
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 ................................................................................................................... 57 
6.3.6 
Immunization review ...................................................................................................................... 57 
6.3.7 
Clinical laboratory evaluations ....................................................................................................... 57 
6.3.8 
Additional testing in case of hypersensitivity/allergic reaction ....................................................... 58 
6.4 
PHARMACOKINETIC PROCEDURES.......................................................................................... 58 
6.4.1 
Pharmacokinetic and ADA blood sample collection and processing ............................................. 58 
6.4.2 
Analytical methodology (PK and ADA) .......................................................................................... 58 
6.5 
PHARMACODYNAMIC PROCEDURES ....................................................................................... 58 
6.5.1 
Pharmacodynamic blood sample collection and processing ......................................................... 58 
6.5.2 
Analytical methodology (PD) .......................................................................................................... 59 
6.6 
SAFETY PROCEDURES ............................................................................................................... 59 
6.7 
ADVERSE EVENTS AND LABORATORY ABNORMALITIES ...................................................... 59 
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 ........................................................................... 61 
6.7.2 
Clinical adverse events .................................................................................................................. 62 
6.7.3 
Laboratory test abnormalities ......................................................................................................... 63 
6.7.4 
Serious adverse event reporting - procedures for Investigators .................................................... 63 
6.7.5 
Follow-up of adverse events .......................................................................................................... 63 
6.7.6 
Follow-up of abnormal laboratory results ....................................................................................... 64 
6.7.7 
Pregnancy ...................................................................................................................................... 64 
6.7.8 
Overdose ........................................................................................................................................ 64 
7 
DATA ANALYSES AND SAMPLE SIZE....................................................................................... 65 
7.1 
DESCRIPTION OF OBJECTIVES AND ENDPOINTS .................................................................. 65 
7.2 
DEMOGRAPHICS AND BASELINE DISEASE CHARACTERISTICS .......................................... 65 
7.3 
EFFICACY - PART A ..................................................................................................................... 65 
7.3.1 
Analysis populations ...................................................................................................................... 65 
7.3.2 
Methods of analysis ....................................................................................................................... 66 
7.4 
EFFICACY - PART B ..................................................................................................................... 66 
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7.4.1 
Analysis populations ...................................................................................................................... 66 
7.4.2 
Methods of analysis ....................................................................................................................... 67 
7.5 
PHARMACOKINETICS .................................................................................................................. 67 
7.5.1 
Analysis population ........................................................................................................................ 67 
7.5.2 
Methods of analysis ....................................................................................................................... 67 
7.6 
PHARMACODYNAMICS ............................................................................................................... 67 
7.6.1 
Analysis population ........................................................................................................................ 67 
7.6.2 
Methods of analysis ....................................................................................................................... 68 
7.7 
IMMUNOGENICITY ....................................................................................................................... 68 
7.7.1 
Analysis population ........................................................................................................................ 68 
7.7.2 
Methods of analysis ....................................................................................................................... 68 
7.8 
SAFETY ......................................................................................................................................... 68 
7.8.1 
Analysis population ........................................................................................................................ 68 
7.8.2 
Methods of analysis ....................................................................................................................... 68 
7.9 
INTERIM ANALYSES .................................................................................................................... 69 
7.10 
SAMPLE SIZE CONSIDERATIONS .............................................................................................. 69 
7.11 
DATA HANDLING AND RECORD KEEPING ............................................................................... 69 
7.12 
QUALITY CONTROL AND QUALITY ASSURANCE .................................................................... 69 
8 
ADMINISTRATIVE ASPECTS ...................................................................................................... 70 
8.1 
CHANGE IN PROTOCOL .............................................................................................................. 70 
8.2 
SITE INITIATION VISIT/INVESTIGATOR MEETING .................................................................... 70 
8.3 
DISCLOSURE ................................................................................................................................ 70 
8.4 
MONITORING ................................................................................................................................ 70 
8.5 
ETHICAL ASPECTS ...................................................................................................................... 71 
8.5.1 
Declaration of Helsinki/Good Clinical Practice ............................................................................... 71 
8.5.2 
Patient information and informed consent ..................................................................................... 71 
8.6 
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD AND 
REGULATORY AUTHORITIES ..................................................................................................... 72 
8.7 
RECORDS ..................................................................................................................................... 72 
9 
REFERENCES ............................................................................................................................... 73 
INVESTIGATOR AGREEMENT ................................................................................................................... 74 
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SPONSOR AGREEMENT............................................................................................................................. 75 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 76 
10.1 
APPENDIX A: CLINICAL LABORATORY EVALUATIONS ........................................................... 76 
10.2 
APPENDIX B: NCI-CTC VERSION 4.03 (CTCAE V4.03) ............................................................. 77 
10.3 
APPENDIX C: FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY 
(FACIT)-FATIGUE SCALE ............................................................................................................. 78 
10.4 
APPENDIX D: EQ-5D-5L ............................................................................................................... 79 
10.5 
APPENDIX E: 12-ITEM SHORT FORM SURVEY (SF-12) ........................................................... 80 
10.6 
APPENDIX F: PATIENT’S GLOBAL IMPRESSION OF CHANGE (PGIC) ................................... 83 
10.7 
APPENDIX G: HEALTHCARE RESOURCE UTILIZATION .......................................................... 84 
10.8 
APPENDIX H: PATIENT’S GLOBAL IMPRESSION OF [FATIGUE] SEVERITY .......................... 85 
10.9 
APPENDIX I: VACCINE SCHEDULE FOR PATIENTS IN JAPAN ONLY ..................................... 86 
10.10 
APPENDIX J: COUNTRY SPECIFIC REQUIREMENT - HOME INFUSIONS WITH 
BIVV009 ......................................................................................................................................... 86 
10.11 
APPENDIX K: HOME INFUSION PATIENT SATISFACTION SURVEY ....................................... 92 
10.12 
APPENDIX L: PROTOCOL AMENDMENT HISTORY .................................................................. 92 
 
LIST OF TABLES  
Table 1 - Transfusion criteria ......................................................................................................................... 30 
Table 2 - Responder definition ...................................................................................................................... 31 
Table 3 - Study schedule of events ............................................................................................................... 42 
Table 4 - Study schedule of events (Part B) for patients with home infusions .............................................. 87 
 
LIST OF APPENDICES  
10.1 
APPENDIX A: CLINICAL LABORATORY EVALUATIONS ........................................................... 76 
10.2 
APPENDIX B: NCI-CTC VERSION 4.03 (CTCAE V4.03) ............................................................. 77 
10.3 
APPENDIX C: FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY 
(FACIT)-FATIGUE SCALE ............................................................................................................................ 78 
10.4 
APPENDIX D: EQ-5D-5L ............................................................................................................... 79 
10.5 
APPENDIX E: 12-ITEM SHORT FORM SURVEY (SF-12) ........................................................... 80 
10.6 
APPENDIX F: PATIENT’S GLOBAL IMPRESSION OF CHANGE (PGIC) ................................... 83 
10.7 
APPENDIX G: HEALTHCARE RESOURCE UTILIZATION .......................................................... 84 
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10.8 
APPENDIX H: PATIENT’S GLOBAL IMPRESSION OF [FATIGUE] SEVERITY .......................... 85 
10.9 
APPENDIX I: VACCINE SCHEDULE FOR PATIENTS IN JAPAN ONLY ..................................... 86 
10.10 
APPENDIX J: COUNTRY SPECIFIC REQUIREMENT - HOME INFUSIONS WITH BIVV009 .... 86 
10.11 
APPENDIX K: HOME INFUSION PATIENT SATISFACTION SURVEY ....................................... 92 
10.12 
APPENDIX L: PROTOCOL AMENDMENT HISTORY .................................................................. 92 
 
 
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LIST OF ABBREVIATIONS  
 
ADA 
antidrug antibody 
ADL 
activities of daily living 
AE 
adverse event 
AMR 
antibody-mediated rejection 
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 
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  
LDH 
lactate dehydrogenase  
LPO 
last patient out 
MAA 
Market Authorization Application 
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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: 
Cardinal Study: A Phase 3, pivotal, open-label, multicenter study to assess the efficacy and 
safety of BIVV009 in patients with primary cold agglutinin disease who have a recent history 
of blood transfusion  
OVERVIEW OF STUDY 
DESIGN: 
This is an open-label, single-arm, multicenter study in patients with primary cold agglutinin 
disease (CAgD) who have a recent history of blood transfusion. Eligible patients will receive 
study drug and undergo safety and efficacy assessments for 6 months (26 weeks) during Part A.  
Following completion of the initial 6-month treatment period, patients will roll into the long-
term safety and durability of response extension phase (Part B) where they will continue to 
receive study drug. 
For the purpose of marketing authorization applications, an interim analysis of safety and 
efficacy data will be performed after all patients have completed the initial 6-month treatment 
period (Part A). The Part B open-label extension study will run for 2 years 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 ≥2 g/dL increase in hemoglobin (Hgb) levels or increases Hgb to 
≥12 g/dL and obviates the need for blood transfusion during treatment in patients 
with primary CAgD who have a recent history of 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 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 assess the effect of BIVV009 on specific complications of CAgD (acrocyanosis, 
Raynaud’s syndrome, hemoglobinuria, and thromboembolism) 
 
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 for the US, the Netherlands, 
Norway, France, Italy, Austria, Germany, and Spain specific amendments 
 
To evaluate the immunogenicity of BIVV009  
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METHODOLOGY/STUDY 
DESIGN: 
This open-label, single-arm study is designed to evaluate the efficacy, safety, and tolerability 
of BIVV009 in patients with the complement-mediated disorder primary CAgD who have a 
recent history of transfusion.  
During the 6-week Screening/Observation Period, prospective patients will have a detailed 
medical history documented (including transfusion history of ≥6 months), physical 
evaluations for screening, and blood samples collected for characterization of CAgD 
biomarkers, including Hgb levels 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 20 primary CAgD patients who have a recent history of 
transfusion, defined as at least 1 transfusion during the last 6 months prior to enrollment. 
Eligible patients will receive an intravenous (IV) infusion of BIVV009 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 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 he or she did not receive a blood 
transfusion from Week 5 through Week 26 (EOT) and did not receive treatment for CAgD 
beyond what is permitted per protocol. Additionally, the patient’s Hgb level must meet 
either of the following criteria: 
 
Hgb level is ≥12 g/dL at treatment assessment endpoint (defined as mean 
value from Weeks 23, 25, and 26), or 
 
Hgb increased ≥2 g/dL from baseline (defined as the last Hgb value before 
administration of the first dose of study drug) at treatment assessment endpoint 
Note: Any patient withdrawing from the study after Week 5 and prior to the Week 23 visit 
will be considered a non-responder. 
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 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. 
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Part B 
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 2 years 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 during Part B will not be withdrawn 
from the study. 
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 pharmacodynamic (PD) and 
pharmacokinetic (PK) samples, ADA samples during the 1st year of treatment in Part B, then 
every 6 months and for additional safety and efficacy measures. PK, PD and antidrug 
antibodies (ADA) 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 24 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 20 male and/or female patients ≥18 years of age with a confirmed diagnosis 
of primary CAgD who have a recent history of blood transfusion will be enrolled. 
NUMBER OF STUDY 
SITES: 
Approximately 55 sites worldwide will be targeted for participation to identify approximately 
20 eligible CAgD patients. 
MAIN CRITERIA FOR 
INCLUSION: 
All patients must meet all the following inclusion criteria to be enrolled: 
1. 
Adult males and females ≥18 years of age at Screening. 
2. 
Body weight of ≥39 kg at Screening. 
3. 
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℃ 
e) 
IgG DAT ≤1+, and 
f) 
No overt malignant disease  
4. 
History of at least one documented blood transfusion within 6 months of 
enrollment. 
5. 
Hemoglobin level ≤10.0 g/dL. 
6. 
Bilirubin level above the normal reference range, including patients with Gilbert’s 
Syndrome. 
7. 
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. 
8. 
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 
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b) 
Acrocyanosis 
c) 
Raynaud’s syndrome 
d) 
Hemoglobinuria 
e) 
Disabling circulatory symptoms, and/or 
f) 
Major adverse vascular event (including thrombosis). 
9. 
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. 
10. 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. 
11. Adequate IV access. 
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. 
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. 
14. Able to comprehend and give informed consent. 
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: 
1. 
Cold agglutinin syndrome secondary to infection, rheumatologic disease, or active 
hematologic malignancy.  
2. 
Clinically relevant infection of any kind within the month preceding enrollment 
(eg, active hepatitis C, pneumonia). 
3. 
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). 
4. 
Positive hepatitis panel (including hepatitis B surface antigen and/or hepatitis C 
virus antibody) prior to or at Screening. 
5. 
Positive human immunodeficiency virus (HIV) antibody at Screening. 
6. 
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. 
7. 
Concurrent treatment with corticosteroids other than a stable daily dose equivalent 
to ≤10 mg/day prednisone for previous 3 months. 
8. 
Erythropoietin deficiency. Concurrent treatment with erythropoietin is permitted if 
the patient has been on a stable dose for the previous 3 months. 
9. 
Concurrent usage of iron supplementation unless the patient has been on a stable 
dose for at least 4 weeks.  
10. 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. 
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11. 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. 
12. Females who are pregnant, lactating, or, if having reproductive potential, are 
considered potentially unreliable with respect to contraceptive practice. 
13. 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 during Part B 
administration of the study drug may be provided in the form of home infusions 
(Section 10.10, Appendix J).  
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. 
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: 
Bi-weekly dosing starting at Week 27 
and continuing for 2 years 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 bilirubin (excluding patients with Gilbert’s 
Syndrome) at the treatment assessment endpoint (mean of values at 
Week 23, 25, and 26) 
 
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 endpoint 
 
Mean change from baseline in lactate dehydrogenase (LDH) at the treatment 
assessment endpoint 
 
Number of transfusions and number of units after the first 5 weeks of study drug 
administration  
 
Mean change from baseline in Hgb at the treatment assessment endpoint 
Exploratory efficacy endpoints: 
 
Time to first transfusion after the first 5 weeks of study drug administration  
 
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 
 
Incidence of solicited symptomatic anemia at EOT 
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 
Proportion of patients with Hgb level of ≥12 g/dL at the 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 obtain Hgb level of ≥12 g/dL  
 
Proportion of patients normalizing haptoglobin at the treatment assessment 
endpoint 
 
Proportion of patients normalizing bilirubin at the treatment assessment endpoint 
 
Proportion of patients normalizing LDH at the 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 EOT 
 
Total healthcare resource utilization at EOT 
Part B 
The following parameters of disease activity will be assessed:  
 
Hemoglobin 
 
Bilirubin (total) 
 
QOL assessments (FACIT-Fatigue, EQ-5D-5L, SF-12, PGIC, and PGIS)  
 
LDH 
 
Transfusion requirements 
 
Haptoglobin 
 
Total healthcare resource utilization at EOT 
 
Satisfaction with home infusion  
SAFETY OUTCOME 
MEASURES 
Safety assessments for this study include adverse events (AEs), serious AEs, 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 
PHARMACOKINETIC 
OUTCOME MEASURES 
Pharmacokinetic endpoints will include: 
 
Plasma concentrations of BIVV009 
 
PK parameters. Appropriate exposure parameters (Cmax, AUC) will be derived 
using a population approach.  
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 patient withdraws early.  
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PK samples will be routinely collected at predose and 1 hour (±15 minutes) postdose. 
Samples will be collected at 3-month intervals during the 1st year of treatment in Part B and 
then at 6-month intervals for the remainder of the time on study. Samples will also be 
collected if a patient experiences a hematologic breakthrough event, or a patient withdraws 
from study. 
PHARMACODYNAMIC 
OUTCOME MEASURES 
PD Primary Outcome Measure: 
 
Wieslab-CP 
Exploratory Complement System Measures: 
 
CH50 
 
Total C4 
 
C1q 
 
C1s 
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 patient withdraws early. 
PD samples will be routinely collected at predose and 1 hour (±15 minutes) postdose. 
Samples will be collected at 3-month intervals during the 1st year of treatment in Part B and 
then at 6-month intervals for the remainder of the time on study. Samples will also be 
collected if a patient experiences a hematologic breakthrough event, or a patient withdraws 
from study. 
IMMUNOGENICITY 
OUTCOME MEASURES: 
Immunogenicity Outcome Measures will include pre-existing ADA and treatment-emergent 
ADA. During Part A, samples were collected at predose on Day 0 and at ET if a patient 
withdraws early or if patient experienced a hematological breakthrough event. For 
immunogenicity assessment in Part A, left over PD samples may be used in patients who 
consented to future use of samples. During the 1st year of treatment in Part B, ADA samples 
will be collected at predose at 3-month intervals, and then at 6-month interval 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. 
SAMPLE SIZE: 
If the true responder rate is estimated to be 66% and a minimum of 30% is required for 
success, then with 20 patients there is 90% probability that the lower limit of the 
95% confidence interval (CI) will be at least 30%. The minimal observed rate for a 
successful efficacy claim is 11/20 = 55%. 
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:  
For Part A, the analysis of the primary endpoint, the proportion of responders will be 
calculated together with a 95% exact Clopper-Pearson CI. The main analysis will be 
conducted on the Full Analysis Set (FAS): FAS population, consisting of all patients who 
received at least one dose of study drug. 
Under the assumption that a response rate of less than or equal to 30% is not clinically 
relevant, the success criteria for the primary endpoint will be that the 95% lower bound CI 
for response rate excludes 30% using the exact Clopper-Pearson method. That is, this 
criterion is equivalent to demonstrating at the 2-sided 0.05 level of significance that the true 
response rate is >30%. 
All secondary endpoints will be analyzed using descriptive statistics, frequency, percentage, 
and CIs as appropriate. Change from baseline for continuous parameters will be analyzed 
using a one-sample t-test.  
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For Part B, the analyses will be performed for all patients who received at least 1 dose of 
study drug during the extension period. All efficacy and safety endpoints will be summarized 
by descriptive statistics. 
Further details regarding other endpoints and proposed analyses will be described in full in 
the Statistical Analysis Plans for Part A and Part B. 
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2 
INTRODUCTION1  
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. 
                                                 
1 Information supplied by the Sponsor. 
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CAgD is an autoimmune hemolytic anemia caused by IgM-induced CP activation, which is 
typically triggered by exposure to cold environmental temperatures or viral infections (Berentsen, 
Beiske et al. 2007, Petz 2008, Berentsen 2011, Swiecicki, Hegerova et al. 2013, Arthold, Skrabs 
et al. 2014, Berentsen 2014). 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). A Phase 1b clinical trial of BIVV009 in patients with 
CAgD showed that it can rapidly induce complete remission of anemia (Jäger, Gilbert et al. 2016). 
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 (Section 10.10 Appendix J). 
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 BIVV009-03. Hence the NOAEL in cynomolgus 
monkeys is more than twice the intended fixed doses of 6.5 grams or 7.5 grams, based on an adult 
weighing ~75 kg. 
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/1b 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. 
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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 
4 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. 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 
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 pharmacokinetic 
(PK)/pharmacodynamic (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, was used to propose dose regimens for the current protocol. 
2.2.3 Pharmacokinetic experience and dose justification  
The 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 BIVV009-03, 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 
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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 
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. 
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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 41 (Day 287) and without evidence of 
intolerance of the study drug as determined by the Investigator. No new risks related to home 
infusions are anticipated. Like with office visits, medications such as epinephrine and 
diphenhydramine, and additional emergency equipment will be available in case an allergic 
reaction or anaphylaxis occurs during home infusion.  Professional healthcare caregiver will be 
qualified to detect and treat allergic reactions and anaphylaxis. The alternating schedule of home 
infusion visits and office visits every 4 weeks each may be found convenient by patients as less 
travels to the study site will be necessary 
The overall risk/benefit balance for participants in Study BIVV009-03 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 
≥2 g/dL increase in hemoglobin (Hgb) levels or increases Hgb to ≥12 g/dL and obviates the need 
for blood transfusion during treatment in patients with primary CAgD who have a recent history 
of blood transfusion. 
3.2 
SECONDARY OBJECTIVES (PART A)  
The 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 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 assess the effect of BIVV009 on specific complications of CAgD (acrocyanosis, 
Raynaud’s syndrome, hemoglobinuria, and thromboembolism) 
 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 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 CAgD. 
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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 (Section 10.10 Appendix J). 
 To evaluate the immunogenicity of BIVV009. 
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4 
INVESTIGATIONAL PLAN  
4.1 
STUDY DESIGN  
This open-label, single-arm study is designed to evaluate the efficacy, safety, and tolerability of 
BIVV009 in patients with the complement-mediated disorder, primary CAgD, who have a recent 
history of blood transfusion.  
During the 6-week Screening/Observation Period, prospective patients will have a detailed 
medical history documented (including transfusion history of ≥6 months), physical evaluations for 
screening, 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 20 primary CAgD patients who have a recent history of 
transfusion, defined as at least 1 transfusion during the last 6 months prior to enrollment. Eligible 
patients will receive an IV infusion of BIVV009 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 on 
Day 182 (Week 26). 
Patients who meet the transfusion criteria in Table 1 during the 6-month 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 he or she did not receive a blood 
transfusion from Week 5 through Week 26 (EOT) and did not receive treatment for CAgD 
beyond what is permitted per protocol. Additionally, the patient’s Hgb level must meet either of 
the following criteria:  
 Hgb level is ≥12 g/dL at the treatment assessment endpoint (defined as mean value from 
Weeks 23, 25, and 26), or 
 Hgb increased ≥2 g/dL from baseline (defined as the last Hgb value before 
administration of the first dose of study drug) at treatment assessment endpoint 
Note: Any patient withdrawing from the study after Week 5 and prior to the Week 23 visit will 
be considered a non-responder. 
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 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 2 years 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 during Part B will not be withdrawn from the study. 
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 during the 1st year 
of treatment in Part B, then every 6 months and for additional safety and efficacy measures. 
A subset of patients from countries pre-selected to participate in home infusion, and who were 
determined 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 only in patients willing to be 
administered study drug in home and who satisfy the criteria mentioned in the Appendix J, 
Section 10.10. 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 10.10 Appendix J). 
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A safety follow-up visit for collection of AE data, PK, PD, and antidrug antibodies (ADA) 
samples will be performed 9 weeks after administration of the last dose of study drug in patients 
who discontinue early. Samples for PK, PD, and ADA will also be collected from patients who 
experience a hematological breakthrough event. The study will be complete 24 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, bullous pemphigoid, warm autoimmune hemolytic anemia, and AMR. 
Under the current protocol, enrolled patients will receive fixed doses of BIVV009 via IV infusion 
of either 6.5 grams (if <75 kg) or 7.5 grams (if ≥75 kg), based on their baseline body weight. 
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 
(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, and 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 bilirubin (excluding patients with Gilbert’s Syndrome) at 
the treatment assessment endpoint (defined as the mean value of Weeks 23, 25, and 26) 
 Mean change from baseline in QOL, as assessed by the change in Functional Assessment 
of Chronic Illness Therapy (FACIT)-Fatigue scale (Section 10.3, Appendix C) scores at 
the treatment assessment endpoint 
 Mean change from baseline in lactate dehydrogenase (LDH) at the treatment assessment 
endpoint 
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 Number of transfusions and number of units after the first 5 weeks of study drug 
administration  
 Mean change from baseline in Hgb at the treatment assessment endpoint 
4.3.3 Exploratory efficacy endpoints (Part A)  
 Time to first transfusion after the first 5 weeks of study drug administration  
 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 
 Incidence of solicited symptomatic anemia at EOT 
 Proportion of patients with Hgb level of ≥12 g/dL at the 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 obtain Hgb level of ≥12 g/dL 
 Proportion of patients normalizing haptoglobin at the treatment assessment endpoint 
 Proportion of patients normalizing bilirubin at the treatment assessment endpoint 
 Proportion of patients normalizing LDH at the 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 EOT 
 Total healthcare resource utilization at EOT 
4.3.4 Efficacy endpoints (Part B)  
 Hemoglobin 
 Bilirubin (total) 
 QOL assessments (FACIT-Fatigue, EQ-5D-5L, SF-12, PGIS, and PGIC) 
 LDH 
 Transfusion requirements 
 Haptoglobin 
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 Total healthcare resource utilization at EOT 
 Satisfaction with home infusion 
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) 
 Incidence of thromboembolic events 
 For patients with home infusions, safety assessments will include AEs with onset within 
24 hours of the infusion at home 
4.3.6  Pharmacokinetic endpoints   
 Plasma concentrations of BIVV009 
 PK parameters. Appropriate exposure parameters (Cmax, AUC) will be derived using a 
population approach 
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.  
PK samples will be routinely collected at predose and 1 hour (±15 minutes) postdose. Samples 
will be collected at 3-month intervals during the 1st year of treatment in Part B and then at 
6-month intervals for the remainder of the time on study. Samples will also be collected if a 
patient experiences a hematologic breakthrough event or a patient withdraws from study. 
4.3.7 Pharmacodynamic endpoints  
PD Primary Outcome Measure: 
 Wieslab-CP 
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Exploratory Complement System Measures: 
 CH50 
 Total C4 
 C1q 
 C1s 
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. 
PD samples will be routinely collected at predose and 1 hour (±15 minutes) postdose. Samples 
will be collected at 3-month intervals during the 1st year of treatment in Part B and then at 
6-month intervals for the remainder of the time on study. Samples will also be collected if a 
patient experiences a hematologic breakthrough event or a patient withdraws from study. 
4.3.8  Immunogenicity endpoints   
Immunogenicity endpoints will include the evaluation of pre-existing ADA and treatment-
emergent ADA. During Part A, ADA samples were collected at predose on Day 0 and at ET if a 
patient withdrew early or if a patient experienced a hematological breakthrough event. During 
Part B, ADA samples will be collected at predose at 3-month intervals during the 1st year of 
treatment in Part B and then at 6-month intervals 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 who consented to the use of their blood samples for future 
research, ADA may be tested using available predose PD back-up samples collected at the 
following time-points Day 7, 35, 77, 133, 175 and Day 182 in Part A and then every 3 months in 
Part B, prior to implementation of protocol version 06.  
4.4 
 DURATION OF THE STUDY   
The planned total study duration per patient is approximately 2.5 to 3.5 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 study 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: bi-weekly dosing starting at 
Week 27 visit. For individual patients, dosing in Part B may last from 2 to 3 years, 
depending on when the patient enters Part B. Part B will run for 2 years following 
completion of LPO in Part A. 
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 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 24 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 6.1.7 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 20 adult patients with primary CAgD who have a recent 
history of transfusion, defined as at least one transfusion during the last 6 months prior to 
enrollment. 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: 
1. Adult males and female patients ≥18 years of age at Screening. 
2. Body weight of ≥39 kg at Screening. 
3. 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  
4. History of at least one documented blood transfusion within 6 months of enrollment. 
5. Hemoglobin level ≤10.0 g/dL. 
6. Bilirubin level above the normal reference range, including patients with Gilbert’s 
Syndrome 
7. 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. 
8. 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 
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c) Raynaud’s syndrome 
d) Hemoglobinuria 
e) Disabling circulatory symptoms, and/or 
f) Major adverse vascular event (including thrombosis)  
9. 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. 
10. 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. 
11. Adequate IV access. 
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. 
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. 
14. Able to comprehend and give informed consent. 
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: 
1. Cold agglutinin syndrome secondary to infection, rheumatologic disease, or active 
hematologic malignancy. 
2. Clinically relevant infection of any kind within the month preceding enrollment (eg, active 
hepatitis C, pneumonia). 
3. 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). 
4. Positive hepatitis panel (including hepatitis B surface antigen and/or hepatitis C virus 
antibody) prior to or at Screening. 
5. Positive human immunodeficiency virus (HIV) antibody at Screening. 
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6. 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. 
7. Concurrent treatment with corticosteroids other than a stable daily dose equivalent to 
≤10 mg/day prednisone for previous 3 months. 
8. Erythropoietin deficiency. Concurrent treatment with erythropoietin is permitted if the 
patient has been on a stable dose for the previous 3 months. 
9. Concurrent usage of iron supplementation unless the patient has been on a stable dose for 
at least 4 weeks. 
10. 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. 
11. 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. 
12. Females who are pregnant, lactating, or, if having reproductive potential, are considered 
potentially unreliable with respect to contraceptive practice. 
13. History of hypersensitivity to BIVV009 or any of its components. 
For country specific requirement - home infusion in/exclusion criteria see Section 10.10, 
Appendix J. 
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:  
 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. 
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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 study 
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 
Patients undergoing home infusions with BIVV009 will return to bi-weekly dosing at the study 
site if they develop 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 the AE, which led 
to the interruption of home infusions according to the Investigator’s judgment is considered to be 
unrelated to BIVV009 and once resolved or stabilized (Section 10.10, Appendix J). 
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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 Section 10.1, Appendix A.
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Table 3 - Study schedule of events  
Study visit (Week/Day)  
Screening/ 
observation 
perioda 
Baseline 
Part A 
Part B  
Extension 
phase 
ET/EOS/Safety 
follow-upb 
Weeks 1-25 
Week 26 (EOT) 
Days -42, -28 
and -14 
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 Section 10.9, Appendix I for the 
vaccination schedule for Japan. 
Revaccination with booster doses should be given according to regional guidelines for patients with persistent complement deficiency 
and in accordance with respective labels. 
Bone marrow biopsy report reviewc 
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 
 
Vital signs (BP, PR, RR, body temperature)g 
X 
X 
X 
X 
Xl 
X 
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Study visit (Week/Day)  
Screening/ 
observation 
perioda 
Baseline 
Part A 
Part B  
Extension 
phase 
ET/EOS/Safety 
follow-upb 
Weeks 1-25 
Week 26 (EOT) 
Days -42, -28 
and -14 
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 
12-lead electrocardiogram (predose and 1 hour 
after infusion on dosing days) 
X 
X 
X (Day 91 only) 
 
Xo 
 
Virology/serology panelh 
X 
 
 
 
 
 
Gilbert’s Syndrome test (UGT1A1 gene) 
X 
 
 
 
 
 
SLE panelh 
X 
 
 
X 
Xs 
X 
Iron panel and erythropoietinh 
X 
 
 
 
 
 
Hematology panelh 
X  
X 
X 
X 
Xt 
X 
Coagulation panelh 
X 
X 
 
X 
 
X 
Clinical chemistry panelh 
X  
X 
X 
X 
Xt 
X 
Urinalysish 
X 
X 
 
X 
Xl 
X 
FACIT-Fatigueq 
 
X 
X  
X 
Xl  
X 
PGISq 
 
X 
X (Days 35, 77, and 119 only) 
X 
Xl 
X 
PGICq 
 
X 
X (Days 35, 77, and 119 only) 
X 
Xl 
X 
SF-12q 
 
X 
X (Days 35, 77, and 119 only) 
X 
Xl 
X 
EQ-5D-5Lq 
 
X 
X (Days 49, 91, and 133 only)  
X 
Xl 
X 
Solicited symptomatic anemia 
X (Day -42 only) 
X 
X 
X 
X 
X 
Study drug administrationi 
 
X 
X 
 
X 
 
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Study visit (Week/Day)  
Screening/ 
observation 
perioda 
Baseline 
Part A 
Part B  
Extension 
phase 
ET/EOS/Safety 
follow-upb 
Weeks 1-25 
Week 26 (EOT) 
Days -42, -28 
and -14 
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 
ADAs against BIVV009 
 
X 
 
 
Xr 
X 
PK samplesj 
 
X 
X 
X 
Xu 
X 
PD samplesh, j 
Xm  
X 
X 
X 
Xu 
X 
Disease-related biomarkersh 
X 
X 
Xn (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 
Xp 
X 
Adverse eventsk 
X 
X 
X 
X 
X 
X 
ADA = antidrug antibodies; BP = blood pressure; EOS = End of Study; EOT = End of Treatment; EQ-5D-5L = five level EuroQol five dimensions questionnaire; SF-12 = 12-Item Short Form Survey; 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; SLE = systemic lupus erythematosus. 
a The 6-week Screening/Observation Period may be extended by 1 week for patients requiring a blood transfusion prior to study drug administration. 
b Patients should return to the 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 course of the study. A second sample will be collected during the study period if a patient presents with symptoms concerning for an infection with 
Streptococcus pneumonaie, Neisseria meningitidis or Haemophilus influenzae and analyzed if the infection is confirmed with one of the aforementioned organisms.  
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 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. 
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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 (Section 10.1, Appendix A). 
i 
BIVV009 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 Section 10.10 Appendix J (US, the Netherlands, Norway, France, Italy, Austria, Germany, Spain, and specific 
amendments. 
j 
During Part A, PK and PD samples will be collected at predose and 1 hour (±15 minutes) 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 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 be 
collected routinely at 3-month intervals during the 1st year of treatment in Part B, and then at 6-month intervals. 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. 
m Refer to the Laboratory Manual for details of sample collection during Screening. 
n Samples will be collected for a subset of the disease-related biomarkers at Day 91 only. Refer to the Laboratory Manual for details. 
o During Part B, a 12-lead ECG will be conducting pre- and postdose at 3 months (Day 273). 
p During Part B, the healthcare resource utilization data will be recorded every 4 weeks. 
q To be performed in the following order: FACIT-Fatigue first, PGIS second, PGIC third, SF-12 fourth, and EQ-5D-5L fifth. 
r 
During Part B, ADA samples will be collected at predose at 3-month intervals during the 1st year of treatment in Part B and then at 6-month intervals 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. 
s SLE panel will be performed every 6 months in Part-B of the study. 
t 
In Part B, hematology and clinical chemistry panels to be performed every 2 weeks after Week 25 and up to Week 79. For the remainder of Part B after Week 79, hematology and clinical chemistry panels to be 
performed every 4 weeks. 
u To be performed at 3-month intervals during the 1st year of treatment in Part B, and then at 6-month intervals. 
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6.1.1 Screening/observation period (Day -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. 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 data 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 
 12-lead ECG  
 Prior bone marrow biopsy report review, prior tissue assessment, or new bone marrow 
biopsy (as applicable) 
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 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 
The Screening/Observation Period may be extended by 1 week for patients requiring a blood 
transfusion during screening to ensure that first study drug administration occurs at least 
1 week following the transfusion. 
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 the study 
procedural manual. 
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. Revaccination with booster doses should be given according to 
regional guidelines for patients with persistent complement deficiency and in accordance 
with respective labels. 
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 the encapsulated bacterial 
pathogens Streptococcus pneumoniae, Neisseria meningitidis, or Haemophilus influenzae 
during the study period will have a blood sample collected to test vaccine related titers if the 
infection is confirmed with one of the aforementioned organisms. 
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A separate vaccination schedule for Japan is provided in Section 10.9, Appendix I. 
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, Section 10.1, 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. Details on the eligibility data review forms and the 
adjudication process may be found in the study procedural manual.  
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 for confirmation of continued eligibility  
 Serum or urine pregnancy test (if applicable) 
 Vaccine titers 
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 Body weight 
 Physical examination (brief) 
 Vital signs 
 12-lead ECG  
 Hematology panel 
 Coagulation panel 
 Clinical chemistry panel  
 Urinalysis  
 Solicited symptomatic anemia assessment 
 QOL assessments  
- 
FACIT-Fatigue (see Section 10.3, Appendix C)  
- 
EQ-5D-5L (see Section 10.4, Appendix D) 
- 
SF-12 (see Section 10.5, Appendix E) 
- 
PGIC (see Section 10.6, Appendix F) 
- 
PGIS (see Section 10.8, Appendix H) 
 ADAs against BIVV009 
 PK and PD sampling 
 Disease related biomarkers  
 Record healthcare resource utilization data (see Section 10.7, Appendix G) since 
previous assessment 
 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. 
6.1.3 Weeks 1-25  
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, if applicable, on Days 21, 49, 77, 105, 133, and 161 
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 Physical examination (brief) 
 Vital signs 
 12-lead ECG (Day 91 only) 
 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 
 PK and PD sampling 
 ADA: In patients who consented to the use of their blood samples for future research, 
PD back-up samples collected at the following time points Day 7, 35, 77, 133 and 
175, may be used to assay ADA. 
 Disease-related biomarkers (subset at Day 91 only); refer to 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. 
Vaccinations should be administered according to Section 6.1.1.1, if applicable, or 
Section 10.9, 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. 
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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 assessments (FACIT-Fatigue, EQ-5D-5L, SF-12, PGIS, and PGIC) 
 PK and PD sampling 
 ADA: In patients who consented to the use of their blood samples for future research, 
PD back-up samples collected at this visit, may be used to assay ADA. 
 Disease-related biomarkers 
 Record healthcare resource utilization data since previous assessment 
 Record concomitant medications/procedures including transfusions  
 Adverse event monitoring 
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: 
 Hematology panel (until Week 79) 
 Clinical chemistry panel (until Week 79) 
 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 
 Hematology panel (beginning at Week 79) 
 Clinical chemistry panel (beginning at Week 79) 
 Record healthcare resource utilization data since previous assessment 
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6.1.5.3 Procedures to be performed every 3 months (unless noted otherwise)  
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 
 12-lead ECG (once at 3 months [Day 273], and at end of treatment visit) 
 Urinalysis  
 QOL assessments:  
- 
FACIT-Fatigue 
- 
EQ-5D-5L 
- 
SF-12 
- 
PGIS 
- 
PGIC  
 SLE panel (every 6 months) 
 PK, PD and ADA sampling during the 1st year of treatment in Part B then every 6 
months 
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 
 12-lead ECG (once at 3 months [Day 273]) at 1 hour (±15 minutes) postdose, and at 
end of treatment visit 
 PK and PD sampling (every 3 months during the 1st year of treatment in Part B then 
every 6 months) at 1 hour (±15 minutes) postdose. 
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). 
6.1.6 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, and in 
whom previous on-site infusions were uncomplicated (for the US, the Netherlands, Norway, 
France, Italy, Austria, Germany, and Spain, specific amendments) (see Section 10.10, 
Appendix J). 
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6.1.7 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) 
 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 vials (18 mg/mL) or 25 mL vials (50 mg/mL). The Sponsor (or designee) will provide 
the Investigators (or designees) with adequate quantities of the study drug. 
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. 
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BIVV009 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) (Section 10.10, Appendix J), 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. Details on 
patient number assignments will be available in the study procedural manual. 
6.2.3 Randomization  
Not applicable.  
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, an 
appropriate number of 10 mL drug product vials (each containing 180 mg of BIVV009) or 
25 mL drug product 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. Details are provided in the Pharmacy Manual. 
BIVV009 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 and time of dosing and if 
the administration is being performed at the patient’s home (Section 10.10, Appendix J) will 
be recorded in the source documents and 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 infusion may be slowed or stopped at the 
discretion of the Investigator or the professional healthcare caregiver in case of home 
infusions (see Section 10.10, Appendix J). 
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 (see Section 10.10, Appendix J). Like with office visits, medications such as 
epinephrine and diphenhydramine, and additional emergency equipment will be available in 
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case an allergic reaction or anaphylaxis occurs during home infusion. Site personnel, or 
professional healthcare caregiver in case of home infusions (see Section 10.10, Appendix J), 
must be qualified to detect and treat allergic reactions and anaphylaxis. 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 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, and in 
case of home infusion, the investigator should be notified immediately (see Section 10.10, 
Appendix J). 
6.2.5 Blinding  
Not applicable; this is an open-label study. 
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. 
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 vitamin 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. 
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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, 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 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 in Section 6.1 for an overview of the study procedures and schedule of 
events. Data will be collected via an eCRF for each enrolled 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. 
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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. 
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. 
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/or Streptococcus pneumoniae within 5 years of enrollment, these will be 
administered following informed consent, as applicable, per Table 3 and Section 6.1.1.1 
(screening procedures) or Section 10.9, Appendix I for Japan.  
6.3.7 Clinical laboratory evaluations  
Clinical laboratory evaluations (including hematology panel, clinical chemistry panel, iron 
panel, erythropoietin, coagulation safety panel, SLE panel, virology/serology panel, disease 
related biomarkers and urinalysis) as outlined in Section 10.1, 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.  
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Local laboratory values may be utilized for eligibility evaluation and medical management of 
the patient, including assessing the Hgb criteria necessitating blood transfusions. For efficacy 
evaluations, results from the central laboratory (when collected and available) will be 
recorded in the eCRF and utilized for analyses. 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 (Simons 2010), 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. 
 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 and ADA 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 (PK and ADA)  
Plasma concentrations of BIVV009 and ADA titer 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 blood sample collection and processing  
Blood samples for 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 analysis will be collected at the time points specified in Table 3. Complement 
assays will also be performed on samples, including: 
 Total complement (CH50)  
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 Total C4 
 C1q  
 C1s 
If an indwelling catheter is used, saline flushes will be used. 
6.5.2 Analytical methodology (PD)  
PD 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. 
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 
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. 
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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: 
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.  
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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 
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. 
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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 
 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 Section 10.2, 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) 
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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 
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 regulatory requirements and procedures. 
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, returned to baseline status, the condition becomes chronic in nature, stabilizes (in 
the case of persistent impairment), or the patient dies. Within 24 hours of receipt of any 
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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.  
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 the 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, results from the central laboratory will be 
used. Local laboratory values will be utilized for medical management of the patient, 
including assessing the Hgb 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 (FAS): The FAS Population is defined as all patients who received at least 
1 dose of study drug.  
Per-Protocol (PP) Population: The PP Population is defined as a subset of FAS Population 
who do not have any important protocol deviations impacting their efficacy assessments. 
The FAS analyses will be the primary analyses and the PP analyses will be considered as 
supportive. 
The patients in the FAS population that are excluded from the PP Population will be listed, 
together with the reason for exclusion from the PP Population. 
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7.3.2 Methods of analysis  
Each patient in the FAS Population will be classified as a responder or non-responder per the 
response criteria, and the proportion of responders will be calculated together with a 
95% exact Clopper-Pearson 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. 
Under the assumption that a response rate of less than or equal to 30% is not clinically 
relevant, the success criteria for the primary endpoint will be that the 95% lower bound CI for 
response rate excludes 30% using the exact Clopper-Pearson method. That is, this criterion is 
equivalent to demonstrating at the 2-sided 0.05 level of significance that the true response 
rate is >30%. 
The hypotheses to be tested are: 
H0: response rate ≤30% 
Ha: response rate >30% 
Because this is a one-sided test, the level of statistical significance (Type I error) will be 
controlled at the one-sided 0.025 level, which is equivalent to a two-sided 0.05 level test and 
corresponds to a two-sided 95% CI. Sensitivity analyses will be carried out to evaluate the 
impact by the missing data, if appropriate. Details will be specified in SAP.  
All secondary endpoints will be analyzed using descriptive statistics, frequency, percentage, 
and 95% CIs as appropriate. Change from baseline for continuous parameters will be 
analyzed using a one-sample t-test. All hypothesis tests will be performed at a two-sided 
0.05 significance level. 
As a secondary 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 populations. 
Other efficacy assessments will be summarized by overall population using descriptive 
statistics, proportions, and graphically where applicable.  
7.4 
EFFICACY - PART B  
7.4.1 Analysis populations  
Full Analysis Set (FAS): FAS 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 FAS Population who do 
not have any important protocol deviations impacting their efficacy assessments.  
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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. 
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. 
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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. 
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. 
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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 20 patients with primary CAgD who have a recent history of transfusion will 
be enrolled.  
If the true responder rate is estimated to be 66% and a minimum of 30% is required for 
success, then with 20 patients, there is 90% probability that the lower limit of the 95% CI will 
be at least 30%. The minimal observed rate for a successful efficacy claim is 11/20 = 55%.  
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 
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 Committee 
(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 Monitor will monitor the study conduct, proper eCRF and source documentation 
completion and retention, and accurate study drug accountability. To this end, the Monitor 
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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. 
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. 
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. 
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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 EC/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 informed consent. 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, 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. 
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 
REFERENCES  
Arthold, C., C. Skrabs, G. Mitterbauer-Hohendanner, R. Thalhammer, I. Simonitsch-Klupp, 
S. Panzer, P. Valent, K. Lechner, U. Jager and C. Sillaber (2014). "Cold antibody 
autoimmune hemolytic anemia and lymphoproliferative disorders: a retrospective study of 20 
patients including clinical, hematological, and molecular findings." Wien Klin Wochenschr 
126(11-12): 376-382. 
Berentsen, S. (2011). "How I manage cold agglutinin disease." Br J Haematol 153(3): 309-
317. 
Berentsen, S. (2014). "Complement, cold agglutinins, and therapy." Blood 123(26): 4010-
4012. 
Berentsen, S., K. Beiske and G. E. Tjonnfjord (2007). "Primary chronic cold agglutinin 
disease: an update on pathogenesis, clinical features and therapy." Hematology 12(5): 361-
370. 
Jäger, U., J. C. Gilbert, S. Panicker, G. C. Parry, M. Fillitz, T. Schenk, C. Sillaber, J. Bartko 
and B. Jilma (2016). "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, Abstract LB2237, 341. 
Petz, L. D. (2008). "Cold antibody autoimmune hemolytic anemias." Blood Rev 22(1): 1-15. 
Simons, F. E. (2010). "Anaphylaxis." J Allergy Clin Immunol 125(2 Suppl 2): S161-181. 
Swiecicki, P. L., L. T. Hegerova and M. A. Gertz (2013). "Cold agglutinin disease." Blood 
122(7): 1114-1121. 
 
 
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INVESTIGATOR AGREEMENT  
 
 
Study Drug: BIVV009 
Protocol: BIVV009-03 
 
A PHASE 3, PIVOTAL, OPEN-LABEL, MULTICENTER STUDY TO ASSESS THE 
EFFICACY AND SAFETY OF BIVV009 IN PATIENTS WITH 
PRIMARY COLD AGGLUTININ DISEASE WHO HAVE A RECENT  
HISTORY OF BLOOD TRANSFUSION 
 
 
Version 06 
19 December 2019 
 
 
 
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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SPONSOR AGREEMENT 
Study Drug: BIVV009 
Protocol: BIVV009-03 
A PHASE 3, PIVOTAL, OPEN-LABEL, MULTICENTER STUDY TO ASSESS THE 
EFFICACY AND SAFETY OF BIVV009 IN PATIENTS WITH 
PRIMARY COLD AGGLUTININ DISEASE WHO HAVE A RECENT 
HISTORY OF BLOOD TRANSFUSION 
Version 06 
19 December 2019 
I have read the foregoing protocol and agree to conduct the study as described herein. 
Date 
Bioverativ USA Inc. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
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 
IgG subsets (IgA, IgD, IgG, IgM) 
Vaccine titers 
CAgD Thermal Amplitude 
For information on the anti-drug antibody (ADA) and PK evaluations, please refer to the 
Laboratory Manual. 
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10.2 
APPENDIX B: NCI-CTC VERSION 4.03 (CTCAE V4.03)  
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
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10.3 
APPENDIX C: FUNCTIONAL ASSESSMENT OF CHRONIC ILLNESS THERAPY 
(FACIT)-FATIGUE SCALE  
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10.4 
APPENDIX D: EQ-5D-5L  
 
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10.5 
APPENDIX E: 12-ITEM SHORT FORM SURVEY (SF-12)  
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10.6 
APPENDIX F: PATIENT’S GLOBAL IMPRESSION OF CHANGE (PGIC)  
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10.7 
APPENDIX G: HEALTHCARE RESOURCE UTILIZATION  
Healthcare resource utilization data will be collected during the Screening/Observation 
Period; on Day 0; on Days 1, 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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10.8 
APPENDIX H: PATIENT’S GLOBAL IMPRESSION OF [FATIGUE] SEVERITY  
Attach when completed. See below for an example. 
 
 
 
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10.9 
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. 
10.10 APPENDIX J: 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 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, 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. No history of hypersensitivity reaction to BIVV009 
3. Considered by the investigator to be a good candidate for home infusions. 
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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, Home Infusion Patient Satisfaction Questionnaires 
(Section 10.11, Appendix K). 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 
completion of the first home infusion and 1 hour after the completion of each subsequent 
home infusion. Any adverse events occurring during home visits should 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. After the 1st and 4th home infusion, the patient will answer 
(by filling up the form) the Home Infusion Patient Satisfaction which will be applied after the 
end of study drug administration. 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 home infusion visit coincides with a visit with assessments scheduled to occur every 
3 months, the patient will attend office visit and will have study drug infused at the site; the 
next home infusion visit will occur 2 weeks after this office visit and the schedule with home 
infusion visits every other bi-weekly visit alternating with regular office visit with drug 
infusion will be resumed. 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.  
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  
Study visit (Week/Day) 
Part B  
Open-label extension 
phase 
Part B  
Open-label 
extension phasem 
ET/EOS/Safety 
follow-upa 
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 
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Study visit (Week/Day) 
Part B  
Open-label extension 
phase 
Part B  
Open-label 
extension phasem 
ET/EOS/Safety 
follow-upa 
On site visit 
Home visit 
9 weeks after last 
dose on site visit 
Visit windows 
2 days 
2 days 
2 days 
Physical examination, full 
 
 
X 
Physical examination, brief 
Xh 
 
 
Vital signs (BP, PR, RR, body 
temperature)c 
Xh 
 
X 
SLE paneld, p 
Xd 
 
X 
Hematology paneld, o 
X 
 
X 
Coagulation paneld 
 
 
X 
Clinical chemistry paneld, o 
X 
 
X 
Urinalysisd 
Xh 
 
X 
FACIT-Fatiguej 
Xh 
 
X 
PGISj 
Xh 
 
X 
PGICj 
Xh 
 
X 
SF-12j 
Xh 
 
X 
EQ-5D-5Lj 
Xh 
 
X 
Solicited symptomatic anemia 
X 
X 
X 
Study drug administratione 
X 
X 
 
ADAs against BIVV009 and 
neutralizing anti bodies 
Xk 
 
X 
PK Samplesf 
X 
 
X 
PD Samplesf 
X 
 
X 
Concomitant medications including 
transfusions 
X 
X 
X 
Healthcare resource utilization 
Xi 
 
X 
Adverse eventsg 
X 
Xn 
X 
Home infusion satisfaction survey 
 
Xl 
 
ECG 
 
 
X 
Vaccination 
Revaccination with booster 
doses should be given 
according to regional 
guidelines for patients with 
persistent complement 
deficiency and in 
accordance with respective 
labels. 
 
 
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. 
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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 Section 10.1, Appendix A.  
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 which will also be given 
at site. 
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 
during the 1st year of treatment in Part B and then every 6 months. 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 
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, ADA samples will be collected every 3 months predose, during the 1st year of treatment in Part B and then every 
6 months 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 (which will be applied after the end of study drug administration). 
m In Part B, 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). 
o In Part B, hematology and clinical chemistry panels to be performed every 2 weeks after Week 25 and up to Week 79 (every 4 weeks 
in patients within the home infusion scheme). For the remainder of Part B after Week 79, hematology and clinical chemistry panels to 
be performed every 4 weeks. 
p SLE panel testing should occur every 6 months at on site visits in Part B. 
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 41 (Day 287) and without 
evidence of intolerance of the study drug as determined by the Investigator. No new risks 
related to home infusions are anticipated. Like with office visits, medications such as 
epinephrine and diphenhydramine, and additional emergency equipment will be available in 
case an allergic reaction or anaphylaxis occurs during home infusion.  Professional healthcare 
caregiver will be qualified to detect and treat allergic reactions and anaphylaxis. The 
alternating schedule of home infusion visits and office visits every 4 weeks each may be 
found convenient by patients as less travels to the study site will be necessary.   
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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 and who were determined 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 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 5.3 (Removal of Patients from Study Participation, and Study Suspension and 
Stopping Rules) 
Patients undergoing home infusions with BIVV009 will return to bi-weekly dosing at the 
study site if they develop any 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 the AE, which led to the interruption of home infusions according to the 
Investigator’s judgement, is considered unrelated to BIVV009 and once resolved or 
stabilized. 
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 (+/-2 days) 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 6.1.6 (Infusion of the study drug at patient’s home) 
Home infusions will be performed at pre-selected countries/sites, during Part B and 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 at home, 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. No history of hypersensitivity reaction to BIVV009 
3. Considered by the investigator to be a good candidate for home infusions. 
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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, Home Infusion Patient Satisfaction 
Questionnaires, after the 1st and 4th home infusions, as well as solicited anemia assessment) 
during home visits which will be applied after the end of study drug administration. 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 2 hours after the completion of the first home infusion or 
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.  
In case a home infusion visit coincides with a visit with assessments scheduled to occur every 
3 months the patient will attend office visit and will have study drug infused at the site; the 
next home infusion visit will occur 2 weeks after this office visit and the schedule with home 
infusion visits every other bi-weekly visit alternating with regular office visit with drug 
infusion will be resumed. 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.  
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.  
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. Like with office visits, medications such as epinephrine and 
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diphenhydramine, and additional emergency equipment will be available in case an allergic 
reaction or anaphylaxis occurs during home infusion. Site personnel, or professional 
healthcare caregiver in case of home infusions, must be qualified to detect and treat allergic 
reactions and anaphylaxis. 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, and in case of home infusion, the Investigator notified immediately.  
10.11 APPENDIX K: 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 
10.12 APPENDIX L: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
Clinical Study Protocol 5 (17 July 2018)  
This clinical study protocol 5 (amendment 5) is not considered to be substantial 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 following corrections or changes were made to the protocol for clarity, consistency, and 
accuracy: 
 The page headers were updated with Version 5 of the protocol. 
 The abbreviation list was updated. 
 The tables of contents were updated. 
 The Investigator’s and Sponsor’s agreement pages were updated with Version 5 and 
the date of approval.  
 Minor grammatical and formatting changes were made throughout the protocol. 
 Clarification as to how data corrections would be shown 
 Changed PK and PD postdose sample collection time from 2 hours to 1 hour postdose 
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Clinical Study Protocol 4 (29 June 2018) 
This clinical study protocol 4 (amendment 4) is not considered to be substantial 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 following corrections or changes were made to the protocol for clarity, consistency, and 
accuracy: 
 The page headers were updated with Version 4 of the protocol. 
 The abbreviation list was updated. 
 The tables of contents were updated. 
 The Investigator’s and Sponsor’s agreement pages were updated with Version 4 and 
the date of approval.  
 Minor grammatical and formatting changes were made throughout the protocol. 
 Added the PGIS [Fatigue] as a QOL assessment at the request of the US FDA. 
 Increased the frequency of sample collection for PK and PD assessments. Specified 
that PK and PD 
- 
samples were to be collected predose and 2 hours (±15 minutes) postdose (1 hour 
after the 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 was to be collected during the EOT visit on Day 182 or at ET 
if a patient withdraws early. 
 Added that “documentation” of all vaccinations was required in text where it was not 
previously included 
 Added the vaccine schedule for Japan as an appendix. 
 Changed the PGIC assessment from every 6 months to every 3 months in Part B to 
coincide with the timing of PGIS assessments. 
Clinical Study Protocol 3.1 (21 March 2018) 
This clinical study protocol 3.1 (amendment 3.1) is not considered to be substantial 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 following corrections or changes were made to the protocol for clarity, consistency, and 
accuracy: 
 The page headers were updated with Version 3.1 of the protocol. 
 The abbreviation list was updated. 
 The tables of contents were updated. 
 The Investigator’s and Sponsor’s agreement pages were updated with Version 3.1 and 
the date of approval.  
 Minor grammatical and formatting changes were made throughout the protocol. 
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 Removed serogroup B meningococcus from vaccination requirements. 
 Specified that vaccinations should be initiated on Day -42 and no later than Day -28. 
 Added the vaccine schedule for Japan as an appendix. 
Clinical Study Protocol 3 (09 March 2018) 
This clinical study protocol 3 (amendment 3) is considered to be substantial 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 following corrections or changes were made to the protocol for clarity, consistency, and 
accuracy: 
 The page headers were updated with Version 3 of the protocol. 
 The abbreviation list was updated. 
 The tables of contents were updated. 
 The Investigator’s and Sponsor’s agreement pages were updated with Version 3 and 
the date of approval.  
 Minor grammatical and formatting changes were made throughout the protocol. 
 Excluded from Part B patients who received prohibited medications in Part A. 
 Clarified that patients who received a transfusion in Part A would not be withdrawn 
and would still be eligible to participate in Part B. 
 Inclusion criterion 7, “Ferritin levels within the normal reference ranges unless 
outside normal range and deemed not clinically significant by the Investigator (or 
designee),” was changed to: “Ferritin above the lower limit of normal. Concurrent 
treatment with iron supplementation is permitted if the patient has been on a stable 
dose for the previous 4 weeks.” 
 Extended the requirement for highly effective contraception from 6 weeks following 
the last administration of study drug to 9 weeks. 
 The exclusion criterion “Clinical diagnosis of systemic lupus erythematosus (SLE) or 
other autoimmune disorders with antinuclear antibodies at Screening” was modified 
to add that antinuclear antibodies of long-standing duration without associated clinical 
symptoms will be adjudicated on a case-by-case basis. 
 Specified that vaccinations should be administered in accordance with regional 
guidelines. 
 Extended the follow-up visit for collection of AE data, PK, PD, and ADA samples 
from 6 weeks to 9 weeks after the last administration of study drug in patients who 
discontinue early. 
 Total healthcare resource utilization was added as an exploratory efficacy endpoint in 
Part A and as an efficacy endpoint in Part B. 
 Safety follow-up visit changed from 6 weeks to 9 weeks after the last dose of study 
drug. 
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 Added the occurrence of clinically significant hematologic breakthrough events 
attributable to the development of ADA and/or the development of positive SLE 
autoantibody titers as a criterion for the removal of a patient from study participation 
if, in the opinion of the Investigator, it could jeopardize the safety of the patient. 
 Increased the frequency of pregnancy testing (serum or urine). 
 Added solicited symptomatic anemia as a study assessment. 
 Clarified that patients must be monitored for allergic reactions and anaphylaxis rather 
than infusion-related reactions. 
 Extended the recording period for AEs from 6 to 9 weeks after administration of the 
last dose of study drug. 
 Extended the reported period for SAEs from 6 to 9 weeks after the last dose of study 
drug or through the final study visit, whichever occurs later. 
Clinical Study Protocol 2 (22 February 2018) 
This clinical study protocol 2 (amendment 2) is considered to be substantial 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 following corrections or changes were made to the protocol for clarity, consistency, and 
accuracy: 
 The page headers were updated with Version 2 of the protocol. 
 The abbreviation list was updated. 
 The tables of contents were updated. 
 The Investigator’s and Sponsor’s agreement pages were updated with Version 2 and 
the date of approval.  
 Minor grammatical and formatting changes were made throughout the protocol. 
 Beginning on Day 0, urine pregnancy testing was changed to serum or urine 
pregnancy testing. 
 Clarified that patients who received a transfusion in Part A would not be withdrawn 
and would still be eligible to participate in Part B. 
 Excluded from Part B patients who received prohibited medications in Part A. 
 Changed the collection of PK, PD, and ADA samples from 6 to 9 weeks after the last 
dose of study drug in patients who discontinue early and those who have a 
hematologic breakthrough event. 
 Inclusion criterion 7, “Ferritin levels within the normal reference ranges unless 
outside normal range and deemed not clinically significant by the Investigator (or 
designee),” was changed to: “Ferritin above the lower limit of normal. Concurrent 
treatment with iron supplementation is permitted if the patient has been on a stable 
dose for the previous 4 weeks.” 
 Extended the requirement for highly effective contraception from 6 weeks following 
the last administration of study drug to 9 weeks. 
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 The exclusion criterion “Clinical diagnosis of SLE or other autoimmune disorders 
with antinuclear antibodies at Screening” was modified to add that antinuclear 
antibodies of long-standing duration without associated clinical symptoms will be 
adjudicated on a case-by-case basis. 
 Total healthcare resource utilization was added as an exploratory efficacy endpoint in 
Part A and as an efficacy endpoint in Part B. 
 Specified that vaccinations should be administered in accordance with regional 
guidelines. 
 Extended the follow-up visit for the collection of AE data, PK, PD, and ADA samples 
from 6 to 9 weeks after the last administration of study drug in patients who 
discontinue early. 
 Added the occurrence of clinically significant hematologic breakthrough events 
attributable to the development of ADA and/or the development of positive SLE 
autoantibody titers as a criterion for the removal of a patient from study participation 
if, in the opinion of the Investigator, it could jeopardize the safety of the patient. 
 Extended the recording period for AEs from 6 to 9 weeks after administration of the 
last dose of study drug. 
 Extended the reporting period for SAEs from 6 to 9 weeks after the last dose of study 
drug or through the final study visit, whichever occurs later. 
 Clarified that patients must be monitored for allergic reactions and anaphylaxis rather 
than infusion-related reactions. 
 Extended the reporting period for pregnancies from 6 to 9 weeks after the last dose of 
study drug. 
Clinical Study Protocol 1.5 (10 January 2018) 
This clinical study protocol 1.5 (amendment 1.5) is not considered to be substantial 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 following corrections or changes were made to the protocol for clarity, consistency, and 
accuracy: 
 The page headers were updated with Version 1.5 of the protocol. 
 The abbreviation list was updated. 
 The tables of contents were updated. 
 The Investigator’s and Sponsor’s agreement pages were updated with Version 1.5 and 
the date of approval.  
 Minor grammatical and formatting changes were made throughout the protocol. 
 Increased the frequency of urine pregnancy tests for women of childbearing potential. 
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Clinical Study Protocol 1.4 (15 December 2017) 
This clinical study protocol 1.4 (amendment 1.4) is considered to be substantial 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 following corrections or changes were made to the protocol for clarity, consistency, and 
accuracy: 
 The page headers were updated with Version 1.4 of the protocol. 
 The abbreviation list was updated. 
 The tables of contents were updated. 
 The Investigator’s and Sponsor’s agreement pages were updated with Version 1.4 and 
the date of approval.  
 Minor grammatical and formatting changes were made throughout the protocol. 
 Extended the requirement for highly effective contraception from 6 weeks following 
the last administration of study drug to 9 weeks. 
 The exclusion criterion “Clinical diagnosis of SLE or other autoimmune disorders 
with antinuclear antibodies at Screening” was modified to add that antinuclear 
antibodies of long-standing duration without associated clinical symptoms will be 
adjudicated on a case-by-case basis. 
 The inclusion criteria “Bilirubin level above the normal reference range” was changed 
to “Bilirubin level above the normal reference range, including patients with Gilbert’s 
Syndrome”. 
 Extended the Early Termination visit from 6 to 9 weeks from the last dose of study 
drug. 
 Extended the safety follow-up visit for patients who discontinue early from 6 to 9 
weeks after the last dose of study drug. 
 Added the occurrence of clinically significant hematologic breakthrough events 
attributable to the development of ADA and/or the development of positive SLE 
autoantibody titers as a criterion for the removal of a patient from study participation 
if, in the opinion of the Investigator, it could jeopardize the safety of the patient. 
 Extended the reporting period for AEs from 6 to 9 weeks after the last dose of study 
drug or through the final study visit, whichever occurs later. 
 Extended the reporting period for pregnancies from 6 to 9 weeks after the last dose of 
study drug. 
Clinical Study Protocol 1.3 (06 December 2017) 
This clinical study protocol 1.3 (amendment 1.3) is not considered to be substantial 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.  
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The following corrections or changes were made to the protocol for clarity, consistency, and 
accuracy: 
 The page headers were updated with Version 1.3 of the protocol. 
 The abbreviation list was updated. 
 The tables of contents were updated. 
 The Investigator’s and Sponsor’s agreement pages were updated with Version 1.3 and 
the date of approval.  
 Minor grammatical and formatting changes were made throughout the protocol. 
 Inclusion criterion 6, “Ferritin levels within the normal reference ranges unless 
outside normal range and deemed not clinically significant by the Investigator (or 
designee),” was removed and reframed as an exclusion criterion: “Ferritin below the 
lower limit of normal. Concurrent treatment with iron supplementation is permitted if 
the patient has been on a stable dose for the previous 4 weeks.” 
 Increased the frequency of urine pregnancy tests for women of childbearing potential 
to monthly. 
Clinical Study Protocol 1.2 (29 November 2017) 
This clinical study protocol 1.2 (amendment 1.2) is not considered to be substantial 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 following corrections or changes were made to the protocol for clarity, consistency, and 
accuracy: 
 The page headers were updated with Version 1.2 of the protocol. 
 The abbreviation list was updated. 
 The tables of contents were updated. 
 The Investigator’s and Sponsor’s agreement pages were updated with Version 1.2 and 
the date of approval.  
 Minor grammatical and formatting changes were made throughout the protocol. 
 Excluded from Part B patients who withdraw from the study after Week 5 and prior to 
Week 23 of Part A. 
 Excluded from Part B patients who received prohibited medications in Part A 
 Specified that patients who receive a transfusion in Part B will not be withdrawn from 
the study and will not be considered nonresponders. 
 Specified that vaccinations should be given in accordance with regional guidelines, 
where applicable. Where no regional guidelines are available, the vaccinations were 
to be initiated on Day -42 or as early as possible during the Screening/Observation 
Period. The primary vaccine series was to be completed during Screening when 
possible and otherwise prior to Week 5 of Part A. 
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Clinical Study Protocol 1.1 (09 September 2017) 
This clinical study protocol 1.1 (amendment 1.1) is not considered to be substantial 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 following corrections or changes were made to the protocol for clarity, consistency, and 
accuracy: 
 The page headers were updated with Version 1.1 of the protocol. 
 The abbreviation list was updated. 
 The tables of contents were updated. 
 The Investigator’s and Sponsor’s agreement pages were updated with Version 1.1 and 
the date of approval.  
 Minor grammatical and formatting changes were made throughout the protocol. 
 The PGIS assessment was removed. 
 The frequency of the ECG assessment was reduced. Specifically, the Day 175 and 
Day 182 time points were removed. In addition, during Part B, the ECGs were only to 
be conducted predose and postdose at 3 months (Day 217). 
 Quantitative immunoglobulin was removed. 
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Signature Page for VV-CLIN-0562006 v1.0  
bivv009-03-16-1-1-amended-protocol06 
 
Approve & eSign  
 
Approve & eSign  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan 
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TABLE OF CONTENTS 
1. 
INTRODUCTION ..................................................................................................................9 
2. 
DESCRIPTION OF OBJECTIVES AND ENDPOINTS ....................................................10 
2.1. 
Study Objectives ................................................................................................................10 
2.1.1. 
Primary Objective ........................................................................................................10 
2.1.2. 
Secondary Objectives...................................................................................................10 
2.2. 
Study Endpoints .................................................................................................................10 
2.2.1. 
Primary Endpoint .........................................................................................................10 
2.2.2. 
Secondary Efficacy Endpoints .....................................................................................11 
2.2.3. 
Exploratory Endpoints .................................................................................................11 
2.2.4. 
Safety Endpoints ..........................................................................................................12 
2.2.5. 
Pharmacokinetic Endpoints .........................................................................................12 
2.2.6. 
Pharmacodynamic Endpoints .......................................................................................12 
3. 
STUDY DESIGN .................................................................................................................13 
3.1. 
Overall Study Design and Plan ..........................................................................................13 
3.1.1. 
Study Sample ...............................................................................................................13 
3.1.2. 
Treatment .....................................................................................................................13 
3.2. 
Statistical Hypothesis .........................................................................................................14 
3.3. 
Sample Size Justification ...................................................................................................14 
3.4. 
Randomization and Blinding .............................................................................................14 
3.5. 
Interim Analysis .................................................................................................................14 
4. 
ANALYSIS POPULATIONS ..............................................................................................15 
4.1. 
Full Analysis Set (FAS) .....................................................................................................15 
4.2. 
Per-protocol Set .................................................................................................................15 
4.3. 
Safety Analysis Set ............................................................................................................15 
4.4. 
PK Analysis Set .................................................................................................................15 
4.5. 
PD Analysis Set .................................................................................................................15 
4.6. 
Definitions of Subgroups ...................................................................................................15 
5. 
DEFINITIONS AND DATA HANDLING .........................................................................17 
5.1. 
General Principles ..............................................................................................................17 
5.1.1. 
Definitions....................................................................................................................17 
5.1.2. 
Pooling Sites for Analysis ............................................................................................21 
5.1.3. 
Estimands .....................................................................................................................21 
5.1.4. 
Handling of Missing Data ............................................................................................22 
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5.1.4.1. 
Mixed-effect Model for Repeated Measures .........................................................23 
5.1.4.2. 
Multiple Imputation ...............................................................................................24 
5.2. 
Data Summaries .................................................................................................................25 
5.2.1. 
Continuous Variables ...................................................................................................25 
5.2.2. 
Categorical Variables ...................................................................................................25 
5.2.3. 
Event Time Variables ..................................................................................................26 
6. 
STUDY SUBJECTS ............................................................................................................27 
6.1. 
Disposition of Subjects ......................................................................................................27 
6.2. 
Demography and Baseline Disease Characteristics ...........................................................27 
6.2.1. 
Demography .................................................................................................................27 
6.2.2. 
General Medical History ..............................................................................................27 
6.2.3. 
Baseline Disease Characteristics ..................................................................................27 
6.3. 
Protocol Deviations ............................................................................................................28 
6.4. 
Non-study Drug Medications .............................................................................................28 
6.4.1. 
Concomitant Medications ............................................................................................28 
6.4.2. 
Other Therapies and Procedures ..................................................................................28 
6.5. 
Study Drug .........................................................................................................................28 
6.5.1. 
Exposure ......................................................................................................................29 
6.5.2. 
Compliance ..................................................................................................................29 
7. 
EFFICACY ANALYSIS ......................................................................................................30 
7.1. 
General Efficacy Principles ...............................................................................................30 
7.1.1. 
Multiplicity ..................................................................................................................30 
7.2. 
Primary Endpoint ...............................................................................................................30 
7.2.1. 
Primary Analysis ..........................................................................................................30 
7.2.2. 
Sensitivity Analyses .....................................................................................................31 
7.2.3. 
Subgroup Analyses ......................................................................................................32 
7.3. 
Secondary Endpoints .........................................................................................................32 
7.3.1. 
Mean Change from Baseline in Bilirubin at the Treatment Assessment 
Timepoint .....................................................................................................................32 
7.3.2. 
Mean Change from Baseline in FACIT-F Score at Treatment Assessment 
Timepoint .....................................................................................................................33 
7.3.3. 
Mean Change from Baseline in Lactate Dehydrogenase (LDH) at the 
Treatment Assessment Timepoint................................................................................34 
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7.3.4. 
Number of Transfusions and Number of Units after the First 5 Weeks of 
Study Drug Administration ..........................................................................................34 
7.3.5. 
Mean Change from Baseline in Hgb at the Treatment Assessment Timepoint ...........34 
7.4. 
Exploratory Endpoints .......................................................................................................35 
7.4.1. 
Part A Exploratory Endpoints ......................................................................................35 
7.4.1.1. 
Continuous Endpoints ............................................................................................35 
7.4.1.2. 
Response Endpoints ...............................................................................................36 
7.4.1.2.1. 
Incidence of Solicited Symptomatic Anemia ..................................................36 
7.4.1.2.2. 
Incidence of Thromboembolic Events after the First 5 Weeks of Study 
Drug Administration ........................................................................................37 
7.4.1.3. 
Time-to-Event Endpoints .......................................................................................37 
7.4.2. 
Part B Exploratory Endpoints ......................................................................................37 
7.5. 
Endpoints Based on Patient-reported Outcomes................................................................38 
7.5.1. 
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale ..............38 
7.5.2. 
EQ-5D-5L ....................................................................................................................38 
7.5.3. 
12-Item Short Form Survey (SF-12) ............................................................................39 
7.5.4. 
Patient Global Impression of Change (PGIC) .............................................................39 
7.5.5. 
Patient’s Global Impression of [Fatigue] Severity.......................................................39 
7.5.6. 
Healthcare Resource Utilization ..................................................................................39 
8. 
SAFETY ANALYSIS ..........................................................................................................40 
8.1. 
Adverse Events ..................................................................................................................40 
8.1.1. 
Overall Summary of Adverse Events ..........................................................................40 
8.1.2. 
Treatment-emergent Adverse Events ...........................................................................41 
8.1.2.1. 
Adverse Events in Descending Order of Incidence ...............................................41 
8.1.2.2. 
Severity of Adverse Events ....................................................................................41 
8.1.2.3. 
Relationship of Adverse Events to Study Drug .....................................................41 
8.1.3. 
Serious Adverse Events ...............................................................................................41 
8.1.4. 
Adverse Events Leading to Treatment Discontinuation and/or Study 
Withdrawal ...................................................................................................................42 
8.1.5. 
Deaths on Study ...........................................................................................................42 
8.1.6. 
Adverse Events of Interest ...........................................................................................42 
8.1.6.1. 
AEs Within 24 Hours after the Start of Infusion ...................................................42 
8.1.6.2. 
Infections and Infections of ≥ Grade 3 Severity ....................................................42 
8.1.6.3. 
Haemolytic Breakthrough ......................................................................................42 
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8.1.6.4. 
Anti-drug Antibody ................................................................................................44 
8.2. 
Clinical Laboratory Evaluations ........................................................................................42 
8.2.1. 
Hematology and Chemistry .........................................................................................42 
8.2.1.1. 
Change from Baseline ............................................................................................43 
8.2.1.2. 
Shifts ......................................................................................................................43 
8.2.1.3. 
Potentially Clinically Significant Laboratory Abnormalities ................................44 
8.2.2. 
SLE Panel and Serum Disease-related Biomarkers .....................................................44 
8.2.3. 
Change from Baseline in ECG Data ............................................................................44 
8.3. 
Vital Signs ..........................................................................................................................44 
9. 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS ..............................46 
9.1. 
Pharmacokinetic Analysis ..................................................................................................46 
9.2. 
Pharmacodynamic Analysis ...............................................................................................46 
10. 
CHANGES FROM PREVIOUS VERSION ........................................................................47 
11. 
REFERENCES .....................................................................................................................48 
12. 
LIST OF TABLES AND FIGURES ....................................................................................49 
13. 
APPENDICES ......................................................................................................................53 
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LIST OF TABLES 
Table 1: 
Analytic Visit Windows .............................................................................18 
Table 2: 
Severity Grade for Symptomatic Anemia Related CAD ...........................19 
Table 3: 
Estimands for Primary Endpoint ................................................................31 
Table 4: 
Estimands for Change from Baseline in Bilirubin .....................................32 
Table 5: 
Estimands for Change from Baseline in FACIT-F Score ..........................33 
Table 6: 
Estimands for Change from Baseline in LDH ...........................................34 
Table 7: 
Estimands for Change from Baseline in Hgb ............................................35 
Table 8: 
Direction of Change Indicating Clinical Concern for Laboratory 
Tests ...........................................................................................................43 
Table 9: 
Criteria to Determine Potentially Clinically Relevant 
Abnormalities in Vital Signs ......................................................................45 
LIST OF APPENDICES 
Appendix A: 
Scoring Algorithm for FACIT-F ................................................................53 
Appendix B: 
EQ-5D-5L Questionnaire Score Definitions ..............................................55 
Appendix C: 
12-item Short Form Survey (SF-12) ..........................................................57 
Appendix D: 
Patient’s Global Impression of Change (PGIC).........................................60 
Appendix E: 
Patient’s Global Impression of [Fatigue] Severity.....................................61 
 
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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 
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 
Patient’s Global Impression of Change 
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 
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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 
 
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1. 
INTRODUCTION 
This is an open-label, single-arm, multicenter study in patients with primary cold agglutinin 
disease (CAD) who have hemoglobin (Hgb) level ≤ 10 g/dL and a recent history of blood 
transfusion.  Eligible patients will receive study drug and undergo safety and efficacy 
assessments for 6 months (26 weeks) during Part A. 
Following completion of the initial 6-month treatment period, patients will roll into the long-term 
safety phase (Part B) where they will continue to receive study drug. 
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. 
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2. 
DESCRIPTION OF OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective  
The primary objective of Part A is to determine whether BIVV009 administration results in a 
≥ 2 g/dL increase in Hgb levels or increases Hgb to ≥ 12 g/dL and obviates the need for blood 
transfusion during treatment in patients with primary CAD who have a recent history of 
transfusion.  
The primary objective of Part B is to evaluate the long-term safety and tolerability of BIVV009 
in patients with primary CAD. 
2.1.2. 
Secondary Objectives  
The secondary objectives in Part A are 
• 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 quality of life (QOL) in patients with primary CAD 
• To evaluate the overall safety and tolerability of BIVV009 in patients with primary CAD 
The secondary objective of Part B is to investigate the durability of response during long-term 
treatment with BIVV009 in patients with primary CAD. 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoint 
The primary efficacy endpoint is the responder rate defined as follows (Table 2 of protocol): 
A patient will be 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 either of 
the following criteria: 
• Hgb level is ≥ 12 g/dL at treatment assessment endpoint (defined as mean value from 
Weeks 23, 25, and 26), or 
• Hgb increased ≥ 2 g/dL from baseline (defined as the last Hgb value before administration of 
the first dose of study drug) at treatment assessment endpoint 
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2.2.2. 
Secondary Efficacy Endpoints 
The secondary endpoints are as follows: 
• Mean change from baseline in bilirubin (excluding patients with Gilbert’s Syndrome) at the 
treatment assessment endpoint (mean of values at Weeks 23, 25, and 26) 
• 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 endpoint 
• Mean change from baseline in lactate dehydrogenase (LDH) at the treatment assessment 
endpoint 
• Number of transfusions and number of units after the first 5 weeks of study drug 
administration 
• Mean change from baseline in Hgb at the treatment assessment endpoint 
2.2.3. 
Exploratory Endpoints 
Part A: 
• Time to first transfusion after the first 5 weeks of study drug administration 
• 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 
• Incidence of solicited symptomatic anemia at EOT 
• Proportion of patients with Hgb level of ≥ 12 g/dL at the 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 obtain Hgb level of ≥ 12 g/dL 
• Proportion of patients normalizing haptoglobin at the treatment assessment endpoint 
• Proportion of patients normalizing bilirubin at the treatment assessment endpoint 
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• Proportion of patients normalizing LDH at the treatment assessment endpoint 
• Patient’s Global Impression of Change (PGIC) to assess patient’s perception of changes in 
CAD 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 EOT 
• Total healthcare resource utilization at EOT 
2.2.4. 
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 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 (i.e., requiring intravenous [IV] antibiotics) 
• Incidence of thromboembolic events 
2.2.5. 
Pharmacokinetic Endpoints  
• Plasma concentrations of BIVV009  
• PK parameters: Appropriate exposure parameters (Cmax, AUC) will be derived using a 
population approach  
2.2.6. 
Pharmacodynamic Endpoints  
• PD Primary Outcome Measure: Wieslab-CP 
• Exploratory Complement System Measures: CH50, Total C4, C1q, C1s 
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3. 
STUDY DESIGN 
3.1. 
Overall Study Design and Plan 
This open-label, single-arm study is designed to evaluate the efficacy, safety, and tolerability of 
BIVV009 in patients with the complement-mediated disorder, primary CAD, who have Hgb 
level ≤ 10 g/dL and a recent history of blood transfusion. 
During the 6-week Screening/Observation Period, prospective patients will have a detailed 
medical history documented (including transfusion history of ≥ 6 months), physical evaluations 
for screening, 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. 
The study will enroll 20 primary CAD patients who have a recent history of transfusion, defined 
as at least 1 transfusion during the last 6 months prior to enrollment.  Additionally, patients who 
withdraw from study early (prior to Week 5) may be replaced.  
3.1.1. 
Study Sample 
Subject inclusion and exclusion criteria can be found in Sections 5.1 and 5.2 of the protocol. 
3.1.2. 
Treatment 
Eligible patients will receive an IV infusion of BIVV009 over approximately 60 minutes on 
Day 0, Day 7, and every 14 days thereafter through Week 25 (i.e., 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.  Patients who weigh 75 kg or more will receive fixed doses of 7.5 g of 
BIVV009.  Patients who miss a dose (i.e., 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. 
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3.2. 
Statistical Hypothesis 
The study is designed to test the hypothesis whether patients treated with BIVV009 will achieve 
a response rate greater than 30%.  Statistical hypothesis is written as 
H0: response rate ≤ 30% 
H1: response rate > 30%, 
where the response rate is the proportion of patients in the intent-to-treat (ITT) population who 
meet the response criteria defined in Table 2 of the protocol.  
Based on discussions with key opinion leaders and experienced clinicians, a response rate of less 
than 30% is not considered clinically relevant.  It is expected that few patients with transfusion 
dependent primary CAD would meet the responder definition for the primary endpoint without 
treatment intervention, and as such a null hypothesis of ≤ 30% responder rate for this patient 
population is reasonable.  
3.3. 
Sample Size Justification 
Approximately 20 patients with primary CAD who have a recent history of transfusion will be 
enrolled.  If the true responder rate is estimated to be 66% and a minimum of 30% is required for 
success, then with 20 patients there is 90% probability that the lower limit of the 95% confidence 
interval (CI) will be at least 30%. 
3.4. 
Randomization and Blinding 
This is an open-label study with no blinding or randomization.  Despite the nature of the open-
label study, the aggregated summary of efficacy endpoints described below will be not be shared 
with the Sponsor study team until the execution of Part A analysis. 
3.5. 
Interim Analysis  
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 BLA/MAA 
following completion of Part A.  Additional analyses of Part B data will be defined in a separate 
Part B SAP.  
Since Part A analysis constitutes the primary analysis of the study hypothesis, no Type I error 
adjustment is necessary. 
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4. 
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. 
4.1. 
Full Analysis Set (FAS) 
The ITT population consists of all 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. 
4.2. 
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. 
4.3. 
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. 
4.4. 
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.  
4.5. 
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. 
4.6. 
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) 
• Number of transfusions within 12 months prior to study entry (≤ 2, > 2 -4, > 4)  
• Baseline Hgb level (< 8.5 g/dL, ≥ 8.5 g/dL)  
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• Previous rituximab therapy and/or cytotoxic therapy (Yes, No)  
In case of very few subjects (e.g., < 5) in a category, the cutoff value may be changed to suit the 
distribution of these factors. 
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5. 
DEFINITIONS AND DATA HANDLING 
Statistical analysis will be performed by Bioverativ, using SAS® version 9.3 or higher and, 
where appropriate, additional validated software.  This SAP is based on protocol Version 5, 
dated 17 July 2018. 
5.1. 
General Principles 
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 otherwise specified.  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 than 0.999 will be presented as 
“> 0.999”.  All baseline, efficacy, and safety data, including derived variables at all visits, will be 
listed.  
5.1.1. 
Definitions 
Study Day 
Study Day is defined as days relative to the date of first dose of BIVV009, Day 0.  In other 
words, Study Day 1 is Day 0 as defined in the protocol.  The start/stop day of events will be 
calculated as (date of event – date of Study Day 1 + 1) if the date of event is on or after the first 
dose date, or (date of event – date of Study Day 1) if the date of event is before the first dose 
date. 
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 
Baseline measures are defined as the last value prior to the administration of the study drug.  If a 
transfusion occurs during the screening period, the baseline measure must be at least 7 days after 
the transfusion.  
Part A Study Treatment Period 
The Part A study treatment period starts at the date of first study drug administration 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. 
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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 EOT/ET/Safety Follow-up Visit will be used, if the Study Day of 
such a visit fits in the analytic window defined in Table 1.  If multiple values are identified 
within the analytic window, the one closest to the target study day will be used.  
Table 1: 
Analytic Visit Windows 
Visit 
Target Study Day 
Analytic Visit Window 
(Study Day) 
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 25 (Day 175) 
176 
170 – 179 
Week 26 (Day 182; EOT Visit in Part A) 
183 
180 – 189 
Treatment Assessment Timepoint 
The value of an assessment (e.g., 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 
these visits, it will be calculated as the average of the available values, unless no value is 
available from all three visits.  
Solicited Symptomatic Anemia 
The severity of CAD symptomatic anemia is defined in Table 2.  The severity grading for 
symptomatic anemia was adopted based on Common Toxicity Criteria for Adverse Events 
(CTCAE) grades and is collected in eCRFs at every visit.  
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Table 2: 
Severity Grade for Symptomatic Anemia Related CAD 
CAD 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 wellbeing; 
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 (e.g., 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, 
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.  
In general, thromboembolic events may include but are not limited to: 
• Any venous events 
o Portal vein obstruction 
o Deep vein thrombosis 
o Pulmonary embolism 
o Mesenteric (abdominal) venous thrombosis 
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• Any cerebral events 
o Cerebral infarction, occlusion, and stenosis of cerebral and precerebral arteries 
o Vascular syndromes of brain in cerebrovascular diseases, transient cerebral ischemic 
attacks, and related syndromes 
• Any arterial events 
o Myocardial infarction 
o Mesenteric arterial thrombosis 
o 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.  
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: 
o An increase in LDH from the last scheduled visit, 
o An increase in bilirubin from the last scheduled visit, or 
o 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: 
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• 
Rituximab alone or as part of combination therapy 
• Cytotoxic drugs (such as fludarabine, bendamustine, ibrutinib, cyclophosphamide) 
• Other investigational drug 
The efficacy endpoint (estimand) accounting for protocol prohibited CAD medication 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. 
5.1.2. 
Pooling Sites for Analysis 
Data from all investigational sites will be pooled for the analysis, unless specified otherwise.  
5.1.3. 
Estimands 
Following International Conference on Harmonisation (2014) and National Research Council 
(2010), 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. (2017) 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.  
Composite Estimand 
• Population: FAS 
• Variable: A composite endpoint: endpoint response criteria, and remain in the study through 
at least Week 23 visit (i.e., patients who discontinued the study participation prior to 
Week 23, including those who discontinued prior to Week 5, are considered non-responder) 
• Measure of Intervention Effect: Proportion of subjects who respond according to the variable 
definition 
Hypothetical Estimand 
• Population: FAS 
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• Variable: Change from baseline at treatment assessment timepoint (Weeks 23, 25, and 26), 
where any post-baseline value after transfusion and prohibited medication (from Week 5 to 
Week 26) is considered missing  
• Measure of Intervention Effect: Mean change from baseline, had transfusion and prohibited 
medications not been available  
De-Facto Estimand 
• Population: FAS 
• Variable: Change from baseline at treatment assessment timepoint (Weeks 23, 25, and 26) 
• Measure of Intervention Effect: Mean change from baseline, irrespective of transfusion or 
prohibited medications  
Observed Estimand 
• Population: a subset of FAS, subjects who remain in the study through at least the visit of 
interest (e.g., Week 23) and have at least 1 evaluable parameter or score at target visits. 
• Variable: Change from baseline at the visit of interest, or response at the visit of interest 
• Measure of Intervention Effect: Mean change from baseline or proportion of subjects who 
respond, irrespective of transfusion or prohibited medications 
5.1.4. 
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 EOT/safety follow up visit. 
For the primary endpoint, which is a composite endpoint of avoidance of transfusion and 
improvement of Hgb at the treatment assessment timepoint (i.e., Weeks 23, 25, and 26), missing 
either component results in a missing value for the endpoint.  The improvement of Hgb at the 
treatment assessment timepoint is missing only if no Hgb value is available for all 3 visits 
(Weeks 23, 25, and 26).  Since pre-treatment Hgb is a key requirement to enroll in the study, it is 
reasonable to assume that all enrolled subjects have at least 1 Hgb prior to the study treatment, 
which constitutes the baseline Hgb value (see Section 5.1.1).  
For the primary analysis of the primary endpoint, the composite estimand is utilized.  Hence, a 
missing value will be considered a non-response.  Other sensitivity analyses specified in 
Section 7.2.2 will be performed to evaluate the impact of missing values, when appropriate.  
However, other responder-type endpoints will be analyzed using observed data only.  
For the analysis of continuous variables (e.g., secondary endpoints), summary statistics will be 
computed based on observed data.  To analyze lab parameter (e.g., Hgb, bilirubin, LDH) changes 
attributable to the study treatment (hypothetical estimand), values post any transfusion (after 
Week 5) or protocol prohibited CAD treatment (defined in Section 5.1.1, after Week 5) will be 
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censored.  The mean change from baseline will be estimated using Mixed Model for Repeated 
Measures (MMRM) along with its 95% CIs.  Multiple Imputation will also be used to estimate 
the mean change from baseline at treatment assessment timepoint and its associated 95% CI.  All 
these analyses assume missing at random (MAR). 
Although the assumption of MAR cannot be verified, the mechanism of missing data due to 
transfusion or prohibited medication use described below supports such an assumption. 
• The protocol (Table 1) specifies the transfusion criteria, which is comprised of the Hgb level. 
• Despite the use of prohibited medications not being allowed by the protocol, the potential 
need for the use of rituximab and/or combination therapy would be mostly due to the lack of 
response or hematologic breakthrough, which is specified in the protocol by changes in the 
level of Hgb and other hemolytic markers. 
Therefore, the missing data due to the occurrence of transfusion and prohibited medication use is 
expected to be triggered by low levels of Hgb and other hemolytic markers, which are 
observable.  Because of this mechanism, it is reasonable to assume that the probability of 
missing data due to transfusion or prohibited medication use is a function of the observed Hgb or 
other hemolytic marker levels; hence, supports the assumption for MAR. 
Additional sensitivity analyses, specified in the particular endpoints, may be carried out to 
examine the validity of the assumption of MAR.  Multiple imputation based on models 
compatible with Missing Not At Random (MNAR) missing mechanism may be used, where 
missing values at treatment assessment visit will be imputed by using Neighboring-Case Missing 
Value (NCMV) restriction.  Certain adjustment may be needed for NCMV approach due to the 
small sample size, where there may be lack of neighboring cases. 
Supportive analysis based on de-facto estimand will also be performed using MMRM to estimate 
the mean change from baseline along with its 95% CIs. 
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 questionnaires at a visit, the prorated FACIT-F score will be 
calculated, if more than 50% of items (a minimum of 7 out of 13 items) are available.  
Otherwise, the score is missing. 
For exploratory endpoints, observed estimands will be used unless specified otherwise. 
5.1.4.1. 
Mixed-effect Model for Repeated Measures 
For normally distributed continuous efficacy endpoints (e.g., lab parameters), a 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 and visit.  A 
heterogeneous Toeplitz (TOEPH) covariance matrix within a subject will be used.  For the 
endpoint at the treatment assessment time points (average of Weeks 23, 25, and 26), the estimate 
will be calculated as the mean of MMRM estimates at Week 23, 25, and 26 visits. 
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Normality assumptions will be checked using graphical methods.  In the event of non-normality, 
alternative methods will be proposed as an addendum to the SAP prior to the Part A DBL. 
The pseudo SAS code for MMRM is as follows: 
Proc mixed data=(ADaM dataset) method=reml; 
class usubjid visit; 
model chg = base visit / ddfm = kenwardroger solution; 
repeat visit / type=TOEPH subject=usubjid; 
estimate ‘treatment assessment timepoint’ visit 0 0 0 0 0 0 0 
0 0 0 0 0 0.333 0.333 0.333/cl; 
run; 
5.1.4.2. 
Multiple Imputation  
The following multiple imputation procedure will be used for continuous endpoints.  The 
regression method with monotone missing patterns will be used for the imputation step 
(implemented by SAS PROC MI, according to Rubin 1987, pp. 166–167).  The pseudo SAS 
code is provided to substantiate the details of the statistical approach.  It does not represent 
runnable SAS codes for the execution of the analysis, as adjustment to the code is necessary to 
accommodate the data structure, variable names, and test runs. 
1. For endpoints with non-monotone missing data patterns, a Markov chain Monte-Carlo 
(MCMC) method will first be used to fill in the intermittent missing values. 
The pseudo SAS code is as follows, when the input dataset is structured such that 
variables chg1 - chg11 represent change from baseline at visit Week 1 (Day 7), Week 3, 
Week 5, Week 7, Week 9, Week 11, Week 13, Week 15, Week 17, Week 19, Week 21, 
and variable chg_ta represents change from baseline at treatment assessment timepoint: 
PROC MI data=dat_in seed=1234 SIMPLE NIMPUTE=1 ROUND=1 
OUT=dat_mon;  
 
MCMC IMPUTE=monotone; 
 
VAR chg1 – chg11 chg_ta;  
RUN; 
2. Missing values will be imputed as the predicted value from a regression model including 
explanatory variables of the number of transfusions within 6 months prior to study entry 
(ntrans),  the value of the same endpoint at baseline (base), and change from baseline at 
all of the previous scheduled visits.  The imputation process may be repeated sequentially 
starting from the earliest visit with missing value (e.g., Day 7) through the treatment 
assessment timepoint.  The forgoing process will be repeated multiple times (i.e., B=100) 
to generate B imputed datasets.  
The pseudo SAS code is as follows: 
PROC MI DATA = dat_mon SEED=4321 NIMPUTE=100 out=mi_mvn SIMPLE;  
 
VAR base ntrans chg1 – chg11 chg_ta;   
 
MONOTONE METHOD=REG; 
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RUN; 
3. The endpoint of interest (e.g., change from baseline at treatment assessment time points) 
will be estimated for all B complete datasets.  
The pseudo SAS code as follows: 
PROC MEANS DATA = mi_mvn out=mi_mvn;  
 
VAR chg_ta;   
 
By _IMPUTATION_; 
ods output statistics=mi_ests; 
RUN; 
4. The method of Rubin 1987 will be used to combine B estimates for the overall estimate 
and its 95% CI. 
The pseudo SAS code is as follows: 
PROC MIANALYZE DATA = mi_ests; 
  MODELEFFECTS mean; 
  STDERR; 
  ods output ParameterEstimates=est; 
run; 
5.2. 
Data Summaries 
5.2.1. 
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. 
5.2.2. 
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.  This number (n) will be included with 
categorical summaries unless the same variable is also being summarized with descriptive 
statistics, in which case ‘n’ will already be provided.  
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5.2.3. 
Event Time Variables 
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, 
the time-to-event will be censored at the study day of last assessment within a study period 
(Part A or Part B). 
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6. 
STUDY SUBJECTS 
6.1. 
Disposition of Subjects 
Subject disposition will be summarized including the number of subjects in the Safety Analysis 
Set, FAS, PP Set, PK Analysis Set, and PD Analysis Set.  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 Part A.  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.  
The number and percentage of subjects attending each visit will be summarized by planned visits 
for the FAS. 
6.2. 
Demography and Baseline Disease Characteristics 
Demographics and baseline disease characteristics will be summarized for FAS. 
6.2.1. 
Demography 
Demographic characteristics including age (years), age category (<65, >=65), gender, race, 
ethnicity, country, geographic location, height (cm), weight (kg), weight category (<75 kg, 
>=75kg) and body mass index (kg/m2) will be summarized.  Geographic locations are defined as 
Europe, North America, Asia/Japan and other. 
6.2.2. 
General Medical History 
A summary of the medical history by system organ class (SOC) and preferred term for FAS will 
be presented.  A subject will be counted only once if they reported one or more occurrences in 
the SOC and preferred term.   
A summary of prior hematological malignancy within the last 5 years and prior thromboembolic 
history within the last 1 year will be presented.  
6.2.3. 
Baseline Disease Characteristics  
Screening and baseline lab parameters, including hematology (such as Hgb, bilirubin, LDH), 
Gilbert's Syndrome testing, bone marrow biopsy results, and DAT panel, will be summarized 
based on the FAS. Prior transfusion history (e.g., number of transfusions within 6 months and 12 
months of study entry) will also be summarized.   
Summaries of prior CAD therapies within the last 5 years, severity of anemia symptoms, and 
other CAD related diseases characteristics (e.g., presence of acrocyanosis, Raynaud’s syndrome, 
hemoglobinuria, disabling circulatory symptoms, and major adverse vascular events) within 3 
months of screening will be presented. 
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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.  
6.3. 
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 the FAS.  All deviations, both major and minor, will be provided in a 
data listing.  
Important protocol deviations (within Part A study treatment period) impacting efficacy 
assessment are defined as any of the following: 
• Not meeting eligibility inclusion criteria #3,  
• Missing at least 2 consecutive doses or 3 intermittent doses,  
• Received protocol prohibited CAD treatment (Section 5.1.1), 
• Free of transfusion after Week 5 but missing study assessments at all three visits of 
Weeks 23, 25, and 26.  
Important protocol deviations will be summarized. Subjects who have had any of the important 
protocol deviations will be excluded from the PP population. 
6.4. 
Non-study Drug Medications 
6.4.1. 
Concomitant Medications 
Prior medications are those taken before the first dose of study drug. 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 2017 version or 
higher) and summarized using the FAS.   
Separate tables will be generated to summarize prior CAD medical treatment, concomitant CAD 
medical treatment, and protocol prohibited CAD treatment.  
6.4.2. 
Other Therapies and Procedures 
All other therapies received during the study (whether for CAD or other condition) will be 
summarized for the FAS and listed.  
6.5. 
Study Drug  
Study drug exposure and compliance will be summarized using the Safety Analysis Set.  
Subject-level information on dosing with study drug will also be provided in a data listing. 
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6.5.1. 
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. 
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 dose administered in Part A.  
6.5.2. 
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 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.  
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7. 
EFFICACY ANALYSIS 
7.1. 
General Efficacy Principles 
Unless specified otherwise, all analyses described will be performed for Part A. 
7.1.1. 
Multiplicity 
The study hypothesis described in Section 3.2 will be tested at a 1-sided significance level of 
0.025.  No other formal hypothesis will be tested, as secondary endpoints will be estimated along 
with associated 95% CIs.  
7.2. 
Primary Endpoint 
The primary endpoint, defined in Section 2.2.1, 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. Hgb at treatment assessment timepoint >= 12 g/dL, or the change from baseline at 
treatment assessment >= 2 g/dL,  
3. Receive no protocol prohibited medications defined in Section 5.1.1.  
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.  
To be evaluable for each of the components, a subject must be observed through at least 
Week 23 visit.  Discontinuation of study treatment prior to Week 23 visit will result in an 
unknown status for Components 1 and 3.  Missing Hgb value at all visits of Week 23, 25, and 26 
will result in an unknown status for Component 2. 
In the event of unknown status in any of the components, a subject may be a responder, non-
responder, or missing for the response status.  A subject is considered responder, if the subject 
meets all of the three components; a subject is considered a non-responder, if the subject is 
known to not meet any of the three components; otherwise, a subject is considered missing in 
response status. 
7.2.1. 
Primary Analysis  
The primary analysis of the primary endpoint involves the composite estimand (Section 5.1.3), 
for which any missing response (above) will be considered a non-responder.  The proportion 
of subjects who respond according to the estimand (Table 3) will be estimated along with a 95% 
exact Clopper-Pearson CI.  
To reject the null hypothesis of the response rate <= 30%, the lower bound of the 95% CI must 
be greater than 30%.  
In addition, the proportion of subjects who meet each of the response criteria will be 
summarized.  
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7.2.2. 
Sensitivity Analyses 
Sensitivity analyses will be carried out based on the completer estimand and the per-protocol 
estimand (defined in Table 3).  The proportion of subjects with treatment response will be 
summarized along with the 95% exact Clopper-Pearson CI.  
Table 3: 
Estimands for Primary Endpoint 
 
Composite Estimand 
Completer Estimand 
Per-protocol Estimand 
Population 
FAS 
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 
A subset of FAS with 
those who are free of 
important protocol 
deviations defined in 
Section 6.3 
Response 
Variable 
Responder if 
• Free of post-baseline 
transfusion within the 
range of Week 5 and 
Week 26 visit dates, 
and 
• Hgb at treatment 
assessment timepoint 
>= 12 g/dL, or the 
change from baseline at 
treatment assessment 
>= 2 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, and 
• Remain in study 
through at least 
Week 23, and  
• At least 1 evaluable 
Hgb from Weeks 23, 
25, and 26 
Responder if 
• Free of post-baseline 
transfusion within the 
range of Week 5 and 
Week 26 visit dates, and 
• Hgb at treatment 
assessment timepoint 
>= 12 g/dL, or the change 
from baseline at treatment 
assessment >= 2 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 
Responder if 
• Free of post-baseline 
transfusion within the 
range of Week 5 and 
Week 26 visit dates, 
and 
• Hgb at treatment 
assessment timepoint 
>= 12 g/dL, or the 
change from baseline at 
treatment assessment 
>= 2 g/dL 
Treatment 
effect 
Proportion of subjects who 
achieve the composite 
response variable (defined 
above) 
Proportion of subjects who 
achieve the treatment 
response 
Proportion of subjects who 
achieve the treatment 
response 
In the case when there are at least 2 subjects who discontinue study participation prior to 
Week 5, a supportive analysis, similar to the primary analysis, will be performed by excluding 
those subjects who discontinue prior to Week 5. 
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In the case of normal ranges (LLN) varying across local labs, a sensitivity analysis will be 
performed for the primary endpoint by qualifying normalization of Hgb using >= LLN, instead 
of >= 12 g/dL. 
7.2.3. 
Subgroup Analyses 
The proportion of subjects with response according to the composite estimand will be 
summarized for subgroups defined in Section 4.6 along with its 95% exact CI.  The consistency 
of the response rates among these sub-populations will be examined by forest plots. 
7.3. 
Secondary Endpoints 
7.3.1. 
Mean Change from Baseline in Bilirubin at the Treatment Assessment 
Timepoint 
The change from baseline in bilirubin at the treatment assessment timepoint will be analyzed for 
FAS excluding subjects with Gilbert’s syndrome.  Gilbert’s syndrome status is determined by the 
result of the genetic test at screening.  If the result of Gilbert’s syndrome test is not available for 
a patient, the patient will be excluded from the analysis.  The primary analysis will be performed 
according to Hypothetical Estimand (defined in Section 5.1.3), while a sensitivity analysis will 
be done via De-facto Estimand (Section 5.1.3).  Additional details are found in Table 4.  
Table 4: 
Estimands for Change from Baseline in Bilirubin 
 
Hypothetical Estimand 
De-facto Estimand 
Population 
FAS excluding subjects with Gilbert’s 
syndrome 
FAS excluding subjects with Gilbert’s 
syndrome 
Variable 
Change from baseline at treatment 
assessment time point, where any value 
after transfusion and prohibited 
medication is considered missing 
Change from baseline at treatment 
assessment time point 
Treatment 
effect 
Mean change from baseline, if transfusion 
or prohibited medications had not been 
available 
Mean change from baseline, irrespective 
of transfusion or prohibited medication 
use 
For either estimand, the mean change from baseline in bilirubin at treatment assessment 
timepoint, along with its 95% CI, will be estimated by the MMRM model (Section 5.1.4.1).  
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), 
whose baseline total bilirubin level is low to be considered less indicative of Gilbert’s syndrome.  
Additional sensitivity analysis based on multiple imputation (Section 5.1.4.2) will be carried out 
for the Hypothetical Estimand, utilizing the regression method with monotone missing patterns.  
Specifically, the following 4 imputation models will be considered: 
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• Change from baseline in bilirubin at treatment assessment timepoint is modeled as a function 
of baseline bilirubin value, weight stratum (< 75 kg, >= 75 kg), and bilirubin values from 
Day 7 through visits Week 21, visits prior to first transfusion, or visits prior to first prohibited 
medication use, whichever occurs first; 
• Change from baseline in bilirubin at treatment assessment timepoint is modeled as a function 
of baseline bilirubin value, weight stratum (< 75 kg, >= 75 kg), and bilirubin values from 
Day 7 through visits Week 21, 2nd last visit prior to first transfusion, or visits prior to first 
prohibited medication use, whichever occurs first;  
• Change from baseline in bilirubin at treatment assessment timepoint is modeled as a function 
of baseline bilirubin value, weight stratum (< 75 kg, >= 75 kg), and bilirubin values from 
Week 5 through visits Week 21 (observed value through visits prior to first transfusion, or 
visits prior to first prohibited medication use, whichever occurs first).  
• Change from baseline in bilirubin at treatment assessment timepoint is modeled as a function 
of baseline bilirubin value, weight stratum (< 75 kg, >= 75 kg), and bilirubin values from 
Day 7 through visits Week 21 (observed value through visits prior to first transfusion, or 
visits prior to first prohibited medication use, whichever occurs first); but with NCMV 
restrictions.  
7.3.2. 
Mean Change from Baseline in FACIT-F Score at Treatment Assessment 
Timepoint  
The change from baseline in FACIT-F score at the treatment assessment timepoint will be 
analyzed for the FAS.  The derivation of FACIT-F score is detailed in Section 7.5.  The primary 
analysis will be performed according to Hypothetical Estimand (defined in Section 5.1.3), while 
a sensitivity analysis will be done via De-facto Estimand (Section 5.1.3).  Additional details are 
found in Table 5.  
Table 5: 
Estimands for Change from Baseline in FACIT-F Score 
 
Hypothetical Estimand 
De-facto Estimand 
Population 
FAS  
FAS  
Variable 
Change from baseline at treatment 
assessment time point, where any value 
after transfusion and prohibited 
medication is considered missing 
Change from baseline at treatment 
assessment time point 
Treatment 
effect 
Mean change from baseline, if transfusion 
or prohibited medications had not been 
available 
Mean change from baseline, irrespective 
of transfusion or prohibited medication 
use 
For either estimand, the mean change from baseline in FACIT-F score at treatment assessment 
timepoint, along with its 95% CI, will be estimated by the MMRM model (Section 5.1.4.1).  
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Additional sensitivity analyses for hypothetical estimand, similar to those specified for bilirubin, 
will be performed for the change from baseline in FACIT-F score at treatment assessment 
timepoint. 
7.3.3. 
Mean Change from Baseline in Lactate Dehydrogenase (LDH) at the Treatment 
Assessment Timepoint  
The change from baseline in LDH at the treatment assessment timepoint will be analyzed for the 
FAS.  The primary analysis will be performed according to Hypothetical Estimand (defined in 
Section 5.1.3), while a sensitivity analysis will be done via De-facto Estimand (Section 5.1.3).  
Additional details are found in Table 6. 
Table 6: 
Estimands for Change from Baseline in LDH 
 
Hypothetical Estimand 
De-facto Estimand 
Population 
FAS  
FAS  
Variable 
Change from baseline at treatment 
assessment time point, where any value 
after transfusion and prohibited 
medication is considered missing 
Change from baseline at treatment 
assessment time point 
Treatment 
effect 
Mean change from baseline, if transfusion 
or prohibited medications had not been 
available 
Mean change from baseline, irrespective 
of transfusion or prohibited medication 
use 
For either estimand, the mean change from baseline in LDH at treatment assessment timepoint, 
along with its 95% CI, will be estimated by the MMRM model (Section 5.1.4.1). 
Additional sensitivity analyses for hypothetical estimand, similar to those specified for bilirubin, 
will be performed for the change from baseline in LDH at treatment assessment timepoint. 
Additional descriptive analyses will be performed for LDH isoforms. 
7.3.4. 
Number of Transfusions and Number of Units after the First 5 Weeks of Study 
Drug Administration 
The number of transfusions after Week 5 through Week 26 visits will be summarized for the 
FAS, where the observed data will be used for subjects who discontinue study treatment early in 
Part A.  The number of units transfused during the same period of time will be summarized for 
subjects who receive at least 1 transfusion.  
The transfusions occurring during the first 5 weeks will be listed.  
7.3.5. 
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 Hypothetical Estimand (defined in 
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Section 5.1.3), while a sensitivity analysis will be done via De-facto Estimand (Section 5.1.3).  
Additional details are found in Table 7. 
Table 7: 
Estimands for Change from Baseline in Hgb 
 
Hypothetical Estimand 
De-facto Estimand 
Population 
FAS  
FAS  
Variable 
Change from baseline at treatment 
assessment time point, where any value 
after transfusion and prohibited 
medication is considered missing 
Change from baseline at treatment 
assessment time point 
Treatment 
effect 
Mean change from baseline, if transfusion 
or prohibited medications had not been 
available 
Mean change from baseline, irrespective 
of transfusion or prohibited medication 
use 
For either estimand, the mean change from baseline in Hgb at treatment assessment timepoint, 
along with its 95% CI, will be estimated by the MMRM model (Section 5.1.4.1). 
Additional sensitivity analyses for hypothetical estimand, similar to those specified for bilirubin, 
will be performed for the change from baseline in Hgb at treatment assessment timepoint. 
7.4. 
Exploratory Endpoints 
7.4.1. 
 Part A Exploratory Endpoints 
The analysis of exploratory endpoints (listed in Section 2.2.3) will be based on Observed 
Estimand (Section 5.1.3).  Additionally, summary of hemolytic parameters (Hgb, bilirubin, LDH, 
haptoglobin, and reticulocyte) over visit is added to the SAP to examine the time trend of the 
improvement.  Unless specified below, the endpoints will be summarized by visit for continuous 
and categorical variables, and for time to event variables (e.g., time to obtain Hgb level of 
≥ 12 g/dL) for the entire Part A.  
7.4.1.1. 
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 endpoint 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 (see Section 7.5.1) 
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The endpoints by visit will be summarized for FAS according to Section 5.2.1. 
7.4.1.2. 
Response Endpoints 
The response endpoints include: 
• Incidence of solicited symptomatic anemia at EOT 
• Incidence of thromboembolic events after the first 5 weeks of study drug administration 
• Proportion of subjects with Hgb level of ≥ 12 g/dL at the treatment assessment endpoint 
• Proportion of subjects normalizing haptoglobin at the treatment assessment endpoint 
• Proportion of subjects normalizing bilirubin at the treatment assessment endpoint 
• Proportion of subjects normalizing LDH at the treatment assessment endpoint 
• PGIC and change from baseline in PGIS to assess subject’s perception of changes in CAD 
disease burden at last scheduled visit of Part A 
• Incidence of disabling circulatory symptoms at last scheduled visit of Part A 
• Proportion of subjects normalizing Hgb (>= 12 g/dL) by visit 
• Proportion of subjects achieving 2 g/dL increase in Hgb by visit 
• Proportion of subjects normalizing bilirubin by visit 
• Proportion of subjects normalizing LDH by visit 
• Proportion of subjects normalizing haptoglobin by visit 
The endpoints will be summarized for FAS according to Section 5.2.2. 
7.4.1.2.1. 
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. Proportion of subjects with 
improvement in anemia symptoms will be summarized by visit.  The improvement is defined as 
at least 1 grade reduction in at least 1 symptom, and no worsening in other remaining symptoms. 
In addition, proportion of subjects with at least 1 grade decrease will be summarized for each 
anemia symptom by visit.  
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7.4.1.2.2. 
Incidence of Thromboembolic Events after the First 5 Weeks of Study 
Drug Administration 
The adverse event data will be reviewed by internal medical staff to identify all thromboembolic 
events reported. The detailed listing for all events will be provided including date (study day) of 
onset, verbatim terms of the event, and the flag whether the event occur after 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-year of 
time for observation (i.e., 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.  
Anti-coagulation medication use will be reviewed and identified based on reported concomitant 
medications, and will be summarized.  
7.4.1.3. 
Time-to-Event Endpoints 
Time-to-event endpoints include: 
• Time to first transfusion after the first 5 weeks of study drug administration 
• Time to first transfusion (including those in the first 5 weeks of study drug administration) 
• Time to first normalization of bilirubin 
• Time to first normalization of LDH 
• Time to first normalization of haptoglobin 
• Time to first normalization of Hgb level (≥ 12 g/dL) 
• Time to first achieving 2 g/dL increase in Hgb level 
• Time to first achieving 2 g/dL increase or normalization of Hgb level (≥ 12 g/dL) 
The endpoints will be analyzed for FAS according to Section 5.2.3.  For subjects who receive a 
transfusion after Week 5, the time to normalization of lab parameters above will be censored at 
the time of transfusion. 
7.4.2. 
Part B Exploratory Endpoints 
A separate SAP will be developed for Part B of the study.  
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7.5. 
Endpoints Based on Patient-reported Outcomes 
The FACIT-Fatigue, the EQ-5D-5L, the SF-12, and the PGIC 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. 
7.5.1. 
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 Appendix A. 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.    
7.5.2. 
EQ-5D-5L 
The questionnaire will be analyzed according to the recommendations of the authors (see 
www.euroqol.org).  EQ-5D consists of 2 pages – a 5 dimension descriptive system and the EQ 
visual analogue scale.  A copy of the questionnaire is provided in Appendix B.  
The descriptive system contains 5 categories: 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 authors 
(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. 
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The derived EQ-5D index scores and change from baseline will be summarized by visit for the 
FAS.   
7.5.3. 
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 
Appendix C. 
The derived scores and change from baseline for the 8 health domains, the physical component 
score, and the mental component score, will be summarized by visit for the FAS.   
7.5.4. 
Patient Global Impression of Change (PGIC) 
The questionnaire (listed in Appendix D) will be summarized as an ordinal variable by visit for 
the FAS.  
7.5.5. 
Patient’s Global Impression of [Fatigue] Severity  
The change from baseline in questionnaire (listed in Appendix E) will be summarized as an 
ordinal variable by visit for the FAS.  
7.5.6. 
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.   
 
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8. 
SAFETY ANALYSIS 
Safety data will be summarized for subjects in Safety Analysis Set defined in Section 4.3. The 
summary tables may also be presented by subgroup based on the baseline weight strata (i.e., 
BIVV009 dose cohorts). However, the limited number of subjects in each dose cohort and non-
randomized assignment preclude a direct comparison between the two dose cohorts.   
8.1. 
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 that 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. The algorithm for the determination of treatment emergence when an onset date is 
partially or completely missing is described below. 
• If the onset time of an adverse event (if time is collected) is missing and the date of onset 
is the date of dosing, the AE is considered to be a TEAE. 
• If the onset day of an adverse event is missing and the month and year of the onset of the 
AE are either the same or later than the month and year of the first treatment, the AE will 
be considered a TEAE. If the month and year of the onset of the AE precede the month 
and year of the first treatment, the AE will not be considered a TEAE. 
• If the onset month of an adverse event is missing and the year of the onset of the AE is 
either the same as or later than the year of first treatment, then the AE will be considered 
a TEAE. If the year of AE onset precedes the year of first treatment, the AE will not be 
considered a TEAE. 
• If the onset day, month, and year of an adverse event are missing, the AE will be 
considered to be a TEAE.  
• If start date is partial but the stop date can be determined to be before the start of the first 
dose of study drug, then the AE will not be considered a TEAE. 
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. 
8.1.1. 
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 
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related SAE, treatment-emergent Grade 3 or higher AE, or TEAE infections of Grade 3 or higher 
severity; the number and percentage of subjects who had a TEAE within 24 hours of the start of 
infusion; 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.   
8.1.2. 
Treatment-emergent Adverse Events 
The incidence of TEAEs will be summarized by SOC and preferred term. 
8.1.2.1. 
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 (i.e., 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. 
8.1.2.2. 
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. 
8.1.2.3. 
Relationship of Adverse Events to Study Drug 
AEs are classified by the Investigator for relationship to study drug (“Unrelated,” “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 “Unrelated”) 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. 
8.1.3. 
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. In addition, if a subject develops a Grade 3 or higher allergic reaction 
per Common Terminology Criteria for Adverse Events (CTCAE) grading or an anaphylactic reaction 
in association with BIVV009 administration, the event should be reported as an SAE per protocol. 
All SAEs will be listed; treatment-emergent SAEs and treatment-emergent related SAEs will be 
summarized by system organ class and preferred term. 
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8.1.4. 
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. 
8.1.5. 
Deaths on Study 
A listing of deaths occurring on study will be provided. 
8.1.6. 
Adverse Events of Interest 
8.1.6.1. 
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.  
8.1.6.2. 
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.  A listing of all 
infections, infections of Grade 3 or higher and serious infections will be provided.  
8.1.6.3. 
Haemolytic Breakthrough 
Proportion of subjects with hemolytic breakthrough (defined in Section 5.1.1) at any visit will be 
summarized.  The date (visit) of onset and hemolytic lab parameters (i.e., Hgb, bilirubin, LDH, 
and haptoglobin) over time will be listed for subjects with haemolytic breakthrough.  
8.2. 
Clinical Laboratory Evaluations 
All laboratory data will be provided in data listings; abnormal values relative to laboratory 
normal ranges will be identified. 
8.2.1. 
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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8.2.1.1. 
Change from Baseline 
Hematology and chemistry results at baseline and post baseline visits, along with change from 
baseline, will be summarized with descriptive statistics for Safety Analysis Set. 
8.2.1.2. 
Shifts 
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 
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 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 8. 
Table 8: 
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 
Indirect bilirubin 
High 
Eosinophils 
Low and High 
Renal 
 
Basophils 
Low and High 
Blood urea nitrogen 
High 
Red blood cell count 
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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8.2.1.3. 
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 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.  
8.2.2. 
SLE Panel and Serum Disease-related Biomarkers 
SLE panel (below) and serum disease-related biomarkers (below) at baseline and post baseline 
visits, along with change from baseline, will be summarized with descriptive statistics for the 
Safety Analysis Set.  Additional exploratory analyses may be performed to examine the 
relationship between biomarkers and efficacy or safety parameters.  
Systemic Lupus Erythematosus Panel 
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  
DAT (polyspecific, anti-IgG & anti-C3d), LDH isoforms, cold agglutinin (CAg) titre, IgG 
subsets (IgA, IgD, IgG, IgM), CAg thermal amplitude. Vaccine titers, if collected, will be 
presented in a listing only. 
8.2.3. 
Anti-drug Antibody (ADA) 
Subjects who discontinue treatment early in Part A will be evaluated for anti-drug antibodies.  
Subjects with negative and positive anti-drug antibodies will be listed along with the associated 
titer if available. 
8.3. 
ECG and Vital Signs 
8.3.1. 
Electrocardiograms (ECG) 
The proportion of subjects with clinically significant change from baseline in ECG findings will 
be summarized by visit.  
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8.3.2. 
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 potentially clinically relevant post-baseline 
abnormalities are shown below in Table 9. 
Table 9: 
Criteria to Determine Potentially 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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9. 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS 
9.1. 
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.  Individual and mean plasma BIVV009 
concentration-versus-time profiles will be plotted. 
9.2. 
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 for all PD 
parameters by time point and study day.  
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10. 
CHANGES FROM PREVIOUS VERSION 
The following changes have been made to Version 1.0 of the SAP:  
• Calculation of exposure have been clarified.  
• Components for the primary endpoint (receiving transfusion and prohibited medication 
from Week 5 to Week 26) have been clarified. 
• Analysis of rate of change in hemoglobin has been removed. 
• Summaries and analyses of solicited symptomatic anemia have been clarified. 
• Summaries of FACIT-Fatigue individual item responses have been removed as they will 
be provided in a separate FACIT-Fatigue analysis plan. 
• Summaries of SF-12 have been clarified. 
 
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11. 
REFERENCES 
International Conference on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (2014), “Final Concept Paper: E9(R1): Addendum to Statistical 
Principles for Clinical Trials on Choosing Appropriate Estimands and Defining Sensitivity 
Analyses in Clinical Trials,” 
Mouna Akacha, Frank Bretz, David Ohlssen, Gerd Rosenkranz & Heinz Schmidli (2017) 
Estimands and Their Role in Clinical Trials, Statistics in Biopharmaceutical Research, 9:3, 
268-271 
National Research Council (2010), “The Prevention and Treatment of Missing Data in Clinical 
Trials,” Washington, DC: The National Academies Press, Panel on Handling Missing Data in 
Clinical Trials. Committee on National Statistics, Division of Behavioral and Social Sciences 
and Education. 
Rubin, D.B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: Wiley. 
 
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12. 
LIST OF TABLES AND FIGURES 
List of tables and figures 
Background/Demography 
Part A: Summary of disposition 
Part A: Summary of enrollment by country and site 
Part A: Summary of subjects attending each visit 
Part A: Summary of demographics and baseline characteristics 
Part A: Summary of all major protocol deviations 
Part A: Summary of important protocol deviations impacting efficacy 
Part A: Summary of medical history 
Part A: Summary of thromboembolic medical history 
Part A: Summary of targeted medical history 
Part A: Summary of prior bone marrow biopsy review 
Part A: Summary of Gilbert’s syndrome testing at screening 
Part A: Summary of selected disease-related biomarkers at screening 
Part A: Summary of CAD related anemia symptoms prior to first dose 
Part A: Summary of other CAD related disease characteristics prior to first dose 
Part A: Summary of hemolytic laboratory parameters prior to first dose 
Part A: Summary of transfusion history 
Part A: Summary of transfusions during screening period 
Part A: Summary of immunization review /vaccination 
Part A: Summary of targeted prior therapy 
Part A: Summary of prior CAD medications 
Part A: Summary of concomitant medication 
Part A: Summary of concomitant CAD medications 
Part A: Summary of protocol-prohibited concomitant CAD medications 
Part A: Summary of concomitant non-drug treatments 
Exposure/Dosing 
Part A: Summary of BIVV009 exposure 
Part A: Summary of BIVV009 administration by visit and overall compliance 
Efficacy: Primary 
Part A: Summary of primary endpoint: components of treatment response 
Part A: Summary of primary endpoint: treatment response - Composite estimand 
Part A: Summary of primary endpoint: components of treatment response based on hemoglobin >= 
lower limit of normal- sensitivity analysis 
Part A: Summary of primary endpoint: treatment response based on hemoglobin >= lower limit of 
normal 
Part A: Summary of primary endpoint: treatment response - Completer estimand - sensitivity analysis 
Part A: Summary of primary endpoint: treatment response - Per-protocol estimand - sensitivity analysis 
Part A: Summary of treatment response by subgroup - Composite estimand 
Part A: Forest plot of treatment response and 95% CI by subgroups – Composite estimand 
Efficacy: Secondary 
Part A: Summary of change from baseline in hemoglobin (g/dL) at treatment assessment timepoint - 
Hypothetical estimand - MMRM 
Part A: Summary of change from baseline in hemoglobin (g/dL) at treatment assessment timepoint - 
De-facto estimand - MMRM 
Part A: Summary of change from baseline in hemoglobin (g/dL) at treatment assessment timepoint - 
Hypothetical estimand – MI 
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Part A: Summary of change from baseline in bilirubin (umol/L) at treatment assessment timepoint 
(excluding subjects with Gilbert’s syndrome) - Hypothetical estimand - MMRM 
Part A: Summary of change from baseline in bilirubin (umol/L) at treatment assessment timepoint 
(excluding subjects with Gilbert’s syndrome) - De-facto estimand - MMRM 
Part A: Summary of change from baseline in bilirubin (umol/L) at treatment assessment timepoint 
(excluding subjects with Gilbert’s syndrome) - Hypothetical estimand - MI 
Part A: Summary of change from baseline in lactate dehydrogenase (U/L) at treatment assessment 
timepoint - Hypothetical estimand - MMRM 
Part A: Summary of change from baseline in lactate dehydrogenase (U/L) at treatment assessment 
timepoint - De-facto estimand - MMRM 
Part A: Summary of change from baseline in lactate dehydrogenase (U/L) at treatment assessment 
timepoint - Hypothetical estimand - MI 
Part A: Summary of change from baseline in FACIT-Fatigue score at treatment assessment timepoint - 
Hypothetical estimand - MMRM 
Part A: Summary of change from baseline in FACIT-Fatigue score at treatment assessment timepoint - 
De-facto estimand - MMRM 
Part A: Summary of change from baseline in FACIT-Fatigue score at treatment assessment timepoint - 
Hypothetical estimand - MI 
Part A: Summary of number of transfusions and units after the first 5 weeks of study drug 
administration 
Efficacy: Exploratory - Hemolytic Parameters 
Part A: Summary of change from baseline in hemoglobin (g/dL) by visit - Observed 
Part A: Summary of change from baseline in bilirubin (umol/L) by visit - Observed 
Part A: Summary of change from baseline in lactate dehydrogenase (U/L) by visit - Observed 
Part A: Summary of change from baseline in haptoglobin (g/L) by visit - Observed 
Part A: Summary of change from baseline in absolute reticulocyte (10^9/L) by visit - Observed 
Part A: Plot of mean hemoglobin (g/dL) (+/- SE) by visit - Observed 
Part A: Plot of mean change from baseline in hemoglobin (g/dL) (+/- SE) by visit - Observed 
Part A: Plot of mean bilirubin (umol/L) (+/- SE) by visit (excluding subjects with Gilbert’s syndrome) - 
Observed 
Part A: Plot of mean change from baseline in bilirubin (umol/L) (+/- SE) by visit (excluding subjects 
with Gilbert’s syndrome) - Observed 
Part A: Plot of mean lactate dehydrogenase (U/L) (+/- SE) by visit - Observed 
Part A: Plot of mean change from baseline in lactate dehydrogenase (U/L) (+/- SE) by visit - Observed 
Part A: Plot of mean haptoglobin (g/L) (+/- SE) by visit - Observed 
Part A: Plot of mean change from baseline in haptoglobin (g/L) (+/- SE) by visit - Observed 
Part A: Plot of mean absolute reticulocyte (10^9/L) (+/- SE) by visit - Observed 
Part A: Plot of mean change from baseline in absolute reticulocyte (10^9/L) (+/- SE) by visit - 
Observed 
Part A: Summary of proportion of subjects normalizing hemolytic parameters at the treatment 
assessment timepoint – Observed 
Part A: Summary of time to first normalization of hemolytic parameters (1) - Observed 
Part A: Summary of time to first normalization of hemolytic parameters (2) - Observed 
Part A: Plot of hemoglobin (g/dL) by visit by response – Observed 
Part A: Summary of shift to non-detectable/detectable in haptoglobin by visit - Observed 
Efficacy: Exploratory - CAD Events 
Part A: Summary of incidence of solicited symptomatic anemia by visit 
Part A: Summary of incidence of solicited symptomatic anemia improvement by visit 
Part A: Summary of incidence of other CAD-related symptoms by visit 
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Part A: Summary of incidence of thromboembolic events after the first 5 weeks of BIVV009 
administration 
Part A: Summary of time to first transfusion after the first 5 weeks of BIVV009 administration 
Part A: Plot of time to first transfusion after the first 5 weeks of BIVV009 administration 
Part A: Summary of time to first transfusion including the first 5 weeks of BIVV009 administration 
Part A: Summary of transfusions by study period 
Efficacy: Exploratory - PRO 
Part A: Summary of FACIT-Fatigue score and change from baseline by visit 
Part A: Plot of mean FACIT-Fatigue score (+/- SE) by visit 
Part A: Summary of EQ-5D index score and change from baseline by visit 
Part A: Summary of EQ-5D-5L visual analogue scale (VAS) and change from baseline by visit 
Part A: Summary of EQ-5D-5L descriptive system 
Part A: Summary of SF-12 component scores and change from baseline by visit 
Part A: Summary of SF-12 sub-scale scores and change from baseline by visit 
Part A: Summary of Patient’s Global Impression of Change (PGIC) 
Part A: Summary of Patient’s Global Impression of Fatigue Severity (PGIS) by visit 
Part A: Summary of Patient’s Global Impression of Fatigue Severity (PGIS) change from baseline by 
visit 
Safety: Adverse Events 
Part A: Overall summary of treatment-emergent adverse events 
Part A: Summary of treatment-emergent adverse events 
Part A: Summary of treatment-emergent adverse events by preferred term in descending order of 
incidence 
Part A: Summary of Grade 3 or higher TEAEs by preferred term in descending order of incidence 
Part A: Summary of treatment-emergent adverse events by severity 
Part A: Summary of treatment-emergent adverse events by relationship to treatment 
Part A: Summary of treatment-emergent serious adverse events 
Part A: Summary of treatment-emergent serious adverse events by preferred term in descending order 
of incidence 
Part A: Summary of related treatment-emergent serious adverse events 
Part A: Summary of treatment-emergent adverse events within 24 hours of the start of infusion 
Part A: Summary of infections of Grade 3 or higher by preferred term 
Part A: Incidence of hemolytic breakthrough 
Safety: Laboratory 
Part A: Summary of hematology values and change from baseline by visit 
Part A: Summary of chemistry values and change from baseline by visit 
Part A: Summary of coagulation panel by visit 
Part A: Shifts from baseline to minimum/maximum post-baseline value for laboratory results: 
Hematology 
Part A: Shifts from baseline to minimum/maximum post-baseline value for laboratory results: 
Chemistry 
Part A: Summary of shift to low (high) for laboratory results: Hematology 
Part A: Summary of shift to low (high) for laboratory results: Chemistry 
Part A: Summary of potentially clinically significant laboratory abnormalities: Hematology 
Part A: Summary of potentially clinically significant laboratory abnormalities: Chemistry 
Part A: Summary of systemic lupus erythematosus (SLE) based on combined SLE panel parameters 
Part A: Summary of systemic lupus erythematosus (SLE) by each SLE panel parameter 
Part A: Summary of laboratory results and change from baseline by visit: Disease-Related Biomarkers 
(1) 
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Part A: Summary of laboratory results by visit: Disease-Related Biomarkers (2) 
Part A: Summary of ECG clinical interpretations by visit 
Part A: Summary of ECG clinical interpretation shifts from baseline 
Part A: Summary of vital signs values and change from baseline 
Part A: Summary of potentially clinically significant vital signs 
PK/PD 
Part A: Summary of BIVV009 plasma concentrations by visit 
Part A: Plot of BIVV009 concentrations over time by subject 
Part A: Plot of mean (+/- SE) BIVV009 concentration over time 
Part A: Summary of PD parameter results and change from baseline by visit 
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13. 
APPENDICES 
Appendix A: 
Scoring Algorithm for FACIT-F 
 
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Appendix B: 
EQ-5D-5L Questionnaire Score Definitions 
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Appendix C: 
12-item Short Form Survey (SF-12) 
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Appendix D: 
Patient’s Global Impression of Change (PGIC) 
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Appendix E: 
Patient’s Global Impression of [Fatigue] Severity 
 
 
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BioverativE 
Protocol 81VV009-03 Part B (C1mli1rnt) 
STATJSTICAL ANALYSIS PLAN 
PARTB 
Product Studied: BIVV009 
Protocol Nuruber(s): BIVV009-03 
Final vl.O 
A Phase 3, Pivotal, Open-Label, Multicenter Study to Assess the Efficacy and Safety of 
BIVV009 in Patients with Primary Cold Agglutinin Disease who have a Recent Histor·y of 
Blood Transfusion 
Approved By: 
Bioverativ USA, Inc. 
Date of Protocol: 17 July 20J 8 (V crsion 5) 
Date of Statistical Analysis Plan: 29 May 20 I 9 
Con lidentia I 
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TABLE OF CONTENTS 
LIST OF TABLES ...........................................................................................................................5 
LIST OF APPENDICES ..................................................................................................................5 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ..................................................................................................................8 
2. 
STUDY OBJECTIVES AND ENDPOINTS .........................................................................9 
2.1. 
Study Objectives ..................................................................................................................9 
2.1.1. 
Primary Objective ..........................................................................................................9 
2.1.2. 
Secondary Objective ......................................................................................................9 
2.2. 
Study Endpoints ...................................................................................................................9 
2.2.1. 
Safety Endpoints ............................................................................................................9 
2.2.2. 
Efficacy Endpoints .........................................................................................................9 
2.2.3. 
Pharmacokinetic Endpoints .........................................................................................10 
2.2.4. 
Pharmacodynamic Endpoints .......................................................................................10 
3. 
STUDY DESIGN .................................................................................................................11 
3.1. 
Overall Study Design and Plan ..........................................................................................11 
3.1.1. 
Study Sample ...............................................................................................................11 
3.1.2. 
Treatment .....................................................................................................................11 
3.1.3. 
End of Study ................................................................................................................11 
3.2. 
Statistical Hypothesis .........................................................................................................12 
3.3. 
Sample Size Justification ...................................................................................................12 
3.4. 
Randomization and Blinding .............................................................................................12 
3.5. 
Interim Analysis .................................................................................................................12 
4. 
ANALYSIS POPULATIONS ..............................................................................................13 
4.1. 
Full Analysis Set (FAS) .....................................................................................................13 
4.2. 
Safety Analysis Set ............................................................................................................13 
4.3. 
PK Analysis Set .................................................................................................................13 
4.4. 
PD Analysis Set .................................................................................................................13 
5. 
DEFINITIONS AND DATA HANDLING .........................................................................14 
5.1. 
General Principles ..............................................................................................................14 
5.1.1. 
Definitions....................................................................................................................14 
5.1.2. 
Pooling Sites for Analysis ............................................................................................16 
5.1.3. 
Handling of Missing Data ............................................................................................16 
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5.2. 
Data Summaries .................................................................................................................16 
5.2.1. 
Continuous Variables ...................................................................................................16 
5.2.2. 
Categorical Variables ...................................................................................................17 
5.2.3. 
Time-to-Event Variables ..............................................................................................17 
6. 
STUDY SUBJECTS ............................................................................................................18 
6.1. 
Disposition of Subjects ......................................................................................................18 
6.2. 
Demography and Baseline Disease Characteristics ...........................................................18 
6.2.1. 
Demography .................................................................................................................18 
6.3. 
Protocol Deviations ............................................................................................................18 
6.4. 
Non-study Drug Medications .............................................................................................18 
6.4.1. 
Concomitant Medications ............................................................................................18 
6.4.2. 
Non-drug treatments and procedures ...........................................................................19 
6.5. 
Study Drug .........................................................................................................................19 
6.5.1. 
Exposure ......................................................................................................................19 
7. 
EFFICACY ANALYSIS ......................................................................................................20 
7.1. 
General Efficacy Principles ...............................................................................................20 
7.2. 
Analysis of Efficacy Endpoints (Part B Study Period) ......................................................20 
7.2.1. 
Continuous Endpoints ..................................................................................................20 
7.2.2. 
Categorical Endpoints ..................................................................................................20 
7.2.3. 
Endpoints Based on Patient-reported Outcomes..........................................................21 
7.2.4. 
Healthcare Resource Utilization ..................................................................................21 
7.3. 
Analysis of Efficacy Endpoints (Combined Study Period) ...............................................21 
7.3.1. 
Continuous Endpoints ..................................................................................................22 
7.3.2. 
Time-to-event Endpoints .............................................................................................22 
8. 
SAFETY ANALYSIS ..........................................................................................................23 
8.1. 
Adverse Events ..................................................................................................................23 
8.1.1. 
Overall Summary of Adverse Events ..........................................................................23 
8.1.2. 
Treatment-emergent Adverse Events ...........................................................................23 
8.1.2.1. 
Adverse Events in Descending Order of Incidence ...............................................23 
8.1.2.2. 
Severity of Adverse Events ....................................................................................24 
8.1.2.3. 
Relationship of Adverse Events to Study Drug .....................................................24 
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8.1.3. 
Serious Adverse Events ...............................................................................................24 
8.1.4. 
Adverse Events Leading to Treatment Discontinuation and/or Study 
Withdrawal ...................................................................................................................24 
8.1.5. 
Deaths on Study ...........................................................................................................24 
8.1.6. 
Adverse Events of Interest ...........................................................................................24 
8.1.6.1. 
AEs within 24 Hours after the Start of Infusion ....................................................24 
8.1.6.2. 
Infections and Infections of ≥ Grade 3 Severity ....................................................25 
8.2. 
Clinical Laboratory Evaluations ........................................................................................25 
8.2.1. 
Hematology and Chemistry .........................................................................................25 
8.2.1.1. 
Change from Baseline ............................................................................................25 
8.2.1.2. 
Shifts ......................................................................................................................25 
8.2.1.3. 
Potentially Clinically Significant Laboratory Abnormalities ................................26 
8.2.2. 
Systemic Lupus Erythematosus (SLE) Panel ..............................................................27 
8.2.3. 
Anti-drug Antibody (ADA) .........................................................................................27 
8.3. 
ECG and Vital Signs ..........................................................................................................27 
8.3.1. 
Electrocardiograms (ECG)...........................................................................................27 
8.3.2. 
Vital signs ....................................................................................................................27 
9. 
PHARMACOKINETIC ANALYSIS ..................................................................................29 
10. 
PHARMACODYNAMIC ANALYSIS ...............................................................................30 
11. 
LIST OF TABLES AND FIGURES ....................................................................................31 
 
 
 
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LIST OF TABLES 
Table 1: 
Analytic Visit Windows .............................................................................15 
Table 2: 
Direction of Change Indicating Clinical Concern for Laboratory 
Tests ...........................................................................................................26 
Table 3: 
Criteria to Determine Clinically Relevant Abnormalities in Vital 
Signs ...........................................................................................................28 
LIST OF APPENDICES 
No table of figures entries found. 
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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 
PK  
pharmacokinetics 
PP 
per-protocol 
PRO 
patient-reported outcome 
QOL 
quality of life 
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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 
 
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1. 
INTRODUCTION 
BIVV009-03 is an open-label, single-arm, multicenter study in patients with primary cold 
agglutinin disease (CAD) who have hemoglobin (Hgb) level ≤ 10 g/dL and a recent history of 
blood transfusion.  Eligible patients received study drug 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. Part B will 
run for 1 year following last patient out (LPO) under Part A. As in Part A, patients will be dosed 
with BIVV009 every 2 weeks. On-site visits will be completed approximately every 3 months (at 
a minimum) for collection of pharmacokinetics (PK) and pharmacodynamics (PD) samples and 
for additional safety and efficacy measures. 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 9 weeks after the last administration of study drug. 
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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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective  
The primary objective of Part B is to evaluate the long-term safety and tolerability of BIVV009 
in patients with CAD. 
2.1.2. 
Secondary Objective  
The secondary objective of Part B is to investigate the durability of response during long-term 
treatment with BIVV009 in patients with CAD. 
2.2. 
Study Endpoints 
2.2.1. 
Safety Endpoints  
The following are the safety-related endpoints for Part B: 
• 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 electrocardiogram (ECG) data 
• Physical examination findings 
• Incidence of infections of ≥ Grade 3 severity (i.e., requiring intravenous [IV] antibiotics) 
Details of the analysis of safety endpoints are described in Section 8. 
2.2.2. 
Efficacy Endpoints 
The efficacy endpoints are the following parameters of disease activity: 
• Hemoglobin 
• Bilirubin (total) 
• Lactate dehydrogenase (LDH) 
• Haptoglobin 
• Reticulocyte Count 
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• Transfusion requirements 
• Incidence of solicited symptomatic anemia 
• Incidence of thromboembolic events 
• Incidence of hemolytic breakthrough 
• Healthcare resource utilization parameters 
• QOL assessments (FACIT-Fatigue, EQ-5D-5L, SF-12, PGIS, and PGIC) 
Details of the analysis of efficacy endpoints are described in Section 7. 
2.2.3. 
Pharmacokinetic Endpoints  
• Plasma concentrations of BIVV009  
Details of the analysis of PK endpoints are described in Section 9.1. 
2.2.4. 
Pharmacodynamic Endpoints  
• PD Primary Outcome Measures: Wieslab-CP 
• Exploratory Complement System Measures: CH50, Total C4, C1q, C1s 
Details of the analysis of PD endpoints are described in Section 9.2. 
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3. 
STUDY DESIGN 
3.1. 
Overall Study Design and Plan 
This open-label, single-arm study is designed to evaluate the efficacy, safety, and tolerability of 
BIVV009 in patients with the complement-mediated disorder, primary CAD, who have Hgb 
level ≤ 10 g/dL and a recent history of blood transfusion. 
Following completion of dosing in the 6-month treatment period in Part A of the study, 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 1 year following LPO under Part A. 
3.1.1. 
Study Sample 
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. 
3.1.2. 
Treatment 
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.  
Patients requiring treatment with permitted concomitant medications and/or transfusions will not 
be discontinued from either Part A or Part B of the study. Patients in Part B will be transfused 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 patients is asymptomatic 
A safety follow-up visit for collection of AE data, PK, PD, and antidrug antibodies (ADA) 
samples will be performed 9 weeks after administration of the last dose of study drug in patients 
who discontinue early. Samples for PK, PD, and ADA will also be collected from patients who 
experience a hemolytic breakthrough event.  
The study will be complete 12 months following LPO for Part A. At this time, all ongoing 
patients receiving treatment in Part B will discontinue additional treatment visits and will follow-
up with an EOS visit 9 weeks after last dose. 
3.1.3. 
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 discontinue treatment and will return to the clinic for EOS 
assessments 9 weeks after last dose. End of study will occur when the last patient has had his or 
her last visit (Last Patient Last Visit). 
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3.2. 
Statistical Hypothesis 
No formal statistical hypotheses will be tested. Analyses of efficacy endpoints will be primarily 
descriptive. 
3.3. 
Sample Size Justification 
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. 
3.4. 
Randomization and Blinding 
This is an open-label study with no blinding or randomization. 
3.5. 
Interim Analysis  
For the purposes of regulatory submission, an interim analysis of safety and efficacy data will be 
performed for Part B after all patients have completed Part A, while Part B is still ongoing. 
Additional interim analyses of Part B data may be performed to obtain interim safety and 
efficacy results at the Sponsor’s discretion for purposes of regulatory filings and requests, 
publications, or future planning. In general, these analyses will include safety and efficacy 
endpoints indicated in Section 2.2.1 and Section 2.2.2 through certain cutoff dates.  
 
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4. 
ANALYSIS POPULATIONS 
The following analysis populations are defined for Part B 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. 
In order to be consistent with Part B study objectives, the Per-Protocol Population described in 
the protocol was determined to have little utility and thus was not included in this SAP. 
4.1. 
Full Analysis Set (FAS)  
The Full Analysis Set is defined as all subjects who enroll into the Part B study 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. 
4.2. 
Safety Analysis Set 
Subjects who receive at least 1 dose (including partial dose) of study drug in Part B will be 
included in the Safety Analysis Set.  Note that Safety Analysis Set is the same as the Full 
Analysis Set in this study. 
4.3. 
PK Analysis Set 
Subjects who received at least 1 dose of study drug in Part B and have evaluable PK 
concentrations will be included in PK analysis set.  
4.4. 
PD Analysis Set 
Subjects who received at least 1 dose of study drug in Part B and have at least 1 evaluable PD 
sample will be included in the PD analysis set. 
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5. 
DEFINITIONS AND DATA HANDLING 
Statistical analysis will be performed by Bioverativ, using SAS® version 9.4 or higher and, 
where appropriate, additional validated software. 
5.1. 
General Principles 
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. All efficacy and safety data, including derived variables, will be listed for all visits. 
No statistical hypothesis testing is planned. 
5.1.1. 
Definitions 
Study Day 
Study Day is defined as days relative to the date of first dose of BIVV009 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 
Baseline is defined as the last non-missing value prior to the first administration of study drug in 
Part A.  If a transfusion occurred during the screening period, the baseline measure must be at 
least 7 days after the transfusion. 
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 subjects’ last dose. 
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. 
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 
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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 in Table 1, below. 
 Table 1: 
Analytic Visit Windows 
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. 
 
 
Solicited Symptomatic Anemia 
Refer to the Part A SAP for definitions regarding the severity of CAD symptomatic anemia. 
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) v20.1 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: 
o An increase of LDH from the last scheduled visit, or 
o An increase of bilirubin from the last scheduled visit, or 
o A decrease in haptoglobin from the last scheduled visit. 
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Protocol Prohibited CAD Medications 
The following concomitant medications are prohibited during the study treatment period: 
• 
Rituximab alone or as part of combination therapy 
• Cytotoxic drugs (such as fludarabine, bendamustine, ibrutinib, cyclophosphamide) 
• Other investigational drug 
The eCRF questionnaire “Did the subject receive any prohibited medications since the last 
visit?” will be used to account for protocol-prohibited CAD medication use. Medical review for 
the list of protocol-prohibited CAD medications will be reconciled with the eCRF questionnaire. 
5.1.2. 
Pooling Sites for Analysis 
Data from all investigational sites will be pooled for the analysis, unless specified otherwise.  
5.1.3. 
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, i.e., 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 
medications as prior and/or concomitant and AEs as treatment emergent or not treatment 
emergent. These inferences are described in Section 8.1. 
5.2. 
Data Summaries 
5.2.1. 
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.  
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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. 
5.2.2. 
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. This number (n) will be included with 
categorical summaries unless the same variable is also being summarized with descriptive 
statistics, in which case ‘n’ will already be provided.  
5.2.3. 
Time-to-Event Variables 
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. Additionally, a Kaplan-
Meier plot over time will be constructed. Partial dates will not be imputed, hence considered 
unknown. In general, for subjects who do not experience the event, the time-to-event will be 
censored at the study day of last assessment within the study period. 
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6. 
STUDY SUBJECTS 
6.1. 
Disposition of Subjects 
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. 
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. 
6.2. 
Demography and Baseline Disease Characteristics 
Demographics and baseline disease characteristics will be summarized for FAS. 
6.2.1. 
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 
follows: 
• Europe includes Austria, Germany, Italy, United Kingdom, and Norway. 
• North America includes the United States. 
• Asia includes Japan. 
•  Other includes Australia and New Zealand. 
6.3. 
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. All deviations occurring in Part B, both major and minor, will be 
provided in a data listing.  
6.4. 
Non-study Drug Medications 
6.4.1. 
Concomitant Medications 
Concomitant medications within Part B are those administered on or after the Part B start date. 
Concomitant medications will be coded using World Health Organization drug enhanced 
dictionary (March 2018 version or higher) and will be summarized using FAS. 
Separate tables will be generated to summarize the concomitant CAD medical treatment(s) and 
protocol prohibited CAD treatment(s) (both determined via medical adjudication). 
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Additionally, all concomitant medications taken during Part B will be provided in a data listing. 
6.4.2. 
Non-drug treatments and procedures 
Non-drug treatments and procedures administered during Part B (whether for CAD or other 
condition), excluding transfusions, will be summarized for FAS and listed. 
6.5. 
Study Drug  
Study drug exposure will be summarized using Safety Analysis Set. Subject-level information on 
dosing with study drug during Part B will also be provided in a data listing. 
6.5.1. 
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.  
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 
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. 
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7. 
EFFICACY ANALYSIS 
7.1. 
General Efficacy Principles 
Unless specified otherwise, all analyses described will be performed using FAS and will include 
summaries (see Section 5.2) and listings only. No formal hypothesis will be tested with regards 
to efficacy endpoints. 
Additionally, all efficacy data will be provided in data listings. 
7.2. 
Analysis of Efficacy Endpoints (Part B Study Period) 
All analyses described below will be performed on the Part B Study Period, starting at Week 27. 
7.2.1. 
Continuous Endpoints 
The continuous endpoints include: 
• LDH 
• Haptoglobin 
• Reticulocyte count 
The above endpoints will be summarized by visit, including change from baseline, starting at 
Week 27, and will continue through the Week 77 visit. All change from baseline tables will also 
include a summary of Baseline statistics and individual summary statistics will follow those 
presented in Section 5.2.1. For patients with more than 12 months of follow-up in Part B, all 
endpoints at the Week 79 visit and beyond will be provided in a data listing. 
7.2.2. 
Categorical Endpoints 
The categorical endpoints include: 
• Incidence of solicited symptomatic anemia  
• Incidence of other CAD-related symptoms 
The above endpoints will be summarized by visit descriptively using the FAS and will be based 
on the observed data starting at Week 27, continuing through the Week 77 visit. Baseline 
summaries will be included for comparative purposes. For patients with more than 12 months of 
follow-up in Part B, observed data at the Week 79 visit and beyond will be provided in the 
listings. 
Additionally, the following endpoints will be summarized using all data in Part B (including data 
from the Week 79 visit and beyond): 
• Incidence of thromboembolic events 
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• Incidence of hemolytic breakthrough 
7.2.3. 
Endpoints Based on Patient-reported Outcomes 
The patient-reported outcome (PRO) endpoints are as follows:  
• Continuous Endpoints 
o FACIT-Fatigue score  
o EQ-5D index score 
o EQ-5D-5L visual analogue scale  
o SF-12 physical component score (PCS) and mental component score (MCS) 
o SF-12 sub-scale scores 
• Categorical Endpoints 
o Patient’s Global Impression of Change (PGIC) 
o Patient’s Global Impression of [Fatigue] Severity (PGIS) 
o 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. For continuous variables, the overall score and its change from baseline will be 
summarized descriptively for each time point, starting at Week 27 and continuing through the 
Week 77 visit based on the FAS.  
PGIC and PGIS will be summarized as ordinal variables by visit for the FAS, starting at Week 
27 and continuing through the Week 77 visit. 
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. For patients with more 
than 12 months of follow-up in Part B, observed data at the Week 79 visit and beyond will be 
provided in the listings. 
7.2.4. 
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. 
7.3. 
Analysis of Efficacy Endpoints (Combined Study Period) 
All analyses below will be conducted on the FAS for the Combined Study Period starting at 
Baseline/Day 0. 
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7.3.1. 
Continuous Endpoints 
The continuous endpoints include: 
• Hemoglobin 
• Bilirubin (total) 
The above endpoints will be summarized by visit, starting at Baseline/Day 0 and will continue 
through the Week 77 visit. Summary tables will include change from baseline and individual 
summary statistics will follow those presented in Section 5.2.1. For patients with more than 12 
months of follow-up in Part B, all endpoints at the Week 79 visit and beyond will be provided in 
a data listing. 
Line plots of mean hemoglobin and bilirubin over time, starting at Baseline/Day 0, will be 
presented. Additionally, a line plot of mean change from baseline in hemoglobin over time, 
starting at Baseline/Day 0, will be presented. 
Additionally, the following continuous endpoints will be summarized by Study Period using 
FAS as specified in Section 5.2.1: 
• Number of transfusions and total transfusion units 
• Annualized number of transfusions and annualized transfusion units  
For number of transfusions and total transfusion units, data up to Week 77 will be considered, for 
both Part B and Combined Study Period summaries. All data after Week 77 will be provided in 
the listing. 
For annualized number of transfusions and annualized transfusion units, all Part B data will be 
considered. Annualized values will be calculated for each patient using the following formula: 
Annualized value = 
× 365.25 
 
7.3.2. 
Time-to-event Endpoints 
The time-to-event endpoints include: 
• Time to first transfusion (after the first 5 weeks of study drug administration in Part A) 
The above endpoint will be summarized using FAS as specified in Section 5.2.3. All data, 
including those beyond the Week 77 visit, will be utilized for calculating the above, time-to-
event endpoints. However, summary tables and figures will only present data up to and including 
Day 539 (ie, Study Day 540, target study day for the Week 77 visit). All other data after Study 
Day 540 will be provided in a listing. 
Number of events during the Study Period 
Total number of days during the Study Period 
 
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8. 
SAFETY ANALYSIS 
Unless stated otherwise, all safety data will be summarized for subjects in the Safety Analysis 
Set defined in Section 4.2. The summary tables may also be presented by subgroup based on the 
BIVV009 dose cohort. However, the limited number of subjects in each dose cohort and non-
randomized assignment preclude a direct comparison between the two dose cohorts. 
8.1. 
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.   
All summary tables and listings will only include treatment-emergent adverse events in Part B 
unless noted otherwise. An AE will be regarded as treatment-emergent for Part B if the date of 
AE onset is on or after the Part B start date. If an AE started in Part A but worsened in Part B, a 
new record will be created in Part B and be treated as a TEAE in Part B.   
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. 
8.1.1. 
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, and TEAEs within 24 hours after the start of 
infusion; 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. 
8.1.2. 
Treatment-emergent Adverse Events 
The incidence of TEAEs will be summarized by SOC and preferred term. 
8.1.2.1. 
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 (i.e., 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. 
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8.1.2.2. 
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. 
8.1.2.3. 
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. 
8.1.3. 
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.  
All SAEs will be listed; treatment-emergent SAEs and treatment-emergent related SAEs will be 
summarized by system organ class and preferred term. 
8.1.4. 
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. 
8.1.5. 
Deaths on Study 
A listing of deaths occurring on study will be provided. 
8.1.6. 
Adverse Events of Interest 
8.1.6.1. 
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.  
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8.1.6.2. 
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.  
8.2. 
Clinical Laboratory Evaluations 
Unless specified otherwise, all analyses described below will be performed on the Part B Study 
Period, starting at Week 27. All laboratory data will be provided in data listings; abnormal values 
relative to laboratory normal ranges will be identified. 
8.2.1. 
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 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.  
8.2.1.1. 
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. 
8.2.1.2. 
Shifts 
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 
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, high, 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 2. 
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All data collected during Part B, including data collected from unscheduled visits, will be 
included in the above-mentioned analyses. 
Table 2: 
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 
 
 
 
 
 
 
8.2.1.3. 
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 v 4.03 where possible, or are defined by 
Bioverativ’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.   
All data collected during Part B, including data collected from unscheduled visits, will be 
included in this analysis.  
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8.2.2. 
Systemic Lupus Erythematosus (SLE) Panel 
SLE panel (below) will be summarized with descriptive statistics for the Safety Analysis Set.   
The number of subjects with all negative results prior to receiving BIVV009, the number of 
subjects with at least one positive prior to receiving BIVV009, the number of subjects who tested 
negative at all post-baseline assessments, and the number of subjects who tested positive at any 
post-baseline assessment will be summarized for the individual SLE parameters as well as the 
combined (overall) SLE panel results. 
Systemic Lupus Erythematosus Panel 
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).  
8.2.3. 
Anti-drug Antibody (ADA) 
Subjects will be evaluated for anti-drug antibodies at Baseline and at the ET/EOS/Safety Follow-
up visit 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. 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. 
8.3. 
ECG and Vital Signs 
Unless specified otherwise, all analyses described below will be performed on the Part B Study 
Period, starting at Week 27, and by-visit summaries will be presented through the end of Part B. 
8.3.1. 
Electrocardiograms (ECG) 
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. 
8.3.2. 
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 
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unscheduled visits, will be included in this analysis. The criteria for potentially clinically 
relevant post-baseline abnormalities are shown below in Table 3. 
Table 3: 
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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9. 
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.  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. 
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10. 
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. The above analyses will be conducted using the PD Analysis Set for the 
Cumulative Study Period. 
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11. 
LIST OF TABLES AND FIGURES  
List of tables and figures 
Background/Demography 
Part B: Summary of disposition 
Part B: Summary of enrollment by country and site 
Part B: Summary of subjects attending each visit 
Part B: Summary of demographics and baseline characteristics 
Part B: Summary of all major protocol deviations 
Concomitant Medications 
Part B: Summary of concomitant medications 
Part B: Summary of concomitant CAD medications 
Part B: Summary of protocol-prohibited concomitant CAD medications 
Part B: Summary of concomitant non-drug treatments (excluding transfusions) 
Exposure 
Part B: Summary of BIVV009 exposure: Part B Study Period 
Part A/B: Summary of BIVV009 exposure: Combined Study Period 
Efficacy (Part B Study Period) 
Part B: Summary of change from baseline in lactate dehydrogenase (U/L) by visit 
Part B: Summary of change from baseline in haptoglobin (g/L) by visit 
Part B: Summary of change from baseline in reticulocyte count (10^9/L) by visit 
Part B: Summary of incidence of solicited symptomatic anemia by visit 
Part B: Summary of incidence of other CAD-related symptoms by visit 
Part B: Summary of incidence of thromboembolic events 
Part B: Summary of incidence of hemolytic breakthrough 
QOL/PRO 
Part B: Summary of change from baseline in FACIT-Fatigue score by visit 
Part B: Summary of change from baseline in EQ-5D-5L scores by visit 
Part B: Summary of EQ-5D-5L descriptive system 
Part B: Summary of change from baseline in SF-12 component scores by visit 
Part B: Summary of change from baseline in SF-12 sub-scale scores by visit 
Part B: Summary of Patient’s Global Impression of Change (PGIC) 
Part B: Summary of Patient’s Global Impression of Fatigue Severity (PGIS) by visit 
Efficacy (Combined Study Period) 
Part A/B: Summary of change from baseline in hemoglobin (g/dL) by visit 
Part A/B: Summary of change from baseline in total bilirubin (umol/L) by visit (excluding subjects 
                with Gilbert’s syndrome) 
Part A/B: Plot of mean hemoglobin (g/dL) (+/- SE) by visit 
Part A/B: Plot of mean total bilirubin (umol/L) (+/- SE) by visit (excluding subjects with Gilbert’s 
                syndrome 
Part A/B: Plot of mean change from baseline in hemoglobin (g/dL) (+/- SE) by visit 
Part A/B: Summary of number of transfusions and units by study period 
Part A/B: Summary of time to first transfusion (after the first 5 weeks of BIVV009 administration in 
                Part A) 
Part A/B: Plot of time to first transfusion (after the first 5 weeks of BIVV009 administration in Part A) 
Safety: Adverse Events 
Part B: Overall summary of treatment-emergent adverse events 
Part B: Summary of treatment-emergent adverse events 
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Part B: Summary of treatment-emergent adverse events by preferred term in descending order of 
            incidence 
Part B: Summary of grade 3 or higher TEAEs by preferred term in descending order of incidence 
Part B: Summary of treatment-emergent adverse events by severity 
Part B: Summary of treatment-emergent adverse events by relationship to treatment 
Part B: Summary of treatment-emergent serious adverse events 
Part B: Summary of treatment-emergent serious adverse events by preferred term in descending order 
            of incidence 
Part B: Summary of related treatment-emergent serious adverse events 
Part B: Summary of treatment-emergent adverse events within 24 hours of the start of infusion 
Part B: Summary of infections of grade 3 or higher by preferred term 
Safety: Laboratory 
Part B: Summary of change from baseline in hematology laboratory values by visit 
Part B: Summary of change from baseline in chemistry laboratory values by visit 
Part B: Shifts from baseline to minimum/maximum post-baseline value for laboratory results: 
            Hematology 
Part B: Shifts from baseline to minimum/maximum post-baseline value for laboratory results: 
            Chemistry 
Part B: Summary of shifts to low (high) for laboratory results: Hematology 
Part B: Summary of shifts to low (high) for laboratory results: Chemistry 
Part B: Summary of potentially clinically significant laboratory abnormalities: Hematology 
Part B: Summary of potentially clinically significant laboratory abnormalities: Chemistry 
Part A/B: Summary of systemic lupus erythematosus (SLE) based on combined SLE panel parameters 
Part A/B: Summary of systemic lupus erythematosus (SLE) by each SLE parameter 
Part A/B: Summary of ADA results 
Part B: Summary of ECG clinical interpretations by visit 
Part B: Summary of ECG clinical interpretation shifts from baseline 
Part B: Summary of change from baseline in vital signs by visit 
Part B: Summary of potentially clinically significant vital signs 
PK/PD 
Part A/B: Summary of BIVV009 plasma concentrations by visit 
Part A/B: Plot of BIVV009 concentrations over time by subject 
Part A/B: Plot of mean (+/- SE) BIVV009 concentration over time 
Part A/B: Summary of change from baseline in PD parameter results by visit 
 
VV-CLIN-0546744 1.0
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