Clinical trial NCT02999984
Conditions: Severe Combined Immunodeficiency Due to ADA Deficiency
Keywords: gene therapy hematopoietic and progenitor cells lentiviral vector ADA-SCID
Sponsor: University of California, Los Angeles
Start date: 2016-12-16; Completion date: 2019-09-26
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical study designed to assess the efficacy and safety of a cryopreserved formulation of OTL-101 (autologous CD34+ hematopoietic stem/progenitor cells transduced ex vivo with EFS (Elongation Factor 1α Short form) Lentiviral Vector (LV) encoding for the human ADA gene) administered to ADA-SCID subjects between the ages of 30 days and 17 years of age, who are not eligible for an Human Leukocyte Antigen (HLA) matched sibling/family donor and meeting the inclusion/exclusion criteria. The OTL-101 product is infused after a minimal interval of at least 24 hours following the completion of reduced intensity conditioning. For subjects who successfully receive the OTL-101 product, pegademase bovine (PEG-ADA) Enzyme Replacement Therapy (ERT) is discontinued at Day+30 (-3/+15) after the transplant. After their discharge from hospital, the subjects will be seen at regular intervals to review their history, perform examinations and draw blood samples to assess immunity and safety.

Detailed description:

Arms: arm 1: Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells
Interventions: intervention 1: Infusion of autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) intervention 2: busulfan intervention 3: PEG-ADA ERT
Intervention descriptions: intervention 1: autologous cryopreserved EFS-ADA LV CD34+ cells (OTL-101) are infused intravenously intervention 2: Busulfan is used for non-myeloablative conditioning intervention 3: PEG-ADA ERT is discontinued at Day +30 (-3/+15 days) after successful engraftment

Protocol documents:
Prot_000.pdf: 
 
 
 
COVER PAGE 
 
 
Official Study Title: Efficacy and safety of a cryopreserved 
formulation of autologous CD34+ hematopoietic stem cells 
transduced ex vivo with EFS lentiviral vector encoding for 
human ADA gene in subjects with Severe Combined 
Immunodeficiency due to Adenosine Deaminase deficiency. 
 
Protocol Version 5.0, 28 March 2018 
 
NCT02999984 


ORCHARD THERAPEUTICS, LTD. 
CONFIDENTIAL 
PROTOCOL AMENDMENT 4: OTL-101-4 (28 March 2018) 
EFFICACY 
AND 
SAFETY 
OF 
A 
CRYOPRESERVED 
FORMULATION 
OF 
AUTOLOGOUS CD34+ HEMATOPOIETIC STEM CELLS TRANSDUCED EX VIVO 
WITH EFS LENTIVIRAL VECTOR ENCODING FOR HUMAN ADA GENE IN SUBJECTS 
WITH 
SEVERE 
COMBINED 
IMMUNODEFICIENCY 
DUE 
TO 
ADENOSINE 
DEAMINASE DEFICIENCY 
STUDY PROTOCOL 
STUDY number:  OTL-101-4 
PRODUCT: A CRYOPRESERVED FORMULATION OF AUTOLOGOUS CD34+ 
HEMATOPOIETIC STEM CELLS TRANSDUCED EX VIVO WITH EFS LENTIVIRAL 
VECTOR ENCODING FOR THE HUMAN ADA GENE (OTL-101) 
 [IND number: 15440] 
Original Protocol, Version 1.0: 24 October 2016 
Protocol Amendment 1, Version 2.0: 18 January 2017 
Protocol Amendment 2, Version 3.0: 05 May 2017 
Protocol Amendment 3, Version 4.0: 08 September 2017 
Protocol Amendment 4, Version 5.0: 28 March 2018 


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Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the Sponsor’s prior written authorisation. 




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PROTOCOL AMENDMENT 4: VERSION 5.0, 28 MARCH 2018 
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PROTOCOL SIGNATURES 
Investigator Agreement and Signature: 
I have read and agree to the protocol titled “Efficacy and safety of a cryopreserved formulation 
of autologous CD34+ hematopoietic stem cells transduced ex vivo with EFS lentiviral vector 
encoding for human ADA gene in subjects with severe combined immunodeficiency due to 
adenosine deaminase deficiency” (protocol number: OTL-101-4). I am aware of my 
responsibilities as an Investigator under the guidelines of Good Clinical Practice (GCP)1, local 
regulations (as applicable) and the study protocol. I agree to conduct the study according to 
these guidelines and to appropriately direct and assist the staff under my control, who will be 
involved in the study. 
1 ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) 
Step 5, adopted by CPMP July 1996/Food and Drug Administration Code of Federal Regulations for Good 
Clinical Practices Parts 50, 56, 312 , 314/ European Directives 2001/20/EC and 2005/28/EC as implemented into 
national legislation 


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SYNOPSIS 
Sponsor 
Orchard Therapeutics, Ltd. 
Investigational 
Product 
A cryopreserved formulation of autologous CD34+ hematopoietic 
stem cells transduced ex vivo with Elongation Factor 1α Short form 
(EFS) lentiviral vector (LV) encoding for the human adenosine 
deaminase deficiency (ADA) gene (OTL-101) 
Study Title: 
Efficacy and safety of a cryopreserved formulation of autologous 
CD34+ hematopoietic stem cells transduced ex vivo with EFS 
lentiviral vector encoding for human ADA gene in subjects with 
Severe Combined Immunodeficiency (SCID) due to Adenosine 
Deaminase Deficiency 
Number 
of 
Planned Centres 
1 
Planned 
Study 
Period 
December 2016 to December 2020 
Study Objectives: 
Primary Study Objectives: 
There are two primary objectives for this study aimed to determine; 
1. The success of treatment at the subject level (“responder 
analysis”) 6 months post OTL-101 infusion, defined as:  
a) Evidence of erythrocyte ADA enzyme activity above 
baseline/pre-treatment level (>0 Units), 
b) Evidence of immune reconstitution (absolute number of CD3 
cells ≥200/mm3),   
c) Detectable 
gene-marked 
granulocytes 
by 
differential 
polymerase chain reaction (dPCR)/qPCR (≥1/10,000 cells). 
This 6 month data will be used to compare the proportion of 
responders among subjects treated with the cryopreserved 
population with a comparable population obtained from one of the 
ongoing Phase I/II studies using the fresh formulation. 
2. The overall survival and event free survival at 12 months among 
ADA-SCID subjects treated with a cryopreserved formulation of 
OTL-101.  
Overall survival is defined as the proportion of subjects alive. 
Event-free survival is defined as the proportion of subjects alive 
with no “event”, an “event” being the resumption of PEG-ADA 
ERT or the need for a rescue allogenic HSCT, or death. 
Secondary Study Objectives 
The secondary objectives to be evaluated among ADA-SCID 
subjects treated with a cryopreserved formulation of OTL-101 
include confirmation of the overall survival and event free survival 
at 24 months, safety evaluation including infection rates, quality of 
life and immune response.  
Exploratory Study Objectives  
Exploratory objectives include the measurement of biological 
correlates of efficacy including; percentage of gene marking in 
peripheral 
blood 
granulocytes, 
vector 
integration 
analysis, 
quantification of clonal diversity of vector integrants, T-cell receptor 


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excision circle (TREC) and fluorescence-activated cell sorting 
(FACS) for T-cell receptor (TCR) V-β family use, ADA enzyme 
activity in erythrocytes, total adenine nucleotides in erythrocytes, and 
immune reconstitution.. 
Study Design: 
This is a prospective, non-randomized, single-cohort, longitudinal, 
single-center, clinical study designed to assess the efficacy and safety 
of OTL-101 cryopreserved formulation administered in ADA-SCID 
subjects aged between ≥30 days to <18 years of age, who are not 
eligible for an HLA-matched sibling/family donor and meeting the 
inclusion/exclusion criteria. This study aims to recruit 10 evaluable 
subjects. 
The aim of this clinical study is also to assess the success of treatment 
at the subject level (“responder analysis”) 6 months post OTL-101 
infusion, using predictive criteria for overall survival and event free 
survival and to compare data obtained from clinical studies using the 
fresh formulation of OTL-101. 
Eligible subjects will be hospitalized to undergo the harvesting of 
autologous CD34+ cells. A backup harvest of non-transduced CD34+ 
cells will be obtained during the harvesting procedure to be used in 
the event of i) product damage during the thawing of the OTL-101 
product that would prevent infusion of OTL-101 although the patient 
has already been conditioned or ii) lack of engraftment/hematopoietic 
reconstitution 42 days post infusion of OTL-101. A failure of 
hematologic reconstitution is defined as persistent ANC < 200/µl or 
platelets < 20,000/µl on three independent and consecutive 
determinations over at least ten days after day 42 from the day of 
OTL-101 infusion. 
OTL-101 is a cryopreserved formulation of autologous CD34+ 
hematopoietic stem cells transduced ex vivo with EFS LV encoding 
for the human ADA gene (OTL 101). To enable the release of OTL-
101 for infusion, the cryopreserved OTL-101 product must meet 
various quality control criteria for safety, identity, viability, purity 
and potency. If OTL-101 meets the acceptance criteria and is 
released, the subjects will be readmitted for conditioning with 
Busulfan. The OTL-101 product will be infused after a minimal 
interval of at least 24 hours following the completion of Busulfan 
administration. Subjects may remain as an in-patient following 
autologous transplantation for approximately three to 35 days.  
For subjects who have successfully received the OTL-101 product, 
PEG-ADA ERT use will be evaluated at the 1 Month follow-up visit 
(30 days post treatment ± 7 days) and discontinued at Day 30 (-3/+15) 
after the transplant. Hematologic reconstitution will be assessed at 
Day 42 (± 7 days), and in the event of no reconstitution the backup 
HSC sample will be administered, if the investigator believes this is 
in the subject’s best interest. The subjects will then be seen at regular 
intervals to review their history, perform examinations and draw 
blood samples at Months 3, 6 and 9 (all ± 2 weeks) as well as Months 


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12, 18 and 24 (all ± 4 weeks). Any medically-indicated interventions, 
including the need to reinstate PEG-ADA ERT, will be assessed at 
all follow-up visits after Month 1. Hematopoietic reconstitution will 
be assessed again at the Month 6 visit and if there is still no evidence 
of cellular recovery, the subject will be given ERT and/or HSCT, if 
available and deemed appropriate by the Investigator. After the 
Month 24 visit, the subjects will have completed the study and may 
enter a long term registry.  
The study will be overseen by an independent Data Safety 
Monitoring Board (DSMB), who will review the nature and severity 
of emerging safety data during the study. The DSMB will also liaise 
with the Principal Investigator directly to ensure the safety of 
participants during the study. The Investigator, subjects and their 
families will be informed about any significant emerging safety data.  
Study Population:  This study aims to enrol 10 eligible subjects aged ≥30 days and 
<18 years, with a diagnosis of ADA-SCID and ineligible for matched 
family allogeneic bone marrow transplantation 
Duration 
of 
Participation: 
The total study duration for each subject is estimated to be up to 
2 years and 4 months. 
Study Evaluations: Primary endpoints for this study include: 
1. Evaluation of OTL-101 at 6 months post infusion, in support of 
CMC assessing comparability of cryopreserved and fresh 
formulations, evaluation of therapy success for each subject based 
on the following parameters and their thresholds: 
 Erythrocyte ADA enzyme activity above baseline/pre-
treatment level (>0 Units),  
 Absolute CD3+ T-cell counts ≥200/mm3, and  
 Peripheral blood samples positive for vector sequences by 
qPCR(≥1/10,000 cells). 
Subjects must meet all three criteria. Subjects not meeting these 
criteria will be designated a failure (non-responder) and will be 
withdrawn from the study. This data will be used to compare 
subject data from one of the ongoing Phase I/II studies using the 
fresh formulation. 
2. Evaluate the overall survival and event free survival 12 months 
post OTL-101 infusion. Overall survival is defined as the 
proportion of subjects alive. Event-free survival is defined as the 
proportion of subjects alive with no “event”, an “event” being the 
resumption of PEG-ADA ERT or the need for a rescue allogenic 
HSCT, or death. 
 
Secondary endpoints include: 
 Evaluate the overall survival and event free survival 
24 months post OTL-101 infusion. 
 Immunoglobulin Replacement therapies prior to and after 
gene therapy.  


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 Performance outcomes and quality of life will be measured 
by the Karnofsky/Lansky scale and questions relevant to 
general well-being, school attendance and ability to practice 
sports, respectively.  
 Rates of severe infections/ opportunistic infectious episodes, 
defined as infections requiring hospitalization or prolonging 
hospitalization 
and/or 
documented 
infections 
by 
opportunistic 
pathogens 
(i.e. 
interstitial 
pneumonia, 
intractable diarrhoea). 
 Response to tetanus vaccination. 
 Immune reconstitution: T and B cell reconstitution. 
 
The exploratory endpoints will include laboratory correlates of 
efficacy that will be used to assess the level of gene correction, 
engraftment and immune reconstitution as exploratory endpoints.. 
Safety 
Evaluations: 
The safety and tolerability of OTL-101 will be assessed throughout 
the study by evaluating AEs, clinical laboratory test results, vital 
signs measurements, electrocardiogram (ECG) and physical 
examination results, and concomitant medication usage.  
Statistical 
Considerations: 
The statistical analyses of efficacy data will be performed in three 
stages: 
1. The first analysis will compare the success/failure data 6-months 
post OTL-101 infusion between fresh and cryopreserved OTL-
101 formulations. The success/failure of the OTL-101  will be 
defined by the three critera listed in the primary objectives. This 
data will be compared with available data from one of the ongoing 
Phase I/II studies using the OTL-101 fresh formulation. This will 
support the CMC comparability data between OTL-101 
cryopreserved and fresh formulations. Secondary and exploratory 
endpoints will also be described. 
2. The second analysis will determine the 12 month overall survival 
and event free survival for all subjects. Secondary and exploratory 
endpoints,  as well as baseline characteristics, subject disposition, 
and safety data will also be described. 
3. The third and final analysis will be performed to determine the 
overall survival and event free survival for all subjects 24 months 
post OTL-101 infusion. Secondary and exploratory endpoints,  as 
well as baseline characteristics, subject disposition, safety and 
Busulfan pharmacokinetic (PK) data will also be described. 
Efficacy analyses will be primarily descriptive in nature. 
 


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Table 1:  Schedule of Events – Screening to Day 24 
Study Period 
 
Screening 
Pre-harvest 
Assessment 
Bone Marrow 
Harvest 
Baseline Conditioning OTL-101 
Treatment 
Short-term Follow-up 
Visit number 
1 
21 
2 
31 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Assessment number 
 
A 
B 
C 
D 
E 
F 
G 
H 
I 
J 
K 
L 
M 
Visit window 
 
 
 
 
 
 
 
+/-2 days 
Day 
Within 
60
days of Visit
2B 
Up to 5 days
prior to Visit
2B 
Approx 30 day
prior to Visit 3F 
Day-10 to
-4 
Day -4
to -3 
Day -2
to -1 
Day 0 
Day 1 Day 4 Day 8 
Day 11 Day 15 Day19 
Day 24 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs  
X 
 
 
X 
 
 
X2 
 
 
 
 
 
 
 
Weight (kg) 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry sample3 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Hematology sample4 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
PT or PTT/INR 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
PB or BM cytogenetics5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1/Hep B/Parvo B19 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test6 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Urinalysis7 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse oxymetry 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Biopsy of skin lesions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA-SCID 
diagnosis 
confirmation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Questionnaire/QofL scale 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious episodes 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Type and cross PRBC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow harvest 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
PRBC transfusion 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Immune function10 
 
 
 
X11 
 
 
 
 
 
 
 
 
 
 
PBMC banking for RCL  
 
 
 
X12 
 
 
 
 
 
 
 
 
 
 


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Study Period 
 
Screening 
Pre-harvest 
Assessment 
Bone Marrow 
Harvest 
Baseline Conditioning OTL-101 
Treatment 
Short-term Follow-up 
Visit number 
1 
21 
2 
31 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Assessment number 
 
A 
B 
C 
D 
E 
F 
G 
H 
I 
J 
K 
L 
M 
Visit window 
 
 
 
 
 
 
 
+/-2 days 
Day 
Within 
60
days of Visit
2B 
Up to 5 days
prior to Visit
2B 
Approx 30 day
prior to Visit 3F 
Day-10 to
-4 
Day -4
to -3 
Day -2
to -1 
Day 0 
Day 1 Day 4 Day 8 
Day 11 Day 15 Day19 
Day 24 
Serum banking for RCL 
 
 
 
X12 
 
 
 
 
 
 
 
 
 
 
Erythrocyte 
ADA 
enzymatic activity 
 
 
 
X12 
 
 
 
 
 
 
 
 
 
 
Erythrocyte deoxyadenine 
nucleotide levels  
 
 
 
X12 
 
 
 
 
 
 
 
 
 
 
Busulfan administration 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
PK samples 
 
 
 
 
X13 
X14 
 
 
 
 
 
 
 
 
OTL-101 administration 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
1. 
Subjects will be admitted to the hospital for Visits 2 and 3. 
2. 
During the infusion of OTL-101 vital signs will be monitored according to standard institute protocols. 
3. 
Biochemistry samples will include the assessment of parameters listed in Table 3. Albumin ALT, AST, ALP will be measured at all time points indicated in this table. Total 
bilirubin, total protein, total protein, creatinine, blood urea, sodium, potassium, chloride, and calcium will be measured at screening, baseline, Day 1 and all follow-up visits 
(Month 1 to Month 24). Magnesium and phosphate will be measured only at pre-harvest and baseline time points. 
4. 
Hematology samples will include the assessment of parameters listed in Table 3 and will be measured at all time points indicated in this table. 
5. 
If cytogenetic testing was not performed on cells from amniocentesis, assessment should be by karyotype, CGH, and WES 
6. 
Serum pregnancy tests are required in females of child-bearing potential at screening, prior to bone marrow harvest, prior to conditioning (Busulfan) treatment, and before the 
infusion of OTL-101.  Any positive test will immediately result in the withdrawal of the subject from the study and should be reported as per guidance in Section 8.2.4 
7. 
Urinalysis will include the assessment of parameters listed in Table 3 and will be measured at all time points indicated in this table. Any abnormalities detected on dipstick at 
Screening, Pre-harvest and Baseline will require repeat dipstick and microscopic examinations. 
8. 
If there is any evidence of severe lung disease on the screening chest X-ray, a CT scan is required in order to establish if the subject meets any of the specified pulmonary 
exclusion criteria defined in Section 4.2. 
9. 
Standard post-transplant medication will be administered from Day 0 and recorded in the eCRF. 
10. 
Immune function will be assessed absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, CD19+ B-lymphocytes and CD56+/CD16+ (or CD56+/CD3-) NK cells, 
CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ (memory) T cells, TREC levels, TCR Vβ usage, lymphocyte response to PHA (if sufficient cells), and serum 
immunoglobulin (IgG, IgA, IgM). 
11. 
The immune function tests required for Visit 3, Assessment C can be performed at any point after provision of consent/assent and prior to Busulfan administration in younger 
subjects if deemed appropriate by the Investigator. 
12. 
These test can be performed at anytime following BM harvest (Visit 2: Assessment B) and prior to OTL-101 administration (Visit 3: Assessment F) in younger subjects if 
deemed appropriate by the Investigator. 
13. 
PK blood samples are required at the end of Busulfan infusion, +1, 2, 4, 8, and 13 hours post-infusion (+/- 15 minutes). These values will be used to determine the second dose 
of Busulfan. 
14. 
One PK blood sample is required immediately before the second dose of Busulfan is administered, and then at the end of Busulfan infusion, +1, 2, 4, 8, and 13 hours post-
infusion (+/- 15 minutes). 


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Study Period 
 
Screening 
Pre-harvest 
Assessment 
Bone Marrow 
Harvest 
Baseline Conditioning OTL-101 
Treatment 
Short-term Follow-up 
Visit number 
1 
21 
2 
31 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Assessment number 
 
A 
B 
C 
D 
E 
F 
G 
H 
I 
J 
K 
L 
M 
Visit window 
 
 
 
 
 
 
 
+/-2 days 
Day 
Within 
60
days of Visit
2B 
Up to 5 days
prior to Visit
2B 
Approx 30 day
prior to Visit 3F 
Day-10 to
-4 
Day -4
to -3 
Day -2
to -1 
Day 0 
Day 1 Day 4 Day 8 
Day 11 Day 15 Day19 
Day 24 
Abbreviations: ADA=adenosine deaminase, ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, BM=bone marrow, CGH= Comparative 
Genome Hybridization, CT=computer tomography, ECG=electrocardiogram, eCRF=electronic case report form, HIV=human immunodeficiency virus, IgA=immunoglobulin A, 
IgG=immunoglobulin G, IgM=immunoglobulin M, INR=international normalized ratio, NK=natural killer, PB=peripheral blood, PBMC=peripheral blood mononuclear cells, PHA= 
Phytohemagglutinin, PK=pharmacokinetic, PRBC=packed red blood cells, PT=prothrombin, PTT=prothrombin time, QofL=quality of life, RCL= Replication Competent Lentivirus, 
SCID=severe combined immunodeficiency, TCR= T-cell receptor, TREC= T-cell receptor excision circle, WES= whole exome sequencing. 
 


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Table 2:  Schedule of Events – Month 1 to Month 24 
Follow-up Period 
 
Month 1 (Day 
30) 
Day 421 
Month 3 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
ET 
Visit number 
4 
5 
6 
7 
8 
9 
10 
11 
N/A 
Visit window 
+/- 1 week 
+/- 1 week 
+/- 2 weeks 
+/- 2 weeks 
+/- 2 weeks 
+/- 4 weeks 
+/- 4 weeks 
+/- 4 weeks 
 
Physical examination 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs  
X 
 
X 
X 
X 
X 
X 
X 
X 
Weight (kg) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Height (cm) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Biochemistry sample2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology sample3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Questionnaire/QofL scale 
 
 
 
X 
 
X 
X 
X 
X 
Infectious episodes 
X 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record IgG and PEG-ADA 
therapy  received 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune function5,6 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum banking for RCL 
 
 
X 
X 
 
X 
 
X 
X 
Vector integration analysis 
 
 
X 
X 
 
X 
X 
X 
 
Leukaemia assessment7 
 
 
 
X 
 
X 
X 
X 
X 
T-cell proliferation to PHA 
 
 
 
X 
X 
X 
X 
X 
X 
Antibodies to tetanus toxoid 
 
 
 
 
 
X 
X 
X 
X 
Presence of ADA gene in 
PBMC/granulocytes and/or 
lineage-sorted cells 
 
 
X 
X 
 
X 
 
X 
X 
RCL assay in PBMC 
 
 
X 
X 
 
X 
 
X 
X 
ADA enzymatic assay 
X 
 
X 
X 
X 
X 
X 
X 
X 
Deoxyadenine 
nucleotides 
in RBC 
X 
 
X 
X 
X 
X 
X 
X 
X 
Responder assessment8 
 
 
 
X 
 
 
 
 
 
1. 
Day 42 assessment will use laboratory parameters to confirm if hematologic reconstitution has occurred.  If this has not happened by Day 42 rescue medication, 
as per standard institute procedure, will be implemented.  Any treatment administered to the subject will be recorded in the eCRF. 
2. 
Biochemistry samples will include the assessment of parameters listed in Table 3. Albumin ALT, AST, ALP will be measured at all time points indicated in 
this table. Total bilirubin, total protein, total protein, creatinine, blood urea, sodium, potassium, chloride, and calcium will be measured at screening, baseline, 
Day 1 and all follow-up visits (Month 1 to Month 24). Magnesium and phosphate will be measured only at baseline and the conditioning time points. 
3. 
Hematology samples will include the assessment of parameters listed in Table 3 and will be measured at all time points indicated in this table. 
4. 
Standard post-transplant medication will be administered from Day 0 and recorded in the eCRF. 


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5. 
Immune function will be assessed by absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, CD19+ B-lymphocytes and CD56+/CD16+ (or 
CD56+/CD3-) NK cells, CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ (memory) T cells, TREC levels, TCR Vβ usage, lymphocyte response to 
PHA (if sufficient cells), and serum immunoglobulin (IgG, IgA, IgM). 
6. 
If IgG treatment is stopped, immunoglobulin levels will be required every month for the first 3 month after discontinuation.  This is to ensure IgG levels hold 
before commencing vaccinations as per standard institute protocols. 
7. 
A blood sample will be taken unless clinical/hematologic findings indicate potential leukoproliferation, whereby a bone marrow sample will be required. In 
addition to the time points specified in this table, this assessment should be performed if the nrLAM-PCR criteria is fulfilled (see Section 7.2). 
8. 
Responder assessment includes: erythrocyte ADA enzyme activity, immune reconstitution, and gene-marked granulocytes as described in Section 2.2.1. 
Abbreviations: ADA=adenosine deaminase, ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, eCRF=electronic case 
report form, ET=early termination, IgA=immunoglobulin A, IgG=immunoglobulin G, IgM=immunoglobulin M, N/A=not applicable, NK=natural killer, 
PBMC=peripheral blood mononuclear cells, PCR=polymerase chain reaction, PEG= polyethylene-glycol, PHA= Phytohemagglutinin, QofL=quality of life, 
RBC=red blood cell, RCL= Replication Competent Lentivirus, TCR= T-cell receptor, TREC= T-cell receptor excision circle. 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................... 19 
1 
BACKGROUND INFORMATION ............................................................................. 22 
1.1 
Introduction ................................................................................................................... 22 
1.1.1 
Severe Combined Immunodeficiency due to Adenosine Deaminase 
Deficiency .................................................................................................... 22 
1.1.2 
Treatment Options ....................................................................................... 22 
1.1.2.1 
Hematopoietic Stem Cell Transplantation ................................................. 22 
1.1.2.2 
Gene Therapy .............................................................................................. 23 
1.2 
Name and Description of Protocol Treatment ........................................................... 23 
1.3 
Findings from Non-Clinical and Clinical Studies ...................................................... 23 
1.3.1 
Non-Clinical Studies ................................................................................... 23 
1.3.2 
Toxicology Studies ....................................................................................... 24 
1.3.3 
Clinical Studies ............................................................................................ 24 
1.4 
Known and Potential Risks and Benefits .................................................................... 25 
1.4.1 
Potential Benefits ........................................................................................ 25 
1.4.2 
Potential Risks ............................................................................................. 26 
1.4.2.1 
Potential Risks Related to the Protocol Treatment .................................... 26 
1.4.2.2 
Potential Risks Related to Bone Marrow Harvesting ................................ 27 
1.4.2.3 
Potential Risks Related to Concomitant Therapy ...................................... 27 
1.4.2.4 
Other Potential Risks .................................................................................. 28 
1.5 
Selection of Protocol Treatment Dosage ..................................................................... 28 
1.6 
Compliance Statement .................................................................................................. 28 
1.7 
Population to be Studied ............................................................................................... 29 
1.8 
Relevant Literature and Data ...................................................................................... 29 
2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES ..................................... 30 
2.1 
Purpose of the Study ..................................................................................................... 30 
2.2 
Study Objectives ............................................................................................................ 31 
2.2.1 
Primary Study Objectives ............................................................................ 31 
2.2.2 
Secondary Study Objectives ........................................................................ 32 
2.2.3 
Exploratory Study Objectives ...................................................................... 32 
3 
STUDY DESIGN ........................................................................................................... 33 
3.1 
General Design and Study Scheme .............................................................................. 33 
3.2 
Primary and Secondary Evaluations and Endpoints ................................................. 35 
3.2.1 
Primary Efficacy Evaluations and Endpoints ............................................ 35 
3.2.2 
Secondary Efficacy Evaluations and Endpoints ........................................ 35 
3.2.3 
Safety Evaluations and Endpoints .............................................................. 35 
3.2.4 
Exploratory Endpoints and Evaluations .................................................... 36 
3.3 
Randomization and Blinding ....................................................................................... 36 
3.4 
Protocol Treatment and Dosage .................................................................................. 36 
3.4.1 
Protocol Treatment ...................................................................................... 36 
3.5 
Duration of Subject Participation ............................................................................... 37 
3.6 
Stopping Rules and Discontinuation Criteria ............................................................ 37 
3.6.1 
Subject Stopping Rules and Criteria for Discontinuation ......................... 37 
3.6.2 
Early Study Termination ............................................................................. 38 
3.7 
OTL-101 Storage, Preparation, Administration, and Accountability ..................... 39 


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3.7.1 
OTL-101 Storage and Security ................................................................... 39 
3.7.2 
OTL-101 Production ................................................................................... 39 
3.7.3 
OTL-101 Administration ............................................................................. 40 
3.7.4 
OTL-101 Accountability .............................................................................. 41 
3.8 
Maintenance of Randomisation and Blinding ............................................................ 41 
3.9 
Source Data Recorded on the Case Report Form ...................................................... 41 
4 
SELECTION AND WITHDRAWAL OF SUBJECTS ............................................. 43 
4.1 
Inclusion Criteria .......................................................................................................... 43 
4.2 
Exclusion Criteria ......................................................................................................... 43 
4.3 
Subject Withdrawal Criteria ....................................................................................... 45 
4.4 
Discontinuation/Withdrawal Procedures.................................................................... 46 
5 
STUDY PROCEDURES ............................................................................................... 47 
5.1 
Study Visits .................................................................................................................... 47 
5.1.1 
Screening (Visit 1) ....................................................................................... 47 
5.1.2 
Autologous Bone Marrow Harvest Period (Visit 2) ................................... 48 
5.1.3 
Baseline (Visit 3) ......................................................................................... 49 
5.1.4 
Busulfan Conditioning (Visit 3) ................................................................. 50 
5.1.5 
OTL-101 Administration (Visit 3) ............................................................... 51 
5.1.6 
Immediate Post-transplant Tests and Care (Visit 3) .................................. 52 
5.1.7 
Follow-Up (Visits 4 to 11) ........................................................................... 53 
5.1.8 
Early Termination Visit .............................................................................. 59 
5.1.9 
Post-Study Registry ..................................................................................... 60 
6 
ADMINISTRATION OF OTL-101 ............................................................................. 61 
6.1 
OTL-101 ......................................................................................................................... 61 
6.1.1 
Administration of OTL-101 ........................................................................ 61 
6.1.2 
Rescue Administration of Autologous HSC Backup ................................. 62 
6.2 
Concomitant Medication/Therapy .............................................................................. 62 
6.2.1 
Permitted Concomitant Medication/Therapy ............................................. 62 
6.2.1.1 
Transplant-related Therapies ..................................................................... 62 
6.2.2 
Prohibited Concomitant Medication/Therapy ............................................ 64 
6.3 
Administration Compliance ......................................................................................... 64 
7 
ASSESSMENT OF EFFICACY .................................................................................. 65 
7.1 
Efficacy Endpoints ........................................................................................................ 65 
7.1.1 
Primary Efficacy Endpoints ........................................................................ 65 
7.1.2 
Secondary Efficacy Endpoints .................................................................... 65 
7.1.3 
Exploratory Efficacy Endpoints ................................................................. 66 
7.2 
Efficacy Assessments ..................................................................................................... 66 
8 
ASSESSMENT OF SAFETY ....................................................................................... 69 
8.1 
Safety Endpoints ........................................................................................................... 69 
8.2 
Safety Assessments ........................................................................................................ 69 
8.2.1 
Adverse Events ............................................................................................. 69 
8.2.1.1 
Severity Classification of Adverse Events .................................................. 69 
8.2.1.2 
Causality Classification ............................................................................... 70 
8.2.1.3 
Assessment of Expectedness ....................................................................... 70 
8.2.1.4 
Laboratory Test Abnormalities ................................................................... 70 
8.2.1.5 
Abnormal Physical Examination Findings ................................................ 70 
8.2.1.6 
Other Investigation Abnormal Findings .................................................... 70 


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8.2.2 
Recording and Follow up of Adverse Events ............................................. 70 
8.2.3 
Reporting of Serious Adverse Events ......................................................... 71 
8.2.4 
Pregnancy .................................................................................................... 73 
8.2.5 
Deaths .......................................................................................................... 73 
8.2.6 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse 
Events ........................................................................................................... 73 
8.2.7 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators ....... 74 
8.3 
Physical Examination ................................................................................................... 74 
8.4 
Vital Signs ...................................................................................................................... 74 
8.5 
Electrocardiograms ....................................................................................................... 74 
8.6 
Laboratory Safety Tests ............................................................................................... 75 
8.6.1 
Biochemistry ................................................................................................ 75 
8.6.2 
Hematology .................................................................................................. 76 
8.6.3 
Urinalysis ..................................................................................................... 76 
8.6.4 
Pregnancy Test ............................................................................................ 76 
8.6.5 
HIV-1, HepB, ParvoB19 ............................................................................. 76 
8.7 
Blood Volume ................................................................................................................ 76 
8.8 
Pharmacokinetic Evaluations of Busulfan .................................................................. 76 
9 
STATISTICAL METHODS ........................................................................................ 77 
9.1 
Background .................................................................................................................... 77 
9.2 
Design Considerations and Data .................................................................................. 77 
9.3 
Study Endpoints ............................................................................................................ 77 
9.3.1 
Primary Efficacy Endpoints ........................................................................ 77 
9.3.2 
Secondary Efficacy ...................................................................................... 78 
9.3.3 
Exploratory Efficacy Endpoints ................................................................. 78 
9.3.4 
Safety Endpoints .......................................................................................... 78 
9.4 
Sample Size Considerations ......................................................................................... 79 
9.5 
Analysis Populations ..................................................................................................... 79 
9.5.1 
Efficacy Population ..................................................................................... 79 
9.5.2 
Safety Population ........................................................................................ 79 
9.5.3 
Pharmacokinetic Population ...................................................................... 79 
9.6 
Statistical Methods ........................................................................................................ 79 
9.6.1 
Overview ...................................................................................................... 79 
9.6.2 
Subject Disposition ...................................................................................... 80 
9.6.3 
Baseline Characteristics .............................................................................. 80 
9.6.4 
Efficacy Analyses ........................................................................................ 80 
9.6.5 
Safety Analyses ............................................................................................ 81 
9.7 
Pharmacokinetic Analysis ............................................................................................ 81 
10 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ............................... 83 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................... 84 
11.1 Protocol Amendments ................................................................................................... 84 
11.1.1 
Protocol Amendments ................................................................................. 84 
11.1.2 
Protocol Deviations, Violations, and Exceptions ....................................... 84 
11.2 Dissemination of Information to Study Personnel ..................................................... 85 
11.3 Study Monitoring .......................................................................................................... 85 
11.4 Routine Monitoring ....................................................................................................... 85 
11.5 Audit and Inspection ..................................................................................................... 86 


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11.6 Data Quality Assurance ................................................................................................ 86 
12 
ETHICS .......................................................................................................................... 87 
12.1 Compliance with Good Clinical Practice and Ethical Considerations ..................... 87 
12.2 Informed Consent ......................................................................................................... 87 
12.3 Health Authorities and Independent Ethics Committees/Institutional Review 
Boards ............................................................................................................................ 88 
12.4 Confidentiality Regarding Study Subjects ................................................................. 88 
13 
DATA HANDLING AND RECORD KEEPING ....................................................... 89 
13.1 Data Recording of Study Data ..................................................................................... 89 
13.2 Data Management ......................................................................................................... 89 
13.2.1 
Investigator Responsibilities ....................................................................... 90 
13.2.2 
Sponsor Responsibilities ............................................................................. 90 
13.3 Record Archiving and Retention ................................................................................. 90 
14 
FINANCING AND INSURANCE ............................................................................... 91 
14.1 Contractual and Financial Details ............................................................................... 91 
14.2 Insurance, Indemnity and Compensation ................................................................... 91 
15 
REPORTING AND PUBLICATION OF RESULTS ................................................ 92 
15.1 Publication Policy .......................................................................................................... 92 
15.2 Clinical Study Report ................................................................................................... 92 
16 
REFERENCES .............................................................................................................. 93 
17 
APPENDICES ............................................................................................................... 95 
 


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LIST OF TABLES 
Table 1:  Schedule of Events – Screening to Day 24 .............................................................. 8 
Table 2:  Schedule of Events – Month 1 to Month 24 ......................................................... 11 
Table 3: Clinical Laboratory Tests ....................................................................................... 75 
 


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LIST OF FIGURES 
Figure 1: Study Scheme ......................................................................................................... 34 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS   
  
Abbreviation 
Definition  
ADA 
Adenosine deaminase 
AEs 
Adverse Events 
AIDS 
Autoimmune deficiency syndrome 
ALC 
Absolute lymphocyte count 
ANC 
Absolute Neutrophil Count 
AUC 
Area under the curve  
BM 
Bone marrow 
CA 
Competent Authorities 
CFR 
Code of Federal Regulations 
CFSE 
Carboxyfluorescein succinimidyl ester 
CGH 
Comparative genome hybridization 
CLIA 
Clinical Laboratory Improvement Amendments 
CMC 
Chemistry, manufacturing, and control 
CofA 
Certificate of Analysis 
CRO 
Contract Research Organisation 
CT 
Computer Tomography 
CTCAE 
Common terminology criteria for adverse events 
CSR 
Clinical Study Report 
d-AXP 
Adenine deoxyribonucleotides 
DFSP 
Dermatofibro sarcoma protuberans 
DMSO 
Dimethylsulfoxide 
DNA 
Deoxynucleic acid 
DSMB 
Data safety monitoring board 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eCRF 
Electronic Case Report Form 
EFS 
Elongation Factor 1α Short form 
ERT 
Enzyme replacement therapy 
FACS 
Fluorescence-activated cell sorting 
FDA 
Food and Drink Administration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
GOSH 
Great Ormond Street Hospital 
GRV 
Gammaretroviral vector 
GTMP 
Gene therapy medicinal product 
GvHD 
Graft versus host disease 
Hb 
hemaglobin 
HCG 
Human Chorionic Gonadotropin 


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HIV 
Human Immunodeficiency Virus 
HLA 
Human leukocyte antigen 
HSC 
Hematopoietic stem cell 
HSCT 
Hematopoietic stem cell transplant 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
INR 
International normalized ratio 
IO 
Insertional oncogenesis 
IRB 
Institutional Review Board 
IVIM 
Immortalization studies in vitro 
LTR 
Long terminal repeat 
LV 
Lentiviral vector 
MedDRA 
Medical Dictionary for regulatory Activities 
MUD 
Matched unrelated donor 
NIAID 
National Institute Allergy and Infectious Diseases 
NK 
Natural Killer 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
PEG 
Polyethylene-glycol 
PHA 
Phytohemagglutinin 
PICC 
Peripherally inserted central catheter 
PJP 
Pneumocystis jirovecii prophylaxis 
PK 
Pharmacokinetics 
PRBC 
Packed red blood cells 
PT 
Prothrombin 
PTT 
Partial thromboplastin time 
ddPCR 
Differential display polymerase chain reaction 
qPCR 
Quantitative polymerase chain reaction 
RBC 
Red Blood Cell(s) 
RCL 
Replication competent lentivirus 
RT 
Reverse transcriptase 
SAE 
Serious Adverse Event/Experience 
SAP 
Statistical analysis plan 
SAS® 
Statistical Analysis System® 
SCID 
Severe combined immunodeficiency 
SIN 
Self-inactivating 
SMX 
Sulfamethoxazole 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 


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TCR 
T-cell receptor 
TMP 
Trimethoprim 
TREC 
T-cell receptor excision circle 
UCB 
Umbilical cord blood 
UCL 
University College London 
UCLA 
University of California Los Angeles 
UK 
United Kingdom 
ULN 
Upper Limit of Normal Range 
US 
United States 
VCN 
Vector copy number 
WES 
Whole exome sequencing 
WHO 
World Health Organisation 
 


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1 
BACKGROUND INFORMATION 
1.1 
Introduction 
A brief overview of the disease and the protocol treatment (OTL-101) is provided in this 
section; however, a comprehensive review is supplied in the Investigator Brochure (IB). 
1.1.1 
Severe Combined Immunodeficiency due to Adenosine Deaminase Deficiency  
Severe combined immunodeficiency (SCID) is a heterogeneous group of inherited disorders 
characterised by a profound reduction or absence of T lymphocyte function (Chinn 2015). 
Adenosine deaminase (ADA)-SCID was identified almost four decades ago and represents 
approximately 15-20% of all cases of SCID. Adenosine deaminase is a ubiquitous enzyme 
whose deficiency results in metabolic toxicity. The main features of the disease are impaired 
differentiation and function of T, B and natural killer (NK) lymphocytes, recurrent infections, 
and failure to thrive. In addition, non-immunological abnormalities occur as the consequence 
of the systemic metabolic defect, indicating that the disease is more complex than other forms 
of SCID. Adenosine deaminase-SCID is a genetic disorder and mutations in the ADA gene 
cause a lack or the poor functioning of the ADA enzyme leading to accumulation of Ado, 
d-Ado, and adenine deoxyribonucleotides (d-AXP) in plasma, red blood cells (RBC), and 
tissues. The severity of genetic mutations and the residual ADA activity are usually related to 
the age of onset, clinical manifestations, and levels of d-AXP (Hirschhorn 1990). 
The majority of ADA-SCID patients are diagnosed in the first year of life. The patients rarely 
survive beyond 1 to 2 years unless immune function is restored, or contact with pathogens is 
avoided by creating a sterile environment around the patient (the so-called “bubble-children”). 
Lymphopenia, absence of both cellular and humoral functions, developmental delay, failure to 
thrive, and recurrent infections due to fungal, viral, and opportunistic agents are the key features 
of these early onset forms. These forms are essentially indistinguishable from other forms of 
SCID, with the exception for bony abnormalities in 50% of patients. 
1.1.2 
Treatment Options 
Two therapeutic methods are currently used for the treatment of ADA SCID, hematopoietic 
stem cell transplantation (HSCT) and ADA enzyme replacement therapy (ERT) but both 
options have significant limitations. This paved the way for the proposed OTL-101 treatment.  
1.1.2.1 
Hematopoietic Stem Cell Transplantation 
Hematopoietic stem cell transplantation from allogeneic human leukocyte antigen (HLA)-
compatible sibling donors is the treatment of choice for patients with SCID and other severe 
variants of primary immunodeficiency resulting in long-term survival of about 90% of patients 
and effective immune reconstitution (Ferrua 2010). However, as only 10–20% of patients are 
able to receive HSCT from an HLA-identical family member (Stephan 1993, Antoine 2003), 
transplants are often performed from mismatched family or matched unrelated donors (MUD). 
Despite improvements in pre-conditioning and post-transplant care, the use of less well matched 
HSCT is associated with reduced survival (Gaspar 2009, Hassan 2012) and delayed or 
suboptimal immune reconstitution in a significant fraction of surviving patients as a result of 
poor early engraftment or gradual decline in immune functions (Railey 2009). Complications 
such as Graft versus Host Disease (GvHD), autoimmune and inflammatory manifestations, 
persistent infections, and disease-related issues are often observed.  
If a matched sibling/family donor is unavailable, most ADA-SCID patients are treated with 
ADA ERT. Enzyme replacement therapy leads to metabolic correction and clinical 


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improvement, but the immunological reconstitution is often incomplete and dysregulated 
(Hershfield 1987, Gaspar 2009, Sauer 2012) and therefore individuals remain at risk of severe 
infection. This approach does not represent a curative treatment modality and is not always 
available as a long-term option. Enzyme replacement therapy with polyethylene-glycol (PEG)-
ADA was developed based on the concept that reduction of ADA substrate concentration in 
plasma results in lowering of intracellular concentrations of metabolites (Hershfield 1995). An 
intramuscular injection of PEG-ADA is administered weekly or bi-weekly, and is considered 
to be an excellent (although very expensive) short-term measure to stabilize children with 
ADA-SCID; however, prolonged use has associated risks as described in the IB. 
1.1.2.2 
Gene Therapy 
Gene therapy offers an alternative treatment for ADA-SCID whereby a correctly functioning 
copy of the ADA gene is introduced into hematopoietic stem cells (HSCs) that have been 
harvested from the patients themselves using a gene transfer vector. The transduced cells are 
then returned to the patient where they initiate immune reconstitution much like HSCs from a 
healthy donor. Because the cells originate from the patient, the likelihood of complications is 
reduced and there is no need to find a suitable donor. Importantly, unlike ERT, the treatment is 
curative. Earlier approaches relied on murine gammaretroviral vectors (GRV) to introduce the 
ADA gene into the patient’s cells. Lentiviral vectors (LV) are derived from components of the 
human immunodeficiency virus (HIV)-1 lentivirus and display several attributes that make 
them potentially more effective and safe than retroviral vectors (Naldini 1996, Zufferey 1998) 
as described in Section 1.4.2.  
No gene therapy treatment has been approved in United States (US) to date.  In Europe, 
Strimvelis® is approved for the “treatment of subjects with ADA-SCID, for whom no suitable 
HLA matched related stem cell donor is available”.  Strimvelis® is a GRV based ex vivo gene 
therapy treatment.  
1.2 
Name and Description of Protocol Treatment 
The protocol treatment (OTL-101) is a cell suspension comprising autologous CD34+ 
hematopoietic stem cells that are transduced ex vivo with Elongation Factor 1α Short form 
(EFS) LV encoding for the human ADA gene. 
To create OTL-101, autologous CD34+ HSCs from ADA-SCID subjects will be modified using 
EFS-ADA LV, a self-inactivating (SIN) LV expressing the ADA gene codon optimized for 
human use and regulated by EFS.  
The cryopreserved formulation will be thawed at the subject’s bedside and infused directly 
without any further manipulation.   
Orphan Drug Designation and Breakthrough Therapy designation were granted for this gene 
therapy medicinal product (OTL-101) from the Food and Drug Administration (FDA) on 
21 October 2014 and 17 August 2015, respectively. 
1.3 
Findings from Non-Clinical and Clinical Studies 
1.3.1 
Non-Clinical Studies 
The non-clinical studies demonstrated the EFS-ADA LV developed by the Sponsor is able to 
transduce different immortalized cell lines as well as CD34+ cells (the target cells for human 
use) from healthy donors and ADA-SCID patients. Transduction efficiency was at levels 
comparable to GRV used successfully in gene therapy clinical studies. However, significant 


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higher levels of ADA expression were seen per vector copy in transduced cells from umbilical 
cord blood (UCB) or bone marrow (BM) of normal or ADA-deficient individuals. In vivo, 
CD34+ cells from ADA-SCID patient bone marrow were transduced with the EFS LV encoding 
for the human ADA gene before being injected in immunodeficient mice. The studies 
demonstrated that the transduced cells engrafted and differentiated in a human xenograft model. 
Finally, a proof-of-concept study was performed in an experimental ADA deficient mouse 
model. This study demonstrated that cells transduced with the EFS LV encoding for the human 
ADA gene enabled T and B cell recovery; in addition to ADA enzymatic activity. Overall these 
results demonstrate the biological activity of CD34+ cells transduced ex vivo with EFS-ADA 
LV.  
1.3.2 
Toxicology Studies 
Toxicology studies were performed to assess safety of the OTL-101 product. Due to its nature, 
a particular focus was made on assessment of potential genotoxicity. A first round of studies 
demonstrated that the EFS LV (encoding the human ADA gene) is not mutagenic and did not 
induce tumors in in vivo models. In addition, in a separate study, the proliferative capacity of 
clones of cells transduced with the vector was assessed and was found to be negligible. 
Therefore, OTL-101 is considered to have a safe profile.  
Overall these results demonstrate that the EFS LV (encoding the human ADA gene or a reporter 
green fluorescent protein gene) is not mutagenic and does not induce tumours in in vivo models.  
1.3.3 
Clinical Studies 
Two parallel Phase I/II studies investigating the clinical effectiveness and safety of EFS-ADA 
LV-modified autologous CD34+ cells have been performed to date.  
A first study, entitled: “Autologous Transplantation of Bone Marrow CD34+ Stem/Progenitor 
Cells after Addition of a Normal Human ADA cDNA by the EFS-ADA LV for Adenosine 
Deaminase-Severe Combined immunodeficiency”) at University of California Los Angeles 
(UCLA) in the US began in May 2013. Currently, 20 subjects have been treated under this 
protocol (as of 14 October 2016) and a single subject has been treated under an expanded access 
program. 
A second study, conducted in parallel, entitled: “Phase I/II, non-controlled, open-label, 
non-randomised, single-centre study to assess the safety and efficacy of EFS-ADA LV 
mediated gene modification of autologous CD34+ cells from ADA-deficient individuals” began 
in August 2012 at Great Ormond Street Hospital (GOSH) University College London (UCL) 
in the United Kingdom (UK). Currently, 10 subjects have been treated under this protocol and 
a further 10 subjects have also been treated under compassionate use in the UK (as of 14 
October 2016).   
In both studies, subjects receive PEG-ADA ERT and Busulfan conditioning before receiving a 
fresh formulation of EFS-ADA LV-transduced CD34+ HSCs . Following treatment, subjects 
continue to receive PEG-ADA ERT for a further 30 days post OTL-101  infusion. This 
continuation of ERT during the peri-transplant period potentially maximizes engraftment of 
cells when the niche is low in cytotoxic substrates and minimizes the extent to which the subject 
becomes transiently more immune-deficient prior to the immune reconstitution induced by the 
gene therapy.   
In both studies, subjects have received comparable doses, characterized by similar viability and 
percent CD34+ HSCs, as well as in transduction efficacy (vector copy number (VCN)) and 


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efficiency (vector positive colony forming unit analysis) in the OTL-101 product. The number 
of vector copies detected over time in peripheral blood cells after OTL-101 infusion is 
consistent across the two studies. Most importantly, there appears to be extremely consistent 
immune reconstitution outcomes between the two studies: cell counts for all of the T and B cell 
populations and subpopulations demonstrate consistent and stable immune reconstitution over 
time post GTMP infusion at 6, 12, and 24 months in both studies. As per 31 March 2016 data 
cut, the overall survival for the both studies is currently 100%. The event free survival for the 
second study (GOSH/UCL, UK) is currently 93.3%. One subject from the second study was 
clinically indicated to restart ERT with PEG-ADA, although none from the first study (UCLA) 
has required a restart of PEG-ADA (N=18, as per 31 March 2016 data cut). 
No serious unexpected adverse events have been reported in both studies to date. There have 
been no vector-related complications and no instances of leukoproliferation, as reported in GRV 
studies for other immune deficiencies. There have been no cases of autoimmunity with the EFS-
ADA LV reported to date. The safety profile of the two ongoing studies have been remarkable 
and the benefit/risk profile remains positive. 
Since both studies are still ongoing, formal analysis comparing both studies has not been 
completed.  
1.4 
Known and Potential Risks and Benefits 
1.4.1 
Potential Benefits 
Adenosine deaminase-SCID represents a paradigmatic approach for gene therapy for inherited 
blood borne disorders. The results of clinical studies from 2000 onwards indicate that gene 
therapy with non-myeloablative conditioning is associated with significant clinical clinical 
benefit and should be considered for all ADA-SCID patients lacking an HLA-identical 
sibling/family donor (Aiuti 2002, Aiuti 2009, Gaspar 2011, Candotti 2012). However, LV offer 
several potential advantages over murine GRV used in the previous studies, including the 
recently European Union approved treatment, Strimvelis®, GlaxoSmithKline. There is no gene 
therapy treatment for ADA-SCID approved in the US to date. 
Lentiviral vectors lack dependence on cell division such that the culture period and exposure to 
cytokines can be minimized and HSC activity can theoretically be preserved.  
Durable, life-long clinical benefit is highly dependent on the successful engraftment of 
genetically modified long term repopulating HSC.  The improved correction of HSCs should 
result in improved immune recovery due to correction of both T and B cell populations. 
Most importantly, LV have potential for a more favorable safety profile. Insertional 
oncogenesis (IO) is a possible consequence of the integration of retroviral vectors into the 
human genome, in which transcription of the therapeutic gene is under the control of the viral 
enhancer promoters present in the long terminal repeat (LTR). In previous GRV studies, 
oncogenesis has been caused by the Moloney Murine Leukemia Virus gene delivery vector 
integrating and transactiving an adjacent oncogene (Hacein-Bey-Abina 2008, Howe 2008, 
Braun 2014). Thus far, none of the ADA-SCID subjects treated with GRV (N=42) have had 
evidence of IO despite integration events in oncogenes associated with IO in other types of 
SCID patients treated with GRV genetically-modified autologous HSC. Nevertheless, the use 
of alternative vector systems such as the LV with the SIN LTR configuration have improved 
integration profiles (Biffi 2011) and allows for the use of safer, less transactivating cellular 
promoters. Immortalization studies in vitro (IVIM) have shown that the potential of SIN LV 


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with cellular promotors to transactivate neighboring genes is significantly diminished (Modlich 
2006, Modlich 2009).  Furthermore, the EFS cellular promoter has resulted in negligible 
outgrowth of clones in the IVIM assay (Zychlinski 2008, Carbonaro 2014).  
Therefore the use of LV and EFS-ADA LV, in particular, can thus promote similar or even 
improved immune recovery with the potential for enhanced genetically-modified HSC activity 
and an enhanced safety, and therefore represents a significant advantage in furthering the use 
of gene therapy for ADA-SCID. 
Transplants of autologous CD34+ HSCs transduced with the EFS-ADA LV have resulted in 
clinical benefits in the vast majority of subjects treated to date. It is too early to determine 
whether these subjects will have durable, life-long ADA gene expression/enzyme production 
and immune function, but the results indicate 100% survival, with all but one subject stopping 
PEG-ADA ERT. The longest follow-up is 58 months. The ideal outcome is for the treated 
subjects to develop improved immune function and not require either a rescue bone marrow 
transplant or further PEG-ADA ERT in the long-term.  
The cryopreserved formulation of OTL-101 will be implemented within this protocol to 
improve the limitations of the fresh cell formulation, which only remains stable for 6 hours after 
manufacture. The rationale of this cryopreserved formulation is to allow the OTL-101 treatment 
to be administered at a local clinic, minimizing the travel burden on the subject and the family, 
to enable standardization of the Busulfan conditioning of subjects prior to dosing and to allow 
the infusion of a fully quality controlled tested and released OTL-101 product.  
The aim of this protocol is to expand the safety and efficacy database for OTL-101 and support 
analytical chemistry, manufacturing, and control (CMC) comparability between fresh and 
cryopreserved OTL-101 formulations.   
1.4.2 
Potential Risks   
1.4.2.1 
Potential Risks Related to the Protocol Treatment 
The major risks to be considered with OTL-101 treatment are: 
1) Insertional oncogenesis (and leukemia) - risks related to IO have occurred during 
clinical studies of gene transfer using GRV in subjects with X-linked SCID and Wiskott 
Aldrich Syndrome, but not ADA-SCID thus far. Studies have demonstrated that the 
risks of insertional mutagenesis are lower with LV that lack strong LTR 
enhancer/promoter sequences (as in the EFS-ADA LV) than with GRV with an intact 
LTR. In current LV subjects (39 subjects treated to date), there have been no cases of 
oncogenicity. Pre-clinical in vitro insertional mutagenesis studies have confirmed that 
the LV used in this clinical program has a lower risk versus the GRV. 
2) Replication-competent virus exposure - there is a small possibility and risk from this 
gene therapy treatment that undetected Replication Competent Lentivirus (RCL) might 
be present and cause an active HIV infection in the subjects. To date there has been no 
instance of RCL in subjects treated with autologous genetically modified HSC with a 
GRV or LV. 
3) Germ-line transmission of vector sequences - as the EFS-ADA LV will be used to 
transduce ex vivo CD34+ cells, rather than a direct administration to subjects via 
parenteral route, the probability of germ-line transmission is considered to be negligible. 


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4) Allergic/immunological responses to cell processing excipients - stem cell factor and 
thrombopoietin are used to maintain stem cell viability and to promote gene transfer 
during the ex vivo transduction process. When these factors are administered 
parenterally, they may have untoward immunologic or allergic consequences such as 
thrombocytopenia or allergic reactions. 
5) Risk of using cryopreserved bone marrow stem cells. Although in vitro tests showed 
that cryopreserved genetically-modified bone marrow CD34+ HSC were similar to the 
fresh cells used in previous clinical studies, it is possible that the cryopreserved 
formulation of OTL-101 will not work as well in subjects, resulting in poorer recovery 
of immune function or even the need to receive back the unmodified bone marrow that 
was saved as back-up.   
6) As thawed OTL-101 is infused, an unusual odor or bad taste in the mouth may be 
experienced. This odor or taste is from the substance dimethylsulfoxide (DMSO) used 
to protect the cells when OTL-101 is cryopreserved . Some subjects may cough or feel 
slightly nauseated or chilled when they receive thawed product containing DMSO. In 
rare cases, DMSO may cause side effects such as low blood pressure, fast heart rate, or 
shortness of breath. Subjects will be monitored closely during the OTL-101 infusion. 
7) Immune response against “normal” ADA – as a result of "immunisation" to normal 
human ADA produced from the transgene. Most subjects will have previously received 
bovine PEG-ADA ERT, which is more likely to be immunogenic than human ADA. 
Also, development of significant inhibitory antibodies has been relatively rare in 
patients treated with PEG-ADA ERT alone. 
8) Other immunological risks - onset of autoimmunity is of concern in post-treatment 
ADA-SCID patients. 
9) Immune dysregulation - gene transfer research may result in only partial improvement 
of the immune system. While this is unlikely to be a problem, it is possible that partial 
improvement leading to an "imbalance" of the immune system could have adverse 
effects. Two children treated in the UCLA study using fresh OTL-101 formulation 
developed an inflammatory response with fevers and rashes requiring hospitalization 
about 4-12 months post OTL-101 infusion. This reaction may have been associated with 
the response to gene therapy treatment, with temporary immune dysregulation occurring 
as the immune system developed. Both children were treated with steroids and have 
fully recovered, suggesting the inflammatory reaction may be temporary. Both children 
remain free of PEG-ADA therapy. 
10) Failure of the treatment. 
These risks are fully described in the IB. 
1.4.2.2 
Potential Risks Related to Bone Marrow Harvesting 
CD34+ cells will be isolated from BM. There is potential risk associated with the BM harvesting 
procedures, which entails general anaesthesia, multiple percutaneous aspirations from the 
posterior pelvic bone and a blood cell transfusion.   
 
 


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1.4.2.3 
Potential Risks Related to Concomitant Therapy  
Busulfan 
Busulfan is used for conditioning prior to the re-infusion of the HSCs. The Busulfan dose to be 
used in this clinical study will target a specific area under the curve (AUC), which will ensure 
more precise dosing and may reduce the risks of toxicity. The risks attached to Busulfan are 
minimal, although there is a very small possibility of Busulfan-related cancer.  
More common risks associated with Busulfan at higher doses include nausea, vomiting, 
diarrhoea, constipation, loss of appetite, mouth sores, stomach/abdominal pain, dizziness, 
swelling ankles/feet/hand, flushing, headache, trouble sleeping and a period of neutropaenia. 
However, the above systemic side-effects have not been seen at the proposed Busulfan dose for 
this study. 
In the Sponsor's experience to date, there have been no Busulfan-related serious adverse events 
(SAEs). 
Pegylated-ADA 
The withdrawal of PEG-ADA, which is required 1 month after OTL-101 administration, can 
have adverse effects on immunity, as well as on other organ systems. It is possible that a very 
severe infection may develop during this time, which could be fatal if the subject does not 
respond to OTL-101 infusion.  
In the Sponsor's experience to date, there have been no severe infections nor causalities, related 
to stopping PEG-ADA ERT, 1 month after OTL-101 infusion as per protocol. 
1.4.2.4 
Other Potential Risks 
Participation in this clinical study may have deleterious effects on subsequent attempts at 
allogeneic HSCT due to the "immunization" to normal human ADA produced from the 
transgene. Gene therapy for ADA-SCID using autologous stem cells, albeit with other vectors, 
has now been performed in 79 subjects, with over 15 years of follow-up. The results show that 
these subjects did not experience any permanently debilitating nor deleterious side effects, 
suggesting that the risk of long term side effects is low. 
As in any new form of therapy, there may be risks that are unknown or not anticipated.   
1.5 
Selection of Protocol Treatment Dosage 
Cryopreserved autologous CD34+ HSCs transduced ex vivo with EFS LV encoding for the 
human ADA gene will be administered at a dose range of 2.0 x 10e6 to 20 x 10e6 CD34+ 
cells/kg. The selected dose is similar to the standard dose of allogeneic HSCT. One infusion of 
a target minimum of 2.0 x 10e6 CD34+ cells/kg of OTL-101 is deemed sufficient to restore 
ADA activity. 
A more detailed description of OTL-101 administration is presented in Section 3.4 and 
Section 3.7.  
1.6 
Compliance Statement 
The clinical study will be conducted in compliance with the requirements of independent ethics 
committees/institutional review boards (IEC/IRB), informed consent regulations, the 
Declaration of Helsinki and the International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) Guidelines. Any episodes of noncompliance will be documented. The 
electronic data capture (EDC) system will comply with the FDA, 21 Code of Federal 


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Regulations (CFR) Part 11, Electronic Records, Electronic Signatures, and FDA, Guidance for 
Industry: Computerized Systems Used in Clinical Trials. In addition, the study will adhere to 
all local regulatory requirements. Before initiating a clinical study, the Investigator/institution 
should have received a written and dated approval/favourable opinion from the IEC/IRB for the 
study protocol/amendment(s), written informed consent forms, any consent form updates, 
subject emergency study contact cards, subject recruitment procedures (e.g. advertisements), 
any written information to be provided to subjects and a statement from the IEC/IRB that they 
comply with GCP requirements. The IEC/IRB approval must identify the protocol version as 
well as the documents reviewed. 
After IEC/IRB approval, changes will require a formal amendment. Once the clinical study has 
started, amendments should be made only in exceptional circumstances. Changes that do not 
affect subject safety or data integrity are classified as administrative changes and generally do 
not require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval on 
administrative changes will be obtained if required by local/site IEC/IRB. 
The Investigator is responsible for performing the clinical study in accordance with this 
protocol and the ICH and GCP guidelines and for collecting, recording, and reporting the data 
accurately and properly. Agreement of the Investigator to conduct and administer this clinical 
study in accordance with the protocol will be documented in separate study agreements with 
the Sponsor and other forms as required by national authorities. 
The Investigator is responsible for ensuring the privacy, health, and welfare of the subjects 
during and after the clinical study and must ensure that trained personnel are immediately 
available in case of a medical emergency. The Investigator must be familiar with the 
background to, and requirements of, the study and with the characteristics and properties of 
OTL-101 as described in the IB.  
1.7 
Population to be Studied 
The population to be studied in this protocol is ADA-SCID subjects who are aged ≥30 days to 
<18 years of age, lacking a medically eligible HLA-matched sibling donor.  
Subjects should meet all of the inclusion criteria specified in Section 4.1 and none of the 
exclusion criteria defined in Section 4.2. 
1.8 
Relevant Literature and Data 
Not applicable. 


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2 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1 
Purpose of the Study 
The primary purpose of the study is to further explore the efficacy and safety of gene therapy 
with OTL-101, as an alternative treatment option for ADA-SCID patients. The current 
treatment of choice for ADA-SCID patients is a HLA-matched sibling/family HSCT, however 
the number of patients eligible for this procedure ranges from 10 to 20% (Hassan 2012). 
OTL-101 is a gene therapy that aims to use genetically modified autologous CD34+ HSC from 
the individual patients to improve the outcome of transplantation to a wider population. Two 
ongoing Phase I/II studies use a fresh cell formulation that is required to be infused within 
6 hours of manufacture. A cryopreserved formulation of OTL-101 was developed to enable the 
treatment, once manufactured from the individual subjects’ CD34+ cells, to be frozen and 
stored until the OTL-101 product is fully released (i.e. all quality control testing performed), 
allowing the subject to receive targeted conditioning prior to transplantation. The cryopreserved 
formulation will also permit the treatment to be shipped and delivered to a local expert site, 
thereby reducing the travel burden on the recipient and their family. The advantages of a 
cryopreserved formulation are not limited to shelf-life and include; an improved manufacturing 
process; improved quality of the OTL-101 product, thus allowing for all quality control tests to 
be performed and to permit standardisation of preconditioning regimens prior to OTL-101 
infusion. Three subjects have already been treated with cryopreserved cells (with a different 
cryoprotectant as the one used under this protocol); two patients treated under Compassionate 
Use Program and one patient treated as an exemption in the US. All three subjects demonstrated 
immune reconstitution and are currently event free indicating success of the OTL-101 
treatment.  
Additionally, the purpose of this study is to support the analytical CMC comparability of the 
cryopreserved versus fresh OTL-101 formulation with an interim analysis of clinical outcomes 
from the five subjects, based on predictive parameters at 6 months of overall survival and event 
free survival: gene-marked granulocytes, ADA enzyme activity, and absolute CD3+ cell 
number. 
These parameters are deemed adequate predictors at 6 months as well as long-term predictors 
for overall survival and event free survival based on the sponsor experience and previous gene 
therapy treatment.  
 Gene- marked granulocytes 
After genetic modification of autologous CD34+ hematopoietic stem cells (HSCs) and 
reinfusion to the subject, the presence of genetically modified cells both in the periphery 
and in the BM can be used as a bona fide marker of the existence and the persistence of 
transduced cells in the subject. Genetically modified cells engraftment is usually 
assessed in the blood compartment that is readily accessible, via evaluation of the pro-
viral VCN by qPCR in various blood cell populations (especially the granulocytes). 
Thus, by measuring the VCN in granulocytes we are able to assess the correction of 
long-lived genetically modified progenitors in the BM (as VCN in BM CD34+ cells 
shows a close positive correlation with VCN in granulocytes). In our ongoing studies 
with fresh product formulation, over 3 months after administration of OTL-101 the 
granulocyte VCN rises and is then stable up to 2 years after gene therapy treatment 
(based on our current follow up), therefore if a plateau is reached at 6 months (above 


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1/10,000 cells), it is predictive of sustained effect. These data are similar between both 
ongoing Phase I/II studies.  
 ADA Enzyme Activity in red blood cells  
ADA enzyme activity in RBC reflects normalized/corrected biological activity of 
transduced CD34+ HSCs. As per experience from fresh formulation studies, there is 
peak observed at 3 months post OTL-101 infusion and then the level stabilizes for up to 
24 months, based on our current data. Therefore, erythrocyte ADA enzyme activity 
above baseline/pre-treatment level compared to post treatment level at 6 months is 
predictive of long-term efficacy. 
 CD3+ cells number 
The engraftment of genetically modified CD34+ HSCs in this disease setting should 
give rise to immune system development. Based on experience from previous clinical 
trials based on gene transfer to CD34+ HSCs, longitudinal copy number quantitative 
determination in T cells revealed that the T cell pattern was stable with time. It is 
important to remind that T cell normal values were reached between 2 to 5 months after 
OTL-101 infusion in subjects. Therefore, corrective levels of T cells were stable from 
6 months to 10 years after OTL-101 infusion. Data suggests that once engraftment of 
genetically modified HSCs occurs and immune development is seen, CD3+ cells 
>200/mm3, there is no diminution of immune cell development (Hacein-Bey-Abina 
2010). The data from the clinical studies using the fresh formulation of OTL-101 concur 
with these findings. Clinically, this also means that once immune recovery is seen and 
is sustained, the need to restart ERT is negated. 
2.2 
Study Objectives 
2.2.1 
Primary Study Objectives 
There are two primary objectives for this study aimed to determine; 
1. The success of treatment at the subject level (“responder analysis”) 6 months post OTL-
101 infusion, defined as:  
a) Evidence of erythrocyte ADA enzyme activity above baseline/pre-treatment level 
(>0 Units), 
b) Evidence of immune reconstitution (absolute number of CD3 cells ≥200/mm3),   
c) Detectable gene-marked granulocytes by differential polymerase chain reaction 
(dPCR)/qPCR (≥1/10,000 cells). 
This 6 month data will be used to compare the proportion of responders among subjects 
treated with the cryopreserved population with that in a comparable population obtained 
from one of the ongoing Phase I/II studies using the fresh formulation. 
2. The overall survival and event free survival at 12 months among ADA-SCID subjects 
treated with a cryopreserved formulation of OTL-101.  
Overall survival is defined as the proportion of subjects alive. Event-free survival is 
defined as the proportion of subjects alive with no “event”, an “event” being the 
resumption of PEG-ADA ERT or the need for a rescue allogenic HSCT, or death. 


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2.2.2 
Secondary Study Objectives 
The secondary objectives to be evaluated among ADA-SCID subjects treated with a 
cryopreserved formulation of OTL-101 include confirmation of the overall survival and event 
free survival at 24 months, safety evaluation including infection rates, quality of life and 
immune response.  
2.2.3 
Exploratory Study Objectives  
Exploratory objectives include the measurement of biological correlates of efficacy including; 
percentage of gene marking in peripheral blood granulocytes, vector integration analysis, 
quantification of clonal diversity of vector integrants, T-cell receptor excision circle (TREC) 
and fluorescence-activated cell sorting (FACS) for T-cell receptor (TCR) V-β family use, ADA 
enzyme activity in erythrocytes, total adenine nucleotides in erythrocytes, and immune 
reconstitution. 


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3 
STUDY DESIGN 
3.1 
General Design and Study Scheme 
This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical study 
designed to assess the efficacy and safety of OTL-101 cryopreserved formulation administered 
in ADA-SCID subjects aged between ≥30 days to <18 years of age, who are not eligible for an 
HLA-matched sibling/family donor and meeting the inclusion/exclusion criteria. This study 
aims to recruit 10 evaluable subjects. 
The aim of this clinical study is also to assess the success of treatment at the subject level 
(“responder analysis”) 6 months post OTL-101 infusion, using predictive criteria for overall 
survival and event free survival and to compare this with data obtained from one of the ongoing 
Phase I/II clinical studies using the fresh formulation of OTL-101. 
Once informed consent has been obtained, the subjects enrolled will be screened to determine 
their full eligibility for participation over 1 month.  
Eligible subjects will be hospitalized to undergo the harvesting of autologous CD34+ cells. A 
backup harvest of non-transduced CD34+cells will be obtained during the harvesting procedure 
to be used in the event of i) product damage during the thawing of OTL-101 that would prevent 
infusion of the product although the patient has already been conditioned or ii) lack of 
engraftment/hematopoietic reconstitution 42 days post infusion of OTL-101. A failure of 
hematologic reconstitution is defined as persistent ANC < 200/µl or platelets < 20,000/µl on 
three independent and consecutive determinations over at least ten days after day 42 from the 
day of OTL-101 infusion.  
OTL-101 is a cryopreserved formulation of autologous CD34+ hematopoietic stem cells 
transduced ex vivo with EFS LV encoding for the human ADA gene (OTL-101). To enable the 
release of the OTL-101 product for infusion, the cryopreserved OTL-101 product must meet 
various quality control criteria for safety, identity, viability, purity and potency. If OTL-101 
meets the acceptance criteria and is released, the subjects will be readmitted for conditioning 
with Busulfan. The OTL-101 product will be infused after a minimal interval of at least 24 hours 
following the completion of Busulfan administration. Subjects may remain as an in-patient 
following autologous transplantation for approximately three to 35 days.  
For subjects who have successfully received the OTL-101 product, PEG-ADA ERT use will be 
evaluated at the 1 Month follow-up visit (30 days post treatment ± 7 days) and discontinued at 
Day 30 (-3/+15) after the transplant. Hematologic reconstitution will be assessed at Day 42 (± 
7 days), and in the event of no reconstitution the backup HSC sample will be administered, if 
the investigator believes this is in the subject’s best interest. The subjects will then be seen at 
regular intervals to review their history, perform examinations and draw blood samples at 
Months 3, 6 and 9 (all ± 2 weeks) as well as Months 12, 18 and 24 (all ± 4 weeks). Any 
medically-indicated interventions, including the need to reinstate PEG-ADA ERT, will be 
assessed at all follow-up visits after Month 1. Hematopoietic reconstitution will be assessed 
again at the Month 6 visit and if there is still no evidence of cellular recovery, the subject will 
be given ERT and/or HSCT, if available and deemed appropriate by the Investigator. After the 
Month 24 visit, the subjects will have completed the study and may enter a long term registry.  
This study will include three statistical analyses:  


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1. The first analysis will compare the success/failure data 6-months post OTL-101 infusion 
between fresh and cryopreserved OTL-101 formulations.  The success/failure of OTL-101 
will be defined by the three critera listed in the primary objectives (Section 2.2.1). This data 
will be compared with available data from one of the ongoing Phase I/II studies using the 
OTL-101 fresh formulation. This will support the CMC comparability data between OTL-
101 cryopreserved and fresh formulations. Secondary and exploratory endpoints will also 
be described. 
2. The second analysis will determine the 12 month overall survival and event free survival 
for all subjects. Secondary and exploratory endpoints,  as well as baseline characteristics, 
subject disposition, and safety data will also be described. 
3. The third and final analysis will be performed to determine the overall survival and event 
free survival for all subjects 24 months post OTL-101 infusion.  Secondary and exploratory 
endpoints, as well as baseline characteristics, subject disposition, safety and Busulfan 
pharmacokinetic (PK) data will also be described. 
Efficacy analyses will be primarily descriptive in nature. 
The study will be overseen by an independent Data Safety Monitoring Board (DSMB), who 
will review the nature and severity of emerging safety data during the study. The DSMB will 
also liaise with the Principal Investigator directly to ensure the safety of participants during the 
study. The Investigator, subjects and their families will be informed about any significant 
emerging safety data. 
The study schema is provided in Figure 1 below. 
 
 
Figure 1: Study Scheme 
# Backup sample will be taken in the event of product damage or failure to achieve hematopoietic reconstitution. 
* The timeframe for the cryopreservation process may vary. 
Abbreviations: ADA= Adenosine deaminase, AUC = area under the curve, BM = bone marrowm, EFS = Elongation Factor 1α 
Short form, ERT = enzyme replacement therapy, LV = lentivirus vector. 


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3.2 
Primary and Secondary Evaluations and Endpoints 
3.2.1 
Primary Efficacy Evaluations and Endpoints 
The primary efficacy endpoints for this study include: 
1. Evaluation of OTL-101 at 6 months, post OTL-101 infusion, in support of CMC 
assessing comparability of cryopreserved and fresh formulations, by evaluating the 
success of therapy for each subject based on all three parameters listed below and their 
thresholds being met: 
a) Erythrocyte ADA enzyme activity above baseline/pre-treatment level (>0 Units),  
b) Absolute CD3+ T-cell counts ≥200/mm3, and  
c) Peripheral blood samples positive for vector sequences by qPCR(≥1/10,000 cells). 
Please note:Subjects not meeting any one criterion will be designated a failure (non-
responder). Further details are described in Section 3.6.1.  
This data will be compared with subject data from the Phase I/II study using the fresh 
formulation. 
2. Evaluate the overall survival and event free survival 12 months post OTL-101 infusion. 
Overall survival is defined as the proportion of subjects alive. Event-free survival is 
defined as the proportion of subjects alive with no “event”, an “event” being the 
resumption of PEG-ADA ERT or the need for a rescue allogenic HSCT, or death. 
Full descriptions of the efficacy assessments are presented in Section 7.1. 
3.2.2 
Secondary Efficacy Evaluations and Endpoints 
Secondary efficacy endpoints include: 
 Evaluation of the overall survival and event free survival 24 months post OTL-101 
infusion. 
 Use of immunoglobulin replacement therapies prior to and after OTL-101 infusion.  
 Performance outcomes and quality of life measured by the Karnofsky/Lansky scale and 
questions relevant to general well-being, school attendance and ability to practice sports, 
respectively.  
 Rates of severe infections/opportunistic infectious episodes, defined as infections or 
severe infections requiring hospitalization or prolonging hospitalization and/or 
documented infections by opportunistic pathogens (e.g. interstitial pneumonia, 
intractable diarrhoea). 
 Response to tetanus vaccination. 
 Immune reconstitution: T and B cell reconstitution. 
Full descriptions of the efficacy assessments are presented in Section 7.1.2. 
3.2.3 
Safety Evaluations and Endpoints 
The safety and tolerability of OTL-101 will be assessed throughout the study by evaluating 
adverse events (AEs), clinical laboratory test results, vital signs measurements, 
electrocardiogram (ECG), physical examination results, and concomitant medication usage.  In 


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addition, the safety of OTL-101 will be assessed through monitoring infections and any 
emergence of replication competent lentivirus, monoclonal expansion or leukemia due to 
chosen vector. 
Full descriptions of the safety assessments are presented in Section 8. 
3.2.4 
Exploratory Endpoints and Evaluations 
The exploratory endpoints will include laboratory correlates of efficacy that will be used to 
assess the level of gene correction, engraftment and immune reconstitution:   
 Quantification of clonal diversity of vector integrants.  
 TREC and FACS for TCR V-beta family use. 
 Percentage gene marking in peripheral blood cells. 
 Adenosine deaminase enzyme activity in erythrocytes.  
 Total adenine nucleotides in erythrocytes. 
 Vector integration analysis.  
 Immune reconstitution 
o Absolute Lymphocyte Count. 
o Absolute numbers of T, B, NK lymphocytes in peripheral blood. 
o T lymphocyte proliferative responses to mitogen (PHA) and to antigens (tetanus 
toxoid after vaccination)  
o Serum immunoglobulin levels (IgG, IgA and IgM).   
3.3 
Randomization and Blinding 
This is a non-randomised study and there is no blinding. 
3.4 
Protocol Treatment and Dosage 
OTL-101 comprises autologous, CD34+ HSCs transduced ex vivo with EFS-ADA LV, 
formulated and cryopreserved in CryoStor® CS5. The OTL-101 product will be manufactured 
using HSCs purified from the subject’s BM. To enable its release for administration, the OTL-
101 product must meet the acceptance criteria for a series of Quality Control assays of safety, 
identity, viability, purity and potency.   
The dose of genetically-modified cells comprises a single administration of 2.0 to 20 x 10e6 
CD34+ cells/kg.  
A detailed description of the procedures for the administration of the OTL-101 product is 
provided in Section 3.7. 
3.4.1 
Protocol Treatment  
OTL-101 is manufactured under Good Manufacturing Practice (GMP) guidelines, using the 
subject’s own CD34+ HSCs. OTL-101 is formulated in Cryostor CS5, filled into cryobags, 
cryopreserved and then stored in the vapor phase of liquid nitrogen (LN2). Final product dose 
and infusion volume calculations are described in Section 6.1.1 and Section 17: Appendix 1. 
On the day the subject is to be infused, the cryopreserved OTL-101 product bag(s) will be 
transported to the bedside in a dry nitrogen shipping container. Immediately prior to infusion, 


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the bag(s) will be removed from the shipping container and thawed using either a plasma 
thawing device or a pre-warmed water bath (using sterile water). For thawing, the OTL-101 
product bag(s) will be placed in an outer bag sleeve in case of a leak. After thawing, the OTL-
101 product bag(s) will be attached to a sterile intravenous line fitted with a three-way stopcock 
and sterile syringe. The cells will be pulled into the syringe from the bag(s), the stopcock will 
be turned and then the contents of the syringe will be pushed through the intravenous line into 
the recipient. The OTL-101 product will be labeled as the Study Agent. Please note: when more 
than one bag is required to be infused, only one OTL-101 product bag per hour will be 
administered (Section 6.1.1).  
3.5 
Duration of Subject Participation 
The study will consist of the following periods:  
- 
Screening: approximately 2 months 
- 
Bone marrow harvest of autologous cells: 1 day 
- 
Manufacture and release of OTL-101: 30-45 days 
- 
Pre-conditioning prior to transplant: 4 days 
- 
OTL-101 administration: this may entail up to 4-6 weeks of in-patient stay, either at 
UCLA or the subject may be transferred from UCLA to a home hospital at 3-7 days 
post-transplant for the pursuit of subsequent hospitalization for up to 4-6 weeks.   
- 
Post treatment follow-up: 2 years after the administration of OTL-101.  
The total study duration for each subject is estimated to be up to 2 years and 4 months.  
The study will start when the first subject has signed the informed consent form. Each subject’s 
participation in the study will end at the time of his/her last visit, or death. The study will have 
ended after the last subject has completed the last study visit at 24 months post OTL-101 
infusion, however the primary endpoints for this study will  be overall survival and event free 
survival at 12 months post OTL-101 infusion.   
On completion of their participation in this study, subjects will be invited and encouraged to 
participate in a registry for long term data collection according to guideline recommendations. 
3.6 
Stopping Rules and Discontinuation Criteria 
3.6.1 
Subject Stopping Rules and Criteria for Discontinuation  
If any one of the following instances occur, all new enrollments to the protocol or the treatment 
of subjects will be halted, pending investigation of the cause and discussion with the DSMB for 
final recommendation/decision:   
1. If there is one death or two Grade 4 treatment-related toxicities (see Section 8.2.1.1) for 
severity definitions). Please note Grade 4 Busulfan-related hematologic AEs such as 
transient leukopenia, anemia, thrombocytopenia that are anticipated, and have resolved 
within 42 days of transplant will not be considered a stopping rule.  
2. If two subjects experience prolonged unresponsive pancytopenia, defined as an initial 
failure of hematologic reconstitution which does not improve following the 
administration of the subject's autologous back-up cells. A failure of hematologic 
reconstitution is defined as persistent ANC < 200/µl or platelets < 20,000/µl on three 


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independent and consecutive determinations over at least ten days after day 42 from the 
day of OTL-101 infusion.   
If, at Day 90 following the initial infusion of OTL-101, the failure of hematologic 
reconstitution persists after the subject's autologous back-up cells have been infused, 
the subject can be said to be experiencing prolonged unresponsive pancytopenia.  The 
subject should then receive standard care for pancytopenia. 
3. If RCL is detected, and confirmed in one subject.   
4. If a subject in the study develops hematological proliferative, monoclonal expansion or 
malignant disease (excluding dermatofibrosarcoma protuberans (DFSP)). A thorough 
investigation of the cause of the proliferation, expansion or malignancy, including 
proviral integration analysis, will be carried out.   
5. If there are three non-responders, as defined in the primary endpoint criteria 
(Section 3.2.1), who will be designated an OTL-101 treatment failure and will be 
withdrawn from the study to permit further treatment with PEG-ADA ERT, or HSCT if 
available.  
Any such finding will be discussed with the Sponsor and DSMB, and an agreement should be 
made and documented to detail the conditions under which the study can be resumed before 
enrolling the next subject. Evaluations of the study endpoints of subjects already enrolled and 
who have received OTL-101, will continue.   
A subject may discontinue participation in the study at any time for any reason (for example 
lack of efficacy, withdrawal of consent, AE). The Investigator and/or Sponsor can withdraw a 
subject from the study at any time for any reason (for example protocol violation or deviation 
as defined in Section 4.3, non-compliance with the protocol, or AE).  
The Investigator should assess the ongoing risk-benefit ratio of each subject during their 
participation in the study, in consideration of any AEs and the potential benefits of continued 
treatment with OTL-101 or any alternative therapies.    
3.6.2 
Early Study Termination 
There are no formal rules for early termination of this study. During the conduct of the study, 
SAEs will be reviewed (see Section 8.2.1.) as they are reported from the study centre(s) to 
identify safety concerns.  
The Sponsor may terminate this study at any time. Reasons for termination may include but are 
not limited to, the following: 
 The incidence or severity of AEs in this or other relevant studies point to a potential 
health hazard for study subjects, 
 Insufficient subject enrolment, 
 Any information becoming available during the study that substantially changes the 
expected benefit risk profile of the study treatments. 


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3.7 
OTL-101 Storage, Preparation, Administration, and Accountability 
3.7.1 
OTL-101 Storage and Security 
OTL-101 is manufactured from the individual subject’s bone marrow CD34+ HSCs. The 
Subject’s BM will be harvested at the clinical site and then transferred to a GMP compliant 
manufacturing facility for onward processing. At the GMP facility CD34+ cells will be isolated, 
transduced, formulated, filled into cryobags and then cryopreserved. The autologous, 
cryopreserved OTL-101 treatment will be stored as part of a controlled inventory at ≤-135°C 
in the vapor phase of LN2 until released for administration to the subject. The storage of OTL-
101 will be in accordance with UCLA standard procedures. Access to OTL-101 will only be 
permitted for individuals designated by the Investigator who are responsible and trained staff 
listed in the site personnel log at the clinical site. For release, the product must meet defined 
acceptance criteria for Quality Control assays of safety, identity, viability, purity and potency.  
During the first harvest, a backup sample of non-transduced CD34+ cells will be retained in i) 
the event of product damage or below product release specifications of the OTL-101 that would 
prevent the infusion taking place even though the patient has already been conditioned or ii) 
lack of engraftment/hematopoietic reconstitution at 42 days post OTL-101 infusion (see 
Section 3.4). In the event that a second BM harvest is required, the same storage and security 
procedures will be followed.  A second backup sample is only required if the first backup is not 
reliable, e.g. if contamination of the initial marrow harvest had occurred. 
3.7.2 
OTL-101 Production 
OTL-101 is manufactured using autologous CD34+ HSC purified from BM as the starting 
material. Following receipt of the subjects BM from the clinical site, OTL-101 will be 
manufactured at the GMP facility according to the following process:  
1. On Day 1:  
i. 
CD34+ HSC from the BM harvest are purified by immunomagnetic selection. 
ii. 
The CD34+ HSC are placed into a pre-stimulation culture to initiate the OTL-101 
manufacturing process.   
NOTE: On Day 1, a back-up fraction of mononuclear cells will be cryopreserved.  
This back-up will constitute ≥3.0 x 10e7 mononuclear cells/kg. 
2. On Day 2: 
i. 
The CD34+ HSC are placed in co-culture with the EFS-ADA LV to begin 
transduction. 
3. On Day 3: 
i. 
The transduced cells are harvested, washed, formulated into Cryostor® CS5, and 
filled into cryobags. 
ii. 
The cryobags are cryopreserved using a controlled rate freezer. 
iii. 
Following completion of the controlled rate freezing process, the cryobags are 
stored in the vapor phase of LN2 at ≤-135°C. 


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3.7.3 
OTL-101 Administration 
The clinical site will inform the GMP facility when the subject will require the OTL-101 
treatment to be delivered. OTL-101 will be transported to the clinical site in a dry nitrogen 
shipping container at least 24 hours prior to the start of Busulfan administration.  The OTL-101 
product will be labeled as the Study Agent. 
Following the receipt of the shipping container from the GMP facility, responsible and trained 
staff (listed in the site personnel log at the clinical site) will document receipt and follow the 
instructions below and as described in Section 17: Appendix 1:   
 Evaluate the outer packaging for damage, 
 Verify the paperwork attached to the exterior of the package (including the certificate 
of analysis CofA), 
 Hold the shipping container in secure storage at ≤-135°C , according to UCLA standard 
procedures, until requested by the Investigator. Storage instructions are specified in 
Section 3.7.1. 
Immediately prior to administration, clinical site staff will: 
 Cross-check the subject's details against the paperwork accompanying the shipping 
container, 
 Open the container and retrieve the temperature monitor (if the lid does not have a 
visible readout) and ensure that no out-of-temperature alarms have been triggered. 
When the team is ready to infuse OTL-101, the cryobag(s) will be removed from the shipping 
container and the team will immediately ensure: 
 A visual inspection of integrity, 
 Verify (by two individuals) that the label is correct and confirm that the cryobag is 
intended for the particular subject. 
Final product dose and infusion volume calculations are specified in Section 6.1.1. The 
cryobag(s) will then be thawed using either a plasma thawing device or a pre-warmed water 
bath (using sterile water). For thawing, the OTL-101 product bag will be placed in an outer bag 
sleeve in case of any fracture.    
When thawed, the OTL-101 product bag will be attached to a sterile intravenous line containing 
a three-way stopcock and sterile syringe. The contents will be pulled into the syringe from the 
bag, the stopcock will be turned and then the contents of the syringe will be infused 
intravenously into the subject’s peripherally inserted central catheter (PICC) line or central 
venous catheter. Please note: when more than one bag is required to be infused, only one OTL-
101 product bag per hour will be administered (Section 6.1.1). If more than one bag is needed 
to achieve the dose, the weight of the subject must be higher than 4 kg to comply with 
recommended limit of DMSO per kg body weight per day prior to infusion. 
If any circumstance occurs which prohibits delivery of the OTL-101 treatment to the subject, 
details on how to return OTL-101 to the GMP facility are specified in Section 17: Appendix 1. 


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3.7.4 
OTL-101 Accountability 
OTL-101 is manufactured on an individual basis for subject-specific use, and all steps for 
manufacturing, storage, final preparation, release and transport are documented by GMP 
facility staff. A specific form for the recording of the product traceability can be found in 
Section 17, Appendix 1 (Global Investigational Product Accountability Log).  All of the product 
thus manufactured will be administered to the subject on one occasion only. The OTL-101 
treatment must be administered by a Investigator or designated clinician/registered nurse (who 
is listed on the site personnel log) and must be documented in the subject notes and the clinical 
care unit records.  
When handling OTL-101 at the clinical site, the Investigator or designated individual (who is 
listed on the site personnel log) must follow the instructions in Section 17: Appendix 1. The 
Investigator, or designated individual, must maintain an inventory of all OTL-101 product 
received from the GMP facility, administered or dispensed to the subject, returned and 
destroyed. The OTL-101 treatmentmust not be infused to any person who is not the biological 
owner of the stem cells. 
On request, or at completion or termination of the study, all prepared and unused OTL-101 must 
be returned to the GMP facility for destruction (unopened cryobags). Bags opened and partially 
used will be discarded at the clinical site. Written authorization from the Sponsor must be 
obtained prior to the destruction of any OTL-101 productat the clinical site. 
Labeling of the OTL-101 product will comply with current GMP guidelines and local regulatory 
requirements. 
It is the Investigator/institution’s responsibility to establish a system for handling the OTL-101 
productso as to ensure that: 
 Deliveries of such products are correctly received by a study designated person (e.g., a 
pharmacist or study coordinator), 
 Deliveries are verified and documented on the appropriate OTL-101 accountability 
form(s), 
 Certificates of delivery and return are signed, by the Investigator or the  designate, and 
copies retained, 
 The OTL-101 productis handled and stored safely and properly, 
 OTL-101 is only administered by trained and designated staff, 
 The OTL-101 productis only administered to study subjects in accordance with the 
protocol requirements. 
3.8 
Maintenance of Randomisation and Blinding 
This is a non-randomised study with no blinding. 
3.9 
Source Data Recorded on the Case Report Form 
All data will be recorded in the electronic case report form (eCRF). As required by GCP, the 
Sponsor assigned monitor will verify, by direct reference to the source documents, that the data 
required by the protocol are accurately reported in the eCRF. The source documents must, as a 
minimum, contain a statement that the subject is included in a clinical study, the date that 
informed consent was obtained prior to participation in the study, the identity of the study, 


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diagnosis and eligibility criteria, visit dates (with subject status), OTL-101 administration, and 
any AEs and associated concomitant medications.   
The items recorded directly in the eCRF and considered as source data must be described at 
each site in a site-specific document signed by the Investigator and filed in the Investigator site 
file. For this study the questionnaire would be considered source data entered directly in the 
study records. 
The definitions of source data and source documents are given below:  
Source Data: all original records and certified copies of original records of clinical findings, 
observations, or other actions necessary for reconstruction and evaluation of the study. Source 
data are contained in source documents (original records or certified copies) and should include 
demography, medical history, physical examination, vital signs, evolution of clinical picture, 
AEs start and stop dates, and withdrawal of a subject and reason. 
Source Documents: Original documents, data and records (for example hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic 
negatives, microfilms or magnetic media, X-rays, subject files, and records kept by the 
pharmacy, laboratories and medicotechnical departments involved in the clinical study).  
The subject must have consented to their medical records being viewed by the Sponsor’s 
authorized personnel/representative, and by local, and possibly foreign, Competent Authorities 
(CAs). This information is included in the informed consent form. 


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4 
SELECTION AND WITHDRAWAL OF SUBJECTS 
4.1 
Inclusion Criteria 
All subjects must fulfill the following criteria to be included in the study: 
1. Provision of written informed consent prior to any study related procedures. In this study 
consent must be provided by the parents/legal guardians and, where applicable 
according to local laws, a signed assent from the child, 
2. Subjects ≥30 days and <18 years of age, 
3. With a diagnosis of ADA-SCID based on: 
Evidence of ADA deficiency, defined as: 
i.  Decreased ADA enzymatic activity in erythrocytes, leukocytes, skin fibroblasts, or 
in cultured fetal cells to levels consistent with ADA-SCID as determined by the 
reference laboratory, or 
ii.  Identified mutations in ADA alleles consistent with a severe reduction in ADA 
activity, 
Evidence of ADA-SCID based on either:  
i. 
Family history of a first order relative with ADA deficiency and clinical and 
laboratory evidence of severe immunologic deficiency, or  
ii. 
Evidence of severe immunologic deficiency in subjects prior to the institution of 
immune restorative therapy, based on 
 
Lymphopenia (absolute lymphocyte count (ALC) <400 cells/µL) OR absence 
or low number of T-cells (absolute CD3+ count < 300 cells/µL), or 
 
Severely 
decreased 
T 
lymphocyte 
blastogenic 
responses 
to 
phytohemagglutinin (either <10% of lower limit of normal controls for the 
diagnostic laboratory, or <10% of the response of the normal control of the 
day, or stimulation index <10), or 
 
Identification of SCID by neonatal screening revealing low TREC levels. 
4. Ineligible for matched family allogeneic BM transplantation, defined as the absence of 
a medically eligible HLA-identical sibling or family donor, with normal immune 
function, who could serve as an allogeneic bone marrow donor. 
5. Females of child-bearing age will be required to provide a negative pregnancy test 
30 days prior to Visit 2. 
6. Subjects and their parents/legal guardians must be willing and able to comply with study 
restrictions and to remain at the clinic for the required duration during the study period 
and willing to return to the clinic for the follow up evaluation as specified in the 
protocol. 
4.2 
Exclusion Criteria 
Subjects will not be eligible for the study if any of the following criteria are met:  
1. Ineligible for autologous HSCT as per clinical site criteria. 


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2. Other conditions which in the opinion of the Principal Investigator and/or 
Co-Investigators, contraindicate the harvest of bone marrow, the administration of 
Busulfan and the infusion of transduced cells, or which indicate an inability of the 
subject or subject’s parent/legal guardian to comply with the protocol. 
3. Hematologic abnormality, defined as: 
- Anemia (Hb <8.0 g/dl).  
- Neutropenia (ANC <500/mm3). Note: ANC <500 with absence of 
myelodysplastic syndrome on bone marrow aspirate and biopsy and normal 
marrow cytogenetics are acceptable for eligibility.    
- Thrombocytopenia (platelet count <50,000/mm3, at any age). 
- Prothrombin time or international normalized ratio (INR) and partial 
thromboplastin time (PTT) >2 x upper limit of normal (ULN) (subjects with a 
correctable deficiency controlled on medication will not be excluded).  
- Cytogenetic abnormalities on peripheral blood or bone marrow or amniotic fluid 
(if available). 
- Prior allogeneic HSCT with cytoreductive conditioning.   
 
4. Pulmonary abnormality, defined as: 
- Resting O2 saturation by pulse oximetry <90% on room air.  
- Chest X-ray indicating active or progressive pulmonary disease. Note: Chest 
X-ray indicating residual signs of treated pneumonitis is acceptable for eligibility. 
5. Cardiac abnormality, defined as: 
- Abnormal ECG indicating cardiac pathology. 
- Uncorrected congenital cardiac malformation with clinical symptoms. 
- Active cardiac disease, including clinical evidence of congestive heart failure, 
cyanosis, hypotension.     
- Poor cardiac function as evidenced by left ventricular ejection fraction <40% on 
echocardiogram.  
6. Neurologic abnormality, defined as: 
- Significant neurologic abnormality revealed by examination.   
- Uncontrolled seizure disorder. 
7. Renal abnormality, defined as: 
- Renal insufficiency: serum creatinine ≥1.2 mg/dl (106 µmol/L), or 
≥3+ proteinuria.    
- Abnormal serum sodium, potassium, calcium, magnesium or phosphate levels at 
>2 x ULN. 
8. Hepatic/gastrointestinal abnormality, defined as: 


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- Serum transaminases >5 x ULN. 
- Serum bilirubin >2 x ULN. 
- Serum glucose >1.5 x ULN. 
9. Oncologic disease, defined as: 
- Evidence of active malignant disease other than DFSP2.. 
- Evidence of DFSP expected to require anti-neoplastic therapy within the 5 years 
following the infusion of genetically corrected cells (if anti-neoplastic therapy has 
been completed, a subject with a history of DFSP can be included). 
- Evidence of DFSP expected to be life limiting within the 5 years following the 
infusion of genetically corrected cells. 
10. Known sensitivity to Busulfan. 
11. Confirmation of an infectious disease by deoxyribonucleic acid (DNA) PCR positive at 
time of screening assessment for the following: 
- HIV-1, 
- Hepatitis B, 
- Parvovirus B19. 
12. The subject is pregnant or has a major congenital anomaly. 
13. Is likely to require treatment during the study with drugs that are not permitted by the 
study protocol. 
14. The subject has previously received another form of gene therapy. 
4.3 
Subject Withdrawal Criteria  
In accordance with the Declaration of Helsinki (and with the applicable country’s approval), 
each subject is free to withdraw from the study at any time for any reason. The Investigator also 
has the right to withdraw a subject from the study in the event of concurrent illness, AEs, 
pregnancy (see Section 8.2.4), or other reasons concerning the health or wellbeing of the 
subject, or in the event of a lack of cooperation. In addition, a subject may be withdrawn from 
the study as described in Section 3.6.  
Should withdrawal occur, all efforts will be made to complete and report the observations up 
to the time of withdrawal as thoroughly as possible. A complete final evaluation should be made 
at the time of the subject’s withdrawal (see Section 5.1.8) and an explanation given of why the 
subject is withdrawing or being withdrawn from the study. The reason for and date of 
withdrawal from the study must be recorded in the eCRF. If a subject withdraws consent, every 
attempt will be made to determine the reason. If the reason for withdrawal is an AE or a 
clinically significant laboratory test abnormality, monitoring will continue until the event has 
                                                          
2 Dermatofibrosarcoma protuberans is a rare, locally invasive tumor with low metastatic 
potential that has been reported to be present in some ADA-SCID patients.   
 


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resolved or stabilized, or until a cause unrelated to OTL-101 or study procedure has been 
determined. The specific AE or test result(s) must be recorded in the eCRF. According to the 
protocol, all evaluations specified for the early termination visit should be carried out. 
4.4 
Discontinuation/Withdrawal Procedures 
If a subject is withdrawn from the study (i.e. ceases participation in the study prior to completion 
of the assessments planned in the protocol), the primary reason should be recorded in the eCRF. 
Withdrawal due to AEs should be distinguished from withdrawal due to insufficient response. 
Where possible the subject should be encouraged to return for the early termination visit 
assessment to ensure required follow-up is organised for ongoing AEs that may be considered 
related to OTL-101. 
The Investigator will provide or arrange for appropriate follow up (if required) for subjects 
withdrawing from the study, and will document the course of the subject’s condition. Where 
the subject has withdrawn due to an AE the Investigator should follow the procedures 
documented in Section 5.1.8 in order to assess the safety of the OTL-101 treatment.  


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5 
STUDY PROCEDURES 
The schedule of observations and assessments during the study are summarised in Table 1 and 
Table 2. 
5.1 
Study Visits 
5.1.1 
Screening (Visit 1) 
Written informed consent must be obtained prior to any screening procedures (unless routine 
medical care assessments are being used within 60 days of the harvest visit as screening 
assessments). A signed and dated informed consent form will be obtained from the parent/legal 
guardian (according to local law requirements), and a signed and dated assent form will be 
obtained from each subject (aged ≥7 years), if required according to local regulations. 
Evaluations obtained as part of routine medical care and performed during the screening period 
may be used in place of the study specific evaluations if performed within 60 days of the harvest 
visit (Visit 2: Assessment B), except for cytogenetics, which may be used independently from 
the time they have been performed. The parents/legal guardians of each subject will 
acknowledge and agree to the possible use of this information for the study by giving informed 
consent. 
After informed consent is obtained, subjects who are screened will be assigned a 3 digit 
identification number consecutively.  
All screened subjects must be identifiable regardless of eligibility. The Investigator will 
maintain a list of subject numbers and names with their identification numbers in order to ensure 
full traceability. Any subject who fails screening may be re-screened at a later date and the same 
3 digit identification number will be used. 
The study will start with a screening period of up to 60 days prior to harvest (Visit 2: 
Assessment B).. The screening visit (Visit 1) is defined as the visit during which the informed 
consent form is signed, before any study-related procedures.  
The following assessments will be performed during the screening period so as to determine 
the subject’s eligibility:   
- Demographic data: date of birth and sex; ethnicity and/or race according to individual 
country requirements, 
- Complete medical history, including history of ADA-SCID: date of first symptoms, 
primary diagnosis and date, therapies and responses, stage of disease at diagnosis and 
at screening.  
- Confirmation of ADA-SCID (if not performed before the screening period) based upon 
biochemical and/or molecular demonstrations of ADA deficiency and T lymphopenia 
at the time of the initial diagnosis. 
- Physical examination, including the recording of height (cm), weight (kg), and vital 
signs (temperature, pulse rate, respiratory rate and blood pressure). Temperature can be 
measured as per standard clinic practice. 
- Blood tests: 
 
o Biochemistry (see Table 3),  
o Hematology (see Table 3),  


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o Prothrombin Time or INR and PTT,  
o Peripheral blood or bone marrow for cytogenetic analysis (if cytogenetic testing has 
not been performed on cells from amniocentesis) by karyotype, Comparative 
Genome Hybridization (CGH), whole exome sequencing (WES) or other and may 
be used independently from the time they have been performed, 
o HIV-1, HepB and ParvoB19, 
o Serum human chorionic gonadotropin (HCG) pregnancy test, if the subject is a 
female of child-bearing age (to be performed within 30 days of Visit 1), 
- Urinalysis, 
- Electrocardiogram, 
- Echocardiogram, 
- Chest X-ray (+/- computer tomography (CT) scan if previous evidence of severe chest 
disease), 
- Pulse oximetry,    
- Biopsy of any suspicious skin lesions, 
- Evaluation of quality of life, as measured by the Karnofsky/Lansky scale and questions 
relevant to general well-being, school attendance, and ability to practice sports, 
respectively, 
- Evaluation of severe infections or opportunistic infectious episodes. 
In addition, the collection of AEs and concomitant medication will start after signature of the 
informed consent form. 
If a subject meets the eligibility criteria, he/she will be enrolled and scheduled for CD34+ HSCs 
harvest. 
5.1.2 
Autologous Bone Marrow Harvest Period (Visit 2) 
The source of CD34+ HSCs will be BM. The harvesting of autologous bone marrow will be 
performed for subjects who meet the inclusion and exclusion criteria at Visit 1. Two 
assessments will be performed during the hospital admission for BM harvest. This planned 
hospitalization for protocol procedures will not constitute a SAE. 
Pre-harvest procedure (Assessment A) 
Once a date for harvest has been scheduled, the pre-harvest procedure will commence up to 
5 days beforehand. The results of these pre-operative tests must meet the requirements that 
permit the harvest of autologous BM, according to standard guidelines in the institution. 
Pre-harvest tests include:  
 Medical history since screening (including AEs and concomitant medications) and 
physical examination, 
 Weight (this measurement will be used for OTL-101 product dose calculation), 
 Hematology (see Table 3), 
 Prothrombin or INR and PTT, 


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 Biochemistry; including magnesium and phosphate (see Table 3), 
 Type and cross-matching for one unit of packed RBC (PRBC) (to be performed within 
the period required by the blood bank), 
 Serum HCG (pregnancy test) if female of child-bearing age (and if more than 28 days 
have elapsed since the screening test), 
 Urinalysis. 
Bone Marrow Harvest (Assessment B) 
For BM harvesting, a central venous access device will be required (if not already in place) for 
ease of phlebotomy and drug administration. The decision between PICC line, a tunneled 
central venous catheter, or an implanted subcutaneous access device will be made by 
discussions with subjects parents and line placement surgeon. A PICC line or central venous 
line may instead be placed as a separate procedure with appropriate sedation or during the 
general anesthesia for the BM harvest.  
The harvest procedure will involve a bilateral BM aspiration in the posterior iliac crests, where 
a total volume required should be between 15-20 ml/kg of the subjects body weight. The BM 
sample will be directly transported to the GMP manufacturing location. 
Compatible irradiated PRBC (10 to 15 cc/kg) may be transfused following the completion of 
marrow harvest, if considered appropriate by the Investigator.  
If the subject is otherwise well, he/she may be discharged to home, 1-2 days after harvest. 
If the first bone marrow harvest fails to collect sufficient HSCs for transplantation or if the 
product fails to meet the release criteria, the Investigator may perform a second harvest. 
Screening studies will not be repeated unless 1 year or more has passed from the time of the 
first harvest. 
Any AEs and concomitant medication use should be recorded. 
Backup Sample 
A back up sample will be taken at the first harvest procedure, in the event of damage during 
thawing, failure to meet product release specifications or lack of engraftment at 42 days post 
OTL-101 infusion (see Section 3.4), and must constitute ≥3.0 x 10e7 mononuclear cells/kg.   
The backup sample will be cryopreserved, and CD34+ cells will be isolated from the remainder. 
The backup harvest will consist of  non-transduced cells that will be retained if required. A 
second backup sample is only required if the first backup is not reliable, e.g. if contamination 
of the initial marrow harvest had occurred. 
5.1.3 
Baseline (Visit 3) 
Pre-Conditioning (Assessment C) 
After BM harvest and if the autologous OTL-101 product has met the release criteria 
(Section 3.7.1), additional baseline samples must be collected for the following tests within 
1 week before the first administration of Busulfan:  
 Physical examination, including vital signs (temperature, pulse rate, respiratory rate and 
blood pressure). Temperature can be measured as per standard clinic practice, 


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 Hematology (see Table 3), 
 Prothrombin or INR and PTT, 
 Biochemistry (see Table 3), 
 Serum HCG (pregnancy test) if female of child-bearing age (and if more than 28 days 
have elapsed since the screening test), 
 Urinalysis, 
 Pulse oximetry, 
 Interval history (including routine review of systems, including infectious symptoms 
(e.g., fever), AEs and concomitant medications), 
 Measurement of immune function:    
o Absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, CD19+ 
B-lymphocytes and CD56+/CD16+ (or CD56+/CD3-) NK cells, 
CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ (memory) T cells, 
o TREC levels,  
o TCR Vβ usage,  
o lymphocyte response to phytohemagglutinin (PHA) (if sufficient cells), 
o Serum immunoglobulin (IgG, IgA, IgM). 
Please note: the above immune function tests can be performed at any point after 
provision of consent/assent and prior to Busulfan administration in younger subjects if 
deemed appropriate by the Investigator. 
 Peripheral blood mononuclear cells (PBMC) and serum banking for RCL determination.  
These tests can be performed at any time following BM harvest (Visit 2: Assessment B) 
and prior to OTL-101 administration (Visit 3: Assessment F) in younger subjects if 
deemed appropriate by the Investigator. 
 Measurements of erythrocyte ADA enzymatic activity and erythrocyte deoxyadenine 
nucleotide levels.   These tests can be performed at any time following BM harvest (Visit 
2: Assessment B) and prior to OTL-101 administration (Visit 3: Assessment F) in 
younger subjects if deemed appropriate by the Investigator. 
The Investigator must ensure a PICC line or central venous catheter is in place prior to the start 
of Busulfan conditioning.  
5.1.4 
Busulfan Conditioning (Visit 3) 
These visits will be performed as part of the subject’s hospital admission at Visit 3 (Baseline). 
Two doses of Busulfan will be administered to the subject as follows: 
Day -4 to -3 (Assessment D): The subject’s weight will be recorded to calculate the dose of 
Busulfan. Busulfan will be administered intravenously at a dose of 3 mg/kg infused over 
3 hours. Blood samples will be taken immediately at the end of the infusion, and then +1, 2, 4, 
8, and 13 hours after the end of infusion, in order to calculate the AUC. These samples may be 
drawn +/-15 minutes of the time-point, but the actual time with reference to the administration 


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of Busulfan should be recorded to enable an accurate AUC calculation. Adverse events and 
concomitant medications will be recorded. 
Day -2 to -1 (Assessment E): Busulfan dose adjusted for AUC taken on Day -3. The clinical 
pharmacist will calculate the AUC from the first dose of Busulfan based on the measured serum 
levels, to calculate the amount needed for second dose to reach total net AUC of 4,900 (this is 
equivalent to 20mg*h/L) (see Section 6.2.1.1). Blood samples will be taken before the second 
infusion (to confirm the previous Busulfan has cleared the blood), immediately at the end of 
the infusion, and then +1, 2, 4, 8, and 13 hours after the end of infusion, in order to re-calculate 
the AUC. These samples may be drawn +/-15 minutes of the time-point, but the actual time 
with reference to the administration of Busulfan should be recorded to enable an accurate AUC 
calculation. The PK samples will ensure the subject receives the minimum acceptable dose to 
achieve good engraftment but at the same time minimising the exposure to the conditioning 
regimen. The tailoring of conditioning treatment is only made possible by using the 
cryopreserved formulation within this protocol due to the prolonged stability. Adverse events 
and concomitant medications will be recorded. 
Dose Calculation 
The calculated AUC from the first Busulfan dose is inserted into the formula below to determine 
the amount of Busulfan required for the second dose in mg/kg.   
(1st dose (mg/kg))/Calculated 1st dose AUC = (Total Dose (mg/kg))/[Target AUC (4,900 
uM*min)] 
(1st dose (mg/kg))/Calculated 1st dose AUC) x Target AUC (4,900)] = (Total dose (mg/kg))  
(1st dose (mg/kg)) x (Target AUC(4,900)]/Calculated 1st dose AUC) = (Total dose (mg/kg)) 
Calculated total dose (mg/kg) – 1st dose (mg/kg) = 2nd dose (mg/kg). 
 
For example 1st dose = 3 mg/kg and the AUC = 3,200 uM*min 
3 mg/kg x 4,900/3,200 = 4.6 mg/kg total dose. 
4.6 mg/kg – 3.0 mg/kg = 1.6 mg/kg for second dose. 
AUC is calculated from serum Busulfan level values using pKsolver3. 
5.1.5 
OTL-101 Administration (Visit 3) 
This visit will be performed as part of the subject’s hospital admission at Visit 3 (Baseline) and 
following completion of the conditioning regimen.  
Day 0 - day of transplantation (Assessment F) 
- Before administration of OTL-101; 
                                                          
3 (https://www.ncbi.nlm.nih.gov/pubmed/20176408 ) Zhang Y1, Huo M, Zhou J, Xie S.  PKSolver: An add-in 
program for pharmacokinetic and pharmacodynamic data analysis in Microsoft Excel. Comput Methods 
Programs Biomed. 2010 Sep;99(3):306-14. PMID: 20176408 


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o The subject will be pre-medicated with an appropriate dosage of acetaminophen 
(e.g., 10 to 15 mg/kg orally), and diphenhydramine (e.g., 0.5 to 1.0 mg/kg 
intravenous or orally), 15 to 90 minutes prior to infusion.  
o Steroids and anticonvulsants will be prepared before infusion and ready to infuse 
if necessary. 
o Serum HCG (pregnancy test) if female of child-bearing age must be performed 
prior to infusion. 
- Monitoring before, during and after the intravenous infusion, as per institution 
standards, of vital signs and adverse events, including allergic reaction(s). Subjects are 
required to be closely monitored for signs of allergic reactions/immune reactions, by 
looking at clinical parameters (fever, rash, difficulties to breath, tremors, tachycardia, 
arrythmias).  
- Administration of OTL-101 product (Day 0) at least 24 hours after the end of the 
infusion of the last dose of non-myeloablative conditioning (Busulfan). For 
administration instructions see Section 17: Appendix 1.  
- Adverse events and concomitant medications will be recorded. 
5.1.6 
Immediate Post-transplant Tests and Care (Visit 3)  
These visits will be performed as part of the subject’s hospital admission which commenced at 
the baseline visit (Visit 3). During the first month after administration of the OTL-101treatment, 
the following tests will be performed on the day after treatment (Day 1) and then twice weekly 
thereafter. 
These visits may be performed +/- 2 days from the scheduled date. 
Post-transplant (Assessments G to M)  
- Interval history (including routine review of systems, including infectious symptoms 
(e.g., fever), AEs and concomitant medications), 
- Hematology (see Table 3), 
- Biochemistry (see Table 3). 
The subjects will be kept in hospital for close monitoring for up to 24 days post OTL-101 
infusion. However, they may be kept in for longer if this is deemed clinically necessary and 
depending on the medical care they require (e.g. central venous catheter care, infections, 
protective isolation, nutritional support), the consequences of toxicity due to Busulfan, the 
engraftment of transduced cells, and immune reconstitution. Alternatively, for subjects who are 
not geographically close to the clinical site who are clinically stable, post-transplant care may 
be transferred to the home physician provided the identified clinician agrees to assume this 
post-transplant monitoring. The home physician will be asked to record all protocol specific 
assessments on a form provided. This data will be transmitted to the Investigator for data entry 
into the eCRF. Monitoring can be assured as either an in-patient or out-patient. In the latter 
case, the subject will stay in hospital for a minimum of 3 days after OTL-101 infusion at the 
investigational site treatment facility, before being transferred. This planned discharge and 
subsequent readmission to a second facility would not meet the criteria for being reported as a 
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After the transplant, the subject will be maintained on prophylactic antibiotics and intravenous 
gamma-globulin replacement as needed and/or as per institutional procedures, and will be 
closely monitored. Any concomitant medication administered to the subject should be recorded 
in the eCRF. A subject will be readmitted to hospital when deemed clinically necessary. These 
reasons include, but are not limited to: fever and neutropenia, bacteremia, possible central 
venous access device infection, or other infections that require initial parenteral antibiotics, 
organ failure, extreme adverse social situations, and/or bleeding.   
5.1.7 
 Follow-Up (Visits 4 to 11) 
Following discharge from the hospital after transplantation, follow-up visits will be performed 
to determine whether the genetically modified cells have engrafted and are able to produce 
mature lymphoid and hematopoietic cells containing and expressing the ADA gene, and the 
extent and time-course of immune reconstitution.   
The subjects will be evaluated at the following time-points: Month 1, 3, 6, 9, 12, 18, and 24 
(end of study visit). Because of the large number of blood tests planned and the limited volumes 
of blood that can be obtained from young children, it may not be possible to perform every 
scheduled investigation listed below at each time-point. Therefore, the priority for the ranking 
of blood tests will be as per the order presented for each visit. The following examinations will 
be performed: 
Month 1/Day 30 (Visit 4 - +/- 1 week)) 
- Physical examination, vital signs, height, weight and interval history (including routine 
review of systems, including infectious symptoms (e.g., fever), AEs and concomitant 
medications), 
- Use of PEG-ADA and IgG replacement therapy will be documented. Please note 
PEG-ADA administration will be stopped at this visit, 
- Hematology and biochemistry panels,  
- Monitoring for severe infections and/or opportunistic infectious episodes at each study 
visit, 
- Immune function testing;  
o 
Determination of absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, 
CD19+ B-lymphocytes and CD56/CD16+ (or CD56+/CD3-) NK cells, 
CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ (memory) T cells, 
o 
Serum immunoglobulin (IgG, IgA, IgM). 
- Gene transduction/expression; 
o 
Measurement of ADA expression in erythrocytes by ADA enzymatic assay and 
deoxyadenine nucleotides in RBC. 
Day 42 (Visit 5 - +/- 1 week)  
The Day 42 assessment will use laboratory parameters to confirm if hematologic reconstitution 
has occurred. A failure of hematologic reconstitution is defined as persistent ANC < 200/µl or 
platelets < 20,000/µl on three independent and consecutive determinations over at least ten days 
after day 42 from the day of cell infusion. If hematologic reconstitution has not taken place by 
Day 42 the backup HSC sample will be processed according to the instructions in Section 3.7 


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and re-infused to overcome more severe myelosuppressive effects of the conditioning regimen. 
If the failure of hematologic reconstitution persist after the back-up marrow has been given 
through day 90 from the initial infusion of the cell product, prolonged unresponsive 
pancytopenia will exist. 
If the Investigator considers the use of the back up HSC sample is not in the best interests of 
the subject, rescue medication, as per standard institute protocols, will be implemented. Any 
treatment administered to the subject will be recorded in the eCRF. Adverse events will also be 
recorded. 
Month 3 (Visit 6 - +/- 2 weeks) 
- Physical examination, vital signs, height, weight and interval history (including routine 
review of systems, including infectious symptoms (e.g., fever), AEs and concomitant 
medications), 
- Assessment of re-initiation of PEG-ADA therapy and use of IgG replacement therapy 
will be documented. Please note: subjects should have discontinued PEG-ADA 
treatment at Visit 4 (Month 1/Day 30),  
- Hematology and biochemistry panels,  
- RCL assay in PBMC, 
- Serum to be banked for possible Western blot testing for RCL (testing performed if the 
RCL assay in PBMC returns a positive result), 
- Monitoring for severe infections and/or opportunistic infectious episodes at each study 
visit, 
- Vector integration analysis, 
- Immune function testing; 
o 
Determination of absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, 
CD19+ B-lymphocytes and CD56/CD16+ (or CD56+/CD3-) NK cells, 
CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ (memory) T cells: 
o Serum immunoglobulin (IgG, IgA, IgM), 
- Gene transduction/expression; 
o Measurement of the proportion of cells containing the inserted ADA gene in PBMC 
and granulocytes and/or lineage-sorted cells, 
o Measurement of ADA expression in erythrocytes by ADA enzymatic assay and 
deoxyadenine nucleotides in RBC. 


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Month 6 (Visit 7 - +/- 2 weeks) 
- Physical examination, vital signs, height, weight and interval history (including routine 
review of systems, including infectious symptoms (e.g., fever), AEs and concomitant 
medications), 
- Evaluation of quality of life using the Karnofsky/Lansky scale and questions relevant to 
generall wel-being, school attendance, and ability to practice sports, respectively, 
- Assessment of re-initiation of PEG-ADA therapy and use of IgG replacement therapy 
will be documented. Please note: subjects should have discontinued PEG-ADA 
treatment at Visit 4 (Month 1/Day 30), 
- Assessment of the success of treatment at the subject level (“responder analysis”) at 
6 months post OTL-101 infusion, by evaluating;  
a) Evidence of erythrocyte ADA enzyme activity above baseline/pre-treatment level (>0 
Units), 
b) Evidence of immune reconstitution (absolute number of CD3 cells ≥200/mm3),   
c) Detectable gene-marked granulocytes by differential polymerase chain reaction 
(dPCR)/qPCR (≥1/10,000 cells). 
If there is no evidence of hematopoietic reconstitution, subjects will require PEG-ADA 
and/or allogenic HSCT, if available and deemed appropriate by the Investigator.  The 
definition applied for lack of hematopoietic reconstitution is the failure to meet ALL 
three criteria listed above (a-c).  Any subject not meeting any of these three criteria will 
be deemed a treatment failure and should be withdrawn from the study as described in 
Section 3.6.1. 
- Hematology and biochemistry panels,  
- RCL assay in PBMC, 
- Serum to be banked for possible Western blot testing for RCL (testing performed if the 
RCL assay in PBMC returns a positive result), 
- Monitoring for leukemia (by nrLAM-PR) if the criteria for triggering nrLAM-PCR are 
fulfilled. A blood sample will be taken unless clinical/hematologic findings indicate 
potential leukoproliferation, whereby a bone marrow sample will be required, 
- Monitoring for severe infections and/or opportunistic infectious episodes at each study 
visit, 
- Vector integration analysis, 
- Immune function testing; 
o 
Determination of absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, 
CD19+ B-lymphocytes and CD56/CD16+ (or CD56+/CD3-) NK cells, 
CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ (memory) T cells, 
o T-cell proliferative responses to PHA, 
o Measurement of serum immunoglobulin levels (IgG, IgA, IgM) if not receiving 
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o TREC, 
o TCR Vβ usage, 
- Gene transduction/expression; 
o Measurement of the proportion of cells containing the inserted ADA gene in PBMC 
and granulocytes and/or lineage-sorted cells, 
o Measurement of ADA expression in erythrocytes by ADA enzymatic assay and 
deoxyadenine nucleotides in RBC. 
Month 9 (Visit 8 - +/- 2 weeks) 
- Physical examination, vital signs, height, weight and interval history (including routine 
review of systems, including infectious symptoms (e.g., fever), AEs and concomitant 
medications), 
- Assessment of re-initiation of PEG-ADA therapy and use of IgG replacement therapy 
will be documented. Please note: subjects should have discontinued PEG-ADA 
treatment at Visit 4 (Month 1/Day 30), 
- Hematology and biochemistry panels,  
- Monitoring for severe infections and/or opportunistic infectious episodes at each study 
visit, 
- Immune function testing; 
o 
Determination of absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, 
CD19+ B-lymphocytes and CD56/CD16+ (or CD56+/CD3-) NK cells, 
CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ (memory) T cells; 
o T-cell proliferative responses to PHA, 
o Serum immunoglobulin (IgG, IgA, IgM), 
- Gene transduction/expression; 
o Measurement of ADA expression in erythrocytes by ADA enzymatic assay and 
deoxyadenine nucleotides in RBC. 
Month 12 (Visit 9 - +/- 4 weeks) 
- Physical examination, vital signs, height, weight and interval history (including routine 
review of systems, including infectious symptoms (e.g., fever), AEs and concomitant 
medications), 
- Evaluation of quality of life using the Karnofsky/Lansky scale and questions relevant to 
general well-being, school attendance, and ability to practice sports, respectively, 
- Assessment of re-initiation of PEG-ADA therapy and use of IgG replacement therapy 
will be documented. Please note: subjects should have discontinued PEG-ADA 
treatment at Visit 4 (Month 1/Day 30), 
- Hematology and biochemistry panels,  
- RCL assay in PBMC, 


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- Serum to be banked for possible Western blot testing for RCL (testing performed if the 
RCL assay in PBMC returns a positive result), 
- Vector integration analysis, 
- Monitoring for leukemia (by nrLAM-PR) if the criteria for triggering nrLAM-PCR are 
fulfilled. A blood sample will be taken unless clinical/hematologic findings indicate 
potential leukoproliferation, whereby a bone marrow sample will be required, 
- Monitoring for severe infections and/or opportunistic infectious episodes at each study 
visit, 
- Immune function testing; 
o 
Determination of absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, 
CD19+ B-lymphocytes and CD56/CD16+ (or CD56+/CD3-) NK cells, 
CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ (memory) T cells; 
o T-cell proliferative responses to PHA, 
o Measurement of serum immunoglobulin levels (IgG, IgA, IgM) if not receiving 
immunoglobulins, 
o Measurement of specific antibodies to tetanus toxoid only if subjects have stopped 
immunoglobulin replacement and have received tetanus vaccination,  
o TREC, 
o TCR Vβ usage, 
- Gene transduction/expression; 
o Measurement of the proportion of cells containing the inserted ADA gene in PBMC 
and granulocytes and/or lineage-sorted cells, 
o Measurement of ADA expression in erythrocytes by ADA enzymatic assay and 
deoxyadenine nucleotides in RBC. 
Month 18 (Visit 10 - +/- 4 weeks) 
- Physical examination, vital signs, height, weight and interval history (including routine 
review of systems, including infectious symptoms (e.g., fever), AEs and concomitant 
medications), 
- Evaluation of quality of life using the Karnofsky/Lansky scale and questions relevant to 
general well-being, school attendance, and ability to practice sports, respectively, 
- Assessment of re-initiation of PEG-ADA therapy and use of IgG replacement therapy 
will be documented. Please note: subjects should have discontinued PEG-ADA 
treatment at Visit 4 (Month 1/Day 30),  
- Hematology and biochemistry panels,  
- Monitoring for leukemia (by nrLAM-PR) if the criteria for triggering nrLAM-PCR are 
fulfilled. A blood sample will be taken unless clinical/hematologic findings indicate 
potential leukoproliferation, whereby a bone marrow sample will be required, 


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- Monitoring for severe infections and/or opportunistic infectious episodes at each study 
visit, 
- Vector integration analysis, 
- Immune function testing; 
o 
Determination of absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, 
CD19+ 
B-lymphocytes 
and 
CD56/CD16+(or 
CD56+/CD3-) 
NK 
cells, 
CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ (memory) T cells, 
o T-cell proliferative responses to PHA, 
o Serum immunoglobulin (IgG, IgA, IgM), 
o Measurement of specific antibodies to tetanus toxoid only if subjects have stopped 
immunoglobulin replacement and have received tetanus vaccination.  
o TREC, 
o TCR Vβ usage. 
- Gene transduction/expression; 
o Measurement of ADA expression in erythrocytes by ADA enzymatic assay and 
deoxyadenine nucleotides in RBC. 
 
Month 24 (Visit 11 - +/- 4 weeks) 
- Physical examination, vital signs, height, weight and interval history (including routine 
review of systems, including infectious symptoms (e.g., fever), AEs and concomitant 
medications), 
- Evaluation of quality of life  using the Karnofsky/Lansky scale and questions relevant 
to general well-being, school attendance, and ability to practice sports, respectively, 
- Assessment of re-initiation of PEG-ADA therapy and use of IgG replacement therapy 
will be documented. Please note: subjects should have discontinued PEG-ADA 
treatment at Visit 4 (Month 1/Day 30),  
- Hematology and biochemistry panels,  
- RCL assay in PBMC, 
- Serum to be banked for possible Western blot testing for RCL (testing performed if the 
RCL assay in PBMC returns a positive result), 
- Vector integration analysis, 
- Monitoring for leukemia (by nrLAM-PR) if the criteria for triggering nrLAM-PCR are 
fulfilled. A blood sample will be taken unless clinical/hematologic findings indicate 
potential leukoproliferation, whereby a bone marrow sample will be required, 
- Monitoring for severe infections and/or opportunistic infectious episodes at each study 
visit, 
- Immune function testing; 


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o 
Determination of absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, 
CD19+ B-lymphocytes and CD56/CD16+ (or CD56+/CD3-) NK cells, 
CD4+/CD45RA+ (naïve) and CD4+/CD45RO+,(memory) T cells 
o T-cell proliferative responses to PHA, 
o Serum immunoglobulin (IgG, IgA, IgM), 
o Measurement of specific antibodies to tetanus toxoid only if subjects have stopped 
immunoglobulin replacement and have received tetanus vaccination,  
o TREC, 
o TCR Vβ usage, 
- Gene transduction/expression; 
o Measurement of the proportion of cells containing the inserted ADA gene in PBMC 
and granulocytes and/or lineage-sorted cells. 
o Measurement of ADA expression in erythrocytes by ADA enzymatic assay and 
deoxyadenine nucleotides in RBC. 
 
5.1.8 
Early Termination Visit 
Subjects who meet any of the criteria specified in Section 3.6.1 and Section 4.3 will be 
encouraged to return for an early termination visit.  
Because of the large number of blood tests planned and the limited volumes of blood that can 
be obtained from young children, it may not be possible to perform every scheduled 
investigation listed below at each time-point. Therefore, the priority for the ranking of blood 
tests will be as per the order presented for each visit. The assessments required for the early 
termination visit are: 
- Physical examination, vital signs, height, weight and interval history (including routine 
review of systems, including infectious symptoms (e.g., fever), AEs and concomitant 
medications), 
- Evaluation of quality of life using the Karnofsky/Lansky scale and questions relevant to 
general well-being, school attendance, and ability to practice sports, respectively 
- Use of PEG-ADA and IgG replacement therapy will be documented, 
- Hematology and biochemistry panels, 
- RCL assay in PBMC,  
- Serum to be banked for possible Western blot testing for RCL (testing performed if the 
RCL assay in PBMC returns a positive result), 
- Monitoring for leukemia (by nrLAM-PR) if the criteria for triggering nrLAM-PCR are 
fulfilled. A blood sample will be taken unless clinical/hematologic findings indicate 
potential leukoproliferation, whereby a bone marrow sample will be required. 
- Incidence of severe infections and/or opportunistic infectious episodes. 
- Immune function testing 


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o 
Determination of absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, 
CD19+ B-lymphocytes and CD56/CD16+ (or CD56+/CD3-) NK cells, 
CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ (memory) T cells; 
o T-cell proliferative responses to PHA, 
o Serum immunoglobulin (IgG, IgA, IgM), 
o Measurement of specific antibodies to tetanus toxoid only if subjects have stopped 
immunoglobulin replacement and have received tetanus vaccination,  
o TREC, 
o TCR Vβ usage, 
- Gene transduction/expression; 
o 
Measurement of the proportion of cells containing the inserted ADA gene in PBMC 
and granulocytes and/or lineage-sorted cells 
o 
Measurement of ADA expression in erythrocytes by ADA enzymatic assay and 
deoxyadenine nucleotides in RBC. 
 
Any subject who has received gene therapy treatment with OTL-101 but has subsequently been 
withdrawn, will be invited to be included in the registry program (see Section 5.1.9). 
5.1.9 
Post-Study Registry  
After completion of the 24 month post-treatment evaluation and end of this study, all subjects 
receiving OTL-101 will be encouraged to participate in a registry program. Subjects and 
parents/legal guardians will be asked to provide separate assent/consent to be included in this 
registry, which will be initiated under a separate protocol. 


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6 
ADMINISTRATION OF OTL-101  
6.1 
OTL-101 
This study does not permit the use of OTL-101 for purposes other than those defined in this 
protocol. Administration of OTL-101 will be supervised by the Investigator, or designee (as per 
site personnel list). 
All participating subjects will be given the same OTL-101 manufactured from their own 
harvested autologous CD34+ cells. 
6.1.1 
Administration of OTL-101  
After appropriate thawing (see Section 3.7.3), the OTL-101 productwill be administered via an 
intravenous infusion over 5 to 15 minutes, according to the instruction described in Section 17: 
Appendix 1, beginning as soon as possible (and no longer than 30 minutes) after the final 
thawing steps. The subject will be pre-medicated with an appropriate dosage of acetaminophen 
(e.g., 10 to 15 mg/kg orally), and diphenhydramine (e.g., 0.5 to 1.0 mg/kg intravenous or 
orally), 15 to 90 minutes prior to infusion.  
Final OTL-101 Dose and Infusion Volume Calculations: 
Dose calculation forms are provided in Section 17: Appendix 1.  Use the Single Product Bag 
form unless there is more than one final product bag.  Use the Multi-Bag form only if there are 
two product bags. A form must be completed for each subject and will be used as source data.  
This form should be filed in the subject’s medical notes. 
Dose calculation: 
1. Prior to Busulfan administration, calculate the total Final Product (FP) CD34+ cells per 
kg as described on the appropriate worksheet. All values required to perform the 
calculation will be found on the Certificate of Analysis for the OTL-101 Final Product. 
2. Select course of action based on the following criteria: 
 The Total FP CD34+ cells per kg is less than 2.0x106 CD34+/kg.  An additional final 
product manufacturing process will be required to obtain the minimum acceptable dose,  
 The Total FP CD34+ cells per kg is greater than 2.0x106 CD34+/kg and less than 
20.0x106 CD34+/kg. Thaw and infuse the entire combined final product volume, 
 The Total FP CD34+ cells per kg is greater than 20.0x106 CD34+/kg. The volume to 
infuse must be calculated as described on the appropriate worksheet.  Do not rinse the 
partially infused OTL-101 bag after infusion. 
The final dose and volume administered to the subjects is required to be recorded in the eCRF. 
When more than one bag is needed, only infuse one OTL-101 product bag per hour, and ensure 
prior to infusion that the weight of the subject is higher than 4 kg to comply with recommended 
limit of DMSO per kg body weight per day. 
 


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6.1.2 
Rescue Administration of Autologous HSC Backup 
If a subject has not achieved hematopoietic reconstitution at Day 30 (Month 1 visit), he/she will 
be closely monitored as per standard medical management in order to determine the need for a 
rescue administration of the autologous back-up. A rescue administration will be given 
according to the physician's criteria if reconstitution is not observed by Day 42. Subjects may 
receive transfusions to give more time to observe whether signs of hematopoietic reconstitution 
are seen. This is not documented in the Schedule of Events tables as rescue procedures would 
follow standard institute protocols. 
- A failure of hematologic reconstitution is defined as persistent ANC < 200/µl or 
platelets < 20,000/µl on three independent and consecutive determinations over at least 
ten days after day 42 from the day of OTL-101 infusion.   
If these conditions are fulfilled, the subject's autologous back-up cells will be infused according 
to standard institute protocols.   
If, at Day 90 from the initial infusion of OTL-101, a failure of hematologic reconstitution 
persists after the subject's autologous back-up cells have been infused and the subject is 
experiencing prolonged unresponsive pancytopenia, the subject will be withdrawn from the 
study. 
6.2 
Concomitant Medication/Therapy 
Any prior or concomitant therapy or medication given to a subject from Visit 1 before OTL-101 
administration and during the study will be documented in the eCRF. Dose and generic name 
or tradename will be indicated. The Sponsor will encode all therapy and medication according 
to the World Health Organization (WHO) drug dictionary. 
6.2.1 
Permitted Concomitant Medication/Therapy 
6.2.1.1 
Transplant-related Therapies 
Non-myeloablative conditioning with Busulfan 
On Day -4 or -3, the subject will be given a loading dose of an anti-convulsant drug (e.g. 
levetiracetam (10 mg/kg intravenous slow infusion) or clonazepam (0.02 mg/kg orally q 
12 hours) prior to the administration of Busulfan, followed by maintenance doses until 24 hours 
after completion of the Busulfan. Anti-emetic therapy will also be started prior to Busulfan 
therapy.  
Busulfan will be administered in two doses (on Days -4 to -3 and -2 to -1 prior to the day of 
transplant which is Day 0). The first dose (3 mg/kg intravenous over 3 hours) will be given on 
Day -4 or -3. Blood samples to determine plasma Busulfan concentrations will be drawn at the 
following time-points: at the end of the infusion, and then 1, 2, 4, 8, and 13 hours after the end 
of infusion of the first dose, in order to calculate the AUC. These samples may be drawn +/-
15 minutes of the time-point, but the actual time with reference to the administration of 
Busulfan should be recorded to enable an accurate AUC calculation.   
The AUC will determine the dosage for the second dose, to target a net AUC of 4,900 µM/min 
(20 mg/l/hr). The pharmacist will calculate the AUC from the first dose based on measured 
serum levels from the PK.The second dose of Busulfan will be given intravenously on Day -2 
or -1 over 3 hours. Busulfan levels will also be measured before the second dose is administered, 
to ensure the previous dose has cleared the blood, and after the second Busulfan dose to 
document the concentrations. Blood samples to determine plasma Busulfan concentrations will 


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be drawn at the following time-points: at the end of the infusion, and then 1, 2, 4, 8, and 13 hours 
after the end of infusion of the first dose, in order to calculate the AUC. These samples may be 
drawn +/-15 minutes of the time-point, but the actual time with reference to the administration 
of Busulfan should be recorded to enable an accurate AUC calculation. 
Calculation of the Busulfan dose will be based on weight at admission for transplant. See 
Section 5.1.4 for the dose calculation instructions. 
A “wash-out period” of at least 24 hours will be required between completion of the Busulfan 
infusion and administration of the OTL-101. 
Enzyme replacement therapy with PEG-ADA 
1. Immediate ERT after OTL-101 infusion 
All subjects included in the study will receive PEG-ADA (Adagen®) prior to OTL-101 
infusion, which will be continued until Day 30 (+/-3 days) post-transplant. If, at Day 30 (+/-
3 days) post infusion of OTL-101, the subject is not suffering from active infections or other 
major medical problems, PEG-ADA administration will be discontinued.   
2. Rules for re-starting ERT or plan allogenic HSCT (if available) 
If, by 6 months after the OTL-101 infusion, there is no evidence of hematopoietic reconstitution 
following the infusion of the back up OTL-101 and rescue medication/treatment, subjects will 
require rescue PEG-ADA or allogenic HSCT if available. Positive evidence of hematopoietic 
reconstitution will require: 
a. RBC ADA >0 Units,  
b. absolute CD3+ T-cell counts ≥200/mm3, and  
c. peripheral blood samples positive for vector sequences by qPCR 
(>1/10,000 cells). 
In addition, PEG-ADA may be re-started if the Investigator deems it in the best interests of the 
subject on clinical grounds, e.g. multiple, serious or unresponsive infections or sub-normal 
immune reconstitution. Once ERT has been re-started, the subject will remain in the study and 
will continue to be followed-up.  If the subject fails to demonstrate hematopoietic reconstitution 
and has the possibility of receiving an allogeneic transplant, the subject should be withdrawn 
from the study in order to follow institute transplantation protocols. 
Once re-started, PEG-ADA may be discontinued if all the following criteria are met: no active 
infection, PBMC ADA >6 Units, absolute CD3+ T-cell counts ≥200/mm3, and peripheral blood 
samples positive for vector sequences by qPCR. 
Prophylaxis for Infections 
Prophylactic antimicrobial agents will be used to provide coverage for Pneumocystis jirovecii 
pneumonia and mucosal yeast:   
- Pneumocystis 
jirovecii 
prophylaxis 
(PJP): 
Trimethoprim/sulfamethoxazole 
(TMP/SMX), which will be stopped prior to CD34+ cell harvest and then resumed when 
ANC >500. If, after Day 30, ANC is <500, an alternative PJP prophylaxis regimen will 
be used. Suitable alternative PJP prophylactic medications include pentamidine 
(intravenous or aerosolized) or atovaquone. Dapsone should be used with caution, 


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because of its potential myelosuppressive effects. PJP prophylaxis can be discontinued 
when CD4 >200/µl (Griffith2009). 
- Subjects will continue to receive prophylactic antifungal medication, such as oral 
nystatin or fluconazole in standard doses. This can be discontinued when CD4 >200/µl.  
- Additional or alternative antibiotics may be administered, based on clinical care 
considerations (these will be recorded as concomitant medications).   
Immunoglobulin Replacement Therapy  
Immunoglobulin G infusions will be given according to institutional standards (e.g., 400 
to 600 mg/kg q 3-4 weeks), and in general are expected to be maintained until through IgG 
levels of at least 500 mg/dL. Indications for considering the discontinuation of immunoglobulin 
replacement therapy include: absolute CD4+ >200, absolute B cell >100/µl, IgA or IgM > lower 
limit of normal for age or gene marking >1% detectable in B cells. IgG levels will be checked 
monthly to document their independence from IgG infusions. If, at least 3 months later, IgG 
levels are >300 mg/dL, the subject will undergo vaccination, which will include three doses of 
tetanus and two to three doses of 13-valent pneumococcal vaccine, according to published 
clinical standards (Griffith2009). Immunoglobulin G antibodies to tetanus will be determined 
at least 4 weeks after completing the three vaccinations. 
Pre-vaccination and post-vaccination titers will be measured and recorded in the eCRF. Until 
protective responses to the vaccines have been documented, the subject should remain on 
antibiotic prophylaxis. If the subject fails to mount a protective antibody response to tetanus, as 
determined by a titer of anti-tetanus antibodies >0.15 IU/ml at least 4 weeks after the third 
immunization, IgG replacement therapy will be reintroduced. This therapy will also be resumed 
in the event of a subject developing an infection that requires hospitalization while off-IgG and 
on antibiotic prophylaxis.   
6.2.2 
Prohibited Concomitant Medication/Therapy 
It is preferable that subjects should abstain from receiving myelosuppressive medications, 
including TMP/SMX, during the peri-transplant period. However, if medications that fit this 
description are clinically warranted, and there are no viable alternatives, then the subject may 
receive the medication and will be closely monitored.  
Subjects should not enrol in any other clinical studies involving gene therapy for 2 years after 
infusion of the OTL-101 product. Insufficient data are available to predict any interactions with 
other study agents. Enrolment in other data collection, sample banking, or registry studies is 
permitted. 
6.3 
Administration Compliance 
The only occasion on which the subjects will be exposed to OTL-101 is the day that they receive 
their 
genetically 
modified 
cells 
(Day 
0). 
If 
a 
subject 
fails 
to 
demonstrate 
engraftment/hematopoietic reconstitution at 42 days post initial OTL-101 infusion, their backup 
sample may be administered. The subjects are required to attend follow-up visits, either at the 
investigational site or to their personal physician, as per the schedule indicated in Table 1 and 
Table 2. These follow-up visits are scheduled by the investigational site staff by actively 
contacting the subject or subject’s parents/legal guardians. 


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7 
ASSESSMENT OF EFFICACY 
For the timing of efficacy assessments in this study, refer to the schedule in Table 1 and Table 2. 
Three analyses will be performed during the study, which are described in Section 9.6. 
7.1 
Efficacy Endpoints 
7.1.1 
Primary Efficacy Endpoints 
The efficacy endpoints for this study include: 
1. Evaluation of OTL-101 treatment at 6 months post administration by assessing, in 
support of CMC assessing comparability of cryopreserved and fresh formulations, 
evaluation of therapy success for each subject based on the following parameters and 
their thresholds: 
d) Erythrocyte ADA enzyme activity above baseline/pre-treatment level (>0 Units),  
e) Absolute CD3+ T-cell counts ≥ 200/mm3, and  
f) Peripheral blood samples positive for vector sequences by qPCR(≥1/10,000 cells). 
Please note: subjects must meet all three criteria. Subjects not meeting any of these 
criteria will be designated a failure (non-responder) and will be withdrawn from the 
study (Section 3.6.1).  
The proportion of responders in this study will be compared with the proportion of 
responders in one of the Phase I/II ongoing studies using the fresh formulation. 
2. Evaluate the overall survival and event free survival 12 months post OTL-101 infusion. 
Overall survival is defined as the proportion of subjects alive. Event-free survival is 
defined as the proportion of subjects alive with no “event”; an “event” being the 
resumption of PEG-ADA ERT or the need for a rescue allogenic HSCT, or death. 
The efficacy assessments are described in Section 7.2. 
7.1.2 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints include: 
 Overall survival and event free survival 24 months post OTL-101 infusion. 
 Use of immunoglobulin replacement therapies prior to and after gene therapy.  
 Performance outcomes and quality of life measured by the Karnofsky/Lansky scale and 
questions relevant to general well-being, school attendance and ability to practice sports, 
respectively.  
 Rate of severe infections/opportunistic infectious episodes, defined as infections 
requiring hospitalization or prolonging hospitalization and/or documented infections by 
opportunistic pathogens (e.g. interstitial pneumonia, intractable diarrhoea). 
 Response to tetanus vaccination. 
 Immune reconstitution: T and B cell reconstitution. 
The efficacy assessments are described in Section 7.2. 


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7.1.3 
Exploratory Efficacy Endpoints 
The following laboratory correlates of efficacy will be used to assess the level of gene 
correction, engraftment and immune reconstitution:   
 Quantification of clonal diversity of vector integrants.  
 TREC and FACS for TCR V-beta family use. 
 Percentage gene marking in peripheral blood cells. 
 Adenosine deaminase enzyme activity in erythrocytes.  
 Total adenine nucleotides in erythrocytes. 
 Vector integration analysis.  
 Immune reconstitution 
o Absolute Lymphocyte Count. 
o Absolute numbers of T, B, NK lymphocytes in peripheral blood. 
o T lymphocyte proliferative responses to mitogen (PHA) and to antigens (tetanus 
toxoid after vaccination)  
o Serum immunoglobulin levels (IgG, IgA and IgM).   
The efficacy assessments are described in Section 7.2. 
7.2 
Efficacy Assessments 
The timing of assessing efficacy data are discussed in Section 5 and summarised in Table 1:  
Schedule of Events – Screening to Day 24 and Table 2:  Schedule of Events – Month 1 to Month 
24.  
Immune Function 
Immune function tests will include the phenotyping of lymphocyte subsets, the quantification 
of immunoglobulins ((IgG, IgA, IgM) and antibodies to Tetanus toxoid, and T-cell proliferation 
to PHA.   
Ongoing T lymphopoiesis will be assessed by quantifying TREC in blood cells at different time 
points after transplant using qPCR with genomic DNA extracted from PBMC or CD3-enriched 
cells (Clinical Immunology Laboratory at UCLA). 
Immune function testing will be assessed using the following endpoint assays: 
- Absolute lymphocyte counts will be determined by routine clinical laboratory tests. 
- Absolute numbers of T, B, NK lymphocytes in peripheral blood will be determined by 
flow cytometry. 
- T lymphocyte proliferative responses to mitogen (PHA) will be determined by tritiated 
thymidine incorporation or Carboxyfluorescein succinimidyl ester (CFSE) analysis by 
routine clinical laboratory tests. 
- TREC and FACS for TCR V-beta family use will be analyzed by measuring PBMC or 
CD3 TREC by qPCR, and TCR Vβ family use by FACS and deep sequencing. 


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- Serum immunoglobulin levels (IgG, IgA and IgM) will be determined using routine 
clinical laboratory tests.   
- Serum titers of isohemagglutinin antibodies and antibodies to vaccine antigen tetanus 
toxoid will be determined by routine clinical laboratory tests. 
Tests Related to the Efficacy of Gene Transfer 
The following will be measured: 
 Measurements of erythrocyte ADA enzymatic activity and deoxyadenine nucleotides in 
RBC (RBC dAXP, RBC ADA activity), 
 Quantitative PCR for vector sequences will be used to measure the frequency of cells 
containing the inserted ADA gene in PBMC and granulocyte fractions, as well as FACS-
sorted T-cells, B-cells, NK cells, and myeloid cells when sufficient samples are 
available.  
 Serum and PBMC samples will be used to detect RCL. 
Gene Transduction/Expression  
Percentage Gene Marking in PB cells     
The efficacy of stem cell transduction/engraftment will be determined by serial quantitative 
DNA-PCR examinations of PBMC and granulocytes  in order to quantify the percentages of 
cells containing ADA cDNA. Serial samples of peripheral blood will be collected and 
fractionated to obtain leukocytes on Ficoll-Hypaque to obtain PBMC and granulocyte 
populations. Genomic DNA isolated from each cell population will be assayed for the frequency 
of cells containing the EFS-ADA LV , using qPCR. If sufficient cells are available, then the 
PBMC cells may be sub-fractionated by immunoaffinity or FACS sorting into T-cells (CD3+), 
B-cells (CD19+), NK cells (CD16+/CD56+) and myeloid cells (CD13+/CD14+, or CD33+), 
and DNA from these cell sub-populations will be assayed by qPCR for vector marking. The 
presence of transduced peripheral blood leukocytes will demonstrate transduction and 
engraftment of the genetically manipulated CD34+ cells. An absence of transduced cells will 
indicate a failure of transduction and/or engraftment. 
Clonal Diversity of Vector Integrants  
Clonal diversity will be quantified and used as an index for the numbers of vector transduced 
HSC that have engrafted in the subjects. The number of LV integration sites will be amplified 
using a modified nrLAM-PCR protocol (Paruzynski 2010) and sequenced via Illumina GAIIx 
high-throughput sequencers. A custom-made software code has been written to process raw 
sequence reads and determine the genomic positions of integration sites. We expect to identify 
>1 x 10e5 integration sites per experiment, which will lend significant statistical power to 
downstream analysis. 
Adenosine deaminase Enzyme Activity in Erythrocytes  
Adenosine deaminase enzymatic activity in erythrocytes will be measured for all subjects at the 
Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory at Duke 
University under the direction of Michael Hershfield. In this laboratory, the reference range for 
ADA enzyme activity in erythrocytes from normal donors is defined. Actual levels of ADA 
enzyme activity, and the attainment of sufficient enzyme levels within the normal reference 


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range, and similar to those of the normal population with functional immune systems, will be 
recorded. 
Total Adenine Nucleotides in Erythrocytes  
The levels of deoxyadenine nucleotides in erythrocytes will be determined at each time point 
(at the laboratory headed by Dr. Michael Hershfield, Duke University). The level of 
deoxyadenine nucleotides in erythrocytes provides an indirect assessment of systemic 
detoxification by ADA enzyme activity. While not a primary study endpoint, this parameter 
will be measured to provide additional information on the effects of the procedure. 
Quality of Life 
An assessment will be made of general quality of life and neurological development according 
to the schedule of events tables. During these visits, the impact of illness on health-related 
quality of life will be determined using the Karnofsky/Lansky performance scale (which is 
recommended for immune deficiencies and transplanted patients) (see Section 17: Appendix 
2).  
Questions relevant to general well-being, school attendance and ability to practice sports, will 
also be posed to the subject and his/her parents/legal guardians by the Investigator. These 
questions will form part of the eCRF.  Questions suitable/relevant to the age of the subject will 
be posed. 
Infections 
Although infections are safety evaluations, in ADA-SCID, they are also a clear feature of the 
disease. Evaluation of the frequency of severe infections or opportunistic infectious episodes is 
an important measure to evaluate efficacy (immune-reconstitution). This is defined as 
infections or severe infections requiring hospitalization or prolonging hospitalization and/or 
documented infections by opportunistic pathogens (e.g. interstitial pneumonia, intractable 
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8 
ASSESSMENT OF SAFETY 
For the timing of safety assessments in this study, refer to the schedule of events in Table 1 and 
Table 2. 
The principal Investigator is responsible for the safety of subjects included in the study. The 
safety of this study will be overseen by an overarching and independent Data Safety Monitoring 
Committee Board. 
8.1 
Safety Endpoints 
The safety and tolerability of OTL-101 will be assessed throughout the study by evaluating 
AEs, clinical laboratory test results, vital signs measurements, ECG, physical examination 
results, and concomitant medication usage. This will include the occurrence of events related 
to safety: 
 Grade  3/4 procedure-related AEs, including GvHD.  
 Episodes of severe and opportunistic infections.  
 Clinical laboratory toxicities, including myelosuppression, abnormal blood cell counts 
and/or biochemistry parameters, according to AE grading scale described in 
Section 8.2.1.4. 
 Toxicity related to the use of LV, specifically the emergence of replication competent 
lentivirus or monoclonal expansion or leukemia, due to vector insertion. 
The safety assessments are described in Section 8.2. 
8.2 
Safety Assessments 
8.2.1 
Adverse Events 
Adverse events will be monitored and recorded from the time that the subject’s parents/legal 
guardians provide informed consent and then throughout the study (see Section 3.5 for 
definition of the study duration) and will be elicited by direct, non-leading questioning or if 
spontaneously reported by the subject/parent/legal guardian. Further details on AE reporting 
can be found in Section 8.2.2.  
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not it is considered to be causally related to the product. An undesirable medical condition 
can be symptoms (e.g. nausea, chest pain), signs (e.g. tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g. laboratory findings, ECG). In clinical studies an AE 
can include an undesirable medical condition occurring at any time, including run in or washout 
periods, even if no OTL-101 has been administered. 
Death due to disease progression will be recorded as part of the efficacy evaluation (due to 
failure of the OTL-101 product) and will be regarded as an SAE unrelated to OTL-101. 
8.2.1.1 
Severity Classification of Adverse Events 
Adverse events will be recorded and graded according to an adapted Pediatric Clinical Toxicity 
Scale from the National Institute Allergy and Infectious Diseases (NIAID), Autoimmuno-
deficiency Syndrome (AIDS) Division (see Section 17: Appendix 3):  
Grade 1 (Mild):  
Symptoms causing no or minimal interference with usual social & 
functional activities.  


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Grade 2 (Moderate):  
Symptoms causing greater than minimal interference with usual 
social & functional activities. 
Grade 3 (Severe):  
Symptoms causing an inability to perform usual social & 
functional activities. 
Grade 4 (Life threatening): Symptoms causing an inability to perform basic self-care functions 
OR medical or operative intervention indicated to prevent 
permanent impairment, persistent disability, or death. 
Grade 5 (Death) 
8.2.1.2 
Causality Classification 
The relationship between an AE and study product administration will be classified according 
to the following:  
Related: reports that contain good reasons and sufficient information (e.g. plausible time 
sequence, dose response relationship, pharmacology, positive de-challenge and/or re-challenge) 
to assume a causal relationship with OTL-101 administration in the sense that it is plausible, 
conceivable or likely.  
Not related: reports that contain good reasons and sufficient information (e.g. implausible time 
sequence and/or attributable to concurrent disease or other drugs) to rule out a causal 
relationship with OTL-101 administration. 
8.2.1.3 
Assessment of Expectedness  
The reference document used to assess the expectedness of AEs in this study will be the current 
IB.  
8.2.1.4 
Laboratory Test Abnormalities 
Abnormalities in laboratory test values should only be reported as AEs if any of the following 
apply:  
 They result in a delay of the OTL-101 treatment or other study procedures, 
 They require an intervention or diagnostic evaluation to assess the risk to the subject,  
 They are considered to be clinically significant by the Investigator. 
8.2.1.5 
Abnormal Physical Examination Findings  
In the judgment of the Investigator, clinically significant changes to the findings of physical 
examinations (abnormalities) will be recorded as AEs. 
8.2.1.6 
Other Investigation Abnormal Findings 
Abnormal test findings judged by the Investigator to be clinically significant (e.g. ECG, echo 
changes) and that require an intervention or diagnostic evaluation to assess the risk to the 
subject, should be recorded as AEs. 
8.2.2 
Recording and Follow up of Adverse Events 
At each study visit, the subject (or parent/legal guardian) should be asked a non-leading 
question such as: “How have you felt since transplantation (or last visit)?” All observed or 
voluntarily reported AEs, regardless of their potential causal relationship with OTL-101, will 
be recorded on the AE page(s) of the eCRF. Events involving drug reactions, accidents, 


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illnesses with onset during the study, or exacerbations of pre-existing illnesses should be 
recorded. Any AEs already recorded and designated as ‘continuing’ should be reviewed at each 
subsequent assessment.  
Any AEs reported at visits to the subject’s general practitioner must be transmitted by the 
healthcare professional to the responsible investigational site staff, if possible on the same day, 
so that they can be recorded in the eCRF, notified to the Sponsor (if an SAE), and followed up 
appropriately by the responsible investigational site staff.  
For all AEs, the Investigator must pursue and obtain information that is adequate both to 
determine the outcome of the AE and to assess whether it meets the criteria for classification as 
an SAE requiring immediate notification to the Sponsor or its designated representative. For all 
AEs, sufficient information should be obtained by the Investigator to make an assessment of 
the causality of the AE (i.e. protocol treatment or other illness). The Investigator is required to 
assess causality and record that assessment on the eCRF. Follow up of the AE, after the date of 
OTL-101 infusion, is required if the AE or its sequelae persist. Follow up is required until the 
event or its sequelae resolve or stabilize at a value acceptable to the Investigator and the 
Sponsor’s clinical monitor or his/her designated representative. 
8.2.3 
Reporting of Serious Adverse Events 
All SAEs (as defined below) regardless of the suspected relationship to OTL-101, must be 
reported immediately (within 24 hours of the Investigator’s knowledge of the event) to the 
pharmacovigilance contact specified at the beginning of this protocol. If the immediate report 
is submitted by telephone, this must be followed by detailed written reports using the SAE 
report form.  
For subjects who are not geographically close to the clinical site who are clinically stable, post-
transplant care may be transferred to the home physician provided the identified clinician agrees 
to assume this post-transplant monitoring. Any discharge from the clinical site and re-admission 
to the local site (second facility) would not meet the criteria for being reported as a serious 
adverse event. 
An SAE is any AE that:  
- 
Results in death,  
- 
Is life threatening, that is any event that places the subject at immediate risk of death 
from the event as it occurred. It does not include an event that, had it occurred in a more 
severe form, might have caused death,  
- 
Results of in-patient hospitalization or a prolongation of existing hospitalization, 
excluding admission for social or administrative reasons (see below),  
- 
Results in a persistent or significant disability/incapacity, where disability is a substantial 
disruption of a person's ability to conduct normal life functions,  
- 
Results in congenital anomaly/birth defect in the offspring of a subject who received 
OTL-101,  
- 
Is an important medical event that may not result in death, be life threatening, or require 
hospitalization, but that, based upon appropriate medical judgment, may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm 


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requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in in-patient hospitalization, or the development of drug 
dependency or drug abuse.  
In addition to the above criteria, any additional AE that the Sponsor or an Investigator considers 
serious should be reported immediately to the Sponsor and included in the corporate SAE 
database system.  
- 
Hospitalization is defined as any in-patient admission (even if less than 24 hours). For 
chronic or long term in-patients, in-patient admission also includes transfer within the 
hospital to an acute/intensive care in-patient unit.  
- 
Prolongation of hospitalization is defined as any extension of an in-patient 
hospitalization beyond the stay anticipated/required in relation to the original reason for 
the initial admission, as determined by the Investigator or treating physician. For 
protocol specified hospitalization in clinical studies, prolongation is defined as any 
extension beyond the length of stay described in the protocol. Prolongation in the 
absence of a precipitating, treatment emergent, clinical AE (i.e. not associated with the 
development of a new AE or worsening of a pre-existing condition) may meet criteria 
for "seriousness" but is not an adverse experience and thus is not subject to immediate 
reporting to the Sponsor.  
- 
Preplanned or elective treatments/surgical procedures should be noted in the subject’s 
screening documentation. Hospitalization for a preplanned or elective treatment/surgical 
procedure should not be reported as an SAE unless there are complications or sequelae 
which meet the criteria for seriousness as described above.  
Any SAE must be reported immediately (within 24 hours), independent of the circumstances 
or suspected cause, if it occurs or comes to the attention of the Investigator at any time during 
the study period.  
Any AE/SAE with a suspected causal relationship to OTL-101 administration occurring at any 
other time after completion of the study must be promptly reported. The following information 
is the minimum that must be provided to Sponsor’s pharmacovigilance contact within 24 hours 
for each SAE:  
- 
Study number  
- 
Center number  
- 
Subject number  
- 
AE  
- 
Investigator's name and contact details  
The additional information included in the SAE form must be provided to the Sponsor or 
nominated representative as soon as it is available. The Investigator should always provide an 
assessment of causality for each event reported to the Sponsor. Upon receipt of the initial report, 
the Sponsor will ask for the Investigator's causality assessment if it was not provided with the 
initial report.  
The Investigator should report a diagnosis or a syndrome rather than individual signs or 
symptoms. The Investigator should also try to separate a primary AE considered as the foremost 
untoward medical occurrence from secondary AEs which occurred as complications. 


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8.2.4 
Pregnancy 
Pregnancy itself is not regarded as an AE unless there is a suspicion that OTL-101 has interfered 
with a contraceptive method. If pregnancy occurs during the study, the outcome of the 
pregnancy will then need to be collected (post-study if necessary).  
The subjects recruited into this study are under the age of 18 years, however it is anticipated 
that most subjects will be pre-pubescent. A serum HCG pregnancy test will be performed on 
all female subjects of childbearing potential at screening, baseline/pre-conditioning assessment, 
before the administration of Busulfan, and before the administration of OTL-101. For females 
of child-bearing potential in whom preventive measures fail, pregnancies will be reported as 
indicated below.  
In the event of any pregnancy reported in a participant no protocol treatment will be 
administered. Any subject who becomes pregnant during the study, before the administration 
of Busulfan or before the administration of OTL-101, will be withdrawn. 
Information regarding pregnancies must be collected on the AE page of the eCRF and reported 
to the Sponsor as an SAE. The Sponsor will request further information from the Investigator 
as to the course and outcome of the pregnancy.  
The Investigator must instruct all female subjects of reproductive age to use a medically 
approved method of contraception throughout study participation. The Investigator must also 
instruct all female/male subjects of reproductive age to inform them immediately should they/or 
their partner become pregnant during the study. The Investigator should counsel the subject, 
discuss the risks of a pregnancy and the possible effects on the fetus. Monitoring of the 
subject/the partner should continue until conclusion of the pregnancy, which may involve 
follow up after the subject’s involvement in the study has ended.  
If the Investigator becomes aware of a pregnancy occurring in the partner of a subject 
participating in the study, this should be reported to the Sponsor. After the partner has given 
written consent, she should be counselled and followed as described above. Monitoring of the 
partner should continue until conclusion of the pregnancy. 
8.2.5 
Deaths 
All AEs resulting in death during the study period must be reported as an SAE within 24 hours 
of the Investigator’s knowledge of the event. 
The convention for recording death is as follows:  
 Adverse event term: lead cause of death (e.g. multiple organ failure, pneumonia, 
myocardial infarction), 
 Outcome: fatal. 
The only exception is if the cause of death is unknown (i.e. sudden or unexplained death), in 
which case the AE term may be ‘Death’ or ‘Sudden death’.  
8.2.6 
Discontinuation/Withdrawal due to Adverse Events/Serious Adverse Events 
Discontinuation/withdrawal due to AEs should be distinguished from discontinuation/ 
withdrawal due to an insufficient response to OTL-101.  


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If the subject withdraws from the study due to an AE/SAE, it must be reported immediately to 
the Sponsor’s designated representative (see Section 8.2.3). In all cases, the Investigator must 
ensure the subject receives appropriate medical follow up. 
8.2.7 
Reporting to Competent Authorities/IECs/IRBs/Other Investigators 
The Sponsor will ensure that processes are in place for the submission of reports of Suspected 
Unexpected Serious Adverse Reactions (SUSARs) occurring during the study to the CA, 
IEC/IRB and other Investigators concerned by OTL-101. Reporting will be done in accordance 
with the applicable regulatory requirements.  
For the single study center in the US, SUSARs and other important safety reports, when 
appropriate, will be submitted directly to the Investigators. It is the responsibility of 
Investigators to notify their IEC/IRB and the FDA in a timely manner. 
8.3 
Physical Examination 
Physical examinations, including weight (kg) and body height (cm) will be conducted at times 
indicated in Table 1 and Table 2. 
Any clinically significant physical examination findings (abnormalities) observed during the 
study will be reported as AEs. Any physical examination findings (abnormalities) persisting at 
the end of the study will be followed by the Investigator until resolution or until reaching a 
clinically stable endpoint. 
A review of all body systems will include the following: 
 General appearance 
 Skin  
 Head, including ears, eyes, nose, throat, if feasible.  
 Respiratory  
 Cardiovascular 
 Abdomen (including liver and kidneys) 
 Neurological examination with sensory testing 
Any abnormalities or changes in intensity noted during this review of body systems should be 
documented in the source document and reported appropriately in the eCRF. In addition, the 
resolution of any abnormal findings during the study will be noted in the source document and 
eCRF, if clinically significant. 
8.4 
Vital Signs 
Vital Signs (including blood pressure, pulse rate, respiratory rate and temperature) will be 
conducted at times indicated in Table 1 and Table 2. Blood pressure and pulse will be recorded 
after five minutes of rest in a sitting position.  
Any clinically significant values or deviations from baseline vital signs will be recorded as an 
AE.  
8.5 
Electrocardiograms 
An ECG will be conducted at times indicated in Table 1 and Table 2. 


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A twelve-lead ECG will be recorded at a paper speed of 25 mm/sec so that the different ECG 
intervals (RR, PR, QRS, QT) can be measured manually/automatically. The ECG will be 
recorded [with the subject in supine position after five minutes of rest] until four regular 
consecutive complexes are available. Automated ECG interval estimates taken from the ECG 
recorder will be used in this study.  
Any clinically significant abnormalities will be recorded as AEs. 
8.6 
Laboratory Safety Tests 
Blood samples for serum chemistry and hematology, and a urine sample for urinalysis will be 
taken for evaluation of laboratory safety parameters listed in Table 3 according to the times 
indicated in Table 1 and Table 2. All clinical laboratory assays will be performed according to 
the relevant laboratory’s normal procedures. Reference ranges will be supplied by the 
laboratory and used to assess the laboratory data for clinical significance and out-of-range 
pathological changes.  
For the evaluation of hematology and biochemistry panels, and urinalysis, the Investigator will 
review the safety laboratory test results, document the review, and record any clinically relevant 
changes occurring or observed during the study in the AE section of the eCRF. Changes 
compared to pre-harvest tests will be recorded as AEs if they are considered to be clinically 
significant by the Investigator. 
All clinically relevant abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return to baseline or to a value deemed acceptable by the 
Investigator and the Sponsor’s clinical monitor (or his/her designated representative) or until 
the abnormality is explained by an appropriate diagnosis.  
Table 3: Clinical Laboratory Tests 
Hematology parameters 
Biochemistry parameters 
Urinalysis 
Red blood cell (RBC) count 
Blood Urea Nitrogen  
pH 
Hemoglobin 
Creatinine 
Glucose 
Hematocrit 
Total bilirubin 
Ketones 
Mean corpuscular volume (MCV) 
Sodium 
Protein 
Mean corpuscular hemoglobin (MCH) 
Potassium 
Bilirubin 
Mean corpuscular hemoglobin concentration (MCHC) Chloride 
Blood 
White blood cell (WBC) count with differential; 
Calcium 
Urobilinogen 
Neutrophils 
Aspartate transaminase (AST) 
Nitrites 
Lymphocytes 
Alanine transaminase (ALT) 
Leukocytes 
Monocytes 
Alkaline phosphatase (ALP) 
Specific gravity 
Eosinophils 
Albumin 
 
Basophils 
Total protein 
 
Platelet count 
Glucose 
 
Coagulation parameters 
Magnesium 
 
Prothrombin time (PT) or partial thromboplastin time 
(PTT) and internal normalised ratio (INR) 
Phosphates 
 
 
 


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8.6.1 
Biochemistry 
Blood samples for biochemistry will include the assessment of parameters listed in Table 3, 
according to the times indicated in Table 1 and Table 2. 
Any unscheduled test (indication and results) will be recorded on the dedicated page in the 
eCRF. 
8.6.2 
Hematology 
Blood samples for hematology will include the assessment of parameters listed in Table 3, 
according to the times indicated in Table 1 and Table 2. 
Any unscheduled test (indication and results) will be recorded on the dedicated page in the 
eCRF. 
8.6.3 
Urinalysis 
Fresh urine samples will be collected and will include the assessment of parameters listed in 
Table 3, according to the times indicated in Table 1 and Table 2. Any abnormalities detected 
on dipstick at Screening (Visit 1), Pre-harvest (Visit 2, Assessment A) and Baseline (Visit 3, 
Assessment C) will require repeat dipstick and microscopic examinations. 
Microscopic tests will be performed, if indicated, but results will not be collected in the eCRF. 
If, in the opinion of the Investigator, there are any clinically significant abnormalities under 
microscopy, they will be recorded as an AE in the eCRF. 
8.6.4 
Pregnancy Test 
Serum HCG pregnancy tests will be performed on all females of child-bearing potential at times 
indicated in Table 1.   
8.6.5 
 HIV-1, HepB, ParvoB19  
These tests will be performed at baseline to determine eligibility. 
8.7 
Blood Volume 
The total volume of blood drawn for each assessment visit is estimated to be between 15 to 
90 ml (2 to 6 tablespoons) for each subject.  
8.8 
Pharmacokinetic Evaluations of Busulfan 
Blood samples to determine plasma Busulfan concentrations will be drawn after the first and 
second doses of Busulfan to calculate the AUC at times indicated in Table 1. 
 


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9 
STATISTICAL METHODS 
9.1 
Background 
The primary objective of this clinical study is to further explore the safety and efficacy of 
OTL-101, an autologous, genetically modified CD34+ HSC based gene therapy for the 
treatment of ADA-SCID. The study will also be supportive of the analytical CMC 
comparability studies between fresh and cryopreserved OTL-101 formulations. The clinical 
outcomes (good predictors of survival and event free survival): RBC ADA >0 Units, absolute 
CD3+ T-cell counts ≥ 200/mm3, and peripheral blood samples positive for vector sequences by 
qPCR(>1/10,000 cells) will be assessed as part of an interim analysis following completion of 
the 6 month follow-up visit.  
9.2 
Design Considerations and Data 
This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical study 
aimed to further evaluate the safety and efficacy of OTL-101.  
Descriptive results will be presented for the study cohort. 
9.3 
Study Endpoints 
The efficacy, including exploratory endpoints, are detailed in Section 7.1 and the safety 
endpoints are detailed in Section 8.1.  
9.3.1 
Primary Efficacy Endpoints 
The primary efficacy endpoints for this study include treatment success at 6 months post OTL-
101 infusion, and overall survival and event-free survival at 12 months post OTL-101 infusion. 
Treatment success at 6 months post OTL-101 infusion, will be performed in support of CMC 
assessing comparability between cryopreserved and fresh formulations. Evaluation of the 
success of therapy will be based on the following parameters and their thresholds: 
a) Erythrocyte ADA enzyme activity above baseline/pre-treatment level (>0 Units),  
b) Absolute CD3+ T-cell counts ≥ 200/mm3, and  
c) Peripheral blood samples positive for vector sequences by qPCR(≥1/10,000 cells). 
Treatment will be deemed sucessful in subjects meeting all three above thresholds.  These 
subjects will be designated as “responders”. Those subjects failing to meet at least one of the 
above thresholds will be considered to be “non-responders.” 
Overall Survival is defined as the time-to death from the OTL-101 infusion if death occurred, 
or to the date of the last evaluation if death did not occur. If no death occurred, the subject’s 
data will be considered censored at the last evaluation. 
Event Free Survival is defined as the time-to event from the OTL-101 infusion if an event 
occurred, or to the date of the last evaluation without an event if no event occurred. If no event 
occurred, the subject’s data will be considered censored at the last evaluation. Event is defined 
as any of the following:  
 Death 
 Returning to PEG-ADA ERT 
 Need of rescue HSCT 


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9.3.2 
Secondary Efficacy 
The secondary efficacy endpoints will be assessed at 12 and 24 months post OTL-101 
administration and include: 
 Overall survival and event free survival 24 months post OTL-101 infusion, 
 Use of immunoglobulin replacement therapies prior to and after OTL-101 infusion,  
 Assessment of performance outcomes and quality of life measured by the 
Karnofsky/Lansky scale and questions relevant to general well-being, school attendance 
and ability to practice sports, respectively,  
 Rate of severe infections/opportunistic infectious episodes, defined as infections 
requiring hospitalization or prolonging hospitalization and/or documented infections by 
opportunistic pathogens (e.g. interstitial pneumonia, intractable diarrhoea), 
 Response to tetanus vaccination, 
 Immune reconstitution: T and B cell reconstitution. 
All summaries of secondary endpoints will be descriptive. 
9.3.3 
Exploratory Efficacy Endpoints 
The following laboratory correlates of efficacy will be used to assess the level of gene 
correction, engraftment and immune reconstitution:   
 Quantification of clonal diversity of vector integrants.  
 TREC and FACS for TCR V-beta family use. 
 Percentage gene marking in peripheral blood cells. 
 Adenosine deaminase enzyme activity in erythrocytes.  
 Total adenine nucleotides in erythrocytes.  
 Vector integration analysis. 
 Immune reconstitution 
o Absolute Lymphocyte Count. 
o Absolute numbers of T, B, NK lymphocytes in peripheral blood. 
o T lymphocyte proliferative responses to mitogen (PHA) and to antigens (tetanus 
toxoid after vaccination)  
o Serum immunoglobulin levels (IgG, IgA and IgM). 
All summaries of exploratory endpoints will be descriptive. 
9.3.4 
Safety Endpoints 
Safety endpoints in this study are AEs, including SAEs, with severity graded by Common 
terminology criteria for adverse events (CTCAE) criteria, including relation to treatment. 
Special attention will be paid to the following AE types: 
1. Clinical toxicities 
2. Exposure to RCL  


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3. Development of monoclonal expansion or leukoproliferative complications from vector 
insertional effects.  
9.4 
Sample Size Considerations 
Due to the ultra-orphan nature of this indication, the sample size for this study is based on 
practical considerations. Specifically, the number of ADA-SCID patients expected to meet 
eligibility criteria yearly is around four to five. With a planned enrollment of three to six 
subjects per year, the sample size (N=10) for this study is considered reasonable.  
It should be noted that the sample size will provide precision of 15% for 100% success 
(survival) at any particular time point. Precision is here defined as the half-width of the two-
sided 95% CI using the Exact Binomial computations.  
Ten subjects receiving OTL-101 will participate in this study. 
Although all subjects will be evaluable for the first analysis at 6 months post OTL-101 infusion, 
the first five subjects will be reviewed to monitor the outcome of the study treatment. Sample 
size considerations for the first analysis of five subjects completing the 6-month follow-up 
assessment is based on realistic enrollment for this orphan indication. Experts in the field of 
HSCT and gene therapy use RBC ADA enzyme activity >0 U, absolute CD3+ T-cell counts 
≥200/mm3, and peripheral blood samples positive for vector sequences by qPCR 
(>1/10,000 cells) as predictors of survival and event free survival and ultimately the success of 
the OTL-101 treatment. These parameters achieve plateau between 3 and 4 months post-
intervention, therefore, a 6-month data cut for this interim analysis should be indicative of the 
final study outcomes. 
9.5 
Analysis Populations 
9.5.1 
Efficacy Population 
The efficacy population will be a modified intent-to-treat population including all subjects 
treated with OTL-101 within this protocol.  
9.5.2 Safety Population 
The safety population will consist of all subjects treated with OTL-101 within this protocol. 
9.5.3 
Pharmacokinetic Population 
The PK population will include all subjects who have received at least one dose of Busulfan 
and for whom there are sufficient plasma samples to allow reliable determination of PK profile. 
Subjects' evaluability will be determined by the Investigator. 
9.6 
Statistical Methods 
9.6.1 
Overview 
Full statistical methods will be detailed in the statistical analysis plan (SAP). The data will be 
summarized in tables displaying the mean, standard deviation, median, minimum, maximum 
and number of subjects for continuous data (e.g. age, weight) or in tables displaying count and 
percentage for categorical data (e.g. gender, previous treatment). Data will be presented by 
visit, if applicable.  
All statistical analyses will be performed using Statistical Analysis System (SAS)® Version 
9.4. or higher. 
Statistical analyses will be performed, and their outcomes presented, in three stages: 


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1. The first (interim) analysis will compare the success/failure data 6-months post OTL-
101 infusion. The success/failure of the OTL-101 cryopreserved formulation will be 
defined by the three criteria listed in the primary objectives (Section 2.2.1). This data 
will be compared with available data from the ongoing UCLA Phase I/II study using the 
OTL-101 fresh formulation. This will support the CMC comparability data between 
OTL-101 cryopreserved and fresh formulations. Secondary and exploratory endpoints 
will also be described. 
2. The second (primary) analysis will determine the 12 month overall survival and event 
free survival for all subjects. Secondary and exploratory endpoints,  as well as baseline 
characteristics, subject disposition, and safety data will also be described. 
3. The third (final) analysis will be performed to determine the overall survival and event 
free survival for all subjects 24 months post OTL-101 infusion.  Secondary and 
exploratory endpoints,  as well as baseline characteristics, subject disposition, safety 
and Busulfan PK data will also be described. 
This study is not designed to be powered to demonstrate statistical significance; therefore, no 
correction for overall Type I Error will be performed. 
9.6.2 
Subject Disposition 
Subject disposition will be tabulated; the number of enrolled, exposed, prematurely terminated, 
ongoing and completed subjects will be summarized. A list of dropouts will be prepared 
including treatment received, reason for discontinuation, and time of discontinuation.  
9.6.3 
Baseline Characteristics 
The following information collected at baseline will be presented: 
 Demographics (Age, Gender, etc.), 
 Method of diagnosis, 
 Previous HSCT including: date, transplant cells, donor type and outcome, 
 Previous PEG-ADA ERT (and duration of treatment), 
 Previous or current immunoglobulin therapy, 
 Listing of relevant medical history, including infections. 
9.6.4 
Efficacy Analyses 
The primary efficacy endpoints will be summarized as follows: 
Responder Analysis 
The proportion of responders in this study will be summarized and compared with the 
proportion of responders in the Phase I/II ongoing studies using the fresh formulation. 
Overall and Event Free Survival 
Overall and event free survival will be summarized using: 
• 
Proportion of patients who survived at each specified analysis timepoint, with the exact 
binomial 95% confidence interval. 
• 
Kaplan-Meier survival curve of time to death/event. 


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All efficacy summaries will be descriptive, there will be no formal statistical comparisons. 
9.6.5 
Safety Analyses 
All AEs will be coded according to the current Medical Dictionary for Regulatory Activities 
(MedDRA) version and will be classified by MedDRA preferred term and system organ class. 
AE listings will be presented by subject, system organ class and preferred term. Incidence of 
treatment emergent AEs (TEAE) and SAEs will be tabulated by system organ class and 
preferred term. In addition, summary tables will be presented by maximum severity, 
relationship to treatment and TEAEs associated with premature withdrawal from the study. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
it was not present prior to receiving the OTL-101 infusion, or  
• 
it was present prior to receiving the OTL-101 infusion but the intensity increased during 
the active phase of the study, or  
• 
it was present prior to receiving theOTL-101 infusion, the intensity is the same but the 
drug relationship became related during the active phase of the study.  
Summary statistics (mean, median, SD and range as appropriate) will be presented for vital 
signs, ECG parameters and clinical laboratory tests at each assessment along with change from 
baseline. For laboratory data, abnormal values will be flagged in the data listings. Shift tables 
will be presented of the number and percentage of subjects with low, normal or high values and 
normal or abnormal examinations at each visit and overall. 
9.7 
Pharmacokinetic Analysis 
Pharmacokinetic blood samples will be collected before each Busulfan dose is administered, at 
the end of Busulfan infusion, +1, 2, 4, 8, and 13 hours post-infusion (+/- 15 minutes). 
The following Busulfan PK parameters will be summarized. In addition, graphical presentation 
of average concentration (using original and log scale) will be presented over time. 
Cmax 
Maximum plasma concentration achieved 
Tmax 
Time to Cmax (peak exposure) 
AUC0-t 
The area under the plasma concentration-time curve up to the last 
quantifiable concentration (LOQ; limit of quantitation) from time of 
administration (t=0) up to the selected interval after the injection, calculated 
by the linear trapezoidal method 
AUC0-
13 
The area under the plasma concentration-time curve during the first 13 hours 
post injection, calculated by the linear trapezoidal method 
AUC0-∞ 
The area under the plasma concentration-time curve extrapolated to infinity, 
calculated as: AUC0-∞ = AUC0-t + Clast/λz, where Clast is the last 
measurable (>LOQ) concentration. 
λz 
Elimination rate constant determined by linear regression of the terminal 
points of the ln-linear plasma concentration-time curve 
t1/2 
Terminal elimination half-life, defined as 0.693/λz 
 
 


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10 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
The Investigator must maintain the primary records (i.e. source documents) of each subject’s 
data at all times. The Investigator will maintain a confidential subject identification list that 
allows the unambiguous identification of each subject. All study related documents must be 
kept until notified by the Sponsor. 
The medical experts, study monitors, auditors, and health authority inspectors (or their agents) 
will be given direct access to source data and documentation (e.g. medical charts/records, 
laboratory test results, printouts, videotapes) for source data verification, provided that subject 
confidentiality is maintained in accordance with local requirements. 
Authorized personnel from external CAs, Clinical Research Organization (CROs) and Quality 
Assurance personnel authorized by the Sponsor may carry out inspections and audits. The 
purpose of an audit is to ensure that ethical, regulatory and quality requirements are fulfilled in 
all studies performed by the Sponsor. Auditors and inspectors must have direct access to the 
study documents and site facilities as specified in Section 11.5, and to any other locations used 
for the purposes of the study in question (e.g. laboratories).  
In the event of the site being notified directly of a regulatory inspection, the Investigator must 
notify the Sponsor’s representative as soon as possible, to assist with preparations for the 
inspection. 


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11 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Protocol Amendments 
11.1.1 
Protocol Amendments  
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB and CAs, except when 
this is necessary to eliminate immediate safety concerns to the subjects or when the change 
involves only logistics or administration. The principal Investigator and the Sponsor will sign 
the protocol amendment.  
In the event that an amendment to this protocol is required, it will be classified into one of the 
following three categories: 
Administrational changes are those that are not considered ‘substantial’ (e.g. administrative 
changes) and as such are not required to be notified to the IEC/IRB or CAs but are contained 
in the protocol under a subsequent notification of a substantial amendment. 
Substantial Amendments are those considered ‘substantial’ to the conduct of the clinical study 
where they are likely to have a significant impact on: 
- 
the safety or physical or mental integrity of the subjects, 
- 
the scientific value of the study, 
- 
the conduct or management of the study, or 
- 
the quality or safety of the protocol treatment used in the study. 
Substantial amendments must be notified to the IEC/IRB and CAs. Prior to implementation, 
documented approval must be received from the IEC/IRB and either explicit approval or no 
raise of grounds of non-acceptance during the regulatory review period (country specific) must 
be received from the relevant CAs. 
Urgent Amendments are those that require urgent safety measures to protect the study subjects 
from immediate hazard and as such may be implemented immediately by the Sponsor with 
subsequent IEC/IRB and CAs notification, forthwith.  
11.1.2 
Protocol Deviations, Violations, and Exceptions 
A protocol deviation concerns non-compliance with protocol-specific study procedures or 
schedules that do not involve inclusion/exclusion criteria, primary objective evaluation criteria, 
and/or GCP guidelines. Such deviations are considered to be minor and do not impact the study.  
A protocol violation is any clinically significant divergence from the protocol, i.e. non-
compliance by the subject, the Investigator, or the Sponsor with protocol-specific 
inclusion/exclusion criteria, primary objective evaluation criteria, and/or GCP guidelines. 
Protocol violations will be identified and recorded, by study center personnel, in the eCRF.  
As a matter of policy, the Sponsor will not grant any exemptions from the protocol-specific 
entry criteria in order to allow subjects to enter a study. If, under extraordinary circumstances, 
such an action is considered ethically, medically and scientifically justified for a particular 
subject, prior approval from the Sponsor and the responsible IEC/IRB is required before the 
subject will be allowed to enter the study. If staff at an investigational center learn that a subject 
who did not meet the protocol eligibility criteria was entered in a study (a protocol violation), 
they must inform the Sponsor immediately. Such subjects will be withdrawn from the study, 


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except in exceptional cases following review and written approval by the Sponsor and the 
responsible IEC/IRB. 
11.2 
Dissemination of Information to Study Personnel 
The Investigator is responsible for giving information on the study to all staff members involved 
in the study or in any element of subject management, both before starting any study procedures 
and during the course of the study (e.g. when new staff become involved). The Investigator 
must ensure that all study staff members are qualified by education, experience and training to 
carry out their specific responsibilities. These study staff members must be listed on the study 
center authorization form, which includes a clear description of each staff member’s 
responsibilities. This list must be updated throughout the study, as necessary.  
The study monitor is responsible for explaining the protocol to all study staff, including the 
Investigator, and for ensuring their compliance with the protocol. Additional information will 
be made available during the study when new staff become involved in the study and as 
otherwise agreed with either the Investigator or the study monitor.  
11.3 
Study Monitoring 
The Investigator is responsible for the validity of all data collected at the site.  
The Sponsor is responsible for monitoring this data to verify that the rights and well-being of 
subjects are protected, that study data are accurate (complete and verifiable to source data) and 
that the study is being conducted in compliance with the protocol, GCP and regulatory 
requirements.  
11.4 
Routine Monitoring 
To ensure compliance with GCP, the study monitor or representative is responsible for ensuring 
that the study is conducted according to applicable standard operating procedures (SOPs), the 
protocol, and other written instructions and regulatory guidelines. 
Sponsor assigned monitors will conduct regular site visits according to the monitoring plan. 
The Investigator will allow direct access to all relevant files (for all subjects) and clinical study 
supplies (dispensing and storage areas) for the purpose of verifying entries made in the eCRF, 
and will assist with the monitor’s activities, if requested. Adequate time and space for 
monitoring visits should be made available by the Investigator.  
The site must complete the eCRFs according to the Sponsor's monitoring manual with respect 
to all visits by the subjects and on an ongoing basis (within a maximum 5 days) to enable their 
regular review by the study monitor, both remotely via the internet and during site visits. The 
study monitors will use functions of the EDC system to address any queries that arise while 
reviewing the data entered by study site personnel, in a timely manner.  
Whenever a subject's name is revealed on a document required by the Sponsor (e.g. laboratory 
print outs) the name must be blacked out permanently by the site personnel leaving only the 
initials visible and annotated with the subject's number as identification. 
As part of the supervision of study progress, other Sponsor personnel may, upon request, 
accompany the study monitor on visits to the study centre. The Investigator and assisting staff 
must agree to cooperate with the study monitor to resolve any problems, errors, or possible 
misunderstandings concerning the findings detected in the course of these monitoring visits. 


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11.5 
Audit and Inspection 
Authorised personnel from external CAs and the Sponsor’s authorised Quality Assurance 
personnel or nominated representative (CRO) may carry out inspections and audits. 
11.6 
Data Quality Assurance 
Monitored eCRFs transferred from the investigational site to the assigned Data Management 
group will be reviewed (secondary monitoring) for completeness, consistency, legibility and 
protocol compliance. 
Reasons should be given on the relevant eCRF for any missing data and other protocol deviations. 
Any electronic queries and items not adequately explained will require additional electronic 
manual queries to be raised to the Investigator by the monitor for clarification/correction. The 
Investigator must ensure that queries are dealt with promptly. All data changes and clarifications 
can be viewed in the audit trail function of the eCRF. 
The handling of data, including data quality assurance, will comply with regulatory guidelines 
(e.g., ICH and GCP) and the Sponsor’s SOPs and working instructions. Data management and 
control processes specific to this study will be described in a data management plan. All steps 
and actions taken regarding data management and quality assurance will be documented in a 
data handling report.  
The Sponsor will implement edit checks on the eCRF to enforce data entry guidelines, data 
consistency, and compliance to the protocol and regulatory requirements. The Study centre 
coordinator(s) will be responsible for entering study data on the eCRFs. Data management will 
track eCRFs and review them for completeness, the presence of mandatory values, consistency, 
and dated electronic signatures. In addition to checking for source data verification flags, data 
management will electronically attach data clarification queries directly onto the eCRFs during 
the review process to ensure data quality. Once study centre personnel have provided acceptable 
responses to the queries and implemented the changes on the eCRFs, data management will 
close the queries with the appropriate resolution status. 
During the study the database will be locked for the interim analysis (first five subjects at the 
6-month visit), 12-month (primary) analysis and the 24-month analysis at the end of study. The 
data will be released for reporting and statistical analysis. 


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12 
ETHICS 
12.1 
Compliance with Good Clinical Practice and Ethical Considerations 
This study will be conducted in compliance with IEC/IRB, local regulation for informed 
consent/assent, the Declaration of Helsinki and ICH GCP Guidelines. 
The EDC system will comply with FDA, 21 CFR Part 11, Electronic Records, Electronic 
Signatures, and FDA, Guidance for Industry: Computerized Systems Used in Clinical Trials.  
In addition, this study will adhere to all local regulatory requirements.  
Before initiating a study, the Investigator/institution must have obtained written and dated 
approval/favorable opinion from the IEC/IRB for the study protocol/amendment(s), written 
informed consent forms, any consent form updates, subject emergency study contact cards, 
subject recruitment procedures (e.g. advertisements), any written information to be provided to 
subjects and a statement from the IEC/IRB that they comply with GCP requirements. The 
IEC/IRB approval must identify the protocol version as well as the documents reviewed.  
After IEC/IRB approval, changes will require a formal amendment. Once the study has started, 
amendments should only be made in exceptional circumstances. Changes that do not affect 
subject safety or data integrity are classified as administrative changes and generally do not 
require ethical approval. If ethically relevant aspects are concerned, the IEC/IRB must be 
informed and, if necessary, approval sought prior to implementation. Ethical approval of 
administrative changes will be obtained if required by local/site IEC/IRB.  
12.2 
Informed Consent 
Prior to study entry, the Investigator, or a person designated by the Investigator, will explain 
the nature, purpose, benefits and risks of participation in the study to each subject, the subject’s 
parents/legal guardians or an impartial witness. The Sponsor will provide sample informed 
consent/assent forms for the parents/legal guardians and subjects to read and sign. The final 
version controlled form must be agreed by the Sponsor, and the IEC/IRB and must contain all 
elements included in the sample form, in language readily understood by the subject. A signed 
and dated informed consent form will be obtained from each parent/legal guardian and a signed 
and dated assent form will be obtained from each subject (according to local regulations) before 
any study specific procedures or assessments are done and after the aims, methods, anticipated 
benefits, and potential hazards are explained, according to local IEC/IRB requirements. 
Sufficient time must be allowed to discuss any questions raised by the subject and parents/legal 
guardians.  
The Investigator will keep the original consent/assent forms and copies will be given to the 
subjects and their parents/legal guardians. It will also be explained to the subjects and their 
parents/legal guardians that they are free to refuse entry into the study and free to withdraw 
from the study at any time without prejudice to future treatment. 
The consent/assent form(s) may need to be revised during the study should important new 
information become available that may be relevant to the safety of the subject or as a result of 
protocol amendments. In this instance, approval should always be given by the IEC/IRB. It is 
the Investigator’s responsibility to ensure that all subjects and the subject’s parents/legal 
guardians (including those subsequently entered into the study and those currently in the study) 
sign the amended form. This is documented in the same way as previously described. Subjects 


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(and their parents/legal guardians) who have completed the study should be informed of any 
new information that may impact their welfare/well-being.  
The Investigator should, with the consent of the subject, inform the subject’s primary physician 
about their participation in the clinical study. 
12.3 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards 
As required by local regulations, the Sponsor’s Regulatory Affairs group will ensure all legal 
regulatory aspects are covered, and obtain approval from the appropriate regulatory bodies prior 
to study initiation in regions where such an approval is required.  
Before this study starts, the protocol will be submitted to the national/local health authorities 
and to each IEC/IRB for review. As required, the study will not start [at a given centre] before 
the IEC/IRB and health authority (where applicable) for the centre give written approval or a 
favourable opinion or does not raise any grounds of non-acceptance within the review 
timeframe. 
12.4 
Confidentiality Regarding Study Subjects 
The Investigator must assure that the privacy of the subjects, including their personal identity 
and all personal medical information, will be maintained at all times. In eCRFs and other 
documents or image materials submitted to the Sponsor, the subjects will be identified not by 
their names, but by an identification code (e.g. initials and identification number).  
Personal medical information may be reviewed for the purposes of verifying data recorded in 
the eCRF. This review may be conducted by the study monitor, properly authorized persons 
acting on behalf of the Sponsor, the quality assurance unit, or regulatory authorities. Personal 
medical information will always be treated as confidential. 


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13 
DATA HANDLING AND RECORD KEEPING 
13.1 
Data Recording of Study Data 
In compliance with GCP, all medical records/medical notes, etc., should be clearly marked and 
permit easy identification of a subject’s participation in the specified clinical study. The 
Investigator must record all data relative to protocol procedures, study product administration, 
laboratory data, safety data and efficacy ratings in the eCRFs provided for the study. The 
Investigator, by completing the signature log, may formally designate authority to complete 
eCRFs to appropriately qualified staff having certified user access to the eCRF. Questionnaires 
completed by the subjects will be printed out.  
The Investigator must, as a minimum, provide an electronic signature (e-signature) for each 
case report book so as to attest to the accuracy and completeness of all the data. If any changes 
are made to the eCRF once a form has been locked and electronically signed, the Investigator 
will be required to approve an additional e-signature indicating his/her agreement with any new 
information or changes to the eCRF. All corrections in the eCRF will be automatically tracked 
and a reason for any change is always required. In the eCRF, the audit trail function will allow 
the changes made to be viewed on each item entered. 
13.2 
Data Management 
Electronic Data Capture will be utilized to collect all subject data. Each site is required to have 
a computer and internet connection available for the site entry of clinical data. All entries in the 
eCRF will be made under the electronic signature of the person performing the action. This 
electronic signature consists of an individual and confidential username and password 
combination. It is declared to be the legally binding equivalent of a handwritten signature. Only 
Sponsor authorized users will have access to the eCRF, as appropriate to their study 
responsibilities. Users must have successfully completed software application training prior to 
entering data in the eCRF.  
Data management will be performed by a CRO. All data management procedures will be carried 
out in accordance with the contracted CRO's SOPs. Prior to data being received in-house by the 
assigned CRO, they will be monitored at the Investigator site, (for further details please see 
Section 11.3). The eCRF and other data documentation removed from the Investigator site(s) 
will be tracked by the CRO and the monitor.  
The Sponsor will ensure that an appropriate eCRF is developed to capture the data accurately, 
and that suitable queries are raised to resolve any missing or inconsistent data. The Investigator 
will receive data from the clinical study in an electronic format (PDF files) that will be an exact 
copy of the eCRF and will include the full audit trail, for archiving purposes and future 
reference. 
Any queries generated during the data management process will also be tracked by the contracted 
data management CRO/will be raised within the EDC system. It is the central study monitor’s 
responsibility to ensure that all queries are resolved by the relevant parties. 
The Sponsor will also ensure that SAE data collected in the eCRF are consistent with 
information provided to the Sponsor’s pharmacovigilance department (and vice versa).  
The coding of an AE, medical history and concomitant medication terms will be performed by the 
contracted CRO, directed by the Medical Monitor, and reviewed and approved by the Sponsor. 


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Concomitant medications will be coded using WHO drug dictionary and AEs/medical history 
terms will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
13.2.1 
Investigator Responsibilities 
All records related to the study (i.e. source data, source documents, CRFs (see Section 10), 
copies of protocols and protocol amendments, drug accountability forms, correspondence, 
subject identification lists, signed informed consent forms, and other essential documents) must 
be retained until the Sponsor notifies the institution, in writing, that records may be destroyed.   
If the Sponsor has not provided written notification of records destruction after 10 years from 
study completion (or earlier in the case of an institution closing), and the institution determines 
the study record retention is unduly burdensome, the institution may submit a written request 
to the Sponsor at least 60 days before the planned disposition of the study records. No study 
document or image (e.g. scan, radiograph, ECG tracing) should be destroyed without prior 
written agreement between the Sponsor and the Investigator. Should the Investigator wish to 
assign the study records to another party or move them to another location, advance written 
notice will be given to the Sponsor. 
13.2.2 
Sponsor Responsibilities 
The Sponsor will be responsible for the processing and quality control of the data.  Data 
management and filing will be carried out as described in the Sponsor’s SOPs for clinical 
studies. 
If data management and filing for this study are delegated to a contract organization, these 
functions will be carried out as described in the SOPs for clinical studies at that organization.  
These SOPs will be reviewed by the Sponsor prior to the start of data management and filing 
activities. 
The original CRFs will be archived by the Sponsor for 30 years (according with gene therapy 
traceability requirement). If eCRFs are used in the study, electronic images will be archived by 
the Sponsor. Centre specific eCRF images will be sent to the study centre for archiving. 
13.3 
Record Archiving and Retention 
During the pre-study and initiation visits, the monitor must ensure that the archiving facilities 
are adequate and the archiving/retention responsibilities of the Investigator have been 
discussed.  
Study documents should be retained for at least 2 years counted from the last approval of a 
marketing application in an ICH region and until there are no pending or planned marketing 
applications in an ICH region (that is at least 15 years), or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the product. However, these documents 
should be retained for a longer period if required by the applicable regulatory requirements or 
by an agreement with the Sponsor. The Investigator should take measures to prevent any 
accidental or premature destruction of these documents. The final archiving arrangements will 
be confirmed by the monitor when closing out the site. The Sponsor will inform the 
Investigator, in writing, as to when these documents no longer need to be retained.  
If the principal Investigator relocates or retires, or otherwise withdraws his/her responsibility 
for the maintenance and retention of study documents, the Sponsor must be notified (preferably 
in writing) so that adequate provision can be made for their future maintenance and retention. 


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14 
FINANCING AND INSURANCE 
14.1 
Contractual and Financial Details 
The Investigator (and/or, as appropriate, the hospital administrative representative) and the 
Sponsor will sign a clinical study agreement prior to the start of the study, outlining the overall 
responsibilities of the Sponsor and Investigator relative to the study. Financial remuneration 
will cover the cost per subject included, based on the calculated costs of performing the study 
assessments in accordance with the protocol, and the specified terms of payment will be 
described in the contract. The contract should describe whether the costs of pharmacy, 
laboratory and other protocol required services are being paid directly or indirectly.  
Financial Disclosure Statements will need to be completed, as requested by FDA 21 CFR 
Part 54.  
14.2 
Insurance, Indemnity and Compensation 
The Sponsor will provide Product Liability insurance for all subjects included in the clinical 
study. Where required, a hospital specific indemnity agreement will be used. 
The study is covered under a liability insurance policy. The certificate of insurance and essential 
information about the insurance coverage can be provided upon request. 


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15 
REPORTING AND PUBLICATION OF RESULTS 
15.1 
Publication Policy 
Publication of the results of this study will be governed by the publication policies of the 
funding institutes. Any presentation, abstract, or manuscript must be made available for review 
by the NIH supporters prior to submission. 
This clinical study will be registered on the ClinicalTrials.gov website. 
15.2 
Clinical Study Report 
A final clinical study report (CSR) will be prepared according to the ICH guideline on structure 
and contents of CSRs. A final CSR will be prepared where any subject has signed informed 
consent, regardless of whether the study is completed or prematurely terminated. Where 
appropriate an abbreviated report may be prepared. The CSR will be in compliance with any 
applicable regulatory requirements, national laws in force and will be in English. 


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16 
REFERENCES 
Aiuti, A., Slavin, S., Aker, M., et al. (2002). Correction of ADA-SCID by stem cell gene therapy 
combined with nonmyeloablative conditioning. Science 296, 2410-2413. 
Aiuti, A., Cattaneo, F., Galimberti, S., et al (2009). Gene therapy for immunodeficiency due to 
adenosine deaminase deficiency. The New England journal of medicine 360, 447-458. 
Antoine, C., S. Muller, et al. (2003). "Long-term survival and transplantation of haemopoietic 
stem cells for immunodeficiencies: report of the European experience 1968-99." Lancet 
361(9357): 553-560. 
Biffi, A., C. C. Bartolomae, et al. (2011). "Lentiviral vector common integration sites in 
preclinical models and a clinical trial reflect a benign integration bias and not oncogenic 
selection." Blood 117(20): 5332-5339. 
Braun, C.J., Boztug, K., Paruzynski, A., et al. (2014). Gene therapy for Wiskott-Aldrich 
syndrome--long-term efficacy and genotoxicity. Science translational medicine 6, 227ra233. 
Candotti, F., Shaw, K.L., Muul, L., et al. (2012). Gene therapy for adenosine deaminase-
deficient severe combined immune deficiency: clinical comparison of retroviral vectors and 
treatment plans. Blood 120, 3635-3646. 
Carbonaro, D.A., Zhang, L., Jin, X., et al. (2014). Preclinical demonstration of lentiviral vector-
mediated correction of immunological and metabolic abnormalities in models of adenosine 
deaminase deficiency. Molecular therapy : the journal of the American Society of Gene Therapy 
22, 607-622. 
Chinn, I. K. and W. T. Shearer (2015). "Severe Combined Immunodeficiency Disorders." 
Immunol Allergy Clin North Am 35(4): 671-694. 
Ferrua, F., I. Brigida, et al. (2010). "Update on gene therapy for adenosine deaminase-deficient 
severe combined immunodeficiency." Curr Opin Allergy Clin Immunol 10(6): 551-556. 
Gaspar, H.B., Aiuti, A., Porta, F., et al. (2009). How I treat ADA deficiency. Blood 114, 3524-
3532. 
Gaspar, H.B., Cooray, S., Gilmour, K.C., et al. (2011). Hematopoietic stem cell gene therapy 
for adenosine deaminase-deficient severe combined immunodeficiency leads to long-term 
immunological recovery and metabolic correction. Science translational medicine 3, 97ra80. 
Griffith, L.M., Cowan, M.J., Notarangelo, L.D., et al. (2009). Improving cellular therapy for 
primary immune deficiency diseases: recognition, diagnosis, and management. The Journal of 
allergy and clinical immunology 124, 1152-1160 e1112. 
Hacein-Bey-Abina, S., Garrigue, A., Wang, G.P., et al. (2008). Insertional oncogenesis in 4 
patients after retrovirus-mediated gene therapy of SCID-X1. The Journal of clinical 
investigation 118, 3132-3142. 
Hacein-Bey-Abina, S., Hauer, J., Lim, A., et al. (2010). Efficacy of gene therapy for X-linked 
severe combined immunodeficiency. N Engl J Med 363(4):355-64. 
 


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Hassan, A., Booth, C., Brightwell, A., et al. (2012). Outcome of hematopoietic stem cell 
transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood 
120, 3615-3624. 
Hershfield, M. S., R. H. Buckley, et al. (1987). "Treatment of adenosine deaminase deficiency 
with polyethylene glycol-modified adenosine deaminase." N Engl J Med 316(10): 589-596. 
Hershfield, M.S. (1995). PEG-ADA replacement therapy for adenosine deaminase deficiency: 
an update after 8.5 years. Clinical immunology and immunopathology 76, S228-232. 
Hirschhorn, R. (1990). "Adenosine deaminase deficiency." Immunodefic Rev 2(3): 175-198. 
Howe, S.J., Mansour, M.R., Schwarzwaelder, K., et al. (2008). Insertional mutagenesis 
combined with acquired somatic mutations causes leukemogenesis following gene therapy of 
SCID-X1 patients. The Journal of clinical investigation 118, 3143-3150. 
Modlich, U., Bohne, J., Schmidt, M., et al. (2006). Cell-culture assays reveal the importance of 
retroviral vector design for insertional genotoxicity. Blood 108, 2545-2553. 
Modlich, U., Navarro, S., Zychlinski, D., et al. (2009). Insertional transformation of 
hematopoietic cells by self-inactivating lentiviral and gammaretroviral vectors. Molecular 
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of nondividing cells by a lentiviral vector. Science 272, 263-267. 
Paruzynski, A., Arens, A., Gabriel, R., et al. (2010). Genome-wide high-throughput integrome 
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Railey, M.D., Lokhnygina, Y., Buckley, R.H. (2009). Long-term clinical outcome of patients 
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J 
Pediatr;155(6):834-840. 
Sauer, A.V., Morbach, H., Brigida, I., et al. (2012). Defective B cell tolerance in adenosine 
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Stephan, J. L., V. Vlekova, et al. (1993). "Severe combined immunodeficiency: a retrospective 
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Zufferey, R., T. Dull, et al. (1998). "Self-inactivating lentivirus vector for safe and efficient in 
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Zychlinski, D., A. Schambach, et al. (2008). "Physiological promoters reduce the genotoxic risk 
of integrating gene vectors." Mol Ther 16(4): 718-725. 


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17 
APPENDICES 
 
 
Appendix 1: OTL-101 Infusion Procedure and Dosing Forms .......................................... 95 
Appendix 2: Global Investigational Product Accountability Log .................................... 101 
Appendix 3: Lanksy and Karnofsky Scales ....................................................................... 103 
Appendix 4: DAIDS Table of Toxicity for Adverse Events .............................................. 104 
 
 
 


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Appendix 1: OTL-101 Infusion Procedure and Dosing Forms 
Required Equipment 
Thaw: 
 Water bath or plasma thawing device  
 Thermometer  
 Sterile water for thawing 
 Sterile plastic zip-lock bag 
 70% isopropanol 
Infusion: 
 Syringes: 20 and/or 30mL 
 3-way stopcock 
 Infusion set 
Additional equipment: 
 Insulated cryogenic gloves  
 PPE (Personal Protective Equipment): Safety glasses, gloves and Disposable gown 
 Emergency medical equipment: 
OTL-101 is an investigational product, and there is a possible risk of anaphylaxis. 
Emergency medical equipment (including emergency medications) must be available 
during the infusion in case the subject has an allergic response, severe hypotensive crisis, 
or any other reaction to the infusion. 
Infusion Procedure 
General 
o Obtain and review the Dose and Infusion Volume Calculation Worksheet which was 
completed prior to Busulfan administration, 
o Prepare the water bath or plasma-thawing device at least 1 hour prior to thawing.  
Verify the temperature is stable at 37oC (acceptable range 36 to 39oC) prior to removing 
the OTL-101 container from the dry shipper, 
o Pre-medicate the subject with acetaminophen and diphenhydramine 30 minutes to 
1 hour prior to infusion. These medications may be repeated every 3 to 4 hours as 
needed. 


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o Prior to beginning the infusion and no more than 1 hour prior to the infusion, record 
the subject’s vital signs on the Infusion Record. 
o The infusion will be via an indwelling latex free 18 gauge/4 French catheter or other 
equivalent IV access. Ensure the subject has a patent catheter and that it has a female 
luer or other access capable of a three-way stopcock connection prior to thawing the 
product. No inline filter or pump should be used,  
o If necessary, start a 0.9% USP normal saline infusion to keep the IV access open until 
the OTL-101 Product is ready for infusion,   
o Collect any blood samples prior to the start of infusion of the OTL-101 product, 
o The nurse or physician must be present during the infusion. 
Infusion 
o 
Attach a 20 or 30 mL syringe and an infusion set to two ports of a 3-way stopcock. 
Disconnect the NS line and attach the remaining port to the IV catheter,  
o 
Prior to thawing, inspect the OTL-101 Product bag for cracks, broken seals or damage. 
Two individuals must verify the subject information on each OTL-101 Product bag 
with the subject ID bracelet. Any discrepancy must be investigated prior to thawing 
the product (be sure to replace the OTL-101 Product bag in the LN2 dry shipper until 
the discrepancy is resolved), 
o 
Thawing of the product bags will take approximately 2 to 5 minutes. Place the 
OTL-101 Product bag into a sterile overwrap container and then place in the plasma 
thawing device or water bath. The OTL-101 Product is ready to infuse when the last 
ice crystals dissolve. If there are multiple bags, each bag must be thawed separately. 
Only one OTL-101 product bag may be infused per hour, 
o 
Record the OTL-101 Product thaw start time in the patient medical record and 
e-CRF, 
o 
Prior to removing the thawed OTL-101 Product bag from the sterile overwrap 
container, inspect for evidence of leakage or gross abnormalities. Refer to the 
institution emergency salvage procedures when necessary and use medical judgement 
to determine if the product bag should not be infused for any reason, 
o 
Remove the thawed OTL-101 Product bag from the sterile overwrap container and 
insert the spike end of the infusion set into the port of the OTL-101 Product bag and 
open the clamp, 
o 
Using the attached syringe, withdraw the OTL-101 Product into the syringe. The air 
in the tubing line may be returned to the product bag to facilitate volume transfer, 
o 
Rotate the stopcock to open the path between the syringe and the subject’s IV access 
and slowly begin to infuse the cells. 


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o 
Record the infusion start time in the patient medical record and e-CRF, 
o 
The cell product should be infused over 5 to 15 minutes and within 30 minutes after it 
has been thawed,  
o 
Rotate the stopcock to close the path to the IV and clamp the infusion tubing. 
o 
If applicable, rinse the OTL-101 product bag by either gravity transfer of 
approximately 10 mL of normal saline or by replacing the syringe with a new syringe 
containing approximately 10 mL of normal saline and rotating the stopcock to open 
the path between the syringe and the OTL-101 Product bag. Gently rotate the OTL-
101 product bag to rinse. Withdraw the rinse into the syringe and infuse the rinse as 
described above,  
NOTE: If only a portion of the product is to be infused, do not rinse the bag after that 
volume is withdrawn and infused to the subject. 
o 
When the infusion is complete, record the stop time in the patient medical record 
and e-CRF, 
o 
If applicable, begin thawing the next OTL-101 Product bag when the prior infusion is 
complete. Do not infuse more than one OTL-101 product bag per hour. 
Post Infusion 
o 
Resume the normal saline infusion for 30 minutes to ensure that no product remains in 
the IV catheter tubing, 
o 
Record the vital signs (blood pressure, pulse, and temperature) after all infusion bags 
are completed, 
o 
Continue to record the vital signs every 30 minutes according to the study center 
procedures for a minimum of 2 hours and until stable after the infusions are completed. 
Record in the patient medical record and e-CRF, 
o 
Discard the OTL-101 Product bags and infusion tubing in biohazard waste. 
 
 


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Final Product Dose and Infusion Volume Calculation – Single Product Bag 
Subject Number / PIN 
Medical Record Number 
ADA - 
 
1. Obtain the Final Product Certificate of Analysis (CofA) which contains the values for the FP 
Total CD34+ cells and the weight at harvest admission.  Record those values below.  Calculate 
and record the FP CD34+ cells per kg as follows:  Divide the FP Total CD34+ cells by the 
Weight.   
 
x 106 
÷ 
 
= 
 
106/ kg 
FP Total CD34+ cells 
 
 
Weight at Harvest 
 
FP CD34+ cells / kg 
 
2. Select course of action based on the following criteria: 
   The FP CD34+ cells per kg is less than 2.0x106 CD34+/kg.  An additional FP manufacturing 
process will be required to obtain the minimum acceptable dose  
   The FP CD34+ cells per kg is greater than 2.0x106 CD34+/kg and less than 20.0x106 CD34+/kg. 
Thaw and infuse the entire FP volume 
   The FP CD34+ cells per kg is greater than 20.0x106 CD34+/kg, calculate the volume to infuse 
as follows and do not rinse the OTL-101 bag after infusion: 
Obtain the FP CofA which contains the values for the FP CD34+ cells/mL and the weight at harvest 
admission 
Calculate the infusion volume by multiplying 20.0x106 CD34+/kg by the weight and then dividing 
by the FP CD34+ cells/mL 
 
20.0x106 CD34+/kg 
x 
kg 
= 
 
x106 CD34+ 
 
 
Weight at Harvest 
 
Total CD34+ to Infuse 
 
 
x106 CD34+ ÷ 
x106CD34+/mL 
= mL 
Total CD34+ to Infuse 
FP CD34+cells/mL 
Infusion Volume 
 
Completed by:  (print & sign) __________________________  Date:  __________________ 
 
 
Verified by:        (print & sign) __________________________  Date:  __________________ 


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Final Product Dose and Infusion Volume Calculation – Multi Product Bag 
Subject Number / PIN 
Medical Record Number 
ADA - 
 
1. Obtain the Final Product Certificate of Analysis (CofA) which contains the values for the FP 
Total CD34+ cells and the subject weight at harvest admission.  Record the values below and 
calculate the FP CD34+ cells per kg as follows:  Divide the FP Total CD34+ cells by the Weight 
at Harvest.   
Bag 1: 
x106 
÷ 
= 
 
x106/kg 
FP Total CD34+ cells 
 
Weight at Harvest 
 Bag 1 CD34+ cells / kg 
 
Bag 2 
 
x106 ÷ 
 
= 
x106/kg 
FP Total CD34+ cells 
 
Weight at Harvest 
 Bag 2 CD34+ cells / kg 
 
2.  Calculate the sum and record the Combined FP CD34+ cells per kg as follows:  
 
x 106/kg ÷ 
 
x 106/kg = 
 
x 106/kg 
Bag 1 CD34+ cells/kg 
 
 
Bag 2 CD34+ cells/kg  
 Combined CD34+ cells/kg 
 
3. Select course of action based on the following criteria: 
   The Combined CD34+ cells per kg is less than 2.0x106 CD34+/kg.  An additional final product 
manufacturing process will be required to obtain the minimum acceptable dose  
   The Combined CD34+ cells per kg is greater than 2.0x106 CD34+/kg and less than 20.0x106 
CD34+/kg. Thaw and infuse both FP bags. Do not infuse more than one FP bag per hour.  
   The Combined CD34+ cells per kg is greater than 20.0x106 CD34+/kg, calculate the volume to 
infuse as follows.  Do not infuse more than one FP bag per hour and do not rinse the second OTL-
101 bag after infusion: 
 
Identify the FP bag contains a smaller FP Total CD34+ cell number.  This bag will be partially 
infused.  If both bags contain the same FP CD34+ cell number, FP Bag 2 will be partially 
infused.   
 Calculate the CD34+ cell number that will be required from the partially infused bag 2 as 
follows: 
20.0x106 CD34+/kg 
x 
 
= 
 
x 106 
 
 
Weight at 2nd Harvest 
 
Total CD34+ cells to infuse 
 
 
 Calculate the CD34+ cell number and volume of the 2nd FP bag to infuse as follows: 


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x 106 
- 
 
x 106 
= 
 
x 106    
Total 
CD34+ 
cells to infuse 
 
 
FP Total CD34+ 
cells (Bag 1) 
 
 
FP Bag 2 CD34+ 
cells to infuse 
 
 
÷ 
= 
mL 
FP Bag 2 CD34+ cells to infuse 
FP Bag 2 CD34+cells/mL 
FP Bag 2 volume to infuse 
  
Completed by:  (print & sign) __________________________  Date:  __________________ 
 
Verified by:        (print & sign) __________________________  Date:  __________________ 
 


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Appendix 2: Global Investigational Product Accountability Log 
Study #: OTL-101-4 
Site #: UCLA 
 
Investigational Product:  (name, dosage, form, etc.):  
 
PIN____________ 
GMP Lab. 
Stem Cell Lab 
UCLA Site 
Subject 
DoB 
Subject 
Medical 
Record # 
Dispensed By
(Initials) 
Date 
Mm/dd/yyyy 
Time 
Dispensed By
(Initials) 
Date 
Time 
Dispensed By
(Initials) 
Date 
Time 
Status 
Verification CRA 
(Initials & Date)  
 
 
 
Click here to 
enter a date. 
 
 
Click here to 
enter a date. 
 
 
Click here to 
enter a date. 
 
☐ Dispensed 
☐ Unused* 
 
 
 
 
Click here to 
enter a date. 
 
 
Click here to 
enter a date. 
 
 
Click here to 
enter a date. 
 
☐ Used 
☐ Unused* 
 
 
 
 
Click here to 
enter a date. 
 
 
Click here to 
enter a date. 
 
 
Click here to 
enter a date. 
 
☐ Used 
☐ Unused* 
 
 
*if “unused” is reported, explanations are required: 
Subject not eligible 
☐ 
Inconsistent paperwork 
☐ 
Inconsistent information on subject ID 
☐ 
Damaged outer packaging 
☐ 
Storage issue 
☐ 
Other: _________________________ 
☐ 
Global Investigational Product Accountability Log (Continued) 


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Study #: OTL-101-4 
Site #: UCLA 
 
Investigational Product:  (name, dosage, form, etc.):  
*If “unused”, please record the follow-up actions: 
Product discarded 
☐ 
Product returned to stem cell lab. 
☐ 
No further action 
☐ 
Product returned to GMP lab.  
☐ 
Product kept at the clinic 
☐ 
Other:__________________________ 
☐ 
 
Comments: 
 
Final Accountability  
 
Investigator: (Print Name) _________________________ Signature __________________________ Date 
____________________ 
 
Monitor: (Print Name) ___________________________ 
Signature __________________________ Date 
____________________ 
 
 


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Appendix 3: Lanksy and Karnofsky Scales 
Karnofsky Scale (recipient age ≥ 16 years) 
Karnofsky Scale (recipient age < 16 years) 
Able to carry on normal activity: no special 
care is needed 
Able to carry on normal activity: no special 
care is needed 
 
100 Normal, no complaints, no evidence of 
disease 
100 Fully active 
90 
Able to varry on normal activity 
90 
Minor 
restrictions 
in 
physically 
strenous play 
80 
Normal activity with effort 
80 
Restricted in strenusou play, tires more 
easily, otherwise active 
Unable to work, able to live at home, cares 
for most personal needs, a varying amount of 
assistance is needed 
Mild to moderate restrictions 
70 
Care for self, unable to carry on normal 
actvitiy or to do active work 
70 
Both greater restrictions of, and less 
time spent in active play 
60 
Requires occasional assistance but is 
able to care for most needs 
60 
Ambulatory up to 50% of time, limited 
active play with assistance/supervision 
50 
Requires considerable assistance and 
frequent medical care 
50 
Considerable assistance required for 
any active play, fully able to engage in 
quiet play 
Unable to care for self, requires equivalent of 
institutional or hospital care, disease may be 
progressing rapdily  
Moderate to severe restriction 
40 
Disabled, requires special care and 
assistance 
40 
Able to initiate quiet activities 
30 
Severely 
disabled, 
hospitalization 
indicated, although death not imminent 
30 
Needs considerable assistance for quiet 
activity 
20 
Very sick, hospitalization necessary 
20 
Limited to very passive activity 
initiated by other (e.g., TV) 
10 
Moribund, fatal process progressing 
rapdily 
10 
Completely disabled, not even passive 
play 
 
The Karnofsky/Lansky Scale should be recorded in the eCRF according to the schedule of 
assessments in Table 1 and Table 2. 
 
 


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Appendix 4: DAIDS Table of Toxicity for Adverse Events 
 
 
 
Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and 
Pediatric Adverse Events 
 
 
Version 2.0 
November 2014 
 
 
 
 
 
 
 
 
 
Division of AIDS 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
US Department of Health and Human Services 
 


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GLOSSARY AND ACRONYMS  
AE  
Adverse event; Any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure regardless 
of whether it is considered related to the medical treatment or 
procedure.  
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
Absolute neutrophil count 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) 
AV 
Atroventricular 
Basic Self-care Functions 
Adult  
Activities such as bathing, dressing, toileting, transfer or movement, 
continence, and feeding.  
Young Children  
Activities that are age and culturally appropriate, such as feeding one’s 
self with culturally appropriate eating implements. 
BMI z-score  
Body mass index z- score; A body reference norm. Specifically, the 
number of standard deviations a participant's BMI differs from the 
average BMI for their age, sex, and ethnicity.  
BMD t-score  
Bone mineral density t-score; The number of standard deviations above 
or below the mean bone mineral density of a healthy 30 year old adult of 
the same sex and ethnicity as the participant.  
BMD z-score  
Bone mineral density z-score; The number of standard deviations a 
participant's BMD differs from the average BMD for their age, sex, and 
ethnicity.  
BPAP  
Bilevel positive airway pressure; A mode used during noninvasive 
positive pressure ventilation.  
Chemical Pregnancy  
A pregnancy in which a positive pregnancy test is followed by a negative 
pregnancy test without evidence of a clinical pregnancy loss.  
CNS  
Central nervous system  
CPAP  
Continuous positive airway pressure  
DAERS  
DAIDS Adverse Experience Reporting System; An internet-based 
system developed for clinical research sites to report Expedited Adverse 
Events (EAEs) to DAIDS.  It facilitates timely EAE report submission 
and serves as a centralized location for accessing and processing EAE 
information for reporting purposes 
Disability  
A substantial disruption of a person’s ability to conduct normal life 
functions.  
ECG 
Electrocardiogram 
eGFR 
Estimated glomerular filtration rate 
Hospitalization 
Does not include the following hospital admissions: under 24 hours,  
unrelated to an adverse event (e.g., for labor and delivery, cosmetic 
surgery, social or administrative for temporary placement [for lack of a 
place to sleep]), protocol-specified, and for diagnosis or therapy of a 
condition that existed before the receipt of a study agent and which has 
not increased in severity or frequency 
INR 
International normalized ratio   


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Intervention 
Medical, surgical, or other procedures recommended or provided by a 
healthcare professional for the treatment of an adverse event 
IV 
Intravenous 
IVIG 
Intravenous immune globulin 
LD 
Low density lipoprotein 
LLN 
Lower limit of normal 
Life-threatening AE  
Any adverse event that places the participant, in the view of the 
investigator, at immediate risk of death from the reaction when it 
occurred (i.e., it does not include a reaction that would have caused death 
if it had occurred in a more severe form).  
NA  
Not applicable  
Participant ID  
The identification number assigned to a study participant which is used 
to track study-related documentation, including any reported AEs.  
PR Interval 
The interval between the beginning of the P wave and the beginning of 
the QRS complex of an electrocardiogram that represents the time 
between the beginning of the contraction of the atria and the beginning 
of the contraction of the ventricles. 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc  Interval  
The measure of time between the onset of ventricular depolarization 
and completion of ventricular repolarization corrected for ventricular 
rate.  
RBC 
Red blood cell 
SI 
Standard international unit 
ULN 
Upper limit of normal 
Usual Social & Functional Activities 
Activities which adults and children perform on a routine basis and 
those which are part of regular activities of daily living, for example:  
Adults  
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, or pursuing a hobby.  
Young Children  
Activities that are age and culturally appropriate, such as social 
interactions, play activities, or learning tasks. 
WBC 
White blood cell 
WHO 
World Health Organization   
WNL 
Within normal limits 
 
 
 


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INTRODUCTION  
The Division of AIDS (DAIDS) oversees clinical trials throughout the world which it sponsors 
and supports.  The clinical trials evaluate the safety and efficacy of therapeutic products, vaccines, 
and other preventive modalities.  Adverse event (AE) data collected during these clinical trials 
form the basis for subsequent safety and efficacy analyses of pharmaceutical products and medical 
devices.  Incorrect and inconsistent AE severity grading can lead to inaccurate data analyses and 
interpretation, which in turn can impact the safety and well-being of clinical trial participants and 
future patients using pharmaceutical products.  
The DAIDS AE grading table is a shared tool for assessing the severity of AEs (including clinical 
and laboratory abnormalities) in participants enrolled in clinical trials.  Over the years as scientific 
knowledge and experience have expanded, revisions to the DAIDS AE grading table have become 
necessary.  
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse  
Events, Version 2.0 replaces the grading table published in 2004 and updated in 2009.  In version 
2.0, AEs not previously included, but which now are deemed medically important events, are 
included while other AEs have been removed.  Some AE severity grading descriptions have been 
revised to more appropriately reflect the presentation of these events in clinical settings and their 
impact on clinical trials.  For example, DAIDS performed an extensive literature search and 
reviews of select DAIDS clinical trial data in revising certain hematology parameters (i.e., 
hemoglobin, white cell counts, and absolute neutrophil counts).  DAIDS also took into 
consideration the U.S. Food and Drug Administration’s guidance regarding the use of local 
laboratory reference values and ethnic differences among certain healthy adolescent and adult 
populations in defining parameter limits.  Finally, the revised DAIDS AE grading table also 
contains an updated glossary and acronyms section, expanded instructions for use section, and an 
appendix that provides more age-specific information for an AE of concern to DAIDS.  
DAIDS is grateful to the DAIDS Grading Table Working Group, numerous government and non-
government affiliated medical subject matter experts and reviewers who were instrumental in the 
revision of the DAIDS AE grading table.  
GENERAL CONSIDERATIONS  
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.0 consists of parameters, or AEs, with severity grading guidance that are to be 
used in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in the 
evaluation of AEs.  The term “severe” is not the same as the term “serious” in classifying AEs.  
The severity of a specific event describes its intensity, and it is the intensity which is graded.  
Seriousness, which is not graded, relates to an outcome of an AE and is a regulatory definition.  
Clinical sites are encouraged to report parameters in the DAIDS AE grading table as they are 
written to maintain data consistency across clinical trials.  However, since some parameters can 
be reported with more specificity, clinical sites are encouraged to report parameters that convey 


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additional clinical information.  For example, diarrhea could be reported as neonatal diarrhea; 
seizures, as febrile seizures; and pain, as jaw pain. 
The DAIDS AE grading table provides an AE severity grading scale ranging from grades 1 to 5 
with descriptions for each AE based on the following general guidelines:   
• 
Grade 1 indicates a mild event  
• 
Grade 2 indicates a moderate event  
• 
Grade 3 indicates a severe event  
• 
Grade 4 indicates a potentially life-threatening event  
• 
Grade 5 indicates death (Note: This grade is not specifically listed on each page of the grading 
table).  
Other points to consider include:  
• 
Use parameters defined by age and sex values as applicable.  
• 
Male and female sex are defined at birth.  
• 
Unless noted, laboratory values are for term neonates.  Preterm neonates should be assessed 
using local laboratory normal ranges.  
• 
Where applicable, Standard International (SI) units are included in italics.  
SELECTING AND REPORTING A PRIMARY AE TERM  
When selecting a primary AE term to report, sites should select the term that best describes what 
occurred to the participant.  For example, a participant may present with itching, urticaria, flushing, 
angioedema of the face, and dyspnea.  If the underlying diagnosis is determined to be an acute 
allergic reaction, sites should report “Acute Allergic Reaction” as the primary AE term.  
Primary AE terms should be reported using the DAIDS Adverse Experience Reporting System 
(DAERS) only if they meet expedited reporting criteria.  However, all primary AE terms should 
be reported using protocol-specific case report forms (CRFs).  Because the reported information 
is stored in different databases (i.e., safety and clinical), sites should report primary AE terms using 
the same terminology for data consistency.   
When reporting using DAERS, other clinically significant events associated with a primary AE 
term that more fully describe the nature, severity, or complications of the primary AE term should 
be entered in the “Other Events” section.  However, the severity grade for these events must be 
lower than or equal to the severity grade of the primary AE term.  In the example above, dyspnea 
and angioedema of the face may be entered in the “Other Events” section, because they are more 
descriptive and provide additional information on the severity of the acute allergic reaction.  
However, their severity grades must be lower than or equal to the severity grade of the primary 
AE term of “Acute Allergic Reaction”.  


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Differences exist in the reporting and recording of information (e.g., signs and symptoms, 
clinically significant events) in DAERS and CRFs.  Therefore, sites should refer to their protocols 
and CRF requirements for further instructions.   
GRADING ADULT AND PEDIATRIC AES  
When a single parameter is not appropriate for grading an AE in both adult and pediatric 
populations, separate parameters with specified age ranges are provided.  If no distinction  between 
adult and pediatric populations has been made, the listed parameter should be used for grading an 
AE in both populations.  
REPORTING PREGNANCY OUTCOMES  
In the Pregnancy, Puerperium, and Perinatal section, all parameters are pregnancy outcomes and 
should be reported using the mother's participant ID.  If an infant is not enrolled in the same study 
as the mother, any identified birth defects should be reported using the mother's participant ID.  
However, if an infant is enrolled in the same study as the mother or in another study, any identified 
birth defects should be reported using the infant's participant ID.  Sites should refer to the 
applicable network standards for reporting abnormal pregnancy outcomes on the CRFs.  
DETERMINING SEVERITY GRADE FOR PARAMETERS BETWEEN GRADES   
If the severity of an AE could fall in either one of two grades (i.e., the severity of an AE could be 
either grade 2 or grade 3), sites should select the higher of the two grades.  
LABORATORY VALUES  
General. An asymptomatic, abnormal laboratory finding without an accompanying AE should not 
be reported to DAIDS in an expedited timeframe unless it meets protocol-specific reporting 
requirements.  Sites should refer to the applicable network standards for reporting abnormal 
laboratory findings on the CRFs.   
Values below Grade 1.  Any laboratory value that is between the ULN and grade 1 (for high values) 
or the LLN and grade 1 (for low values) should not be graded or reported as an AE.  Sites should 
consult the Manual for Expedited Reporting of Adverse Events to DAIDS, Version 2.0 and their 
protocol when making an assessment of the need to report an AE.  
Overlap of Local Laboratory Normal Values with Grading Table Ranges.  When local laboratory 
normal values fall within grading table laboratory ranges, the severity grading is based on the 
ranges in the grading table unless there is a protocol-specific grading criterion for the laboratory 
value.  For example, “Magnesium, Low" has a grade 1 range of 1.2 to < 1.4 mEq/L, while a 
particular laboratory’s normal range for magnesium may be 1.3 to 2.8 mEq/L.  If a study 
participant’s magnesium laboratory value is 1.3 mEq/L, the laboratory value should be graded as 
grade 1.  
 
 


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ESTIMATING SEVERITY GRADE FOR PARAMETERS NOT IDENTIFIED IN THE 
GRADING TABLE  
The functional table below should be used to grade the severity of an AE that is not specifically 
identified in the grading table.  In addition, all deaths related to an AE are to be classified as grade 
5.   
PARAMETER  
GRADE 1 MILD  GRADE 2  
MODERATE  
GRADE 3 SEVERE  GRADE 4  
POTENTIALLY  
LIFE-THREATENING  
Clinical 
adverse 
event 
NOT 
identified 
elsewhere in the 
grading table  
Mild 
symptoms 
causing 
no 
or 
minimal interference 
with usual social & 
functional 
activities 
with intervention not 
indicated  
Moderate 
symptoms 
causing greater than 
minimal 
interference 
with usual social & 
functional 
activities 
with 
intervention 
indicated  
Severe symptoms  
causing 
inability 
to 
perform usual social & 
functional activities with 
intervention 
or 
hospitalization indicated  
Potentially 
life-threatening 
symptoms causing inability to 
perform 
basic 
self-care 
functions with intervention 
indicated to prevent permanent 
impairment, 
persistent 
disability, or death  
  
  


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PARAMETER  
GRADE 1 MILD  
GRADE 2  
MODERATE  
GRADE 3 SEVERE  
GRADE 4  
POTENTIALLY LIFE- 
THREATENING  
CARDIOVASCULAR 
Arrhythmia   (by 
ECG or physical 
examination)  
Specify type, if applicable  
No symptoms AND  
No 
intervention 
indicated  
No symptoms AND 
Non-urgent 
intervention indicated  
Non-life-threatening 
symptoms  AND Non-
urgent  
intervention indicated   
Life-threatening 
arrhythmia OR Urgent 
intervention indicated  
Blood Pressure  
Abnormalities4  
Hypertension (with the 
lowest reading taken 
after 
repeat 
testing 
during a visit)  
≥ 18 years of age  
140 to < 160 mmHg  
systolic  
OR  
90 to < 100 mmHg  
diastolic  
≥ 
160 
to < 180  
≥ 180 mmHg systolic 
OR  
≥ 110 mmHg diastolic  
Life-threatening 
consequences 
in 
a 
participant not previously 
diagnosed 
with 
hypertension 
(e.g., 
malignant hypertension) 
OR 
Hospitalization 
indicated  
< 18 years of age  
> 120/80 mmHg  
≥ 
95th 
to 
< 
99th  
percentile + 5 mmHg 
adjusted 
for 
age, 
height, 
and 
gender 
(systolic 
and/or 
diastolic)  
≥ 99th percentile   
+ 5 mmHg adjusted for 
age, height, and gender 
(systolic 
and/or 
diastolic)  
Life-threatening 
consequences 
in 
a 
participant not previously 
diagnosed 
with 
hypertension 
(e.g., 
malignant hypertension) 
OR 
Hospitalization 
indicated  
Hypotension  
No symptoms  
Symptoms 
corrected 
with 
oral 
fluid 
replacement  
Symptoms AND IV  
fluids indicated  
Shock requiring use of 
vasopressors 
or 
mechanical assistance to 
maintain blood pressure  
Cardiac Ischemia or  
Infarction  
Report only one  
NA  
NA  
New symptoms with 
ischemia 
(stable 
angina) OR New  
testing consistent with 
ischemia   
Unstable angina OR 
Acute 
myocardial 
infarction  
Heart Failure  
No symptoms AND  
Laboratory 
or 
cardiac imaging 
abnormalities  
Symptoms with mild 
to moderate activity or 
exertion  
Symptoms at rest or 
with minimal activity  
or 
exertion 
(e.g., 
hypoxemia) 
OR 
Intervention indicated  
(e.g., oxygen)  
Life-threatening 
consequences OR Urgent 
intervention 
indicated 
(e.g., 
vasoactive 
medications, ventricular 
assist 
device, 
heart 
transplant)  
Hemorrhage  
(with 
significant 
acute 
blood loss)  
NA  
Symptoms AND No  
transfusion indicated  
Symptoms AND  
Transfusion of  ≤ 2 
units 
packed 
RBCs 
indicated   
Life-threatening 
hypotension OR  
Transfusion of  > 2 units 
packed 
RBCs 
(for 
children, packed RBCs  > 
10 cc/kg) indicated  
                                                          
4 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular Health and 
Risk Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published online November 14, 2011; DOI: 
10.1542/peds.20092107C.  


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Prolonged PR Interval  or 
AV Block  
Report only one  
> 16 years  of age  
PR interval 0.21 to <  
0.25 seconds  
PR interval ≥ 0.25 
seconds OR Type I 2nd 
degree AV block  
Type II 2nd degree AV 
block OR Ventricular 
pause ≥ 3.0 seconds  
Complete AV block   
≤ 16 years of age  
1st degree AV block  
(PR interval   
> normal for age and  
rate)  
Type I 2nd degree AV 
block   
Type II 2nd degree AV  
Complete AV block  
Prolonged QTc  
Interval5  
0.45 to 0.47 seconds  
> 0.47 to 0.50 seconds  > 0.50 seconds OR  
≥ 0.06 seconds above 
baseline  
Life-threatening 
consequences 
(e.g., 
Torsade de pointes, other 
associated 
serious 
ventricular dysrhythmia)  
Thrombosis or Embolism  
Report only one  
NA  
Symptoms AND No  
intervention indicated   
Symptoms AND  
Intervention indicated   
Life-threatening embolic 
event (e.g., pulmonary 
embolism, thrombus)   
DERMATOLOGIC 
 Alopecia (scalp only)   
Detectable by study 
participant, caregiver, 
or physician AND 
Causing 
no 
or 
minimal interference 
with usual social & 
functional activities  
Obvious 
on 
visual 
inspection 
AND 
Causing greater than 
minimal 
interference 
with usual social & 
functional activities  
NA  
NA  
Bruising  
Localized to one area  Localized to more than 
one area  
Generalized  
NA  
Cellulitis  
NA  
Non-parenteral 
treatment indicated  
(e.g., oral antibiotics, 
antifungals, antivirals)  
IV treatment indicated 
(e.g., IV antibiotics, 
antifungals, antivirals)  
Life-threatening 
consequences 
(e.g., 
sepsis, tissue necrosis)  
Hyperpigmentation  
Slight or localized 
causing 
no 
or 
minimal interference 
with usual social & 
functional activities  
Marked or generalized 
causing greater than 
minimal interference 
with usual social & 
functional activities  
NA  
NA  
Hypopigmentation  
Slight or localized 
causing 
no 
or 
minimal interference 
with usual social & 
functional activities  
Marked or generalized 
causing greater than 
minimal interference 
with usual social & 
functional activities  
NA  
NA  
Petechiae  
Localized to one area  Localized to more than 
one area  
Generalized  
NA  
                                                          
5 As per Bazett’s formula.  


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Pruritus6  
(without skin lesions)  
Itching causing no or 
minimal interference 
with usual social & 
functional activities  
Itching causing greater 
than 
minimal 
interference with usual 
social & functional 
activities  
Itching 
causing 
inability to perform 
usual 
social 
& 
functional activities   
NA  
Rash  
Specify type, if applicable  
Localized rash   
Diffuse 
rash 
OR 
Target lesions   
Diffuse 
rash 
AND 
Vesicles 
or 
limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site  
Extensive or generalized 
bullous 
lesions 
OR 
Ulceration 
of 
mucous 
membrane involving two 
or more distinct mucosal 
sites OR Stevens- 
Johnson syndrome OR 
Toxic 
epidermal 
necrolysis   
ENDOCRINE AND METABOLIC 
 Diabetes Mellitus  
Controlled 
without 
medication  
Controlled 
with 
medication 
OR 
Modification 
of 
current 
medication 
regimen  
Uncontrolled despite 
treatment modification 
OR  
Hospitalization 
for 
immediate 
glucose 
control indicated  
Life-threatening 
consequences 
(e.g., 
ketoacidosis, 
hyperosmolar nonketotic 
coma, end organ  
failure)   
Gynecomastia  
Detectable by study 
participant, 
caregiver, 
or 
physician 
AND 
Causing 
no 
or 
minimal interference 
with usual social & 
functional activities  
Obvious 
on 
visual 
inspection 
AND 
Causing 
pain 
with 
greater than minimal 
interference with usual 
social & functional 
activities  
Disfiguring 
changes 
AND Symptoms  
requiring intervention 
or causing inability to 
perform usual social & 
functional activities  
NA  
Hyperthyroidism  
No symptoms AND 
Abnormal laboratory 
value  
Symptoms 
causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
suppression 
therapy 
indicated  
Symptoms 
causing 
inability to perform 
usual 
social 
& 
functional 
activities 
OR 
Uncontrolled 
despite 
treatment 
modification   
Life-threatening 
consequences 
(e.g., 
thyroid storm)  
Hypothyroidism  
No symptoms AND 
Abnormal laboratory 
value  
Symptoms 
causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Thyroid 
replacement therapy  
indicated  
Symptoms 
causing 
inability to perform 
usual 
social 
& 
functional 
activities 
OR 
Uncontrolled 
despite 
treatment 
modification   
Life-threatening 
consequences 
(e.g., 
myxedema coma)  
                                                          
6 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).  


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Lipoatrophy7  
Detectable by study 
participant, 
caregiver, 
or 
physician 
AND 
Causing 
no 
or 
minimal interference 
with usual social & 
functional activities  
Obvious 
on 
visual 
inspection 
AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities  
Disfiguring changes  
NA  
Lipohypertrophy8  
Detectable by study 
participant, 
caregiver, 
or 
physician 
AND 
Causing 
no 
or 
minimal interference 
with usual social & 
functional activities  
Obvious 
on 
visual 
inspection 
AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities  
Disfiguring changes   
NA  
GASTROINTESTINAL 
Anorexia  
Loss 
of 
appetite 
without 
decreased 
oral intake  
Loss 
of 
appetite 
associated 
with 
decreased oral intake 
without 
significant 
weight loss  
Loss 
of 
appetite 
associated 
with 
significant weight loss  
Life-threatening 
consequences OR  
Aggressive 
intervention 
indicated 
(e.g., 
tube 
feeding, total parenteral 
nutrition)  
Ascites  
No symptoms  
Symptoms AND  
Intervention indicated  
(e.g., 
diuretics, 
therapeutic 
paracentesis)  
Symptoms recur or 
persist 
despite 
intervention  
Life-threatening 
consequences  
Bloating or Distension 
Report only one  
Symptoms 
causing 
no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
Symptoms 
causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms 
causing 
inability to perform 
usual 
social 
& 
functional activities  
NA  
Cholecystitis  
NA  
Symptoms AND  
Medical intervention 
indicated  
Radiologic, 
endoscopic, 
or 
operative intervention 
indicated  
Life-threatening 
consequences 
(e.g., 
sepsis, perforation)   
Constipation  
NA  
Persistent  
constipation requiring 
regular use of dietary 
modifications, 
laxatives, or enemas   
Obstipation 
with 
manual 
evacuation 
indicated  
Life-threatening 
consequences 
(e.g., 
obstruction)  
Diarrhea  
≥ 1 year of age  
Transient 
or 
intermittent episodes 
of unformed stools 
OR Increase of ≤ 3 
stools over baseline 
per 24-hour period  
Persistent episodes of 
unformed to watery 
stools OR Increase of 
4 to  6 stools over 
baseline per 24-hour 
period  
Increase of  ≥ 7 stools 
per 24-hour period OR 
IV fluid replacement 
indicated  
Life-threatening 
consequences 
(e.g., 
hypotensive shock)  
                                                          
7 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks.  
8 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen.  


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< 1 year of age  
Liquid stools (more 
unformed than usual) 
but usual number of 
stools  
Liquid 
stools 
with 
increased number of 
stools 
OR 
Mild 
dehydration  
Liquid 
stools 
with 
moderate dehydration  
Life-threatening 
consequences (e.g., liquid 
stools resulting in severe 
dehydration, hypotensive 
shock)  
Dysphagia 
or  
Odynophagia  
Report 
only 
one 
and 
specify location  
Symptoms but able to 
eat usual diet  
Symptoms causing  
altered dietary intake 
with no intervention 
indicated  
Symptoms 
causing 
severely 
altered 
dietary intake with 
intervention indicated  
Life-threatening reduction 
in oral intake  
Gastrointestinal 
Bleeding  
Not 
requiring 
intervention 
other 
than iron supplement  
Endoscopic 
intervention indicated  
Transfusion indicated  
Life-threatening 
consequences 
(e.g., 
hypotensive shock)  
Mucositis or Stomatitis 
Report only one and 
specify location  
Mucosal erythema   
Patchy  
pseudomembranes or 
ulcerations   
Confluent 
pseudomembranes or 
ulcerations 
OR 
Mucosal bleeding with 
minor trauma  
Life-threatening 
consequences 
(e.g., 
aspiration, choking) OR 
Tissue 
necrosis 
OR 
Diffuse 
spontaneous 
mucosal bleeding   
Nausea   
Transient 
(< 
24 
hours) or  
intermittent AND No 
or 
minimal 
interference with oral 
intake  
Persistent 
nausea 
resulting in decreased 
oral intake for 24 to  
48 hours  
Persistent 
nausea 
resulting in minimal  
oral intake for > 48 
hours OR  
Rehydration indicated  
(e.g., IV fluids)  
Life-threatening 
consequences 
(e.g., 
hypotensive shock)  
Pancreatitis  
NA  
Symptoms with  
hospitalization 
not 
indicated  
Symptoms 
with 
hospitalization 
indicated   
Life-threatening 
consequences 
(e.g., 
circulatory 
failure, 
hemorrhage, sepsis)  
Perforation  
(colon or rectum)  
NA  
NA  
Intervention indicated  
Life-threatening 
consequences  
Proctitis  
Rectal 
discomfort 
with no intervention 
indicated  
Symptoms 
causing 
greater than minimal 
interference with usual 
social & functional 
activities OR Medical  
intervention indicated   
Symptoms 
causing 
inability to perform 
usual 
social 
& 
functional 
activities 
OR 
Operative 
intervention indicated   
Life-threatening 
consequences 
(e.g., 
perforation)  
Rectal Discharge  
Visible discharge  
Discharge 
requiring 
the use of pads  
NA  
NA  
Vomiting  
Transient 
or  
intermittent AND No 
or 
minimal 
interference with oral 
intake  
Frequent episodes with 
no or mild dehydration  
Persistent 
vomiting 
resulting in orthostatic 
hypotension 
OR 
Aggressive  
rehydration indicated  
(e.g., IV fluids)  
Life-threatening 
consequences 
(e.g., 
hypotensive shock)  
MUSCULOSKELETAL 
 Arthralgia  
Joint pain causing no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
Joint 
pain 
causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Joint 
pain 
causing 
inability to perform 
usual 
social 
& 
functional activities  
Disabling 
joint 
pain 
causing 
inability 
to 
perform basic self-care 
functions  


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Arthritis  
Stiffness 
or 
joint 
swelling causing no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
Stiffness 
or 
joint 
swelling 
causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Stiffness 
or 
joint 
swelling 
causing 
inability to perform 
usual 
social 
& 
functional activities  
Disabling joint stiffness 
or 
swelling 
causing 
inability to perform basic 
self-care functions   
Myalgia (generalized)  
Muscle pain causing 
no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
Muscle pain causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Muscle pain causing 
inability to perform 
usual 
social 
& 
functional activities  
Disabling muscle pain 
causing 
inability 
to 
perform basic self-care 
functions  
Osteonecrosis  
NA  
No symptoms but with 
radiographic findings 
AND No operative 
intervention indicated  
Bone 
pain 
with 
radiographic findings 
OR 
Operative 
intervention indicated  
Disabling bone pain with 
radiographic 
findings 
causing 
inability 
to 
perform basic self-care 
functions  
Osteopenia9 ≥ 30 
years of age  
BMD t-score  -2.5 
to -1  
NA  
NA  
NA  
   < 30 years of age  
BMD z-score   
-2 to -1  
NA  
NA  
NA  
Osteoporosis6 ≥ 30 
years of age  
NA   
BMD t-score < -2.5  
Pathologic 
fracture 
(e.g., 
compression 
fracture causing loss of 
vertebral height)  
Pathologic 
fracture 
causing 
life-threatening 
consequences   
< 30 years of age  
NA  
BMD z-score < -2  
Pathologic 
fracture 
(e.g., 
compression 
fracture causing loss of 
vertebral height)  
Pathologic 
fracture 
causing 
life-threatening 
consequences   
NEUROLOGIC 
 Acute CNS Ischemia  
NA  
NA  
Transient 
ischemic 
attack  
Cerebral 
vascular 
accident (e.g., stroke with 
neurological deficit)  
Altered Mental Status 
(for Dementia, see  
Cognitive, Behavioral, or 
Attentional 
Disturbance 
below)   
Changes causing no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
Mild 
lethargy 
or 
somnolence 
causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Confusion, 
memory 
impairment, lethargy, 
or 
 
somnolence 
causing inability to 
perform usual social 
& functional activities  
Delirium OR   
Obtundation OR   
Coma  
Ataxia   
Symptoms 
causing 
no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
OR No symptoms  
with ataxia detected 
on examination  
Symptoms 
causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms 
causing 
inability to perform 
usual 
social 
& 
functional activities   
Disabling 
symptoms 
causing 
inability 
to 
perform basic self-care 
functions  
                                                          
9 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). Assessment of 
osteoporosis at the primary health-care level. Technical Report. World Health Organization Collaborating Centre for Metabolic Bone 
Diseases, University of Sheffield, UK. 2007: Printed by the University of Sheffield.   


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Cognitive, Behavioral, or 
Attentional Disturbance 
(includes dementia and 
attention deficit disorder)  
Specify type, if applicable  
Disability causing no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities 
OR 
Specialized 
resources 
not 
indicated  
Disability 
causing 
greater than minimal 
interference 
with 
usual 
social 
& 
functional 
activities 
OR 
Specialized 
resources on part time 
basis indicated  
Disability 
causing 
inability to perform 
usual 
social 
& 
functional 
activities 
OR 
Specialized 
resources on a fulltime 
basis indicated  
Disability 
causing 
inability 
to 
perform 
basic self-care functions 
OR Institutionalization 
indicated  
Developmental Delay  
< 18 years of age  
  
Specify type, if applicable  
Mild developmental 
delay, either motor or 
cognitive, 
as 
determined 
by 
comparison with a 
developmental 
screening 
tool 
appropriate for the 
setting   
Moderate  
developmental delay, 
either 
motor 
or 
cognitive, 
as 
determined 
by 
comparison 
with 
a 
developmental 
screening 
tool 
appropriate 
for 
the 
setting   
Severe developmental 
delay, either motor or 
cognitive, 
as 
determined 
by 
comparison 
with 
a 
developmental 
screening 
tool 
appropriate 
for 
the 
setting   
Developmental 
regression, either motor 
or 
cognitive, 
as 
determined 
by 
comparison 
with 
a 
developmental screening 
tool appropriate for the 
setting  
Headache   
Symptoms 
causing 
no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
Symptoms 
causing 
greater than minimal 
interference with usual 
social & functional 
activities   
Symptoms 
causing 
inability to perform 
usual 
social 
& 
functional activities   
Symptoms 
causing 
inability 
to 
perform 
basic self-care functions 
OR 
Hospitalization 
indicated  OR Headache 
with 
significant 
impairment of alertness 
or 
other 
neurologic 
function   
Neuromuscular 
Weakness 
(includes 
myopathy and neuropathy)  
Specify type, if applicable  
Minimal 
muscle 
weakness causing no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
OR 
No 
symptoms 
with 
decreased 
strength 
on 
examination  
Muscle 
weakness 
causing greater than 
minimal 
interference 
with usual social & 
functional activities  
Muscle 
weakness 
causing inability to 
perform usual social & 
functional activities   
Disabling 
muscle 
weakness 
causing 
inability to perform basic 
self-care functions OR 
Respiratory 
muscle 
weakness 
impairing 
ventilation  
Neurosensory Alteration 
(includes paresthesia and 
painful neuropathy) Specify 
type, if applicable  
Minimal paresthesia 
causing 
no 
or 
minimal  interference 
with usual social & 
functional activities  
OR 
No 
symptoms 
with 
sensory 
alteration 
on 
examination  
Sensory alteration or 
paresthesia 
causing 
greater than minimal 
interference with usual 
social & functional 
activities   
Sensory alteration or 
paresthesia 
causing 
inability 
to 
perform 
usual 
social 
& 
functional activities  
Disabling 
sensory 
alteration or  paresthesia 
causing 
inability 
to 
perform basic self-care 
functions  
Seizures  
New Onset Seizure  
≥ 18 years of age  
NA  
NA   
1 to  3 seizures   
Prolonged and repetitive 
seizures 
(e.g., 
status 
epilepticus) OR Difficult 
to 
control 
(e.g., 
refractory epilepsy)  


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< 18 years of age 
(includes 
new 
or 
preexisting 
febrile 
seizures)  
Seizure lasting < 5 
minutes with < 24 
hours postictal state  
Seizure lasting 5 to <  
20 minutes with  < 
24 hours postictal 
state  
Seizure lasting ≥ 20 
minutes OR > 24 hours 
postictal state  
Prolonged and repetitive 
seizures 
(e.g., 
status 
epilepticus) OR Difficult 
to 
control 
(e.g., 
refractory epilepsy)  
Pre-existing Seizure  
NA  
Increased 
frequency 
from previous level of 
control 
without 
change 
in 
seizure 
character  
Change 
in 
seizure 
character 
either 
in 
duration 
or 
quality 
(e.g., 
severity 
or 
focality)  
Prolonged and repetitive 
seizures 
(e.g., 
status 
epilepticus) OR Difficult 
to 
control 
(e.g., 
refractory epilepsy)  
Syncope   
Near syncope without 
loss of consciousness 
(e.g., pre-syncope)  
Loss of consciousness 
with no intervention 
indicated  
Loss of consciousness 
AND 
Hospitalization 
or intervention required 
NA  
PREGNANCY, PUERPERIUM, AND PERINATAL 
  Fetal 
Death 
or 
Stillbirth (report using 
mother’s participant ID) 
Report only one  
NA  
NA  
Fetal loss occurring at  
≥ 20 weeks gestation  
NA  
Preterm Delivery7 (report 
using mother’s participant 
ID)  
Delivery at 34 to  < 
37 
weeks  
gestational age  
Delivery at 28 to  < 
34 
weeks 
gestational age  
Delivery at 24 to  < 
28 
weeks 
gestational age  
Delivery at < 24 weeks 
gestational age  
Spontaneous Abortion or 
Miscarriage8 
(report 
using mother’s participant 
ID)  
Report only one  
Chemical pregnancy   Uncomplicated 
spontaneous abortion 
or miscarriage  
Complicated 
spontaneous 
abortion 
or miscarriage  
NA  
PSYCHIATRIC 
  


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PROTOCOL AMENDMENT 4: VERSION 5.0, 28 MARCH 2018 
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 Insomnia   
Mild 
difficulty 
falling 
asleep, 
staying 
asleep, 
or 
waking up early   
Moderate 
difficulty 
falling asleep, staying 
asleep, or waking up 
early  
Severe 
difficulty 
falling asleep, staying 
asleep, or waking up 
early  
NA  
Psychiatric 
Disorders 
(includes 
anxiety, 
depression, 
mania, and psychosis) 
Specify disorder  
Symptoms 
with 
intervention 
not 
indicated 
OR 
Behavior causing no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
Symptoms 
with 
intervention indicated 
OR Behavior causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Symptoms 
with 
hospitalization 
indicated OR Behavior 
causing 
inability 
to 
perform usual social & 
functional activities  
Threatens harm to self or 
others 
OR 
Acute 
psychosis OR Behavior 
causing 
inability 
to 
perform basic self-care 
functions  
Suicidal 
Ideation 
or 
Attempt  
Report only one  
Preoccupied 
with 
thoughts 
of 
death 
AND No wish to kill 
oneself  
Preoccupied 
with 
thoughts 
of 
death 
AND Wish to kill 
oneself 
with 
no 
specific plan or intent  
Thoughts of killing 
oneself with partial or 
complete plans but no 
attempt to do so OR 
Hospitalization 
indicated  
Suicide attempted  
RESPIRATORY 
 Acute Bronchospasm  
Forced 
expiratory 
volume in 1 second 
or peak flow reduced 
to  ≥ 70 to < 80% OR 
Mild symptoms with 
intervention 
not 
indicated  
Forced 
expiratory 
volume in 1 second or 
peak flow 50 to   
< 70% OR Symptoms  
with 
intervention 
indicated 
OR 
Symptoms 
causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Forced 
expiratory 
volume in 1 second or 
peak flow 25 to   
< 50% OR Symptoms  
causing inability to 
perform usual social 
& functional activities  
Forced 
expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or  
hemodynamic 
compromise OR  
Intubation   
Dyspnea or Respiratory  
Distress  
Report only one  
Dyspnea on exertion 
with no or minimal  
interference 
with 
usual 
social 
& 
functional activities  
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age  
Dyspnea on exertion 
causing greater than 
minimal 
interference 
with usual social & 
functional 
activities 
OR Nasal flaring OR  
Intercostal retractions 
OR Pulse oximetry 90 
to < 95%  
Dyspnea 
at 
rest 
causing inability to 
perform usual social 
& functional activities 
OR Pulse oximetry < 
90%  
Respiratory failure with 
ventilator 
support 
indicated (e.g., CPAP, 
BPAP, intubation)  
SENSORY 
 Hearing Loss ≥ 12 
years of age  
  
NA  
  
Hearing 
aid 
or 
intervention 
not 
indicated  
  
Hearing 
aid 
or 
intervention indicated  
 Profound 
bilateral 
hearing loss (> 80 dB at 2 
kHz and above) OR  
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and 
<50% 
speech 
discrimination)  


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< 12 years of age  
(based on a 1, 2, 3, 4, 6 
and 8 kHz audiogram)  
> 20 dB hearing loss 
at  ≤ 4 kHz  
> 20 dB hearing loss at 
> 4 kHz  
> 20 dB hearing loss at  
≥ 3 kHz in one ear with 
additional 
speech 
language related  
Hearing loss sufficient 
to indicate therapeutic 
intervention, including 
hearing aids  
Audiologic indication for 
cochlear 
implant 
and 
additional 
speech 
language related services 
indicated 
(where 
available)  
Tinnitus  
Symptoms 
causing 
no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities 
with intervention not 
indicated  
Symptoms 
causing 
greater than minimal 
interference with usual 
social & functional 
activities 
with 
intervention indicated  
Symptoms 
causing 
inability to perform 
usual 
social 
& 
functional activities  
NA  
Uveitis  
No symptoms AND  
Detectable 
on 
examination  
Anterior uveitis with 
symptoms 
OR 
Medicamylasal 
intervention indicated  
Posterior 
or 
panuveitis 
OR 
Operative 
intervention indicated  
Disabling visual loss in 
affected eye(s)   
Vertigo  
Vertigo causing no or 
minimal interference 
with usual social & 
functional activities  
Vertigo 
causing 
greater than minimal 
interference with usual 
social & functional 
activities  
Vertigo 
causing 
inability to perform 
usual 
social 
& 
functional activities  
Disabling vertigo causing 
inability to perform basic 
self-care functions  
Visual Changes  
(assessed from baseline)  
Visual 
changes 
causing 
no 
or 
minimal interference 
with usual social & 
functional activities  
Visual 
changes 
causing greater than 
minimal 
interference 
with usual social & 
functional activities  
Visual 
changes 
causing inability to 
perform usual social & 
functional activities  
Disabling visual loss in 
affected eye(s)  
SYSTEMIC 
 Acute 
Allergic 
Reaction   
Localized 
urticaria 
(wheals) 
with 
no 
medical 
intervention 
indicated  
Localized 
urticaria 
with 
intervention 
indicated OR Mild 
angioedema with no 
intervention 
indicated  
Generalized 
urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of mild 
bronchospasm  
Acute anaphylaxis OR 
Life-threatening 
bronchospasm 
OR 
Laryngeal edema  
Chills  
Symptoms causing no 
or minimal  
interference with usual 
social 
& 
functional 
activities  
Symptoms causing 
greater than minimal 
interference 
with 
usual 
social 
& 
functional activities   
Symptoms 
causing 
inability 
to 
perform 
usual 
social 
& 
functional activities  
NA  


ORCHARD THERAPEUTICS, LTD 
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CONFIDENTIAL 
 
 
PROTOCOL AMENDMENT 4: VERSION 5.0, 28 MARCH 2018 
PAGE 121/130 
 
Cytokine 
Release 
Syndrome10  
Mild signs and  
symptoms AND  
Therapy (i.e., antibody 
infusion)  interruption 
not indicated  
Therapy 
(i.e., 
antibody 
infusion) 
interruption 
indicated 
AND 
hours  
Prolonged severe signs 
and 
symptoms 
OR 
Recurrence 
of 
symptoms 
following 
initial improvement  
Life-threatening 
consequences 
(e.g., 
requiring 
pressor 
or 
ventilator support)  
Fatigue 
or 
Malaise 
Report only one  
Symptoms causing no 
or minimal  
interference with usual 
social 
& 
functional 
activities  
Symptoms causing 
greater than minimal 
interference 
with 
usual 
social 
& 
functional activities  
Symptoms 
causing 
inability 
to 
perform 
usual 
social 
& 
functional activities  
Incapacitating symptoms of 
fatigue or malaise causing 
inability to perform basic 
self-care functions  
Fever 
(non-axillary 
temperatures only)  
38.0 to < 38.6°C or  
100.4 to < 101.5°F  
≥ 38.6  to < 39.3°C 
or ≥ 101.5 to  < 
102.7°F  
≥ 39.3 to < 40.0°C or  
≥ 102.7 to < 104.0°F  
≥ 40.0°C or ≥ 104.0°F  
Pain11 (not associated 
with 
study 
agent 
injections 
and 
not 
specified elsewhere)  
Specify location  
Pain causing no or 
minimal 
interference 
with usual social & 
functional activities  
Pain causing greater 
than 
minimal 
interference 
with 
usual 
social 
& 
functional activities   
Pain causing inability 
to perform usual social  
& functional activities   
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated  
Serum Sickness12  
Mild 
signs 
and 
symptoms  
Moderate signs and  
symptoms AND  
Intervention 
indicated 
(e.g., 
antihistamines)  
Severe 
signs 
and 
symptoms AND  
Higher 
level 
intervention indicated 
(e.g., steroids or IV 
fluids)  
Life-threatening 
consequences 
(e.g., 
requiring 
pressor 
or 
ventilator support)  
Systemic 
Underweight13  
> 5 to 19 years of age  
NA  
WHO BMI z-score  
< -2 to ≤ -3  
WHO BMI z-score   
< -3  
WHO BMI z-score   
< -3 with life-threatening 
consequences  
2 to 5 years of age  
NA  
WHO Weight-for- 
height z-score  < 
-2 to ≤ -3  
WHO Weight-for- 
height z-score < -3  
WHO Weight-for-height 
z-score < -3 with life-
threatening consequences  
< 2 years of age  
NA  
WHO Weight-for- 
length z-score  < 
-2 to ≤ -3  
WHO Weight-for- 
length z-score < -3  
WHO Weight-for-length 
z-score < -3 with life-
threatening consequences  
Weight Loss (excludes  
postpartum weight  
loss)  
NA  
5 to < 9% loss in 
body weight from 
baseline  
≥ 9 to < 20% loss in 
body 
weight 
from 
baseline  
≥ 20% loss in body weight 
from 
baseline 
OR  
Aggressive 
intervention 
indicated 
(e.g., 
tube 
                                                          
10 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath.  
11 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23).    
12 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or dyspnea.  
13 WHO reference tables may be accessed by clicking the desired age range or by accessing the following URLs:   
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and  
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age.  


ORCHARD THERAPEUTICS, LTD 
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CONFIDENTIAL 
 
 
PROTOCOL AMENDMENT 4: VERSION 5.0, 28 MARCH 2018 
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feeding, total parenteral 
nutrition)  
URINARY 
 Urinary 
Tract 
Obstruction   
NA  
Signs or symptoms of 
urinary 
tract 
obstruction 
without  
hydronephrosis 
or 
renal dysfunction  
Signs or symptoms of 
urinary 
tract 
obstruction 
with 
hydronephrosis 
or 
renal dysfunction  
Obstruction causing life-
threatening consequences  
SITE REACTIONS TO INJECTIONS AND INFUSIONS  
  Injection Site Pain or   
Tenderness  
Report only one  
Pain or tenderness 
causing 
no 
or 
minimal limitation of 
use of limb  
Pain 
or 
tenderness 
causing greater than 
minimal limitation of 
use of limb   
Pain 
or 
tenderness 
causing 
inability 
to 
perform usual social & 
functional activities  
Pain or tenderness causing 
inability to perform basic 
self-care function OR  
Hospitalization indicated  
Injection Site Erythema 
or Redness14 Report only 
one  
> 15 years of age  
  
2.5 to < 5 cm in 
diameter OR 6.25 to 
< 25 cm2 surface area 
AND  
Symptoms causing no 
or 
minimal 
interference 
with 
usual 
social 
& 
functional activities  
≥ 5 to < 10 cm in 
diameter OR ≥ 25  to < 
100 cm2 surface area 
OR Symptoms causing 
greater than minimal 
interference with usual 
social & functional 
activities  
≥ 10 cm in diameter OR 
≥ 100 cm2 surface area 
OR 
Ulceration 
OR 
Secondary  
infection OR Phlebitis  
OR Sterile abscess  
OR Drainage OR  
Symptoms 
causing 
inability 
to 
perform 
usual 
social 
& 
functional activities  
Potentially 
life-
threatening consequences 
(e.g., abscess, exfoliative 
dermatitis, 
necrosis 
involving 
dermis 
or 
deeper tissue)   
≤ 15 years of age  
≤ 2.5 cm in diameter  
> 2.5 cm in diameter 
with < 50% surface 
area of the extremity 
segment involved (e.g., 
upper arm or thigh)  
≥ 50% surface area of 
the extremity segment 
involved (e.g., upper 
arm 
or 
thigh) 
OR 
Ulceration OR  
Secondary infection  
OR Phlebitis OR  
Sterile abscess OR  
Drainage  
Potentially 
life-
threatening consequences 
(e.g., abscess, exfoliative 
dermatitis, 
necrosis 
involving 
dermis 
or 
deeper tissue)  
Injection Site  
Induration or Swelling  
Report only one  
> 15 years of age  
Same as for  
Injection Site  
Erythema 
or 
Redness, > 15 years 
of age  
Same as for Injection 
Site 
Erythema 
or 
Redness, > 15 years of 
age  
Same as for Injection 
Site 
Erythema 
or 
Redness, > 15 years of 
age  
Same as for Injection Site 
Erythema or Redness, > 
15 years of age  
≤ 15 years of age  
Same as for  
Injection Site  
Erythema 
or 
Redness, ≤ 15 years 
of age  
Same as for Injection 
Site 
Erythema 
or 
Redness, ≤ 15 years of 
age  
Same as for Injection 
Site 
Erythema 
or 
Redness, ≤ 15 years of 
age  
Same as for Injection Site 
Erythema or Redness, ≤ 
15 years of age  
                                                          
14 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area.  


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Injection Site Pruritus   
  
Itching localized to 
the injection site that 
is relieved  
spontaneously or in < 
48 hours of treatment  
Itching 
beyond 
the 
injection site that is not 
generalized OR Itching 
localized 
to 
the 
injection site requiring 
≥ 48 hours treatment   
Generalized 
itching 
causing 
inability 
to 
perform usual social & 
functional activities   
NA  
LABORATORY VALUES   
CHEMISTRIES 
Acidosis  
NA  
pH ≥ 7.3 to < LLN  
pH < 7.3 without life-
threatening 
consequences  
pH < 7.3 with life-
threatening consequences  
Albumin, Low  
(g/dL; g/L)  
3.0 to < LLN  
30  to < LLN  
≥ 2.0 to < 3.0   
≥ 20  to < 30   
< 2.0   
< 20   
NA  
Alkaline 
Phosphatase, 
High  
1.25  to < 2.5   
x ULN  
2.5  to < 5.0 x ULN  
5.0 to < 10.0 x ULN  
≥ 10.0 x ULN  
Alkalosis  
NA  
pH > ULN to ≤ 7.5  
pH > 7.5 without life-
threatening 
consequences  
pH > 7.5 with life-
threatening consequences   
ALT or 
SGPT, 
High 
Report only one  
1.25  to < 2.5   
x ULN  
2.5 to < 5.0 x ULN  
5.0  to < 10.0 x ULN  
≥ 10.0 x ULN  
Amylase (Pancreatic) or  
Amylase 
(Total), 
High 
Report only one  
1.1  to < 1.5 x ULN  
1.5  to < 3.0 x ULN  
3.0  to < 5.0 x ULN  
≥ 5.0 x ULN  
AST or SGOT, High 
Report only one  
1.25  to < 2.5  x 
ULN  
2.5  to < 5.0 x ULN  
5.0  to < 10.0 x ULN  
≥ 10.0 x ULN  
Bicarbonate, 
Low 
(mEq/L; mmol/L)  
16.0 to <  LLN  
16.0 to <  LLN  
11.0  to < 16.0   
11.0  to < 16.0   
8.0  to < 11.0   
8.0  to < 11.0   
< 8.0   
< 8.0   
Bilirubin  
Direct Bilirubin15, High  
> 28 days of age  
  
  
NA  
  
NA  
  
> ULN   
  
> 
ULN 
with 
life-
threatening  
consequences (e.g., signs 
and symptoms of liver  
failure)  
≤ 28 days of age  
ULN to ≤ 1 mg/dL  
> 1 to ≤ 1.5 mg/dL  
> 1.5 to ≤ 2 mg/dL  
> 2 mg/dL  
Total Bilirubin, High > 
28 days of age  
  
1.1 to < 1.6 x ULN  
  
1.6 to < 2.6 x ULN  
  
2.6 to < 5.0 x ULN  
  
≥  5.0 x ULN  
≤ 28 days of age  
See Appendix A.  
Total Bilirubin for  
Term and Preterm  
Neonates  
See Appendix A.  
Total Bilirubin for  
Term and Preterm  
Neonates  
See Appendix A.  
Total Bilirubin for  
Term and Preterm  
Neonates  
See Appendix A. Total  
Bilirubin for Term and  
Preterm Neonates  
Calcium, High  
(mg/dL; mmol/L)  
10.6   to < 11.5  
2.65  to < 2.88  
11.5  to < 12.5   
2.88  to < 3.13  
12.5   to < 13.5   
3.13  to < 3.38  
                                                          
15 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total bilirubin.  


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CONFIDENTIAL 
 
 
PROTOCOL AMENDMENT 4: VERSION 5.0, 28 MARCH 2018 
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≥ 7 days of age  
 
< 7 days of age  
11.5  to < 12.4   
2.88  to < 3.10  
12.4  to < 12.9   
3.10  to < 3.23  
12.9  to < 13.5   
3.23  to < 3.38  
Calcium (Ionized), High 
(mg/dL; mmol/L)  
> ULN to < 6.0  
> ULN  to < 1.5  
6.0 to < 6.4  
1.5 to < 1.6  
6.4 to < 7.2  
1.6 to < 1.8   
≥ 7.2  
≥ 1.8   
Calcium, Low  
(mg/dL; mmol/L)  
≥ 7 days of age  
7.8  to < 8.4   
1.95  to < 2.10  
7.0   to < 7.8   
1.75  to < 1.95  
6.1  to < 7.0  
1.53  to < 1.75  
< 6.1  < 
1.53  
< 7 days of age  
6.5  to < 7.5  
1.63  to < 1.88  
6.0 to < 6.5  
1.50  to < 1.63  
5.50  to < 6.0  
1.38  to < 1.50  
< 5.50  
< 1.38  
Calcium (Ionized), Low 
(mg/dL; mmol/L)  
< LLN  to 4.0   
< LLN  to 1.0  
3.6 to < 4.0   
0.9 to < 1.0  
3.2 to < 3.6  
0.8 to < 0.9   
< 3.2  
< 0.8   
Cardiac Troponin I, High  NA  
NA  
NA  
Levels consistent with 
myocardial infarction or 
unstable angina as defined 
by the local laboratory  
Creatine Kinase, High  
3 to < 6 x ULN  
6 to < 10 x ULN  
10 to < 20 x ULN  
≥ 20 x ULN  
Creatinine, High  
1.1 to 1.3 x ULN  
> 1.3 to 1.8 x ULN 
OR Increase of > 
0.3 mg/dL above 
baseline  
> 1.8  to < 3.5   
x ULN OR Increase of 
1.5 to < 2.0 x above 
baseline  
≥ 3.5 x ULN OR  
 
Creatinine Clearance16 
or eGFR, Low Report 
only one  
NA  
< 90 to 60 ml/min or  
ml/min/1.73 m2   
OR  
10 to < 30% decrease  
from baseline  
< 60 to 30 ml/min or 
ml/min/1.73 m2  
baseline  
< 
30 
ml/min 
or 
ml/min/1.73 m2  
needed  
Glucose  
(mg/dL; 
mmol/L) 
Fasting, High  
  
  
110 to 125   
6.11 to < 6.95  
  
  
> 125 to 250   
6.95 to < 13.89  
  
  
> 250 to 500   
13.89 to < 27.75  
  
  
> 500   
≥ 27.75  
Nonfasting, High  
116 to 160  
6.44 to < 8.89   
> 160 to 250  
8.89 to < 13.89  
> 250 to 500  
13.89  to < 27.75   
27.75   
Glucose, Low   
(mg/dL; mmol/L)  
≥ 1 month of age  
55  to 64   
3.05  to 3.55   
40  to < 55  
2.22  to < 3.05   
30  to < 40  
1.67 to < 2.22   
< 30  
< 1.67   
< 1 month of age  
50 to 54  
2.78  to 3.00   
40 to < 50  
2.22 to < 2.78   
30 to < 40  
1.67 to < 2.22   
< 30  
< 1.67   
Lactate, High  
ULN to  < 2.0 
x ULN without 
acidosis  
≥ 2.0 x ULN without 
acidosis  
Increased lactate with 
pH < 7.3 without life-
threatening 
consequences   
Increased lactate with pH 
< 
7.3 
with 
life-
threatening consequences  
Lipase, High  
1.1  to < 1.5 x ULN  
1.5  to < 3.0 x ULN  
3.0  to < 5.0 x ULN  
≥ 5.0 x ULN  
                                                          
16 Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2).  


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PROTOCOL AMENDMENT 4: VERSION 5.0, 28 MARCH 2018 
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Lipid Disorders   
(mg/dL; mmol/L)  
Cholesterol, Fasting,  
High  
≥ 18 years of age  
  
200  to < 240   
5.18  to < 6.19   
  
240  to < 300   
6.19  to < 7.77   
  
≥  300  
≥  7.77   
  
NA  
< 18 years of age  
170  to < 200   
4.40  to < 5.15   
200  to < 300  
5.15  to < 7.77   
≥  300   
≥  7.77   
NA  
LDL, Fasting, High ≥ 
18 years of age  
  
130  to < 160   
3.37  to < 4.12   
  
160 to < 190   
4.12  to < 4.90   
  
≥ 190   
≥ 4.90   
  
NA  
> 2 to < 18 years of 
age  
110  to < 130   
2.85  to < 3.34   
130 to < 190   
3.34  to < 4.90   
≥ 190 ≥ 
4.90   
NA  
Triglycerides, Fasting, 
High  
150 to 300   
1.71 to 3.42   
>300  to 500  >3.42 
to 5.7   
>500 to < 1,000   
>5.7 to 11.4   
> 1,000   
> 11.4  
Magnesium17, 
Low 
(mEq/L; mmol/L)  
1.2   to < 1.4   
0.60  to < 0.70   
0.9  to < 1.2   
0.45  to < 0.60   
0.6  to < 0.9   
0.30  to < 0.45   
< 0.6   
< 0.30   
Phosphate, Low   
(mg/dL; mmol/L)  
> 14 years of age  
2.0 to < LLN  
0.81 to < LLN  
1.4 to < 2.0  
0.65 to < 0.81   
1.0 to < 1.4  
0.32 to < 0.65   
< 1.0  
< 0.32   
1 to 14 years of age  
3.0  to < 3.5  
0.97  to < 1.13   
2.5  to < 3.0  
0.81  to < 0.97   
1.5  to < 2.5  
0.48  to < 0.81   
< 1.5  
< 0.48   
< 1 year of age  
3.5  to < 4.5  
1.13  to < 1.45   
2.5  to < 3.5  
0.81  to < 1.13   
1.5  to < 2.5  
0.48  to < 0.81   
< 1.5  
< 0.48   
Potassium, 
High 
(mEq/L; mmol/L)  
5.6  to < 6.0  
5.6  to < 6.0   
6.0  to < 6.5  
6.0  to < 6.5   
6.5  to < 7.0  
6.5  to < 7.0   
≥ 7.0  
≥ 7.0   
Potassium, Low (mEq/L; 
mmol/L)  
3.0  to < 3.4  
3.0  to < 3.4   
2.5  to < 3.0  
2.5  to < 3.0  
2.0  to < 2.5  
2.0  to < 2.5   
< 2.0  
< 2.0   
Sodium, High (mEq/L; 
mmol/L)  
146  to < 150  
146  to < 150   
150  to < 154  
150  to < 154   
154  to < 160  
154  to < 160   
≥ 160  
≥ 160   
Sodium, Low (mEq/L; 
mmol/L)  
130  to < 135  
130  to < 135   
125  to < 130  
125  to < 135   
121  to < 125  
121  to < 125   
≤ 120  
≤ 120   
Uric Acid, High (mg/dL; 
mmol/L)  
7.5  to < 10.0  
0.45  to < 0.59   
10.0  to < 12.0  
0.59  to < 0.71   
12.0  to < 15.0  
0.71  to < 0.89   
  
0.89   
HEMATOLOGY 
Absolute CD4+ Count,  
Low  
(cell/mm3; cells/L)  
> 5 years of age   
(not HIV infected)  
  
300 to < 400  
300 to < 400  
  
 200 to <  300 200 to < 
300  
  
100 to < 200  
100  to < 200  
  
< 100  
< 100  
                                                          
17 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114.  


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Absolute Lymphocyte  
Count, Low   
(cell/mm3; cells/L)  
> 5 years of age   
(not HIV infected)  
  
  
  
600  to < 650  
0.600 x 109  to  
< 0.650 x 109  
  
  
  
500  to < 600  
0.500 x 109  to  
< 0.600 x 109  
  
  
  
350 to < 500  
0.350 x 109  to  
< 0.500 x 109  
  
  
  
< 350  
< 0.350 x 109  
Absolute Neutrophil  
Count (ANC), Low  
(cells/mm3; cells/L)  
> 7 days of age  
  
  
  
800 to 1,000  
0.800 x 109 to 1.000 
x 109  
  
  
  
600 to 799  
0.600 x 109 to 0.799 x  
109  
  
  
  
400 to 599  
0.400 x 109 to 0.599 x  
109  
  
  
  
< 400  
< 0.400 x 109  
2 to 7 days of age  
1,250 to 1,500  
1.250 x 109 to 1.500 x 
109  
1,000 to 1,249  
1.000 x 109 to 1.249 x  
109  
750 to 999  
0.750 x 109 to 0.999 x  
109  
< 750  
< 0.750 x 109  
≤ 1 day of age  
4,000 to 5,000  
4.000 x 109 to  
5.000 x 109  
3,000 to 3,999  
3.000 x 109 to 3.999 x  
109  
1,500 to 2,999  
1.500 x 109 to 2.999 x  
109  
< 1,500  
< 1.500 x 109  
Fibrinogen, 
Decreased 
(mg/dL; g/L)  
100  to < 200  
1.00 to < 2.00   
OR  
0.75 to < 1.00 x 
LLN  
75  to < 100  
0.75  to < 1.00   
OR   
x LLN   
50  to < 75  
0.50  to < 0.75   
OR  
0.25 to < 0.50 x 
LLN  
< 50  
< 0.50   
OR  
< 0.25 x LLN OR 
Associated 
with 
gross bleeding  
Hemoglobin18, Low  
(g/dL; mmol/L)19  
≥ 13 years of age  (male 
only)  
  
  
10.0 to 10.9 6.19 
to 6.76  
  
  
9.0 to < 10.0  
5.57 to < 6.19  
  
  
7.0 to < 9.0  
4.34 to < 5.57  
  
  
< 7.0  
< 4.34  
≥ 13 years of age   
(female only)  
9.5 to 10.4  
5.88 to 6.48  
8.5 to < 9.5  
5.25 to < 5.88  
6.5 to < 8.5  
4.03 to < 5.25  
< 6.5  
< 4.03  
  
 57 days of age 
to < 13 years of age  
(male and female)  
9.5 to 10.4  
5.88 to 6.48  
8.5 to < 9.5  
5.25 to < 5.88  
6.5 to < 8.5  
4.03 to < 5.25  
< 6.5  
< 4.03  
36 to 56 days of age  
(male and female)  
8.5 to 9.6  
5.26 to 5.99  
7.0 to < 8.5  
4.32 to < 5.26  
6.0 to < 7.0  
3.72 to < 4.32  
< 6.0  
< 3.72  
22 to 35 days of age  
(male and female)  
9.5 to 11.0  
5.88 to 6.86  
8.0 to < 9.5  
4.94 to < 5.88  
6.7 to < 8.0  
4.15 to < 4.94  
< 6.7  
< 4.15  
8 to ≤ 21 days of age  
(male and female)  
11.0 to 13.0  
6.81 to 8.10  
9.0 to < 11.0  
5.57 to < 6.81  
8.0 to < 9.0  
4.96 to < 5.57  
< 8.0 < 
4.96  
≤ 7 days of age  
(male and female)  
13.0 to 14.0  
8.05 to 8.72  
10.0 to < 13.0  
6.19 to < 8.05  
9.0 to < 10.0  
5.59 to < 6.19  
< 9.0  
< 5.59  
INR, High   
1.1  to < 1.5 x ULN  
1.5  to < 2.0 x ULN  
2.0  to < 3.0 x ULN  
≥  3.0 x ULN  
                                                          
18 Male and female sex are defined as sex at birth.  
19 The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor.  For grading 
hemoglobin results obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using the 
appropriate conversion factor for the particular laboratory.  
  


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(not on anticoagulation 
therapy)  
Methemoglobin  (% 
hemoglobin)  
5.0  to < 10.0%  
10.0  to < 15.0%  
15.0  to < 20.0%  
≥  20.0%  
PTT, High   
(not on anticoagulation 
therapy)  
1.1  to < 1.66  x 
ULN  
1.66 to < 2.33   
x ULN  
2.33 to < 3.00   
x ULN  
≥  3.00 x ULN  
Platelets, 
Decreased 
(cells/mm3; cells/L)  
100,000  to  
< 124,999   
100.000 x 109  to  
< 124.999 x 109  
50,000  to  
< 100,000  
50.000 x 109  to  
< 100.000 x 109  
25,000  to  
< 50,000   
25.000 x 109  to   
< 50.000 x 109  
< 25,000   
< 25.000 x 109  
PT, High   
(not on anticoagulation 
therapy  
1.1  to < 1.25  x 
ULN  
1.25  to < 1.50   
x ULN  
1.50  to < 3.00   
x ULN  
≥  3.00 x ULN  
WBC, Decreased  
(cells/mm3; cells/L)  
> 7 days of age  
  
  
2,000 to 2,499  
2.000 x 109 to 2.499 x 
109  
  
  
1,500 to 1,999  
1.500 x 109 to 1.999 x  
109  
  
  
1,000 to 1,499  
1.000 x 109 to 1.499 x  
109  
  
  
< 1,000  
< 1.000 x 109  
≤ 7 days of age  
5,500 to 6,999  
5.500 x 109 to 6.999 x 
109  
4,000 to 5,499  
4.000 x 109 to 5.499 x  
109  
2,500 to 3,999  
2.500 x 109 to 3.999 x  
109  
< 2,500  
< 2.500 x 109  
URINALYSIS 
 
Glycosuria (random 
collection tested by 
dipstick)  
Trace to 1+ or  
≤ 250 mg  
2+ or ˃ 250 to    
≤ 500 mg  
> 2+ or > 500 mg  
NA  
Hematuria (not to be 
reported based on dipstick 
findings 
or 
on 
blood 
believed to be of menstrual 
origin)  
6  to < 10 RBCs per 
high power field  
≥ 10 RBCs per high 
power field  
Gross, 
with 
or 
without clots OR 
With RBC casts OR  
Intervention indicated  
Life-threatening 
consequences  
Proteinuria (random 
collection tested by 
dipstick)  
1+  
2+  
3+  or higher  
NA  
  
 
 


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UNIVERSITY COLLEGE LOS ANGELES (UCLA) 
 
CONFIDENTIAL 
 
  
PROTOCOL AMENDMENT 1: OTL-101-4 (18 JANUARY 2017) 
 EFFICACY AND SAFETY OF A CRYOPRESERVED FORMULATION OF 
AUTOLOGOUS CD34+ HEMATOPOIETIC STEM CELLS TRANSDUCED EX VIVO 
WITH EFS LENTIVIRAL VECTOR ENCODING FOR HUMAN ADA GENE IN 
SUBJECTS WITH SEVERE COMBINED IMMUNODEFICIENCY DUE TO ADENOSINE 
DEAMINASE DEFICIENCY 
 
STUDY PROTOCOL 
STUDY number:  OTL-101-4 
PRODUCT: A CRYOPRESERVED FORMULATION OF AUTOLOGOUS CD34+ 
HEMATOPOIETIC STEM CELLS TRANSDUCED EX VIVO WITH EFS LENTIVIRAL 
VECTOR ENCODING FOR THE HUMAN ADA GENE (OTL-101) 
 [IND number: 15440] 
 
Original Protocol, Version 1.0: 24 October 2016 
 Protocol Amendment 1, Version 2.0: 18 January 2017 
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the Sponsor’s prior written authorisation. 
 
 


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CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY  
STUDY number:  OTL-101-4 
Protocol Amendment 1, Version 2.0: 18 January 2017 
RATIONALE AND SUMMARY OF CHANGES  
The purpose of protocol amendment 1 (18 January 2017) is to provide further clarity on 
procedures, align consistent language and terms throughout the document, and provide 
flexibility for blood sample volume due to the age of the subjects to be treated under the 
protocol. 
This document will summarise the key changes accordingly: 
1. Baseline immune function tests can be performed following consent/assent and prior 
to conditioning for subjects (particularly infants) where blood volume is restricted per 
visit. The window for screening assessments has also been aligned with standard 
practice to permit prior assessments to be used within 60 days to confirm eligibility. 
2. A vector integration analysis has been added to assessments post-transplant. 
3. The protocol has been updated in terms of current available information on the 
disease, current treatment options, trial details for the OTL-101 program, and 
permitted concomitant medication (including risks and benefits). 
4. Language consistency applied throughout the document: 
o Age of subjects eligible for inclusion, 
o Quality of life tools to be used (with an added statement to apply age appropriate 
tools), 
o Hematopoietic instead of immune reconstitution, 
o Removal of “possible RT-PCR” from gene transduction assessment 
o Duplicate text removed. 
5. Further details are provided regarding the bone marrow harvesting procedures and the 
requirement to obtain a back-up sample at bone marrow harvest. Further clarification 
on when to use the back-up sample and the withdrawal of subjects from the study if 
there is no evidence of hematopoietic reconstitution.   
6. Busulfan pharmacokinetic data description is removed from the second analysis. 
7. Further clarification of OTL-101 product storage and administration. Dose calculation 
forms (single and multi-bag) have been appended to the protocol for ease of use by the 
Investigator. In addition, an accountability log is provided in the appendix to ensure 
adequate recording and verification of OTL-101 product use. 
8. Clarification on a post-registry study that subjects will be invited to participate in.   
9. Subjects that are enrolled but do not receive the OTL-101 product (regardless of 
reason) will be included in the intention-to-treat population.   
10. Administrative changes and typographical errors (which are not shown in the table 
below). 


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PROTOCOL AMENDMENT TEXT REVISIONS 
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale.  Text that has 
been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font.  
Section No./Title 
Revision 
Relates to 
Change 
No. 
Schedule of 
assessments:  
Table 1 
Assessment timeframes have been specified in the table for Screening, pre-harvest assessment, 
bone marrow harvest, and baseline visits for clarity.  
Text added to parameter assessment in the table: 
ADA-SCID diagnosis confirmation  
Footnote added: 
11. 
The immune function tests required for Visit 3, Assessment C can be performed at any 
point after provision of consent/assent and prior to busulfan administration in younger subjects 
if deemed appropriate by the Investigator. 
12. 
These test can be performed at anytime following BM harvest (Visit 2: Assessment B) 
and prior to OTL-101 administration (Visit 3: Assessment F) in younger subjects if deemed 
appropriate by the Investigator. 
4 
 
 
 
1 
Schedule of 
assessments:  
Table 2 
5.1.7 Follow-Up 
(Visits 4 to 11) 
Vector integration analysis added to the table at Month 3, Month 6, Month 12, Month 18, and 
Month 24 visits. 
Antibodies to tetanus toxoid assessment removed at Month 6 visit. 
FACS T-cells/myeloid by PCR for RCLVCN 
2 
 
4 
1.1.2 Treatment 
Options 
Two current therapeutic methods are currently used for the treatment of ADA SCID, 
hematopoietic stem cell transplantation (HSCT) and ADA enzyme replacement therapy (ERT) 
but both options have significant limitations. 
3 
1.1.2 Treatment 
Options 
Subheadings added: 
1.1.2.1 Hematopoietic Stem Cell Transplantation 
1.1.2.2 Gene Therapy 
3 
1.1.2.2 Gene 
Paragraph added: 
3 


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Section No./Title 
Revision 
Relates to 
Change 
No. 
Therapy 
No gene therapy treatment has been approved in United States (US) to date.  In Europe, 
Strimvelis® is approved for the “treatment of subjects with ADA-SCID, for whom no suitable 
HLA matched related stem cell donor is available”.  Strimvelis® is a GRV based ex vivo gene 
therapy treatment. 
1.4.1 Potential 
Benefits 
Sentence added to third paragraph: 
Durable, life-long clinical benefit is highly dependent on the successful engraftment of 
genetically modified long term repopulating HSC.  The improved correction of HSCs should 
result in improved immune recovery due to correction of both T and B cell populations. 
Edits to sixth paragraph, third sentence: 
The longest follow-up is 4 years58 months. 
3 
1.4.2.1 Potential 
Risks Related to 
the Protocol 
Treatment 
Bullet 1, third sentence: 
In current LV studiessubjects (39 subjects treated to date), there have been no cases of 
oncogenicity. 
3 
1.4.2.3 Potential 
Risks Related to 
Concomitant 
Therapy 
Busulfan 
Busulfan is used for conditioning prior to the re-infusion of the HSCs. The busulfan dose to be 
used in this clinical study will target a specific area under the curve (AUC), which will ensure 
more precise dosing and may reduce the risks of toxicity. The risks attached to busulfan are 
minimal, although there is a very small possibility of busulfan-related cancer.  
More common risks associated with busulfan at higher doses include nausea, vomiting, 
diarrhoea, constipation, loss of appetite, mouth sores, stomach/abdominal pain, dizziness, 
swelling ankles/feet/hand, flushing, headache, or trouble sleeping and a period of neutropaenia. 
However, the above systemic side-effects have not been seen at the proposed busulfan dose for 
this study. 
In the Sponsor's experience to date, there have been no busulfan-related serious adverse events 
(SAEs). 
Pegylated-ADA 
3 


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Section No./Title 
Revision 
Relates to 
Change 
No. 
The withdrawal of PEG-ADA, which is required 1 month after OTL-101 administration, can 
have adverse effects on immunity, as well as on other organ systems. It is possible that a very 
severe infection may develop during this time, which could be fatal if the subject does not 
respond to OTL-101 infusion.  
In the Sponsor's experience to date, there have been no busulfan-related serious adverse events 
(SAEs), neither severe infections nor causalities, related to stopping PEG-ADA ERT, 1 month 
after OTL-101 infusion as per protocol. 
2.1 Purpose of the 
Study 
Eigth sentence: 
Three subjects have already been treated with cryopreserved cells (with a different 
cryoprotectant as the one used under this protocol); two patients treated under Compassionate 
Use Program and one patient treated as an exemption in the USfrom the Phase I/II studies 
conducted at GOSH/UCL and UCLA have received a cryopreserved formulation (not the exact 
cyropreseved formulation used in this protocol). 
3 
2.2.3 Exploratory 
Study Objectives 
9.3.4 Exploratory 
Efficacy 
Vector integration analysis added to the list of exploratory parameters. 
2 
3.1 General 
Design and Study 
Scheme 
First paragraph: 
This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical study 
designed to assess the efficacy and safety of OTL-101 cryopreserved formulation administered 
in ADA-SCID subjects aged between ≥30 days to <18 30 days and 17 years of age, who are not 
eligible for an HLA-matched sibling/family donor and meeting the inclusion/exclusion criteria. 
This study aims to recruit 10 evaluable subjects. 
Fourth paragraph: 
Eligible subjects will be hospitalized to undergo the harvesting of autologous CD34+ cells. A 
backup harvest of non-transduced CD34+cells will be obtained during the harvesting procedure 
to be used in the event of i) product damage during the thawing of the GTMP that would 
4 
 
 
 
 
 
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Section No./Title 
Revision 
Relates to 
Change 
No. 
prevent infusion of the GTMP although the patient has already been conditioned or ii) lack of 
engraftment/hematopoeitic reconstitution  42 days post infusion of the protocol treatment. A 
failure of hematologic reconstitution is defined as at least two of the following: absolute 
neutophil count (ANC) <200/mm3, platelets <20,000/mm3 without transfusions, hemaglobin 
(Hb) <8.0 g/dl without transfusions on three independent and consecutive determinations over at 
least 10 days beyond Day 42 from initial GTMP infusion.  
Sixth paragraph: 
For subjects who have successfully received the OTL-101 product, PEG-ADA ERT will be 
discontinued at Day+30 (+/-3) after the transplant. After their discharge from hospital, the 
subjects will be seen at regular intervals to review their history, perform examinations and draw 
blood samples at Months 1, 3, 6, 9, 12, 18, and 24. Any medically-indicated interventions will 
be determined at these visits. Hematopoietic reconstitution will be assessed at Day 42, and in 
the event of no reconstitution the backup HSC sample will be administered.  Hematapoietic 
reconstitution will be reassessed at Month 6 visit and if there is still no evidence of cellular 
recovery, the subject will be given ERT and/or HSCT, if available, and deemed appropriate by 
the Investigator. After Month 24 visit, the subjects will have completed the study and may enter 
a long term registry. 
 
 
 
 
 
5 
3.1 General 
Design and Study 
Scheme 
9.6.5 Efficacy 
Analyses 
Busulfan pharmacokinetic (PK) data will not be summarised as part of the second analysis.  
This will only be performed as part of the third analysis. 
6 
3.1 General 
Design and Study 
Scheme 
Figure 1 has been revised to reflect the above changes. 
Figure footnotes and abbreviations added: 
# Backup sample will be taken in the event of product damage or failure to achieve hematopoietic reconstitution. 
* The timeframe for the cryopreservation process may vary 
Abbreviations: ADA= Adenosine deaminase, AUC = area under the curve, BM = bone marrowm, EFS = Elongation Factor 1α 
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Section No./Title 
Revision 
Relates to 
Change 
No. 
Short form, ERT = enzyme replacement therapy, LV = lentivirus vector. 
3.2.1 Primary 
Efficacy 
Evaluations and 
Endpoints 
Bullet 1, last sentence: 
This data will be used to compare subject data from the ongoing Phase I/II ongoing studies 
study using the fresh formulation. 
4 
3.4.1 Protocol 
Treatment 
The protocol treatment, OTL-101, is manufactured under Good Manufacturing Practice (GMP) 
guidelines, using the subject’s own CD34+ HSCs. OTL-101 is formulated in Cryostor CS5, 
filled into cryobags, cryopreserved and then stored in the vapor phase of liquid nitrogen (LN2). 
Final product dose and infusion volume calculations are described in Section 6.1.1 and Section 
17: Appendix 1. On the day the subject is to be infused, the cryopreserved OTL-101 product 
bag(s) will be transported to the bedside in a dry nitrogen shipping container. Immediately prior 
to infusion, the bag(s) will be removed from the shipping container and thawed using either a 
plasma thawing device or a pre-warmed sterile water bath (using sterile water). For thawing, the 
OTL-101 product bag(s) will be placed in an outer bag sleeve in case of a leak. After thawing, 
the OTL-101 product bag(s) will be attached to a sterile intravenous line fitted with a three-way 
stopcock and sterile syringe. The cells will be pulled into the syringe from the bag(s), the 
stopcock will be turned and then the contents of the syringe will be pushed through the 
intravenous line into the recipient. The OTL-101 product will be labeled as the Study Agent. 
Please note: when more than one bag is required to be infused, only one OTL-101 product bag 
per hour will be administered (Section 6.1.1). 
7 
3.5 Duration of 
Subject 
Participation 
Sentence added at the end of this section: 
After finalization of this study subjects will be invited and encouraged to participate in a 
registry for long term data collections according to guideline recommendations. 
8 
3.6.1 Subject 
Stopping Rules 
and Criteria for 
Discontinuation 
Bullet 2: 
If two subjects experience prolonged unresponsive pancytopenia, defined as an initial failure of 
hematologic reconstitution which does not improve following the administration of the subject's 
autologous back-up cells. A failure of hematologic reconstitution is defined as at least two of 
the following: absolute neutophil count (ANC) <200/mm3, platelets <20,000/mm3 without 
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Section No./Title 
Revision 
Relates to 
Change 
No. 
transfusions, hemaglobin (Hb) <8.0 g/dl without transfusions on three independent and 
consecutive determinations over at least 10 days beyond Day 42 from initial GTMP infusion.   
If these conditions are met, the subject's autologous back-up cells will be infused via the 
intravenous route. If, at Day 90 following the initial infusion of OTL-101, the failure of 
hematologic reconstitution persists after the subject's autologous back-up cells have been 
infused, the subject can be said to be experiencing prolonged unresponsive pancytopenia.  The 
subject should then receive standard care for pancytopenia. 
3.6.1 Subject 
Stopping Rules 
and Criteria for 
Discontinuation 
Paragraph following the list stopping criteria: 
Any such finding will be discussed with the Sponsor and DSMB, and an agreement should be 
made and documented to detail the conditions under which the study can be resumed before 
enrolling the next subjectwhich must agree to the conditions under which the study can be 
resumed before enrolling the next subject. Evaluations of the study endpoints of subjects 
already enrolled and who have received OTL-101, will continue 
4 
3.7.1 OTL-101 
Storage and 
Security 
Sentence added: 
A backup harvest of non-transduced CD34+ cells will be retained in i) the event of product 
damage during the thawing of the GTMP that would prevent infusion of the GTMP although the 
patient has already been conditioned or ii) lack of engraftment/hematopoeitic reconstitution at 
42 days post GTMP (see Section 3.4). 
5 
3.7.2 OTL-101 
Production 
Bullet 1: 
NOTE: On Day 1, a back-up fraction of mononuclear cells will be cryopreserved .  This back-
up will constitute 3.05.0 x 10e7 mononuclear cells/kg OR 3.0 x 10e7 total nucleated cells/kg. 
5 
3.7.3 OTL-101 
Administration 
Sentence added to the end of the first paragraph: 
The OTL-101 product will be labeled as the Study Agent. 
Sentence added to the end of the second paragraph: 
The OTL-101 product should be stored in the vapor phase of liquid nitrogen (LN2) until 
required to be infused into the subject (see Section 3.4.1). 
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Section No./Title 
Revision 
Relates to 
Change 
No. 
Text added to second bullet: 
(including the certificate of analysis CofA) 
Edits to the third paragraph: 
Final product dose and infusion volume calculations are specified in Section 6.1.1. The 
cryobag(s) will then be thawed using either a plasma thawing device or a pre-warmed sterile 
water bath (using sterile water). For thawing, the OTL-101 product bag will be placed in an 
outer bag sleeve in case of any fracture. 
Sentence addd to the end of the fourth paragraph: 
Please note: when more than one bag is required to be infused, only one OTL-101 product bag 
per hour will be administered (Section 6.1.1). 
3.7.4 OTL-101 
Accountability 
Text added after the first sentence: 
A specific form for the recording of the product traceability can be found in Section 17, 
Appendix 1 (Global Investigational Product Accountability Log).   
5 
5.1 Study Visits 
Consistency applied when referencing the quality of life assessments performed at Screening, 
Month 6, Month 12, Month 18, Month 24 and early termination visits: 
Evaluation of quality of life, as measured by the Karnofsky/Lansky scale and questions relevant 
to generall well-being, absences from school attendance, and ability to practice sports, 
respectivelya quality of life questionnaire and cognitive development 
4 
5.1.1 Screening 
(Visit 1) 
First paragraph, text edited: 
Written informed consent must be obtained prior to any screening procedures (unless routine 
medical care assessments are being used within 60 days of the harvest visit as screening 
assessments). A signed and dated informed consent form will be obtained from the parent/legal 
guardian (according to local law requirements), and a signed and dated assent form will be 
obtained from each subject (aged ≥7 years) before screening procedures, if required according 
to local regulations. Evaluations obtained as part of routine medical care and performed during 
the screening period may be used in place of the study specific evaluations if performed within 
60 days of the harvest visit (Visit 2: Assessment B). The parents/legal guardians of each subject 
1 


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Section No./Title 
Revision 
Relates to 
Change 
No. 
will acknowledge and agree to the possible use of this information for the study by giving 
informed consent. 
Edits to the fourth paragraph: 
The study will start with a screening visit followed by a screening period of up to 60 days prior 
to harvest (Visit 2: Assessment B). The screening visit (Visit 1, Day -33) is defined as the visit 
during which the informed consent form is signed, before any study-related procedures. 
Edits to the third bullet in the list of screening visit parameters: 
Confirmation of ADA-SCID (if not performed before the screening period) 
Duplicate ADA-SCID confirmation paragraph has been removed 
5.1.2 Autologous 
Bone Marrow 
Harvest Period 
(Visit 2)  
Bone Marrow 
Harvest 
(Assessment B) 
For BM harvesting, a central venous access device will be required (if not already in place) for 
ease of phlebotomy and drug administration. The decision between PICC line, a tunneled 
central venous catheter, or an implanted subcutaneous access device will be made by 
discussions with subjects parents and line placement surgeon. A PICC line or central venous 
line may instead be placed as a separate procedure with appropriate sedation or during the 
general anesthesia for the BM harvest.  
The harvest procedure will involve a bilateral BM aspiration in the posterior iliac crests, where 
a total volume required should be between 15-20 ml/kg of the subjects body weight. The BM 
sample will be directly transported to the GMP manufacturing location. 
Compatible irradiated PRBC (10 to 15 cc/kg) may be transfused following the completion of 
marrow harvest, if considered appropriate by the Investigator.This harvesting procedure should 
be followed by the transfusion of PRBC.  
If the subject is otherwise well, he/she may be discharged to home, 1-2 days after harvest. 
If the bone marrow harvest fails to collect sufficient HSCs for transplantation, the Investigator 
may perform a second harvest according to local protocols.  
Any AEs and concomitant medication use should be recorded. 
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Section No./Title 
Revision 
Relates to 
Change 
No. 
Backup Sample 
A back up sample will be taken in the event of damage during thawing or lack of engraftment at 
42 days post GTMP (see Section 3.4), and must constitute 5 x 10e7 mononuclear cells/kg or 3 x 
10e7 total nucleated cells/kg.   
The backup sample will be cryopreserved, and CD34+ cells will be isolated from the remainder. 
The backup harvest will consist of  non-transduced cells that will be retained if required. 
5.1.3 Baseline 
(Visit 3) 
Pre-Conditioning 
(Assessment C) 
Bullet nine, text added: 
Please note: the above immune function tests can be performed at any point after provision of 
consent/assent and prior to busulfan administration in younger subjects if deemed appropriate 
by the Investigator. 
Bullet ten, text added: 
Peripheral blood mononuclear cells (PBMC) and serum banking for RCL determination.  These 
test can be performed at anytime following BM harvest (Visit 2: Assessment B) and prior to 
OTL-101 administration (Visit 3: Assessment F) in younger subjects if deemed appropriate by 
the Investigator. 
Bullet eleven, text added: 
Measurements of erythrocyte ADA enzymatic activity and erythrocyte deoxyadenine nucleotide 
levels.   These test can be performed at anytime following BM harvest (Visit 2: Assessment B) 
and prior to OTL-101 administration (Visit 3: Assessment F) in younger subjects if deemed 
appropriate by the Investigator. 
Second paragraph deleted: 
If the OTL-101 product does not meet the release criteria (see Section 3.7.1), the subject may be 
readmitted once again for a further harvest procedure, if this is deemed appropriate by the 
Investigator. 
1 
5.1.7 Follow-Up 
(Visits 4 to 11) 
Gene transduction/expression edited replacing RCL with VCN at Month 3, Month 6, Month 12, 
Month 24 and early termination visits: 
4 


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Section No./Title 
Revision 
Relates to 
Change 
No. 
Measurement of the proportion of cells containing the inserted ADA gene in PBMC and 
granulocytes as well as FACS-sorted T-cells and myeloid cells by PCR for RCLVCN 
5.1.7 Follow-Up 
(Visits 4 to 11) 
Gene transduction/expression bullet, text removed from Month 1, Month 3, Month 6, Month 
9,and Month 12; 
Measurement of ADA expression in erythrocytes by ADA enzymatic assay and possibly reverse 
transcriptase (RT)-PCR (if samples are positive by DNA-PCR) and deoxyadenine nucleotides in 
RBC. 
4 
5.1.7 Follow-Up 
(Visits 4 to 11) 
Day 42 (Visit 5 - 
+/- 1 week)  
 
Day 42 assessment will use laboratory parameters to confirm if immune reconstitution has 
occurred. If this has not happened by Day 42 the backup HSC sample will be processed 
according to instructions in Section 3.7.  If the Investigator consider the use of the back up HSC 
sample is not in the best interests of the subject, rescue medication, as per standard institute 
protocols, will be implemented. Any treatment administered to the subject will be recorded in 
the eCRF. Adverse events will also be recorded. 
5 
5.1.7 Follow-Up 
(Visits 4 to 11) 
Month 6 (Visit 7 - 
+/- 2 weeks) 
Fourth bullet edited: 
Assessment of the success of treatment at the subject level (“responder analysis”) at 6 months 
post GTMP administration, by evaluating:  
a) Evidence of erythrocyte ADA enzyme activity above baseline/pre-treatment level (>0 
Units), 
b) Evidence of hematopoieticimmune reconstitution (absolute number of CD3 cells 
≥200/mm3),   
c) Detectable gene-marked granulocytes by differential polymerase chain reaction 
(dPCR)/qPCR (≥1/10,000 cells). 
If there is no evidence of hematopoietic reconsitution, subjects will require PEG-ADA and/or 
allogenic HSCT, if available, and deemed appropriate by the Investigator.  The definition 
applied for lack of hematopoietic reconstitution is the failure to meet ALL three criteria listed 
above (a-c).  If a subject fails to meet allAny subject not meeting these three criteria, they will 
be deemed a treatment failure and should be withdrawn from the study as described in 
5 


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Section No./Title 
Revision 
Relates to 
Change 
No. 
Section 3.6.1. 
5.1.7 Follow-Up 
(Visits 4 to 11) 
 
Immune function test bullet, third sub-bullet text added t Month 12, Month 18, Month 24 and 
early termination visits: 
Measurement of specific antibodies to tetanus toxoid only if subjects have stopped 
immunoglobulin replacement and have received tetanus vaccination 
4 
6.1.1 Autologous 
Bone Marrow 
Harvest and 
Processing 
 
Section removed: 
In the US, because of the early detection of the disease through the screening of newborns, bone 
marrow will be used as the source of CD34+ HSCs for the manufacture of OTL-101.  
If the subject does not already have a central venous access device, a central venous access 
device will be placed for ease of phlebotomy and drug administration. The decision between 
PICC line, a tunneled central venous catheter, or an implanted sub-cutaneous access device will 
be made by discussions with parents and line placement surgeon. A PICC line may instead be 
placed as a separate procedure with appropriate sedation or a central venous line may be placed 
during the general anesthesia for the bone marrow harvest.  
Bone marrow will be harvested from the subject under general anesthesia from the posterior 
iliac crests on both sides by multiple punctures. The amount of marrow collected will be 
equivalent to 15 to 20 ml/kg of body weight and will be directly transported to the GMP 
manufacturing location. Compatible irradiated PRBC (10 to 15 cc/kg) will be transfused at the 
completion of marrow harvest. 
4 
6.1.1 
Administration of 
OTL-101  
Final Product 
Dose and Infusion 
Volume 
Calculations 
Section edited: 
Dose calculation forms are provided in Section 17: Appendix 1.  Use the Single Product Bag 
form unless there is more than one final product bag.  Use the Multi-Bag form only if there are 
two product bags. A form must be completed for each subject and will be used as source data.  
This form should be filed in the subject’s medical notes. 
Dose calculation: 
1. Prior to busulfan administration, calculate the total Final Product (FP) CD34+ cells per kg 
7 


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Section No./Title 
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Relates to 
Change 
No. 
as described on the appropriate worksheet. All values required to perform the calculation 
will be found on the Certificate of Analysis for the OTL-101 Final Product. 
2. Select course of action based on the following criteria: 
• The Total FP CD34+ cells per kg is less than 2.0x106 CD34+/kg.  An additional final 
product manufacturing process will be required to obtain the minimum acceptable dose  
• The Total FP CD34+ cells per kg is greater than 2.0x106 CD34+/kg and less than 
20.0x106 CD34+/kg. Thaw and infuse the entire combined final product volume 
• The Total FP CD34+ cells per kg is greater than 20.0x106 CD34+/kg, The volume to 
infuse must be calculated as described on the appropriate worksheet.  Do not rinse the 
partially infused OTL-101 bag after infusion. 
The final dose and volume administered to the subjects is required to be recorded in the eCRF. 
When more than one bag is used, only infuse one OTL-101 product bag per hour. 
Dose calculation: 
3. Calculate the Final Product CD34+ cells per kg by multiplying the Final Product Total Cells 
by the % CD34+ Purity and then dividing by the subject Weight (obtained at harvest).  
Obtain these values from the Final Product certificate of analysis: 
 
x 106 
 
÷ 
 
= 
 
106/ kg 
Final Product 
Total cells 
 
% CD34 
Purity 
 
Subject 
weight 
 
Final Product 
CD34 cells / kg 
 
4. Select course of action based on the following criteria: 
− The Final Product CD34+ cells per kg is less than 2.0x106 CD34+/kg.  An additional final 


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Section No./Title 
Revision 
Relates to 
Change 
No. 
product manufacturing process will be required to obtain the minimum acceptable dose  
− The Final Product CD34+ cells per kg is greater than 2.0x106 CD34+/kg and less than 
20.0x106 CD34+/kg. Thaw and infuse the entire final product volume 
− The Final Product CD34+ cells per kg is greater than 20.0x106 CD34+/kg, calculate the 
volume to infuse as follows and do not rinse the OTL-101 bag after infusion: 
a) Obtain the Final Product Certificate of Analysis which contains the values for the 
Final Product (FP) Total Cells, %CD34+ Purity, and Final Product Volume 
b) Calculate the Final Product CD34+ cells/mL by multiplying the Final Product 
Total Cell Number by the %CD34+ Purity and dividing by the Final Product 
volume 
 
x 106 
 
= 
 
x 106 ÷  
= 
 
Final product 
total cells 
 
% CD34 
Purity 
 Final product 
CD34 cells 
 
 Final product 
volume (mL) 
 
Final product 
CD34 cells/mL 
Calculate the infusion volume by dividing 20.0x106 CD34+/kg by the FP CD34+ cells/mL. 
20.0x106 CD34+/kg 
 
÷ x106CD34+/mL = 
 
 
Final product CD34+ 
cells/mL 
 
 
 Infusion volume (mL) 
The final dose and volume administered to the subjects is required to be recorded in the eCRF. 
6.2.1.1 Transplant-
related Therapies 
Enzyme 
replacement 
2. Rules for re-starting ERT or plan allogenic HSCT (if available) 
If, by 6 months after the cell product infusion, there is no evidence of hematopoietic 
reconsitution following the infusion of the back up sample and rescue medication,as defined 
below, subjects will require rescue PEG-ADA or allogenic HSCT if available. Positive evidence 
5 


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Section No./Title 
Revision 
Relates to 
Change 
No. 
therapy with PEG-
ADA 
of hematopoietic reconstitution will require: 
a. RBC ADA >0 Units,  
b. absolute CD3+ T-cell counts ≥200/mm3, and  
c. peripheral blood samples positive for vector sequences by qPCR 
(>1/10,000 cells). 
In addition, PEG-ADA may be re-started if the Investigator deems it in the best interests of the 
subject on clinical grounds, e.g. multiple, serious or unresponsive infections or sub-normal 
immune reconstitution. Once ERT has been re-started, the subject will remain in the study and 
will continue to be followed-up.  If the subject fails to demonstrate hematopoietic reconsitution 
and has the possibility of receiving a transplant, the subject should be withdrawn from the study 
in order to follow institute transplantation protocols. 
7.2 Efficacy 
Assessments 
Quality of Life 
Sentence added to the end of the last paragraph: 
Questions suitable/relevant to the age of the subject will be posed. 
4 
8.6.3 Urinalysis 
Text removed: 
Fresh urine samples (at least 10 mL) will be collected and will include the assessment of 
parameters listed in Table 3, according to the times indicated in Table 1 and Table 2 
4 
9.5.2 Full Analysis 
Set 
Text added: 
The full analysis set will be identical in composition to the safety analysis set. Subjects not 
receiving the product due to failure of the manufacturing process will be part of Intent To Treat 
group. 
9 
17 Appendices 
Appendix 1: OTL-
101 Infusion 
Procedure and 
Dosing Forms 
First bullet added to “Infusion Procedure”, subheading “General” 
Obtain and review the Dose and Infusion Volume Calculation Worksheet which was completed 
prior to Busulfan administration, 
Third bullet, last sentence edited in “Infusion Procedure”, subheading “Infusion” 
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Section No./Title 
Revision 
Relates to 
Change 
No. 
Do not thaw subsequent bags until the previous bag’s infusion is complete Only one OTL-101 
product bag may be infused per hour, 
Fourteenth bullet, sentence added in “Infusion Procedure”, subheading “Infusion” 
Do not infuse more than one OTL-101 product bag per hour. 
First bullet edited in “Infusion Procedure”, subheading “Post Infusion” 
Resume the normal saline infusion for 30 minutes to ensure that no product remains in the IV 
catheter tubing 
The following worksheets (regarding dose calculation for single and multi-product bag infusion) 
and accountability log were added to Appendix 1: 
Final Product Dose and Infusion Volume Calculation – Single Product Bag 
Final Product Dose and Infusion Volume Calculation – Multi Product Bag 
Global Investigational Product Accountability Log 
Entire document 
1. Clarity on the use of bone marrow as the source of hematopoistic stem cells. 
2. Hematopoietic reconstitution replaces immune reconstitution. 
3. Spelling corrections and abbreviations. 
4 
 


UNIVERSITY COLLEGE LOS ANGELES (UCLA) 
 
CONFIDENTIAL 
 
  
PROTOCOL AMENDMENT 2: OTL-101-4 (05 MAY 2017) 
 EFFICACY AND SAFETY OF A CRYOPRESERVED FORMULATION OF 
AUTOLOGOUS CD34+ HEMATOPOIETIC STEM CELLS TRANSDUCED EX VIVO 
WITH EFS LENTIVIRAL VECTOR ENCODING FOR HUMAN ADA GENE IN 
SUBJECTS WITH SEVERE COMBINED IMMUNODEFICIENCY DUE TO ADENOSINE 
DEAMINASE DEFICIENCY 
 
STUDY PROTOCOL 
STUDY number:  OTL-101-4 
PRODUCT: A CRYOPRESERVED FORMULATION OF AUTOLOGOUS CD34+ 
HEMATOPOIETIC STEM CELLS TRANSDUCED EX VIVO WITH EFS LENTIVIRAL 
VECTOR ENCODING FOR THE HUMAN ADA GENE (OTL-101) 
 [IND number: 15440] 
 
Original Protocol, Version 1.0: 24 October 2016 
 Protocol Amendment 1, Version 2.0: 18 January 2017 
Protocol Amendment 2, Version 3.0: 05 May 2017 
 
Persons supplied with this information must understand that it is strictly confidential. 
Information contained herein cannot be disclosed, submitted for publication or used for any 
purpose other than that contemplated herein without the Sponsor’s prior written authorisation. 


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OTL-101-4 
 
CONFIDENTIAL 
 
 
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CLINICAL STUDY PROTOCOL AMENDMENT SUMMARY  
STUDY number:  OTL-101-4 
Protocol Amendment 2, Version 3.0: 05 May 2017 
RATIONALE AND SUMMARY OF CHANGES  
The purpose of protocol amendment 2 (05 May 2017) is to align the protocol with the 
statistical analysis plan and provide flexibility in the timelines for administration of the 
Busulfan-conditioning regimen reflecting current clinical practices. 
This document will summarise the key changes accordingly: 
1. Align the protocol with the statistical analysis plan and apply consistency across 
objectives and endpoints. 
2. Provide flexibility in the timelines for administration of the Busulfan-conditioning 
regimen reflecting current clinical practices and screening assessment windows. 
3. Change in CRO contact details. 
4. Clarification of back up sample timings and storage requirements of the OTL-101 
product. 
5. Revision of multi-bag infusion form. 
6. Administrative changes and typographical errors (which are not shown in the table 
below). 
o Change all references of gene therapy medicinal product (GTMP) or 
protocol treatment to OTL-101 throughout the document, 
o Update of subject recruitment figures for existing studies as of 14 October 
2016, 
o Readability, 
o Correct typographical errors 


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PROTOCOL AMENDMENT 2: VERSION 3.0, 05 MAY 2017 
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PROTOCOL AMENDMENT TEXT REVISIONS 
The following table summarizes the revisions made to the protocol and relates the changes to the appropriate rationale.  Text that has 
been added or inserted is indicated by underlined font, and deleted text is indicated by strikethrough font.  
Section No./Title 
Revision 
Relates to 
Change No. 
3 
Table 1:  Schedule 
of Events – 
Screening to Day 
24 
Study Period 
Conditioning 
Visit 
3 
3 
Assessment 
D 
E 
Day 
Day -4 to -3 
Day -2 to -1 
2 
2.2.1 Primary 
Study Objectives 
First primary objective: 
This 6 month data will be used to compare the proportion of “responders analysis” obtained 
fromamong subjects treated with the cryopreserved population with that in a comparable 
population obtained from one of the ongoing Phase I/II studies using the fresh formulation 
1 
3.1 General 
Design and Study 
Scheme 
Second paragraph: 
The aim of this clinical study is also to assess the success of treatment at the subject level 
(“responder analysis”) 6 months post OTL-101 infusionGTMP administration, using predictive 
criteria for overall survival and event free survival and to compare this with data obtained from 
one of the ongoing Phase I/II clinical studies using the fresh formulation of OTL-101. 
Sixth paragraph, first bullet, third sentence: 
This data will be compared with available data from one of the ongoing Phase I/II studies 
UCLA ongoing Phase I/II study, treated withusing the OTL 101 fresh formulation 
1 
3.1 General 
Design and Study 
Figure 1 updated to reflect the revised schedule for conditioning as specified in Table 1:  
Schedule of Events – Screening to Day 24  
2 


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Section No./Title 
Revision 
Relates to 
Change No. 
Scheme 
3.2.1 Primary 
Efficacy 
Evaluations and 
Endpoints 
 
And 
 
7.1.1 Primary 
Efficacy 
Endpoints 
The primary efficacy endpoints for this study include: 
1. Evaluation of OTL-101 at 6 months, post OTL-101 infusionGTMP administration, in 
support of CMC assessing comparability of cryopreserved and fresh formulations, by 
evaluatingevaluation of the success of therapy success for each subject based on all three 
the following parameters listed below and their thresholds being met: 
a) Erythrocyte ADA enzyme activity above baseline/pre-treatment level Red blood cells 
ADA (>0 Units),  
b) Absolute CD3+ T-cell counts ≥200/mm3, and  
c) Peripheral blood samples positive for vector sequences by qPCR(≥1/10,000 cells). 
Please note: subjects must meet all three criteria. Subjects not meeting any these one 
criteriona will be designated a failure (non-responder). Further details are described in 
Section 3.6.1.  
This data will be used to compared with subject data from the ongoing Phase I/II study using 
the fresh formulation. 
1 
3.2.3 Safety 
Evaluations and 
Endpoints 
The safety and tolerability of OTL-101 will be assessed throughout the study by evaluating 
adverse events (AEs), clinical laboratory test results, vital signs measurements, 
electrocardiogram (ECG), physical examination results, and concomitant medication usage.  In 
addition, the safety of OTL-101 will be assessed through monitoring infections and any 
emergence of replication competent lentivirus, monoclonal expansion or leukemia due to 
chosen vector. 
1 
3.2.4 Exploratory 
Endpoints and 
Evaluations 
 
 
 
The exploratory endpoints will include laboratory correlates of efficacy that will be used to 
assess the level of gene correction, engraftment and immune reconstitution as exploratory 
endpoints.:   
• 
Quantification of clonal diversity of vector integrants.  
• 
TREC and FACS for TCR V-beta family use. 
• 
Percentage gene marking in peripheral blood cells. 
• 
Adenosine deaminase enzyme activity in erythrocytes.  
• 
Total adenine nucleotides in erythrocytes. 
• 
Vector integration analysis.  
1 


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Section No./Title 
Revision 
Relates to 
Change No. 
• 
Immune reconstitution 
o Absolute Lymphocyte Count. 
o Absolute numbers of T, B, NK lymphocytes in peripheral blood. 
o T lymphocyte proliferative responses to mitogen (PHA) and to antigens (tetanus toxoid 
after vaccination)  
o Serum immunoglobulin levels (IgG, IgA and IgM).   
Full descriptions of the exploratory assessments are presented in Section 7.1.3. 
3.7.1 OTL-101 
Storage and 
Security 
The protocol treatment being investigated in this study (OTL-101) is manufactured from the 
individual subject’s bone marrow CD34+ HSCs. The Subject’s BM will be harvested at the 
clinical site and then transferred to a GMP compliant manufacturing facility for onward 
processing. At the GMP facility CD34+ cells will be isolated, transduced, formulated, filled 
into cryobags and then cryopreserved. The autologous, cryopreserved OTL 101 protocol 
treatment will be stored as part of a controlled inventory at ≤-135°C in the vapor phase of LN2 
until released for administration to the subject. The storage of OTL-101 will be in accordance 
with UCLA standard procedures. Access to OTL-101 will only be permitted for individuals 
designated by the Investigator who are responsible and trained staff listed in the site personnel 
log at the clinical site. For release, the product must meet defined acceptance criteria for 
Quality Control assays of safety, identity, viability, purity and potency.  During the first 
harvest, Aa backup harvest sample of non-transduced CD34+ cells will be retained in i) the 
event of product damage or below product release specifications during the thawing of the 
GTMP OTL-101 that would prevent the infusion to takinge place evenof the GTMP although 
the patient has already been conditioned or ii) lack of engraftment/hematopoeitic reconstitution 
at 42 days post GTMP OTL-101 infusion (see Section 3.4). In the event that a second BM 
harvest is required, the same storage and security procedures will be followed.  A second 
backup sample is only required if the first backup is not reliable, e.g. if contamination of the 
initial marrow harvest had occurred. 
4 
3.7.2 OTL-101 
Production 
First bullet: 
NOTE: On Day 1, a back-up fraction of mononuclear cells will be cryopreserved .  This back-
up will constitute ≥35.0 x 10e7 mononuclear cells/kg OR 3.0 x 10e7 total nucleated cells/kg. 
Third bullet, sub-bullet iii: 
4 


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Section No./Title 
Revision 
Relates to 
Change No. 
Temperature has been added at ≤-135°C. 
3.7.3 OTL-101 
Administration 
Third bullet: 
Hold the shipping container in secure storage at ≤-135°C , according to UCLA standard 
procedures, until requested by the Investigator. Storage instructions are specified in Section 
3.7.1. 
Penultimate paragraph, sentence added: 
If more than one bag is needed to achieve the dose, the weight of the subject must be higher 
than 4 kg to comply with recommended limit of DMSO per kg body weight per day prior to 
infusion. 
4 and 5 
3.7.4 OTL-101 
Accountability 
Second paragraph, last sentence: 
The OTL-101 protocol treatment mustis not to be administered or dispensed toinfused to any 
person who is not a study subject under this protocol.the biological owner of the stem cells. 
4 
5.1.1 Screening 
(Visit 1) 
First paragraph, third sentence: 
Evaluations obtained as part of routine medical care and performed during the screening period 
may be used in place of the study specific evaluations if performed within 60 days of the 
harvest visit (Visit 2: Assessment B), except for cytogenetics, which may be used 
independently from the time they have been performed. 
List of screening assessment, blood tests, fourth bullet: 
Peripheral blood or bone marrow for cytogenetic analysis (if cytogenetic testing has not been 
performed on cells from amniocentesis) by karyotype, Comparative Genome Hybridization 
(CGH), whole exome sequencing (WES) or other and may be used independently from the 
time they have been performed. 
2 
5.1.2 Autologous 
Bone Marrow 
Harvest Period 
(Visit 2) 
Fifth paragraph: 
If the first bone marrow harvest fails to collect sufficient HSCs for transplantation or if the 
product fails to meet theany release criteria, the Investigator may perform a second harvest 
according to local protocols. Screening studies will not be repeated unless 1 year or more has 
passed from the time of the first harvest. 
Backup Sample sub-heading: 
A back up sample will be taken at the first harvest procedure, in the event of damage during 
thawing, failure to meet product release specifications or lack of engraftment at 42 days post 
2 and 4 
 
 
 
 
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Section No./Title 
Revision 
Relates to 
Change No. 
GMTPOTL-101 infusion (see Section 3.4), and must constitute ≥3.05 x 10e7 mononuclear 
cells/kg or 3 x 10e7 total nucleated cells/kg 
The backup sample will be cryopreserved, and CD34+ cells will be isolated from the 
remainder. The backup harvest will consist of  non-transduced cells that will be retained if 
required. A second backup sample is only required if the first backup is not reliable, e.g. if 
contamination of the initial marrow harvest had occurred. 
6.1.1 
Administration of 
OTL-101 
Last paragraph edited: 
When more than one bag is usedneeded, only infuse one OTL-101 product bag per hour, and 
ensure prior to infusion that the weight of the subject is higher than 4 kg to comply with 
recommended limit of DMSO per kg body weight per day. 
5 
6.2.1.1 Transplant-
related Therapies, 
Non-
myeloablative 
conditioning with 
Busulfan 
Any reference to Day -3 has been changed to Day-4 to -3. 
Any reference to Day -1 has been changed to Day -2 to -1 
2 
6.3 Administration 
Compliance 
Second sentence added: 
If a subject fails to demonstrate engraftment/hematopoietic reconstitution at 42 days post initial 
OTL-101 infusion, their backup sample may be administered. 
4 
7.1.1 Primary 
Efficacy 
Endpoints 
Last paragraph: 
The proportion of responders in this studyis data will be used to compared with the proportion 
subject data from of responders in one of the Phase I/II ongoing studies using the fresh 
formulation 
1 
7.1.3 Exploratory 
Efficacy 
Endpoints 
 
And  
 
9.3.3 Exploratory 
Removal of timepoints for the assessment of exploratory endpoints. 
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Section No./Title 
Revision 
Relates to 
Change No. 
Efficacy 
Endpoints 
Section 9 
The presentation of the study endpoints has been re-ordered. 
1 
9.3.2 9.3.1 
Primary Efficacy 
Endpoints 
The primary efficacy endpoints for this study include treatment success at 6 months, post OTL-
101 infusion, and overall survival and event-free survival at 12 months post OTL-101 infusion. 
Treatment success at 6 months, post OTL-101 infusion, will be performed in support of CMC 
assessing comparability between cryopreserved and fresh formulations. Evaluation of the 
success of therapy will be based on the following parameters and their thresholds: 
a) 
Erythrocyte ADA enzyme activity above baseline/pre-treatment level (>0 Units),  
b) 
Absolute CD3+ T-cell counts ≥ 200/mm3, and  
c) 
Peripheral blood samples positive for vector sequences by qPCR(≥1/10,000 cells). 
Treatment will be deemed sucessful in subjects meeting all three above thresholds.  These 
subjects will be designated as “responders”. Those subjects failing to meet at least one of the 
above thresholds will be considered to be “non-responders.” 
The primary efficacy endpoints of the study include overall survival and event-free survival at 
12 months post OTL-101 administration. 
Overall Survival is defined as the time-to death from the start of protocol treatmentOTL-101 
infusion if death occurred, or to the date of the last evaluationfurthest point observed if death 
did not occur. If no death occurred, the subject’s data will be considered censored from at the 
last observed time pointevaluation. 
Event Free Survival is defined as the time-to event from the start of protocol treatment OTL-
101 infusion if an event occurred, or to the date of the last evaluationfurthest point observed 
without an event if no event occurred. If no event occurred, the subject’s data will be 
considered censored from at the last evaluationobserved time point. Event is defined as any of 
the following:  
• 
Death    
• 
Returning to PEG-ADA ERT 
• 
Need of rescue HSCT 
In addition, to allow the evaluation of GTMP OTL-101treatment at 6 months post 
administration in support of CMC assessing comparability between cryopreserved and fresh 
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Section No./Title 
Revision 
Relates to 
Change No. 
formulations, evaluation of the success of therapy success will be based on the following 
parameters and their thresholds will be performed: 
a) 
Red blood cells ADA >0 Units,  
b) 
Absolute CD3+ T-cell counts ≥ 200/mm3, and  
c) 
Peripheral blood samples positive for vector sequences by qPCR(≥1/10,000 cells). 
Subjects meeting all three thresholds will be designated “success” and those failing to meet at 
least one of the thresholds will be designated “failure.” 
9.5 Analysis 
Populations 
Analysis sets has been changed to analysis populations throughout. 
1 
9.5.2 9.5.1 Full 
Analysis 
SetEfficacy 
Population 
The efficacy population will be a modified intent-to-treat population including all subjects 
treated with OTL-101 within this protocolfull analysis set will be identical in composition to 
the safety analysis set.  Subjects not receiving the product due to failure of the manufacturing 
process will be part of Intent To Treat group. 
1 
9.6.1 Overview 
Second paragraphs onwards: 
Data listings by subject will be provided and, where applicable, presented graphically. 
All statistical analyses will be performed and data appendices will be created using Statistical 
Analysis System (SAS)® Version 9.4. or higher. 
Three analyses will be performed during this study as summarized in Section 9.6.5. At the 
same time, subject disposition, baseline characteristics and safety analysis will also be 
performed at these three stages. 
The text below has been moved from Efficacy analysis section and revised.  
Statistical analyses will be performed, and their outcomes presented, in three stages: 
1. 
The first (interim) analysis will compare the success/failure data 6-months post OTL-
101 infusion.  The success/failure of the OTL-101 cryopreserved formulation will be defined 
by the three criteria listed in the primary objectives (Section 2.2.1). This data will be 
compared with available data from the ongoing UCLA Phase I/II study, treated with using 
the OTL 101 fresh formulation. This will support the CMC comparability data between 
OTL-101 cryopreserved and fresh formulations. Secondary and exploratory endpoints will 
also be described. 
2. 
The second (primary) analysis will determine the 12 month overall survival and event 
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Section No./Title 
Revision 
Relates to 
Change No. 
free survival for all subjects. Secondary and exploratory endpoints,  as well as baseline 
characteristics, subject disposition, and safety data will also be described. 
3. 
The third (and final) analysis will be performed to determine the overall survival and 
event free survival for all subjects 24 months post OTL-101 infusion.  Secondary and 
exploratory endpoints,  as well as baseline characteristics, subject disposition, safety and 
Busulfan PK data will also be described. 
This study is not designed to be powered to demonstrate statistical significance; therefore, no 
correction for overall Type I Error will be performed. 
9.6.2 Subject 
Disposition 
Subject disposition will be tabulated; the number of enrolled, exposed, prematurely terminated, 
ongoing and completed subjects will be summarized by visit (where relevant). 
1 
9.6.4 Efficacy 
Analyses 
 
The primary efficacy endpoints will be summarized as follows: 
Responder Analysis 
The proportion of responders in this study will be summarized and compared with the 
proportion of responders in the Phase I/II ongoing studies using the fresh formulation. 
Overall and Event Free Survival 
Overall and event free survival will be summarized using: 
• 
Proportion of patients who survived at each specified analysis timepoint, with the exact 
binomial 95% confidence interval. 
• 
Kaplan-Meier survival curve of time to death/event. 
All efficacy summaries will be descriptive, there will be no formal statistical comparisons. 
1 
9.6.4 9.6.5 Safety 
Analyses 
 
All AEs will be coded according to the current Medical Dictionary for Regulatory Activities 
(MedDRA) version and will be classified by MedDRA preferred term and system organ class. 
AE listings will be presented by subject, system organ class and preferred term. Incidence of 
treatment emergent AEs (TEAE) and SAEs will be tabulated by system organ class and 
preferred term. In addition, summary tables will be presented by maximum severity, 
relationship to treatment and TEAEs associated with premature withdrawal from the study. 
A TEAE is defined as any AE that occurs during the active phase of the study if:  
• 
it was not present prior to receiving the OTL-101 infusion, or  
• 
it was present prior to receiving the OTL-101 infusion but the intensity increased 
during the active phase of the study, or  
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Section No./Title 
Revision 
Relates to 
Change No. 
• 
it was present prior to receiving theOTL-101 infusion, the intensity is the same but the 
drug relationship became related during the active phase of the study.  
Summary statistics (mean, median, SD and range as appropriate) will be presented for vital 
signs, ECG parameters and, clinical laboratory tests at each assessment along with change 
from baseline. For laboratory data, abnormal values will be flagged in the data listings. Shift 
tables will be presented of the number and percentage of subjects with low, normal or high 
values and normal or abnormal examinations at each visit and overall. 
Safety will be analyzed descriptively over time. Coding will be performed using CTCAE 
MedDRA Version 4.0 or higher. Adverse events, including SAE’s, will be presented by: 
• 
System organ class and preferred term 
• 
Relation to autoimmunity  
• 
Whether or not the event led to administration of PEG-ADA, use of immunoglobulin 
replacement therapy, high-dose steroids, or infusion of additional cells (back-up cells) 
Where appropriate, shift tables will be presented for vital signs and physical examination. 
9.7 
Pharmacokinetic 
Analysis 
Second paragraph, first sentence: 
The following Busulfan PK parameters will be examined summarizedand will be graphically 
presentated for each subject (concentration versus time). 
1 
17: Appendix 1 
Replacement of Final Product Dose and Infusion Volume Calculation – Multi Product Bag 
5 
 


IND 15440, Study no. OTL-101-4 
 
 List of protocol changes from v3.0 to v4.0 – 08 September 2017 
UNIVERSITY OF CALIFORNIA, LOS ANGELES (UCLA)  
 
 
 
Confidential 
IND 15440 
Study no.: OTL-101-4 
 
Summary of protocol changes 
Study protocol version 3.0, dated 05 May 2017 
Updated document: Study Protocol Version 4.0, dated 08 September 2017 
 
• 
Page 4, Synopsis, and Section 3.1, General Design and Study Scheme – version 3.0 of the protocol included language regarding administration of 
enzyme replacement therapy (ERT). This was modified to clarify that ERT use and discontinuation is to be evaluated in treated patients at the 1 
month follow-up visit. Additionally, the text was updated to clearly state that the need to reinstate ERT will be assessed at all follow-up visits after 
month 1. The windows for all study visits were clearly stated in the synopsis, and the window for ERT discontinuation was modified from (Day 30 
plus or minus 3 days) to (Day 30 minus 3 plus 15 days), allowing the Investigator to delay ERT discontinuation by a few days if in the best interest of 
the subject; 
• 
Page 5, Synopsis; Section 3.1, General Design and Study Scheme; Section 3.6.1, Subject Stopping Rules and Criteria for Discontinuation; Section 
5.1.7, Follow-up (Visits 4 to 11); Section 6.1.2, Rescue Administration of Autologous HSC Backup -  hematologic reconstitution at Day 42 was more 
clearly defined throughout the text, and the parameters used to define a failure of hematologic reconstitution at Day 42 were simplified according 
to the Investigator’s clinical judgement; 
• 
Pages 9, 11 and 12, Schedule of Events – changes were made to the assessments required, their schedule and the legend. The “TREC and TCR Vβ” 
and “IgG, IgA, IgM levels” assessments were removed to avoid repetition, as already contemplated under “immune function”. The “Presence of 
ADA gene in PBMC/granulocytes” assessment was updated to include the possibility of being carried out in lineage-sorted cells. The “RCL assay in 
PBMC” assessment was added, and the schedules of the “ADA enzymatic assay” and “Deoxyadenine nucleotides in RBC” assessments were 
updated, in order to collect necessary safety data and data on treatment effect and patient status. Flow cytometry markers in the legend of the 
schedule of events were updated to match those described in the body of the protocol, and footnotes were updated and rearranged for clarity; 
• 
Section 3.6.1, Subject Stopping Rules and Criteria for Discontinuation – this section was updated following confirmation of treatment failure for 
patient 602, upon suggestion by the FDA; 
• 
Section 5.1.7, Follow-up (Visits 4 to 11) – the text was modified to reflect the changes made in the schedule of events; 
• 
Minor readability and typographical errors were corrected in the text (not shown in the table below). 
 
 
 
 


IND 15440, Study no. OTL-101-4 
 
 List of protocol changes from v3.0 to v4.0 – 08 September 2017 
UNIVERSITY OF CALIFORNIA, LOS ANGELES (UCLA)  
 
 
 
Confidential 
Section 
Previous wording (v3.0) 
New wording (v4.0) 
Rationale 
Synopsis, Study Design 
(page 4)  
A failure of hematologic 
reconstitution is defined as at 
least two of the following: 
absolute neutophil count (ANC) 
<200/mm3, platelets 
<20,000/mm3 without 
transfusions, hemaglobin (Hb) 
<8.0 g/dl without transfusions on 
three independent and 
consecutive determinations over 
at least 10 days beyond Day 42 
from initial OTL-101 infusion. 
A failure of hematologic reconstitution is defined as 
persistent ANC < 200/µl or platelets < 20,000/µl on 
three independent and consecutive determinations 
over at least ten days after day 42 from the day of 
OTL-101 infusion.at least two of the following: 
absolute neutophil count 
(ANC) 
<200/mm3, 
platelets 
<20,000/mm3 
without 
transfusions, 
hemaglobin (Hb) <8.0 g/dl without transfusions on 
three independent and consecutive determinations 
over at least 10 days beyond Day 42 from initial 
OTL 101 infusion. 
The parameters used to define a 
failure of hematologic 
reconstitution were simplified 
according to the Investigator’s 
clinical judgement. 
Synopsis, Study Design 
(Page 4) 
For 
subjects 
who 
have 
successfully received the OTL-101 
product, PEG-ADA ERT will be 
discontinued at Day+30 (+/-3) 
after the transplant. After their 
discharge 
from 
hospital, 
the 
subjects will be seen at regular 
intervals to review their history, 
perform examinations and draw 
blood samples at Months 1, 3, 6, 
9, 12, 18, and 24. Any medically-
indicated interventions will be 
determined 
at 
these 
visits. 
Hematopoietic reconstitution will 
be assessed at Day 42, and in the 
event of no reconstitution the 
backup HSC sample will be 
administered. 
 
Hematapoietic 
reconstitution will be reassessed 
at Month 6 visit and if there is still 
For subjects who have successfully received the 
OTL-101 product, PEG-ADA ERT use will be 
evaluated at the 1 Month follow-up visit (30 days 
post treatment ± 7 days) and discontinued at Day 
30 (-3/+15) after the transplant. Hematologic 
reconstitution will be assessed at Day 42 (± 7 days), 
and in the event of no reconstitution the backup 
HSC sample will be administered, if the investigator 
believes this is in the subject’s best interest. The 
subjects will then be seen at regular intervals to 
review their history, perform examinations and 
draw blood samples at Months 3, 6 and 9 (all ± 2 
weeks) as well as Months 12, 18 and 24 (all ± 4 
weeks). Any medically-indicated interventions, 
including the need to reinstate PEG-ADA ERT, will 
be assessed at all follow-up visits after Month 1.For 
subjects who have successfully received the OTL
101 product, PEG ADA ERT will be discontinued at 
Day+30 (+/ 3) after the transplant. After their 
discharge from hospital, the subjects will be seen at 
The language was updated for 
clarity and ease of reading; the ERT 
discontinuation window following 
the 1 month follow-up visit was 
extended, allowing the Investigator 
to delay ERT discontinuation by a 
few days if in the best interest of 
the subject. 


IND 15440, Study no. OTL-101-4 
 
 List of protocol changes from v3.0 to v4.0 – 08 September 2017 
UNIVERSITY OF CALIFORNIA, LOS ANGELES (UCLA)  
 
 
 
Confidential 
no evidence of cellular recovery, 
the subject will be given ERT 
and/or HSCT, if available, and 
deemed 
appropriate 
by 
the 
Investigator. After Month 24 visit, 
the subjects will have completed 
the study and may enter a long 
term registry.  
 
regular intervals to review their history, perform 
examinations and draw blood samples at Months 1, 
3, 6, 9, 12, 18, and 24. Any medically indicated 
interventions will be determined at these visits. 
Hematopoietic reconstitution will be assessed at 
Day 42, and in the event of no reconstitution the 
backup 
HSC 
sample 
will 
be 
administered.   
Hemataopoietic reconstitution will be reassessed 
again at the Month 6 visit and if there is still no 
evidence of cellular recovery, the subject will be 
given ERT and/or HSCT, if available, and deemed 
appropriate by the Investigator. After the Month 24 
visit, the subjects will have completed the study and 
may enter a long term registry.   
 
Schedule of Events, 
Legend (page 9) 
CD3+, CD4+ and CD8+ T-
lymphocytes, CD19+ B-
lymphocytes and CD56+/CD16+ 
NK cells. 
CD3+, CD4+ and CD8+ T-lymphocytes, CD19+ B-
lymphocytes and CD56/CD16+ (or CD56+/CD3-) NK 
cells., CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ 
(memory) T cells 
The flow cytometry markers were 
modified to match those indicated 
in the body of the protocol. 
Schedule of Events 
(page 11/12) 
Immune function5 
Leukemia Assessment6 
Immune function5 6 
Leukemia Assessment67 
The order of footnotes 6 and 7 was 
modified to account for the removal 
of the “IgG, IgA, IgM levels” 
assessment, already included in the 
Immune function assessment. 
Schedule of Events 
(page 11) 
“IgG, IgA, IgM levels” assessment 
required at Month 1, 3, 6, 9, 12, 
18, 24 and Early Termination 
visits 
Line removed 
An IgG, IgA and IgM levels 
assessment is already included in 
the Immune Function assessment, 
so this constituted a repetition. 
Schedule of Events 
(page 11) 
“TREC, TCR Vβ” assessment 
required at Month 6, Month 12, 
Month 18, Month 24 and Early 
Termination visits 
Line removed 
A TREC and TCR Vβ assessment is 
already included in the Immune 
Function assessment, so this 
constituted a repetition. 


IND 15440, Study no. OTL-101-4 
 
 List of protocol changes from v3.0 to v4.0 – 08 September 2017 
UNIVERSITY OF CALIFORNIA, LOS ANGELES (UCLA)  
 
 
 
Confidential 
Schedule of Events 
(page 11) 
Presence of ADA gene in 
PBMC/granulocytes 
Presence of ADA gene in PBMC/granulocytes 
and/or lineage-sorted cells 
The header was updated to allow 
the investigators to also assess the 
presence of the ADA gene in 
lineage-sorted cells. 
Schedule of Events 
(page 11) 
“FACS T-cells/myeloid by PCR for 
VCN” assessment required at the 
Month 3, 6, 12, 24 and Early 
Termination visits 
Line removed 
This assessment was meshed with 
the previous line, adding the 
possibility to detect the ADA gene in 
lineage-sorted cells. 
Schedule of Events 
(page 11) 
New line entered 
The “RCL assay in PBMC” will be performed at the 
Month 3, 6, 12, 24 and Early Termination visits 
A line was added to clarify the 
Replication Competent Lentivirus 
assay, a required safety assay, is to 
be carried out at the Month 3, 6, 12, 
24 and Early Termination visits. 
Schedule of Events 
(page 11) 
The “ADA enzymatic assay” was 
performed at the Month 1, 3, 6, 9 
and 12 visits 
The “ADA enzymatic assay” will be performed at 
the Month 1, 3, 6, 9, 12, 18, 24 and Early 
Termination visits 
The Investigator believes the ADA 
enzymatic assay should also be 
performed at 18 months, 24 months 
and early termination visits to 
appropriately assess the effects of 
the treatment and the status of the 
patients. 
Schedule of Events 
(page 11) 
“Deoxyadenine nucleotides in 
RBC” were assessed at the Month 
1, 3, 6, 9 and 12 visits 
“Deoxyadenine nucleotides in RBC” will be assessed 
at the Month 1, 3, 6, 9, 12, 18, 24 and Early 
Termination visits 
The Investigator believes the 
assessment of deoxyadenine 
nucleotides in RBC should also be 
performed at 18 months, 24 months 
and early termination visits to 
appropriately assess the effects of 
the treatment and the status of the 
patients. 
Schedule of Events, 
Legend (page 12) 
CD3+, CD4+ and CD8+ T-
lymphocytes, CD19+ B-
lymphocytes and CD56+/CD16+ 
NK cells 
CD3+, CD4+ and CD8+ T-lymphocytes, CD19+ B-
lymphocytes and CD56+/CD16+ (or CD56+/CD3-) 
NK 
cells, 
CD4+/CD45RA+ 
(naïve) 
and 
CD4+/CD45RO+ (memory) T cells 
The flow cytometry markers were 
modified to match those indicated 
in the body of the protocol. 


IND 15440, Study no. OTL-101-4 
 
 List of protocol changes from v3.0 to v4.0 – 08 September 2017 
UNIVERSITY OF CALIFORNIA, LOS ANGELES (UCLA)  
 
 
 
Confidential 
Schedule of Events, 
Legend (page 12) 
FACS=fluorescence-activated cell 
sorting 
Text removed 
“FACS” does not appear in the 
schedule of events anymore. 
Schedule of Events, 
Legend (page 12) 
VCN = vector copy number 
Text removed 
“VCN” does not appear in the 
schedule of events anymore. 
Section 3.1, 
General Design and 
Study Scheme 
A failure of hematologic 
reconstitution is defined as at 
least two of the following: 
absolute neutophil count (ANC) 
<200/mm3, platelets 
<20,000/mm3 without 
transfusions, hemaglobin (Hb) 
<8.0 g/dl without transfusions on 
three independent and 
consecutive determinations over 
at least 10 days beyond Day 42 
from initial OTL-101 infusion. 
A failure of hematologic reconstitution is defined as 
persistent ANC < 200/µl or platelets < 20,000/µl on 
three 
independent 
and 
consecutive 
determinations over at least ten days after day 
42 from the day of OTL-101 infusion.at least two of 
the following: absolute neutophil count (ANC) 
<200/mm3, 
platelets 
<20,000/mm3 
without 
transfusions, hemoglobin (Hb) <8.0 g/dl without 
transfusions on three independent and consecutive 
determinations over at least 10 days beyond 
Day 42 from initial OTL 101 infusion. 
The parameters used to define a 
failure of hematologic 
reconstitution were simplified 
according to the Investigator’s 
clinical judgement. 
Section 3.1, 
General Design and 
Study Scheme 
For 
subjects 
who 
have 
successfully received the OTL-101 
product, PEG-ADA ERT will be 
discontinued at Day+30 (+/-3) 
after the transplant. After their 
discharge 
from 
hospital, 
the 
subjects will be seen at regular 
intervals to review their history, 
perform examinations and draw 
blood samples at Months 1, 3, 6, 
9, 12, 18, and 24. Any medically-
indicated interventions will be 
determined 
at 
these 
visits. 
Hematopoietic reconstitution will 
be assessed at Day 42, and in the 
event of no reconstitution the 
backup HSC sample will be 
For subjects who have successfully received the 
OTL-101 product, PEG-ADA ERT use will be 
evaluated at the 1 Month follow-up visit (30 days 
post treatment ± 7 days) and discontinued at Day 
30 (-3/+15) after the transplant. Hematologic 
reconstitution will be assessed at Day 42 (± 7 days), 
and in the event of no reconstitution the backup 
HSC sample will be administered, if the investigator 
believes this is in the subject’s best interest. The 
subjects will then be seen at regular intervals to 
review their history, perform examinations and 
draw blood samples at Months 3, 6 and 9 (all ± 2 
weeks) as well as Months 12, 18 and 24 (all ± 4 
weeks). Any medically-indicated interventions, 
including the need to reinstate PEG-ADA ERT, will 
be assessed at all follow-up visits after Month 1.For 
subjects who have successfully received the OTL
The language was updated for 
clarity and ease of reading; the ERT 
discontinuation window following 
the 1 month follow-up visit was 
extended, allowing the Investigator 
to delay ERT discontinuation by a 
few days if in the best interest of 
the subject. 


IND 15440, Study no. OTL-101-4 
 
 List of protocol changes from v3.0 to v4.0 – 08 September 2017 
UNIVERSITY OF CALIFORNIA, LOS ANGELES (UCLA)  
 
 
 
Confidential 
administered. 
 
Hematapoietic 
reconstitution will be reassessed 
at Month 6 visit and if there is still 
no evidence of cellular recovery, 
the subject will be given ERT 
and/or HSCT, if available, and 
deemed 
appropriate 
by 
the 
Investigator. After Month 24 visit, 
the subjects will have completed 
the study and may enter a long 
term registry.  
 
101 product, PEG ADA ERT will be discontinued at 
Day+30 (+/ 3) after the transplant. After their 
discharge from hospital, the subjects will be seen at 
regular intervals to review their history, perform 
examinations and draw blood samples at Months 1, 
3, 6, 9, 12, 18, and 24. Any medically indicated 
interventions will be determined at these visits. 
Hematopoietic reconstitution will be assessed at 
Day 42, and in the event of no reconstitution the 
backup 
HSC 
sample 
will 
be 
administered.   
Hemataopoietic reconstitution will be reassessed 
again at the Month 6 visit and if there is still no 
evidence of cellular recovery, the subject will be 
given ERT and/or HSCT, if available, and deemed 
appropriate by the Investigator. After the Month 24 
visit, the subjects will have completed the study and 
may enter a long term registry.   
Section 3.6.1, Subject 
Stopping Rules and 
Criteria for 
Discontinuation 
2. If two subjects experience 
prolonged unresponsive 
pancytopenia, defined as an 
initial failure of hematologic 
reconstitution which does not 
improve following the 
administration of the subject's 
autologous back-up cells. A 
failure of hematologic 
reconstitution is defined as at 
least two of the following: 
absolute neutophil count 
(ANC) <200/mm3, platelets 
<20,000/mm3 without 
transfusions, hemoglobin (Hb) 
<8.0 g/dl without transfusions 
2. If 
two 
subjects 
experience 
prolonged 
unresponsive pancytopenia, defined as an initial 
failure of hematologic reconstitution which 
does not improve following the administration 
of the subject's autologous back-up cells. A 
failure of hematologic reconstitution is defined 
as persistent ANC < 200/µl or platelets < 
20,000/µl 
on 
three 
independent 
and 
consecutive determinations over at least ten 
days after day 42 from the day of OTL-101 
infusion.A failure of hematologic reconstitution 
is defined as at least two of the following: 
absolute neutophil count (ANC) <200/mm3, 
platelets <20,000/mm3 without transfusions, 
hemoglobin (Hb) <8.0 g/dl without transfusions 
The parameters used to define a 
failure of hematologic 
reconstitution were simplified 
according to the Investigator’s 
clinical judgement. 


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 List of protocol changes from v3.0 to v4.0 – 08 September 2017 
UNIVERSITY OF CALIFORNIA, LOS ANGELES (UCLA)  
 
 
 
Confidential 
on three independent and 
consecutive determinations. 
on 
three 
independent 
and 
consecutive 
determinations. 
Section 3.6.1, Subject 
Stopping Rules and 
Criteria for 
Discontinuation 
5. Non-responders as defined in 
the primary endpoint criteria 
(Section 3.2.1), will be 
designated a OTL-101 
treatment failure and will be 
withdrawn from the study to 
permit further treatment with 
PEG-ADA ERT, or HSCT if 
available.  
 
If there are three Nnon-responders, as defined in 
the primary endpoint criteria (Section 3.2.1), who 
will be designated an OTL-101 treatment failure 
and will be withdrawn from the study to permit 
further treatment with PEG-ADA ERT, or HSCT if 
available.  
 
The language was updated following 
confirmation of treatment failure 
for patient 602, upon suggestion by 
the FDA. 
Section 5.1.3, Baseline 
(Visit 3) 
 
Measurement of immune 
function:    
o Absolute numbers of 
CD3+, CD4+ and CD8+ T-
lymphocytes, CD19+ B-
lymphocytes and 
CD56+/CD16+ (or 
CD56+/CD3-) NK cells, 
CD4+/CD45RA+, 
CD4+/CD45RO+ 
 
Measurement of immune function:    
o Absolute numbers of CD3+, CD4+ and 
CD8+ T-lymphocytes, CD19+ B-
lymphocytes and CD56+/CD16+ (or 
CD56+/CD3-) NK cells, CD4+/CD45RA+ 
(naïve), and CD4+/CD45RO+ (memory) T 
cells, 
 
The language was updated for 
clarity. 
Section 5.1.7, Follow-
up (Visits 4 to 11) 
 
Measurement of immune 
function:    
o Absolute numbers of 
CD3+, CD4+ and CD8+ T-
lymphocytes, CD19+ B-
lymphocytes and 
CD56+/CD16+ (or 
CD56+/CD3-) NK cells, 
 
Measurement of immune function:    
o Absolute numbers of CD3+, CD4+ and 
CD8+ T-lymphocytes, CD19+ B-
lymphocytes and CD56+/CD16+ (or 
CD56+/CD3-) NK cells, CD4+/CD45RA+ 
(naïve), and CD4+/CD45RO+ (memory) T 
cells, 
 
The language was updated for 
clarity, at the Month 1, 3, 6, 9, 12, 
18, 24 and Early Termination visits. 


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 List of protocol changes from v3.0 to v4.0 – 08 September 2017 
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Confidential 
CD4+/CD45RA+, 
CD4+/CD45RO+ 
Section 5.1.7, 
Follow-up (Visits 4 to 
11) 
Day 42 assessment will use 
laboratory parameters to confirm 
if immune reconstitution has 
occurred. If this has not 
happened by Day 42 the backup 
HSC sample will be processed 
according to instructions in 
Section 3.7. 
The Day 42 assessment will use laboratory 
parameters to confirm if immune reconstitution 
has occurred. A failure of hematologic 
reconstitution is defined as persistent ANC < 
200/µl or platelets < 20,000/µl on three 
independent and consecutive determinations over 
at least ten days after day 42 from the day of cell 
infusion. If this hematologic reconstitution has not 
taken placehappened by Day 42 the backup HSC 
sample will be processed according to the 
instructions in Section 3.7. and re-infused to 
overcome more severe myelosuppressive effects of 
the conditioning regimen. If the failure of 
hematologic reconstitution persist after the back-
up marrow has been given through day 90 from 
the initial infusion of the cell product, prolonged 
unresponsive pancytopenia will exist. 
The parameters used to define a 
failure of hematologic 
reconstitution at the Day 42 visit 
were clarified. 
Section 5.1.7, 
Follow-up (Visits 4 to 
11) 
New text added 
- 
RCL assay in PBMC, 
 
The language was updated to reflect 
the change in the schedule of 
assessments, for the Month 3, 6, 12, 
24 and Early Termination visits. 
Section 5.1.7, 
Follow-up (Visits 4 to 
11) 
Serum to be banked for possible 
Western blot testing for RCL, 
Serum to be banked for possible Western blot 
testing for RCL (testing performed if the RCL assay 
in PBMC returns a positive result), 
The language was updated for 
clarity, for the Month 3, 6, 12, 24 
and Early Termination visits. 
Section 5.1.7, 
Follow-up (Visits 4 to 
11) 
Measurement of the proportion 
of cells containing the inserted 
ADA gene 
in 
PBMC 
and 
granulocytes as well as FACS 
sorted T cells and myeloid cells by 
PCR for VCN  
Measurement of the proportion of cells containing 
the inserted ADA gene in PBMC and granulocytes 
and/or lineage-sorted cellsas well as FACS sorted T 
cells and myeloid cells by PCR for VCN  
The language was updated to reflect 
the change in the schedule of 
assessments, for the Month 3, 6, 12, 
24 and Early Termination visits. 


IND 15440, Study no. OTL-101-4 
 
 List of protocol changes from v3.0 to v4.0 – 08 September 2017 
UNIVERSITY OF CALIFORNIA, LOS ANGELES (UCLA)  
 
 
 
Confidential 
Section 5.1.7, 
Follow-up (Visits 4 to 
11) 
- 
Assessment of the success of 
treatment at the subject level 
(“responder analysis”) at 
6 months post OTL-101 
infusion, by evaluating;  
a) Evidence of erythrocyte 
ADA enzyme activity above 
baseline/pre-treatment level 
(>0 Units), 
b) Evidence of hematopoietic 
reconstitution 
(absolute 
number 
of 
CD3 
cells 
≥200/mm3), 
- 
Assessment of the success of treatment at the 
subject level (“responder analysis”) at 
6 months post OTL-101 infusion, by evaluating;  
a) Evidence of erythrocyte ADA enzyme 
activity above baseline/pre-treatment level 
(>0 Units), 
b) 
Evidence 
of 
hematopoietic 
immune 
reconstitution (absolute number of CD3 cells 
≥200/mm3), 
The language was updated for 
clarity. 
Section 5.1.7, Follow-
up (Visits 4 to 11) 
New text entered 
- 
Gene transduction/expression; 
o Measurement of ADA expression in 
erythrocytes by ADA enzymatic assay and 
deoxyadenine nucleotides in RBC. 
The text was updated to reflect the 
change in the schedule of 
assessments, for the Month 18, 24 
and Early Termination visits. 
Section 6.1.2, Rescue 
Administration of 
Autologous HSC Backup 
The failure of hematologic 
reconstitution is defined by at 
least any one of the following:  
- 
ANC <200/mm3, and/or,  
- 
Platelets <20,000/mm3 
without transfusions, 
and/or,  
- 
Hb <8.0 g/dl without 
transfusions on three 
independent and 
consecutive 
A failure of hematologic reconstitution is defined 
as persistent ANC < 200/µl or platelets < 20,000/µl 
on three independent and consecutive 
determinations over at least ten days after day 
42 from the day of OTL-101 infusion.The failure of 
hematologic reconstitution is defined by at least 
any one of the following:  
- 
ANC <200/mm3, and/or,  
- 
Platelets <20,000/mm3 without 
transfusions, and/or,  
The parameters used to define a 
failure of hematologic 
reconstitution were simplified 
according to the Investigator’s 
clinical judgement. 


IND 15440, Study no. OTL-101-4 
 
 List of protocol changes from v3.0 to v4.0 – 08 September 2017 
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Confidential 
determinations over at 
least 10 days, beyond 
Day 42 from the initial 
infusion of the cell 
product. 
- 
Hb <8.0 g/dl without transfusions on three 
independent and consecutive 
determinations over at least 10 days, 
beyond Day 42 from the initial infusion of 
the cell product. 
Section 7.2, Efficacy 
Assessments 
• 
Serum samples will be used to 
detect RCL. 
 
• 
Serum and PBMC samples will be used to 
detect RCL. 
 
The language was updated to reflect 
the change in the schedule of 
assessments. 
 

SAP_001.pdf: 
 
 
 
COVER PAGE 
 
 
Official Study Title: Efficacy and safety of a cryopreserved 
formulation of autologous CD34+ hematopoietic stem cells 
transduced ex vivo with EFS lentiviral vector encoding for 
human ADA gene in subjects with Severe Combined 
Immunodeficiency due to Adenosine Deaminase deficiency. 
 
Statistical Analysis Plan Version 1.0, 25 January 2018 
 
NCT02999984 


 
 
 
 
Statistical Analysis Plan 
 
 
Study Name:  
Efficacy and safety of a cryopreserved 
formulation of autologous CD34+ 
hematopoietic stem cells transduced ex 
vivo with EFS lentiviral vector 
encoding for human ADA gene in 
subjects with severe combined 
immunodeficiency (SCID) due to 
adenosine deaminase deficiency 
 
Protocol Number:   OTL-101-4 
 
Protocol Version: 
4.0 
 
Protocol Date:  
08 September 2017 
 
SAP Version 1.0:  
25 January 2018 
 
 
 


Study: OTL-101-4 
 
 
 
 
 
 
Statistical Analysis Plan 
Final Version 1.0 
Page 2 of 27 


Study: OTL-101-4 
 
 
 
 
 
 
Statistical Analysis Plan 
Final Version 1.0 
Page 3 of 27 
Table of Contents 
Table of Contents 
3 
1 
Introduction 
8 
2 
Study Design 
8 
3 
Study Schedule 
10 
4 
Study Objectives 
15 
4.1 
Primary Objectives 
15 
4.2 
Secondary Objectives 
15 
4.3 
Exploratory Objectives 
15 
5 
Endpoints 
16 
5.1 
Primary Endpoints 
16 
5.2 
Secondary Endpoints 
16 
5.3 
Exploratory Endpoints 
16 
6 
Timing of Analyses 
16 
7 
Analysis Populations 
17 
7.1 
Efficacy Population 
17 
7.2 
Safety Population 
17 
7.3 
Pharmacokinetic Population 
Error! Bookmark not defined. 
8 
Statistical Methods 
17 
8.1 
Subject Disposition 
17 
8.1.1 
Summary of Populations 
17 
8.1.2 
Summary of Withdrawals 
17 
8.2 
Demography and Baseline Characteristics 
17 
8.2.1 
Demography 
18 
8.2.2 
Medical History 
18 
8.2.3 
Diagnosis of ADA-SCID 
18 
8.2.4 
Previous Treatment 
18 
8.2.5 
Cytogenetics 
18 
8.2.6 
Coagulation Tests 
18 
8.2.7 
Urinalysis and Urine Culture 
19 
8.2.8 
ECG 
19 
8.2.9 
Echocardiogram 
19 
8.2.10 
Chest X-ray and Computed Tomography (CT) Scan 
19 
8.2.11 
Skin Lesions 
19 
8.2.12 
Bone Marrow Harvest 
20 
8.2.13 
Busulfan Administration 
20 
8.2.14 
Parameters for Busulfan Pharmacokinetics 
20 


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8.2.15 
OTL-101 Administration 
20 
8.2.16 
Exposure 
20 
8.3 
Efficacy Evaluations 
21 
8.3.1 
Primary Efficacy Endpoints 
21 
8.3.1.1 
Response to OTL-101 Treatment at 6 Months 
21 
8.3.1.2 
Overall Survival at 12 Months 
21 
8.3.1.3 
Event Free Survival at 12 Months 
21 
8.3.2 
Secondary Efficacy Endpoints 
22 
8.3.2.1 
Overall and Event Free Survival at 24 Months 
22 
8.3.2.2 
Use of Immunoglobulin Replacement Therapy 
22 
8.3.2.3 
Performance Outcomes and Quality of Life 
22 
8.3.2.4 
Rate of Severe Infections 
23 
8.3.2.5 
Response to Tetanus Vaccination 
23 
8.3.2.6 
Immune Reconstitution 
23 
8.3.3 
Exploratory Efficacy Endpoints 
23 
8.3.3.1 
Use of PEG-ADA Enzyme Replacement Therapy 
23 
8.3.3.2 
T Cell Receptor Excision Circles (TREC) 
24 
8.3.3.3 
T Cell Receptor Vβ Panel Results 
24 
8.3.3.4 
T Lymphocyte Response to Phytohemagglutinin (PHA) 
24 
8.3.3.5 
Engraftment 
24 
8.3.3.6 
ADA Expression, Enzyme Activity and Detoxification 
24 
8.3.3.7 
Vector Integration Analysis 
24 
8.4 
Safety Evaluations 
24 
8.4.1 
Adverse Events 
24 
8.4.1.1 
Definition of Treatment-emergent Adverse Events 
24 
8.4.1.2 
Adverse Events 
25 
8.4.2 
Concomitant Medications 
25 
8.4.3 
Infectious Episodes 
26 
8.4.4 
RCL Testing 
26 
8.4.5 
Leukaemia Assessment 
26 
8.4.6 
Laboratory Evaluations 
26 
8.4.6.1 
Haematology 
26 
8.4.6.2 
Biochemistry 
26 
8.4.7 
Vital Signs, Height and Weight 
27 
8.4.8 
Physical Examination 
27 
9 
Analysis Software 
27 
 


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List of Abbreviations 
 
ADA 
Adenosine deaminase 
ADA-SCID 
Adenosine deaminase deficient severe combined immunodeficiency 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ANC 
Absolute neutrophil count 
AUC 
Area under the curve 
CI 
Confidence interval 
CMC 
Chemistry, manufacturing and control 
CT 
Computer tomography 
dAXP 
Adenine deoxyribonucleotides 
dPCR 
Digital polymerase chain reaction 
ECG 
Electrocardiogram 
EFS 
Elongation Factor 1α Short form 
ERT 
Enzyme replacement therapy 
FACS 
Fluorescence-activated cell sorting 
GTMP 
Gene therapy medicinal product 
Hb 
Hemoglobin 
HLA 
Human leukocyte antigen 
HSC 
Hematopoietic stem cell 
HSCT 
Hematopoietic stem cell transplant 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IgRT 
Immunoglobulin replacement therapy 
INR 
International normalized ratio 
LV 
Lentiviral vector 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular haemoglobin concentration 
MCV 
Mean corpuscular volume 
NK 
Natural Killer 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
PEG 
Polyethylene-glycol 
PHA 
Phytohemagglutinin 
PK 
Pharmacokinetic 
PRBC 
Packed red blood cells 
PT 
Preferred term 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
qPCR 
Quantitative polymerase chain reaction 
RBC 
Red blood cell(s) 
RCL 
Replication competent lentivirus 
SAE 
Serious Adverse Event 


Study: OTL-101-4 
 
 
 
 
 
 
Statistical Analysis Plan 
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SAS® 
Statistical Analysis System® 
SCID 
Severe combined immunodeficiency 
SOC 
System Organ Class 
TCR 
T-cell receptor 
TREC 
T-cell receptor excision circle 
UCLA 
University of California Los Angeles 
 
 


Study: OTL-101-4 
 
 
 
 
 
 
Statistical Analysis Plan 
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1 Introduction 
The primary objective of this clinical study is to further explore the safety and efficacy of OTL-
101, an autologous, genetically modified CD34+ HSC based gene therapy for the treatment of 
ADA-SCID. The study will also be supportive of the analytical CMC comparability studies 
between the fresh and cryopreserved OTL-101 formulations. The following clinical outcomes, 
which are known to be good predictors of survival and event free survival: RBC ADA >0 Units, 
absolute CD3+ T-cell counts ≥ 200/mm3, and peripheral blood samples positive for vector 
sequences by qPCR (>1/10,000 cells), will be assessed as part of an interim analysis following 
completion of the 6 month follow-up visit.  
2 Study Design 
This is a prospective, non-randomized, single-cohort, longitudinal, single-center, clinical study 
designed to assess the efficacy and safety of OTL-101 cryopreserved formulation administered 
in ADA-SCID subjects aged between ≥30 days to <18 years of age, who are not eligible for an 
HLA-matched sibling/family donor and meeting the inclusion/exclusion criteria. This study 
aims to recruit 10 evaluable subjects. 
 
The aim of this clinical study is also to assess the success of treatment at the subject level 
(“responder analysis”) 6 months post GTMP administration, using predictive criteria for 
overall survival and event free survival and to compare data obtained from clinical studies 
using the fresh formulation of OTL-101. 
 
Eligible subjects will be hospitalized to undergo the harvesting of autologous CD34+ cells. A 
backup harvest of non-transduced CD34+cells will be obtained during the harvesting procedure 
to be used in the event of i) product damage during the thawing of the GTMP that would prevent 
infusion of the GTMP although the patient has already been conditioned or ii) lack of 
engraftment/hematopoietic reconstitution 42 days post infusion of the protocol treatment. A 
failure of hematologic reconstitution is defined as at least two of the following: absolute 
neutrophil count (ANC) <200/mm3, platelets <20,000/mm3 without transfusions, haemoglobin 
(Hb) <8.0 g/dl without transfusions on three independent and consecutive determinations over 
at least 10 days beyond Day 42 from initial GTMP infusion. 
 
The protocol treatment is a cryopreserved formulation of autologous CD34+ hematopoietic 
stem cells transduced ex vivo with EFS LV encoding for the human ADA gene (OTL-101). To 
enable the release of the GTMP for infusion, the cryopreserved OTL-101 product must meet 
various quality control criteria for safety, identity, viability, purity and potency. If OTL-101 
meets the acceptance criteria and is released, the subjects will be readmitted for conditioning 
with busulfan. The OTL-101 product will be infused after a minimal interval of at least 24 
hours following the completion of busulfan administration. Subjects may remain as an in-
patient following autologous transplantation for approximately three to 35 days.  
For subjects who have successfully received the OTL-101 product, PEG-ADA ERT will be 
discontinued at Day+30 (+/-3) after the transplant. After their discharge from hospital, the 
subjects will be seen at regular intervals to review their history, perform examinations and draw 
blood samples at Months 1, 3, 6, 9, 12, 18, and 24. Any medically-indicated interventions will 
be determined at these visits. Hematopoietic reconstitution will be assessed at Day 42, and in 
the event of no reconstitution the backup HSC sample will be administered.  Hematopoietic 
reconstitution will be reassessed at the Month 6 visit and if there is still no evidence of cellular 
recovery, the subject will be given ERT and/or HSCT, if available, and deemed appropriate by 


Study: OTL-101-4 
 
 
 
 
 
 
Statistical Analysis Plan 
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the Investigator. After Month 24 visit, the subjects will have completed the study and may enter 
a long-term follow-up study.  
 
 


Study: OTL-101-4 
 
 
 
 
 
 
Statistical Analysis Plan 
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3 Study Schedule 
Table 1:  Schedule of Events – Screening to Day 24 
Study Period 
 
Screening 
Pre-harvest 
Assessment 
Bone Marrow 
Harvest 
Baseline Conditioning 
OTL-101 
Treatment 
Short-term Follow-up 
Visit number 
1 
21 
2 
31 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Assessment number 
 
A 
B 
C 
D 
E 
F 
G 
H 
I 
J 
K 
L 
M 
Visit window 
 
 
 
 
 
 
 
+/-2 days 
Day 
Within 60 
days of Visit 
2B 
Up to 5 days 
prior to Visit 
2B 
Approx 30 day 
prior to Visit 3F 
Day-10 to 
-4 
Day -4 
to -3 
Day -2 
to -1 
Day 0 
Day 1 Day 4 
Day 8 
Day 11 Day 15 
Day19 
Day 24 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic Data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs  
X 
 
 
X 
 
 
X2 
 
 
 
 
 
 
 
Weight (kg) 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
Height (cm) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biochemistry sample3 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
Hematology sample4 
X 
X 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
PT or PTT/INR 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
PB or BM cytogenetics5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1/Hep B/Parvo B19 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test6 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
Urinalysis7 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest X-ray8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pulse oxymetry 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Biopsy of skin lesions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADA-SCID diagnosis 
confirmation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Questionnaire/QofL scale 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Infectious episodes 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication9 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Type and cross PRBC 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow harvest 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 


Study: OTL-101-4 
 
 
 
 
 
 
Statistical Analysis Plan 
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Study Period 
 
Screening 
Pre-harvest 
Assessment 
Bone Marrow 
Harvest 
Baseline Conditioning 
OTL-101 
Treatment 
Short-term Follow-up 
Visit number 
1 
21 
2 
31 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Assessment number 
 
A 
B 
C 
D 
E 
F 
G 
H 
I 
J 
K 
L 
M 
Visit window 
 
 
 
 
 
 
 
+/-2 days 
Day 
Within 60 
days of Visit 
2B 
Up to 5 days 
prior to Visit 
2B 
Approx 30 day 
prior to Visit 3F 
Day-10 to 
-4 
Day -4 
to -3 
Day -2 
to -1 
Day 0 
Day 1 Day 4 
Day 8 
Day 11 Day 15 
Day19 
Day 24 
PRBC transfusion 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Immune function10 
 
 
 
X11 
 
 
 
 
 
 
 
 
 
 
PBMC banking for RCL  
 
 
 
X12 
 
 
 
 
 
 
 
 
 
 
Serum banking for RCL 
 
 
 
X12 
 
 
 
 
 
 
 
 
 
 
Erythrocyte ADA 
enzymatic activity 
 
 
 
X12 
 
 
 
 
 
 
 
 
 
 
Erythrocyte deoxyadenine 
nucleotide levels  
 
 
 
X12 
 
 
 
 
 
 
 
 
 
 
Busulfan administration 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
PK samples 
 
 
 
 
X13 
X14 
 
 
 
 
 
 
 
 
OTL-101 administration 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
1. 
Subjects will be admitted to the hospital for Visits 2 and 3. 
2. 
During the infusion of OTL-101 vital signs will be monitored according to standard institute protocols. 
3. 
Biochemistry samples will include the assessment of parameters listed in Table 3. Albumin ALT, AST, ALP will be measured at all time points indicated in this table. Total 
bilirubin, total protein, total protein, creatinine, blood urea, sodium, potassium, chloride, and calcium will be measured at screening, baseline, Day 1 and all follow-up visits 
(Month 1 to Month 24). Magnesium and phosphate will be measured only at pre-harvest and baseline time points. 
4. 
Hematology samples will include the assessment of parameters listed in Table 3 and will be measured at all time points indicated in this table. 
5. 
If cytogenetic testing was not performed on cells from amniocentesis, assessment should be by karyotype, CGH, and WES 
6. 
Serum pregnancy tests are required in females of child-bearing potential at screening, prior to bone marrow harvest, prior to conditioning (Busulfan) treatment, and before 
the infusion of OTL-101.  Any positive test will immediately result in the withdrawal of the subject from the study and should be reported as per guidance in Section Error! 
Reference source not found. 
7. 
Urinalysis will include the assessment of parameters listed in Table 3 and will be measured at all time points indicated in this table. Any abnormalities detected on dipstick at 
Screening, Pre-harvest and Baseline will require repeat dipstick and microscopic examinations. 
8. 
If there is any evidence of severe lung disease on the screening chest X-ray, a CT scan is required in order to establish if the subject meets any of the specified pulmonary 
exclusion criteria defined in Section Error! Reference source not found.. 
9. 
Standard post-transplant medication will be administered from Day 0 and recorded in the eCRF. 
10. 
Immune function will be assessed absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, CD19+ B-lymphocytes and CD56+/CD16+ (or CD56+/CD3-) NK cells, 
CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ (memory) T cells, TREC levels, TCR Vβ usage, lymphocyte response to PHA (if sufficient cells), and serum 
immunoglobulin (IgG, IgA, IgM). 
11. 
The immune function tests required for Visit 3, Assessment C can be performed at any point after provision of consent/assent and prior to Busulfan administration in 
younger subjects if deemed appropriate by the Investigator. 
12. 
These test can be performed at anytime following BM harvest (Visit 2: Assessment B) and prior to OTL-101 administration (Visit 3: Assessment F) in younger subjects if 
deemed appropriate by the Investigator. 


Study: OTL-101-4 
 
 
 
 
 
 
Statistical Analysis Plan 
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Study Period 
 
Screening 
Pre-harvest 
Assessment 
Bone Marrow 
Harvest 
Baseline Conditioning 
OTL-101 
Treatment 
Short-term Follow-up 
Visit number 
1 
21 
2 
31 
3 
3 
3 
3 
3 
3 
3 
3 
3 
3 
Assessment number 
 
A 
B 
C 
D 
E 
F 
G 
H 
I 
J 
K 
L 
M 
Visit window 
 
 
 
 
 
 
 
+/-2 days 
Day 
Within 60 
days of Visit 
2B 
Up to 5 days 
prior to Visit 
2B 
Approx 30 day 
prior to Visit 3F 
Day-10 to 
-4 
Day -4 
to -3 
Day -2 
to -1 
Day 0 
Day 1 Day 4 
Day 8 
Day 11 Day 15 
Day19 
Day 24 
13. 
PK blood samples are required at the end of Busulfan infusion, +1, 2, 4, 8, and 13 hours post-infusion (+/- 15 minutes). These values will be used to determine the second 
dose of Busulfan. 
14. 
One PK blood sample is required immediately before the second dose of Busulfan is administered, and then at the end of Busulfan infusion, +1, 2, 4, 8, and 13 hours post-
infusion (+/- 15 minutes). 
Abbreviations: ADA=adenosine deaminase, ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, BM=bone marrow, CGH= Comparative 
Genome Hybridization, CT=computer tomography, ECG=electrocardiogram, eCRF=electronic case report form, HIV=human immunodeficiency virus, IgA=immunoglobulin A, 
IgG=immunoglobulin G, IgM=immunoglobulin M, INR=international normalized ratio, NK=natural killer, PB=peripheral blood, PBMC=peripheral blood mononuclear cells, 
PHA= Phytohemagglutinin, PK=pharmacokinetic, PRBC=packed red blood cells, PT=prothrombin, PTT=prothrombin time, QofL=quality of life, RCL= Replication Competent 
Lentivirus, SCID=severe combined immunodeficiency, TCR= T-cell receptor, TREC= T-cell receptor excision circle, WES= whole exome sequencing. 
 


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Statistical Analysis Plan 
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Table 2:  Schedule of Events – Month 1 to Month 24 
Follow-up Period 
 
Month 1 
(Day 30) 
Day 421 
Month 3 
Month 6 
Month 9 
Month 12 
Month 18 
Month 24 
ET 
Visit number 
4 
5 
6 
7 
8 
9 
10 
11 
N/A 
Visit window 
+/- 1 week 
+/- 1 week 
+/- 2 weeks 
+/- 2 weeks 
+/- 2 weeks 
+/- 4 weeks 
+/- 4 weeks 
+/- 4 weeks 
 
Physical examination 
X 
 
X 
X 
X 
X 
X 
X 
X 
Vital Signs  
X 
 
X 
X 
X 
X 
X 
X 
X 
Weight (kg) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Height (cm) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Biochemistry sample2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology sample3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Questionnaire/QofL scale 
 
 
 
X 
 
X 
X 
X 
X 
Infectious episodes 
X 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record IgG and PEG-ADA 
therapy  received 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Immune function5,6 
X 
 
X 
X 
X 
X 
X 
X 
X 
Serum banking for RCL 
 
 
X 
X 
 
X 
 
X 
X 
Vector integration analysis 
 
 
X 
X 
 
X 
X 
X 
 
Leukaemia assessment7 
 
 
 
X 
 
X 
X 
X 
X 
T-cell proliferation to PHA 
 
 
 
X 
X 
X 
X 
X 
X 
Antibodies to tetanus toxoid 
 
 
 
 
 
X 
X 
X 
X 
Presence of ADA gene in 
PBMC/granulocytes and/or 
lineage-sorted cells 
 
 
X 
X 
 
X 
 
X 
X 
RCL assay in PBMC 
 
 
X 
X 
 
X 
 
X 
X 
ADA enzymatic assay 
X 
 
X 
X 
X 
X 
X 
X 
X 
Deoxyadenine nucleotides 
in RBC 
X 
 
X 
X 
X 
X 
X 
X 
X 
Responder assessment8 
 
 
 
X 
 
 
 
 
 
1. 
Day 42 assessment will use laboratory parameters to confirm if hematologic reconstitution has occurred.  If this has not happened by Day 42 rescue 
medication, as per standard institute procedure, will be implemented.  Any treatment administered to the subject will be recorded in the eCRF. 
2. 
Biochemistry samples will include the assessment of parameters listed in Table 3. Albumin ALT, AST, ALP will be measured at all time points indicated in 
this table. Total bilirubin, total protein, total protein, creatinine, blood urea, sodium, potassium, chloride, and calcium will be measured at screening, baseline, 
Day 1 and all follow-up visits (Month 1 to Month 24). Magnesium and phosphate will be measured only at baseline and the conditioning time points. 
3. 
Hematology samples will include the assessment of parameters listed in Table 3 and will be measured at all time points indicated in this table. 
4. 
Standard post-transplant medication will be administered from Day 0 and recorded in the eCRF. 


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Statistical Analysis Plan 
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5. 
Immune function will be assessed by absolute numbers of CD3+, CD4+ and CD8+ T-lymphocytes, CD19+ B-lymphocytes and CD56+/CD16+ (or 
CD56+/CD3-) NK cells, CD4+/CD45RA+ (naïve) and CD4+/CD45RO+ (memory) T cells, TREC levels, TCR Vβ usage, lymphocyte response to 
PHA (if sufficient cells), and serum immunoglobulin (IgG, IgA, IgM). 
6. 
If IgG treatment is stopped, immunoglobulin levels will be required every month for the first 3 month after discontinuation.  This is to ensure IgG levels hold 
before commencing vaccinations as per standard institute protocols. 
7. 
A blood sample will be taken unless clinical/hematologic findings indicate potential leukoproliferation, whereby a bone marrow sample will be required. In 
addition to the time points specified in this table, this assessment should be performed if the nrLAM-PCR criteria is fulfilled (see Section Error! Reference 
source not found.). 
8. 
Responder assessment includes: erythrocyte ADA enzyme activity, immune reconstitution, and gene-marked granulocytes as described in Section Error! 
Reference source not found.. 
Abbreviations: ADA=adenosine deaminase, ALP=alkaline phosphatase, ALT=alanine aminotransferase, AST=aspartate aminotransferase, eCRF=electronic case 
report form, ET=early termination, IgA=immunoglobulin A, IgG=immunoglobulin G, IgM=immunoglobulin M, N/A=not applicable, NK=natural killer, 
PBMC=peripheral blood mononuclear cells, PCR=polymerase chain reaction, PEG= polyethylene-glycol, PHA= Phytohemagglutinin, QofL=quality of life, 
RBC=red blood cell, RCL= Replication Competent Lentivirus, TCR= T-cell receptor, TREC= T-cell receptor excision circle. 
 


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4 Study Objectives 
4.1 Primary Objectives 
There are two primary objectives for this study: 
• The success of treatment at the subject level (“responder analysis”) 6 months post OTL-
101 infusion, defined as:  
o Evidence of erythrocyte ADA enzyme activity above baseline/pre-treatment 
level (>0 Units), 
o Evidence of immune reconstitution (absolute number of CD3 cells ≥200/mm3),   
o Detectable gene-marked granulocytes by differential polymerase chain reaction 
(dPCR)/qPCR (≥1/10,000 cells). 
This 6 month data will be used to compare the proportion of responders among subjects 
treated with the cryopreserved population with a comparable population obtained from 
one of the ongoing Phase I/II studies using the fresh formulation. 
• Overall survival and event free survival at 12 months among ADA-SCID subjects 
treated with a cryopreserved formulation of OTL-101.  
o Overall survival is defined as the proportion of subjects alive.  
o Event-free survival is defined as the proportion of subjects with no “event”, an 
“event” being: 
▪ the resumption of PEG-ADA ERT 
▪ the need for a rescue allogenic HSCT, or  
▪ death. 
4.2 Secondary Objectives 
The secondary objectives to be evaluated among ADA-SCID subjects treated with a 
cryopreserved formulation of OTL-101 include: 
• confirmation of the overall survival and event free survival at 24 months,  
• safety evaluation including infection rates,  
• quality of life, and  
• immune response.  
 
4.3 Exploratory Objectives 
Exploratory objectives include the measurement of biological correlates of efficacy including:  
• percentage of gene marking in peripheral blood granulocytes,  
• vector integration analysis,  
• quantification of clonal diversity of vector integrants,  
• T-cell receptor excision circle (TREC) and fluorescence-activated cell sorting (FACS) 
for T-cell receptor (TCR) V-β family use,  
• ADA enzyme activity in erythrocytes, total adenine nucleotides in erythrocytes, and 
• immune reconstitution. 
 


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Statistical Analysis Plan 
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5 Endpoints 
5.1 Primary Endpoints 
Primary endpoints for this study are: 
• Response to OTL-101 treatment at 6 months post infusion based on the following 
parameters and their thresholds: 
o Erythrocyte ADA enzyme activity above baseline/pre-treatment level (>0 
Units),  
o Absolute CD3+ T-cell counts ≥200/mm3, and  
o Peripheral blood samples positive for vector sequences by qPCR (≥1/10,000 
cells). 
Subjects must meet all three criteria. Subjects not meeting one or more of these criteria 
will be designated a failure (non-responder) and will be withdrawn from the study. This 
data will be used for comparison with subject data from the ongoing Phase I/II study 
using the fresh formulation. 
• Overall survival and event free survival at 12 months post GTMP administration. 
o Overall survival is defined as the proportion of subjects alive.  
o Event-free survival is defined as the proportion of subjects with no “event”, an 
“event” being: 
▪ resumption of PEG-ADA ERT, or 
▪ the need for a rescue allogenic HSCT, or  
▪ death. 
5.2 Secondary Endpoints 
Secondary endpoints for this study are: 
• Overall survival and event free survival 24 months post GTMP administration 
• Immunoglobulin replacement therapies prior to and after gene therapy.  
• Safety and tolerability. 
• Performance outcomes and quality of life measured by the Karnofsky/Lansky scale and 
questions relevant to general well-being, school attendance and ability to practice 
sports, respectively.  
• Severe infections or opportunistic infectious episodes, defined as infections or severe 
infections requiring hospitalization or prolonging hospitalization and/or documented 
infections by opportunistic pathogens (i.e. interstitial pneumonia, intractable 
diarrhoea). 
• Response to tetanus vaccination. 
• Immune reconstitution: T and B cell reconstitution. 
5.3 Exploratory Endpoints 
Exploratory endpoints for this study are laboratory correlates of efficacy that will be used to 
assess the level of gene correction, engraftment and immune reconstitution. 
6 Timing of Analyses 
The statistical analyses of efficacy data from this study will be performed in three stages: 
• The first analysis will be carried out when a minimum of 5 subjects have completed 6-
months follow-up post OTL-101 infusion.  At this analysis, the success/failure of the OTL-
101 cryopreserved infusion will be defined by the three criteria listed in the primary 


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Statistical Analysis Plan 
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objectives. This data will be compared with available data from UCLA ongoing Phase I/II 
study, treated with the OTL-101 fresh formulation. This will support the CMC 
comparability data between OTL-101 cryopreserved and fresh formulations. Secondary 
and exploratory endpoints will also be described and compared with the data from the fresh 
study. 
• The second analysis will be carried out when all subjects have completed 12-months 
follow-up post GTMP administration.  At this analysis, overall survival and event free 
survival will be evaluated. Secondary and exploratory endpoints, as well as baseline 
characteristics, subject disposition, and safety data will also be described. 
• The third and final analysis will be performed to determine the overall survival and event 
free survival for all subjects 24 months post GTMP administration. Secondary and 
exploratory endpoints, as well as baseline characteristics, subject disposition, safety and 
busulfan pharmacokinetic (PK) data will also be described. 
7 Analysis Populations 
7.1 Efficacy Population 
The efficacy population will be a modified intent-to-treat population including all subjects 
treated with OTL-101 within this protocol. 
7.2 Safety Population 
The safety population will consist of all subjects treated with OTL-101 within this protocol. 
8 Statistical Methods 
In general, continuous variables will be summarized using the mean, standard deviation, 
minimum, median, maximum and number of subjects.  Categorical variables will be 
summarized using number of subjects and percentages. 
8.1 Subject Disposition 
8.1.1 Summary of Populations 
Number and percentage (%) of subjects enrolled, treated, and in efficacy and safety populations 
will be summarized.  The denominator for the percentages will be the number of subjects 
enrolled.  
8.1.2 Summary of Withdrawals 
Number of subjects enrolled, number treated, number (%) of subjects who completed the study 
period will be summarized along with the reason for withdrawal.  The denominator for the 
percentages will be the number of subjects treated.  
 
For subjects in whom the treatment failed, the number (%) who had a second gene therapy, a 
rescue HSCT or other therapy will be summarized, the denominator will be the number of 
subjects who failed treatment. 
8.2 Demography and Baseline Characteristics 
Demography and baseline characteristics will be summarized for the safety population. 


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8.2.1 Demography 
Age in months will be calculated as:  
12*(date informed consent signed – date of birth)/365.25. 
 
Age, weight and height at screening will be summarized using descriptive statistics. 
 
Sex, race, ethnicity and location will be summarized using the number (%) of subjects in each 
category. 
8.2.2 Medical History 
The number (%) of subjects reporting medical history will be summarized overall and by 
category. 
8.2.3 Diagnosis of ADA-SCID 
First symptoms and primary diagnosis will be summarized using the number (%) of subjects 
with each symptom/diagnosis. 
 
Age at symptom onset and age at diagnosis in months will be calculated as  
12*(date of onset/diagnosis – date of birth)/365.25. 
 
Age at symptom onset and age at diagnosis in months will be summarized using descriptive 
statistics. 
8.2.4 Disease Treatment History 
The number (%) of subjects previously receiving PEG-ADA ERT, immunoglobulin therapy, 
prophylactic agents and other therapies will be summarized. 
 
The number (%) of subjects with a previous transplant, type of transplant cells, donor type and 
outcome will be summarized. 
 
Time since transplant in months will be calculated as  
12*(date informed consent signed – date of transplant)/365.25. 
8.2.5 Cytogenetics 
Cytogenetics will be assessed at screening and categorised as normal or abnormal. 
 
The number (%) of subjects falling into each category for type of test, source and result 
(normal/abnormal) will be summarized. 
 
8.2.6 Coagulation Tests 
Coagulation tests (prothrombin time (PT), partial thromboplastin time (PTT) and internal 
normalised ratio (INR)) will be evaluated over time prior to the OTL-101 infusion. 
 
For each parameter, the actual value will be summarized at each visit using descriptive 
statistics. 
 


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Coagulation tests will be flagged against the normal range as low/normal/high.  For each 
parameter, the number (%) of subjects with evaluations that were low/normal/high relative to 
the normal range will be summarized by visit.  Out of range values will be assessed for their 
clinical significance.  For each parameter, the number (%) of subjects with clinically significant 
evaluations will be summarized by visit. 
8.2.7 Urinalysis 
Urinalysis tests (pH, glucose, ketones, protein, bilirubin, blood, urobilinogen, nitrites, 
leukocytes, specific gravity) will be evaluated over time prior to the OTL-101 infusion. 
 
The urinalysis evaluations are assessed as ‘Normal/Negative’ or ‘Abnormal/Positive’.  If any 
urine cultures are taken, the results will be categorized as ‘positive’, ‘negative’ or ‘mixes’.  
These data will be listed. 
8.2.8 ECG 
An ECG will be taken at screening. 
 
RR interval, PR interval, QRS interval and QT interval will be summarized using descriptive 
statistics.   
 
The ECG will be categorised as ‘normal’/ ‘abnormal, not clinically significant’/ ‘abnormal, 
clinically significant’.  The number (%) of subjects with evaluations falling into each category 
will be summarized along with the number (%) with each type of abnormal finding. 
8.2.9 Echocardiogram 
An echocardiogram will be taken at screening. 
 
Left ventricular ejection fraction will be summarized using descriptive statistics.   
 
The echocardiogram will be categorised as ‘normal’/ ‘abnormal, not clinically significant’/ 
‘abnormal, clinically significant’.  The number (%) of subjects with evaluations falling into 
each category will be summarized. 
8.2.10 
Chest X-ray and Computed Tomography (CT) Scan 
A chest x-ray will be taken at screening, in addition a CT scan will be performed if the x-ray 
shows evidence of severe lung disease. 
 
Both the chest x-ray and the CT scan will be categorised as ‘normal’/ ‘abnormal, not clinically 
significant’/ ‘abnormal, clinically significant’.  The number (%) of subjects with evaluations 
falling into each category will be summarized. 
8.2.11 
Skin Lesions 
The number (%) of subjects with any suspicious skin lesions at screening, having a biopsy and 
falling into each category of result (‘normal’/ ‘abnormal, not clinically significant’/ ‘abnormal, 
clinically significant’) will be summarized. 


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8.2.12 
Bone Marrow Harvest 
The number (%) of subjects with each blood type, having a transfusion of PRBC and with each 
reason for a lack of back-up stem cells (if appropriate) will be summarized.  If there is a 
repeated harvest, these data will be summarized for each evaluation. 
 
Total number of nucleated cells and total CD34+ cell count in the bone marrow harvest will be 
summarized using descriptive statistics along with the number of mononuclear and total 
nucleated cells stored for back-up. 
8.2.13 
Busulfan Administration 
For each administration of Busulfan, the duration of administration, dose given and AUC will 
be summarized using descriptive statistics.  In addition, for Day -4/-3, the calculated Busulfan 
dose for Day -2/-1 will be summarized. 
8.2.14 
Busulfan Pharmacokinetics 
For each administration of Busulfan, the PK parameters (Cmax, Tmax, AUC0-t, AUC0-13, AUC0-
∞) will be summarized using descriptive statistics. 
 
8.2.15 
OTL-101 Administration 
The number (%) of subjects who received OTL-101 will be summarized along with any reasons 
for non-administration. 
 
The number (%) of subjects who were pre-medicated with acetaminophen or diphenhydramine 
will be summarized. 
 
For each bag of product, the volume, number of CD34+ cells and the planned volume to be 
infused, the duration of infusion, the volume administered and the % cell viability will be 
summarized using descriptive statistics. 
 
For each additional infusion, the number of CD34+ cells, the number per kg, the final product 
volume, the total cells in the final product, the %CD34+, the CD34+ cells per mL and the final 
volume to be infused will be summarized using descriptive statistics. 
8.2.16 
Exposure 
Duration of follow-up in months will be calculated as:  
12*(date of final evaluation – date of infusion + 1)/365.25. 
 
Duration of follow-up will be summarized using descriptive statistics.  In addition, the total 
subject-years of follow-up will be presented. 
 


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8.3 Efficacy Evaluations 
8.3.1 Primary Efficacy Endpoints 
8.3.1.1 
Response to OTL-101 Treatment at 6 Months 
Response to OTL-101 treatment at 6 months post administration will be based on the following 
criteria: 
• 
ADA activity in red blood cells: change from baseline >0 Units,  
• 
Absolute CD3+ T-cell count ≥200/mm3, and  
• 
Detectable gene-marked granulocytes by differential polymerase chain reaction 
(dPCR)/qPCR ≥1/10,000 cells. 
Subjects who meet all three criteria will be said to have mounted a response.  
 
For any subjects with missing values at 6 months, the earliest assessments after month 6 will 
be used.  In addition, if ADA activity at baseline is not available, any positive value will be 
considered as a positive response. 
 
The number (%) of subjects mounting a response will be summarized and descriptively 
compared with the proportion from the UCLA “Fresh” study.  In addition, the number (%) of 
subjects with a response to each of the individual criteria will be summarized. 
8.3.1.2 
Overall Survival at 12 Months 
Overall survival will be evaluated using the time in months from transplant to either the 
subject’s death or their last evaluation calculated as: 
12*(date of death/last evaluation – date of transplant)/365.25. 
 
The number (%) of subjects who were still alive at 12 months post-transplant will be 
summarized.  For the purpose of this analysis, any subject who withdrew from the study prior 
to 12 months, who was known to be alive at the last evaluation, will have a status of 
“unknown”.  The proportion and exact 95% confidence interval (CI) for survivors at 12 months 
post-transplant will be calculated.   
 
Overall survival will also be represented using a Kaplan-Meier curve for time to death.  For 
the purpose of this analysis, any subject who withdrew from the study prior to 12 months and 
was known to be alive at the last evaluation will be censored at the date of their last evaluation.  
If appropriate, the proportion alive at 12 months and the associated 95% CI will be estimated 
from the Kaplan-Meier curve along with the median survival time (and interquartile range), if 
they can be estimated from the data. 
8.3.1.3 
Event Free Survival at 12 Months 
Event-free survival will be evaluated using the time in months from transplant to either the 
first event or their last evaluation calculated as: 
12*(date of event/last evaluation – date of transplant)/365.25. 
   
For the purpose of this analysis, the events of interest are:  
• death; 
• reinstitution of PEG-ADA ERT; 
• requirement for a second transplant. 


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Event-free survival will be summarized in the same way as overall survival described in 
Section 8.3.1.2. 
 
8.3.2 Secondary Efficacy Endpoints 
8.3.2.1 
Overall and Event Free Survival at 24 Months 
Overall and event-free survival at 24 months will be summarized in the same way as for the 
analyses at 12 months described in Sections 8.3.1.2 and 8.3.1.3. 
 
8.3.2.2 
Use of Immunoglobulin Replacement Therapy 
The number (%) of subjects receiving immunoglobulin replacement therapy will be 
summarized by visit. 
 
The time to cessation of Ig RT will be calculated (in months), using the stop date on the 
concomitant medication form, as: 
 
12*(stop date of Ig RT – date of infusion) /365.25. 
 
Time to cessation of IgRT will be summarized using descriptive statistics and, if appropriate, 
estimated from a Kaplan-Meier curve in which subjects who are still receiving IgRT will be 
censored at the time of their last visit. 
 
The number (%) of subjects who have stopped treatment with IgRT at 12, 18 and 24 months 
without restarting at any subsequent time point will be summarized. 
 
In addition, serum immunoglobulin levels (IgG, IgA and IgM) will be measured at each visit.  
Levels of IgG, IgA and IgM and changes from baseline will be summarized by visit using 
descriptive statistics.  In addition, plots of the median value and range over time on a 
logarithmic scale will be produced for each parameter along with individual plots for each 
subject which will include age-dependent normal ranges provided by the study site. 
 
8.3.2.3 
Performance Outcomes and Quality of Life 
The baseline evaluation for the quality of life outcomes will be the final evaluation prior to the 
OTL-101 infusion. 
 
The number (%) of subjects choosing each answer to the questions “How have you been feeling 
in general?” and “Can the patient practice sports?” will be summarized at each visit.  Changes 
from baseline to each subsequent visit will be summarized using the number (%) of subjects 
whose status improved/no change/deteriorated. 
 
The number of days absent from school and the change from baseline will be summarized by 
visit. 
 
Scores on the Lansky and Karnofsky performance scales and the change from baseline will be 
summarized by visit. 
 


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8.3.2.4 
Rate of Severe Infections 
Infections will be recorded as adverse events.  The infections of interest in this study are 
severe infections or opportunistic infectious episodes, defined as infections requiring 
hospitalization or prolonging hospitalization and/or documented infections by opportunistic 
pathogens (e.g. interstitial pneumonia, intractable diarrhoea). 
 
The number (%) of subjects reporting severe infections or opportunistic infectious episodes 
along with the number of events reported will be summarized.  In addition, the infection rate 
will be calculated as the number of infections/the total follow-up time.  The rate will be 
calculated both for the entire group and for each individual subject.  The subject infection rate 
will be summarized using descriptive statistics.  In addition to the rate for the entire follow-up 
period, the rate will be calculated for both the first 12 months following transplant and for the 
remaining study period. 
8.3.2.5 
Response to Tetanus Vaccination 
Tetanus antibodies will be measured in subjects who have stopped immunoglobulin 
replacement and have received a tetanus vaccination. 
 
Pre-vaccination and post-vaccination titres will be summarized by vaccination number.  
 
Subjects will be to considered to have mounted a protective antibody response to tetanus if they 
have a titre of anti-tetanus antibodies >0.15 IU/ml.  The number (%) of subjects who mounted 
a protective antibody response to tetanus will be summarized.  
8.3.2.6 
Immune Reconstitution 
Immune reconstitution will be assessed using lymphocyte subsets.  Absolute numbers and 
percentage of CD3+, CD4+, CD8+ and CD4+/CD45RO+ T-lymphocytes, CD19+ B-lymphocytes 
and CD56+/CD16+ NK cells will be measured. 
 
For each of the lymphocyte subsets, the actual value and change from baseline will be 
summarized at each visit.  The median value and range will be plotted over time on a 
logarithmic scale and individual counts will be plotted along with the age-dependent normal 
ranges provided by the study site. 
 
8.3.3 Exploratory Efficacy Endpoints 
8.3.3.1 
Use of PEG-ADA Enzyme Replacement Therapy 
The time to withdrawal of PEG-ADA ERT will be calculated (in months), using the stop date 
on the concomitant medication form, as: 
 
12*(stop of PEG-ADA ERT – date of infusion) /365.25. 
 
Time to withdrawal of PEG-ADA ERT will be summarized using descriptive statistics and, if 
appropriate, estimated from a Kaplan-Meier curve in which subjects who are still receiving 
PEG-ADA ERT will be censored at the time of their last visit. 


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8.3.3.2 
T Cell Receptor Excision Circles (TREC) 
TREC levels will be summarized at each visit using descriptive statistics.  Plots of the median 
and range over time on a logarithmic scale will be produced.  In addition, individual subject 
plots of TREC levels over time will be produced. 
8.3.3.3 
T Cell Receptor Vβ Panel Results 
TCR V-β usage, categorized as normal/abnormal, will be summarized by visit and overall using 
the number (%) with an abnormal evaluation at any post-infusion visit.   
8.3.3.4 
T Lymphocyte Response to Phytohemagglutinin (PHA) 
T lymphocyte response to PHA, categorized as normal/abnormal, will be summarized by visit 
and overall using the number (%) with an abnormal evaluation at any visit. 
8.3.3.5 
Engraftment 
Engraftment of transduced cells will be assessed over time using vector gene marking in 
peripheral blood cells (PBMC, granulocytes, T-cells, B-cells, NK cells, myeloid cells).  The 
vector copy numbers in each type of cell will be summarized using descriptive statistics.  In 
addition, for each cell type, plots of the median and range over time on a logarithmic scale 
will be produced along with individual subject plots. 
8.3.3.6 
ADA Expression, Enzyme Activity and Detoxification  
RBC ADA activity, deoxyadenine nucleotides, AXP, dAXP and %dAXP will be summarized 
by visit.  The median value and range will be plotted over time on a logarithmic scale as will 
the values for individual subjects.  Deoxyadenine nucleotide evaluations that are 
‘undetectable’ will use the limit of quantitation in the summary. 
 
ADA activity and deoxyadenine nucleotides in erythrocytes will also be categorized as 
normal/abnormal, not clinically significant/abnormal clinically significant.  The number (%) 
of subjects with evaluations in each category will be summarized by visit.   
8.3.3.7 
Vector Integration Analysis 
The number (%) of subjects with one integration site representing > 30% of total integration 
will be summarized by visit.  The number (%) of subjects for whom one integration site 
contributed > 30% of total integration at two or more time points will also be summarized.  In 
addition, the total number of integration sites will be summarized by visit. 
 
8.4 Safety Evaluations 
8.4.1 Adverse Events 
All adverse events will be coded using MedDRA version 20.0 or higher. 
8.4.1.1 
Definition of Treatment-emergent Adverse Events 
Adverse events (AEs) will be summarised on the basis of treatment emergence.  An adverse 
event is considered to be treatment emergent if it occurred on or after the date and time of the 


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start of the IMP infusion.  If the start time of the event is not present, any event starting on the 
same day as the infusion will be considered to be treatment emergent.  If the start date of the 
adverse event is partial or missing, it will be considered to be treatment emergent if: 
• the day is missing, the month and year are present and are the same as or after the month 
and year of the infusion and the end date is missing or is not before the date of infusion, 
• the day and month are missing, the year is present and is the same as or after the year 
of the infusion and the end date is missing or is not before the date of infusion, 
• the entire date is missing and the end date is missing or is not before the date of infusion. 
8.4.1.2 
Adverse Events 
Treatment emergent adverse events will be summarized in an overall summary presenting the 
number (%) of subjects with: 
• any AE,  
• AE grade 2 or higher (at least moderate in severity),  
• AE grade 3 or higher (at least severe in severity),  
• treatment related AE,  
• AE related to autoimmunity, 
• AE leading to study discontinuation, 
• any serious adverse event (SAE),  
• treatment related SAE, 
• SAE related to autoimmunity, 
• SAE leading to death. 
 
Incidence and frequency of treatment emergent AEs will be summarised by system organ 
class (SOC) and preferred term (PT): 
• overall, 
• by maximum severity, 
• treatment related AEs, 
• SAEs (if sufficient events), 
• AEs leading to study discontinuation (if sufficient events). 
 
In addition, a summary table for the most frequently reported treatment emergent adverse 
events (those reported in 2 or more subjects) will be presented by PT in descending order of 
incidence and frequency. 
 
In each table, if the same SOC or PT is reported on multiple occasions for a single subject, it 
will only be included once in the summary.  In the table by maximum severity, only the most 
severe occurrence for each SOC and PT for each subject will be included in the summary.  In 
the table by maximum relationship, only the most related occurrence for each SOC and PT 
for each subject will be included in the summary. 
 
Any adverse events that are not treatment emergent (occurred prior to the infusion) will be 
listed. 
8.4.2 Concomitant Medications 
Concomitant medications taken during the study will be listed. 


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8.4.3 Infectious Episodes 
Number (%) of subjects with an active infection will be summarized at each visit along with 
the number (%) with each type/location of infection.  In addition, an overall summary of the 
number (%) of subjects with an active infection and each type/location of infection at any time 
post-infusion will be presented.  
8.4.4 Replication Competent Lentivirus (RCL) Testing 
Number (%) of subjects testing positive for RCL will be summarized by visit and at any time. 
8.4.5 Leukaemia Assessment 
Blood samples for leukaemia assessments will be taken over time.  The number (%) of subjects 
with potential leukoproliferation will be summarized by visit and at any time post-infusion. 
 
The number (%) with a bone marrow sample taken, with morphology assessed, with an 
abnormal morphology assessment, tested for integration analysis and with an abnormal 
assessment for integration analysis will summarized by visit and at any time post-infusion. 
8.4.6 Laboratory Evaluations 
8.4.6.1 
Haematology 
Haematology parameters (red blood cell (RBC) count, hemoglobin, hematocrit, mean 
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), white blood cell count (WBC), neutrophils, lymphocytes, 
monocytes, eosinophils, basophils and platelet count) will be evaluated over time.  The baseline 
evaluation for each parameter will be the final evaluation prior to the OTL-101 infusion. 
 
For each parameter, the actual value and change from baseline will be summarized at each visit 
using descriptive statistics. 
 
Hematology evaluations will be flagged against the normal range as low/normal/high.  For each 
parameter, the number (%) of subjects with evaluations that were low/normal/high relative to 
the normal range will be summarized by visit.  In addition, shift tables will be constructed 
comparing the flags at the baseline evaluation with the minimum and maximum evaluation 
post-infusion.  Out of range values will be assessed for their clinical significance.  For each 
parameter, the number (%) of subjects with clinically significant evaluations will be 
summarized by visit and at any time post-infusion. 
8.4.6.2 
Biochemistry 
Biochemistry parameters (blood urea nitrogen, creatinine, total bilirubin, sodium, potassium, 
chloride, calcium, aspartate transaminase (AST), alanine transaminase (ALT), alkaline 
phosphatase (ALP), albumin, total protein, glucose, magnesium, phosphates) will be evaluated 
over time.  The baseline evaluation for each parameter will be the final evaluation prior to the 
OTL-101 infusion. 
 
For each parameter, the actual value and change from baseline will be summarized at each visit 
using descriptive statistics. 
 


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Biochemistry evaluations will be flagged against the normal range as low/normal/high.  For 
each parameter, the number (%) of subjects with evaluations that were low/normal/high relative 
to the normal range will be summarized by visit.  In addition, shift tables will be constructed 
comparing the flags at the baseline evaluation with the minimum and maximum evaluation 
post-infusion.  Out of range values will be assessed for their clinical significance.  For each 
parameter, the number (%) of subjects with clinically significant evaluations will be 
summarized by visit and at any time post-infusion. 
8.4.7 Vital Signs, Height and Weight 
Vital signs (temperature, pulse rate, respiratory rate, systolic and diastolic blood pressure and 
oxygen saturation), height and weight are measured over time. 
 
The baseline evaluation for each of the vital signs, height and weight will be the final evaluation 
prior to the OTL-101 infusion. 
 
For each parameter, the actual value and change from baseline will be summarized at each visit 
using descriptive statistics. 
 
Any vital signs found to be out of range will be categorized as not clinically significant or 
clinically significant.  For each vital sign, the number (%) of subjects with clinically significant 
evaluations will be summarized by visit and at any time post-infusion. 
8.4.8 Physical Examination 
Physical examinations will be performed over time.  The number (%) of subjects with abnormal 
evaluations will be summarized by body system at each visit.  An overall summary will also 
be produced for each body system showing the number (%) of subjects with normal evaluations 
at all pre-treatment evaluations who had one or more abnormal evaluations post-treatment. 
9 Analysis Software 
All summaries and analyses will be carried out using SAS® version 9.4.