Clinical trial NCT02151526
Conditions: Beta-Thalassemia Major Sickle Cell Disease
Sponsor: bluebird bio
Start date: 2013-06-07; Completion date: 2019-02-26
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a Phase 1/2, open label, safety, and efficacy study of the administration of LentiGlobin BB305 Drug Product to participants with either transfusion dependent beta-thalassemia (TDT) or sickle cell disease (SCD).

Detailed description:

Arms: arm 1: Following myeloablative conditioning with IV busulfan for 4 consecutive days (dose may be adjusted as per protocol) and subsequent daily monitoring of busulfan levels for confirmation of adequate washout, a single dose cluster of differentiation (CD) 34+ cells/kg LentiGlobin BB305 Drug Product was administered to participants by IV infusion.
Interventions: intervention 1: LentiGlobin BB305 Drug Product
Intervention descriptions: intervention 1: LentiGlobin BB305 Drug Product was administered by intravenous (IV) infusion.

Protocol documents:
Prot_000.pdf: 
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1 
INTRODUCTION .............................................................................................................. 19 
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7KHEKHPRJORELQRSDWKLHVDV'LVHDVH7DUJHWVIRU*HQH7KHUDS\ 
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2 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 28 
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6WXG\2EMHFWLYHV 
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3 
INVESTIGATIONAL PLAN ............................................................................................ 29 
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4 
Study Population ................................................................................................................. 34 
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5 
Study Treatments ................................................................................................................ 38 
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6 
STUDY ASSESSMENTS ................................................................................................... 46 
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REFERENCES ................................................................................................................... 72 
INVESTIGATOR STATEMENT ............................................................................................ 76 
 


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The E-hemoglobinopathies as Disease Targets for Gene Therapy 
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1.2
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1.2.1
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Figure 1-1 
Changes Made between Lentiviral Vector LentiGlobin HPV569 and 
LentiGlobin BB305 Lentiviral Vector 
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Treatment Discontinuation and Enrollment Suspension Criteria 
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Stopping Rules for Individual Subjects for Busulfan IV Conditioning 
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Individual Subject Stopping Rules 
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Subject Exclusion Criteria 
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4.4
Subject Identification and Registration 
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4.5
Subject Withdrawal from the Study 
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5
STUDY TREATMENTS 
5.1
Description of LentiGlobin BB305 Lentiviral Vector and LentiGlobin 
BB305 Drug Product 
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5.2
Summary of Treatments to be Performed or Administered 
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Table 5-1 
Cell Source, Usage, and Minimum Dose of LentiGlobin BB305 Drug 
Product or Rescue for E-ThalM and SCD 
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5.2.1
Mobilization and Apheresis Procedure (for E-ThalM Subjects) 
5.2.1.1
Mobilization 
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5.2.1.2
Apheresis Procedure 
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5.2.2
Bone Marrow Harvest Procedure (All SCD Subjects and Some 
β-ThalM Subjects) 
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5.2.3
Drug Product Manufacturing Process 
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5.2.4
Conditioning 
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5.2.4.1
Rationale for the Use of Busulfan IV for Conditioning 
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5.2.5
Infusion Procedures 
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5.3
Storage and Stability 
5.3.1
LentiGlobin BB305 Lentiviral Vector 
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LentiGlobin BB305 Drug Product 
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Blinding and Breaking the Blind 
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LentiGlobin BB305 Lentiviral Vector Packaging, Labeling, Shipment, 
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Duration of Subject Participation 
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Product Accountability 
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LentiGlobin BB305 Drug Product 
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Prior and Concomitant Treatment 
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Concomitant Treatments during Conditioning 
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6
STUDY ASSESSMENTS 
6.1
Schedule of Events 
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Testing for Replication Competent Lentivirus (RCL) 
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6.3.15
Proviral Integration Site Analysis in Blood and Bone Marrow by 
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6.3.16
Assessment of Clonal Dominance and/or Suspicion of 
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6.3.16.1
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6.3.16.2
Other Criteria that can Trigger Clinical Work-up for Malignancy 
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6.3.16.3
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6.3.17
Adverse Events 
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Procedures for SAE Reporting 
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6.3.18
Pregnancy 
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6.3.19
Unscheduled Visits 
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6.3.20
Long-Term Follow-Up Protocol 
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6.4
Appropriateness of Measurements 
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7
STATISTICAL PROCEDURES 
7.1
Sample Size Estimation 
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Populations for Analysis 
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7.3
Procedures for Handling Missing, Unused, and Spurious Data 
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7.4
Statistical Methods 
7.4.1
General Methods 
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Disposition of Subjects 
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7.4.3
Demographic and Baseline Characteristics 
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7.5
Efficacy Analysis 
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7.5.1
For All Subjects 
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7.5.2
For SCD Subjects 
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7.6
Safety Analysis 
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Procedures for Reporting Deviations to Original Statistical Analysis 
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ADMINISTRATIVE AND REGULATORY REQUIREMENTS 
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Ethical Considerations 
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Comité de Surveillance 
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Subject Information and Informed Consent 
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Subject Confidentiality 
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Protocol Compliance 
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Direct Access to Source Data 
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Case Report Form Completion 
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8.8
Record Retention 
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Liability and Insurance 
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Publication of Study Findings and Use of Information 
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8.10.1
Publications 
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Presentations 
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REFERENCES 
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene Therapy of the 
-Hemoglobinopathies (Sickle Cell Anemia and -Thalassemia Major) by Transplantation 
of Autologous CD34+ Stem Cells Transduced Ex Vivo with a Lentiviral A-T87Q-Globin 
Vector (LentiGlobin BB305 Drug Product) 
Protocol HGB-205 
EudraCT No. 2012-000695-42 
Protocol Number: 
Protocol Version and Date: 
HGB-205 
Version 7.0, 19 May 2016 
Name of Test Drug: 
LentiGlobin BB305 Drug Product 
Phase: 
Phase 1/2 
Methodology: 
Open-label, Safety, and Efficacy 
Sponsor: 
bluebird bio, Inc. 
60 Binney Street 
Cambridge, MA 02142 USA 
Tel:  (001) 339-499-9300 
Fax:  (001) 339-499-9432 
Sponsor Representative: 
, MD, PhD 
, Clinical Development 
Analysis Plan Date: 
22 May 2019 
Analysis Plan Version: 
Version 4.0 
PPD
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Statistical Analysis Plan, Protocol HGB-205 
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Page 2 
APPROVAL OF STATISTICAL ANALYSIS PLAN 
SIGNATURE PAGE 
Title: 
A Phase 1/2 Open Label Study Evaluating the Safety and Efficacy of Gene 
Therapy of the -Hemoglobinopathies (Sickle Cell Anemia and -Thalassemia 
Major) by Transplantation of Autologous CD34+ Stem Cells Transduced Ex 
Vivo with a Lentiviral A-T87Q-Globin Vector (LentiGlobin BB305 Drug 
Product) 
Sponsor: bluebird bio, Inc. 
 
 
 
Author: 
, PhD 
, Biostatistics 
bluebird bio, Inc. 
60 Binney Street 
Cambridge, MA 02142 
 
Signature:___________________________________ 
 
Date:_______________________________________ 
 
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Reviewer Approval: 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. 
 
, MD, PhD  
, Clinical Research Development 
bluebird bio, Inc. 
60 Binney Street 
Cambridge, MA 02142 
 
 
Signature:____________________________ 
 
Date:________________________________ 
, MD, PhD 
, Clinical Research Development 
bluebird bio, Inc. 
60 Binney Street 
Cambridge, MA 02142 
 
 
Signature:____________________________ 
 
Date:________________________________ 
, MS 
, Regulatory 
bluebird bio, Inc. 
60 Binney Street 
Cambridge, MA 02142 
 
 
Signature:____________________________ 
 
Date:________________________________  
, MD 
, Pharmacovigilance 
bluebird bio, Inc. 
60 Binney Street 
Cambridge, MA 02142 
 
 
Signature:____________________________ 
 
Date:________________________________ 
, PhD 
, Biostatistics 
bluebird bio, Inc. 
60 Binney Street 
Cambridge, MA 02142 
 
 
Signature:____________________________ 
 
Date:________________________________ 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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TABLE OF CONTENTS 
TABLES INCLUDED IN THE TEXT ............................................................................................7 
VERSION HISTORY ......................................................................................................................8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................9 
1. 
INFORMATION FROM THE STUDY PROTOCOL ......................................................11 
1.1. 
Introduction and Objectives ...................................................................................11 
1.1.1. 
Introduction .......................................................................................................11 
1.1.2. 
Study Objectives ...............................................................................................11 
1.2. 
Study Design ..........................................................................................................12 
1.2.1. 
Synopsis of Study Design .................................................................................12 
1.2.2. 
Randomization Methodology ............................................................................12 
1.2.3. 
Unblinding ........................................................................................................12 
1.2.4. 
Study Stopping Rules ........................................................................................12 
1.2.5. 
Study Procedures ...............................................................................................12 
1.2.6. 
Safety, Efficacy, and Pharmacodynamic Parameters ........................................12 
2. 
SUBJECT POPULATION.................................................................................................15 
2.1. 
Population Definitions ...........................................................................................15 
2.2. 
Protocol Deviations ................................................................................................15 
3. 
GENERAL STATISTICAL METHODS ..........................................................................16 
3.1. 
Sample Size Justification .......................................................................................16 
3.2. 
General Methods ....................................................................................................16 
3.3. 
Computing Environment ........................................................................................16 
3.4. 
Baseline Definitions ...............................................................................................16 
3.5. 
Methods of Pooling Data .......................................................................................17 
3.6. 
Adjustments for Covariates....................................................................................17 
3.7. 
Subpopulations .......................................................................................................17 
3.8. 
Withdrawals, Dropouts, Loss to Follow-up ...........................................................17 
3.9. 
Missing, Unused, and Spurious Data .....................................................................17 
3.9.1. 
Transfusion Information....................................................................................17 
3.9.2. 
Partial Dates ......................................................................................................18 
3.10. 
Visit Windows .......................................................................................................18 
3.11. 
Multiple Comparisons/Multiplicity .......................................................................19 


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3.12. 
Interim Analyses ....................................................................................................19 
3.13. 
Final Analyses ........................................................................................................19 
4. 
STUDY ANALYSES ........................................................................................................20 
4.1. 
Subject Disposition ................................................................................................20 
4.2. 
Demographic and Baseline Characteristics ...........................................................20 
4.3. 
Mobilization, Harvest, Transplant and Conditioning Details ................................21 
4.4. 
Safety Analyses ......................................................................................................22 
4.4.1. 
Adverse Events..................................................................................................23 
4.4.2. 
Laboratory Data ................................................................................................25 
4.4.3. 
Transplant-Related Mortality ............................................................................27 
4.4.4. 
Vital Signs, Karnofsky Performance Status, and Physical Examination ..........27 
4.4.5. 
Concomitant Medications and Procedures ........................................................27 
4.4.6. 
Overall Survival ................................................................................................27 
4.4.7. 
Integration Site Analysis ...................................................................................27 
4.4.8. 
Replication Competent Lentivirus ....................................................................28 
4.5. 
Efficacy Evaluation ................................................................................................28 
4.5.1. 
Red Blood Cell Transfusion Requirements and Transfusion Reduction 
(subjects with TDT or SCD) .............................................................................28 
4.5.2. 
Characterization of Transfusion Independence (subjects with TDT 
only) ..................................................................................................................29 
 
 
4.5.4. 
Sickle Cell Disease Related Parameters (subjects with SCD only) ..................30 
 
 
 
 
 
 
4.5.8. 
Other Clinical Measures (subjects with TDT or SCD) .....................................31 
4.6. 
Pharmacokinetic and Pharmacodynamic Evaluations ...........................................32 
5. 
CHANGES TO PLANNED ANALYSES .........................................................................33 
6. 
CLINICAL STUDY REPORT APPENDICES .................................................................46 
 
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TABLES INCLUDED IN THE TEXT 
Table 1: 
Midpoint Windows for VCN, Fraction Data, and Laboratory Data ...........................19 
Table 2: 
SCD-Related Events ...................................................................................................30 
 


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VERSION HISTORY 
Version Number 
Approval Date 
Version 1.0 
23MAR2016 
Version 2.0 
13MAR2017 
Version 3.0 
27JUN2017 
Version 4.0 
22MAY2019 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
ACS 
Acute chest syndrome 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ALP 
Alkaline phosphatase 
AST 
Aspartate aminotransferase 
CBC 
Complete blood count 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria For Adverse Events 
DLco 
Carbon monoxide diffusing capacity 
ECG 
Electrocardiogram 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
G-CSF 
Granulocyte-colony stimulating factor 
GGT 
Gamma glutamyl transferase 
GRRs 
Global reference ranges 
Hb 
Hemoglobin 
HSA 
Human serum albumin 
HSC 
Hematopoietic stem cell 
HSCT 
Hematopoietic stem cell transplant 
ICH 
International Conference on Harmonisation 
ISA 
Integration Site Analysis 
ITT 
Intent-to-treat [population] 
IV 
Intravenous 
LDH 
Lactic dehydrogenase 
LVEF 
Left ventricular ejection fraction 
MAA 
Marketing authorization application 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRA 
Magnetic resonance angiography 
MRI 
Magnetic resonance imaging 
NE 
Neutrophil Engraftment  
PBL 
Peripheral blood leukocyte 
PT 
Preferred term 


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Abbreviation 
Definition 
PTT 
Partial Thromboplastin Time 
pRBC 
Packed red blood cell(s) 
RBC 
Red blood cell 
RCL 
Replication competent lentivirus 
Rel Day 
Relative study day 
RV 
Respiratory volume 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SCD 
Sickle cell disease 
SD 
Standard deviation 
SEP 
Successful engraftment population 
SI 
International system of units 
SOC 
System organ class 
TBL 
Total bilirubin 
TDT 
Transfusion-dependent β-thalassemia 
TI 
Transfusion independence 
TLC 
Total lung capacity 
TP 
Transplant population 
TR 
Transfusion reduction 
VC 
Vital capacity 
VCN 
Vector copy number 
VOC 
Vaso-occlusive crises 
VOEs 
Vaso-occlusive event 
WBC 
White blood cell 
WHO 
World Health Organization 


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1. 
INFORMATION FROM THE STUDY PROTOCOL 
1.1. 
Introduction and Objectives 
1.1.1. 
Introduction 
This document is the statistical analysis plan (SAP) for Study HGB-205, A Phase 1/2, Open 
Label Study Evaluating the Safety and Efficacy of Gene Therapy in Subjects with 
β-Hemoglobinopathies (Sickle Cell Anemia and β-Thalassemia Major) by Transplantation of 
Autologous CD34+ Stem Cells Transduced Ex Vivo with a Lentiviral βA-T87Q-Globin Vector 
(LentiGlobin BB305 Drug Product). It is based on protocol version 7.0, dated 19 May 2016. 
The SAP is designed to outline the methods to be used in the analysis of study data in order to 
answer the study objectives. Populations for analysis, data handling rules, statistical methods, 
and formats for data presentation are provided. The statistical analyses and summary tabulations 
described in this SAP will provide the basis for the results sections of the final clinical study 
report (CSR) for this trial. 
An interim analysis of subjects with β-thalassemia major (also referred to as transfusion-
dependent β-thalassemia [TDT]) was performed in support of the regulatory submission of a 
marketing authorization application (MAA) for LentiGlobin BB305 Drug Product for the 
treatment of TDT. The interim analysis was conducted when the last subject with TDT treated in 
Study HGB-205 completed their Month 24 Visit. Subjects with sickle cell disease (SCD) were 
not included in this interim analysis. This SAP is intended to be used for the interim analysis as 
well as the final analysis when the last subject for either indication has completed their Month 24 
Visit as specified in the protocol or discontinued from the study. The SAP also includes 
additional statistical analyses that, in conjunction with those outlined in the current protocol, are 
designed to demonstrate the consistency of efficacy and safety results across multiple clinical 
studies. Any additional analyses outside of the current protocol will be detailed in Section 5 of 
this SAP. 
1.1.2. 
Study Objectives 
The primary study objective is to determine the safety, tolerability, and success of engraftment 
with an autologous CD34+ cell-enriched population that contains cells transduced with 
LentiGlobin BB305 lentiviral vector encoding the βA-T87Q_ globin gene and suspended in human 
serum albumin (HSA) (Albunorm™ 5%) (drug product) after conditioning with busulfan IV in 
subjects with severe SCD or TDT. 
Secondary objectives are to: 
 Quantify gene transfer efficiency and expression: 
 Evaluate expression of βA-T87Q_ globin in whole blood. 
 Quantify the hematopoietic chimerism resulting from treatment with drug product 
(vector copy number [VCN]). 


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 Measure the effects of transplantation with drug product on the expression of disease-
specific biological parameters and clinical events, including the volume of blood 
transfusions for both severe SCD and TDT, and for subjects with severe SCD, the 
number of vaso-occlusive crises (VOCs) and acute chest syndrome (ACS) events in 
each subject compared with the 2-year pre-treatment period prior to informed 
consent. 
1.2. 
Study Design 
1.2.1. 
Synopsis of Study Design 
This is a single arm, single site, single dose, Phase 1/2 study in subjects with severe SCD, or 
TDT [transfusion dependence is defined as having received at least 100 mL/kg/year of packed 
red blood cells (pRBCs) in each of the 2 years preceding enrollment]. 
The study will evaluate the safety and efficacy of autologous hematopoietic stem cell transplant 
(HSCT) using a CD34+ cell-enriched population that contains cells transduced with LentiGlobin 
BB305 lentiviral vector encoding βA-T87Q-globin. 
The study has 4 distinct stages, as follows: 
Stage 1: 
Screening to determine eligibility 
Stage 2: 
Autologous CD34+ cell collection, LentiGlobin BB305 Drug Product 
manufacture and disposition 
Stage 3: 
Myeloablative conditioning and infusion of LentiGlobin BB305 Drug Product 
Stage 4: 
Follow-up, through engraftment and 24 months after drug product infusion 
1.2.2. 
Randomization Methodology 
Randomization was not performed as this is a single treatment, open-label study. 
1.2.3. 
Unblinding 
Unblinding is not applicable to this open-label study. 
1.2.4. 
Study Stopping Rules  
See study protocol section 3.4.2.2 for stopping rules for this study. 
1.2.5. 
Study Procedures 
The schedule of events to be performed is provided in the study protocol section 6.1. 
1.2.6. 
Safety, Efficacy, and Pharmacodynamic Parameters 
The endpoints stated in the protocol are included, but additional analyses intended to allow 
consistent evaluation across multiple studies using LentiGlobin BB305 Drug Product to treat 
TDT or SCD have been added. These additional analyses are outlined in Section 5 of this SAP. 


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1.2.6.1. 
Safety Parameters 
The safety endpoints are: 
 Success and kinetics of hematopoietic stem cell (HSC) engraftment 
 Incidence of transplant-related mortality through 100 and 365 days post drug product 
infusion 
 Overall survival 
 Detection of vector-derived replication competent lentivirus (RCL) in any subject 
 Characterization of events of insertional mutagenesis leading to clonal dominance or 
leukemia. 
 Monitoring of laboratory parameters and frequency and severity of clinical adverse 
events (AEs) 
1.2.6.2. 
Efficacy Parameters 
The efficacy endpoints include the effects on the expression of disease-specific biological 
parameters and clinical events and differ for subjects with TDT and SCD. It was anticipated to 
have N=4 subjects with TDT and N=3 subjects with SCD at study’s end. 
Data for the N=4 subjects with TDT were included for the analysis in support of the MAA. 
Efficacy Endpoints for Subjects with TDT: 
Characterization of Transfusion Reduction (TR) 
 Reduction of at least 50%, 60%, 75%, 90% or 100% in average annual pRBC 
transfusion volume from 6 months post-drug product infusion through last visit 
(compared to the average annual pRBC transfusion volume requirement during the 2 
years prior to enrollment). Frequency of pRBC transfusions from 6 months post-drug 
product infusion through last visit (normalized to a 12-month period) compared to the 
annual frequency of transfusions during the 2 years prior to enrollment. 
 Average annual pRBC transfusion volume (mL/kg/year) from 6 months post-drug 
product infusion through last visit, including change and percent change from the 
average annual transfusion volume during the 2 years prior to enrollment. 
 Where available, weighted average nadir hemoglobin (Hb) from 6 months post-drug 
product infusion through last visit compared to weighted average nadir Hb during the 
2 years prior to enrollment, where nadir is defined as: 
 Pre-treatment: most recent Hb level within 3 days prior to each pRBC transfusion. 
 Post-treatment:  
 most recent Hb level within 3 days prior to each pRBC transfusion, and  
 if there is a period of more than 60 days without transfusion, all Hb records 
between Day 61 and up to day of last visit or next transfusion (inclusive) will 
also be included. 


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Characterization of Transfusion Independence (TI)  
 Proportion of subjects with TI, defined as a weighted average Hb ≥9 g/dL without 
any pRBC transfusions for a continuous period of ≥12 months at any time during the 
study after drug product infusion. See Section 4.5.1 for details on characterization of 
TI. 
 Duration of TI. 
 Time from drug product infusion to last RBC transfusion prior to becoming TI. 
 Time from drug product infusion to TI.  
 Weighted average nadir Hb during period of TI. 
Endpoints for Subjects with SCD: 
 Number of vaso-occlusive crises (VOC), acute chest syndrome (ACS) and vaso-
occlusive events (VOEs), which includes both VOC or ACS, through 24 months post 
drug-product infusion compared to 2 years prior to enrollment. 
 Evaluation of changes in the nature or frequency of the subject-specific main 
inclusion criteria, not described by the above bullet, including cardiac, neurologic, 
and bone.  
 RBC transfusion requirements (measured in milliliters [mL] per kilogram [kg]) per 
year post-transplant compared to the 2 years prior to enrollment, adjusted for time, as 
applicable. 
Exploratory Efficacy Endpoints (for TDT or SCD subjects): 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
. 
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Pharmacodynamic Parameters (for TDT or SCD subjects): 
The pharmacodynamic endpoints of gene transfer efficiency and expression will be quantified by 
measurement of the following: 
 Therapeutic globin expression, as measured by HbA-T87Q in peripheral blood and the 
ratio of α-globin and to all β-like-globins. 
 Vector copy number in cell populations from peripheral blood and, if collected, bone 
marrow. 
2. 
SUBJECT POPULATION 
2.1. 
Population Definitions 
The following subject populations will be evaluated and used for presentation and analysis of the 
data: 
 Intent-to-Treat (ITT) Population: All subjects who initiate any study procedures, 
beginning with mobilization (by granulocyte-colony stimulating factor [G-CSF] with 
or without plerixafor) or bone marrow harvest. 
 Transplant Population (TP): All subjects in the ITT population who undergo 
LentiGlobin BB305 Drug Product infusion. 
 Successful Engraftment Population (SEP): All subjects who have successful 
neutrophil engraftment after LentiGlobin BB305 Drug Product infusion. 
The ITT population is the primary population for the analysis of safety parameters. The TP is the 
primary population for the analysis of efficacy and pharmacodynamic parameters. The TP is also 
the primary population for transplant-related safety parameters (e.g., success and kinetics of 
engraftment and incidence of transplant-related mortality through 100 days and 365 days post 
drug product infusion) in the event that TP and ITT are not identical. The SEP will be used to 
provide supportive evidence for subjects who successfully engraft, defined as 3 consecutive 
absolute neutrophil count [ANC] laboratory values ≥0.5×109/L obtained on different days. If the 
populations are the same, separate analyses will not be performed. 
2.2. 
Protocol Deviations 
All protocol deviations will be presented in a data listing; major deviations will be indicated. 
Categorization of protocol deviations will be determined by a review of the protocol deviation 
data collected on the case report form (CRF). Determination of major/minor and categorization 
of each protocol deviation type will be made prior to database lock. 


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3. 
GENERAL STATISTICAL METHODS 
3.1. 
Sample Size Justification 
Sample size was not determined by formal statistical methods, but by extent and availability of 
data. 
3.2. 
General Methods 
All output will be incorporated into Microsoft Word or Adobe Acrobat PDF files, sorted and 
labeled according to International Conference on Harmonisation (ICH) recommendations, and 
formatted to the appropriate page size(s). 
Summary tabulations will be produced for a subset of parameters identified in Section 4, with the 
remaining data reported in data listings. For categorical variables, summary tabulations of the 
number and percentage of subjects within each category (with a category for missing data) of the 
parameter will be presented. For continuous variables, the number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum values will be presented. 
Longitudinal data (collected serially over time on study and follow-up) will be presented by 
appropriate time intervals, such as monthly, quarterly and so forth, depending on the nature of 
the data. 
This study is primarily descriptive in nature; therefore, there are no formal statistical hypothesis 
tests planned. Data will be presented by indication, and within indication by subject. 
For purposes of calculations, a month will be defined as 365.25/12 (30.4375) days and a year as 
365.25 days. For reporting by month, calculations should be rounded to the nearest day (i.e., the 
calculated value at 18 months, 547.88, would be rounded to 548 days). 
All data listings that contain an evaluation date will contain a relative study day (Rel Day). Pre- 
and post-drug product infusion study days are numbered relative to the day of infusion, which is 
designated as Day 1. 
3.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software Version 9.3 
or higher, unless otherwise noted. Medical history and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA, version 19.0 or higher). Concomitant 
medications will be coded using the World Health Organization (WHO) Drug Dictionary (March 
2016 or later). 
3.4. 
Baseline Definitions 
Two years of retrospective pre-enrollment data will be collected for each subject in the study, so 
that each subject may serve as his/her own control for the parameters of pRBC transfusion 
requirements (mL/kg, number of pRBC transfusions), VOC, ACS and VOEs (for SCD subjects) 
and number of in-patient hospitalizations/hospitalization days. Baseline will be defined as the 
average of the transfusion requirements per year or number of in-patient 
hospitalizations/hospitalization days per year, as relevant, over the 2 years prior to study 


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enrollment (date of informed consent). For other efficacy parameters as well as for 
pharmacodynamic parameters, baseline will be defined as the most recent measurement prior to 
conditioning for TDT subjects and the first measurement obtained during screening for SCD 
subjects. The conditioning start date will be defined as the first date of busulfan administration. 
For safety, including key laboratory (hematology and chemistry) parameters, the most recent 
value prior to mobilization (subjects with TDT) or the first value during screening (subjects with 
SCD) will be used as the baseline assessment. 
3.5. 
Methods of Pooling Data 
Tabular summaries will report data by indication (SCD, TDT). 
3.6. 
Adjustments for Covariates 
No formal statistical analyses that adjust for possible covariate effects are planned. 
3.7. 
Subpopulations 
Due to small numbers of subjects, no analysis of subgroups will be performed. 
3.8. 
Withdrawals, Dropouts, Loss to Follow-up 
Subjects withdrawn from the study prior to conditioning (myeloablation) will be replaced. 
Subjects who begin conditioning but are subsequently withdrawn will not be replaced. 
3.9. 
Missing, Unused, and Spurious Data 
3.9.1. 
Transfusion Information  
If a subject is missing a pRBC volume (mL) when it is known a transfusion took place, but the 
number of pRBC units is reported, then the standard volume per unit for that transfusion 
provided on the CRF will be substituted and normalized for subject weight in kg. If neither 
number of units nor volume is reported, then the imputed volume, for transfusions rendered 
before study drug infusion, will be the mean volume that the patient has received in the 2 years 
prior to enrollment. If the unknown blood volume was transfused after study drug infusion, then 
the imputed volume will be the mean volume that that patient received between study drug 
infusion and most recent study visit; if no other transfusions have been given during this time 
frame, then the pre-study drug mean volume will be used. If all volumes are reported in units and 
there is no standard volume per unit provided, then 300 mL/unit will be imputed. 
After drug product infusion, subjects who do not have a documented Hb value for any period 
greater than 6 months will be analyzed as follows for TI: if the values before and after the gap 
are both ≥9 g/dL and there are no transfusions during the gap, they are evaluable for TI during 
this period. If either value is <9 g/dL, this period cannot be counted towards the definition of TI. 
Subjects must have a minimum of 12 months of pre-study enrollment transfusion data available 
to be included in the analysis of reduction of transfusion requirements. 


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3.9.2. 
Partial Dates 
When tabulating AE and concomitant medication data, partial onset/start dates will be handled as 
follows: if the day of the month is missing, the onset day will be set to the first day of the month 
unless it is the same month and year as study drug treatment (i.e., drug product infusion). In this 
case, in order to conservatively report the event as treatment-emergent, the onset date will be 
assumed to be the date of study drug treatment, except in cases where this will lead to a start date 
being after stop date. In these situations, the original rule will be applied. If the onset day and 
month are both missing, the day and month will be assumed to be January 1, unless the event 
occurred in the same year as the study drug treatment. In this case, the event onset will be coded 
to the day of study dug treatment to conservatively report the event as treatment-emergent, 
except in cases where this would lead to a start date being after stop date. In these situations, the 
original rule will apply. A missing onset date will be coded as the day of study drug treatment. 
For AE end dates, an event missing the day of the month will be set to the last day of the month, 
and an end date missing both day and month will be set to missing. 
Partial dates for diagnosis of β-Thalassemia Major/TDT and SCD will be handled as follows: if 
the day of the month is missing, the onset day will be set to the first day of the month. If the 
onset day and month are both missing, the day and month will be assumed to be January 1. If 
imputation of partial date results in a date of diagnosis less than the date of birth, then the date of 
birth is used as the date of diagnosis; age at diagnosis will be zero for these subjects. 
For partial hospitalization dates: if there are partial hospitalization dates (date admitted, date 
discharged) and the month and year of the admission and discharge dates are the same, then the 
duration of hospitalization is imputed as 1 day. If the month of discharge is after the month of 
admission and the day of discharge is missing, the day of discharge is set to the first day of the 
month. If the month of discharge is after the month of admission and the day of admission and 
the day of discharge are both missing, both days will be set to the first day of the month.  
3.10. 
Visit Windows 
It is expected that all visits should occur according to the protocol schedule. All data used in 
summaries will be tabulated per the evaluation visit as recorded on the CRF even if the 
assessment is outside of the visit window. If the evaluation visit is missing in the database but 
there is data from an unscheduled or additional visit that falls within a pre-defined midpoint 
window, the data from the unscheduled or additional visit will be used in data summaries. For 
subjects with multiple evaluations within a midpoint window, the evaluation closest to the target 
visit date will be used. 
Midpoint windows for VCN, fraction data, and laboratory parameters (hematology, chemistry, 
and iron studies) are listed in Table 1. 


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Table 1: 
Midpoint Windows for VCN, Fraction Data, and Laboratory Data 
Timepoint 
 
Follow-Up 
Month: 
 
M1 
M2 
M3 
M4.5* 
M6 
M9 
M12 
M15 
M18 
M21 
M24 
Day: 
 
D30 
D60 
D90 
D135 
D180 
D270 
D360 
D450 
D540 
D630 
D720 
Analysis 
Window 
(Day)  
Start 
> 1 
46 
76 
114 
159 
226 
316 
406 
496 
586 
676 
End 
45 
75 
113 
158 
225 
315 
405 
495 
585 
675 
776 
*Only available for some subjects.  
 
Windows for time course distributions of AEs and concomitant medications are based on the 
following time periods relative to drug product infusion: 
 Date of informed consent until either date of initiation of mobilization (TDT subjects) 
or bone marrow harvest (SCD subjects). 
 Date of initiation of mobilization/bone marrow harvest until date of initiation of 
conditioning. 
 Date of initiation of conditioning until the date of neutrophil engraftment (NE). 
 Date of NE through Month 24 Visit. 
 Day 1 (date of drug product infusion) through Month 24 Visit. 
 Date of informed consent through Month 24 Visit 
Windows for time course distributions of clinical laboratory shift tables (shift categories defined 
by Common Terminology Criteria for Adverse Events [CTCAE] grade [version 4.03]) will 
include the same time periods but exclude date of informed consent to mobilization/bone marrow 
harvest and date of informed consent through Month 24 Visit. Reporting intervals for treatment-
emergent AEs are defined in Section 4.4.1 (Adverse Events).  
3.11. 
Multiple Comparisons/Multiplicity 
Multiplicity is not of concern for this study with a descriptive interpretation. 
3.12. 
Interim Analyses 
The efficacy and safety of drug product in subjects with TDT was analyzed when all subjects 
with TDT in HGB-205 completed the study (Month 24), to provide supportive data for the 
regulatory submission of a MAA for LentiGlobin BB305 Drug Product for the treatment of TDT. 
Data from subjects with SCD were not included in this TDT analysis.  
3.13. 
Final Analyses 
A final analysis will be performed per protocol when all subjects treated have either completed 
their Month 24 Visit or discontinued from the study.  


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4. 
STUDY ANALYSES 
4.1. 
Subject Disposition 
A tabulation of the disposition of subjects will be presented overall and by indication, including 
the number who initiate cell harvesting, the number who initiate myeloablative conditioning, and 
the number infused with LentiGlobin BB305 drug product. Tables and listings will be provided 
for subjects in each analysis data set. The number of subjects completing the study through their 
Month 24 Visit and reasons for study discontinuation will be reported. 
4.2. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics data will be reported in data listings. 
The following demographic and baseline characteristic factors will be reported: age (age at 
diagnosis, at first transfusion, at starting regular transfusions, at starting iron chelation, at 
informed consent or assent, and at drug product infusion), specific SCD and thalassemia-related 
mutations (including mutations on both HBB alleles using both HGVS terminology as well as 
β+/β0/βS terminology, grouped by genotype and including any other thalassemia-related non-HBB 
genetic results), genotype category (non-β0/β0) mutation, country of birth, race, ethnicity, gender, 
and splenectomy (yes/no). 
In addition, baseline data from the 2-year retrospective collection (pRBC transfusion 
requirements and/or SCD-related data, where applicable) will be reported. All available data 
from the retrospective data collection period will be listed by subject. The identification of SCD-
related data is described in Section 4.5.4, and will be reported in a separate data listing. The 
mean total volume of pRBCs transfused in the 2 years prior to the date of consent will be listed 
by subject in mL/kg/year: calculations will utilize the weight closest to the transfusion (in 
absolute days). Other data to be reported from the 2-year retrospective data collection include the 
following where available: 
 The Hb transfusion trigger (i.e., the Hb concentration that the investigator designated 
as the value that would “trigger” a pRBC transfusion during the 2 years prior to study 
enrollment) (TDT subjects only). 
 Weighted mean nadir Hb concentrations (i.e., the Hb concentration that immediately 
preceded a pRBC transfusion within 3 days) during the 2 years prior to study 
enrollment (TDT subjects only). 
 Iron chelation usage at informed consent. 
 In-patient hospitalizations during the 2 years prior to enrollment. For SCD subjects, 
primary reason for hospitalizations was also reported by the investigator, such as due 
to pain crisis, stroke, and ACS etc. (see Table 2). 
Additional Screening results to be listed will include the following: 
 Hemolysis markers at Screening: reticulocyte count and %, total bilirubin, and lactate 
dehydrogenase (SCD subjects only). 


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 Echocardiogram status (normal, abnormal (not clinically significant [NCS]), 
abnormal (clinically significant [CS]), missing). 
 Left ventricular ejection fraction (LVEF) %. 
 Liver iron concentration (mg/g dry weight) and liver diagnostic method (biopsy 
and/or MRI and/or superconducting quantum interference device [SQUID]), Cardiac 
T2* measurement (ms). 
 Cerebral MRA/MRI and/or doppler (SCD subjects only) 
 Subjects who opted in for fertility preservation (Y/N/unknown). 
4.3. 
Mobilization, Harvest, Transplant and Conditioning Details 
For TDT subjects, information to be listed includes the following: 
 Number of mobilization cycles/subject. 
 Number of apheresis procedures performed per mobilization cycle. 
 Number of subjects requiring bone marrow harvest for rescue. 
 Average filgrastim (µg/kg) and plerixafor (mg/kg) used per subject per day; the 
weight at screening will be utilized. 
 Number of nucleated cells collected (cells×108). 
 Total blood volume processed during apheresis (mL) 
 Number of CD34+ cells sent for transduction (cells×106/kg). 
 Number of CD34+ cells sent for rescue (cells×106/kg). 
For SCD subjects, information to be listed includes the following: 
 Number of harvest procedures/subject. 
 Number of nucleated cells collected (cells×108). 
 Number of mono-nucleated cells collected (cells×108). 
 Volume sent for transduction (mL). 
 Volume sent for rescue (mL). 
 Number of CD34+ cells sent for transduction (cells ×106/kg). 
 Number of CD34+ cells sent for rescue (cells ×106/kg). 
Dosing details to be listed include the following: 
 Time in months from informed consent to drug product infusion. 
 Duration of hospitalization (from initiation of conditioning to post-drug product 
infusion discharge). 
 Number of drug product lots infused. 


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 Total number of infused CD34+ cells (cells×106/kg). (Combined total number of cells 
if more than one drug product lot). 
 VCN of drug product (average per subject if more than one drug product lot, and 
average per lot) 
 Time to neutrophil engraftment (NE) (defined as the day on which the first of 3 
consecutive ANC laboratory values obtained on different days was ≥0.5×109/L after a 
post-transplant value <0.5×109/L). 
For NE, if ANCs are not collected on a day but the white blood cell (WBC) count is 
less than 0.75×109 cells/L, the ANC count is considered to be <0.5×109/L for the 
purposes of calculating time to neutrophil recovery. 
 Time from Day 1 to platelet engraftment (defined as the first day of 3 consecutive 
platelet values ≥20×109/L (TDT subjects) or ≥50×109/L (SCD subjects) obtained on 
different days while no platelet transfusions were administered for 7 days 
immediately preceding and during the evaluation period).  
Subjects who were treated with G-CSF during the post-drug product infusion period, 
as identified by review of concomitant medications, will be footnoted in all tables 
describing engraftment parameters. 
The use of medications for myeloablative conditioning (busulfan as well as any prophylactic and 
empiric anti-convulsive, antifungal, and antibiotic treatments, and other supportive care usage for 
the preparative regimen) will be listed. For busulfan, the total dose infused (mg), the average 
daily dose (mg/kg/day), the daily AUC (µM*min), and average daily AUC will be reported in a 
by-subject listing; the weight used in busulfan calculations will be the weight immediately prior 
to the first conditioning cycle. Other conditioning medications will be reported as concomitant 
medications as indicated in Section 4.4.5.  
The number of transfusions of any blood products (platelets, pRBC) prior to hospital discharge 
will also be reported, along with the volume of each type of blood product transfusion (in 
mL/kg). If the amount of transfusion is reported in ‘units,’ volume will be calculated as indicated 
in Section 3.9.1. The weight used in transfusion calculations will be the weight closest to the 
transfusion.  
4.4. 
Safety Analyses 
The safety of treatment will be analyzed through the longitudinal evaluation of AEs and 
laboratory assessments in the ITT population. Analyses will be performed in the TP on rates of 
failure to engraft, rates of infection, and adverse effects of the transplant procedure. 
Since the safety profile will be assessed for several different time intervals relative to 
mobilization or bone marrow harvest, conditioning, and post-drug product infusion, there may be 
subjects in the ITT population who are not candidates for analyses during some of these 
intervals. For example, if a subject has conditioning-regimen related events and does not receive 
drug product, that subject would not be considered in the analyses of safety data post-drug 
product infusion.  


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4.4.1. 
Adverse Events 
All AEs will be coded using the MedDRA coding system and displayed in tables (overall and by 
indication) and data listings using system organ class (SOC) and preferred term. 
Incidence of AEs will be summarized by SOC and preferred term (PT) using MedDRA. Some 
AEs reported to the Investigations SOC will be recoded to their synonyms under Blood and 
Lymphatic System Disorders. A listing of these recoded PTs will be provided. The relationship 
of AEs to LentiGlobin BB305 Drug Product will be based on the Investigator’s assessment. For 
the assessment of relationship to study drug product, a classification of ‘Possibly Related’ or 
‘Related’ will be classified as related to drug product. 
Incidence of AEs will be summarized by the following periods: 
 Date of informed consent until either initiation of mobilization (TDT subjects: ICF to 
M) or bone marrow harvest (SCD subjects: ICF to BM). 
 Date of initiation of mobilization (TDT subjects: M to C) /bone marrow harvest (SCD 
subjects: BM to C) until date of initiation of conditioning. 
 Date of initiation of conditioning until the date of NE (C to NE).  
 Date of NE through Month 24 Visit (NE to M24). 
 Day 1 (date of LentiGlobin BB305 Drug Product infusion) through Month 24 Visit 
(D1 to M24). 
 Date of informed consent through Month 24 Visit (ICF to M24). 
The terminology “treatment-emergent” would be reserved for events that occur during or after 
the drug product infusion (i.e. D1 through M24 visit period). For treatment-emergent AEs only 
the following periods will be assessed: "D1 to <NE", "NE to M24 Visit", and "D1 to M24 Visit". 
For AEs in which there is ambiguity as to whether it was treatment-emergent, it will be 
conservatively ascribed as treatment-emergent. 
For the above periods, the appropriate denominators for rates of events would consist of the 
number of subjects “at risk” in each interval. Summaries will be provided for the following by 
period: 
 Incidence of all AEs 
 Incidence of all serious AEs (SAEs) 
 Incidence of Grade 3 or higher AEs 
 Incidence of all study drug product related AEs* 
 Incidence of all study drug product related SAEs* 
 Incidence of all AEs by System Organ Class (SOC) frequency. 
 Incidence of all AEs by maximum severity  
 Incidence of all study drug product related AEs by maximum severity* 
 AEs attributed to Mobilization/Apheresis (TDT) or BM harvest (SCD)** 


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 AEs attributed to Conditioning** 
* Treatment-emergent.     
**Based on investigator attribution on CRF for events not related to study drug.  
There was an administrative memo issued to clarify a change in adverse event collection in order 
to be aligned with the efficacy endpoints for sever SCD subjects only:  
 ≥Grade 1 AEs: through 30 days after LentiGlobin BB305 Drug Product infusion; 
  ≥Grade 2 AEs and SAEs: through 12 months after LentiGlobin BB305 Drug Product 
infusion;  
 LentiGlobin BB305 Drug Product-related AEs: through 24 months after LentiGlobin 
BB305 Drug Product infusion; 
 For SCD patients only: VOC and ACS must be reported throughout the study and 
regardless of the severity and/or the relationship with the LentiGlobin BB305 Drug 
Product:  
o For any events with ‘pain’ in the verbatim term, the investigator will be asked if 
this is related to a VOC to ensure we are capturing all VOC events; 
o [All events with pain in the verbatim were queried and none of those were 
determined as related to a VOC according to the investigator.] 
A by-subject listing for all AEs occurring on study will be provided, and in addition, by-subject 
listings will be provided for subject deaths, SAEs, and SAEs related to drug product. 
Events Attributed to Mobilization (TDT subjects only) 
Toxicities associated with filgrastim and plerixafor may be considered by investigators as related 
to mobilization. AEs designated on the CRF as attributed to mobilization/apheresis will be 
summarized. 
Events Attributed to Bone Marrow Harvest (SCD subjects only) 
Toxicities associated with filgrastim and plerixafor may be considered by investigators as related 
to mobilization. AEs designated on the CRF as attributed to bone marrow harvest will be 
summarized. 
Events Attributed to Conditioning 
Busulfan intravenous (IV) is a cytotoxic drug that causes profound myelosuppression. 
Accordingly, subjects will experience intended hematologic events (e.g., neutropenia, 
thrombocytopenia, anemia) and expected non-hematologic events (e.g., mucositis [stomatitis], 
nausea, vomiting, alopecia, pyrexia) as a result of receiving busulfan IV. For the purposes of this 
protocol, these events, which are familiar to transplant physicians, may be considered by 
investigators as related to conditioning. All AEs designated on the CRF to be attributed to 
conditioning will be summarized. 


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Engraftment 
The incidence of NE and platelet engraftment will be calculated and displayed in a summary 
table by indication. The relative day of NE and platelet engraftment will also be summarized 
using descriptive statistics as indicated in Section 4.3. 
Neutrophil engraftment failure will be defined as not meeting the NE criteria by 42 days after 
drug product infusion (Day 43). A listing of subjects that are engraftment failures will be 
provided. 
4.4.2. 
Laboratory Data 
Laboratory data will be reported by local labs, except for Integration Site Analysis (ISA) data 
which will be reported by a specialty lab, Geneworks, and Replication Competent Lentivirus, 
which will be reported by a specialty lab, Genezen Labs. Clinical laboratory values will be 
expressed using the International System of Units (SI), with the exception of hemoglobin figures, 
which will be displayed using g/dL. 
Internationally accepted ranges published by the New England Journal of Medicine and the 
Mayo Clinic are utilized. For purposes of this plan, these ranges are referred to as Global 
Reference Ranges (GRRs). Age-specific (age at informed consent/assent as applicable) and 
gender specific ranges (i.e., adult or pediatric, male or female) will be used to flag out of range 
values and to categorize into CTCAE (version 4.03) grades where applicable. 
The versions of the GRRs being utilized for this study are as footnoted below. If updated GRRs 
are published during the course of the study, the version used will not be automatically updated. 
Source 
Version 
Purpose 
New England Journal of Medicine 
2004;351:1548-63 
Adult Ranges 
Mayo Clinic 
(As provided by bluebird bio 
on 04-AUG-2014) 
Child Ranges 
 
These sources along with any additional sources and/or additional ranges will be maintained in a 
separate document and provided as an appendix in the CRF. 
The following clinical laboratory parameters are to be evaluated: 
Hematology 
 
Iron Studies* 
 
Complete blood count (CBC) with 
differential* 
 
Platelet count 
 
Reticulocyte count* 
 
Erythropoietin 
 
Prothrombin Time 
 
Partial Thromboplastin Time (PTT) 
 
 
Iron 
 
Ferritin 
 
Serum transferrin receptor 
 
Transferrin 
 
Iron saturation 


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Serum Chemistry and Liver Function 
 
 
 
Sodium 
 
Potassium 
 
Chloride 
 
Bicarbonate 
 
Albumin 
 
Total protein 
 
Alanine transaminase (ALT) 
 
Aspartate transaminase (AST) 
 
Gamma glutamyl transferase 
(GGT) 
 
Blood urea nitrogen 
 
Creatinine 
 
Glucose 
 
Calcium 
 
Phosphate 
 
Total bilirubin (TBL) 
 
Alkaline phosphatase (ALP) 
 
Lactate dehydrogenase (LDH) 
 
Uric acid 
 
* Laboratory parameter evaluated for efficacy. CBC parameters to be evaluated for efficacy include RBC, 
Hematocrit, and Hemoglobin.  
 
Additional clinical laboratory tests may be performed at the investigator’s discretion and will be 
listed. Urinalysis was performed as described in the SOE. 
Shift tables which will indicate abnormally high or abnormally low changes in laboratory 
parameter grade based on CTCAE criteria from baseline will be performed using the most 
abnormal value in the following periods: date of initiation of mobilization (for TDT subjects) or  
bone marrow harvest (for SCD subjects) until date of initiation of conditioning, date of 
conditioning until the date of NE, date of NE through Month 24 Visit, Day 1 (date of 
LentiGlobin BB305 Drug Product infusion) through Month 24 Visit.  
Haematology 
Haemoglobin (Hb) (SCD only) 
Both 
 
White blood cell count (WBC) 
Both  
 
Absolute neutrophils count (ANC) 
Decrease 
 
Platelets 
Decrease 
Chemistry 
ALT 
Increase 
 
AST 
Increase 
 
ALP 
Increase 
 
Calcium 
Both 
 
Creatinine 
Increase 
 
GGT (SCD only) 
Increase 
 
Phosphorus 
Decrease 
 
Potassium 
Both 
 
TBL 
Increase 
The parameters included in the CTCAE shift tables are Hb, ANC, platelets, WBC, serum 
creatinine, GGT, AST, ALT, TBL, ALP, calcium, phosphorus, and potassium.  
Laboratory values for selected hematology and chemistry parameters will be presented 
graphically as appropriate. The following by-subject figures may be provided: reticulocyte count, 
ANC, iron, serum ferritin, serum transferrin receptor, transferrin, iron saturation, creatinine, total 
bilirubin, AST, ALT, ALP, and LDH. In addition, by-subject figures may be provided including 


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a single subject for each parameter: Hb (pRBC transfusions noted) and platelets (with platelet 
transfusions noted).  
All laboratory data will be listed by indication and subject using descriptive statistics, with 
listings including change from baseline, where baseline is defined as the most recent value prior 
to mobilization (TDT subjects) or the first value during screening (SCD subjects), as well as 
results for immunological testing, serology and hormonal testing. A subset listing will be 
presented for all subjects with any laboratory values ≥Grade 3 based on CTCAE version 4.03 
criteria. 
4.4.3. 
Transplant-Related Mortality 
Transplant-related mortality will be determined by the investigator and provided in a listing by 
indication for the following intervals: from Screening through 100 days post-drug product 
infusion, and from Screening through 365 days post-drug product infusion. 
4.4.4. 
Vital Signs, Karnofsky Performance Status, and Physical Examination 
Vital signs to be measured include systolic/diastolic blood pressure, pulse, respiration rate, and 
temperature, and will be performed in accordance with institutional standards, as per the 
Schedule of Events located in the protocol. 
Karnofsky score for subjects ≥16 years of age will be assessed at multiple time points prior to 
drug product infusion, and at all scheduled follow-up visits along with change scores from 
screening and from time of drug product infusion. 
Vital sign measurements, weight, change from Screening to each on-study evaluation of vital 
signs and weight, height, and Karnofsky performance status will be presented for each subject in 
data listings. 
4.4.5. 
Concomitant Medications and Procedures 
Concomitant medications will be coded using the WHO Drug Dictionary. 
The use of concomitant medications will be included in a by-subject data listing. Periods similar 
to the AE periods will be indicated, with the exception of an additional <ICF period. 
Concomitant treatments/procedures (including transfusions) will also be displayed separately in 
listings. These listings will include iron chelator and phlebotomy use. 
4.4.6. 
Overall Survival 
Overall survival is defined as time from date of drug product infusion (Day 1) to date of death. 
Overall survival will be censored at the date of last visit if subject is alive. A by-subject listing of 
time from Day 1 to date of death or censorship will be provided by indication. 
4.4.7. 
Integration Site Analysis 
An ISA will be performed on peripheral blood leukocytes (PBLs) starting 6 months after the 
infusion of drug product, and more frequently if clonal dominance is suspected (see protocol for 
details). 


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The subjects who meet the ISA clonal dominance criteria at each applicable visit will be 
provided in a listing. 
4.4.8. 
Replication Competent Lentivirus 
Blood will be tested for RCL at Month 3, 6, 12, and 24 Visits. Results will be listed as RCL 
screen detected, detected but not quantified, and not detected, and by co-culture assays (if 
applicable) detected or not detected, for each visit by indication. 
4.5. 
Efficacy Evaluation 
Statistical methods will be primarily descriptive in nature. All efficacy information will be 
presented in data listings. 
The efficacy analyses identified below will be performed on the TP unless otherwise specified. 
4.5.1. 
Red Blood Cell Transfusion Requirements and Transfusion Reduction (subjects 
with TDT or SCD) 
The change from baseline (2 years prior to study enrollment) in pRBC transfusion requirements, 
as measured in both volume mL/kg and frequency (number of transfusions) will be calculated. 
The annualized change per subject from 6 months post-drug product infusion to Month 24 Visit 
will be reported in a listing according to indication.  
The measurements of pRBC requirements will be annualized at the reporting intervals of 24 
months, and last study visit post drug product infusion to account for variability in the number of 
days observed relative to Day 183 (6 months post-drug product infusion). Subjects will not be 
included in a time interval unless they have completed that visit. For the last study visit analysis, 
the day of the last available visit up to the Month 24 Visit (inclusive) will be used. For example, 
if a subject has only 23 months of observation post-drug product infusion (visit on Day 700), the 
standardized value at last visit will be defined as (total volume/(700-183))*365.25. The use of the 
actual visit day will also apply to derivations for the Month 24 Visit time interval analyses post-
drug product infusion.  
In addition to the standardized values, the actual number of transfusions and total volume pRBC 
at the time points above will be reported. 
For all calculations of pRBC transfusion requirements, the weight at or closest to the date of 
transfusion will be used. The weight will be selected using the absolute value of the difference 
from the date of transfusion.  
In addition, these data will also be presented as follows: 
 List of treated subjects into categories as follows: <50%, ≥50%, ≥60%, ≥75%, ≥90% 
or 100% reduction in annualized pRBC transfusion volume from 6 months post-drug 
product infusion through last study visit (compared to the annualized pRBC 
transfusion volume requirement during the 2 years prior to enrollment). The day of 
the last available visit up to the Month 24 Visit (inclusive) will be used. 
 Where available for subjects with TDT, weighted average nadir Hb during 2 years 
prior to enrollment and weighted average nadir Hb from 6 months post-drug product 


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infusion through the Month 12, 18, and 24 Visit and at last study visit will be 
compared. Nadir is defined as the Hb closest but within 3 days prior to a transfusion. 
Hb values on the day of the transfusion will be considered for nadir calculations; if 
multiple values occur on the same day, the lowest value will be selected. If no Hb fits 
these criteria, then no imputed Hb will be reported. Hemoglobin values prior to drug 
product infusion will not be used for imputation of missing Hb values after drug 
product infusion. If there is a period of more than 60 days without transfusion, all Hb 
records between Day 61 and up to day of last visit or next transfusion (inclusive) will 
also be included; if multiple Hb records occur on the same day, the lowest value will 
be selected. 
 Where available for subjects with SCD, % HbS prior to each pRBC transfusion 
should be listed. 
 Where available for subjects with TDT, the weighted average Hb nadir for the period 
24 to 12 months prior to screening will be compared with the weighted average Hb 
nadir from 12 months prior to screening. If these values are not within 25%, a 
sensitivity analysis will be performed for change from baseline in pRBC transfusion 
requirements, as measured in both volume mL/kg/year and frequency (number of 
transfusions)/year. For this sensitivity analysis, baseline will be calculated from the 
12 month period with the lower Hb nadir value. Post-baseline calculations will be the 
same as the primary analyses. Where available, Hb values for the 2 years prior to 
study enrollment (date of informed consent) will be listed, along with date of 
measurement and date of any pRBC transfusions that occurred, with Hb nadir values 
indicated. 
4.5.2. 
Characterization of Transfusion Independence (subjects with TDT only) 
TI is defined as a weighted average Hb ≥9 g/dL without any pRBC transfusions for a continuous 
period of ≥12 months at any time during the study after drug product infusion, where: 
 Calculation of time period of TI will start when subjects achieve an Hb ≥9 g/dL with 
no transfusions in the preceding 60 days 
 To meet the initial TI criteria, the weighted Hb must be ≥9 g/dL at the end of the 
12 month period 
 To remain in the TI state beyond the 12 month period, the treated subject needs to 
maintain a weighted Hb of ≥9 g/dL from that point forward, without receiving a 
pRBC transfusion 
 A transfusion of pRBCs for a single acute event (e.g., surgery, trauma, parvovirus 
infection, or sepsis) will not be counted towards the definition of TI. For the 
calculation of the weighted Hb when an allowed transfusion has occurred, the Hb that 
triggered the transfusion would be carried forward for 60 days and Hb values during 
those 60 days would be imputed by the carried-forward value. Post 60 days, the actual 
Hb drawn would again be used in the calculation of TI. 
The weighted average Hb for determining TI will be defined as follows. Let t0, t1, t2,, … 
represent the consecutive time points for assessment of Hb, where t0 denotes the time when Hb is 


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first ≥9 g/dL with no transfusions in the preceding 60 days, and where the ti are continuing as 
long as no transfusions are given. Further, let h0, h1, h2, … represent the Hb level at each of these 
time points. Then the weighted average Hb is defined as: 
[(t1-t0)x((h0+h1)/2)+ (t2-t1)x((h1+h2)/2)+…+ (tk-tk-1)x((hk-1+hk)/2)]/(tk-t0) 
where tk represents the time point such that (tk-t0) represents at least 12 consecutive months. This 
calculation is invariant to the metric used for the time points, e.g., calendar dates or days from 
drug product infusion, since the consecutive differences in times would always be measured as a 
number of days. Note that the weighted average may be considered as an average AUC 
calculation for Hb. To determine if a subject remains TI beyond 12 months, the calculation of 
weighted average Hb will always start at t0. If a subject loses TI status, defined as starting 
transfusion again or weighted Hb falls below 9 g/dL, a new t0 will be identified to determine 
future TI status. The calculation of the duration of TI will begin with t0. 
The subjects who meet the definition of TI overall and (separately) at Month 24 Visit will be 
provided in a listing, along with the following parameters: 
 Duration of TI. 
 Time from drug product infusion to last pRBC transfusion prior to becoming TI. 
 Time from drug product infusion to TI. 
 Weighted average Hb nadir during the period of the most recent TI.  
 
 
 
 
 
 
4.5.4. 
Sickle Cell Disease Related Parameters (subjects with SCD only) 
Sickle cell disease-related parameters will be collected as described in Table 2 and provided in a 
listing. For all event types, the source to identify events prior to consent will be the Medical 
History and Hospitalization Prior to Screening forms. The forms used to identify events post-
consent are listed below by event type. 
Table 2: 
SCD-Related Events 
Event Type 
CRF Forms to Identify Events Post Consent 
VOC 
AE/SAE, Hospitalization (Pain crisis per investigator) 
ACS 
AE/SAE, Hospitalization (ACS per investigator) 
VOEs  
AE/SAE, Hospitalization (VOC+ACS per investigator) 
Significant Cerebral Abnormality 
(MRA/MRI), stroke 
AE/SAE, Hospitalization (Stroke per investigator), 
MRA/MRI, transcranial doppler or CT head (additional 
assessment visit) 
Cardiac function  
Cardiac MRI, echocardiography 
CCI


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Note:  
For events from AE CRF page, ACS= PT of “acute chest syndrome”, VOC= PT of “sickle cell anemia with crisis” 
or pain related events as determined as VOC-related by investigator as indicated in verbatim term.  
Stroke: all hospitalization for which primary reason for hospitalization is indicated by investigator as being due to 
stroke. 
The SCD-related events post-drug product infusion through Month 24 Visit and last study visit 
will be reported, along with these events reported in the 2 years prior to enrollment. In addition, 
the number of events over each reporting interval will be converted to a yearly average and 
compared to the yearly average obtained for the 2 years prior to study enrollment, as appropriate. 
While converting to a yearly average, the number will be standardized for each reporting interval 
to account for variability in the number of days observed. For example, if a subject has only 9 
months of observation (visit on Day 279), the standardized number of VOC events at 12 months 
will be defined as (number of events/279)*365.25). These data will be listed for each SCD 
subject. 
Changes in SCD-specific laboratory tests from baseline values will be summarized for hemolysis 
markers (e.g., reticulocyte count, total bilirubin, and lactate dehydrogenase) as part of the 
laboratory reporting in Section 4.4.2. 
Primary reason for hospitalizations, such as pain crisis, acute chest syndrome, stroke, infection or 
other, will be presented.  The annualized rates in the 2 years prior to enrollment will be 
compared to the annualized rate post discharge after transplantation to the last study visit, as 
appropriate, where the admission date > date of discharge from the Hospital Admission CRF. 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
4.5.8. 
Other Clinical Measures (subjects with TDT or SCD) 
The following data will be listed: 
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 Pulmonary function testing (PFT) (Including oxygen saturation, FVC; FEV1; TLC; 
RV, VC; and DLco; % predicted FVC, % predicted FEV1; % predicted RV; and % 
predicted DLco (corrected for Hb) at Screening and at any unscheduled visit. Change 
from baseline in PFT measures will also be included in a listing for subjects with 
SCD. 
 Echocardiography results at Screening and Month 24. 
 SCD-specific testing. 
4.6. 
Pharmacokinetic and Pharmacodynamic Evaluations 
Analyses will be conducted using the TP and SEP according to indication, and will include 
summary tables with descriptive statistics, and figures (TDT or SCD subjects, all values versus 
time on x-axis), and displaying the items below: 
 The VCN post drug product infusion in cell populations from peripheral blood or 
whole blood. Bone marrow and lineage cells will be included in a listing only, if 
available; peripheral or whole blood VCN over time (TDT or SCD subjects in 1 
figure) 
 The ratio of α-globin to all non-α-globin-chains (i.e., including all β, γ, and δ chains) 
and ratio of α-globin to all β-globin-chains (i.e. βA, βE, and βA-T87Q chains) in whole 
blood (HPLC data, tabulated overall and by subject). (TDT subjects) 
 Hemoglobin AT87Q (HbAT87Q) (g/dL) over time (table and TDT or SCD subjects in 1 
figure). 
 Hemoglobin fractions over time (including HbAT87Q, HbA, HbA2, HbE (for TDT 
subjects only), HbS (for SCD subjects only) and HbF, as relevant, calculated using 
ratio data from HPLC and total Hb), by subject (g/dL) and overall summaries by 
timepoint (will include by-subject figures with all fractions for a given subject in one 
plot). The ratios and total Hb used to derive the fractions will also be included in a by-
subject listing. 
 HbAT87Q = βA-T87Q-Globin to All β-Like-Globin-Chains/100*total Hb 
 HbA = βA-Globin to All β-Like-Globin-Chains/100*total Hb 
 HbA2 = δ-Globin to All β-Like-Globin-Chains/100*total Hb 
 HbE = βE-Globin to All β-Like-Globin-Chains/100*total Hb  
 HbS = βS-Globin to All β-Like-Globin-Chains/100*total Hb  
 HbF = (γG-Globin to All β-Like-Globin-Chains+γA-Globin to All β-Like-Globin-
Chains)/100*total Hb 
For the Hb fraction analysis, the globin chain sample will first be merged with the Hb 
hematology sample by date. If a globin chain sample exists but there is no corresponding 
hematology sample with the same date, then the sample will be merged with a hematology 
record whose sample date is within 7 days prior to the globin chain sample. If there are multiple 
hematology records within the 7-day window, the one closest to the globin chain sample will be 


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used. If there are multiple Hb records on the same date, the one assigned with the scheduled visit 
will be used. If there is no hematology record within the 7-day window, the one closest to the 
globin chain sample will be used, with a footnote in data listings. In addition, any globin chain 
samples with a pRBC transfusion within 30.4375 days prior should be noted in the data listings. 
The Hb fractions can then be derived as defined above. Note that when calculating Hb, values 
should first be converted to g/dL. A midpoint window will be applied for by-visit summary 
tables and figures (see Table 1). Within a given midpoint window for a particular subject, if there 
are multiple fraction results, an average will be calculated. 
5. 
CHANGES TO PLANNED ANALYSES 
All major changes from procedures outlined in the protocol and procedures outlined in this SAP 
will be summarized in the study report. Decisions to deviate from planned analyses will be 
documented at the time they are made. 
The table below identifies changes from SAP (V3.0) to this version, SAP (V2.0) to SAP (V3.0), 
SAP (V1.0) to SAP (V2.0), and the protocol defined analyses to SAP (V1.0). 
Major changes between SAP Version 3.0 and Version 4.0  
Section Number 
Section 
Changes from Prior SAP Version 
1.2.6.2 
Efficacy Parameters 
Further defined efficacy/exploratory endpoints for 
SCD subjects, to be aligned with Study HGB-206.  
3.2 
General Methods 
Removed Excel files as a formal output format. 
3.4 
Baseline Definition 
Refined baseline definition for SCD subjects, to 
be aligned all SCD studies. 
3.5 
Methods of Pooling Data 
Dropped pooled analyses of TDT and SCD 
indications, given the fact that the small sample 
size for both indications is relatively small. 
4.2 
Demographic and Baseline 
Characteristics  
 
Further clarified what baseline data to be 
presented for SCD subjects.  
 
eGFR at baseline was dropped since this 
analysis was not conducted for TDT subjects, 
and it is not a critical analysis for SCD 
subjects either. 
4.4.1 
Adverse Events  
 
Further clarified AE analysis/reporting 
periods for SCD subjects.  
 
Removed analyses towards event of interest 
since it was deemed less applicable to this 
drug product and it was not conducted for 
interim CSR. 
4.4.2  
Laboratory Data  
 
Further clarified the source of lab data. 
 
Added GGT and LDH to shift table for SCD 
subjects; also clarified Hb shift table is 
intended for SCD subjects only. 
 
Dropped eGFR wording as the analysis was 
removed from baseline. 


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Section Number 
Section 
Changes from Prior SAP Version 
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD) 
Removed timepoint Month 6, 18 from the planned 
analysis, since the analyses were not conducted 
for TDT subjects, and it is sufficient to report data 
at Month 24 for SCD subjects. 
4.5.4. 
 
Sickle Cell Disease Related 
Parameters (subjects with SCD 
only) 
Further refined SCD-related endpoints and 
analyses per data collected on eCRF. 
4.5.7 
 
 
 
 
4.5.8. 
 
Other Clinical Measures (subjects 
with TDT or SCD) 
Further defined analyses related SCD subjects. 
4.6 
Pharmacokinetic and 
Pharmacodynamic Evaluations 
Further defined analyses pertaining to SCD 
subjects. 
5 
Changes to Planned Analyses 
Added major changes from SAP (V3.0) to this 
version. 
Changes between SAP Version 2.0 and Version 3.0  
Section Number 
Section 
Changes from Prior SAP Version 
1.1.1 
Introduction  
Changed interim analysis timing from 18 to 24 
months. 
1.2.6.2 
Efficacy parameters 
Limited Hb nadir definition to only consider Hb 
values within 3 days prior to pRBC transfusion.  
1.2.6.2 
Efficacy parameters 
Removed 18-month summaries 
1.2.6.2 
Efficacy parameters 
Added ‘Time from drug product infusion to TI’  
1.2.6.2 
Efficacy parameters 
Added ‘Weighted average nadir Hb during period 
of TI 
2.1 
Population definitions  
Specified TP as primary population for 
pharmacodynamics parameters. 
2.1 
Population definitions  
Clarified neutrophil successful engraftment 
definition (3 consecutive values values 
≥0.5×109/L obtained on different days). 
3.2  
General Methods  
Modified year and month calculations to 365.25 
days and 365.25/12 (40.4375) respectively.    
3.9.1 
Transfusion Information 
 (TDT Subjects) 
Added imputed value of 300 mL/unit when there 
all volumes reported in units and there is no 
standard volume per unit provided.  
3.10  
Visit Windows  
Added midpoint visit windows to assign reporting 
periods for use in summarizations.  These 
windows apply to VCN, fraction data, and 
unscheduled laboratory visits.   
3.10 
Visit Windows  
Add new reporting period: Date of informed 
consent to Month 24.    
4.1 
Subject Disposition  
Remove tabulation at Month 18.  
4.2 
Demographic and Baseline 
Characteristics 
Removed summary of ongoing medical history 
and time from diagnosis to both informed consent 
and drug product infusion.  
4.2 
Demographic and Baseline 
Characteristics 
Specify that the baseline calculation for pRBC 
transfusions (mL/kg/year) will use the weight 
closest to the transfusion (in absolute days).  
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Section Number 
Section 
Changes from Prior SAP Version 
4.3 
Mobilization, Transplant, and 
Conditioning Details  
 Clarified filgrastim and plerixafor reporting: 
Average filgrastim (µg/kg) and plerixafor (mg/kg) 
used per subject per day; the weight at screening 
will be utilized. 
4.3 
Mobilization, Transplant, and 
Conditioning Details  
Dosing details, remove the following:  
 
Time in months from diagnosis of β-
hemoglobinopathy type … 
 
Incidence of use of back-up cells for 
subjects with neutrophil engraftment 
failure. 
4.3 
Mobilization, Transplant, and 
Conditioning Details  
Clarified VCN and CD34+ cell summaries if 
more than one drug product lot used.  
4.3 
Mobilization, Transplant, and 
Conditioning Details  
Change busulfan reporting and added average 
daily AUC   
4.4.1 
Adverse Events  
Added summary period for all AE reporting:  date 
of informed consent through Month 24 visit.  
4.4.1  
Adverse Events  
Add specific treatment-emergent AE reporting 
periods: Day 1 to < NE, NE to Month 24 Visit, 
and Day 1 to Month 24 Visit.    
4.4.1 
Adverse Events  
New AE tables added: Events of Interest, Adverse 
Events by System Organ Class Frequency, 
Adverse Events by Reporting Period and 
Maximum Grade.         
4.4.2  
Laboratory Data  
Indicated efficacy labs 
4.4.2 
Laboratory Data 
Clarify Hemoglobin will not be presented in SI, 
but rather as g/dL for figure displays  
4.4.2 
Laboratory Data 
Added by subject figures for iron studies   
4.4.2 
Laboratory Data 
Removed mobilization figures and, for 
adolescents, figures for hormonal results.  
4.4.2 
Laboratory Data 
Clarified ≥Grade 3 CTCAE listing applies to all 
parameters using CTCAE grading. 
4.4.5 
Concomitant medications 
< ICF period added for reporting.  
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD). 
Changed 30.4 to 30.4375 and adjusted Month 6 to 
Day 183.  Change text to “Day 183 (Month 6 
post-drug product infusion).  
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD). 
Clarified that use of actual Visit day is used for 
derivations for Months 12, 18 and 24 
comparisons; last study visit analysis will use the 
last visit available up to Month 24 Visit 
(inclusive) 
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD). 
Add “<50%” to pRBC transfusion volume 
reporting (baseline to last visit). Also clarified last 
study visit analysis will use the last visit available 
up to Month 24 Visit (inclusive) 
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD). 
Nadir definition updated to use a 3-day window 
for Hb prior to transfusion. Hb values on the day 
of the transfusion will be considered for nadir 
calculations; if multiple values occur on the same 
day, the lowest value will be selected 


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22 May 2019, Version 4.0 
 
Page 36 
Section Number 
Section 
Changes from Prior SAP Version 
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD). 
Added a sentence: If there is a period of more 
than 60 days without transfusion, all Hb records 
between Day 61 and last visit or next transfusion 
(inclusive) will also be included. If multiple Hb 
records occur on the same day, the lowest value 
will be selected. 
4.5.2 
Characterization of Transfusion 
Independence (subjects with TDT 
only)  
Synchronized definition with other LentiGlobin 
studies.   
4.5.2 
Characterization of Transfusion 
Independence (subjects with TDT 
only)  
Added reporting of time from drug product 
infusion to TI 
4.5.2 
Characterization of Transfusion 
Independence (subjects with TDT 
only)  
Added reporting of weighted average Hb nadir 
during the period of the most recent TI 
4.5.3 
 
  
 
   
4.5.6 
Pharmacokinetic and 
Pharmacodynamic Evaluations 
Added clarity on fraction derivation analysis. 
Added ratios to the analysis. 
Changes between SAP Version 1.0 and Version 2.0  
Section Number 
Section 
Changes from Prior SAP Version 
1.1.1 
Introduction  
Have removed descriptive text regarding 
indication and drug product.  
Modified header to “Introduction”  
1.2.1 
Synopsis of Study Design 
Shortened text 
1.2.4 
Study Stopping Rules  
Shortened text and referenced protocol section. 
1.2.5 
Study Procedures  
Shortened text and referenced protocol section. 
1.2.6 
Safety, Efficacy, and 
Pharmacodynamics Parameters 
Reordered presentation to start with Safety in 
alignment with the protocol.  
1.2.6.1 
Safety Parameters 
Removed the safety endpoint "Characterization of 
events of insertional mutagenesis leading to clonal 
dominance or leukemia"” 
1.2.6.2 
Efficacy Parameters 
Replaced endpoint of reporting from ‘Month 18 
(or later as applicable’ to ‘last visit’. 
1.2.6.2 
Efficacy Parameters 
Specified ‘weighted’ mean nadir Hb 
concentrations for reporting. 
1.2.6.2 
Efficacy Parameters 
Removed the efficacy endpoints: Transfusion free 
survival,  
Description of markers of dyserythropoiesis, by 
subject, as measured in blood and bone marrow,  
Number of total in-patient hospitalization days 
(post-transplant discharge) at 6, 12, 18, and 24 
months.  
1.2.6.3 
Pharmacodynamic Parameters 
Removed and reference to exploratory PD 
assessments, as they will be covered in a separate 
PD analysis plan.  
2.1 
Population definitions  
Added successful engraftment population (SEP) 
for consistency with HGB-204 
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Section Number 
Section 
Changes from Prior SAP Version 
3.2  
General Methods  
Removed time-to-event methods as it is no longer 
applicable to this study due to small number of 
subjects.  
3.3 
Computing Environment  
Added MedDRA reporting version (19.0 or 
higher)  
3.3 
Computing Environment 
Added World Health Organization (WHO) Drug 
Dictionary (March 2016 or later). 
3.4  
Baseline Definitions 
For pRBC transfusion requirements, removed 
baseline average per month parameter due to 
current reporting requirements.  
3.4  
Baseline Definitions 
Added number of in-patient hospitalizations / 
hospitalization days  
3.4  
Baseline Definitions 
For safety parameters, changed baseline 
assessment from screening to the most recent 
value prior to mobilization.  
3.9 
Missing, Unused and Spurious 
Data 
Moved specific rules for missing Hb values into 
Efficacy section (4.6.1) and removed text 
‘immediately prior to pRBC transfusion’ for ease 
of reference. 
3.9.1 
Transfusion Information (TDT 
Subjects)  
Removed use of 300 mL/unit if transfusion 
volume is missing and average volume per ml per 
site is missing.  
Replaced 300 mL/unit with average mean volume 
in 2 years prior to study (prior to infusion) and 
average mean volume post infusion to time of 
transfusion (post infusion).  
3.9.2 
Partial Dates 
Added a new paragraph for handling partial 
hospitalization dates. 
3.10 
Visit Windows  
Added table from protocol for visit windows, as 
protocol Schedule of Events was deleted from 
Section 1.2.5.  
3.10 
Visit Windows  
Added text and table for midpoint visit windows, 
to be used in analysis of Hb fractions and VCN.  
3.10 
Visit Windows  
Added reporting windows for adverse events, 
laboratory shift tables, and concomitant 
medications.  
3.12 
Interim Analysis 
Clarified text to specify that TDT only subjects 
would be reported in the interim report for the 
MAA submission.  
3.13 
Final Analysis  
Added section to clarify timing of final analysis.  
4.1 
Subject Disposition  
Removed reporting by β-Thalassemia genotype. 
4.1 
Subject Disposition  
Clarified reporting format for interim analysis.  
4.1 
Subject Disposition  
Removed text for reporting deviations from 
protocol treatment, as described in Section 2.2.  
4.2 
Demographics and Baseline 
Characteristics 
Explained the genotype and mutation categories 
in detail 
4.2 
Demographics and Baseline 
Characteristics 
For retrospective data reporting added additional 
parameters: Number of total in-patient 
hospitalizations, total in-patient hospitalization 
days, number of ACS, VOC and SCD events. 


Statistical Analysis Plan, Protocol HGB-205 
22 May 2019, Version 4.0 
 
Page 38 
Section Number 
Section 
Changes from Prior SAP Version 
4.2 
Demographics and Baseline 
Characteristics 
Changed format of reporting to listings from 
summaries, removed specific categories of 
information (items I – VIII in Version 1.0 SAP) to 
be reported together.  
4.2 
Demographics and Baseline 
Characteristics 
Added reporting of liver diagnostic method.  
4.2 
Demographics and Baseline 
Characteristics 
Specified ‘weighted’ mean nadir Hb 
concentrations for baseline reporting.  
4.3 
Mobilization, Transplant, and 
Conditioning Details  
Separated mobilization and conditioning 
requirements by indication.  
4.3 
Mobilization, Transplant, and 
Conditioning Details 
Added reporting for total blood volume processed 
during apheresis (ml).  
4.3 
Mobilization, Transplant, and 
Conditioning Details  
For dosing details, added incidence of use of 
back-up cells for subjects with neutrophil 
engraftment failure 
4.3 
Mobilization, Transplant, and 
Conditioning Details  
Moved ANC failure criteria to Section 4.4.1 
(Adverse Events)  
4.3 
Mobilization, Transplant, and 
Conditioning Details  
Added reporting and definition of time to platelet 
recovery.  
4.3 
Mobilization, Transplant, and 
Conditioning Details  
Added timing of weight measurement to be used 
in reporting busulfan use in mg/kg.  
4.3 
Mobilization, Transplant, and 
Conditioning Details 
Added busulfan reporting in AUC (µM*min) as 
well 
4.4 – 4.6 
Safety Analyses,  
Efficacy Analyses,  
Pharmacodynamic Analyses  
Changed ordering of sections to more accurately 
reflect the protocol: Safety (4.4), Efficacy (4.5), 
Pharmacodynamics (4.6).  
4.4 
Safety Analysis  
Changed population from ITT to TP population 
on rates of failure to engraft, rates of infection, 
and rates of SAEs of transplant procedure or 
preparation of procedure.  
4.4.1 
Adverse Events  
Added language to indicate that some AEs 
reported to the Investigations SOC will be 
recoded to their synonyms under Blood and 
Lymphatic System Disorders 
4.4.1  
Adverse Events 
Removed absolute days for conditioning and 
ANC engraftment (Day -8 and 43 respectively). 
Now based on individual subject timing.  
4.4.1  
Adverse Events 
Modified time-period reporting to be consistent 
with other Lenti-G studies.  
4.4.1 
Adverse Events  
Added event classifications used to define 
‘related’ events (‘Possibly Related’ or ‘Related’) 
4.4.1 
Adverse Events  
Removed category of events reported at each 
reporting period but added text for an AE table 
footnote to describe degree of reporting in the 
study by type of event.  
4.4.1 
Adverse Events  
Added and defined “study procedure related 
adverse events” as a category of events to be 
summarized.  
4.4.1 
Adverse Events  
Added and defined “malignancy” as a category of 
events to be summarized.  


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22 May 2019, Version 4.0 
 
Page 39 
Section Number 
Section 
Changes from Prior SAP Version 
4.4.1 
Adverse Events  
Modified listing of subjects withdrawing due to 
adverse events, now not limited to prior to drug 
product infusion.  
4.4.1 
Adverse Events  
Added listing of subjects with malignancies.  
4.4.1 
Adverse Events  
Defined engraftment failure as failure to meet 
ANC criteria by Day 43.  
4.4.1 
Adverse Events  
Moved platelet engraftment, now reported in 
Section 4.3.  
4.4.1 
Adverse Events  
Added text for a footnote for AE summaries to 
indicate collection periods 
4.4.2 
Laboratory Data 
Removed time periods as covered in an earlier 
section.  
4.4.2 
Laboratory Data 
Additional Clinical laboratory parameters to be 
evaluated were added – Erythropoietin, 
Prothrombin Time, and PTT  
4.4.2 
Laboratory Data 
Additional parameters were added for CTCAE 
shift tables – AP, Calcium. Phosphorous and 
Potassium 
4.4.2 
Laboratory Data 
A table added to indicate the direction of shift 
considered for CTCAE shift tables 
4.4.3 
Transplant-Related Mortality 
Removed KM analysis and summarization (any 
subjects meeting criteria to be reported in a 
listing).  
4.4.4 
Vital Signs, Karnofsky 
Performance Status, and Physical 
Examination 
Removed summaries of Karnofsky data; data will 
be reported in a listing 
4.4.4 
Vital Signs, Karnofsky 
Performance Status, and Physical 
Examination 
For Karnofsky score analysis, added that used for 
subjects ≥16 years.  
4.4.5 
Concomitant Medication and 
Procedures  
Removed summaries; data will be reported in a 
listing 
4.4.5 
Concomitant Medication and 
Procedures  
Change time periods for reporting (to match AE 
periods)  
4.4.6 
Overall survival  
Removed summaries; data will be reported in a 
listing  
4.4.6 
Overall survival  
Limited reporting to TP from study Day 1.  
4.4.7 
Integration Site Analysis  
Retitled section to “Integration site analysis 
(ISA)” and changed reporting to listings only.  
New section combines two endpoints from 
Version 1.0 SAP.  
4.4.7 
Integration Site Analysis  
Removed specific information to be reported in 
listing (‘number of unique mappable integration 
sites’). 
4.4.8 
Replication Competent Lentivirus  
Retitled section and changed reporting to listings 
only. 
4.4.8 
Replication Competent Lentivirus  
Updated information to be reported in listings.  
4.5 
Efficacy Evaluation 
Changed the order of the subsections. 
4.5 
Efficacy Evaluation  
Removed summary reporting with point estimates 
and 2-sided 90% confidence intervals.  


Statistical Analysis Plan, Protocol HGB-205 
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Page 40 
Section Number 
Section 
Changes from Prior SAP Version 
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD) 
Added reporting (listings) by indication.  
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD) 
Added that measurements will be ‘annualized’. 
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD) 
Added ‘Day 182’ (Month 6) as relative start point 
for post infusion reporting, and corresponding 
changes in text to align with this modification.  
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD) 
Replaced endpoint of reporting from ‘Month 18 
(or later as applicable’ to ‘last visit’.  
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD) 
Added secondary analysis for post-treatment 
reporting: if there is a period of more than 60 days 
without transfusion, all Hb records between Day 
61 and up to the day before next transfusion 
(inclusive) will also be included.  Specified that 
the lowest value will be selected if multiple Hb 
records occur on the same day.  
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD) 
Moved reporting when there is a missing Hb 
value to this section from Section 3.9.  
4.5.1 
Red Blood Cell Transfusion 
Requirements and Transfusion 
Reduction (subjects with TDT or 
SCD) 
Added paragraph for weighted average Hb nadir 
reporting and comparison to baseline.  
4.5.2 
Characterization of Transfusion 
Independence (subjects with TDT 
only) 
Retitled section to ‘Characterization of 
Transfusion Independence’ 
4.5.2 
Characterization of Transfusion 
Independence (subjects with TDT 
only) 
Removed statement that a transfusion of RBCs for 
a single acute event would not be counted towards 
the definition of TI.  
4.5.2 
Characterization of Transfusion 
Independence (subjects with TDT 
only) 
Removed summary of proportion of subjects 
meeting TI. 
4.5.2 
Characterization of Transfusion 
Independence (subjects with TDT 
only) 
Removed reporting of transfusion-free survival.  
4.5.3 
 
 
  
.  
4.5.4 
Sickle Cell Disease Related 
Parameters (subjects with SCD 
only) 
Added paragraph on reporting of hospitalizations 
due to SCD-related events.  
4.5.5 
 
  
 
 
  
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Section Number 
Section 
Changes from Prior SAP Version 
4.5.5 
 
  
 
  
4.5.6 
 
  
 
 
  
 
  
4.5.6 
 
 
 
4.5.7 
 
 
 
 
4.5.7 
 
 
 
 
4.5.8 
Other Clinical Measures (subjects 
with TDT or SCD)  
Added listing reporting change from baseline in 
PFT measures for SCD subjects.  
4.5.8 
Other Clinical Measures (subjects 
with TDT or SCD) 
Oxygen Saturation was added as an additional 
PFT parameter 
4.5.8 
Other Clinical Measures (subjects 
with TDT or SCD) 
Removed that echocardiology results at 
unscheduled visits will be presented in the listing. 
4.6 
Pharmacokinetic and 
Pharmacodynamic Evaluations 
Added reporting for SEP population, and 
reporting by indication.  
4.6 
Pharmacokinetic and 
Pharmacodynamic Evaluations 
Added calculations for each Hb fraction and 
details for the algorithm when more than one 
evaluation in the visit window.  
4.6 
Pharmacokinetic and 
Pharmacodynamic Evaluations 
For VCN, added ‘average by subject and by lot’ 
reporting.  
Changes between Protocol Defined Analysis and SAP Version 1.0: 
There will be an interim analysis for an MAA submission specifically for the indication of TDT, 
in which no SCD analyses will be performed. Data from this interim analysis for 205 TDT 
subjects will be reported in an interim CSR. There will be a second interim analysis for this 
MAA using a later data-cut in which safety data only from all subjects in Study HGB-205 (TDT 
+ SCD) will be pooled with that of other TDT and SCD subjects from other clinical studies in an 
integrated summary of safety. 
Protocol 
Section  
Section Title 
Text in Protocol 
Change from Protocol in SAP and 
Rationale 
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CCI


Statistical Analysis Plan, Protocol HGB-205 
22 May 2019, Version 4.0 
 
Page 42 
Protocol 
Section  
Section Title 
Text in Protocol 
Change from Protocol in SAP and 
Rationale 
2.2.2 
Efficacy Endpoints 
For all subjects: 
 RBC transfusion 
requirements (measured in 
milliliters [mL] per 
kilogram [kg]) per month 
and per year post-transplant. 
 Number of total in-patient 
hospitalization days 
(post-transplant discharge) 
at 6, 12, and 24 months. 
For severe SCD subjects only: 
 Number of VOC or acute 
chest syndrome events at 6, 
12, and 24 months. 
 Evaluation of changes in the 
nature or frequency of the 
subject-specific main 
inclusion criteria. 
 
For TDT subjects only additions 
include:  
Clarification of transfusion requirements 
in the SAP including the following 
(where post-treatment is measured from 
6 months post drug product infusion) 
% reduction,  
frequency of pRBC transfusions, 
 average annual pRBC transfusion 
volume,  
Weighted average nadir Hb 
Note:  the number of total in-patient 
hospitalization days has been modified 
in the current SAP to be post-transplant 
discharge to last visit. 
Note: % reduction in the SAP is also 
categorized into the following 
categories: ≥ 50%, 60%, 75%, 90% or 
100% in average annual pRBC 
transfusion volume.  
The clarification above and additional 
endpoints below for TDT subjects were 
added for consistency of evaluation 
across multiple studies using 
LentiGlobin BB305 to treat TDT, and to 
support marketing authorization. The 
endpoints pertained to the following 
areas:  
Characterization of Transfusion 
Independence 
Iron burden 
Iron chelation and phlebotomy 
 
For SCD subjects only changes include: 
Further specification of SCD events to 
include strokes and transient ischemic 
attacks.  
2.2.1 
Safety Endpoints 
Monitoring of laboratory 
parameters and frequency and 
severity of clinical AEs. 
“Monitoring of” is changed to “Changes 
in”. 
Integration site analysis (ISA) is added 
to clarify that this analysis will be done 
to allow evaluation of clonal dominance 
(another endpoint). 
Added transplant-related mortality 
assessment at Day 365 as well as 100 
days post treatment.  


Statistical Analysis Plan, Protocol HGB-205 
22 May 2019, Version 4.0 
 
Page 43 
Protocol 
Section  
Section Title 
Text in Protocol 
Change from Protocol in SAP and 
Rationale 
7.2 
Populations for 
Analysis 
The primary population for 
analysis of both efficacy and 
safety will consist of those 
subjects who initiate any study 
procedures, beginning with 
mobilization (subjects with 
β-ThalM) or anesthesia for bone 
marrow harvest (subjects with 
SCD); this population will be 
denoted as the intent-to-treat 
(ITT) population. All subjects 
must have at least 2 years of 
follow-up at a specialized 
center, in order to be used as 
their own control for key 
measurements of clinical events 
and transfusion requirements. 
Additionally, analysis will be 
performed on those who 
undergo the gene therapy 
transplantation; should this be a 
smaller number of subjects, this 
population will be denoted as 
the transplant population (TP). 
…an evaluable population will 
be defined as those subjects 
who successfully engraft and 
have sufficient study visit 
compliance to acquire primary 
efficacy data through 24 months 
post-treatment. Subjects in this 
population must be compliant 
with the visit window for the 
Month 24 evaluations. 
The ITT population is defined as the 
primary population for safety analysis, 
and TP is the primary population for the 
analysis of transplant-related safety 
parameters and efficacy parameters.  
Successful Engraftment Population 
(SEP) is defined as all subjects who 
have successful neutrophil engraftment 
after drug product infusion.  
 
Definitions were added for consistency 
of populations across multiple studies 
using LentiGlobin BB305 to treat TDT, 
and to support marketing authorization 
7.3 
Procedures for 
Handling Missing, 
Unused, and Spurious 
Data 
No imputation will be 
performed for missing data 
elements. Subjects in the ITT or 
TP analysis groups will be 
considered treatment failures in 
the primary analysis of 
stabilization, if they have less 
than 24 months post-transplant 
follow-up. 
Details of missing data handling rules 
are added, e.g. rules needed for analysis 
of safety and efficacy endpoints. 
7.4.1 
General Methods  
Two-sided 90% confidence 
intervals will be calculated as 
appropriate.  
No confidence intervals will be 
calculated given the limited sample size 
(7 subjects, 4 TDT subjects)  


Statistical Analysis Plan, Protocol HGB-205 
22 May 2019, Version 4.0 
 
Page 44 
Protocol 
Section  
Section Title 
Text in Protocol 
Change from Protocol in SAP and 
Rationale 
 
 
For disease-specific biological 
parameters and clinical events, 
including RBC transfusion 
requirements and number of 
total hospitalization days at 6, 
12, and 24 months, baseline will 
be defined as the average of 
these parameters over the 2 
years prior to study entry. For 
other change from baseline 
analyses, baseline will be 
defined as the value closest to, 
but prior to transplant. 
Added additional specification to 
baseline definitions. 
Other efficacy and pharmacodynamic 
parameters, most recent measure prior to 
conditioning.  
For safety including key laboratory 
(hematology and chemistry) parameters, 
the most recent value prior to 
mobilization (subjects with TDT) or 
bone marrow harvest (subjects with 
SCD).  
Changes were made to provide most 
clinically relevant baseline. 
7.4.2 
Disposition of 
Subjects 
The number of subjects 
completing the study through 2 
years post-transplant and 
reasons for study 
discontinuation will be reported.  
“through 2 years post-transplant” is 
changed to “through Month 18’ (interim 
analysis for TDT subjects) as well as 
through Month 24 (if data are available).  
Change made to allow an interim 
analysis when all subjects have 
completed at least 18 months of follow-
up or discontinued. 
7.4.3 
Demographic and 
Baseline 
Characteristics 
The following demographic and 
baseline characteristic factors 
will be summarized: age 
(current and age at diagnosis), 
country of origin, race and 
ethnicity, time from diagnosis 
of β-hemoglobinopathy type to 
confirmation for inclusion in the 
study, the presence of any 
significant co-morbid 
conditions, and the time from 
diagnosis of 
β-hemoglobinopathy type to 
treatment. 
Modifications include: 
Addition of characteristics (all subjects 
as well as specific to TDT or SCD 
indication). 
Eliminate summary table for interim 
analysis due to small number of 
subjects; data will be listed. 
 
Changes were made to provide most 
clinically relevant baseline information.  
7.5 
Efficacy Analysis  
The following parameters will 
be evaluated using descriptive 
statistics. (reference to sections 
7.5.1 and 7.5.2 in addition to 
the text below).  
Efficacy reporting to be limited to data 
listings.  
 
Change made given small number of 
subjects in HGB-205 (overall and by 
indication)  
7.5.2  
For SCD Subjects  
The number of VOC or acute 
chest syndrome events at 6, 12, 
and 24 months 
Added additional event types Significant 
Cerebral Abnormality, Stroke, and TIA, 
Osteonecrosis, and presence of sickle 
cell cardiomyopathy. 


Statistical Analysis Plan, Protocol HGB-205 
22 May 2019, Version 4.0 
 
Page 45 
Protocol 
Section  
Section Title 
Text in Protocol 
Change from Protocol in SAP and 
Rationale 
7.6 
Safety Analysis 
AEs will be summarized for 
those events that occur 1) after 
signing the informed consent 
and prior to conditioning; 2) 
from the start of conditioning 
until Day 1 (immediately before 
the start of LentiGlobin BB305 
Drug Product infusion); 3) from 
the start of LentiGlobin BB305 
Drug Product infusion on Day 1 
through 42 days post-infusion; 
Adverse Events: 
Incidence of AEs will be summarized as 
follows to align periods analyzed with 
those of the MAA: 
After signing the ICF and prior to 
mobilization 
Start of mobilization until start of 
conditioning  
Start of conditioning until date prior to 
ANC engraftment  
Date of ANC engraftment through 
Month 24 visit. 
Day 1 through the Month 24 Visit 
Added categories for summarizing AEs 
related to study procedures, 
mobilization/apheresis, and conditioning 
Added summarization of Malignancies 
(based on MedDRA SMQ categories) 
7.6 
Safety Analysis 
Laboratory measures will be 
compared with their 
corresponding normal ranges 
and the incidence of abnormal 
laboratory values will be 
calculated for each relevant 
protocol-specified laboratory 
test 
Defined abnormal laboratory reporting 
Added specific reporting summaries for 
lab parameters (shift tables using 
CTCAE version 4.03 criteria),  
subset listings of ≥ Grade 3 events  
figures for selected parameters. 
7.6 
Safety Analysis 
Replication-competent 
lentivirus (RCL) testing will be 
performed and any positive 
results will be confirmed 
Detailed RCL information to be reported 
in separate section. 
7.6 
Safety Analysis 
Banked leukocytes will be 
assayed for insertional 
mutagenesis by LAM-PCR and 
sequencing in the event that a 
malignancy is observed. 
Expanded section on ISA reporting 
 
Additional 
Information (not 
defined in Section 7 
of protocol)  
 
Addition of section for reporting 
mobilization, conditioning, and 
transplant details. 
 
 
 
Added section on transplant related 
mortality reporting  
 
 
 
Added section on vital sign, Karnofsky 
performance status, and physical 
examination reporting. 
 
 
 
Added section on concomitant 
medications and procedure reporting. 
 
 
 
Added section on overall survival 
reporting. 
 


Statistical Analysis Plan, Protocol HGB-205 
22 May 2019, Version 4.0 
 
Page 46 
6. 
CLINICAL STUDY REPORT APPENDICES 
A list of statistical tables, figures, and data listings, along with a complete set of reporting shells, 
will be provided in a separate document. 


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