A Phase 2/3 Study of the Efficacy and Safety of Hematopoietic Stem Cells Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral Adrenoleukodystrophy (CALD)
Phase: PHASE2
Conditions: Cerebral Adrenoleukodystrophy (CALD)
Sponsor: Genetix Biotherapeutics Inc.

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CLINICAL STUDY PROTOCOL ALD-102 
EudraCT No. 2011-001953-10  
 
 
A Phase 2/3 Study of the Efficacy and Safety of Hematopoietic Stem Cells 
Transduced With Lenti-D Lentiviral Vector for the Treatment of Cerebral 
Adrenoleukodystrophy (CALD) 
 
 
Study Sponsor: bluebird bio, Inc. 
60 Binney Street 
Cambridge, MA 02142 USA 
Telephone: +1. 339-499-9300 
Fax: +1. 339-499-9432 
 
 
Responsible Medical 
Officer: 
 
 
 Clinical Development 
bluebird bio, Inc. 
Telephone (mobile): 
 
E-mail: 
 
 
Protocol Version: Version 10.0 
 
Protocol Date: 23 September 2020 
 
 
 
CONFIDENTIAL 
Information and data in this document are privileged and confidential. No person is authorized to make 
any part of this document public without written permission from bluebird bio, Inc., unless such 
disclosure is required by government regulations or laws. 
This study will be conducted according to the protocol and in compliance with Good Clinical Practice, 
the ethical principles stated in the Declaration of Helsinki, and other applicable regulatory requirements. 
CCI
CCI

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MEDICAL OFFICER CONTACT INFORMATION 
Country-Specific 24-hour Emergency Contact Phone Numbers 
Country 
Phone Number 
Argentina 
0 800 345 5462 
Australia 
1 800 270 922 
France 
0 800 90 95 95 
 
Germany 
0 800 100 2341  
UK 
0 800 069 8015 
USA 
1 888 225 1854 
 
CCI

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SUMMARY OF CHANGES 
Substantial changes implemented in version 10.0 (23 September 2020) compared to 
version 9.0 (24 August 2018) of the protocol are described in the table below and include a 
revised algorithm for assessing clonal predominance, a clarification of safety endpoints, a 
notification for subjects of the potential for further investigations following unexpected 
laboratory results, instructions for sites on vaccine administration, new guidelines around the 
impact of the COVID-19 pandemic, and a revised guideline around the follow-up of newborns. 
Non-substantial changes implemented are also described in the following list. In addition, several 
minor changes were made to correct typographical errors and to rephrase some sentences to 
improve clarity. 

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DESCRIPTION OF EACH SUBSTANTIAL AMENDMENT 
Note: added text is bold and deleted text shown in strikeout. 
Initial wording 
Amended or New Wording 
Reason/Justification for change 
Section 2.2.2 Safety Endpoints 
The secondary safety endpoints are the following: 
Unedited endpoints are not listed 
• 
Incidence of insertional mutagenesis 
leading to clonal dominance or leukemia 
by Month 24 
 
Section 2.2.2 Safety Endpoints 
The secondary safety endpoints are the following: 
Unedited endpoints are not listed 
• 
Incidence of insertional mutagenesis leading 
to clonal dominance or leukemia by Month 24 
• 
The number of subjects with insertional 
oncogenesis (myelodysplasia, leukemia, 
lymphoma, etc.) by Month 24 
 
The exploratory safety endpoint is: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
Section 2.2.3 Other Exploratory Endpoints 
Exploratory endpoints include : 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Section 2.2.3 Other Exploratory Endpoints 
Exploratory endpoints include : 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Revised efficacy endpoints to provide 
individual outputs rather than change 
over time, as absolute values are a 
more informative parameter for 
analysis. 

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Section 6.1 Schedule of Events 
 
Section 6.1 Schedule of Events 
 
Impact of the COVID-19 Pandemic on Study Visits 
Due to the COVID-19 pandemic, subjects may not 
be able to attend normal study visits. If a visit is 
missed due to COVID-19 reasons (e.g. unable to 
fly, unwilling to travel, family or subject affected 
by COVID-19, hospital closure, etc.), the subject 
may be able to complete study assessments at a 
facility that is local to his home. 
Added text to provide guidelines 
around study procedures and 
assessments impacted by the COVID-
19 pandemic. 

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Section 6.1 Schedule of Events 
Table 3 Schedule of Events: Drug Product Infusion 
through End of Study 
Hematology2 
2 Hematology parameters include white blood cell 
(WBC) count with differential, hemoglobin, 
hematocrit, red blood cell (RBC), and platelet 
count. 
Section 6.1 Schedule of Events 
Table 3 Schedule of Events: Drug Product Infusion 
through End of Study 
Hematology2 
2 Hematology parameters include white blood cell 
(WBC) count with differential, hemoglobin, 
hematocrit, red blood cell (RBC), and platelet count. 
If the results from blood tests are not as expected, 
additional testing may need to be performed and 
may include a physical exam, blood tests, imaging 
tests, or a bone marrow biopsy to allow for further 
investigation of stem cells. 
 
Allows for further investigation when 
additional follow-up is required. 
Section 6.5.11.4 Specialty Laboratory Sample 
Collection 
Section 6.5.11.4 Specialty Laboratory Sample 
Collection 
 
Clinical work-up for unexpected blood test results: 
If the results from blood tests are not as expected, 
additional testing may need to be performed to 
allow for further investigation of stem cells and 
may include. 
• 
Physical exam 
• 
Blood tests 
• 
Imaging tests 
• 
Bone marrow biopsy 
 

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Section 6.5.12 Assessment of Clonal Dominance 
and/or Suspicion of Leukemia/Lymphoma 
 
Section 6.5.12.1 Assessment of Clonal Dominance 
 
An integration site analysis (ISA) will be 
performed on whole blood according to the SOE. 
The frequency of the ISA should be increased for 
subjects with VCN of ≥0.3 if the ISA demonstrates 
that a mappable insertion site (IS) contributes 
>30% to the total number of retrieved IS as follows 
(see also schematic in Figure 1), or at any time at 
the discretion of the Investigator and Sponsor: 
• 
If ISA detects an IS contributing >30% to 
the total IS, ISA should be repeated twice, 
each test approximately 3 months apart.  
• 
If result is ≤30% clonal contribution at 
either repeat ISA, monitoring of the subject 
returns to the protocol-defined schedule.  
• 
If result is >30% and ≤90% clonal 
contribution at the first repeat, and ≤50% 
clonal contribution at the second repeat, 
monitoring of the subject also returns to 
the protocol-defined schedule. 
• 
If result is >30% and ≤90% clonal 
contribution at the first repeat, and >50% 
clonal contribution at the second repeat, 
clonal dominance criteria are met and 
clinical work-up for malignancy should be 
initiated.  
• 
If ISA result is >90% clonal contribution at 
any time, clonal dominance criteria are met 
and clinical work-up for malignancy 
should be initiated.  
Section 6.5.12 Assessment of Clonal Predominance 
Dominance and/or Suspicion of 
Leukemia/Lymphoma Insertional Oncogenesis 
(Malignancy)  
 
Section 6.5.12.1 Assessment of Clonal 
Predominance Dominance 
 
An integration site analysis (ISA) will be performed 
on whole blood according to the SOE. The frequency 
of the ISA should be increased for subjects with VCN 
of ≥0.3 if the ISA demonstrates that a mappable 
insertion site (IS) contributes >30% to the total 
number of retrieved IS as follows (see also schematic 
in Figure 1), or at any time at the discretion of the 
Investigator and Sponsor: 
• 
If ISA detects an IS contributing >30% to the 
total IS, ISA should be repeated twice, each 
test approximately 3 months apart.  
• 
If result is ≤30% clonal contribution at either 
repeat ISA, monitoring of the subject returns 
to the protocol-defined schedule.  
• 
If result is >30% and ≤90% clonal 
contribution at the first repeat, and ≤50% 
clonal contribution at the second repeat, 
monitoring of the subject also returns to the 
protocol-defined schedule. 
• 
If result is >30% and ≤90% clonal 
contribution at the first repeat, and >50% 
clonal contribution at the second repeat, 
clonal dominance criteria are met and clinical 
work-up for malignancy should be initiated.  
• 
If ISA result is >90% clonal contribution at 
any time, clonal dominance criteria are met 
The assessment of clonal 
predominance will now be assessed 
based on frequency of clones with 
LVV insertions rather than based on 
frequency of individual LVV insertion 
sites. Based on clinical experience, the 
previous algorithm, which depended 
on Relative IS-Frequencies to identify 
clones that may have expanded to 
become predominant within a subject, 
was unable to account for multiple 
integration sites (IS) in a single cell. 
Our evolving understanding of the 
strengths and weaknesses of the ISA 
methods suggest that clonal 
contribution as determined by IS-
specific qPCR normalized against 
human genomic genes is the most 
suitable current method available to 
accurately determine the relative 
predominance of each given clone 
independent of how many unique IS 
may be present within that clone. 

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Note that for the purposes of this protocol, the term 
“oligoclonality” is used to describe situations in 
which the above clonal dominance criteria apply. 
Therefore, if a subject meets the above criteria and 
further work-up is required, a regulatory 
submission will be performed as per FDA 
Guidance for Industry: Gene Therapy Clinical 
Trials - Observing Subjects for Delayed Adverse 
Events (November 2006). 
and clinical work-up for malignancy should 
be initiated.  
 
Note that for the purposes of this protocol, the term 
“oligoclonality” is used to describe situations in 
which the above clonal dominance criteria apply. 
Therefore, if a subject meets the above criteria and 
further work-up is required, a regulatory submission 
will be performed as per FDA Guidance for Industry: 
Gene Therapy Clinical Trials - Observing Subjects for 
Delayed Adverse Events (November 2006). 
 
Figure 1 outlines the updated algorithm for 
assessment of clonal predominance. Screening 
integration site (IS) analysis (ISA) will be 
performed as indicated in the schedule of events 
using high-throughput, semi-quantitative methods 
which identify IS based on vector sequence 
primers. IS identified in the screening assay are 
considered as being of interest when the overall 
peripheral blood VCN is > 0.3 c/dg AND either any 
relative IS frequency is > 30% OR multiple IS are 
apparently in the same clone and add up to > 30%. 
Multiple IS apparently in the same clone is defined 
as more than one relative frequency where values 
are within 20% of each other (e.g. 5% ± 1%, 10% 
± 2%, 15% ± 3%, etc.), as well as any additional 
cases identified through bluebird bio internal 
review of ISA reports. When multiple IS are 
apparently in the same clone, it will be 
recommended to confirm that those IS are in a 
single clone (e.g. bone marrow or peripheral blood 
colony-forming unit assay). IS of interest will be 
interrogated, from the timepoint of interest and 

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available previous timepoints, using a quantitative 
assay (e.g. qPCR) designed to detect the specific IS 
and determine an IS-specific VCN to estimate 
clonal contribution. 
If results of the quantitative, IS-specific follow-up 
assay reveal an IS-specific VCN ≤ 0.5 c/dg, 
estimating ≤ 50% clonal contribution, repeat ISA 
screening will continue at the regularly scheduled 
timepoints. However, according to scientific 
judgement or interest, investigative follow-up may 
be initiated by bluebird bio in collaboration with 
an investigator and additional interval, 
unscheduled ISA testing may be performed. 
If results of the quantitative, IS-specific follow-up 
assay reveal an IS-specific VCN > 0.5 c/dg, 
estimating > 50% clonal contribution, criteria will 
be met to consider the subject as having a 
predominant clone. This threshold also applies to 
individual lineage evaluations (myeloid, lymphoid, 
etc.) when performed. Clinical work-up will be 
recommended for a predominant clone (see next 
sections). A report to relevant regulatory 
authorities will be required when a persistent, 
predominant clone is identified (2 or more 
timepoints), and the report will be made within 30 
days of receipt of IS-specific VCN results from the 
second timepoint when the persistent, 
predominant clone is identified. 
 
Figure 1 was updated to reflect the updated ISA 
algorithm 

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Section 6.5.12.3 Clinical Work-up for Malignancy 
 
If any of the above criteria is met, the Medical 
Monitor will be notified, and a work-up will be 
performed that may include the following: 
• 
Physical exam  
• 
CBC with differential lymphocyte subsets 
• 
Studies to rule out infectious cause 
• 
Studies to rule out autoimmune disease 
• 
Imaging studies, as appropriate 
• 
Bone marrow analysis 
Section 6.5.12.3 Clinical Work-up for Malignancy 
 
If any of the above criteria is met, the Medical 
Monitor will be notified, and a work-up will be 
performed that may occur in stages and may include 
some of the following at each stage:  
• 
Physical exam  
• 
CBC with differential and lymphocyte subsets 
• 
Lymphocyte subsets 
• 
Studies to rule out infectious cause 
• 
Studies to rule out autoimmune disease 
• 
Imaging studies, as appropriate 
• 
Bone marrow analysis 
 
Bone Marrow Aspiration 
The subject will undergo BM aspiration if clonal 
dominance is observed. The procedure may also be 
done at the Investigator's discretion, if there is 
concern about clonal expansion. The BM aspiration 
will be performed in accordance with institutional 
practices under aseptic conditions. It is anticipated 
that institutional guidelines will specify that 
approximately 5 to 20 mL of BM will be collected 
each time. 
Bone Marrow Aspiration 
The subject will may undergo BM aspiration if clonal 
predominance is observed. The procedure may also 
be done at the Investigator's discretion, if there is 
concern about clonal expansion. The BM aspiration 
will be performed in accordance with institutional 
practices under aseptic conditions. It is anticipated 
that institutional guidelines will specify that 
approximately 5 to 20 mL of BM will be collected 
each time. 
 

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Section 6.7 Pregnancies and Contraception 
 
The course of all pregnancies, including perinatal 
and neonatal outcome, regardless of whether the 
subject has discontinued participation in the study, 
will be followed until outcome, including follow-
up of the health status of the newborn to 6 weeks of 
age. SAEs experienced by newborn within 6 weeks 
of age are required to be immediately reported (i.e. 
within 24 hours) on the SAE report form. 
Section 6.7 Pregnancies and Contraception 
 
The course of all pregnancies, including perinatal and 
neonatal outcome, regardless of whether the subject 
has discontinued participation in the study, will be 
followed until outcome resolution. Information will 
be requested on the status of the mother and infant 
at 6 weeks of age an annually thereafter for 2 
years, including follow-up of the health status of the 
newborn to 6 weeks of age. SAEs experienced by the 
newborn within 6 weeks of age are required to be 
immediately reported (i.e. within 24 hours) on the 
SAE report form. In cases of a male study subject, 
pregnancies resulting from sperm banking prior to 
the receipt of drug product will not be followed. 
Following regulatory guidance, added 
text to extend the time period for 
follow-up of newborns. 
Section 7.3 Planned Analyses 
Section 7.3 Planned Analyses 
Section 7.3.4 Impact of the COVID-19 Pandemic 
 
A review will be performed to determine which 
assessments are likely to have been affected by the 
COVID-19 pandemic, and analyses will be 
performed to measure the effect of disruptions due 
to the pandemic on these assessments. 
Added text to provide guidelines 
around study procedures and 
assessments impacted by the COVID-
19 pandemic. 

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DESCRIPTION OF EACH NON-SUBSTANTIAL AMENDMENT 
• Updated the Title page to reflect a change in Responsible Medical Officer. 
• Added information page for country-specific 24-hour emergency contact phone 
numbers to reach the Responsible Medical Officer. 
• Replaced “Lenti-D Drug Product” in the synopsis and body text with “elivaldogene 
autotemcel” or the abbreviation “eli-cel”, which is the designated INN/USAN. 
• Replaced “clonal dominance” with “clonal predominance” in the synopsis and body 
text to reflect a change in nomenclature. 
• Removed detail of point estimate needed for meeting success criterion from synopsis  
• Updated language and references in Section 1.5.1 to more accurately account for the 
number of subjects treated in gene therapy studies since the previous amendment as 
per the most recent Investigator’s Brochure v10.0. 
• Clarified in Section 4.5 that only subjects who receive drug product will be asked to 
complete Early Termination Visit assessments if they withdraw before study 
completion. 
• Added text to Section 5.10 instructing sites to follow institutional guidelines when 
administering vaccines. 
• Removed text in Section 6.5.11.4 that indicated ISA would only be performed if 
VCN is ≥ 0.01 c/dg, since ISA is run in parallel with VCN and RCL, therefore a 
preliminary VCN check in not performed. 
• Corrected a statement in Section 6.6 to reflect that SAEs, not AEs, will continue to be 
monitored following subject discontinuation from the study. 
• Amended language in Section 6.6.1 to direct Investigators to reference the prescribing 
information for conditioning agents for conditioning-related AEs and that that 
conditioning-related AEs should be attributed to conditioning in the eCRF rather than 
a “conditioning-related event” which is not an available category. 
• Clarified that AEs are graded by the general guidelines per the CTCAE rather than 
the specific criteria for individual AE terms in Section 6.6.2. 
• Details have been added to Section 7.3 clarifying how interim and final data analyses 
will be performed and how safety data will be reviewed.  
• Clarified the definition of treatment emergent adverse event in Section 7.4.5 as 
occurring on or after initiation of eli-cel infusion rather than on the day of eli-cel 
infusion to align with language in the Statistical Analysis Plan. 
• Added statement in Section 7.4.5 to see the Statistical Analysis Plan for a 
comprehensive list of study periods and additional details. 

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CLINICAL STUDY SYNOPSIS 
Protocol Title: 
A phase 2/3 study of the efficacy and safety of hematopoietic stem cells 
transduced with Lenti-D lentiviral vector for the treatment of cerebral 
adrenoleukodystrophy (CALD) 
Protocol Number: 
ALD-102 
EudraCT Number: 
2011-001953-10 
Objectives: 
The study objectives are to: 
• 
Evaluate the efficacy of Lenti-D Drug Product (also known as 
elivaldogene autotemcel, hereafter referred to as eli-cel) in subjects with 
CALD 
• 
Evaluate the safety of eli-cel in subjects with CALD 
Study Design: 
This will be an international, non-randomized, open-label, multi-site, single-dose 
study in male subjects with CALD (≤ 17 years of age at enrollment). 
Approximately 30 subjects will be infused with eli-cel. The study will begin 
with a staggered infusion schedule. The data monitoring committee (DMC) will 
review safety and neutrophil engraftment data on Subject 1 prior to approving 
infusion of Subject 2. Following a review of safety and neutrophil engraftment 
data from the first 2 subjects, and with the recommendation of the DMC, parallel 
infusions will be allowed.  
Selected subjects must meet the inclusion criteria, have none of the exclusion 
criteria, and have provided informed consent. The study has 4 distinct phases 
after informed consent: 
• 
Screening  
• 
CD34+ Cell Collection, Transduction, Disposition of eli-cel, and 
Re-confirmation of Eligibility  
• 
Conditioning and Washout followed by eli-cel Infusion (transplant) on 
Day 0 
• 
Maintenance (Follow-up) (Day 1 through 24 ± 1 month [Month 24]) 
From Screening through when it is assessed that the subject is stably 
transplanted (by approximately the Month 3 Visit), visits will occur at one of a 
small number of sites (referred to as primary study sites). However, due to the 
rarity of CALD, it is likely that some subjects may have to travel far for 
participation at the primary study sites. Therefore, after the subject is stably 
transplanted, arrangements may be made to open up a suitable site closer to the 
subject’s home (referred to as secondary study sites) where they could attend 
subsequent visits. In all cases, subjects will be asked to return to their primary 
study site for their assessments for Month 12 and Month 24 Visits to ensure 
consistency in key efficacy assessments. 
Prior to the Screening Phase, the Investigator will identify candidates 
potentially meeting the study eligibility criteria, based on review of medical 
records and clinical test findings performed routinely as standard of care for 
the treatment of the subject. The competent legal parent(s)/guardian of 
subjects who are determined by the Investigator to be potentially eligible, will 
be informed of the option to participate in the study and all associated risks of 
the study procedures as well as the investigational nature of gene therapy 
treatment (eli-cel). In addition, if consistent with local regulation, the 
Investigator will seek assent from the subject if he is at least 7 years of age. 

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Sites will follow their standard institutional practice for obtaining informed 
consent. The subject and his legal parent(s)/guardian should be provided with 
adequate time to ask questions about the study, treatment, and required 
procedures. A physician not associated with the study team, but knowledgeable 
about the gene therapy, hematopoietic stem cell transplantation (HSCT), and 
CALD clinical management, must participate in the initial consent process to 
provide an independent perspective on the benefit-risk of study participation 
and other available treatment options. Written informed consent and assent 
(if applicable) must be obtained before the conduct of any screening tests not 
performed routinely in the treatment of the subject.  
The consent process will be performed in accordance with International 
Conference of Harmonization (ICH)/Good clinical practice (GCP), local 
regulations, and site-specific institutional practice.  
Subjects who are pre-screened and considered by the Investigator to be eligible 
and for whom written informed consent has been provided will enter the 
Screening Phase and undergo the tests and procedures necessary to confirm 
study eligibility.  
Subjects who are confirmed to be eligible, based on Screening assessments, will 
undergo G-CSF-mediated, and potentially plerixafor-mediated, hematopoietic 
stem cell (HSC) mobilization and harvest by apheresis using institutional 
practice treatment guidelines. G-CSF is defined for this protocol to mean either 
filgrastim or lenograstim. The harvested cells will be selected for the CD34+ 
marker to enrich for HSC, transduced with Lenti-D lentiviral vector, stored 
frozen in cryopreservative solution while aliquots are being tested to ensure they 
meet product quality specifications, and returned by IV infusion through a 
central venous catheter to the same subject after the subject is myeloablated with 
cyclophosphamide IV and busulfan IV. The subject will only undergo 
myeloablation after the transduced cells are dispositioned for clinical use and the 
drug product is at the clinical site.  
Back-up cells (mobilized peripheral blood mononuclear cells [PBMCs]) will 
also be harvested during apheresis and stored frozen in accordance with 
institutional guidelines. If back up cells cannot be procured from apheresis, a 
bone marrow harvest may be performed. 
All subjects will be followed for 24 months post-drug product infusion under 
this protocol. Then, if appropriate consent is obtained, subjects will be followed 
for an additional 13 years under a separate follow-up protocol (LTF-304). 
Number of Subjects 
Planned: 
Approximately 30 subjects will be infused with eli-cel. 
Inclusion Criteria: 
1. Informed consent is obtained from a competent custodial parent or guardian 
with legal capacity to execute a local Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) approved consent. (Informed 
assent will be sought from capable subjects, in accordance with the directive 
of the IRB/IEC and with local requirements.) 
2. Males aged 17 years and younger, at the time of parental/guardian consent 
and, where appropriate, subject assent. 
3. Active cerebral ALD as defined by: 
a. 
Elevated very long chain fatty acids (VLCFA) values, and 
b. 
Active central nervous system (CNS) disease established by central 
radiographic review of brain magnetic resonance imaging (MRI) 
demonstrating 

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i. Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and 
ii. Gadolinium enhancement on MRI of demyelinating lesions. 
4. Neurologic Function Score (NFS) ≤ 1. 
Exclusion Criteria: 
1. Receipt of an allogeneic transplant or gene therapy. 
2. Availability of a willing 10/10 human leukocyte antigen (HLA)-matched 
sibling donor (excluding female heterozygotes). 
3. Use of statins, Lorenzo’s Oil, or dietary regimens used to lower VLCFA 
levels. Note: subjects must discontinue use of these medications at time of 
consent. 
4. Receipt of an investigational study drug or procedure within 3 months 
before Screening that might confound study outcomes. Use of 
investigational study drugs is prohibited throughout the course of the study. 
5. Any conditions that make it impossible to perform MRI studies (including 
allergies to anesthetics or contrast agents). 
6. Hematological compromise as evidenced by: 
o Peripheral blood absolute neutrophil count (ANC) < 1500 cells/mm3, 
o Platelet count < 100,000 cells/mm3, or  
o Hemoglobin < 10 g/dL.  
o Uncorrected bleeding disorder. 
7. Hepatic compromise as evidenced by: 
o Aspartate transaminase (AST) value > 2.5 × ULN  
o Alanine transaminase (ALT) value > 2.5 × ULN 
o Total bilirubin value > 3.0 mg/dL, except if there is a diagnosis of 
Gilbert’s Syndrome and the subject is otherwise stable  
8. Renal compromise as evidenced by abnormal renal function (actual or 
calculated creatinine clearance < 50 mL/min) 
9. Cardiac compromise as evidenced by left ventricular ejection fraction < 40% 
10. Immediate family member with a known or suspected Familial Cancer 
Syndrome (including but not limited to hereditary breast and ovarian cancer 
syndrome, hereditary non-polyposis colorectal cancer syndrome, and 
familial adenomatous polyposis).  
11. Clinically significant active bacterial, viral, fungal, parasitic, or prion-
associated infection  
12. Positive for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2); 
hepatitis B; hepatitis C; human T lymphotropic virus 1 (HTLV-1). 
(Note that subjects who have been vaccinated against hepatitis B 
[hepatitis B surface antibody-positive] who are negative for other markers 
of prior hepatitis B infection [e.g., negative for hepatitis B core Ab] are 
eligible. Subjects with past exposure to HBV [HBcAb positive and/or 
HBeAb positive] are also eligible for the study provided they have a 
negative test for HBV DNA. Also note that subjects who are positive for 
anti-hepatitis C Ab are eligible as long as they have a negative hepatitis C 
viral load).  
13. Any clinically significant cardiovascular or pulmonary disease, or other 
disease or condition that would be contraindicated for any of the other study 
procedures. 
 
 
14. Absence of adequate contraception for fertile subjects. Male subjects and 
their female partners are required to use two different effective methods of 

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contraception from Screening through at least 6 months after drug product 
infusion. If subjects are truly sexually abstinent (where true sexual 
abstinence is defined as being in line with the preferred and usual lifestyle of 
the subject), no second method is required. 
15. Any contraindications to the use of G-CSF during the mobilization of HSCs, 
and any contraindications to the use of busulfan or cyclophosphamide, 
including known hypersensitivity to the active substances or to any of the 
excipients in their formulations. 
Duration of Subject 
Participation: 
Each subject will remain on this study for approximately 26 months from time 
of consent, inclusive of an approximately 24-months post-drug product infusion 
follow up; subjects will then be asked to consent for a follow-up study for 
another 13 years post-drug product infusion. 
Duration of Study: 
From enrollment of the first subject to post-drug product infusion observation of 
the last subject enrolled, the study duration is expected to be 56 months. 
Test Product, Dose 
and Mode of 
Administration: 
Eli-cel (autologous CD34+ cell-enriched population that contains cells 
transduced with lentiviral vector encoding human adrenoleukodystrophy protein, 
suspended in a cryopreservative solution) is administered intravenously; dose 
≥ 5.0 × 106 CD34+ cells/kg.  
Reference Therapy, 
Dose and Mode of 
Administration: 
Not applicable. 
Data Monitoring 
Committee:  
An independent Data Monitoring Committee (DMC) composed of members 
with appropriate scientific and medical expertise to monitor the study will be 
convened before the study is opened. A charter describing the composition and 
conduct of the DMC will be drafted by the Sponsor and agreed to by all DMC 
members prior to the DMC’s initial meeting. The DMC will review safety and 
neutrophil engraftment data on Subject 1 prior to proceeding with the transplant 
of Subject 2; and on Subject 2 prior to allowing the transplant of subsequent 
subjects. Following a review of safety and neutrophil engraftment data from the 
first 2 subjects and, with the recommendation of the DMC, parallel treatment 
(transplant) will be allowed. The DMC will meet by teleconference at regular 
intervals, approximately once every 6 months, or more frequently if needed, and 
depending on speed of subject enrollment and amount of new data generated. 
The DMC will be charged with review of all unexpected eli-cel treatment-related 
SAEs following notification by the Sponsor. The DMC will have the right to 
recommend halting the study at any time due to concerns for the safety of the 
subjects. 
Criteria for 
Evaluation – Efficacy: 
The primary efficacy endpoint is: 
• 
Proportion of subjects who are alive and have none of the 6 major 
functional disabilities (MFDs) at Month 24 (i.e. Month 24 MFD-free 
survival). MFDs are: loss of communication, cortical blindness, tube 
feeding, total incontinence, wheelchair dependence, complete loss of 
voluntary movement 
Secondary efficacy endpoints include the following: 
• 
Proportion of subjects who demonstrate resolution of gadolinium 
positivity on MRI (i.e., GdE-) at Month 24 
• 
Time to sustained resolution of gadolinium positivity on MRI 
(i.e., GdE‑). Sustained is defined as gadolinium resolution without a 

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subsequent evaluation indicating gadolinium positivity  
• 
Change in total NFS from Baseline to Month 24 
• 
MFD-free survival over time 
• 
Overall survival 
 
  
 
 
 
 
Criteria for 
Evaluation – Safety: 
The primary safety endpoint is: 
• 
The proportion of subjects who experience either acute (≥ Grade II) or 
chronic graft versus host disease (GVHD) by Month 24. 
The secondary safety endpoints are the following: 
• 
Proportion of subjects with neutrophil engraftment by 42 days post-drug 
product infusion 
• 
Time to neutrophil engraftment post-drug product infusion 
• 
Proportion of subjects with platelet engraftment by Month 24 
• 
Time to platelet engraftment post-drug product infusion 
• 
Proportion of subjects with loss of engraftment post-drug product 
infusion by Month 24 
• 
Proportion of subjects who undergo a subsequent HSC infusion by 
Month 24 
• 
Proportion of subjects with transplant-related mortality through 100 and 
365 days post-drug product infusion 
• 
Proportion of subjects with and severity of clinical ≥ Grade 3 AEs, all 
drug-product related AEs, all SAEs, ≥ Grade 3 infections, and changes 
in laboratory parameters by Month 24 
• 
Proportion of subjects with ≥ Grade II acute GVHD by Month 24 
• 
Proportion of subjects with chronic GVHD by Month 24 
• 
Number of emergency room visits (post-neutrophil engraftment) by 
Month 24 
• 
Number and duration of in-patient hospitalizations (post-neutrophil 
engraftment) by Month 24 
• 
Number and duration of ICU stays (post-neutrophil engraftment) by 
Month 24 
• 
Incidence of vector-derived RCL at Month 24 
• 
The number of subjects with insertional oncogenesis (myelodysplasia, 
leukemia, lymphoma, etc.) by Month 24 
The exploratory safety endpoint is: 
• 
 

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Criteria for 
Evaluation – 
Exploratory 
Exploratory endpoints include: 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
Suspension Criteria: 
Enrollment in this study may be suspended at any time for safety reasons. It will 
be the responsibility of the DMC to make a recommendation to the Sponsor if 
they believe there is reasonable cause for suspending enrollment. The Sponsor 
will inform the regulatory authorities and the Investigators, and each site’s 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and 
other appropriate institutional regulatory bodies will be promptly notified, if a 
decision to suspend enrollment is made. In the event enrollment is suspended, no 
new mobilization, conditioning, or drug product infusion of subjects will be 
initiated, but subjects who have already been treated with eli-cel will continue in 
the study. If mobilization has been initiated, cell collection will be completed at 
Investigator’s discretion. Likewise, if the study is halted while a subject is 
undergoing conditioning, conditioning will be completed at Investigator’s 
discretion, and every effort will be made to restart the study prior to their 
scheduled infusion. However, a subject may be infused with their back-up cells 
following conditioning if the study cannot be restarted in time. 
Enrollment and treatment with drug product will be temporarily suspended for 
any of the following reasons pending review and recommendations from the 
DMC and the appropriate communication with the relevant regulatory 
agency(ies): 
• 
Death, until the cause of the death is determined 
• 
Detection of leukemia/lymphoma due to vector-mediated insertional 
oncogenesis 
 

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• 
Detection of vector-derived RCL in any subject  
• 
Failure in 1 subject to achieve reconstitution with transduced cells, 
requiring use of back-up cells or HSCs from an appropriately allogeneic 
donor. Engraftment failure is defined as a failure to achieve 3 
consecutive ANC laboratory values of ≥ 0.5 × 109 cells/L (after initial 
post-infusion nadir) obtained on different days by 42 days post-infusion 
(transplant) of eli-cel. 
• 
Determination of unexpected, clinically significant, or unacceptable risk 
to subjects (e.g., development of study treatment-related Grade 3 or 
4 toxicities in at least 3 subjects). 
Statistical Methods: 
Three populations will be evaluated for safety, efficacy, and exploratory 
analyses. 
• The Intent-to-treat population (ITT) will consist of those subjects who 
initiate any study procedures, beginning with stimulation by G-CSF. This 
population will be used for the analyses of some of the safety endpoints and 
for the supportive analysis of the primary efficacy endpoint, if it is different 
from the Transplant Population (TP). 
• The Transplant population (TP) will consist of subjects who receive eli-cel. 
This population will be used for the analyses of all efficacy endpoints and 
some of the safety endpoints.  
• The Successful Neutrophil Engraftment Population (NEP) will consist of 
subjects who received eli-cel and achieved neutrophil engraftment defined as 
having 3 consecutive ANC laboratory values of ≥ 0.5 × 109 cells/L (after 
initial post-infusion nadir) obtained on different days by 42 days post-
infusion of eli-cel. The NEP will be used for the supportive analysis of the 
primary efficacy endpoint as well as for some of the other efficacy and safety 
endpoints, if it is different from the TP. 
It is recognized that formal, confirmatory statistical hypotheses are extremely 
difficult to formulate in the context of this subject population, where few 
historical data are available regarding the efficacy endpoints. Further, it is not 
possible to have a truly randomized comparison of eli-cel to other potentially 
curative modes of treatment, such as allogeneic HSCT, due to the rarity of the 
disease. Therefore, statistical methods will be primarily descriptive in nature, 
and will include point estimates and confidence limits as appropriate. 
The analysis of the primary efficacy endpoint, Month 24 MFD-free survival, 
will be performed on the TP. The lower bound of the 2-sided 95% exact 
confidence interval of the Month 24 MFD-free survival must be > 50% in order 
for the primary endpoint to be met. 
The analyses of the secondary and exploratory efficacy endpoints will be 
performed on the TP. 
The analysis of the primary safety endpoint will be to compare the proportion of 
subjects who have experienced either acute (≥ Grade II) or chronic GVHD at 
Month 24 in the TP population from Study ALD-102 to the rate seen in the allo-
HSCT-treated population in Study ALD-103. 
The general safety profile of treatment with eli-cel will be summarized through 
the longitudinal evaluation of AEs, laboratory assessments, vital signs, ECG, 
and physical examination findings. Safety parameters will be summarized across 
each time point. 
The planned statistical methodology will be presented in detail in the SAP. 

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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ABCD1 
ATP-binding cassette, sub-family D, member 1 
ABW 
actual body weight 
ADL 
activities of daily living 
AE 
adverse event 
ALD 
adrenoleukodystrophy 
ALDP 
adrenoleukodystrophy protein 
allo-HSCT 
allogeneic hematopoietic stem cell transplantation 
ALT 
alanine transaminase 
ANC 
absolute neutrophil count 
AST 
aspartate transaminase 
AUC 
area under the curve 
BAER 
brain stem auditory evoked response 
 
 
BM 
bone marrow 
 
 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CALD 
Cerebral Adrenoleukodystrophy 
CI 
confidence interval 
CMV 
Cytomegalovirus 
CNS 
central nervous system 
CRE 
conditioning-related event 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DMSO 
dimethyl sulfoxide 
EBV 
Epstein-Barr virus 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eli-cel 
elivaldogene autotemcel 
EU 
European Union 
FDA 
Food and Drug Administration 
FSIQ 
Full Scale Intelligence Quotient 
GCP 
Good Clinical Practice 
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Abbreviation 
Definition 
G-CSF 
granulocyte colony stimulating factor 
GdE+ 
gadolinium enhancement 
GMP 
Good Manufacturing Practice 
GVHD 
graft-versus-host disease 
Hb 
hemoglobin 
HBcAb 
hepatitis B core antibody  
HBeAb 
hepatitis B e-antigen antibody 
HBsAb 
hepatitis B surface antibody 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HEENT 
head, ears, eyes, nose, and throat 
HIV 
human immunodeficiency virus 
HIV-1 
human immunodeficiency virus type 1 
HIV-2 
human immunodeficiency virus type 2 
HLA 
human leukocyte antigen 
HPC-A 
Hematopoietic Progenitor Cell, Apheresis 
HRQoL 
Health Related Quality of Life Assessment 
HSC 
hematopoietic stem cell 
HSCT 
hematopoietic stem cell transplant(ation) 
HSV 
herpes simplex virus 
HTLV-1 
human T lymphotropic virus 1 
HTLV-2 
human T lymphotropic virus 2 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IBW 
ideal body weight 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IQ 
intelligence quotient 
IRB 
Institutional Review Board 
IS 
integration site(s) 
ISA 
integration site analysis 
ITT 
the intent-to-treat population 
IV 
intravenous 
LLN 
lower limit of normal 
LTR 
long terminal repeat 
LVV 
lentiviral vector 

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Abbreviation 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MFD 
major functional disability 
MMP 
matrix metalloproteinase(s) 
MRI 
magnetic resonance imaging 
MUD 
matched unrelated donor 
NCI 
National Cancer Institute 
NCS 
Nerve Conduction Study 
NE 
neutrophil engraftment 
NEP 
Neutrophil Engraftment Population 
NFS 
Neurologic Function Score 
PBL 
peripheral blood leukocyte 
PBMC 
peripheral blood mononuclear cell 
PCR 
polymerase chain reaction 
 
 
PIQ 
Performance Intelligence Quotient 
qPCR 
quantitative polymerase chain reaction 
RBC 
red blood cell 
RCL 
replication competent lentivirus 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcriptase polymerase chain reaction 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SCGM 
stem cell growth media 
SCID-X1 
X-linked severe combined immunodeficiency 
SES 
socioeconomic status 
SIN 
self-inactivating 
SOE 
Schedule of Events 
SOM 
Study Operations Manual 
SSEP 
somatosensory evoked potential 
SUSAR 
suspected unexpected serious adverse drug reaction 
TMT 
Trail Making Test 
TP 
Transplant Population 
TPE 
ALD-102-Eligible Transplant Population 
TPES 
Strictly ALD-102-Eligible Transplant Population 
TPG 
GdE+ Transplant Population 
ULN 
upper limit of normal 
UK 
United Kingdom 
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Abbreviation 
Definition 
US 
United States 
 
 
VCN 
vector copy number 
VEP 
Visual Evoked Potential 
VIQ 
Verbal Intelligence Quotient 
VLCFA 
very long chain fatty acids 
VOD 
veno-occlusive disease 
VMI 
Developmental Test of Visual-Motor Integration, 6th ed 
VSV-G 
vesicular stomatitis virus G 
 
 
WBC 
white blood cell 
 
 
 
 
 
CCI
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CCI
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TABLE OF CONTENTS 
MEDICAL OFFICER CONTACT INFORMATION .................................................................. 2 
SUMMARY OF CHANGES ....................................................................................................... 3 
CLINICAL STUDY SYNOPSIS ............................................................................................... 13 
LIST OF ABBREVIATIONS.................................................................................................... 20 
TABLE OF CONTENTS .......................................................................................................... 24 
LIST OF TABLES IN THE TEXT ............................................................................................ 27 
LIST OF FIGURES IN THE TEXT .......................................................................................... 27 
1. 
INTRODUCTION .................................................................................................. 28 
1.1. 
Cerebral X-Linked Adrenoleukodystrophy (CALD) ............................................... 28 
1.2. 
Retrospective Study ALD-101 ................................................................................ 28 
1.3. 
Eli-cel ..................................................................................................................... 29 
1.4. 
Rationale for Study Design ..................................................................................... 30 
1.5. 
Potential Risks ........................................................................................................ 31 
1.5.1. 
Abnormal Proliferation of Hematopoietic Cells ...................................................... 31 
1.5.2. 
Use of a Lentiviral Vector Derived from Human Immunodeficiency Virus 
Type 1 .................................................................................................................... 32 
1.5.3. 
Risks of Mobilization and Transplantation .............................................................. 33 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................... 34 
2.1. 
Study Objectives ..................................................................................................... 34 
2.2. 
Study Endpoints ..................................................................................................... 34 
2.2.1. 
Efficacy Endpoints ................................................................................................. 34 
2.2.2. 
Safety Endpoints ..................................................................................................... 34 
2.2.3. 
Other Exploratory Endpoints .................................................................................. 36 
3. 
INVESTIGATIONAL PLAN ................................................................................. 37 
3.1. 
Overall Design and Plan of the Study...................................................................... 37 
3.1.1. 
Data Monitoring Committee ................................................................................... 39 
3.2. 
Rationale for the Study ........................................................................................... 39 
3.3. 
Rationale for the Dose Selected .............................................................................. 40 
3.4. 
Treatment Discontinuation and Enrollment Suspension Criteria .............................. 41 
3.4.1. 
Stopping Rules Prior to Conditioning...................................................................... 41 
3.4.2. 
Enrollment Suspension Criteria............................................................................... 41 

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3.5. 
End of Trial Definition ........................................................................................... 42 
4. 
STUDY POPULATION ......................................................................................... 43 
4.1. 
Number of Subjects ................................................................................................ 43 
4.2. 
Subject Inclusion Criteria ....................................................................................... 43 
4.3. 
Subject Exclusion Criteria ...................................................................................... 43 
4.4. 
Subject Identification and Registration.................................................................... 45 
4.5. 
Subject Withdrawal from the Study ........................................................................ 45 
4.6. 
Investigator or Sponsor Termination of Subject Participation .................................. 45 
5. 
STUDY TREATMENTS ........................................................................................ 46 
5.1. 
Description of the Lenti-D Lentiviral Vector and Eli-cel Product ............................ 46 
5.2. 
Summary of Treatments to be Performed or Administered ...................................... 46 
5.2.1. 
Mobilization and Apheresis Procedure .................................................................... 46 
5.2.2. 
Bone Marrow Harvest Procedure ............................................................................ 48 
5.2.3. 
Transduction Process and Release Testing .............................................................. 48 
5.2.4. 
Conditioning ........................................................................................................... 48 
5.2.5. 
Infusion (Transplant) Procedures, Dose, and Administration ................................... 49 
5.3. 
Storage and Stability of Eli-cel ............................................................................... 50 
5.4. 
Storage and Administration of Back-up Cells ......................................................... 50 
5.5. 
Method of Assigning Subjects to Treatment ............................................................ 50 
5.6. 
Blinding, Packaging, and Labeling ......................................................................... 50 
5.6.1. 
Blinding and Breaking the Blind ............................................................................. 50 
5.6.2. 
Packaging and Labeling .......................................................................................... 50 
5.7. 
Duration of Subject Participation ............................................................................ 50 
5.8. 
Assessment of Treatment and Study Compliance .................................................... 51 
5.9. 
Product Accountability ........................................................................................... 51 
5.10. 
Prior and Concomitant Medication and Therapy ..................................................... 52 
6. 
STUDY ASSESSMENTS....................................................................................... 53 
6.1. 
Schedule of Events ................................................................................................. 53 
6.2. 
Concurrent Human Leukocyte Antigen Search for Allogeneic Donor ..................... 59 
6.3. 
Confirmation of Eligibility...................................................................................... 59 
6.4. 
Fertility Preservation .............................................................................................. 59 
6.5. 
Assessments ........................................................................................................... 59 
6.5.1. 
Demographics and Medical History ........................................................................ 59 

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6.5.2. 
Physical Examination ............................................................................................. 59 
6.5.3. 
Vital Signs and Weight ........................................................................................... 59 
6.5.4. 
Electrocardiogram/Echocardiogram ........................................................................ 59 
6.5.5. 
Neurologic Examination ......................................................................................... 60 
6.5.6. 
................................................... 60 
6.5.7. 
Major Functional Disabilities (MFDs) .................................................................... 60 
6.5.8. 
Neuropsychological Tests ....................................................................................... 60 
6.5.9. 
Evoked Potential (Electrophysiology) ..................................................................... 64 
6.5.10. 
Brain Magnetic Resonance Imaging (Loes Score) ................................................... 64 
6.5.11. 
Clinical Laboratory Tests ........................................................................................ 64 
6.5.12. 
Assessment of Clonal Predominance and/or Suspicion of Insertional 
Oncogenesis (Malignancy) ..................................................................................... 69 
6.6. 
Adverse Events ....................................................................................................... 71 
6.6.1. 
Definitions, Documentation, and Reporting ............................................................ 72 
6.6.2. 
Procedures for AE and SAE Reporting ................................................................... 73 
6.7. 
Pregnancy and Contraception.................................................................................. 75 
6.8. 
Unscheduled Visits ................................................................................................. 76 
6.9. 
Long-term Follow-Up Protocol ............................................................................... 76 
7. 
STATISTICAL PROCEDURES ............................................................................. 77 
7.1. 
Sample Size Estimation .......................................................................................... 77 
7.2. 
Populations for Analysis ......................................................................................... 77 
7.2.1. 
Populations for Comparison in Inter-study Analysis: .............................................. 77 
7.3. 
Planned Analyses.................................................................................................... 78 
7.3.1. 
Interim Analysis. .................................................................................................... 78 
7.3.2. 
Final Analysis ......................................................................................................... 78 
7.3.3. 
Additional Data Review .......................................................................................... 78 
7.3.4. 
Impact of the COVID-19 Pandemic ........................................................................ 78 
7.4. 
Statistical Methods ................................................................................................. 78 
7.4.1. 
General Methods .................................................................................................... 78 
7.4.2. 
Disposition of Subjects ........................................................................................... 79 
7.4.3. 
Demographic and Baseline Characteristics.............................................................. 79 
7.4.4. 
Analysis of Efficacy Endpoints ............................................................................... 79 
7.4.5. 
Analysis of Safety Endpoints .................................................................................. 81 
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7.4.6. 
Analysis of Other Exploratory Endpoints ................................................................ 83 
8. 
ADMINISTRATIVE AND REGULATORY REQUIREMENTS ........................... 84 
8.1. 
Good Clinical Practice (GCP) ................................................................................. 84 
8.2. 
Ethical Considerations ............................................................................................ 84 
8.3. 
Subject Information and Informed Consent ............................................................. 84 
8.4. 
Subject Confidentiality ........................................................................................... 84 
8.5. 
Protocol Compliance .............................................................................................. 84 
8.6. 
Direct Access to Source Data .................................................................................. 85 
8.7. 
Electronic Case Report Form Completion ............................................................... 85 
8.8. 
Record Retention .................................................................................................... 86 
8.9. 
Liability and Insurance ........................................................................................... 86 
8.10. 
Publication and Presentation of Study Findings and Use of Information ................. 86 
9. 
REFERENCES ....................................................................................................... 87 
10. 
APPENDICES ........................................................................................................ 92 
10.1. 
Dose Adjustment Formulas for Ideal Body Weight ................................................. 92 
10.2. 
Major Functional Disabilities .................................................................................. 92 
10.3. 
Neurologic Function Score for ALD ....................................................................... 92 
10.4. 
 
INVESTIGATOR STATEMENT ........................................................................................... 106 
LIST OF TABLES IN THE TEXT 
Table 1: 
Dose specification of Eli-cel and Back-up Cells for Rescue for CALD ................... 40 
Table 2: 
Schedule of Events: Screening through Drug Product Infusion ............................... 54 
Table 3: 
Schedule of Events: Drug Product Infusion through End of Study........................... 57 
Table 4: 
Neuropsychological Tests to be Performed ............................................................. 61 
Table 5: 
Blood Collection: Order of Priority ......................................................................... 66 
Table 6: 
Major Functional Disabilities (MFD) ...................................................................... 92 
Table 7: 
Neurologic Function Score (NFS) for CALD .......................................................... 94 
LIST OF FIGURES IN THE TEXT 
Figure 1: 
Schematic for Assessment of Clonal Predominance ................................................ 70 
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1. 
INTRODUCTION 
1.1. 
Cerebral X-Linked Adrenoleukodystrophy (CALD) 
Cerebral adrenoleukodystrophy (CALD) is a rare X-linked genetic disease caused by a defect 
in the ATP-binding cassette, sub-family D, member 1 (ABCD1) gene, which encodes for 
adrenoleukodystrophy protein (ALDP), a peroxisomal transporter involved in the breakdown 
of very long chain fatty acids (VLCFA) (Moser et al. 2007). The resulting accumulation of 
VLCFA leads to progressive demyelination and cerebral inflammation within the brain, which 
(if untreated) leads to severe loss of neurological function over time, and death. In boys 
diagnosed with CALD, learning and behavioral problems are often observed in mid-childhood 
after the age of 3 years (median age 7). Most patients will die within a decade of diagnosis if 
they are not treated by stem cell transplantation (Moser et al. 2007). 
One of the hallmarks of inflammatory disease in CALD is the presence of a compromised 
blood‑brain-barrier behind the leading edge of demyelinating lesions, as evidenced 
by gadolinium enhancement (GdE+) on brain magnetic resonance imaging (MRI) 
(Engelen et al. 2012). Studies have shown that GdE+ is a predictive biomarker of disease 
progression as the severity of the inflammatory process appears to be correlated with the 
rapidity of progression (Powers et al. 1992; Melhem et al. 1996, 2000; Engelen et al. 2012). 
The goal of treatment for CALD is to delay or prevent progression of the disease, thereby 
preventing the development of impairments which compromise the ability to function 
independently. The current standard of care for treatment of boys with CALD is 
allogeneic hematopoietic stem cell transplantation (allo-HSCT), which can improve overall 
survival and functional outcomes (Baumann et al. 2003; Peters et al. 2004; Mahmood et al. 2007; 
Miller et al. 2011). 
Allo-HSCT is optimally performed early in the course of the disease using a human 
leukocyte antigen (HLA)-matched sibling hematopoietic stem cell (HSC) donor who does not 
carry the mutation. However, a matched sibling donor is available for only ≤ 30% of patients 
(Miller et al. 2011), so alternative options include transplantation with cells derived from an 
HLA-mismatched related donor, a matched unrelated donor (MUD)-HSCT, or transplant with 
cells derived from banked cord blood (umbilical cord blood transplantation). 
1.2. 
Retrospective Study ALD-101 
bluebird bio, Inc. (bluebird bio) has completed a multi-institutional, retrospective case review 
and data collection study of 137 boys with CALD, including 72 untreated cases and 65 cases 
who underwent allo-HSCT in or after 2001 (Study ALD-101). Data were collected from 
5 centers including 4 in the US and 1 in France.  
Review of the literature and findings from Study ALD-101 have shown that while there are a 
wide number of cognitive, behavioral, functional, and radiological modalities utilized to assess 
patients with CALD, only 2 are utilized widely: 1) the Neurologic Function Score (NFS), a 
relatively simple 25-point scale that assesses functional domains typically compromised by 
CALD (Moser et al. 2000); and 2) brain MRI (with or without gadolinium), with MRI findings 

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scored using a system developed expressly for CALD, the Loes score (a 34-point scale that 
roughly describes disease burden throughout the brain (Loes et al. 1994). 
In Study ALD-101, Baseline (defined as the value closest to the date of CALD diagnosis) MRI 
findings, as assessed by Loes score, and NFS were major predictors of survival, with longer 
median survival in the Untreated Cohort observed in patients with lower Baseline scores than in 
those with higher scores (clinical study report [CSR] ALD-101, v2.0). Estimated 2- and 5-year 
survival rates were 74% and 55%, respectively for the entire Untreated Cohort with a median 
survival time of 91.9 months. Improved 2- and 5-year survival rates were observed in the 
Untreated Cohort for boys with a Baseline NFS ≤1, 92% and 74%, respectively, than for boys 
with an NFS >1, 52% and 25%, respectively. Higher 2- and 5-year survival rates also were 
observed for patients with Loes ≤ 5 than for those with Loes > 5. 
Consistent with the literature (e.g., (Melhem et al. 2000)) data from Study ALD-101 show that 
GdE+ is highly predictive of the likelihood of rapid progression (CSR ALD-101). Most (18/21) 
GdE+ untreated subjects had increased NFS scores, whereas most (7/9) subjects without 
gadolinium enhancement (i.e., negative for gadolinium enhancement; GdE-) had stable low NFS 
scores, for at least 18 months after initial GdE- MRI.  
Findings from Study ALD-101 also support the efficacy of allogeneic HSCT, as evidenced 
by stabilization of NFS and Loes score. After a period of decline in the post-allogeneic 
HSCT period, the majority of NFS and Loes scores stabilized post-allogeneic HSCT 
Unfortunately, allogeneic HSCT is unlikely to be of benefit to patients with an NFS > 1 or 
Loes score > 10 (Peters et al. 2004; Miller et al. 2011) (CSR ALD-101). 
Safety findings from Study ALD-101 were consistent with the CALD literature. Previous studies 
reported a 10% to 30% risk of failure of engraftment, life-threatening infection, and acute or 
chronic graft-versus-host disease (GVHD) (Hahn et al. 2008; Miller et al. 2011), with the risk of 
chronic GVHD being approximately 30% (Carlens et al. 1998). Findings from Study ALD-101 
included an overall incidence of serious adverse events (SAEs) of 51%, including a 29% 
incidence of infections as the SAE; an 18% incidence of graft failure; a 45% incidence of acute 
GVHD; and a 21% incidence of chronic GVHD. The risk of life-threatening adverse events 
(AEs) associated with allogeneic HSCT highlights the unmet need for safe treatment of CALD, 
particularly for patients without a willing matched sibling donor. 
1.3. 
Eli-cel 
With an objective to provide an effective and safer alternative to allo-HSCT, bluebird bio is 
investigating the use of Lenti-D Drug Product (also known as elivaldogene autotemcel, hereafter 
referred to as eli-cel) in the treatment of subjects with CALD. Eli-cel’s mode of action is based 
on treating patients with their own HSCs that have been transduced ex vivo with the Lenti-D 
lentiviral vector (LVV) that encodes a normal ALDP. After transplantation, these HSCs then 
differentiate into different cell types, including cerebral microglia, which produce functional 
ALDP. The functional ALDP can then enable the peroxisomal beta-oxidation of VLCFAs, which 
in turn can stabilize the disease by preventing further inflammation and demyelination.  
It is anticipated that transplantation of autologous CD34+ HSCs genetically modified ex vivo 
by the Lenti-D LVV should circumvent many of the limitations and risks associated with 
allo-HSCT. The use of a patient’s own stem cells would eliminate the risks of graft rejection 

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and acute and chronic GVHD due to immune-incompatibility, and also reduce complications due 
to long-term immunosuppression.  
Nonclinical data indicate that in vitro transduction of human HSCs and fibroblasts with Lenti-D 
LVV results in expression of ALDP, and both in vitro and in vivo nonclinical studies suggest 
that eli-cel can be used safely in clinical studies for the treatment of CALD (see nonclinical 
section of the Investigator’s Brochure).  
Long-term follow-up of 4 subjects from clinical Study TG04.06.01, that utilized a LVV that is 
closely related to Lenti-D LVV (CG1711hALD) to transduce autologous HSCs, suggest that this 
approach is well-tolerated and can arrest disease progression. The results of the first 2 treated 
subjects have been published (Cartier et al. 2009), and after follow-up of 6 and 10 years post-
transplantation in May 2017 for 2 subjects, and 4 and 6 years post-transplantation in March 2013 
for the other 2 subjects (who did not give consent for follow up studies after this date), no AE 
considered by the Investigator to be related to drug product has been observed, and specifically 
no development of human immunodeficiency virus (HIV) positivity, vector-derived replication 
competent lentivirus (RCL), clonal predominance, leukemia, or lymphoma has been observed. 
Additionally, 3 of the 4 subjects treated with drug product had stabilization of Loes and NFS and 
no major functional disabilities. 
1.4. 
Rationale for Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.5. 
Potential Risks 
1.5.1. 
Abnormal Proliferation of Hematopoietic Cells 
LVVs are retroviruses, which integrate into the chromosome of target cells upon transduction. 
A potential risk of this type of vector is insertional mutagenesis leading to oncogenesis. 
The risk of mutagenesis for this study is limited to the hematopoietic cell compartment, since 
the LVV is designed not to mobilize after integration into the chromosomal DNA of HSCs. 

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Gene transfer with γ-retroviral vectors has resulted in oncogenesis in the clinical studies for 
X‑linked severe combined immunodeficiency (SCID-X1) (Hacein-Bey-Abina et al. 2008; 
Howe et al. 2008), chronic granulomatous disease (Stein et al. 2010), and Wiskott-Aldrich 
Syndrome (Boztug et al. 2010).  
Due to insertional mutagenesis, 5 of 20 subjects in the SCID-X1 study developed acute 
lymphocytic leukemia. One of the 5 subjects succumbed to leukemia, while the remaining 
4 were successfully treated. In the Wiskott-Aldrich study, 4 subjects developed leukemia 
(Paruzynski et al. 2012).  
The different nature of the Lenti-D LVV should minimize, but not completely eliminate, the risk 
of oncogenesis by insertional mutagenesis. Unlike the γ-retroviral vectors that led to leukemia, 
self-inactivating (SIN) LVVs, such as Lenti-D LVV, may represent a substantial improvement in 
terms of safety (Montini et al. 2006). SIN LVVs, in general, provide significant safety 
improvements over γ-retroviral vectors used in earlier studies (Riviere et al. 2012). SIN LVVs 
lack the strong enhancer/promoter long terminal repeat (LTR) sequences of γ-retroviral 
vectors, and, unlike γ -retroviral vectors, do not preferentially integrate near gene promoter 
regions. Therefore, LVVs are less likely to transactivate oncogenes, and have demonstrated 
a significantly curtailed probability of oncogenic transformation in vitro and in vivo 
(Biffi et al. 2011).  
To date, more than 200 subjects have been treated in gene therapy studies involving lentiviral 
vectors and HSCs, with follow-up times up to 10 years in some studies, with no published cases 
of LVV therapy-related leukemia or lymphoma in any patient (e.g., (Cartier et al. 2009; 
Cavazzana-Calvo et al. 2010; Aiuti et al. 2013; Biffi et al. 2013; Hacein-Bey Abina et al. 2015; 
Ribeil et al. 2017; Eichler et al. 2017; Thompson et al. 2018) (data on file). Safety results for 
bluebird bio's CALD studies can be found in the Investigator’s Brochure. 
1.5.2. 
Use of a Lentiviral Vector Derived from Human Immunodeficiency Virus 
Type 1 
Because the Lenti-D LVV was derived from human immunodeficiency virus type 1 (HIV-1), a 
potential risk is mobilization or recombination with wild-type HIV-1. This risk is estimated to be 
very low for several reasons - the LVV is replication incompetent, the probability of producing a 
recombinant virus from a multi-plasmid transfection is very low, the transduction is ex vivo so 
there is no opportunity for the vector to be exposed to HIV, and a highly sensitive, validated 
assay is used prior to transduction to detect RCL. 
Subjects treated with eli-cel will be monitored from Baseline for 24 months under the current 
protocol and then for an additional 13 years under the separate, long-term follow-up protocol 
(LTF-304; EudraCT No: 2015-002805-13; NCT02698579) that will focus on long-term safety 
with an emphasis on detection of insertional oncogenesis and RCL. If a vector-derived RCL is 
detected in any subject, enrollment in the study will be suspended until a full investigation by the 
Data Monitoring Committee (DMC) occurs with notification of the appropriate regulatory 
authorities. 

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1.5.3. 
Risks of Mobilization and Transplantation  
Reported warnings for granulocyte colony stimulating factor (G-CSF; where G-CSF is 
defined for this protocol to mean either filgrastim or lenograstim) can be found in the 
prescribing information for each product. They may include the potential for allergic reactions, 
splenic rupture, acute respiratory distress syndrome, and alveolar hemorrhage and hemoptysis 
(e.g., Neupogen prescribing information; note that some additional warnings reported apply 
only to clinical populations with sickle cell disorders or severe chronic neutropenia and thus 
would not be relevant for the study population to be enrolled in the ALD-102 study). 
Additionally, reported precautions include the potential for immunogenicity or cutaneous 
vasculitis (Thornley et al. 2004). Refer to the prescribing information (package insert) for 
additional product details regarding G-CSF, including all reported AEs from clinical trials. 
Reported warnings for plerixafor include increased circulation of leukocytes, decreased 
platelet counts, and potential for splenic rupture (e.g., Mozobil prescribing information; note that 
some additional warnings reported apply only to patients with leukemia, female patients who 
may become pregnant, or patients with the potential for tumor cell mobilization). The most 
common AEs, reported in ≥ 10% of patients, include diarrhea, nausea, fatigue, injection site 
reactions, headache, arthralgia, dizziness, and vomiting. Refer to the prescribing information 
(package insert) for additional product details regarding plerixafor, including all reported AEs 
from clinical trials. 
Toxicity associated with the busulfan IV plus cyclophosphamide IV conditioning regimen 
(i.e., conditioning regimen-related toxicity) is a frequent cause of morbidity and mortality in 
allogeneic HSCT (Clift et al. 1993; Thornley et al. 2004). Most notably, given that the goal of 
conditioning is immunosuppression, subjects receiving such treatment are at significant risk for 
development of potentially fatal, opportunistic infections (e.g., cytomegalovirus [CMV], Epstein 
Barr Virus [EBV]). In fact, this risk is low with autologous HSCT because the hematologic 
reconstitution is very rapid and long-term immunosuppression is not required. Veno-occlusive 
disease (VOD), marked by weight gain due to ascites, hepatomegaly, and hyperbilirubinemia, 
may also occur (Nevill et al. 1991; Clift et al. 1993; Andersson et al. 2002). VOD can be severe, 
leading to multi-organ failure and ultimately death in up to 30% of cases (Richardson et al. 
1998). Central nervous system toxicities, primarily seizure, also can occur with the conditioning 
regimen. Although generally less significant, mucositis, skin complications, including 
hyperpigmentation and desquamation, and gastrointestinal disturbances, primarily nausea, 
vomiting and diarrhea, commonly occur with cyclophosphamide IV and busulfan IV 
conditioning (Richardson et al. 1998; Tran et al. 2000; Andersson et al. 2002). Male infertility 
(i.e., reduced testosterone levels) has also been associated with use of the busulfan IV plus 
cyclophosphamide IV conditioning regimen (Grigg et al. 2000; Meistrich 2009). Refer to the 
prescribing information (package insert) regarding additional toxicities associated with busulfan 
IV and cyclophosphamide IV. 
Engraftment failure is defined as a failure to achieve 3 consecutive absolute neutrophil count 
(ANC) laboratory values of ≥ 0.5 × 109 cells/L (after initial post-infusion nadir) obtained on 
different days by 42 days post-infusion (transplant) of eli-cel. Management of neutrophil 
engraftment failure is at the discretion of the Investigator. Subject will be followed as per 
protocol-scheduled visits (Table 2 and Table 3). 

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2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
• Evaluate the efficacy of eli-cel in subjects with CALD  
• Evaluate the safety of eli-cel in subjects with CALD 
2.2. 
Study Endpoints 
2.2.1. 
Efficacy Endpoints 
The primary efficacy endpoint is: 
• Proportion of subjects who are alive and have none of the 6 MFDs at Month 24 
(i.e. Month 24 MFD-free survival). MFDs are:  
o loss of communication 
o cortical blindness 
o tube feeding 
o total incontinence 
o wheelchair dependence 
o complete loss of voluntary movement 
Secondary efficacy endpoints are the following: 
• Proportion of subjects who demonstrate resolution of gadolinium positivity on MRI 
(i.e., GdE-) at Month 24 
• Time to sustained resolution of gadolinium positivity on MRI (i.e., GdE-). Sustained 
is defined as gadolinium resolution without a subsequent evaluation indicating 
gadolinium positivity  
• Change in total NFS from Baseline to Month 24 
• MFD-free survival over time 
• Overall survival 
 
 
  
 
 
 
 
 
 
2.2.2. 
Safety Endpoints 
The primary safety endpoint is: 
• The proportion of subjects who experience either acute (≥ Grade II) or chronic 
GVHD by Month 24. 

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The secondary safety endpoints are the following: 
• Proportion of subjects with neutrophil engraftment by 42 days post-drug product 
infusion 
• Time to neutrophil engraftment post-drug product infusion 
• Proportion of subjects with platelet engraftment by Month 24 
• Time to platelet engraftment post-drug product infusion 
• Proportion of subjects with loss of engraftment post-drug product infusion by 
Month 24 
• Proportion of subjects who undergo a subsequent HSC infusion by Month 24 
• Proportion of subjects with transplant-related mortality through 100 and 365 days 
post-drug product infusion 
• Proportion of subjects with and severity of clinical ≥ Grade 3 AEs, all drug-product 
related AEs, all SAEs, ≥ Grade 3 infections, and changes in laboratory parameters by 
Month 24 
• Proportion of subjects with ≥ Grade II acute GVHD by Month 24 
• Proportion of subjects with chronic GVHD by Month 24 
• Number of emergency room visits (post-neutrophil engraftment) by Month 24 
• Number and duration of in-patient hospitalizations (post-neutrophil engraftment) by 
Month 24 
• Number and duration of ICU stays (post-neutrophil engraftment) by Month 24 
• Incidence of vector-derived RCL at Month 24 
• The number of subjects with insertional oncogenesis (myelodysplasia, leukemia, 
lymphoma, etc.) by Month 24 
The exploratory safety endpoint is: 
 
 
 
 

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2.2.3. 
Other Exploratory Endpoints 
Exploratory endpoints include: 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Design and Plan of the Study 
This will be an international, non-randomized, open-label, multi-site, single-dose study in male 
subjects with CALD (≤ 17 years of age at enrollment). Approximately 30 subjects will be 
infused with eli-cel. The study will begin with a staggered infusion schedule. The DMC will 
review safety and neutrophil engraftment data on Subject 1 prior to approving infusion of 
Subject 2. Following a review of safety and neutrophil engraftment data from the first 2 subjects, 
and with the recommendation of the DMC, parallel infusions will be allowed.  
Selected subjects must meet the inclusion criteria, have none of the exclusion criteria, and have 
provided informed consent. The study has 4 distinct phases after informed consent: 
• Screening  
• CD34+ Cell Collection, Transduction, Disposition of eli-cel, and Re-confirmation of 
Eligibility  
• Conditioning and Washout, followed by eli-cel Infusion (transplant) on Day 0 
• Maintenance (Follow-up) (Day 1 through Month 24) 
From Screening through when it is assessed that the subject is stably transplanted (by 
approximately the Month 3 Visit), visits will occur at one of a small number of sites (referred to 
as primary study sites). However, due to the rarity of CALD, it is likely that some subjects may 
have to travel far for participation at the primary study sites. Therefore, after the subject is stably 
transplanted, arrangements may be made to open up a suitable site closer to the subject’s home 
(referred to as secondary study sites) where they could attend subsequent visits. In all cases, 
subjects will be asked to return to their primary study site for their assessments for Month 12 and 
Month 24 Visits to ensure consistency in key efficacy assessments. 
Prior to the Screening Phase, the Investigator will identify candidates potentially meeting the 
study eligibility criteria, based on review of medical records and clinical test findings performed 
routinely as standard of care for the treatment of the subject. The competent legal 
parent(s)/guardian of subjects who are determined by the Investigator to be potentially eligible, 
will be informed of the option to participate in the study and all associated risks of the study 
procedures as well as the investigational nature of gene therapy treatment (eli-cel). In addition, if 
consistent with local regulation, the Investigator will seek assent from the subject if he is at least 
7 years of age. Sites will follow their standard institutional practice for obtaining informed 
consent. The subject and his legal parent(s)/guardian should be provided with adequate time to 
ask questions about the study, treatment, and required procedures. A physician not associated 
with the study team, but knowledgeable about the gene therapy, HSCT, and CALD clinical 
management, must participate in the initial consent process to provide an independent 
perspective on the benefit-risk of study participation and other available treatment 
options. Written informed consent and assent (if applicable) must be obtained before the conduct 
of any screening tests not performed routinely in the treatment of the subject. The consent 
process will be performed in accordance with International Conference of Harmonization 
(ICH)/Good clinical practice (GCP), local regulations, and site-specific institutional practice.  

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Subjects who are pre-screened and considered by the Investigator to be eligible and for whom 
written informed consent has been provided will enter the Screening Phase and undergo the tests 
and procedures necessary to confirm study eligibility.  
Subjects who are confirmed to be eligible, based on Screening assessments, will undergo 
G-CSF-mediated, and potentially plerixafor-mediated, HSC mobilization and harvest by 
apheresis using institutional practice treatment guidelines. G-CSF is defined for this protocol to 
mean either filgrastim or lenograstim. The harvested cells will be selected for the CD34+ marker 
to enrich for HSC, transduced with Lenti-D LVV, stored frozen in cryopreservative solution 
while aliquots are being tested to ensure they meet product quality specifications, and returned 
by IV infusion through a central venous catheter to the same subject after the subject is 
myeloablated with cyclophosphamide IV and busulfan IV. The subject will only undergo 
myeloablation after the transduced cells are dispositioned for clinical use and the drug product is 
at the clinical site.  
Back-up cells for rescue (mobilized peripheral blood mononuclear cells [PBMCs]) will also be 
harvested during apheresis and stored frozen in accordance with institutional guidelines. If 
back‑up cells cannot be procured from apheresis, a bone marrow (BM) harvest may be 
performed. 
All subjects will be followed for 24 months post-drug product infusion under this protocol. Then, 
if appropriate consent is obtained, subjects will be followed for an additional 13 years under a 
separate follow-up protocol (Study LTF-304). The 13-year follow-up study will focus on 
long-term safety, with an emphasis on integration site analysis (ISA), and long-term efficacy to 
evaluate durability of response. 
Efficacy evaluations to be performed during the study include assessment of functional 
status using NFS for an overall score and for determination of MFDs. Additional efficacy 
evaluations include determination of effects of cerebral demyelination, as measured by 
Loes score, and gadolinium enhancement on MRI. 
 
 
 
 
 Based 
on treatment experience with allogeneic HSC transplant in CALD subjects (Miller et al. 2011) 
and the post-drug product infusion follow-up of 4 subjects treated in Study TG04.06.01 in 
France, it is expected that it will take at least 12 months to observe evidence of disease 
stabilization. 
The success of the transplant procedure will be assessed by time to neutrophil engraftment 
defined as achieving 3 consecutive ANC laboratory values of ≥ 0.5×109 cells/L (after initial 
post‑infusion nadir) obtained on different days by 42 days post-infusion (transplant) of eli-cel. 
Peri-transplant and post-drug product infusion morbidity and mortality will be recorded. Each 
subject will be evaluated on a predetermined schedule for 24 months post-drug product infusion 
to assess disease progression using efficacy evaluations.  
CCI

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Neutrophil engraftment failure will be defined as follows: 
• Primary neutrophil engraftment failure: failure to achieve neutrophil engraftment 
(as defined above). 
• Secondary neutrophil engraftment failure: i) achieved neutrophil engraftment 
followed by ii) sustained decline in ANC to < 0.5×109 cells/L for 3 consecutive 
measurements on different days after primary neutrophil engraftment 
Subjects who experience neutrophil engraftment failure will be treated at the Investigator’s 
discretion, and will continue to be followed for safety and efficacy assessments as detailed in the 
schedule of events (SOE) (Table 2 and Table 3). 
Safety evaluations to be performed during the study include determination of survival status; 
documentation of AEs, including SAEs; monitoring of vital signs; physical examinations; 
electrocardiogram (ECG); serology panel testing; standard clinical chemistry and hematology 
testing; concomitant medications; and testing for proviral insertion sites and evidence of 
insertional mutagenesis.  
Periodic efficacy and safety examinations will be performed by a specialist in pediatric 
transplant medicine, and a pediatric neurologist or other appropriately trained and qualified 
healthcare provider with expertise in CALD. 
Additional details regarding study evaluations and procedures, including administrative 
information, will be provided by the Sponsor in the Study Operations Manual (SOM). 
The coordinating Investigator assigned on this study will be responsible for signing off on the 
final ALD-102 CSR. 
3.1.1. 
Data Monitoring Committee 
An independent DMC composed of members with appropriate scientific and medical expertise 
to monitor the study will be convened before the study is opened. A charter describing the 
composition and conduct of the DMC will be drafted by the Sponsor and agreed to by all DMC 
members prior to the DMC’s initial meeting. The DMC will review safety and neutrophil 
engraftment data on Subject 1 prior to proceeding with the transplant of Subject 2; and on 
Subject 2 prior to allowing the transplant of subsequent subjects. Following a review of safety 
and neutrophil engraftment data from the first 2 subjects and, with the recommendation of the 
DMC, parallel treatment (transplant) will be allowed. The DMC will meet by teleconference at 
regular intervals, approximately once every 6 months, or more frequently if needed, and 
depending on speed of subject enrollment and amount of new data generated. The DMC will be 
charged with review of all unexpected eli-cel treatment-related SAEs following notification by 
the Sponsor. The DMC will have the right to recommend halting the study at any time due to 
concerns for the safety of the subjects. (Refer to Section 3.4.2 for the enrollment suspension 
criteria). 
3.2. 
Rationale for the Study 
 
 

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3.3. 
Rationale for the Dose Selected 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 number 
of cells and viability to determine if it is appropriate to proceed with myeloablation. 

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3.4. 
Treatment Discontinuation and Enrollment Suspension Criteria 
3.4.1. 
Stopping Rules Prior to Conditioning 
Subjects will be withdrawn from the study if they meet any of the following criteria as related to 
pre-conditioning assessments: 
• Failure to continue to satisfy eligibility criteria 
• Neurological decline (progression of cerebral disease) between Screening and 
Day -11 as evidenced by an NFS > 1 or a Loes Score > 9.  
• Failure of eli-cel to be dispositioned for clinical use. Conditioning will not begin until 
it is confirmed that the eli-cel has been dispositioned for clinical use. 
Once myeloablation with busulfan IV and cyclophosphamide IV has begun on Day -10, there are 
no stopping rules for conditioning, except for the enrollment suspension criteria for the study 
as outlined in Section 3.4.2. In the anticipated very rare event of consent withdrawal during 
conditioning or the development of a new medical condition that, in the Investigator’s opinion, 
puts the subject at risk with continued busulfan IV and cyclophosphamide IV treatment, the 
Medical Monitor should be contacted immediately. In such situations in which busulfan IV and 
cyclophosphamide IV conditioning has not been completed per protocol, eli-cel should not be 
given, and it is likely that rescue therapy with back-up cells (mobilized PBMCs), or with HSCs 
from an appropriate allogeneic donor if available, will be required. 
3.4.2. 
Enrollment Suspension Criteria 
Enrollment in this study may be suspended at any time for safety reasons. It will be the 
responsibility of the DMC to make a recommendation to the Sponsor if they believe there is 
reasonable cause for suspending enrollment. The Sponsor will inform the regulatory authorities 
and the Investigators, and each site’s Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC) and other appropriate institutional regulatory bodies will be promptly notified, 
if a decision to suspend enrollment is made. In the event enrollment is suspended, no new 
mobilization, conditioning, or drug product infusion of subjects will be initiated, but subjects 
who have already been treated with eli-cel will continue in the study. If mobilization has been 
initiated, cell collection will be completed at Investigator’s discretion. Likewise, if the study is 
halted while a subject is undergoing conditioning, conditioning will be completed at 
Investigator’s discretion, and every effort will be made to restart the study prior to their 
scheduled infusion. However, a subject may be infused with their back-up cells following 
conditioning if the study cannot be restarted in time. 
Enrollment and treatment with drug product will be temporarily suspended for any of the 
following reasons pending review and recommendations from the DMC and the appropriate 
communication with the relevant regulatory agency(ies): 
• Death, until the cause of the death is determined* 
• Detection of leukemia/lymphoma due to vector-mediated insertional oncogenesis** 
(see Section 6.5.12 ). 
• Detection of vector-derived RCL in any subject  

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• Failure in 1 subject to achieve reconstitution with transduced cells, requiring use 
of back-up cells or HSCs from an appropriately allogeneic donor. Engraftment 
failure is defined as a failure to achieve 3 consecutive ANC laboratory values of 
≥ 0.5 × 109 cells/L (after initial post-infusion nadir) obtained on different days by 
42 days post-infusion (transplant) of eli-cel. 
• Determination of unexpected, clinically significant, or unacceptable risk to 
subjects (e.g., development of study treatment-related Grade 3 or 4 toxicities in at 
least 3 subjects). 
*The death of a subject on Study ALD-102 after receiving eli-cel will result in a hold of further enrollment and 
treatment with drug product until an investigation into the cause of death is performed. If it is determined that the 
death was not related to the drug product, then enrollment/treatment with drug product may resume. If the 
relationship between the drug product and the death is not clear, or it appears that the death may be related to the 
drug product, enrollment and treatment with drug product will be held until the DMC assessment and 
recommendations as described above. 
**If a subject is diagnosed with leukemia or lymphoma after receiving eli-cel, enrollment will be held until 
determination is made as to whether the malignancy was related to a vector-mediated insertion. Once this 
assessment occurs, if the malignancy is not related to a vector-mediated insertion, enrollment may resume. If the 
relationship between the malignancy and an insertion is not clear or it appears they may be related, enrollment will 
be held until the DMC assessment and recommendations as described above. 
(For assessment of clonal predominance see Section 6.5.12 ).  
3.5. 
End of Trial Definition 
The end of the trial is defined as the last visit of the last subject. 

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4. 
STUDY POPULATION 
Males aged 17 years and younger who have been definitively diagnosed with CALD (by finding 
elevated levels of VLCFA) who have a MRI Loes score between 0.5 and 9 (inclusive), an 
NFS ≤ 1, and gadolinium enhancement on MRI may be enrolled. 
4.1. 
Number of Subjects 
Approximately 30 subjects will be infused with eli-cel. 
4.2. 
Subject Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for inclusion in this study.  
1. Informed consent is obtained from a competent custodial parent or guardian with legal 
capacity to execute a local IRB/IEC approved consent. (Informed assent will be sought 
from capable subjects, in accordance with the directive of the IRB/IEC and with local 
requirements.) 
2. Males aged 17 years and younger, at the time of parental/guardian consent and, where 
appropriate, subject assent. 
3. Active cerebral ALD as defined by: 
a. Elevated VLCFA values, and 
b. Active central nervous system (CNS) disease established by central radiographic 
review of brain MRI demonstrating 
i. Loes score between 0.5 and 9 (inclusive) on the 34-point scale, and 
ii. Gadolinium enhancement (GdE+) on MRI of demyelinating lesions. 
4. NFS ≤ 1. 
4.3. 
Subject Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1. Receipt of an allogeneic transplant or gene therapy. 
2. Availability of a willing 10/10 HLA-matched sibling donor (excluding female 
heterozygotes). 
3. Use of statins, Lorenzo’s Oil, or dietary regimens used to lower VLCFA levels. 
Note: subjects must discontinue use of these medications at time of consent. 
4. Receipt of an investigational study drug or procedure within 3 months before Screening 
that might confound study outcomes. Use of investigational study drugs is prohibited 
throughout the course of the study. 
5. Any conditions that make it impossible to perform MRI studies (including allergies to 
anesthetics or contrast agents). 

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6. Hematological compromise as evidenced by: 
a. Peripheral blood ANC count < 1500 cells/mm3, 
b. Platelet count < 100,000 cells/mm3, or 
c. Hemoglobin (Hb) < 10 g/dL. 
d. Uncorrected bleeding disorder. 
7. Hepatic compromise as evidenced by: 
a. Aspartate transaminase (AST) value > 2.5 × upper limit of normal (ULN) 
b. Alanine transaminase (ALT) value > 2.5 × ULN 
c. Total bilirubin value > 3.0 mg/dL, except if there is a diagnosis of Gilbert’s 
Syndrome and the subject is otherwise stable 
8. Renal compromise as evidenced by abnormal renal function (actual or calculated 
creatinine clearance < 50 mL/min) 
9. Cardiac compromise as evidenced by left ventricular ejection fraction < 40% 
10. Immediate family member with a known or suspected Familial Cancer Syndrome 
(including but not limited to hereditary breast and ovarian cancer syndrome, 
hereditary non-polyposis colorectal cancer syndrome, and familial adenomatous 
polyposis). 
11. Clinically significant active bacterial, viral, fungal, parasitic, or prion-associated infection 
12. Positive for human immunodeficiency virus type 1 or 2 (HIV-1, HIV-2); hepatitis B virus 
(HBV); hepatitis C virus (HCV); human T lymphotropic virus 1 (HTLV-1). (Note that 
subjects who have been vaccinated against HBV [positive for HBV surface antibodies] 
who are negative for other markers of prior HBV infection [e.g., negative for HBV core 
Ab] are eligible. Subjects with past exposure to HBV [HBcAb positive and/or HBeAb 
positive] are also eligible for the study provided they have a negative test for HBV DNA. 
Also note that subjects who are positive for anti-hepatitis C Ab are eligible as long as 
they have a negative hepatitis C viral load). 
13. Any clinically significant cardiovascular or pulmonary disease, or other disease or 
condition that would be contraindicated for any of the other study procedures. 
14. Absence of adequate contraception for fertile subjects. Male subjects and their female 
partners are required to use two different effective methods of contraception from 
Screening through at least 6 months after drug product infusion. If subjects are truly 
sexually abstinent (where true sexual abstinence is defined as being in line with the 
preferred and usual lifestyle of the subject), no second method is required. 
15. Any contraindications to the use of G-CSF during the mobilization of HSCs, and any 
contraindications to the use of busulfan or cyclophosphamide, including known 
hypersensitivity to the active substances or to any of the excipients in their formulations. 

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4.4. 
Subject Identification and Registration 
Prior to the Screening Phase, the Investigator will identify candidates potentially meeting the 
study eligibility criteria, based on review of medical records and clinical test findings performed 
routinely as standard of care for the treatment of the subject. The legal parent(s)/guardian of 
subjects who are determined by the Investigator to be potentially eligible, will be informed of the 
option to participate in the study and all associated risks of the study procedures as well as the 
investigational nature of gene therapy treatment (eli-cel). The subject’s consent/assent will be 
obtained as described previously in Section 3.1. Once consent is obtained, the potential subject 
will be registered and assigned a unique 10-digit subject number. As confirmation, bluebird bio 
will provide the Investigator with written verification of each subject’s registration. Once a 
subject number has been assigned, it cannot be reused, and the number stays with the subject 
even if the subject is subsequently determined to be ineligible for the study or transfers to 
another study center. This subject number will also be carried into the long-term follow up study. 
After provision of written informed consent and, if applicable, assent, the Investigator will 
further evaluate the subject for study eligibility through the screening assessments to ensure all 
entrance criteria are satisfied.  
Additional details regarding the identification and registration of subjects, including details 
regarding the informed consent process, are outlined in the SOM. 
4.5. 
Subject Withdrawal from the Study 
In accordance with the Declaration of Helsinki, subjects have the right to withdraw from the 
study at any time for any reason, without prejudice to further medical follow up. Should a subject 
decide to withdraw, all efforts will be made to complete and report the observations as 
thoroughly as possible. Subjects who have received infusion of eli-cel and withdraw before study 
completion will be asked to complete the same assessments as specified in the SOE for Month 24 
(Early Termination Visit assessments). 
Although subjects have the right to withdraw from the study at any time, withdrawal after the 
start of conditioning and before administration of the eli-cel is strongly discouraged, as this 
would be considered deleterious to the subject. In such cases, the subject’s stored back-up cells 
(mobilized PBMCs), or HSCs from an appropriate allogeneic donor, will be infused; see 
Section 5.2.1. The subject’s reason for and date of withdrawal from the study is to be recorded 
on the electronic case report form (eCRF).  
4.6. 
Investigator or Sponsor Termination of Subject Participation  
The Investigator and Sponsor also have the right to withdraw subjects from the study at any 
time due to protocol noncompliance, poor tolerance or potential safety risks, or stopping rules 
(see Section 3.4 for stopping rules). Subjects who have received infusion of eli-cel and are 
discontinued from the study prior to study completion will be asked to complete the same 
assessments as specified in the SOE for Month 24 (Early Termination Visit assessments) and 
will be asked to participate in the long-term follow-up study (LTF-304), except subjects who 
have withdrawn their consent. 

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5. 
STUDY TREATMENTS 
5.1. 
Description of the Lenti-D Lentiviral Vector and Eli-cel Product 
Lenti-D Lentiviral Vector: Lenti-D LVV is a replication defective, SIN, HIV-1 based LVV 
pseudotyped with the vesicular stomatitis virus G (VSV-G) envelope protein and containing the 
functioning human ABCD1 complementary DNA. Lenti-D LVV is produced by transient 
transfection using transfer vector pLBP100, 3 packaging plasmids, and the envelope plasmid. 
It is formulated in animal component free Stem Cell Growth Media (SCGM). 
Eli-cel: Eli-cel is defined as an autologous CD34+ cell-enriched population that contains cells 
transduced with LVV encoding human adrenoleukodystrophy protein, suspended in 
cryopreservative solution in the final immediate container for the intended medical use. 
5.2. 
Summary of Treatments to be Performed or Administered 
After confirmation of eligibility, HSCs must be collected from the subject following stimulation 
by G-CSF (mobilization) (see Section 5.2.1) for 2 purposes – transduction for eli-cel and for 
back-up cells (to be used if the subject fails to engraft). The isolated and transduced autologous 
CD34+ HSCs are infused (transplanted) back into the subject after they have received a 
myeloablative conditioning with busulfan IV and cyclophosphamide IV.  
Table 1 outlines the source of the subject cells, usage, and the minimum dose of eli-cel or back-
up cells for rescue. Additional details are provided in the following subsections. 
5.2.1. 
Mobilization and Apheresis Procedure 
More than one mobilization cycle may be performed if needed in order to meet the required dose 
for eli-cel. Each mobilization cycle may include up to 3 apheresis collection days. Drug product 
will be manufactured from cells collected from either one day or over 2 consecutive days. 
Additional apheresis collections should be used to obtain back-up cells for rescue.  
If more than one mobilization cycle is required, mobilization cycles must be separated by at least 
2 weeks. A BM harvest is also allowed, but only to procure back-up cells.  
For details regarding traceability of the collected HSCs, see Section 5.9. 
Mobilization Cycle 1 
Subjects will be mobilized with G-CSF (starting dose 10 μg/kg) for 4 to 6 days. Complete 
blood counts (CBCs) should be performed daily during mobilization and the dosage of G-CSF 
should be decreased if white blood cell (WBC) count is > 70 × 109 cells/L. The morning after the 
4th G‑CSF dose, apheresis will be performed according to standard clinical procedures. If 
peripheral blood CD34+ count on that morning is < 50 cells/µL, a 5th dose of G-CSF will be 
administered and plerixafor will be administered by subcutaneous injection at 0.24 mg/kg of 
body weight approximately 10 hours prior to the next day’s collection. Plerixafor can be given 
daily for up to 4 days. 

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On each day of apheresis, the subject should have a physical exam, including abdominal 
palpation to rule out splenomegaly, and vital signs performed prior to beginning apheresis and 
again after completion of apheresis. Apheresis will be performed per standard clinical site 
practice. Up to 3 total collections may be performed as part of any one mobilization cycle. 
Apheresis product from Mobilization Cycle 1 should be evaluated and managed as follows: 
• If the Apheresis Procedure Day 1 collection is > 15 × 106 CD34+ cells/kg: 
Remove back-up cells to be stored at the clinical site and send a minimum of 
12 × 106 CD34+ cells/kg to the transduction facility.  
• If the Apheresis Procedure Day 1 collection is between 12 and 15 × 106 CD34+ 
cells/kg, send the entire collection to the transduction facility. The subject should 
return for an additional apheresis procedure on Day 2 to collect back-up cells 
(≥ 1.5 × 106 CD34+ cells/kg), stored at the clinical site.  
• If the Apheresis Procedure Day 1 collection is < 12 × 106 CD34+ cells/kg, this 
collection should be held at an overnight, controlled storage facility at the clinical site 
and the subject should return for Apheresis Procedure Day 2. The collections from 
Apheresis Procedure Day 1 and Apheresis Procedure Day 2 will be sent for 
transduction. If the total collection over Day 1 and Day 2 is > 15 × 106 CD34+ 
cells/kg, back-up cells may first be removed. Otherwise, the subject should 
return for an additional apheresis procedure on Day 3 to collect back-up cells 
(≥ 1.5 × 106 CD34+ cells/kg), stored at the study site.  
• If the Apheresis Procedure Day 1 collection is < 1 × 106 CD34+ cells/kg, this 
collection should be stored at the clinical site for back-up. The subject should return 
for Apheresis Procedures on Days 2-3 until the target of 12 × 106 CD34+ cells/kg is 
obtained for transduction.  
Mobilization Cycle 2 
After completion of Mobilization Cycle 1, the Sponsor will inform the clinical site of the eli-cel 
cell dose. Once all release testing has been completed, the Sponsor will inform the clinical site if 
the drug product has met specification or not. 
If the minimum recommended cell dose has been met and the drug product has met specification, 
then the subject should only undergo Mobilization Cycle 2 if additional collection of autologous 
cells is needed for back-up cells (i.e., if < 1.5 × 106 CD34+ cells/kg have been collected and 
stored for rescue during Mobilization Cycle 1).  
If additional autologous cells are needed, then the subject should begin Mobilization Cycle 2. 
Mobilization Cycle 2 should begin no sooner than 2 weeks after the completion of Mobilization 
Cycle 1 with the same guidelines as Mobilization Cycle 1.  
If Mobilization Cycle 2 is for the procurement of additional autologous cells for eli-cel, the 
management of the collection from each Apheresis Procedure day will be discussed with the 
Medical Monitor on a case-by-case basis prior to Apheresis Procedure Day 1.  

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5.2.2. 
Bone Marrow Harvest Procedure 
If sufficient back-up cells for rescue are not procured after 1 or 2 mobilization cycles, the 
Investigator can proceed with a BM harvest. BM harvest will be performed according to 
institutional practice and will occur at a minimum of 2 weeks after completion of the last 
mobilization cycle.  
5.2.3. 
Transduction Process and Release Testing 
All cell manipulation procedures and release testing will be performed in accordance with Good 
Manufacturing Practice (GMP) following process specific standard operating procedures.  
After each mobilization and apheresis procedure (Section 5.2.1), each drug product manufacture 
will result in an independent drug product lot. Eli-cel lots which have been dispositioned for 
clinical use will be sent to the site with a Certificate of Analysis(es), documenting that all release 
testing is complete. 
If eli-cel does not meet pre-defined specifications, it will not be dispositioned for clinical use. In 
such cases, the Investigator may either withdraw the subject from the study or discuss further 
mobilization options with the subject. 
5.2.4. 
Conditioning 
Pre-conditioning assessments will be performed on Day -11 (with a window of -3 days; 
i.e., Day ‑14 through Day -11) prior to myeloablative conditioning as outlined in the SOE. 
If neurological decline is observed (see Section 3.4.1), as evidenced by a NFS >1 or a 
Loes Score > 9, the subject will be discontinued from the study. 
Conditioning will only begin once eli-cel has been dispositioned for clinical use and the drug 
product is at the clinical site. Myeloablative conditioning will be performed on an in-patient 
basis using busulfan IV and cyclophosphamide IV. 
Weight-based dosing of busulfan IV will be administered on Days -10, -9, -8, and -7 and 
weight‑based dosing of cyclophosphamide IV will be administered on Days -5, -4, -3, and -2.  
Additional information on busulfan dosing: 
• Busulfan IV will be administered as a 2-hour IV infusion in 16 single doses on 
4 consecutive days 
• If using cumulative exposure to calculate busulfan dose, the cumulative busulfan 
exposure (or cumulative area under the curve [AUC] [AUCcum]) will be targeted to 
17,000 to 21,000 µmol*min/L. 
• If using the first dose to calculate busulfan exposure, the target AUC range for a 
single dose is 1190 to 1310 µmol*min/L. 
• If the AUC for the 1st single dose falls outside the specified target range, subsequent 
doses can be adjusted to ensure appropriate exposure to the AUCcum target range. 
Subjects should be monitored for AUCcum as necessary. 
• Busulfan IV weight-based dosing will be calculated as follows:  

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• For subjects ≤ 12 kg: busulfan 1.1 mg/kg/dose IV every 6 hours on Days –10, –9, –8, 
and –7  
• For subjects >12 kg: busulfan 0.8 mg/kg/dose IV every 6 hours on Days –10, –9, –8, 
and –7  
If any subjects are obese (i.e., actual body weight [ABW] is over 125% of ideal body weight 
[IBW]), dosing will be adjusted for IBW (see Section 10.1 for calculations). 
Additional information on cyclophosphamide dosing: 
Cyclophosphamide 50 mg/kg/day will be administered as a 2-hour IV infusion with hydration as 
per institutional protocol. 
Cyclophosphamide dose adjustments for IBW are recommended but not required. If any subjects 
are obese (i.e., subject ABW is over 125% of IBW), dosing will be adjusted for IBW (see 
Section 10.1 for calculations). 
Prior to and during the administration of busulfan IV and cyclophosphamide IV, prophylactic 
and empiric anti-convulsive, antifungal, and antibiotic treatments, and all other supportive care, 
including management of any complications resulting from myeloablation, will be administered 
by the institutional transplant team per institutional standards.  
Refer to the current Package Inserts for busulfan IV and cyclophosphamide IV, including 
associated AEs.  
5.2.5. 
Infusion (Transplant) Procedures, Dose, and Administration 
Infusion of eli-cel is to be given approximately 48 hours (see Section 5.2.4) after completion of 
the busulfan IV and cyclophosphamide IV conditioning regimen.  
All procedures involving eli-cel must be performed using aseptic techniques by trained personnel 
per institutional practice at the clinical site, including a saline line flush. Prior to administration, 
the eli-cel is to be thawed in a 37°C water bath and must be infused immediately, but no later 
than 4 hours after it has been thawed.  
Eli-cel will be administered via IV infusion (transplant) through a central venous catheter in a 
volume between 20 and 80 mL, according to institutional practice for infusion of hematologic 
stem cells at the clinical site. Do not use an infusion filter. The dose to be administered is 
≥ 5.0 × 106 CD34+ cells/kg. If more than one lot of eli-cel is manufactured to achieve the 
minimum cell dose, infusions of each lot will occur consecutively. Consecutive infusions will 
also occur if a single lot is split into 2 drug product bags due to volume constraints. The subject’s 
weight immediately prior to the first apheresis collection will be used to calculate the final dose 
of eli-cel for that lot. 
There is no current evidence that eli-cel must be adjusted for obesity. If, during Screening, a 
subject is determined to be obese (i.e., subject ABW is over 125% of IBW), the Sponsor and 
the Investigator will discuss adjusting for IBW. IBW dosing that results in an ABW dose 
≤ 1.5 × 106 CD34+ cells/kg would not be acceptable.  
Each eli-cel bag contains 1 g dimethyl sulfoxide (DMSO). Limiting the amount of DMSO 
infused to no more than 1 g/kg/day is recommended (Junior et al. 2008), and thus no subject in 
Study ALD-102 would exceed this amount.  

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Vitals signs are to be monitored concurrently during eli-cel infusion (transplant) per institutional 
practice at the clinical site, but no less frequently than at the start, once during, and upon 
completion of the infusion (transplant). Infusion reactions, including anaphylaxis, will be 
managed according to the medical judgment of the physician overseeing the infusion.  
5.3. 
Storage and Stability of Eli-cel 
Eli-cel will be frozen and stored in cryopreservative solution in the vapor phase of liquid 
nitrogen at the transduction facility until release testing and dispositioning for clinical use.  
Once dispositioned for clinical use, eli-cel will be stored in the vapor phase of liquid nitrogen at 
the clinical site until thawed for clinical use. 
For details regarding traceability of eli-cel, see Section 5.9. 
5.4. 
Storage and Administration of Back-up Cells 
Mobilized back-up cells will be frozen and stored in accordance with institutional guidelines. In 
the event of neutrophil engraftment failure (failure to achieve 3 consecutive ANC laboratory 
values of ≥ 0.5 × 109 cells/L (after initial post-infusion nadir) obtained on different days by 
42 days post-infusion of eli-cel), back-up cells will be administered at a dose of ≥ 1.5 × 106 
CD34+ cells/kg, or ≥ 1.0 × 108 TNC/kg (see Table 1. Back-up cells may also be administered 
in the event that the subject has received myeloablation and is unable to receive infusion 
(transplant) of eli-cel for any reason (see Section 3.4). For details regarding traceability of 
back‑up cells, see Section 5.9. 
5.5. 
Method of Assigning Subjects to Treatment 
In this open-label study, all subjects entered into the study will be assigned to active treatment. 
5.6. 
Blinding, Packaging, and Labeling 
5.6.1. 
Blinding and Breaking the Blind 
This is an unblinded, open-label study. 
5.6.2. 
Packaging and Labeling 
Eli-cel consists of an autologous CD34+ cell-enriched population that contains cells transduced 
with LVV encoding human adrenoleukodystrophy protein. Eli-cel is suspended in 
cryopreservative solution in the final immediate container for the intended medical use 
(infusion bag). 
Eli-cel will be labeled by the transduction facility according to GMP. Refer to Section 5.9 for 
additional details regarding product accountability. 
5.7. 
Duration of Subject Participation 
Each subject will remain on this study for approximately 26 months from time of consent, 
inclusive of an approximately 24-months post-drug product infusion follow-up; subjects will 
then be asked to consent for a follow-up study for another 13 years post-drug product infusion. 

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5.8. 
Assessment of Treatment and Study Compliance 
Treatment compliance will not be an issue in this study as eligible subjects receive a one-time 
administration of eli-cel and will be monitored by hospital personnel. 
Subject compliance with the subsequent post-drug product infusion study visits will be assessed 
through Month 24. 
5.9. 
Product Accountability 
Eli-cel accountability and traceability are ultimately the responsibility of the Investigator and 
Sponsor. However, this responsibility may be delegated to a suitably qualified Investigator listed 
on Food and Drug Administration (FDA) Form 1572 who has had appropriate study-specific 
training and whose name has been appropriately listed on the Delegation of Responsibility Log 
for this task. 
Detailed records will be maintained throughout the duration of the study to enable accurate 
accountability of the subject’s autologous cells from procurement to eli-cel infusion. Procured 
CD34+ HSCs will be traceable back to the subject from apheresis through infusion via 2 unique 
identifiers and their Hematopoietic Progenitor Cell, Apheresis [HPC-A] product number (unique 
for each HPC-A collection). In the event that two apheresis collections are required for a subject 
during the same mobilization cycle, the HPC-A product numbers will act as additional 
traceability to the collection event. Clinical sites will enter the HPC-A product number and the 
2 unique identifiers on the label of the collection bag for each subject’s respective apheresis 
product. Once these cells have arrived at the transduction facility, GMP procedures will be 
utilized throughout each step of the manufacturing process to generate a final drug product 
(CD34+ HSCs transduced with Lenti-D LVV) to ensure traceability. Each drug product lot is 
assigned a unique manufacturing lot number. Eli-cel accountability is confirmed by utilization of 
the same 2 unique identifiers, HPC-A product number(s), and drug product manufacturing lot 
number on the final Drug Product label. Clinical site staff will verify the 2 unique identifiers 
upon receipt of the Drug Product from the manufacturer and once again prior to infusion. The 
above procedure is also followed if more than one lot of eli-cel is manufactured to achieve the 
minimum cell dose or if a single lot is split into 2 drug product bags due to volume constraints. 
In this situation, the eli-cel lots or bags will be shipped together to clinical site staff. Each of 
these steps will be documented by the appropriate party who is handling subject cells. 
These records will include details of storage and use of the eli-cel as well as storage of back-up 
cells. Transfer of eli-cel from the transduction facility through administration to the subject will 
be recorded. 
The Investigator will ensure that the eli-cel is used only in accordance with this protocol. Drug 
accountability records indicating eli-cel inventory at the clinical site, administration to each 
subject, and disposal will be maintained by the clinical site. These records will adequately 
document that the subject was provided the eli-cel dose as specified in the protocol and should 
reconcile each eli-cel received by the clinical site. Accountability records will include dates, 
quantities, lot numbers, expiration dates (if applicable), and subject numbers. The Sponsor or its 
designee will review eli-cel accountability at the clinical site on an ongoing basis during 
monitoring visits. Additional information regarding traceability can be found in the SOM. 

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All material containing eli-cel will be treated and disposed of as hazardous waste in accordance 
with governing regulations and clinical site procedures. 
In the event that drug product cannot be administered due to triggering of stopping rules or other 
reasons, drug product will be kept cryopreserved in the vapor phase of liquid nitrogen until 
further instruction by the Sponsor. The Sponsor will instruct the site staff to either destroy the 
drug product via their institutional procedures or return the drug product to bluebird bio. 
5.10. 
Prior and Concomitant Medication and Therapy 
 
 
 
 
 
  
  
 
 
 
 
 
 
 

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6. 
STUDY ASSESSMENTS 
6.1. 
Schedule of Events 
Table 2 and Table 3 provide the Schedule of Events (SOE) to be conducted during the study. 
Detailed descriptions of the efficacy, safety, and exploratory procedures to be conducted during 
this study are provided in the following sections. Additional details, including administrative 
information, regarding the efficacy, safety, and exploratory procedures, will be provided by the 
Sponsor in the SOM. 
Subjects who experience neutrophil engraftment failure (defined as failure to achieve 
3 consecutive ANC laboratory values of ≥ 0.5 × 109 cells/L [after initial post-infusion nadir] 
obtained on different days by 42 days post-infusion [transplant] of eli-cel) will receive infusion 
with back-up cells (mobilized PBMCs) or with allogeneic HSCs. These subjects will continue to 
be followed for safety and efficacy.  
Study treatments and evaluations can be considered as 4 distinct phases after informed consent: 
• Screening 
• CD34+ Cell Collection, Transduction, Disposition of eli-cel, and Re-confirmation of 
Eligibility 
• Conditioning and Washout followed by eli-cel Infusion (transplant) on Day 0 
• Maintenance (Follow-up) (Day 1 through Month 24) 
Study Day 0 is defined as the day of infusion (transplant). 
Subjects will be asked to comply with the protocol specified assessments according to the time 
periods enumerated in the SOE. If the timing of assessments is shifted due to scheduling 
conflicts (e.g., limited bed availability at the hospital, delays in screening assessments, repeat 
mobilization, delays in scheduling conditioning and eli-cel infusion), these will not be considered 
protocol deviations. In such cases, the subject will resume their schedule beginning on Day -10. 
Note: Unscheduled visits may be performed at any time during the study whenever necessary to 
assess for or to follow-up on AEs or as deemed necessary by the Investigator. Evaluations and 
procedures identified in the SOE may be performed at unscheduled visits, as clinically indicated, 
at the Investigator’s discretion in consultation with the Sponsor. 
The study treatments are described in detail in Section 5.2. 
Impact of the COVID-19 Pandemic on Study Visits 
Due to the COVID-19 pandemic, subjects may not be able to attend normal study visits. If a visit 
is missed due to COVID-19 reasons (e.g. unable to fly, unwilling to travel, family or subject 
affected by COVID-19, hospital closure, etc.), the subject may be able to complete study 
assessments at a facility that is local to his home. 

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Table 2: 
Schedule of Events: Screening through Drug Product Infusion  
Screening 
Mobilization
1 
CD34+  
Harvest 
(Apheresis) 
Pre- 
Conditioning 
Assessments 
Conditioning 
and 
Monitoring 
Study Day (D): 
D -60 to -45 
D -44 to -37 
D -40 to -37 
D -11 
D -10 to -1 
Visit Window (Days): 
-10 to +5 
-10 
- 
-3 
- 
Informed Consent 
+ 
 
 
 
 
Search for allogeneic donor & HLA typing 
2 
+ 
 
 
 
 
Demographics & Medical History 
+ 
 
 
 
 
ABCD1 genotype
3 
(+) 
 
 
 
 
Adrenal function
4 
+ 
 
 
 
 
Local lab: Blood for immunological studies 
+ 
 
 
 
 
Sperm/testicular tissue banking, if requested
6 
+ 
 
 
 
 
Serology panel 
+ (I) 
+ (II) 
 
 
 
Physical examination, Vital signs
7 
+ 
+
8 
+
9 
+ 
+
10 
Hematology
11 
+ 
+
12 
+
12  
+ 
+13 
 
1 If more than one mobilization cycle is required, they must be separated by an interval of at least 2 weeks. See 
Section 5.2.1 for additional details. 
2 A preliminary search for a suitable donor will be initiated at Screening for all subjects in the event that a subject is 
not eligible for drug product at Day -11, experiences engraftment failure, or cannot receive Lenti-D Drug Product 
(e.g., drug product does not meet specifications). HLA typing does not need to be performed if historical results are 
available. 
3 Genotyping of ABCD1 gene will occur in subjects for whom no historical data is available; documented ABCD1 
mutation required prior to initiating myeloablative conditioning (Day -10) 
4 Adrenal function tests (cortisol and adrenocorticotropic hormone [ACTH]) are to be performed in the morning 
(approximately 8:00 am) during Screening before the subject has taken hydrocortisone unless subject is on steroid 
replacement therapy. If ACTH is significantly elevated, tests should be repeated 3 hours after taking hydrocortisone. 
Mineralocorticoid functions (aldosterone and plasma renin activity) are to be performed at the same time points with 
the subject sitting in an upright position. 
5 
 
6 May occur any time before conditioning; hormonal treatment, if applicable as part of banking, should stop at least 
7 days prior to conditioning. 
7 Physical examinations will include measurement of weight at all visits and height at Screening only. Full physical 
exam to be performed at Screening only. During hospitalization, focused physical examinations will be performed 
twice per week until discharge; Vital signs will include blood pressure, pulse, respiratory rate, and temperature. 
8 Focused physical examinations and vital signs will be performed prior to the first dose of G-CSF. 
9 On each day of apheresis, the subject should have a focused physical exam, including abdominal palpation to rule 
out splenomegaly, and vital signs performed prior to beginning apheresis and again after completion of apheresis.  
10 Focused physical examinations and vital signs will be performed each day during conditioning. 
11 Hematology parameters to be determined include white blood cell (WBC) count with differential, hemoglobin, 
hematocrit, red blood cell (RBC), and platelet count 
12 Hematology will be performed each day of mobilization and apheresis. 
CCI
CCI

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Screening 
Mobilization
1 
CD34+  
Harvest 
(Apheresis) 
Pre- 
Conditioning 
Assessments 
Conditioning 
and 
Monitoring 
Study Day (D): 
D -60 to -45 
D -44 to -37 
D -40 to -37 
D -11 
D -10 to -1 
Visit Window (Days): 
-10 to +5 
-10 
- 
-3 
- 
Clinical chemistry 
+ 
 
 
+ 
+13  
Blood specialty labs:  
• Dried blood spot collection 
+ 
 
 
 
 
Neurological exam 
+ 
 
 
+ 
 
NFS assessment
16 
+ 
 
 
(+)16 
 
MFD assessment
16, 17 
+ 
 
 
(+)16 
 
Echocardiogram 
+ 
 
 
 
 
Electrocardiogram 
+ 
 
 
 
 
Brain MRI (with and without contrast) 16 
+ 
 
 
(+)16 
 
Evoked potentials
19 
+ 
 
 
 
 
Confirmation of eligibility 
+ 
 
 
+ 
 
G-CSF (and plerixafor if required) 
administration 
 
+ 
 
 
 
 
13 Chemistry and hematology parameters will be measured daily during conditioning; blood will be collected prior to 
infusion of busulfan IV and cyclophosphamide IV 
 
 
 
 
 
16 NFS assessments, MFD assessments, and brain MRIs may be repeated at any time during the study if there is 
evidence of clinical decline. These assessments must be repeated if more than 60 days has passed since the NFS and 
MRI at Screening and the start of Pre-Conditioning assessments. However, if subject requires sedation for MRI, 
performing this repeat assessment is based on Investigator judgment. 
17 May be performed concurrently with NFS assessment. 
18 Only the Socioeconomic Status test derived from Hollingshead and Redlich will be done at Screening. 
19 Evoked potentials to be performed may include BAER, visual evoked potential (VEP), nerve conduction studies 
(NCS), and somatosensory evoked potential (SSEP) from all 4 limbs, depending on subject age and ability to 
participate in the assessments. NCS may be performed in the upper and lower limbs (sural, peroneal, tibial, and 
median nerves). The VEP will be performed at Screening, Month 12 and Month 24. The BAER, SSEP, and NCS 
will be performed at Screening and Month 24. It is at PI’s discretion whether to perform SSEP and NCS. 
CCI
CCI
C
C
I

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Screening 
Mobilization
1 
CD34+  
Harvest 
(Apheresis) 
Pre- 
Conditioning 
Assessments 
Conditioning 
and 
Monitoring 
Study Day (D): 
D -60 to -45 
D -44 to -37 
D -40 to -37 
D -11 
D -10 to -1 
Visit Window (Days): 
-10 to +5 
-10 
- 
-3 
- 
CD34+ count 
20 
 
+ 
+ 
 
 
Busulfan and Cyclophosphamide administration 
 
 
 
 
+ 
Busulfan level monitoring 
 
 
 
 
+ 
Concomitant medication 
Continuous from ICF signing 
Adverse event monitoring 
Continuous from ICF signing 
 
 
20 Peripheral blood CD34+ count should be performed either the day prior to or on the first planned day of apheresis. 

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Table 3: 
Schedule of Events: Drug Product Infusion through End of Study  
Lenti-D Drug 
Product  
Infusion  
Follow Up  
Week 2 
Follow Up 
Month 1 
Follow Up  
Month 2 
Follow Up 
Month 3 
Follow Up 
Month 6 
Follow Up 
Month 9 
Follow Up 
Month 12 
Follow Up 
Month 15 
Follow Up 
Month 18 
Follow Up 
Month 21 
Follow Up 
Month 24 
Early  
Termination 
Study Day (D): 
D 0 
D 15 
D 30 
D 60 
D 90 
D 180 
D 270 
D 360 
D 450 
D 540 
D 630 
D 720 
- 
Visit Window (Days): 
- 
±7 
±7 
±14 
±14 
±14 
±14 
±30 
±30 
±30 
±30 
±30 
NA 
Drug Product infusion 
+ 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination, Vital signs
1 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Hematology
2 
 
+
3 
+
3 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Clinical chemistry 
 
+
3 
+
3 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Local lab: Blood for immunological studies 
 
 
 
 
+ 
+ 
 
+ 
 
 
 
+ 
+ 
Blood specialty labs:  
• Dried blood spot collection 
 
 
 
 
 
 
 
+
5 
 
 
 
+
5 
+
5 
• RCL
6 
 
 
 
 
+ 
+ 
 
+ 
 
 
 
+
7 
+
7 
• Integration site analysis 
 
 
 
 
 
+ 
 
+ 
 
+ 
 
+ 
+ 
• Exploratory biomarkers 
8 
 
 
+ 
+ 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
 
1 Physical examinations will include measurement of weight at all visits. During hospitalization, focused physical examinations will be performed twice per week 
until discharge. Vital signs will include blood pressure, pulse, respiratory rate, and temperature. Vital signs are to be monitored concurrently during Lenti-D Drug 
Product infusion according to institutional practice at the clinical site, but no less frequently than at the start, once during, and upon completion of the infusion. 
Following infusion, vital signs will be performed daily during hospitalization and at least twice per week after discharge until neutrophil engraftment occurs. 
2 Hematology parameters to be determined include white blood cell (WBC) count with differential, hemoglobin, hematocrit, red blood cell (RBC), and platelet 
count. If the results from blood tests are not as expected, additional testing may need to be performed and may include a physical exam, blood tests, imaging 
tests, or a bone marrow biopsy to allow for further investigation of stem cells. 
 
 
 
 
 
 
6 Two samples are required, one for RCL screening test, another for potential co-culture of PBLs if RCL screening test is positive. 
7 If a subject’s previous RCL tests were all negative, this sample will be archived. 
8 Blood for analyses of chitotriosidase (central laboratory) and for storage for potential analysis of antibodies against the transgene. 
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Lenti-D Drug 
Product  
Infusion  
Follow Up  
Week 2 
Follow Up 
Month 1 
Follow Up  
Month 2 
Follow Up 
Month 3 
Follow Up 
Month 6 
Follow Up 
Month 9 
Follow Up 
Month 12 
Follow Up 
Month 15 
Follow Up 
Month 18 
Follow Up 
Month 21 
Follow Up 
Month 24 
Early  
Termination 
Study Day (D): 
D 0 
D 15 
D 30 
D 60 
D 90 
D 180 
D 270 
D 360 
D 450 
D 540 
D 630 
D 720 
- 
Visit Window (Days): 
- 
±7 
±7 
±14 
±14 
±14 
±14 
±30 
±30 
±30 
±30 
±30 
NA 
• Optional: blood for storage 
 
 
 
 
 
+ 
 
+ 
 
 
 
+ 
+ 
Neuropsychological tests  
 
 
 
 
 
 
 
+ 
 
 
 
+ 
+ 
Global assessment 
 
 
 
 
 
 
 
+ 
 
 
 
+ 
+ 
Electrocardiogram 
 
 
 
 
 
 
 
 
 
 
 
+ 
+ 
Brain MRI (with and without contrast)
10  
 
 
+ 
 
 
+ 
 
+ 
 
+ 
 
+ 
+ 
Evoked potentials
12 
 
 
 
 
 
 
 
+ 
 
 
 
+ 
+ 
Health economic data13 
 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Concomitant medication 
Continuous from ICF signing 
Adverse event monitoring 
Continuous from ICF signing 
 
 
9 (+) To be performed only if peripheral blood shows a single clone with integrated lentiviral vector sequences persistently representing >10% of total PBLs and 
concurrent presence of leukocytosis (WBC count >30,000 cells/µL/mm3) or at the Investigator’s discretion.  
 
  
 
12 Evoked potentials to be performed may include BAER, visual evoked potential (VEP), nerve conduction studies (NCS), and somatosensory evoked potential 
(SSEP) from all 4 limbs, depending on subject age and ability to participate in the assessments. NCS may be performed in the upper and lower limbs (sural, 
peroneal, tibial, and median nerves). The VEP will be performed at Screening, Month 12 and Month 24. The BAER, SSEP, and NCS will be performed at 
Screening and Month 24. It is at PI’s discretion whether to perform SSEP and NCS. 
13 Includes number and duration of in-patient hospitalizations (including ICU stay), clinic/doctor visits, therapy, and emergency room visits. 
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6.2. 
Concurrent Human Leukocyte Antigen Search for Allogeneic Donor 
During Screening, HLA typing for the subject does not need to be performed if historical results 
are available. A preliminary search for a suitable donor will be initiated at Screening for all 
subjects in the event that a subject is not eligible for drug product at Day -11, experiences 
engraftment failure, or cannot receive eli-cel (e.g., drug product does not meet specifications).  
6.3. 
Confirmation of Eligibility 
Subject’s eligibility will be confirmed prior to the start of conditioning as detailed in the SOE. 
If a subject is determined to be ineligible, the Medical Monitor should be contacted. 
6.4. 
Fertility Preservation 
Fertility preservation (e.g., sperm or testicular tissue banking) will be done as appropriate at the 
discretion of the subject, their legal guardian (as applicable), and the Investigator. 
6.5. 
Assessments 
6.5.1. 
Demographics and Medical History 
Subject demographic data such as gender, age, race, and ethnicity, will be obtained during 
Screening, and a complete medical history will be obtained during Screening and updated 
on Day 0 as needed. The medical history is to include all prior and current medical 
history, including relevant family history, and CALD disease history (including ABCD1 
genotype and imaging information). 
6.5.2. 
Physical Examination 
Complete physical examinations (including general appearance; head, eyes, ears, nose, and 
throat [HEENT]; cardiovascular; dermatologic, abdominal; genitourinary; lymph nodes; hepatic; 
musculoskeletal; respiratory; and neurological) and focused physical examinations are to be 
conducted according to the SOE. 
6.5.3. 
Vital Signs and Weight 
Vital signs to be measured include systolic/diastolic blood pressure, pulse, respiration rate, and 
temperature.  
Vital signs and subject weight (in kgs) will be measured and recorded according to the SOE; 
measurement details are included in the SOM.  
6.5.4. 
Electrocardiogram/Echocardiogram 
A 12-lead ECG will be obtained as per the SOE and read locally.  
A standard 2D Doppler echocardiogram will be performed at Screening and read by the site 
cardiologist. Ejection fraction and overall clinical interpretation will be captured. 

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6.5.5. 
Neurologic Examination 
The neurologic examination is to include ophthalmologic and audiologic examinations 
administered by a pediatric neurologist or other appropriately trained and qualified physician 
according to the SOE. Visual fields will be assessed by perimetry testing or by visual 
confrontation by neurological examination. Examination details are included in the SOM. Refer 
to Section 6.6 for the reporting of CALD-related changes as AEs. 
6.5.6. 
Neurologic Functioning Score (NFS) Assessment 
Assessment of subject status using NFS is to be performed by a pediatric neurologist or other 
appropriately trained and qualified physician according to the SOE. The presence or absence of 
disabilities that prevent independent functioning will be recorded during these examinations 
using the definitions described in Section 10.3. As noted in the SOE, if the Screening through 
Pre-conditioning period exceeds 60 days or there is clinical suspicion of neurological decline, the 
NFS assessment should be repeated ahead of myeloablative conditioning (see Section 3.4.1).  
As indicated in Table 7 of Section 10.2, a score of “0” denotes absence of clinical signs of 
cerebral disease. Maximal signs within a domain score the total of all grades within that domain. 
For example, score of a subject with cortical blindness is 3, which is sum of the scores of the 
vision impairment/field cut and cortical blindness.  
Study-specific training will be administered to the assessors and documented prior to study start 
and throughout the study to ensure standardization of administration of the NFS. Refer to the 
SOM for additional details regarding the administration of the NFS.  
6.5.7. 
Major Functional Disabilities (MFDs)  
MFDs include loss of communication, cortical blindness, tube feeding, total incontinence, 
wheelchair dependence, and complete loss of voluntary movement, which are defined in Table 6 
of Section 10.2. MFDs, as assessed by a pediatric neurologist or other appropriately trained and 
qualified physician, must be immediately reported as SAEs (See Section 6.6). 
6.5.8. 
Neuropsychological Tests 
The goal of neuropsychological testing is to assess the subject in key areas for signs of 
dysfunction due to CALD. A series of neuropsychological tests are recommended based on the 
subject’s age at the time of the assessment. If possible, it is recommended that the same assessor 
administer the tests throughout the course of the study and that the tests be administered in the 
same order each time. Details regarding the sequence of testing administration and scoring are 
included in the SOM. The same test version should be administered throughout the study even if 
the subject ages out of a particular test. If an assessment cannot be administered or completed 
due to subject non-compliance or a language barrier, that will not be considered a protocol 
deviation. 
At Screening, only the socioeconomic status (SES) test derived from Hollingshead and Redlich 
is to be administered. 
Age-appropriate neuropsychological tests will be administered on other visits according to 
the SOE.  

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6.5.9. 
Evoked Potential (Electrophysiology) 
Electrophysiological assessment to be performed, when feasible, and with consideration for the 
subjects age. This will include the Visual Evoked Potential (VEP), Brain Stem Auditory Evoked 
Response (BAER), and Somatosensory Evoked Potential (SSEP) from all 4 limbs and of Nerve 
Conduction Study (NCS) of the upper and lower limbs (the sural, peroneal [fibular], tibial, and 
median nerves). These should be performed according to the SOE.  
VEP provides objective information about the visual system; BAER tests auditory brainstem 
function; SSEPs are recorded by stimulating peripheral nerves, most commonly the tibial, 
median, or ulnar nerves, typically with an electrical stimulus, and are used to assess the function 
of a subject's spinal cord; and NCS is commonly used to evaluate the function, especially the 
ability of electrical conduction, of the motor and sensory nerves of the human body.  
It is at the Principal Investigator’s discretion to administer SSEP and NCS.  
6.5.10. 
Brain Magnetic Resonance Imaging (Loes Score) 
Brain MRI, with and without contrast, will be performed according to the SOE; image 
acquisition details and shipping details are included in the Site Procedure Manual. Additional 
advanced imaging techniques may be performed on an exploratory basis to better characterize 
the degree of cerebral involvement; refer to Site Procedure Manual for additional details. 
All MRIs will be assessed by a central reviewer who is blinded to the subject identification and 
time point, using the 34-point Loes scoring scale, which is widely used to diagnose and follow 
subjects with CALD. The Independent Review Manual will be used by the central reviewer. This 
charter describes the procedure for the image blinding, reading, and scoring. 
As noted in the SOE, brain MRIs may be repeated at any time during the study if there is 
evidence of clinical decline. If more than 60 days has passed since the screening MRI was 
performed, or there is clinical suspicion of neurological decline, the MRI should be repeated 
ahead of myeloablative conditioning (see Section 3.4.1). However, if subject requires sedation 
for MRI, performing this repeat assessment is based on Investigator judgment.  
6.5.11. 
Clinical Laboratory Tests 
Laboratory tests of hematology and serum chemistries will be performed as specified in the 
following sub-sections and in the SOE. 
Clinical laboratory tests are to be performed locally and reviewed by the Investigator or qualified 
designee (e.g., physician’s assistant, nurse practitioner). 
All hematology and chemistry results from assessments performed at unscheduled visits should 
also be entered into the clinical database.  
6.5.11.1. Hematology, Clinical Chemistry, Liver and Adrenal Function 
Blood samples for hematology, clinical chemistry, liver, and adrenal function are to be collected 
as specified in the SOE.  

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The following clinical laboratory parameters are to be determined: 
Hematology 
• 
Hematocrit 
• 
Hemoglobin 
• 
Red blood cell (RBC) count 
• 
White blood cell (WBC) count with differential 
• 
Platelet count 
 
Clinical chemistry 
 
• 
Sodium (Na) 
• 
Blood urea nitrogen (BUN) 
• 
Potassium (K) 
• 
Creatinine 
• 
Chloride (Cl) 
• 
Glucose 
• 
Magnesium (Mg) 
• 
Calcium (Ca) 
• 
Phosphorus (P) 
 
Liver Function Tests 
• 
Aspartate aminotransferase (AST) 
• 
Alkaline phosphatase 
• 
Alanine aminotransferase (ALT) 
• 
Bilirubin (total and direct a) 
Adrenal Function Tests 
• 
Cortisol 
• 
Adrenocorticotropic hormone (ACTH) 
• 
Aldosterone (subject in upright position) 
• 
Plasma renin activity (subject in upright position) 
a Direct bilirubin only required if total bilirubin is abnormal. 
Additional instances of clinical laboratory tests listed in this section may be performed at the 
Investigator’s discretion as needed. 
6.5.11.2. Immunological Studies 
Immunological testing includes measuring levels of T cell subsets (CD4, CD8), B cells (CD19), 
and NK cells (CD16 or CD56). In addition, levels of immunoglobulins (immunoglobulin G 
[IgG], IgM, and IgA) will be quantified. 
6.5.11.3. Serology Panel (Infectious Disease Testing) 
Screening: Serology Panel I 
Screening serology will be evaluated using standard methods. The serology panel for eligibility 
includes HIV-1 and HIV-2; HBV surface antigen (HBsAg) and HBV core Ab (HBcAb); 
hepatitis C virus (HCV) Ab; and HTLV-1. Any other serology required by the contract drug 
product manufacturing organization or local guidelines or based on subject’s risk factors or 
clinical evidence of infection with other communicable disease agents or disease before 
mobilization or infusion of drug product (including for example testing for CMV, EBV, HSV, 
HCV core antigen, VZV IgG, HTLV-2, syphilis, toxoplasmosis, tuberculosis, Trypanosoma 
cruzi, and West Nile Virus) are permitted; if any of these tests are performed and a clinically 
relevant result is obtained, results must be discussed with the Medical Monitor to determine 
eligibility.  

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On Day 1 of Mobilization: Serology Panel II 
Blood samples will be collected according to country-specific and institutional guidelines. 
If screening serology (Panel I) was completed within the timeframe before HSC collection or 
transplant allowed by institutional and country-specific guidelines, those specific tests need not 
be repeated for Panel II. In case apheresis begins later than 30 days after screening, then 
infectious disease labs should be drawn again. 
6.5.11.4. Specialty Laboratory Sample Collection 
As this is a pediatric study, blood volume limitations will sometimes preclude the collection of 
all samples during a particular study visit. Table 5 enumerates the priorities for blood collection. 
Safety labs (see Section 6.5) have been prioritized over labs for efficacy and exploratory 
analyses. 
Per European recommendation on clinical trials conducted in the pediatric population, trial-
related blood loss per individual, should not exceed 3% of the total blood volume during a period 
of four weeks and should not exceed 1% at any single time (European-Commission 2002). Any 
deviations to these recommendations should be justified. 
Examples of guidelines for blood draw limits in pediatrics can be found at: 
http://www.who.int/bulletin/volumes/89/1/BLT-10-080010-table-T2.html  
Table 5: 
Blood Collection: Order of Priority 
• 
Adrenal Function Tests 
• 
Serology Panels (infectious disease screening) 
• 
Chemistry 
• 
Hematology 
 
  
• 
Proviral Integration Site Analysis in PBLs  
• 
RCL test  
• 
ABCD1 genotype  
• 
 
 
  
 
 
 
 
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Clinical work-up for unexpected blood test results: 
If the results from blood tests are not as expected, additional testing may need to be performed to 
allow for further investigation of stem cells and may include. 
• Physical exam 
• Blood tests 
• Imaging tests 
• Bone marrow biopsy 
Dried Blood Spot Collection 
Given the rarity of this disease, a blood sample will be collected on filter paper according to the 
SOE for measurement of lyso-PC in the dried blood spot. This sample is intended to facilitate the 
development of a newborn screening assay for ALD. Refer to the Laboratory Manual for further 
details regarding the collection, processing, and storage of this sample. 
  
 
 
 
 
 
  
 
 
  
 
 
ABCD1 Genotype 
Blood samples for mutational analysis of the ABCD1 gene will be collected according to the 
SOE if a historical result is not available. The results of the mutational analysis should be 
determined before commencing conditioning. 
Replication Competent Lentivirus (RCL) Testing 
Blood samples for RCL testing will be collected and tested using an RCL screening assay. If the 
RCL screening assay is positive, the site may be requested to perform local HIV-1 screening assay, 
and if positive, follow-up with an HIV-1 Western blot, at the subject’s next scheduled visit, or earlier 
at the discretion of the Investigator. Once available, the results of these tests must be shared with the 
Sponsor immediately. Additionally, a confirmatory test to assess the presence of RCL in PBLs 
will be performed.  
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Confirmation of RCL would lead to suspension of the enrollment of new subjects (see 
Section 3.4.2). Further, presence of RCL will be considered an SAE and will be handled and 
reported as described in Section 6.6.2. 
Proviral Integration Site Analysis 
Blood samples for proviral ISA are to be collected according to the SOE; collection, processing 
and shipping details are included in the Laboratory Manual. 
Exploratory Biomarkers: MMP, Chitotriosidase, Antibodies Against Transgenic Product  
 
  
 
 
Optional Blood for Storage 
Optional blood and tissue samples will be collected per the SOE for future research. 
 
 
Such samples may be stored until repository is discontinued. 
The Sponsor will be the custodian of the samples in the repository and any unused samples will 
be destroyed at the Sponsor’s discretion. If possible, optional blood, BM, and tissue samples also 
are to be collected in the event of a subject’s death if an autopsy is performed. Leftover samples 
from protocol procedures (e.g., blood draw for ISA or BM collection) will also be stored for 
potential optional future analyses as described above. 
Collection and storage of the optional samples described above will be subject to discretionary 
approval from each center’s IRB/IEC and the subject’s specific written consent. Samples will be 
labeled with a unique identification number that includes no subject identifying information. 
Note that apheresis product collected as part of the manufacture of the drug product may be used 
to study the manufacturing process. In particular, extra apheresis product may be used to 
understand how the process may be improved or made more robust. These potential studies are 
not optional.  
Other potential uses of the apheresis product are for non-manufacturing improvement research, 
such as
 
are optional. 
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6.5.12. 
Assessment of Clonal Predominance and/or Suspicion of Insertional Oncogenesis 
(Malignancy) 
6.5.12.1. Assessment of Clonal Predominance  
Figure 1 outlines the updated algorithm for assessment of clonal predominance. Screening 
integration site (IS) analysis (ISA) will be performed as indicated in the Schedule of Events 
using high-throughput, semi-quantitative methods which identify IS based on vector sequence 
primers. IS identified in the screening assay are considered as being of interest when the overall 
peripheral blood VCN is > 0.3 c/dg AND either any relative IS frequency is > 30% OR multiple 
IS are apparently in the same clone and add up to > 30%. Multiple IS apparently in the same 
clone is defined as more than one relative frequency where values are within 20% of each other 
(e.g. 5% ± 1%, 10% ± 2%, 15% ± 3%, etc.), as well as any additional cases identified through 
bluebird bio internal review of ISA reports. When multiple IS are apparently in the same clone, it 
will be recommended to confirm that those IS are in a single clone (e.g. bone marrow or 
peripheral blood colony-forming unit assay). IS of interest will be interrogated, from the 
timepoint of interest and available previous timepoints, using a quantitative assay (e.g. qPCR) 
designed to detect the specific IS and determine an IS-specific VCN to estimate clonal 
contribution. 
If results of the quantitative, IS-specific follow-up assay reveal an IS-specific VCN ≤ 0.5 c/dg, 
estimating ≤ 50% clonal contribution, repeat ISA screening will continue at the regularly 
scheduled timepoints. However, according to scientific judgement or interest, investigative 
follow-up may be initiated by bluebird bio in collaboration with an investigator and additional 
interval, unscheduled ISA testing may be performed. 
If results of the quantitative, IS-specific follow-up assay reveal an IS-specific VCN > 0.5 c/dg, 
estimating > 50% clonal contribution, criteria will be met to consider the subject as having a 
predominant clone. This threshold also applies to individual lineage evaluations (myeloid, 
lymphoid, etc.) when performed. Clinical work-up will be recommended for a predominant clone 
(see next sections). A report to relevant regulatory authorities will be required when a persistent, 
predominant clone is identified (2 or more timepoints), and the report will be made within 
30 days of receipt of IS-specific VCN results from the second timepoint when the persistent, 
predominant clone is identified. 

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Figure 1: 
Schematic for Assessment of Clonal Predominance  
 
Abbrev.: c/dg, copies per diploid genome; IS, integration site; ISA, integration site analysis; qPCR, quantitative 
polymerase chain reaction; VCN, vector copy number;  
6.5.12.2. Other Criteria that can Trigger Clinical Work-up for Malignancy 
• Any clinical suspicion of malignancy including leukemia or lymphoma 
• Unexplained WBC count > 30,000 (cells/μL) on two consecutive measurements  
• After achievement of a WBC count within the normal range post-drug product 
infusion and engraftment of gene-modified cells, the development of a WBC 
< 1000 (cells/μL) on two consecutive measurements  
6.5.12.3. Clinical Work-up for Malignancy 
If any of the above criteria is met, the Medical Monitor will be notified, and a work-up will be 
performed that may occur in stages and may include some of the following at each stage:  
• Physical exam  
• CBC with differential 
• Lymphocyte subsets 

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• Studies to rule out infectious cause 
• Studies to rule out autoimmune disease 
• Imaging studies, as appropriate 
• Bone marrow analysis  
If clinical results indicate a diagnosis of a malignancy or myelodysplasia, enrollment into this 
study will be suspended, and further analyses will be determined by the Sponsor, in consultation 
with the DMC (see also Section 3.1.1). It should be noted it may not be possible to distinguish 
the source of malignancy, e.g. arising from transplant-related medications or procedures, or from 
expansion of gene-modified cells due to insertional mutagenesis, and all efforts should be made 
to confirm the source of malignancy before determining to halt or alternatively to resume the 
study.  
If there is no evidence of malignancy or myelodysplasia, subject will continue to be monitored as 
per the protocol-defined SOE, or more frequently at discretion of the Investigator and Sponsor. 
Bone Marrow Aspiration 
The subject may undergo BM aspiration if clonal predominance is observed. The procedure may 
also be done at the Investigator's discretion, if there is concern about clonal expansion. The BM 
aspiration will be performed in accordance with institutional practices under aseptic conditions. 
It is anticipated that institutional guidelines will specify that approximately 5 to 20 mL of BM 
will be collected each time. 
Vector Copy Number by qPCR: Bone Marrow CD34+  
If clonal predominance is observed, BM samples are to be used for determination of VCN in BM 
by qPCR, as indicated in the SOE. Testing will be performed by a central laboratory. 
6.6. 
Adverse Events 
Monitoring of AEs will be conducted from informed consent through the duration of the study. 
AEs, as defined in Section 6.6.1, will be monitored and recorded in the case report forms (CRFs) 
from the time informed consent is signed as follows: 
• All SAEs, as defined in Section 6.6.1, through Month 24 
• All drug product-related AEs (related or possibly related, as defined in Section 6.6.2) 
through Month 24 
• CALD-related ≥ Grade 2 AEs, through Month 24 
• All ≥ Grade 2 AEs, through Month 12 
• All ≥ Grade 1 AEs, through 30 days after drug product infusion 
All AEs will be monitored until they are completely resolved or determined to be a stable or 
chronic condition. For subjects who withdraw for reasons other than withdrawal of consent, any 
SAEs open at the time of discontinuation should be followed-up until resolution or are 
determined to be a stable or chronic condition. 

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6.6.1. 
Definitions, Documentation, and Reporting 
Adverse Event: An AE is any untoward medical occurrence associated with the use of a drug in 
subjects, whether or not considered drug related. An AE may include a change in physical signs, 
symptoms, and/or clinically significant laboratory change occurring in any phase of a clinical 
study. This definition includes concurrent illnesses or injuries, and exacerbation of pre-existing 
conditions. A pre-existing condition is a clinical condition (including a condition being treated) 
that is diagnosed before the subject signs the Informed Consent Form (ICF) and is documented 
as part of the subject’s medical history. Any worsening of CALD that qualify as a ≥ Grade 2 AE 
should be reported (see Section 6.5.6). 
Unexpected Adverse Events 
An AE is considered unexpected with eli-cel if it is not consistent in nature or severity with eli-
cel reference safety information which is contained in the current eli-cel Investigator’s Brochure. 
Conditioning-related Events 
Busulfan and cyclophosphamide are cytotoxic drugs that cause 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 and cyclophosphamide 
IV. For the purposes of this protocol, the prescribing information for busulfan and 
cyclophosphamide should be consulted for full information on these side effects. 
The intended profound myelosuppression (manifested by neutropenia, thrombocytopenia, and/or 
anemia) and expected events that occur after the initiation of busulfan IV and 
cyclophosphamide IV conditioning are considered to be the direct consequence of the 
conditioning regimen and are to be reported as AEs but should be attributed to conditioning on 
the AE CRF, as applicable. 
Serious Adverse Events 
An SAE is any AE, occurring at any dose and regardless of causality that: 
• Results in death. 
• Is life-threatening. Life-threatening means that the subject was at immediate risk of 
death from the reaction as it occurred, i.e., it does not include a reaction which 
hypothetically might have caused death had it occurred in a more severe form. 
• Requires subject hospitalization or prolongation of existing hospitalization. 
Hospitalization admissions and/or surgical operations scheduled to occur during the 
study period but planned prior to study entry are not considered AEs if the illness or 
disease existed before the subject was enrolled in the study, provided that it did not 
deteriorate in an unexpected manner during the study (e.g., surgery performed earlier 
than planned). 
• Results in persistent or significant disability/incapacity. Disability is defined as 
a substantial disruption of a subject’s ability to conduct normal life functions 
(e.g. MFDs as defined in Section 10.2 are required to be reported as an SAE; see 
Section 6.6.2 for SAE reporting). 

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• Is a congenital anomaly/birth defect. 
• Is an important medical event. 
ο An important medical event is an event that may not result in death, be life 
threatening, or require hospitalization but may be considered an SAE when, 
based upon appropriate medical judgment, it may jeopardize the subject and 
may require medical or surgical intervention to prevent one of the outcomes 
listed in the definitions for SAEs. 
ο For the purposes of this study, any new malignancy or new diagnosis of a 
neurologic, rheumatologic, or hematologic disorder that, in the Investigator’s 
opinion, is clinically significant and requires medical intervention will be 
considered medically important and therefore serious. 
ο For the purposes of this protocol, while the subject remains hospitalized for 
study treatment, Grade 3 and Grade 4 lab values (per CTCAE criteria) that are 
related to myeloablative conditioning (i.e. busulfan and cyclophosphamide) 
will not be reported as an SAE unless they meet the requirement of being 
immediately life threatening. 
6.6.2. 
Procedures for AE and SAE Reporting 
Each subject must be carefully monitored for the development of any AEs. This information 
should be obtained in the form of non-leading questions (e.g., “How are you feeling?”) and from 
signs and symptoms detected during each examination, observations of study personnel, and 
spontaneous reports from subjects.  
All AEs (serious and non-serious) spontaneously reported by the subject and/or in response to an 
open question from study personnel or revealed by observation, physical examination or other 
diagnostic procedures will be recorded on the appropriate page of the CRF. Any clinically 
relevant deterioration in laboratory assessments or other clinical findings are considered an 
AE and the AE must be recorded on the appropriate pages of the CRF. When possible, signs and 
symptoms indicating a common underlying pathology should be noted as one comprehensive 
event.  
All unexpected, related Grade 3 to 4 AEs must be reported to the Sponsor, and IRB/IEC, within 
5 days (unless an SAE then must be reported within 24 hours - see below). All AEs reported to 
the Sponsor will be included in the Annual Reports, and reports to the DMC at periodic reporting 
intervals. 
All SAEs that occur during the course of the study must be promptly reported by the Investigator 
to the Sponsor (or designee) within 24 hours from the point in time when the Investigator 
(or designee) becomes aware of the SAE. All SAEs must be reported whether or not they are 
considered causally related to eli-cel. SAE forms, created specifically by bluebird bio, will be 
provided to each clinical site. If the SAE report is supplied as a narrative, it will include, at 
minimum, the protocol number, Investigator name and site number, subject number, a 
description of the event, an assessment by the Investigator regarding the severity of the SAE, the 
relatedness of the SAE to eli-cel, date of onset, and time and amount of study treatment infusion 
(i.e., total number of transduced CD34+ HSCs that were transplanted). A sample of the SAE 

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form can be found in the SOM. Follow-up information on the SAE may be requested by bluebird 
bio. 
Please refer to the SAE report form and associated guidelines for information on how to 
immediately submit SAE reports to the Sponsor or designee. 
If there are suspected unexpected serious adverse drug reactions (SUSARs) associated with the 
use of eli-cel, the Sponsor or designee will notify the appropriate regulatory agency(ies), central 
ethics committees, and all participating Investigators in accordance with applicable regulations. 
The Investigator or Sponsor will notify the IRB/IEC and other appropriate institutional 
regulatory bodies of all SUSARs or unanticipated problems, in accordance with local 
regulations. 
For both serious and non-serious AEs, the Investigator must determine the severity of the event, 
and the relationship of the event to study treatment.  
Severity will be assessed by the Investigator using the following criteria per the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 including 
for AEs that are a result of a laboratory abnormality. The CTCAE displays Grades 1 through 5 
with unique clinical descriptions of severity for each AE based on the general guideline below. 
• Grade 1: Mild, asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL) 
• Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL. 
• Grade 4: Life-threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 
If the severity (grade) changes within a day, the maximum severity (grade) should be recorded. 
If the severity (grade) changes over a longer period of time, the changes should be recorded as 
separate events (having separate onset and stop dates for each grade). Decreases in AE severity 
should not be captured. The AE should remain open at the highest grade until the AE resolves. 
Relationship (i.e. ‘Causality assessment’): The Investigator is required to provide their 
assessment of the relationship of eli-cel to all AEs. Relationship to other study related procedures 
other than eli-cel (i.e. mobilization, apheresis, conditioning, or study procedure) may also be 
required. The following is a guideline for determining the relationship of eli-cel to an AE: 
• Not Related: Exposure to the defined study treatment did not occur, or the 
occurrence of the AE is not reasonably related in time. 
• Unlikely Related: The AE occurred in a reasonable time after the defined study 
treatment and is doubtfully related to the investigational agent/procedure. 

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• Possibly Related: The defined study treatment and the AE were reasonably related in 
time, and the AE could be explained equally well by causes other than exposure to the 
defined study treatment. 
• Related: The defined study treatment and the AE were reasonably related in time, 
and the AE was more likely explained by exposure to the defined study treatment 
than by other causes, or the defined study treatment was the most likely cause of the 
AE. 
For the purpose of safety reporting and analyses, all AEs that are classified as “possibly related” 
or “related” will be considered eli-cel treatment-related events. 
6.7. 
Pregnancy and Contraception 
Pregnancy of female partners is neither an AE nor an SAE, unless a complication relating to the 
pregnancy occurs (e.g., spontaneous abortion, which requires reporting as an SAE). However, all 
pregnancies of female partners occurring during this study are to be reported in the same time 
frame as SAEs using the Pregnancy Form. SAEs experienced by a female partner of a male 
subject during the course of the pregnancy are required to be immediately reported (i.e. within 
24 hours) on the SAE report form. 
The course of all pregnancies, including perinatal and neonatal outcome, regardless of whether 
the subject has discontinued participation in the study, will be followed until resolution. 
Information will be requested on the status of the mother and infant at 6 weeks of age and 
annually thereafter for 2 years. SAEs experienced by the newborn within 6 weeks of age are 
required to be immediately reported (i.e. within 24 hours) on the SAE report form. In cases of a 
male study subject, pregnancies resulting from sperm banking prior to the receipt of drug product 
will not be followed. 
Busulfan has been shown in animal studies to be teratogenic (see package insert for drug used). 
Male subjects and their female partners are required to use two different effective methods of 
contraception from Screening through at least 6 months after drug product infusion. Birth control 
methods considered to be highly effective include hormonal contraception associated with 
inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), 
bilateral tubal occlusion, vasectomized partner, and sexual abstinence. Acceptable birth control 
methods which may not be considered as highly effective include progestogen-only oral 
hormonal contraception where inhibition of ovulation is not the primary mode of action, male or 
female condom with or without spermicide, and cap, diaphragm, or sponge with spermicide 
(http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/
CTFG/2014_09_HMA_CTFG_Contraception.pdf). If subjects are truly sexually abstinent 
(where true sexual abstinence should be defined as being in line with the preferred and usual 
lifestyle of the subject), no second method is required. (Periodic abstinence [calendar, 
symptothermal, post-ovulation methods], withdrawal [coitus interruptus], spermicides only, and 
lactational amenorrhea method are not acceptable methods of contraception). Beyond 6 months, 
subjects should discuss with their physician prior to resuming unprotected intercourse.  

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6.8. 
Unscheduled Visits 
Unscheduled visits may be performed at any time during the study whenever necessary to assess 
for or to follow-up on AEs or as deemed necessary by the Investigator. Evaluations and 
procedures to be performed at unscheduled visits will be at the Investigator’s discretion in 
consultation with the Sponsor and may be based on those listed in the SOE. 
6.9. 
Long-term Follow-Up Protocol 
All subjects will be followed for 24 months post-drug product infusion under this protocol unless 
they withdraw consent. For subjects with 24 months follow-up, if appropriate consent (or assent 
if applicable) is obtained, subjects will be followed for an additional 13 years under a separate 
long-term follow-up protocol (LTF-304) which will focus on long-term safety and efficacy.  

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7. 
STATISTICAL PROCEDURES 
Details of the statistical analysis will be provided in the ALD-102 study Statistical analysis Plan 
(SAP) and the associated inter-study SAP. This section provides a general overview of these 
plans. 
7.1. 
Sample Size Estimation 
The number of subjects planned to be infused with eli-cel is approximately 30. 
The sample size for this study was not determined by formal statistical methods. The rarity, 
severity, and rapidly progressive nature of CALD significantly constrain enrollment. For 
example, from 2009 through 2013, there were only approximately 20 to 24 allo-HSCTs per year 
performed on subjects with ALD in the US (http://www.cibmtr.org). 
7.2. 
Populations for Analysis 
Three populations will be evaluated for safety, efficacy, and exploratory analyses. 
The Intent-to-treat population (ITT) will consist of those subjects who initiate any study 
procedures, beginning with stimulation by G-CSF. This population will be used for the analyses 
of some of the safety endpoints and for the supportive analysis of the primary efficacy endpoint, 
if it is different from the Transplant Population (TP). 
The Transplant population (TP) will consist of subjects who receive eli-cel. This population 
will be used for the analyses of all efficacy endpoints and some of the safety endpoints.  
The Successful Neutrophil Engraftment Population (NEP) will consist of subjects who 
received eli-cel and achieved neutrophil engraftment defined as having 3 consecutive ANC 
laboratory values of ≥ 0.5 × 109 cells/L (after initial post-infusion nadir) obtained on different 
days by 42 days post-infusion of eli-cel. The NEP will be used for the supportive analysis of the 
primary efficacy endpoint as well as for some of the other efficacy and safety endpoints, if it is 
different from the TP. 
7.2.1. 
Populations for Comparison in Inter-study Analysis: 
The Strictly ALD-102-Eligible Transplant Population (TPES) consists of subjects in 
Studies ALD-101 and ALD-103 who received allo-HSCT and satisfied the following criteria: 
i) NFS ≤ 1 at Baseline, ii) Loes score ≥ 0.5 and ≤ 9 at Baseline, iii) GdE+ at Baseline.  
The ALD-102-Eligible Transplant Population (TPE) consists of subjects in Studies ALD-101 
and ALD-103 who received allo-HSCT and satisfied the following criteria: i) NFS≤ 1 at 
Baseline, ii) Loes score ≤ 9 at Baseline, iii) GdE+ at Baseline or Loes ≥ 0.5)  
GdE+ Transplant Population (TPG) consists of subjects in Studies ALD-101 and ALD-103, 
who received allo-HSCT and were GdE+ at Baseline. 
 

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7.3. 
Planned Analyses 
The initial analysis is planned after the first cohort of 17 subjects treated with eli-cel complete 
Study ALD-102. This initial analysis reflects the analysis that was planned at the time of 
protocol inception, and results of the initial analysis will be the basis for determining the success 
or failure of the study. To gather experience at EU manufacturing site, a second cohort of 
subjects was opened. A final analysis will be performed when all subjects in the second cohort 
complete the study and will be considered supportive.  
7.3.1. 
Interim Analysis. 
Interim analyses are planned in support of regulatory submissions. The timing of these analyses 
and the number of subjects included in each analysis will take into account specific requests 
from regulatory agencies and applicable regulatory guidance. The rationale for each analysis will 
be documented. 
7.3.2. 
Final Analysis 
A final analysis will be performed when all subjects treated with eli-cel complete the study.  
7.3.3. 
Additional Data Review 
Safety data are reviewed on an ongoing basis for signal detection and to support preparation of 
regulatory submission documents. Analyses of study data may also be performed for the 
purposes of internal data review, preparing for regulatory meetings, and updating the scientific 
community. 
7.3.4. 
Impact of the COVID-19 Pandemic 
A review will be performed to determine which assessments are likely to have been affected by 
the COVID-19 pandemic, and analyses will be performed to measure the effect of disruptions 
due to the pandemic on these assessments. 
7.4. 
Statistical Methods  
7.4.1. 
General Methods 
It is recognized that formal, confirmatory statistical hypotheses are extremely difficult to 
formulate in the context of this subject population, where few historical data are available 
regarding the efficacy endpoints. Further, it is not possible to have a truly randomized 
comparison of eli-cel to other potentially curative modes of treatment, such as allo-HSCT, due to 
the rarity of the disease. Therefore, statistical methods will be primarily descriptive in nature, 
and will include point estimates and confidence limits as appropriate.  
Tabulations will be produced for appropriate demographic, Baseline, efficacy, and safety 
parameters. For categorical variables, summary tabulations of the number and percentage of 
subjects within each category of the parameter will be presented. For continuous variables, the 
number of observations, mean, median, standard deviation, minimum, and maximum values will 
be presented, along with 1- or 2-sided CIs of the mean as appropriate. Time to event data will be 
summarized using Kaplan-Meier methodology using 25th, 50th (median), and 75th percentiles 
with associated two-sided 95% CIs, as well as percent of censored observations and events. 

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In addition to the analyses described below, additional supportive efficacy and safety analyses 
will be performed on the ITT population and the NEP, as outlined in the SAP. Note, however, 
that in the likely event that there is no difference in the ITT and TP populations, reference to 
ITT analyses will not be necessary. 
7.4.2. 
Disposition of Subjects 
A tabulation of the disposition of subjects will be presented, including the number enrolled, the 
number with any post-drug product infusion data available for analysis, and the extent of data 
available, as described in the SAP. 
Subject disposition will also be presented by investigational site. 
The number of subjects in each analysis population will be presented, with reasons for exclusion 
from any specific population. 
7.4.3. 
Demographic and Baseline Characteristics 
The following demographic and Baseline characteristic factors will be summarized: age at 
enrollment, age at CALD diagnosis, gender, country of origin, race and ethnicity, family history, 
method of diagnosis of CALD, signs and symptoms of CALD, NFS at Baseline, Loes score and 
pattern at Baseline, time from CALD diagnosis to eli-cel infusion (months), time from informed 
consent to eli-cel infusion (days), and the presence of any significant co‑morbid conditions 
(defined as any ongoing medical history). Subject genotype will be presented in a listing. 
7.4.4. 
Analysis of Efficacy Endpoints 
7.4.4.1. 
Analysis of Primary Efficacy Endpoint 
Population to be analyzed 
The analysis of the primary efficacy endpoint, Month 24 MFD-free survival, will be performed 
on the TP. Analyses will also be produced on the NEP and ITT if different from the TP, but these 
will be considered as supportive (i.e., as sensitivity analyses) of the results in the TP. 
Additionally, supportive analysis of comparison of Month 24 MFD-free survival will be made 
between the TP and the TPE, TPES, and TPG populations of Study ALD-103.  
Analysis 
In order to be considered a success for the primary endpoint, a subject must be alive at or after 
the Month 24 Visit, and must not develop an MFD (i.e., subjects who do not have an NFS 
evaluation at Month 24 but are MFD-free after the Month 24 Visit window, will be considered a 
success for the primary endpoint). Subjects who (i) die or develop an MFD on or before their 
Month 24 Visit, (ii) withdraw or are lost to follow-up before their Month 24 Visit, (iii) require 
(and undergo) rescue cell administration or a second transplant before their Month 24 Visit, will 
be considered treatment failures in this primary efficacy analysis. 
The lower bound of the 2-sided 95% exact CI of the Month 24 MFD-free survival must be 
> 50% in order for the primary endpoint to be met. The clinically meaningful benchmark of 
50% is supported by data from published literature and the ALD-101 retrospective observational 
study.  

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In Study ALD-101, the MFD-free survival rate in untreated GdE+ subjects within 2 years of their 
first GdE+ MRI is 21%, with an exact 95% CI of 6.1% to 45.6%. Therefore, the defined 
clinically meaningful benchmark of 50% is above the upper 95% CI of the Month 24 MFD-free 
survival in untreated GdE+ subjects in Study ALD-101.  
Furthermore, the threshold value of 50% is also consistent with ALD-101 data in the “ALD-102 
eligible” allo-HSCT treated cohort that excluded matched siblings: the lower 95% CI of the 
mean MFD-free survival rate at 24 months is 50.1% (mean 76% with exact 95% CIs of 50.1% to 
93.2%). These findings are supported by Month 24 MFD-free survival rates published in the 
literature, which ranged between 50% and 90% (Baumann et al. 2003; Peters et al. 2004; Beam 
et al. 2007; Miller et al. 2011).  
This success criterion of the lower bound of the 2-sided 95% exact CI of the Month 24 MFD-free 
survival having to be > 50% would be met with a point estimate of 76.5% (13 of 17 subjects) in 
the initial analysis, and with a point estimate of 70.0% (21 of 30 subjects) in the final analysis. 
7.4.4.2. 
Analysis of Secondary and Exploratory Efficacy Endpoints 
Populations to be analyzed 
The analyses of the secondary and 
efficacy endpoints (Section 2.2.1) will be 
performed on the TP. Analyses may also be produced on the NEP, but these will be considered 
as supportive of the results in the TP. 
Analyses 
The following endpoints will be presented with 2-sided 95% exact CIs: 
• Proportion of subjects who demonstrate resolution of gadolinium positivity on MRI 
(i.e., GdE-) at Month 24 
• Proportion of subjects who maintain a Loes score ≤ 9 or do not increase their Loes 
score by ≥ 6 points from Baseline 
• 
 
 
 
 
  
 
 
In addition, the change over time in individual efficacy parameters will be described by 
presentation of summary statistics at each evaluation time. For each subject, figures that display 
NFS and Loes Score will be presented.  
The following time-to-event endpoints will be evaluated longitudinally over time, using 
Kaplan‑Meier statistics: 
• MFD-free survival over time. Time from drug product infusion to either second 
transplant, MFD, or death due to any cause, whichever occurs first, will be analyzed.  
CCI
CCI

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• Subjects who do not experience second transplant, MFD, or death, and subjects who 
discontinue the study prematurely, will be censored at the time of the last observation 
at which they were MFD-free. 
• Time to resolution of gadolinium positivity on MRI (i.e., GdE-)  
• Overall survival 
For primary and secondary efficacy endpoints and 
 
, Baseline is defined as the timepoint closest, but prior to conditioning. 
Comparison to Efficacy Data from Studies ALD-101 and ALD-103 
Comparison of selected ALD-102 efficacy endpoints in an inter-study analysis will be performed 
on the TPE, TPES, and TPG of ALD-101 and ALD-103. 
Additionally, efficacy comparisons will be performed between Study ALD-102 subjects and 
untreated subjects in Study ALD-101 who are similar to those enrolled in Study ALD-102.  
Analyses to be performed will be detailed in the inter-study SAP. 
7.4.5. 
Analysis of Safety Endpoints 
For safety endpoints, all laboratory data 
 
levels), vital signs, echo- and electro-cardiograms, Baseline is defined 
to be the assessment closest to but prior to mobilization. 
The general safety profile of treatment with eli-cel will be summarized through the longitudinal 
evaluation of AEs, laboratory assessments, vital signs, ECG, and physical examination findings. 
Safety parameters will be summarized across each time point. 
The primary safety endpoint will be the proportion of subjects who experience either acute 
(≥ Grade II) or chronic GVHD by Month 24. This analysis will be to compare the rates of 
≥ Grade II and chronic GVHD in the TP population from Study ALD-102 to the rates seen in the 
allo-HSCT-treated population in Study ALD-103, using exact methods for binomial data.  
Adverse Events 
All subjects receiving any part of at least 1 dose of the mobilizing agent (G-CSF) prior to eli-cel 
infusion will be evaluated for safety (the ITT population). The safety analyses will include 
evaluation of the incidence of treatment emergent AEs (i.e. AEs that occur on or after the 
initiation of eli-cel infusion) by preferred term and body system coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). AEs will be summarized for those events that 
occur: 
1. after signing the informed consent to before start of mobilization; 
2. from the start of mobilization up to before start of conditioning;  
3. from the start of conditioning until the day before neutrophil engraftment (for subjects 
who do not achieve neutrophil engraftment, the study period is 42 days post-drug product 
infusion); 
CCI
CCI

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4. from neutrophil engraftment through Month 24 (for subjects who do not achieve 
neutrophil engraftment, the beginning of this study period is 42 days post-drug product 
infusion); 
5. from the start of eli-cel infusion through Month 12; 
6. from Month 12 through Month 24; 
7. from the start of eli-cel infusion through Month 24; and 
8. from signing of the informed consent through Month 24 
Summaries will be provided for all AEs, serious AEs, Grade 3, 4, and 5 AEs (as assessed using 
NCI CTCAE Version 4.03), drug-product related AEs, and AEs leading to early termination. 
See the Statistical Analysis Plan for a comprehensive list of study periods and additional details. 
All AEs occurring on study will be provided in data listings, and in addition, by-subject listings 
will be provided for subject deaths, SAEs, subjects requiring hospitalization due to an adverse 
effect of therapy, drug product-related AEs, and AEs leading to withdrawal (defined as the 
inability to receive the therapy). 
Transplant-related mortality through 100 and 365 days post-drug product infusion will be 
summarized for 2 intervals: from Study Day 0 through 100 days post-drug product infusion, 
and from Study Day 0 through 365 days post-drug product infusion. The number and percent of 
transplant-related deaths as well as the exact 95% CIs will be presented for the TP. 
Blood will be tested for replication-competent lentivirus at Months 3, 6, 12, and 24. Results will 
be listed. 
Laboratory Data 
Baseline for laboratory data will be the value closest but prior to mobilization.  
The actual value and change from baseline to each on-study evaluation and to the last on-study 
assessment will be summarized for each clinical laboratory parameter (hematology, clinical 
chemistry, and liver function tests) using the ITT population. 
Potentially clinically significant (PCS) values will be defined and analyzed in the SAP. 
Vital Signs and Physical/Neurological Examinations 
The change from Baseline to each on-study evaluation will be summarized for vital signs. Vital 
sign measurements will be presented for each subject in a data listing. 
Physical/neurological examination results will be summarized to indicate change in status 
(normal/abnormal) from Baseline to each post-Baseline assessment. All physical/neurological 
examination findings will be presented in a data listing. 
Echo- and electro-cardiograms 
Echo- and electro-cardiogram data for each subject will be provided in a data listing. 

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Concomitant Medications 
 
 
 
 
 
Comparison to Safety Data from Studies ALD-101 and ALD-103 
Additional comparison of ALD-102 safety endpoints in the inter-study analysis will be 
performed on the overall Transplant Population that were treated with allo-HSCT in Studies 
ALD-101 and ALD-103. 
Analyses to be performed will be detailed in the SAP, and include incidence of SAEs, ≥ Grade 3 
AEs, ≥ Grade 3 infections, successful engraftment, transplant-related mortality, and acute and 
chronic GVHD. 
The AE analysis period starts at the day of HSC infusion for the cross-study analysis, per study 
ALD-103 reporting requirements. 
7.4.6. 
Analysis of Other Exploratory Endpoints 
 
 
 

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8. 
ADMINISTRATIVE AND REGULATORY REQUIREMENTS 
8.1. 
Good Clinical Practice (GCP) 
The study will be conducted in accordance with the ICH Guideline for GCP and all other 
applicable local regulatory requirement(s). The consent (or assent if applicable) process will 
be performed in accordance with local regulations and site specific institutional practice, if 
applicable. The Investigator will be thoroughly familiar with the appropriate use of the eli-cel as 
described in the protocol and Investigator’s Brochure. Essential clinical documents will be 
maintained to demonstrate the validity of the study and the integrity of the data collected. Site 
Master Files should be established at the beginning of the study, maintained for the duration of 
the study and retained according to the appropriate regulations.  
8.2. 
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB/IEC will review all appropriate study documentation in order to safeguard the 
rights, safety, and well-being of the subjects. The study will only be conducted at sites where 
IRB/IEC approval has been obtained. The Protocol, Investigator’s Brochure, ICF, advertisements 
(if applicable), written information given to the subjects, safety updates, annual progress reports, 
and any revisions to these documents will be provided to the IRB/IEC.  
8.3. 
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject’s parent, guardian, or legal representative prior to study participation. For subjects who 
have already received eli-cel, an ICF addendum may be used to share protocol updates or new 
information with the subject. The method of obtaining and documenting the informed consent 
and the contents of the consent will comply with ICH-GCP and all applicable regulatory 
requirement(s). In addition, if consistent with local regulations, the Investigator will seek assent 
from the subject if he is at least 7 years of age. Sites will follow their standard institutional 
practice for obtaining informed consent. See Section 3.1.  
8.4. 
Subject Confidentiality 
In order to maintain subject privacy, all CRFs, eli-cel accountability records, study reports, and 
communications will identify the subject by initials and the assigned subject number. The 
Investigator will grant monitor(s) and auditor(s) from bluebird bio or its designee and regulatory 
authority(ies) access to the subject’s original medical records for verification of data gathered on 
the CRFs and to audit the data collection process. The subject’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable laws 
and regulations. 
8.5. 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol provided by bluebird bio 
and given approval/favorable opinion by the IRB/IEC and the appropriate regulatory 
authority(ies). Modifications to the protocol should not be made without agreement of both the 

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Investigator and bluebird bio. Changes to the protocol will require written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to subjects. The IRB/IEC may provide, if applicable regulatory 
authority(ies) permit, expedited review and approval/favorable opinion for minor change(s) in 
ongoing studies. bluebird bio will submit all protocol modifications to the regulatory 
authority(ies) in accordance with the governing regulations.  
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) 
to subjects, the Investigator will contact bluebird bio, if circumstances permit, to discuss the 
planned course of action. Any departures from the protocol must be fully described in the 
CRF and source documentation.  
8.6. 
Direct Access to Source Data 
Monitoring and auditing procedures developed by bluebird bio will be followed in compliance 
with GCP guidelines.  
The study will be monitored by bluebird bio or its designee. Monitoring will be done by personal 
visits from a representative of the Sponsor (site monitor) and will include on-site review of the 
CRFs for completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters. The review of medical records will be performed in a manner to ensure 
that subject confidentiality is maintained. 
The site monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, e-mail, telephone, and fax). 
Regulatory authorities, the IEC/IRB, and/or bluebird bio’s clinical quality assurance group may 
request access to all source documents, CRFs, and other study documentation for on-site audit or 
inspection. Direct access to these documents must be guaranteed by the Investigator, who must 
provide support at all times for these activities. 
8.7. 
Electronic Case Report Form Completion 
bluebird bio, Inc., will provide the study sites with an eCRF for each subject. Required study 
data will be captured on eCRFs via electronic data capture (EDC) unless otherwise specified in 
this document. Except for data points for which the protocol or SOM indicate that the eCRF may 
serve as source documentation, data are to be obtained from the subject’s source documents and 
then entered into the eCRF by authorized site personnel. Clinical data that are not recorded on 
the eCRF will be electronically captured and transferred to the Sponsor or its designee through a 
secure external data transfer process. 
It is the Investigator’s responsibility to ensure the accuracy, completeness, and timeliness of the 
data reported in the subject’s eCRF. Source documentation supporting the eCRF data should 
indicate the subject’s participation in the study and should document the dates and details of 
study procedures, AEs, and subject status.  
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected, preferably on the same day that a study subject is seen for an 
examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 

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The Investigator must sign and date the Investigator’s Statement at the end of the eCRF to 
endorse the recorded data.  
bluebird bio will retain the originals of all CRFs. The Investigator will retain a copy of all 
completed eCRFs. 
8.8. 
Record Retention 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s). Records will be retained for at least 2 years after the last marketing application 
approval or 2 years after formal discontinuation of the clinical development of the investigational 
product or according to applicable regulatory requirement(s). If the Investigator withdraws from 
the responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility. bluebird bio, Inc., must be notified in writing if a custodial change 
occurs. 
The Sponsor has full rights over any invention, discovery, or innovation, patentable or not, that 
may occur when performing the study. 
8.9. 
Liability and Insurance 
bluebird bio, Inc., has subscribed to an insurance policy covering, in its terms and provisions, 
its legal liability for injuries caused to participating persons and arising out of this research 
performed strictly in accordance with the scientific protocol as well as with applicable law and 
professional standards. 
8.10. 
Publication and Presentation of Study Findings and Use of 
Information 
All information regarding eli-cel supplied by bluebird bio to the Investigator is privileged and 
confidential information. The Investigator agrees to use this information to accomplish the study 
and will not use it for other purposes without consent from bluebird bio. It is understood that 
there is an obligation to provide bluebird bio with complete data obtained during the study. The 
information obtained from the clinical study will be used towards the development of eli-cel and 
may be disclosed to regulatory authority(ies), other Investigators, corporate partners, or 
consultants as required.  
It is anticipated that the results of this study will be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal. A Publications Committee comprised 
of Investigators participating in the study and representatives from bluebird bio, as appropriate, 
will be formed to oversee the publication of the study results, which will reflect the experience of 
all participating study centers. Subsequently, individual Investigators may publish results from 
the study in compliance with their agreement with bluebird bio.  
A pre-publication manuscript is to be provided to bluebird bio at least 30 days prior to the 
submission of the manuscript to a publisher. Similarly, bluebird bio will provide any company 
prepared manuscript to the Investigators for review at least 30 days prior to submission to a 
publisher. 

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9. 
REFERENCES 
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10. 
APPENDICES 
10.1. 
Dose Adjustment Formulas for Ideal Body Weight  
Ideal Body Weight (IBW) Formulas (Subjects 1 to 18 Years of Age): 
Height (ht) less than 60 inches (less than 152 cm) 
IBW = [(ht2) x 1.65] ÷ 1000, where ht = cm, IBW = kg 
Height (ht) greater than 60 inches (greater than 152 cm) 
Males IBW = 39 + [2.27 × (ht – 60)], where ht = inches, IBW = kg 
Adjusted Ideal Body Weight (AIBW) Formula: 
AIBW = IBW + [(0.25) × (ABW- IBW)], where ABW= actual body weight 
10.2. 
Major Functional Disabilities 
The 6 disabilities considered MFDs in this study are defined in Table 6 , and these were chosen 
based on their clinical significance and their impact on independent functioning. 
Table 6: 
Major Functional Disabilities (MFD) 
MFD 
Definition 
Loss of 
communication 
Individual should meet one of the following criteria (psychogenic syndromes, 
such as catatonia, should be ruled out): (1) With normal consciousness and 
ability to perform movements, individual does not follow command and/or 
permanently fails to perform verbal or nonverbal simple task on neurologic 
evaluation, or (2) Individual is permanently mute and unable to communicate 
by verbal or non-verbal ways.  
Cortical blindness 
Individual fails to visually track, find objects, or count fingers. Individual has 
permanent and complete vision loss affecting bilateral vision. Pupils may react 
to light. 
Tube feeding 
Individual is not able to swallow safely by mouth to maintain nutrition and 
hydration. Alternative method of feeding required. 
Wheelchair 
dependence 
Individual is unable to take more than a few steps, restricted to wheelchair; 
may need aid to transfer; wheels himself, but may require motorized chair for 
full day's activities. 
Complete loss of 
voluntary movement 
Individual is unable to effectively use his upper and lower extremities to 
perform simple or one-step activities. The criteria may still be met if there are 
singular apparently random movements of the arms. 
Total incontinence 
In an individual who was previously continent, the permanent and continuous 
loss of urinary and/or fecal control.  
10.3. 
Neurologic Function Score for ALD 
The Neurologic Function Scale (NFS) is a 25-point composite scale that assesses functional 
disabilities (Moser et al. 2000). It was designed by Dr. Gerald Raymond and colleagues 
specifically for the consistent and reproducible clinical evaluation of patients with CALD.  

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It assesses 15 functional domains affected by the disease and is the most common clinical 
evaluation tool used by clinical specialists caring for these patients (Moser et al. 2000; 
Miller et al. 2011). 
Assessment of subject status using NFS is to be performed by a pediatric neurologist or other 
appropriately trained and qualified physician as described in Section 6.5.6.

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Table 7: 
Neurologic Function Score (NFS) for CALD 
Symptom / Neuroexam 
Definition 
Score 
Hearing / auditory processing 
problems 
Individual with previously normal hearing develops permanent auditory processing difficulties and 
impairment of comprehension to verbal sounds on neurologic evaluation. 
1 
Aphasia / apraxia 
Individual should meet one of the following two criteria: (1) Individual with previously age appropriate 
speech and language development has impaired fluency or naming or repetition or content or comprehension 
or motor speech on the clinical examination; patient may have partial or incomplete aphasia or motor speech 
disorder of the speech, or (2) Individual with newly developed apraxia. Apraxia can be defined as ‘loss of the 
ability to execute or carry out any complicated learned and purposeful movements, despite having the desire 
and the physical ability to perform the movement’, examples of apraxia include, but are not limited to, limb-
kinetic apraxia, ideomotor apraxia, conceptual apraxia, speech apraxia etc. 
1 
Loss of communication  
Individual should meet one of the following criteria (psychogenic syndromes, such as catatonia, should be 
ruled out): (1) With normal consciousness and ability to perform movements, individual does not follow 
command and/or permanently fails to perform verbal or nonverbal simple task on neurologic evaluation, or 
(2) Individual is permanently mute and unable to communicate by verbal or non-verbal ways.  
3 
Vision impairment /field cut An individual with previously normal (corrected) vision develops visual field defect affecting one or both 
eyes, and/or maximal visual acuity (corrected) worse than 20/30 using bedside pocket vision screening card. 
1 
Cortical blindness 
Individual fails to visually track, find objects, or count fingers. Individual has permanent and complete vision 
loss affecting bilateral vision. Pupils may react to light. 
2 
Swallowing / other CNS 
dysfunctions 
Swallowing is safe; however individual requires minimal cueing to use compensatory strategies. The 
individual may occasionally self-cue. All nutrition and hydration needs are met by mouth at mealtime. 
2 
Tube feeding 
Individual is not able to swallow safely by mouth to maintain nutrition and hydration. Alternative method of 
feeding required. 
2 
Running difficulties / 
hyperreflexia 
An individual with previously normal gait develops minimal but permanent difficulties during running. He 
may be fully ambulatory without aid, or may have some limitation of full activity or requires minimal 
assistance. 
1 
Walking difficulties / 
spasticity / spastic gait 
(no assistance) 
Individual develops walking difficulties but is ambulatory without aid; disability severe enough to preclude 
full daily activities. 
1 
Spastic gait (needs 
assistance) 
Individual requires constant bilateral assistance (canes, crutches, braces). 
2 
Wheelchair dependence 
Individual is unable to take more than a few steps, restricted to wheelchair; may need aid to transfer; wheels 
himself, but may require motorized chair for full day's activities. 
2 

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Table 7: 
Neurologic Function Score (NFS) for CALD 
Symptom / Neuroexam 
Definition 
Score 
Complete loss of voluntary 
movement 
Individual is unable to effectively use his upper and lower extremities to perform simple or one-step 
activities. The criteria may still be met if there are singular apparently random movements of the arms. 
3 
Episodes of incontinence 
Individual who was previously continent for at least 6 months develops permanent and frequent episodes of 
hesitance, urgency, retention of bowel or bladder, or urinary incontinence during daytime and nighttime 
(diurnal and nocturnal enuresis). 
1 
Total incontinence 
In an individual who was previously continent, the permanent and continuous loss of urinary and/or fecal 
control.  
2 
Nonfebrile seizures 
Individual who develops non-febrile seizure. 
1 

CCI

CCI

CCI

CCI

CCI

CCI

CCI

CCI

CCI

CCI

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Protocol Title: 
A phase 2/3 study of the efficacy and safety of hematopoietic stem cells 
transduced with Lenti-D lentiviral vector for the treatment of cerebral 
adrenoleukodystrophy (CALD) 
Protocol Number: 
ALD-102 Version 10.0, 23 September 2020 
INVESTIGATOR STATEMENT 
I have read, understood, and agree to abide by all the conditions and instructions contained in 
this protocol. 
I understand that all documentation provided to me by bluebird bio or its designated 
representative(s) concerning this study that has not been published previously will be kept in the 
strictest confidence. This documentation includes the study protocol, Investigator’s Brochure, 
case report forms, and other scientific data. 
I agree to personally conduct or supervise the described investigation(s). 
I agree to inform any subjects, or any persons used as controls, that the Drug Product is being 
used for investigational purposes and I will ensure that the requirements relating to obtaining 
informed consent, as per local regulations and under Good Clinical Practice (GCP), are met. 
I agree to report to the Sponsor adverse events that occur in the course of the investigation(s) in 
accordance with this protocol and as required by local regulations and under GCP.  
I have read and understand the information in the Investigator’s Brochure, including the 
potential risks and side effects of the drug product. 
I agree to maintain adequate and accurate records and to make those records available for 
inspection in accordance with local regulations and under GCP. 
I will ensure that an ethics committee that complies with all local regulations and GCP 
requirements will be responsible for the initial and continuing review and approval of the clinical 
investigation.  
I also agree to promptly report to the ethics committee all changes in the research activity and all 
unanticipated problems involving risks to human subjects or others.  
I agree that this study will not commence without the prior approval of the appropriate national 
health authorities together with a properly constituted ethics committee. I agree that no changes 
will be made to the study protocol without the prior written approval of bluebird bio and the 
aforementioned regulatory bodies, as applicable in the relevant laws and regulations. 
I agree to ensure that all associates, colleagues, and employees assisting in the conduct of the 
study(ies) are informed about their obligations in meeting the above commitments. 
 
Investigator Name 
 
Investigator Signature 
 
Date 
 
Investigational site or name of institution and location (printed)