A Long Term Follow-up Protocol to Evaluate the Safety and Survival of Autologous CD34+ Hematopoietic Progenitor Cells Transduced With an Anti-HIV-1 Ribozyme (OZ1) in Patients With HIV-1 Infection
Phase: PHASE2
Conditions: HIV-1
Sponsor: Janssen-Cilag Pty Ltd

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Janssen-Cilag Pty Ltd, Australia 
Clinical Protocol
A long term follow-up protocol to evaluate the safety and survival of 
autologous CD34+ hematopoietic progenitor cells transduced with an anti-
HIV-1 ribozyme (OZ1) in patients with HIV-1 infection
BB-IND: 10183
PROTOCOL OZ1-HV1-202
Amendment 4
PHASE II
Status:
Approved
Issue/Report Date:
07 June 2017
Prepared by:
Janssen-Cilag Pty Ltd, Australia 
EDMS No:
EDMS-ERI-139809326
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed 
unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information is disclosed must be informed 
that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to 
all future information supplied to you that is indicated as privileged or confidential.
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TABLE OF CONTENTS
CONTACT INFORMATION†......................................................................................................4
PROTOCOL VERSION INFORMATION†..................................................................................5
SYNOPSIS.................................................................................................................................6
INVESTIGATOR AGREEMENT†...............................................................................................8
1. 
INTRODUCTION...........................................................................................................9
1.1
BACKGROUND† ...........................................................................................................9
1.2
RATIONALE FOR STUDY†...........................................................................................9
2.
OBJECTIVES .............................................................................................................10
3.
OVERVIEW OF STUDY DESIGN...............................................................................10
4.
COMPLIANCE†...........................................................................................................10
5.
STUDY POPULATION ...............................................................................................11
5.1
INCLUSION CRITERIA...............................................................................................11
5.2
EXCLUSION CRITERIA..............................................................................................11
6.
CONCOMITANT THERAPY AND ACTIVITIES .........................................................11
7.
STUDY EVALUATIONS .............................................................................................11
7.1
STUDY PROCEDURES BY VISIT† ............................................................................11
7.2 
SAFETY EVALUATIONS............................................................................................14
8.
PATIENT COMPLETION† ..........................................................................................16
9.
STATISTICAL METHODS† ........................................................................................16
9.1
EFFICACY EVALUATION† .........................................................................................16
9.2
SAFETY EVALUATIONS............................................................................................16
10.
ADVERSE EVENT REPORTING ...............................................................................17
10.1
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS†...................................17
10.2 
PROCEDURES...........................................................................................................19
Non-Serious Adverse Events......................................................................................19
Serious Adverse Events..............................................................................................19
Pregnancy ...................................................................................................................21
10.3
CONTACTING SPONSOR REGARDING SAFETY ...................................................21
11.
ETHICAL ASPECTS...................................................................................................21
11.1
INVESTIGATOR RESPONSIBILITIES .......................................................................21
11.2
INDEPENDENT ETHICS COMMITTEE OR INSTITUTIONAL REVIEW BOARD  
(IEC/IRB).....................................................................................................................21
11.3
INFORMED CONSENT ..............................................................................................22
12
ADMINISTRATIVE REQUIREMENTS .......................................................................22
12.1
PROTOCOL MODIFICATIONS ..................................................................................22
12.2
REGULATORY DOCUMENTATION ..........................................................................23
12.3
PATIENT IDENTIFICATION REGISTER....................................................................24
12.4
RECORD RETENTION...............................................................................................24
12.5
CASE REPORT FORM COMPLETION......................................................................25
12.6
MONITORING.............................................................................................................25
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12.7
DATA QUALITY ASSURANCE...................................................................................26
12.8
ON-SITE AUDITS .......................................................................................................26
12.9
USE OF INFORMATION AND PUBLICATION...........................................................26
13.
REFERENCES† ..........................................................................................................27
14.
APPENDICES.............................................................................................................29
Appendix 1: TOXICITY GRADING TABLE.............................................................................30
Appendix 2:† TELEPHONE FOLLOW-UP QUESTIONNAIRE...............................................35
Appendix 3: PROTOCOL AMENDMENT HISTORY..............................................................41
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CONTACT INFORMATION†
SPONSOR
Name
Janssen-Cilag Pty Ltd
Address
1-5 Khartoum Rd
Macquarie Park, NSW 2113
Australia
General Contact Number:
Fax
Serious Adverse Event Reporting:
Name
Janssen-Cilag Pty Ltd Drug Safety Department
Office Phone Number
SAE Fax Number
E-mail
Appropriate Sponsor Contact Personnel:
Name
Dr.
Function
Project Physician
Office Fax Number
Cell Phone Number
Name
Function
Project Manager
Office Phone Number
Office Fax Number
Home Phone Number
NA
Cell Phone Number
Name
Function
Office Phone Number
Office Fax Number
Cell Phone Number
If any Sponsor contact information needs to be changed during the course of the study, written notification will be 
provided to the Investigator and will not require (a) Protocol amendment(s).
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PROTOCOL VERSION INFORMATION†
Sections of this protocol have been revised. Amendment 1 was issued on 23 June 2006. 
Amendment 2 was issued on 28 August 2007. Amendment 3 was issued on 15 October 2008. 
Sections marked “†” have been revised as Amendment 4; 07 June 2017. Please refer to 
Appendix 3 – Protocol Amendment History for a detailed description of the specific changes.
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A long term follow-up protocol to evaluate the safety and survival of autologous CD34+ 
hematopoietic progenitor cells transduced with an anti-HIV-1 ribozyme (OZ1) in patients 
with HIV-1 infection
SYNOPSIS
OBJECTIVE†
The objective of this study is to evaluate the long-term safety of a cell-delivered ribozyme gene transfer product 
(OZ1) in patients infected with HIV-1. OZ1 comprises a Moloney Murine Leukemia Virus based retroviral vector 
(LNL6) containing a gene that encodes an anti-HIV ribozyme. It is currently a recommendation of the United States 
Food and Drug Administration (FDA) and Australian Therapeutic Goods Administration (TGA) that all individuals 
receiving retroviral gene transfer products are followed to collect data on delayed adverse events.
OVERVIEW OF STUDY DESIGN†
This will be a follow-up study of patients previously enrolled in the OTH/OZ1-INT-1 trial. All patients in this 
protocol will be reviewed at six monthly intervals until year 5 post infusion. Thereafter all patients will be reviewed 
annually, on the anniversary of the infusion until withdrawal or study completion. Patients who were enrolled in the 
placebo arm will be discontinued after OTH/OZ1-INT-1 has been unblinded.
STUDY POPULATION
Participants in the OTH/OZ1-INT-1 Phase II study entitled “A Randomized Phase II, double blind, controlled trial 
to evaluate the safety and efficacy of autologous CD34+ hematopoietic progenitor cells transduced with placebo or 
an anti-HIV-1 ribozyme (OZ1) in patients with HIV-1 infection” will be asked to consent to continue safety 
monitoring and gene marking as described in this protocol. 
DOSAGE AND ADMINISTRATION
All participants of the OTH/OZ1-INT-1 Phase II study received a single dose of placebo or OZ1 transduced CD34+ 
cells.
SAFETY EVALUATIONS†
Follow-up will be conducted as per current FDA/Center for Biologics Evaluation and Research (CBER) 
recommendations. Evaluations will include monitoring for related adverse events such as the development of 
replication competent retrovirus (RCR), predominant integration sites and insertional oncogenesis. Blood samples 
will be collected for archival storage for assessment of replication competent retrovirus (RCR) and other safety 
testing as necessary.
EFFICACY EVALUATIONS
Ongoing analysis of quantitative marking of the gene transfer product (OZ1 and LNL6) in peripheral blood 
mononuclear cells (PBMC) will be performed as part of the testing of predominant integration sites. These marking 
data will also be analyzed independently of the integration analysis to detect changes in the number of cells carrying 
the gene transfer product.
TIME AND EVENTS SCHEDULE
Follow up visits may be part of routine clinic visits where possible, but must be performed as described in the Time 
and Events Schedule. Additional unscheduled visits will be made if clinical or biological findings, as described in 
this protocol, require additional evaluation or investigation or as directed by the Investigator.
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TIME AND EVENTS SCHEDULE†
Follow up visit
Yr 2.5 Yr 3 Yr 3.5 Yr 4 Yr 4.5
Annual
Yr 5+
/End-of-
Study4
Clinical history and examination
X
X
X
X
X
X
Complete Blood Count/Differential and Platelets
X
X
X
X
X
X
Plasma archive
X
X
X
PBMC archive1
X
X
X
OZ1 integration site (PCR)2
X
X
X
X
X
X
Adverse Events Assessment
X
X
X
X
X
X
Contact details updated for subject and nominated secondary contact
X
X
X
X
X
X
Volume of blood drawn at visit (ml)3
30
73
30
73
30
73
1The PBMCs will be stored as cryopreserved cells and cell pellets for assessment of replication competent retrovirus 
(RCR) and other safety testing as required.
2This includes both marking (quantitative OZ1/LNL6 DNA-PCR) and the detection of predominant integration sites. 
If the percentage of cells marked by the vector (quantitative OZ1/LNL6 DNA-PCR) is less than 1% of the test cell 
population, the site of integration will not be investigated. If a predominant OZ1 integration site is detected, the 
patient will be retested within 3 months to determine if it persists. If so, the site of integration of OZ1 will be 
sequenced and mapped to the human genome to determine any association with a known human oncogene. In all 
instances that a predominant integration site is present and, particularly when there is expansion of a cellular clone, 
the patient will be monitored for signs of cancer, so that treatment can be initiated as early as possible. Ongoing 
analysis of quantitative marking of the gene transfer product will be performed as part of the testing of predominant 
integration sites. These marking data will also be analyzed independently to detect any changes in the number of
cells carrying the gene transfer product.
3Blood can be collected up to 1 week prior to the other assessments.
4 End-of-Study assessments will be performed after all ongoing patients have been followed up for least 10 years 
post-infusion. End-of-Study visits will be completed by 30 November 2017. In the event that a patient cannot attend 
a site visit, telephonic follow-up will be an acceptable alternative.
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INVESTIGATOR AGREEMENT†
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1. 
INTRODUCTION
1.1
Background†
OZ1 is a Moloney Murine Leukemia Virus based retroviral vector (LNL6) 
containing a gene that encodes an anti-HIV-1 ribozyme directed against the human 
immunodeficiency virus type 1 (HIV-1) regulatory gene tat.13,14,15 A Phase I study 
demonstrated that the introduction of OZ1 into CD34+ cells ex vivo is technically 
feasible and safe.1 The international, multi-center, Phase II, randomized, double-
blind trial, OTH/OZ1-INT-1, was initiated to investigate the safety and efficacy of 
OZ1-transduced autologous CD34+ cells in patients with HIV-1 infection.9 One 
patient was enrolled in a Phase II protocol comparing the retroviral vector alone 
(LNL6) and OZ1. In a protocol amendment, OTH/OZ1-INT-1 became a placebo-
controlled trial. Of the 74 patients to be enrolled in the placebo controlled protocol, 
approximately half received a placebo and half OZ1. The primary efficacy end 
point is the difference in viral load between the two groups at weeks 47 and 48 post-
infusion. Patients continue in the OTH/OZ1-INT-1 treatment interruption follow-on 
phase until week 100 post-infusion as long as the viral load remains below 
100,000 copies/ml, the CD4+ cell count is greater than 150 cells/mm3 and there are 
no other reasons to recommence antiretroviral therapy. At the end of the 
OTH/OZ1-INT-1 study (week 100 post-infusion), patients are invited to enter this 
long term follow-up (LTFU) protocol.
1.2
Rationale for Study†
Food and Drug Administration (FDA)/Center for Biologics Evaluation and Research
(CBER) recommends a 15-year time-period for follow-up observations. However, 
CBER also recognizes that assessment of risk is a continuous process, and the nature 
and duration of follow up observations may be revised accordingly.4 This follow up 
protocol is to assess the long-term safety of OZ1/LNL6 gene transfer product in 
patients who were enrolled in the OTH/OZ1-INT-1 study. Based on the integrated 
safety analysis of observations up to 10 years in this LFTU study, up to 15 years 
with the same OZ1/LNL6 gene transfer product in 2 Phase 1 LTFU studies 
(OZ1-HV1-101 and OZ1-HV1-102), and published reports of adverse events 
observed with gene therapeutic products using the same type of retroviral 
vector,2,3,5,6,7,8,10,11,12 the sponsor has determined that the risk to OZ1/LNL6 gene 
transfer product to recipients beyond 10 years post-infusion is minimal. Accordingly, 
this long term follow up study will conclude by 30 November 2017. This completion 
date represents a minimum of 10 years follow up following the receipt of 
OZ1/LNL6-modified CD34+ cells.
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2.
OBJECTIVES
1. To undertake long term safety monitoring for any development of:
a.
Clonal expansion of cells with a predominant OZ1 insertion site
b. Insertional oncogenesis
2. To archive/store plasma and PBMC samples for other safety testing that may 
be required.
3. To assess quantitative marking of the gene transfer product in PBMCs over 
time.
3.
OVERVIEW OF STUDY DESIGN
The patients who were enrolled in the OTH/OZ1-INT-1 trial entitled “A 
randomized Phase II, double blind, controlled trial to evaluate the safety and 
efficacy of autologous CD34+ hematopoietic progenitor cells transduced with 
placebo or an anti-HIV-1 ribozyme (OZ1) in patients with HIV-1 infection” will 
continue to be assessed under this long term follow-up protocol. Where possible 
follow up visits will coincide with routine clinic visits. 
4.
COMPLIANCE†
1.
The semi-annual visit interval is 6 months 6 weeks (for years 2.5-5). The 
annual visit interval is 12 months 12 weeks (year 5+) except the End-of-Study 
visit. End-of-Study assessments will be performed after all ongoing patients 
have been followed up for least 10 years post-infusion. End-of-Study visits will 
be completed by 30 November 2017. In the event that a recipient cannot attend 
a site visit, a telephonic follow-up will be an acceptable alternative.
2.
Complete Blood Count/Differential data will be obtained specifically as part of 
the follow up procedures. 
3.
In the event that a recipient dies, irrespective of cause of death or time after the 
gene transfer procedure, a request will be made by the Principal Investigator to 
the next of kin for an autopsy to assess for the presence of 1) RCR and 2) LNL6 
or OZ1 containing cells. If efforts to obtain permission for an autopsy are 
unsuccessful or not practicable, failure to undertake an autopsy will not be 
considered protocol non-compliance. If an autopsy is performed, a copy of the 
autopsy report will be obtained and the cause of death and any significant 
observations noted in the Serious Adverse Event report.
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4.
In the event that the recipient undergoes a biopsy or surgical removal of a 
tumor, an attempt will be made by the Principal Investigator to obtain a sample 
of tissue for the assessment of the presence of 1) RCR and 2) LNL6 or OZ1 
containing cells. If efforts to obtain a tissue sample are unsuccessful or not 
practicable, it will not be considered as protocol non-compliance.
5.
STUDY POPULATION
5.1
Inclusion Criteria
Patients must satisfy the following criteria before entering the study:

Received the Final Cell Product infusion in the Phase II trial, OTH/OZ1-
INT-1.

Signed Informed Consent Form for this study.
5.2
Exclusion Criteria
All patients who were enrolled in the OTH/OZ1-INT-1 study and received the final 
cell product will be invited to participate in this long term follow-up study. After 
unblinding of the OTH/OZ1-INT-1 study, any patients in the placebo arm will be 
withdrawn from this protocol. 
6.
CONCOMITANT THERAPY AND ACTIVITIES
Information on current medications or other therapies will not be collected, unless 
required for submission of a Serious Adverse Event report.
7.
STUDY EVALUATIONS
7.1
Study Procedures By Visit†
The Time and Events Schedule included in the Synopsis summarizes the frequency 
and timing of the various efficacy and safety measurements.
Visit schedules are fixed from the day of the original infusion of autologous CD34+ 
cells as per the OTH/OZ1-INT-1 protocol. Blood samples may be taken up to 1 
week prior to the other assessments.
Table 3: Long term follow-up allowed visit intervals.
Visit interval
Allowed window
6 months
6 weeks
12 months*
12 weeks*
* Except the End-of-Study visit, which will be scheduled at a date no later than
30 November 2017.
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In the event that a subject is unable to attend the clinic within the allowed visit 
window, a telephone interview can be conducted to collect information on 
important medical events since the last study visit (or telephone interview). Refer to 
Appendix 2 for the interview questionnaire. If the clinical trial site is unable to 
contact the patient directly a nominated secondary contact will be contacted. A 
patient will be considered to be lost-to-follow-up, at any stage of the clinical trial, 
after three failed documented attempts (telephone calls, certified letters, e-mail 
requests) to contact either the patient or a nominated secondary contact. A lost or 
withdrawn patient may re-enter this long term follow-up protocol at any stage up 
until 30 November 2017.
2.5 to 5.0 years post-infusion†
Visits will be at six monthly intervals from year 2.5 to year 5.0 post-infusion. 
The long term follow-up visits at Year 2.5, 3.5 and Year 4.5 post-infusion will have 
the following assessments:

Clinical history and physical examination including a detailed record of:
o
exposure 
to 
possible 
mutagenic 
agents 
e.g. 
radiotherapy 
or 
chemotherapeutic agents
o
new malignancies
o
new or exacerbated preexisting neurologic, rheumatologic, autoimmune and 
hematologic disorders

Complete Blood Count (CBC)/differential and platelet count.

Testing for clonality of OZ1/LNL6 integration in PBMC samples (PCR) if the 
percentage of cells marked by the vector (quantitative OZ1 DNA-PCR) is 
greater than or equal to 1% of the test cell population. 

Analysis of quantitative marking of the gene transfer product (OZ1 and LNL6) 
in peripheral blood mononuclear cells (PBMC) will be performed as part of the 
testing of predominant integration sites. These marking data will also be 
analyzed independently of the integration analysis to detect changes in the 
number of cells carrying the gene transfer product.

Recording of AEs.

Contact details updated for subject and nominated secondary contact.
The long term follow-up visits at Year 3, 4 and 5 post-infusion will have the 
following assessments:

Clinical history and physical examination including a detailed record of:
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o
exposure 
to 
possible 
mutagenic 
agents 
e.g. 
radiotherapy 
or 
chemotherapeutic agents
o
new malignancies
o
new or exacerbated preexisting neurologic, rheumatologic, autoimmune and 
hematologic disorders

Complete Blood Count (CBC), differential and platelet count.

Archival storage of plasma and PBMC samples for safety testing including 
Replication-Competent Retrovirus (RCR) as required.

Testing for clonality of OZ1/LNL6 integration in PBMC samples (PCR) if the 
percentage of cells marked by the vector (quantitative OZ1/LN6 DNA-PCR) is 
greater than or equal to 1% of the test cell population.

Analysis of quantitative marking of the gene transfer product (OZ1 and LNL6) 
in peripheral blood mononuclear cells (PBMC) will be performed as part of the 
testing of predominant integration sites. These marking data will also be 
analyzed independently of the integration analysis to detect changes in the 
number of cells carrying the gene transfer product.

Recording of AEs.

Contact details updated for subject and nominated secondary contact.
Annual Visits Year 5+ post infusion and End-of-Study visit†

Clinical History and Physical Examination including a detailed record of:
o
exposure 
to 
possible 
mutagenic 
agents 
e.g. 
radiotherapy 
or 
chemotherapeutic agents
o
new malignancies
o
new or exacerbated preexisting neurologic, rheumatologic, autoimmune and 
hematologic disorders

Complete Blood Count (CBC), differential and platelet count.

Archival storage of plasma and PBMC samples for safety testing including 
Replication-Competent Retrovirus (RCR) as required.

Testing for clonality of OZ1/LNL6 integration in PBMC samples (PCR) if the 
percentage of cells marked by the vector (quantitative OZ1/LNL6 DNA-PCR) 
is greater than or equal to 1% of the test cell population.

Analysis of quantitative marking of the gene transfer product (OZ1 and LNL6) 
in peripheral blood mononuclear cells (PBMC) will be performed as part of the 
testing of predominant integration sites. These marking data will also be 
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analyzed independently of the integration analysis to detect changes in the 
number of cells carrying the gene transfer product.

Recording of AEs.

Contact details updated for subject and nominated secondary contact.
In the event that a recipient does not report for an in-person End-of-Study visit, a 
telephonic follow-up will be an acceptable alternative.
Unscheduled Assessments†
In addition to the annual follow up visit, unscheduled procedures may be 
performed in the event of an adverse event or as directed by the Investigator.
7.2 
Safety Evaluations
The study will include the following evaluations of safety and tolerability:

Adverse Events (AEs): AEs will be reported by the patient (or where 
appropriate by the patient’s legally authorized representative) for the duration 
of the study. Further details on adverse event reporting are provided in Section 
10.

Clinical Laboratory tests as follows:
The following testing will be completed as designated in the Time & Events 
Schedule:
Gene Transfer Product Safety Testing
1.
Testing for clonality of OZ1/LNL6 integration in PBMC using PCR. 
–Testing for clonality of OZ1/LNL6 integration in PBMC samples (PCR) will 
proceed if the percentage of cells marked by the vector (quantitative 
OZ1/LNL6 DNA-PCR) is greater than or equal to 1% of the test cell 
population.
–If a predominant integration site is detected, the patient will be retested 
within three months to determine if it persists. If so, the site of integration of 
OZ1 will be sequenced and mapped to the human genome to determine any 
association with a known human oncogene. In all instances that a 
predominant integration site is present and, particularly when there is 
expansion of a cellular clone, the patient will be monitored closely for signs 
of cancer, so that any potential treatment can be initiated as early as possible. 
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–“Predominant integration site” is defined as an integration site which has a 
density of at least 50% of the total signal detected by PCR, when the 
percentage of cells marked by the vector (quantitative OZ1/LNL6 DNA 
PCR) is >1% of the test cell population.
–Any confirmed finding of a predominant integration site, i.e. present on at 
least two consecutive samples, will be reported as an SAE.
2. PBMC samples will be archived and will be tested for the presence of RCR 
using primers specific for amphotropic env retroviral gene sequences if 
required.
–
PBMC cell pellets and cryopreserved cells will be archived for RCR 
testing. RCR testing by PCR will be completed on these samples only if 
there is a clinically relevant adverse event (e.g. neoplasm) or an RCR test 
during the OTH/OZ1-INT-1 study was positive.
–
Any samples found to be positive for amphotropic env sequences will be 
analyzed further by biological assay to confirm and identify any putative 
RCR. 
–
Any confirmed positive finding of RCR will be reported as a SAE.
3. Archival plasma and PBMC samples will be collected annually for the duration 
of the long term follow-up protocol. 
Hematology
This will include red blood cell count, hemoglobin, hematocrit and platelets, white 
blood cell count with differential (neutrophils, lymphocytes, monocytes, eosinophils 
and basophils).
An Investigator must interpret the laboratory reports. Any clinically significant 
changes that require an intervention (e.g. concomitant medication or other treatment
or investigation) must be recorded in the source documents.
Autopsy
If a patient dies during the long-term follow up, an autopsy will be requested to 
determine the extent of gene transfer into bone marrow, spleen, lymph nodes and 
gonadal tissue, as well as any potentially transformed tissues (e.g. lymphomas, 
leukemia). A separate informed consent for autopsy will be requested. Patients may 
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sign the consent for autopsy at the time of enrollment. Autopsy will not be required 
for patients randomized to placebo (after unblinding of the OTH/OZ1-INT-1 trial).
8.
PATIENT COMPLETION†
Patients will complete long term follow up with an End-of-Study visit to be 
completed by 30 November 2017.
Patients must be withdrawn from the study if:

They received placebo in the OTH/OZ1-INT-1 trial. This will only become 
known when the OTH/OZ1-INT-1 study has been unblinded. 

They withdraw their consent.
If a patient withdraws, the reason for withdrawal is to be documented on the CRF 
and in the source document. A withdrawn patient or a patient who was lost to 
follow-up can re-enter this long term follow-up protocol at any time up until 
30 November 2017.
9.
STATISTICAL METHODS†
Statistical analysis of data collected during the long term follow-up study will be 
performed every 5 years. After patients complete an End-of Study visit, the final 
analysis of data will be done. The primary focus of analysis will be descriptive 
summarizing changes over time. Patterns over time will be analysed using 
appropriate techniques. Factors associated with quantitative changes may be 
assessed.
9.1
Efficacy Evaluation†
Ongoing analysis of quantitative marking of the gene transfer product (OZ1 and 
LNL6) in peripheral blood mononuclear cells will be performed as part of the testing 
of OZ1 or LNL6 vector integration sites. These data will be used to independently 
assess changes in the number of peripheral blood mononuclear cells that carry the 
gene transfer product over time. 
9.2
Safety Evaluations
All AE data will be coded to a System Organ Class and Preferred Term using the 
current MedDRA coding dictionary.
Clinical history, physical examination findings, CBC and AEs will be listed and 
summarized in a tabular form. AE data will be summarized annually for regulatory 
reporting.
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10.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from 
clinical studies are crucial for the protection of subjects, investigators, and the 
Sponsor, and are mandated by regulatory agencies worldwide. The Sponsor has 
established Standard Operating Procedures (SOPs) in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of safety information; all 
clinical trials sponsored by JC will be conducted in accordance with those 
procedures.
10.1
Adverse Event Definitions and Classifications†
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject 
administered a pharmaceutical product. An adverse event does not necessarily have a 
causal relationship with the treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. (Definition per 
International Conference on Harmonisation [ICH]). This includes any occurrence 
that is new in onset or aggravated in severity or frequency from the baseline 
condition, or abnormal results of diagnostic procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the informed 
consent until completion of the subject's last study-related procedure.
Serious Adverse Event
A serious adverse event (SAE) as defined by ICH is any untoward medical 
occurrence that at any dose meets any of the following conditions:
-
results in death;
-
is life-threatening (the subject was at risk of death at the time of the event. It 
does not refer to an event that hypothetically might have caused death if it were 
more severe);
-
requires inpatient hospitalisation or prolongation of existing hospitalisation;
-
results in persistent or significant disability/incapacity; 
-
is a congenital anomaly/birth defect.
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Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is also appropriate in situations other than those listed above; for example, 
important medical events may not be immediately life-threatening or result in death 
or hospitalisation but may jeopardize the subject or may require intervention to 
prevent one of the outcomes listed in the definition above. Any adverse event is 
considered a serious adverse event if it is associated with clinical signs or symptoms 
judged by the investigator to have a significant clinical impact.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs 
during the course of a subject’s participation in a clinical study must be reported as 
a serious adverse event, except hospitalizations for:
-
social reasons in the absence of an adverse event;
-
surgery or procedure planned before entry into the study (must be documented 
in the source documentation and CRF)
In addition to the ICH defined serious adverse events, the following events are to be 
considered an SAE:
-
a confirmed finding of a “predominant integration site”; or
-
a confirmed finding of Replication Competent Retrovirus (RCR).
Unlisted (Unexpected) Serious Adverse Event
An SAE which is unlisted, or the nature or severity of which is not consistent with 
the applicable product information. For an investigational product, the expectedness 
of an adverse event will be determined by whether or not it is listed in the 
Investigator's Brochure.
Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution 
is possible, probable, or very likely by the definitions listed. 
Not related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, e.g. 
concomitant drug(s), concomitant disease(s), or the relationship in time suggests that 
a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative 
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explanation, e.g. concomitant drug(s), concomitant disease(s), is inconclusive. The 
relationship in time is reasonable; therefore, the causal relationship cannot be 
excluded.
Probable
An adverse event that might be due to the use of the drug. The relationship in time 
is suggestive (e.g. confirmed by dechallenge). An alternative explanation is less 
likely, e.g. concomitant drug(s), concomitant disease(s).
Very likely
An adverse event that is listed as a possible adverse reaction and cannot be 
reasonably explained by an alternative explanation, e.g. concomitant drug(s), 
concomitant disease(s). The relationship in time is very suggestive (e.g. it is 
confirmed by dechallenge and rechallenge).
10.2 Procedures
NON-SERIOUS ADVERSE EVENTS
Non-serious adverse events must be recorded using medical terminology in the 
source document and in the case report form if they have a possible, probable or 
very likely suspect association to the study drug.
SERIOUS ADVERSE EVENTS
All adverse events meeting the definition of serious, regardless of severity or 
presumed relationship, must be recorded using medical terminology in the source 
document and in the case report form. Only SAEs that are “possibly”, “probably” or 
“very likely” related to the study drug must be reported using the Sponsor Serious 
Adverse Event Form within 24 hours of knowledge of the event. Exceptions to this 
include:
–
Death, regardless of the cause, is considered a reportable SAE;
–
Malignancy (except Basal Cell or Squamous Cell Carcinomas), regardless 
of causality, is considered a reportable SAE.
Whenever possible, diagnoses should be given when signs and symptoms are due to 
a common etiology (e.g. cough, runny nose, sneezing, sore throat, and head 
congestion should be reported as “upper respiratory infection”). Investigators must 
record in the CRF their opinion concerning the relationship of the SAE to study 
therapy. All measures required for serious adverse event management must be 
recorded in the source document.
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Subjects (or their designees, if appropriate) must be provided with a “study card” 
indicating the name of the investigational product, the study number, the 
investigator’s name, and a 24-hour emergency contact number.
All reportable SAEs occurring during the study period must be reported to the 
appropriate sponsor contact person by investigational staff within 24 hours of their 
knowledge of the event. If the SAE is a death or a life threatening event the 
Investigator must notify the Sponsor immediately by both telephone and FAX.
Information regarding serious adverse events will be transmitted to the sponsor 
using the Sponsor Serious Adverse Event Form, which must be signed by a member 
of the investigational staff. The initial report of a serious adverse event may be 
made by facsimile (fax) or telephone. It is preferable that serious adverse events be 
reported via fax. Subsequent to a telephone report of a serious adverse event, a 
Serious Adverse Event Form must be completed by the investigational staff and 
transmitted to the sponsor within 24 hours.
All SAEs must be followed until any of the following occurs:
–
the event resolves;
–
the event stabilizes;
–
the event returns to baseline, if a baseline value is available;
–
the event can be attributed to agents other than the study drug or to 
factors unrelated to study conduct; or
–
when it becomes unlikely that any additional information can be obtained 
(subject or health care practitioner refusal to provide additional 
information, lost to follow-up after demonstration of due diligence with 
follow-up efforts).
The sponsor assumes responsibility for appropriate reporting of serious adverse 
events to the regulatory authorities. This includes expedited reporting of leukemia 
(proven or strong clinical suspicion), confirmed positive RCR or predominant 
integration site. The sponsor will also report to the investigator all serious adverse 
events that are unlisted and associated with the use of the drug. The investigator (or 
sponsor where required) must report these events to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol 
unless otherwise required and documented by the IEC/IRB.
The sponsor will evaluate any safety information that is spontaneously reported by a 
subject outside their participation in the formal study program.
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PREGNANCY
The investigational staff must report pregnancy within 24 hours of their knowledge 
of the event using the Sponsor Benefit Risk Management Pregnancy Notification 
Form. Follow-up information regarding the outcome of the pregnancy and any 
postnatal sequelae in the infant will be required, and is to be reporting using the 
Sponsor follow up collection Forms A & B.
Because the study drug may have an effect on sperm, pregnancies in partners of 
male subjects included in the study will be reported by the investigational staff in 
the same manner as above. The outcome of the pregnancy and any postnatal 
sequelae in the infant is also to be reported using the Sponsor pregnancy 
notification and follow up forms.
Any pregnancy abnormal outcomes (e.g. spontaneous abortion, fetal demise, 
stillbirth, congenital abnormality, ectopic pregnancy) or pregnancy associated 
adverse events must be reported as SAEs, as per SAE reporting procedures 
described above.
10.3
Contacting Sponsor Regarding Safety
The names of the individuals (and corresponding phone numbers) who should be 
contacted regarding safety issues are listed on the CONTACT INFORMATION 
page(s) in the front of the protocol.
11.
ETHICAL ASPECTS
11.1
Investigator Responsibilities
The Investigator is responsible for ensuring that the clinical study is performed in 
accordance with the Protocol, the Declaration of Helsinki, current International 
Conference on Harmonization (ICH) and Good Clinical Practice (GCP) guidelines, 
and applicable regulatory requirements. These documents set forth that the 
informed consent of the patients is an essential precondition for participation in the 
clinical study.
11.2
Independent Ethics Committee or Institutional Review Board 
(IEC/IRB)
This trial will be undertaken only after full approval of the Protocol and adjunctive 
materials (e.g. informed consent form, advertising) has been obtained from a local 
IEC/IRB and a copy of this approval has been received by the Sponsor.
The IEC/IRB must be informed of all subsequent Protocol amendments issued by 
the Sponsor.
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The Investigator will submit reports on, and reviews of, the trial and its progress to 
the IEC/IRB at intervals stipulated in their guidelines and in accordance with 
pertinent regulations and guidelines.
11.3
Informed Consent
Each patient (or a legally authorized representative) must give written consent (and 
sign other locally required documents) according to local requirements after the 
nature of the study has been fully explained. The consent form must be signed prior 
to performance of any study-related activity. The consent form that is used must be 
approved both by the Sponsor and by the reviewing IEC/IRB. The informed consent 
should be in accordance with the current revision of the Declaration of Helsinki, 
current ICH and GCP guidelines, applicable regulatory requirements, and JC policy.
The Investigator must explain to potential patients or their legal representatives the 
aims, methods, reasonably anticipated benefits and potential hazards of the study 
and any discomfort it may entail. Patients will be informed that they are free not to 
participate in the study and that they may withdraw consent to participate at any 
time. They will be told which alternative treatments are available if they refuse to 
take part and that such refusal will not prejudice future treatment. Finally, they will 
be told that the Investigator will maintain a patient identification register for the 
purposes of long-term follow-up if needed and that their records may be examined 
by competent authorities and authorized persons but that personal information will 
be treated as strictly confidential and will not be publicly available. Patients must be 
given the opportunity to ask questions. After this explanation and before entry into 
the study, consent should be appropriately recorded by means of the patient’s or 
his/her legal representative’s dated signature. If a patient and his/her legal 
representative are unable to read, an impartial witness must be present during the 
entire informed consent discussion. The signature of the impartial witness will 
certify the patient’s consent. The patient or his/her legal representative will be given 
a signed and dated copy of the informed consent form.
12
ADMINISTRATIVE REQUIREMENTS
12.1
Protocol Modifications
Neither the Investigator nor Sponsor will modify this Protocol without obtaining the 
concurrence of the other. All Protocol amendments must be issued by the Sponsor, 
signed and dated by the Investigator, and should not be implemented without prior 
IEC/IRB approval, except where necessary to eliminate immediate hazards to the 
patients or when the change(s) involves only logistical or administrative aspects of 
the trial (e.g. change in monitor(s), change of telephone number(s)). 
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Responsibilities for reporting Protocol amendments to IEC/IRBs are further 
described in the Ethical Aspects section of the Protocol.
In situations requiring a deviation from the Protocol, the Investigator or other 
physician in attendance will contact the site manager or other appropriate Sponsor 
representative by FAX or telephone (see Contact Information page). If possible, this 
contact will be made before implementing any deviation from the Protocol. In all 
cases, contact with the Sponsor must be made as soon as possible in order to discuss 
the situation and agree on an appropriate course of action. The CRF and source 
document will describe any deviation from the Protocol and the circumstances 
requiring it.
12.2
Regulatory Documentation
Documents that must be provided to the Sponsor prior to study start are as follows:

A copy of the formal written notification to the Investigator regarding 
approval of the Protocol by an IEC/IRB that is in compliance with 
regulatory guidelines. The written notification is to be signed by the 
chairman or authorized designee and must identify the specific Protocol. In 
cases where an IEC/IRB member has a known conflict of interest, 
abstention of that individual from voting should be documented; an 
Investigator (or sub-Investigator) may be a member of the IEC/IRB, but 
may not participate in the deliberation or vote on any research in which he 
or she is involved;

A copy of the IEC/IRB approved informed consent form and other 
adjunctive materials (e.g. advertising) to be used in the study, including 
written documentation of IEC/IRB approval of these items;

Name and address of the IEC/IRB with a statement that it is organized and 
operates according to GCP and the applicable laws and regulations, and a 
current list of the IEC/IRB members. If accompanied by a letter of 
explanation from the IEC/IRB, a general statement may be substituted for 
this list;

Regulatory authority approval or notification, if applicable;

Applicable local regulatory documentation (e.g. FDA 1572 Form);

Financial disclosure statement(s) for each Investigator and sub-Investigator;
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
Signed and dated Investigator Agreement page of the final Protocol and, 
where applicable, amendments;

Signed and dated trial agreement and financial agreement, if applicable;

Current curricula vitae for each Investigator and sub-Investigator;

Name and address of any local laboratory conducting tests for the study, a 
dated copy of the laboratory reference values for tests to be performed 
during the study and a copy of the certification or other documentation 
establishing adequacy of the facility.
In addition to the documents required prior to the study, other documentation may 
be required during the course of the study.
12.3 Patient Identification Register
The Investigator agrees to complete a patient identification register, which will be 
used for the purpose of long-term follow-up. This form will be treated as 
confidential, and will be filed by the Investigator in the Trial Center File. 
Otherwise, all reports and communications relating to the study will identify 
patients by initials, date of birth and assigned number only.
Where applicable, patient specific information required by local regulatory 
agencies will be provided.
12.4 Record Retention
In compliance with the ICH/GCP guidelines, the Investigator/Institution will 
maintain all CRFs and all source documents that support the data collected from 
each patient, and all trial documents as specified in Essential Documents for the 
Conduct of a Clinical Trial and as specified by the applicable regulatory 
requirement(s). The Investigator/Institution will take measures to prevent 
accidental or premature destruction of these documents. Essential documents must 
be retained until at least 2 years have elapsed since the formal discontinuation of 
the long term follow-up study. These documents will be retained for a longer 
period if required by the applicable regulatory requirements or by an agreement 
with the Sponsor. It is the responsibility of the Sponsor to inform the 
Investigator/Institution as to when these documents no longer need to be retained. 
If an Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, the Institution with which the 
Investigator is associated must transfer the responsibility to another person within 
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the Institution. The Sponsor must be notified in writing of the name and address of 
the new custodian.
12.5 Case Report Form Completion
CRFs are provided for each entered patient. An entered patient is one who has 
signed the informed consent document.
Data must be entered onto CRFs or Telephone Follow-up Questionnaire in 
English. All forms must be filled out in blue or black ballpoint pen or typed. The 
Study Completion Information page of the CRF must be signed and dated by the 
Investigator. The CRFs are to be completed at the time of the patient’s visit, with 
the exception of results of tests performed outside the Investigator’s office, so that 
they always reflect the latest observations on the patients participating in the trial. 
All CRF corrections are to be made by the Investigator or other authorized study 
site personnel. The Investigator must authorize changes to the recorded safety and 
efficacy data.

Completed CRFs will be continuously submitted according to the Sponsor’s 
instructions, and reviewed by the Sponsor to determine their acceptability. If 
necessary, Data Correction Forms (DCFs) will be generated and transmitted to 
the study site for resolution.
12.6 Monitoring
The Sponsor will perform on-site monitoring visits annually or more frequently as 
necessary. Visit intervals will be dependent on both the time post infusion and 
number of patients at the site. The dates of the visits will be recorded by the 
monitor in a trial center visit log to be kept at the site. At these visits, the monitor 
will compare the data entered onto the CRFs with the hospital or clinic records 
(source documents). At a minimum, source documentation must be available to 
substantiate patient identification, eligibility and participation, proper informed 
consent procedures, dates of visits, adherence to Protocol procedures, record of 
safety and efficacy parameters, adequate reporting and follow-up of adverse 
events, date of completion and reason. Specific items required as source 
documents will be reviewed with the Investigator prior to the study. Findings from 
this review of CRFs and source documents will be discussed with the 
investigational staff. The Sponsor expects that, during monitoring visits, the 
relevant investigational staff will be available, the source documentation will be 
available, and a suitable environment will be provided for review of study-related 
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documents. The monitor will meet with the Investigator on a regular basis during 
the trial to provide feedback on the trial conduct.
12.7 Data Quality Assurance
Steps to be taken to assure the accuracy and reliability of data include the selection 
of qualified Investigators and appropriate study centers, review of Protocol 
procedures with the Investigator and associated personnel prior to the study and 
periodic monitoring visits by the Sponsor. The Sponsor will review CRFs for 
accuracy and completeness during on-site monitoring visits and after their return to 
JC, and any discrepancies will be resolved with the Investigator or designees, as 
appropriate. The data will be entered into the clinical trial database and verified for 
consistency.
12.8 On-Site Audits
Representatives of the Sponsor’s Global Clinical Quality Assurance Department 
may visit the site to carry out an audit of the study in compliance with regulatory 
guidelines and company policy. Such audits will require access to all study 
records, including source documents, for inspection and comparison with the 
CRFs. Patient privacy must, however, be respected. Sufficient prior notice will be 
provided to allow the Investigator to prepare properly for the audit.
Similar auditing procedures may also be conducted by agents of any regulatory 
body reviewing the results of this study. The Investigator should immediately 
notify the Sponsor if they have been contacted by a regulatory agency concerning 
an upcoming inspection.
12.9 Use of Information and Publication
All information concerning placebo and OZ1, JC operations, patent application, 
formulas, manufacturing processes, basic scientific
data, and formulation 
information, supplied by the Sponsor to the Investigator and not previously 
published, is considered confidential and remains the sole property of JC. The 
Investigator agrees to use this information only to accomplish this study and will 
not use it for other purposes without the Sponsor’s written consent.
The Investigator understands that the information developed in the clinical study 
will be used by JC in connection with the continued development of OZ1, and thus 
may be disclosed as required to other clinical Investigators or government 
regulatory agencies. To permit the information derived from the clinical studies to 
be used, the Investigator is obligated to provide the Sponsor with all data obtained 
in the study.
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13.
REFERENCES†
1.
Amado RG, Mitsuyasu RT, Rosenblatt JD, et al, Anti-human immunodeficiency 
virus hematopoietic progenitor cell-delivered ribozyme in a phase I study: Myeloid 
and lymphoid reconstitution in human immunodeficiency virus Type-1- infected 
patients. Human Gene Therapy 2004;15:251-262.
2.
Boztug K, Schmidt M, Schwarzer A, et al, Stem-Cell Gene Therapy for the 
Wiskott-Aldrich Syndrome. N Engl J Med. 2010;363(20):1918-1927.
3.
Braun CJ, Boztug K, Paruzynski A, et al, Gene Therapy for Wiskott-Aldrich 
Syndrome –
Long Term Efficacy and Genotoxicity. Sci Transl Med. 
2014;6(227):227ra33
4.
FDA Guidance for Industry: Gene Therapy Clinical Trials - Observing Subjects 
for Delayed Adverse Events; U.S. Department of Health and Human Services; 
Food and Drug Administration; Center for Biologics Evaluation and Research 
(CBER) November 2006.
5.
Hacein-Bey-Abina S, Le Deist F, Carlier F, et al, Sustained correction of X-linked 
severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med. 
2002;346(16):1185-1193.
6.
Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al, LMO2-Associated Clonal T 
Cell Proliferation in Two Patients after Gene Therapy for SCID-X1.” Science 
2003;302(5644):415-419.
7.
Hacein-Bey-Abina S, Garrigue A, Wang GP, et al, Insertional oncogenesis in 4 
patients after retrovirus-mediated gene therapy of SCID-X1.” J Clin Invest. 
2008;118(9):3132-3142.
8.
Howe SJ, Mansour MR, Schwarzwaelder K, et al, Insertional mutagenesis 
combined with acquired somatic mutations causes leukemogenesis following gene 
therapy of SCID-X1 patients. J Clin Invest. 2016;118(9):3143-3150.
9.
Mitsuyasu RT, Merigan TC, Carr A, et al, Phase 2 gene therapy trial of an anti-
HIV ribozyme in autologous CD34+ cells. Nat Med. 2009;15:285-292
10.
Mukherjee S, Thrasher AJ. Gene therapy for PIDs: Progress, pitfalls and prospects. 
Gene 2013;525:174-181.
11.
Ott MG, Schmidt M, Schwarzwaelder K, et al, Correction of X-liked chronic 
granulomatous disease by gene therapy, augmented by insertional activation of 
MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006;12(4):401-409.
12.
Stein S, Ott MG, Schultze-Strasser S, et al,
Genomic instability and 
myelodysplasia with monosomy 7 consequent to EXI1activation after gene therapy 
for chronic granulomatous disease. Nat Med. 2010;16(2):198-205.
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13.
Sun LQ, Warrilow D, Wang L, Witherington C, Macpherson J, Symonds G. 
Ribozyme-mediated suppression of Moloney murine leukemia virus and human 
immunodeficiency virus type I replication in permissive cell lines. Proc Natl Acad 
Sci. 1994;91(21):9715-9719.
14.
Sun LQ, Pyati J, Smythe D, et al, Resistance to human immunodeficiency virus 
type 1 infection conferred by transduction of human peripheral blood lymphocytes 
with ribozyme, antisense or polymeric trans-activation response element 
constructs. Proc Natl Acad Sci. 1995a;92(16):7272-7276.
15.
Sun LQ, Wang L, Gerlach W and Symonds G. Target sequence-specific inhibition 
of HIV-1 replication by ribozymes directed to tat RNA. Nucleic Acids Res 
1995b;23(15):2909-2913.
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14.
APPENDICES
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Appendix 1:
TOXICITY GRADING TABLE
TABLE FOR GRADING SEVERITY OF ADULT ADVERSE EXPERIENCES
ACTG 285
DIVISION OF AIDS
ABBREVIATIONS: Abbreviations used in the table:
ULN =
Upper Limit of Normal
LLN =
Lower Limit of Normal
Rx
=
Therapy
Req =
Required
Mod =
Moderate
IV
=
Intravenous
ADL =
Activities of Daily Living
Dec =
Decreased
ESTIMATING SEVERITY OF GRADE
For abnormalities NOT found elsewhere on the Toxicity Table use the scale below to 
estimate grade of severity:
GRADE 1 Mild
Transient or mild discomfort; no limitation in activity; no medical 
intervention/ therapy required
GRADE 2 Moderate
Mild or moderate limitation in activity - some assistance may be needed; 
no or minimal medical intervention/therapy required
GRADE 3 Severe
Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalisations possible
GRADE 4 Life-threatening
Extreme limitation in activity, significant assistance required; significant 
medical intervention/therapy required, hospital or hospice care probable
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Appendix 1:
ATCG Toxicity Grading Table
SERIOUS OR LIFE-THREATENING AE’s
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 adverse experience. Clinical events considered to be serious or 
life-threatening include, but are not limited to:
seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular coagulation, 
diffuse petechiae, paralysis, acute psychosis
PARAMETER
GRADE MILD
GRADE 
MODERATE
GRADE 
SEVERE
GRADE 
POTENTIALLY 
LIFE-
THREATENING
HEMATOLOGY
Hemoglobin
8.0g/dL - 9.4g/dL
7.0g/dL - 7.9g/dL
6.5g/dL - 6.9g/dL
< 6.5g/dL
Absolute Neutrophil 
Count
1000 -1500/mm3
750 -999/mm3
500 -749/mm3
< 500/mm3
Platelets
75,000 - 99,000/mm3
50,000 -
74,999/mm3
20,000 -
49,999/mm3
< 20,000/mm3
Prothrombin Time 
(PT)
> 1.0 - 1.25 X ULN
> 1.25 - 1.5 X ULN
> 1.5 - 3.0 X ULN
> 3.0 X ULN
BT
> 1.0 - 1.66 X ULN
> 1.66 - 2.33 X 
ULN
> 2.33 - 3.0 X 
ULN
> 3.0 X ULN
Methemoglobin
5.0 - 10.0%
10.0 - 15.0%
15.0 - 20.0%
> 20.0%
CHEMISTRIES
SODIUM
Hyponatremia
130 - 135meq/L
123 - 129meq/L
116 - 122meq/L
< 116meq/L
Hypernatremia
146 - 150meq/L
151 - 157meq/L
158 - 165meq/L
> 165meq/L
POTASSIUM
Hyperkalemia
5.6 - 6.0meq/L
6.1 -6.5meq/L
6.6 - 7.0meq/L
> 7.0meq/L
Hypokalemia
3.0 - 3.4meq/L
2.5 - 2.9meq/L
2.0 - 2.4meq/L
< 2.0meq/L
PHOSPHATE
Hypophosphatemia
2.0 - 2.4 mg/dL
1.5 - 1.9 mg/dL
1.0 - 1.4 mg/dL
< 1.0 mg/dL
CALCIUM
Hypocalcemia
7.8 - 8.4 mg/dL
7.0 - 7.7 mg/dL
6.1 - 6.9 mg/dL
< 6.1 mg/dL
Hypercalcemia
10.6 - 11.5 mg/dL
11.6 - 12.5 mg/dL
12.6 - 13.5 mg/dL
> 13.5 mg/dL
MAGNESIUM
Hypomagnesemia
1.2 - 1.4 meq/L
0.9 - 1.1 meq/L
0.6 - 0.8 meq/L
< 0.6 meq/L
BILIRUBIN
> 1.0 - 1.5 x ULN
> 1.5 - 2.5 x ULN
> 2.5 - 5.0 x ULN
> 5.0 x ULN
GLUCOSE
Hypoglycemia
55 - 64 mg/dL
40 - 54 mg/dL
30 - 39 mg/dL
< 30 mg/dL
Hyperglycemia 
(nonfasting and no 
prior diabetes
116 - 160 mg/dL
161 - 250 mg/dL
251 - 500 mg/dL
> 500 mg dL
Triglycerides
----------------------
400 - 750 mg/dL
751 - 1200 mg/dL
> 1200 mg/dL
Creatinine
> 1.0 - 1.5 x ULN
> 1.5 -3.0 x ULN
> 3.0 -6.0 x ULN
> 6.0 x ULN
URIC ACID
Hyperuricemia
7.5 - 10.0 mg/dL
10.1 - 12.0 mg/dL
12.1 - 15.0mg/dL
>15.0mg/dL
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Appendix 1:
ATCG Toxicity Grading Table
PARAMETER
GRADE MILD
GRADE 
MODERATE
GRADE 
SEVERE
GRADE 
POTENTIALLY 
LIFE-
THREATENING
LIVER TRANSAMINASE (LFTs)
AST (SGOT)
1.25 - 2.5 x ULN
2.5 - 5.0 x ULN
5.0 - 10.0 x ULN
> 10.0 x ULN
ALT (SGPT)
0.25 - 2.5 x ULN
2.5 - 5.0 x ULN
5.0 - 10.0 x ULN
> 10.0 x ULN
GGT
1.25 - 2.5 x ULN
2.5 - 5.0 x ULN
5.0 - 10.0 x ULN
> 10.0 x ULN
Alkaline Phosphatase
1.25 - 2.5 x ULN
2.5 - 5.0 x ULN
5.0 - 10.0 x ULN
> 10.0 x ULN
PANCREATIC ENZYMES
Amylase
> 1.0 - 1.5 x ULN
> 1.5 - 2.0 x ULN
> 2.0 - 5.0 x ULN
> 5.0 x ULN
Pancreatic amylase
> 1.0 - 1.5 x ULN
> 1.5 - 2.0 x ULN
> 2.0 - 5.0 x ULN
> 5.0 x ULN
Lipase
> 1.0 - 1.5 x ULN
> 1.5 - 2.0 x ULN
> 2.0 - 5.0 x ULN
> 5.0 x ULN
CARDIOVASCULAR
Cardiac Arrhythmias
-----------------------
Asymptomatic; 
transient 
dysrhythmia, no 
Rx req
Recurrent/persist
ent dysrhythmia; 
Rx req
Unstable dysrhythmia; 
symptomatic; 
hospitalisation and Rx 
req
Hypertension
Transient increase > 
20mmHg; no Rx
Recurrent; chronic 
increase > 
20mmHg; Rx req
Acute Rx req; 
outpatient, 
hospitalisation 
possible
Hospitalisation req
Hypotension
Transient 
orthostatic 
hypotension; no RX
Symptoms 
correctable with 
oral fluid Rx
IV fluid req; no 
hospitalisation 
req
Hospitalisation req
Pericarditis
Minimal effusion
Mild/mod 
asymptomatic 
effusion, no RX
Symptomatic 
effusion, pain, 
EKG changes
Tamponade OR 
pericardiocentesis OR 
surgery req
Hemorrhage, blood
-----------------------
Mildly 
symptomatic; no 
Rx req
gross blood loss 
OR 1-2 units 
transfused
Massive blood loss OR > 
2 units transfused
GASTROINTESTINAL
Nausea
Mild Or transient; 
reasonable intake 
maintained
Mod discomfort 
OR intake 
decreased for > 3 
days
Severe 
discomfort OR 
minimal intake 
for 3 days
Hospitalisation req
Vomiting
Mild OR transient; 
2-3 episodes per day 
OR mild vomiting 
lasting < 1 week
Mod OR 
persistent; 4-5 
episodes per day; 
OR vomiting 
lasting > 1 week
severe vomiting 
of all food/fluids 
in 24 hours OR 
orthostatic 
hypotension OR 
IV Rx req
Hypotensive shock OR 
hospitalisation req for 
IV Rx
Diarrhea
Mild OR transient; 
3-4 loose stools per 
day OR mild 
diarrhea lasting < 1 
week
Mod OR persistent 
5-7 loose stools per 
day OR diarrhea 
lasting 1 week
Bloody diarrhea 
OR orthostatic 
hypotension OR 
> 7 loose 
stools/day OR IV 
Rx req
Hypotensive shock OR 
hospitalisation req
Oral 
Discomfort/Dysphagia
Mild discomfort; no 
difficulty in 
swallowing
Difficulty 
swallowing but 
able to eat drink 
fluids
Unable to 
swallow solids; 
IV fluids req
Unable to drink fluids; 
severe distension with 
vomiting
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Appendix 1:
ATCG Toxicity Grading Table
PARAMETER
GRADE MILD
GRADE 
MODERATE
GRADE 
SEVERE
GRADE 
POTENTIALLY 
LIFE-
THREATENING
RESPIRATORY
Cough
Transient; no Rx
Treatment 
associated cough; 
inhaled 
bronchodilator
Uncontrolled 
cough; systemic 
Rx req
_____________________
Bronchospasm
Acute transient; no 
Rx; FEV1 < 80% -
70% (or peak flow)
Rx req; normalizes 
with 
bronchodilator; 
FEV1 50% - < 
70% (or peak flow)
No normalization 
with 
bronchodilator; 
(or FEV! 25% - < 
50% or peak flow 
Cyanosis OR 
retractions; FEV1 < 
25% (or intubated peak 
flow)
Dyspnea
Dyspnea on exertion
Dyspnea with 
normal activity
Dyspnea at rest
Dyspnea req O2 Rx
NEUROLOGIC
Neuro-cerebellar
Slight 
incoordination OR 
dysdiadochokinesia
Intention tremor 
OR dysmetria OR 
slurred speech OR 
nystagmus
Ataxia requiring 
assistance to walk 
or arm 
incoordination 
interfering with 
ADLs
Unable to stand
Neuro-psych/mood
-----------------------
----------------------
Severe mood 
changes req 
medical 
intervention
Acute psychosis req 
hospitalisation
Paresthesia
Mild discomfort; no 
Rx req (burning, 
tingling etc)
Mod discomfort; 
Rx req with 
symptomatic 
improvement
Severe 
discomfort OR 
non-narcotic 
analgesia req
Incapacitating OR 
narcotic analgesia req; 
not responsive to non-
narcotic analgesia
Neuro-motor
Mild weakness in 
muscles of feet but 
able to walk and/or 
mild decrease in r 
flexes and/or loss of 
previously present 
reflex or 
development of 
hyperreflexia and/or 
unable to do deep 
knee bends due to 
weakness 
Mod weakness in 
feet (unable to 
walk on heels 
and/or toes); mild 
weakness in hands, 
still able to do 
most tasks
Marked distal 
weakness (unable 
to dorsiflex toes 
or foot drop) and 
proximal 
weakness e.g., in 
hands interfering 
with |ADLs 
and/or req 
assistance to walk 
and/or unable to 
rise from chair 
unassisted
Confined to bed or 
wheel chair because of 
muscle weakness
Neuro-sensory
Mild impairment 
(dec sensation e.g., 
vibratory, pinprick, 
hot/cold in great 
toes) in focal area or 
symmetrical 
distribution
Mod impairment 
(mod dec sensation 
e.g., vibratory, 
pinprick, hot/cold 
to ankles) and/or 
joint position or 
mild impairment 
that is not 
symmetrical
Severe 
impairment (dec 
or loss of 
sensation to 
knees or wrists) 
or loss of 
sensation of at 
least mod degree 
in multiple 
different body 
areas (i.e., upper 
and lower
extremities)
Sensory loss involves 
limbs and trunk
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Appendix 1:
ATCG Toxicity Grading Table
PARAMETER
GRADE MILD
GRADE 
MODERATE
GRADE 
SEVERE
GRADE 
POTENTIALLY 
LIFE-
THREATENING
URINALYSIS
Proteinuria - spot 
urine
24 hr urine
+1
200mg - 1g loss/day 
OR < 0.3% OR < 3 
g/L
2-3 +
1-2 g loss/day OR 
0.3-1.0% OR 3-
10g/L
+4
2 - 3.5g loss/day 
OR >1.0% OR > 
10g/L
Nephrotic syndrome
Nephrotic syndrome OR 
> 3.5g loss/day
Gross Hematuria
Microscopic only
Gross; no clots
Gross plus clots
Obstructive
MISCELLANEOUS
Fever 
(oral > 12 hours)
37.7 - 38.5C OR
100.0 - 101.5F
38.6 - 39.5C OR 
101.6 - 102.9F 
39.6 40.5C OR
103 -105F
> 40.5C OR
> 105F
Headache
Mild; no Rx req
Mod; or non-
narcotic analgesia 
Rx
Severe; OR 
responds to 
initial narcotic 
Rx
Intractable; OR req 
repeated narcotic Rx
Allergic Reaction
Pruritus without
Localized urticaria
Generalised 
urticaria; 
angioedema
Anaphylaxis
Cutaneous/Rash/Der
matitis
Erythema, pruritus
Diffuse 
maculopapular 
rash OR dry 
desquamation
Vesiculation OR 
moist 
desquamation 
OR ulceration
ANY ONE: mucous 
membrane involvement, 
suspected Stevens-
Johnson (TEN), 
erythema multiforme, 
necrosis req surgery, 
exfoliative dermatitis
Local Reaction (2
parenteral Rx)
Erythema
Induration < 
10mm OR 
inflammation OR 
phlebitis
Induration 
>10mm OR 
ulceration
Necrosis of skin
Fatigue
Normal activity 
reduced < 25%
Normal activity 
reduced 25-50%
Normal activity 
reduced >50%; 
cannot work
Unable to care for self
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Appendix 2:†
TELEPHONE FOLLOW-UP QUESTIONNAIRE 
FOR SEMI-ANNUAL, ANNUAL, OR END-OF-STUDY REVIEW OF CLINICAL HISTORY
Instructions for Interviewer: This interview will be conducted over the phone by a study investigator only if a patient is unable to be 
reviewed in the clinic.
SUBJECT NAME: ........................................................
Date of Birth: |__|__| - | __|__|__| - |__|__|
DD
MMM
YY
INTERVIEWER SIGNATURE: ..................................
Date of Interview: |__|__| - |__|__|__| - |__|__|
DD
MMM
YY
Study Physician: Circle all appropriate answers for PARTS A, B & C. If respondent answers 'yes' to any of the PART A questions, 
complete sub-sections and add any additional comments.
All questions refer to the time since the since the last study visit or interview.
PART A: Targeted Review of Clinical History
Please elicit a history to determine whether the subject currently has or has experienced any of the following diseases/conditions (new or 
exacerbation of existing) since the last review. 
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Disease, condition or problem
Approximately 
when did they 
FIRST notice this 
condition?
Over the past 12 
months have they 
seen a health care 
provider for this 
condition?
Over the past 12 months, 
have they been 
hospitalized for this 
condition?
Study Physician’s 
Comments including 
Diagnosis
1. New or exacerbated hematologic 
disorders including laboratory 
abnormalities?
No (skip to Q2)
Yes
|__|__|-|__|__|-|__|__|
  dd      mm     yy
No…..
Yes…
No
Yes: ..........................
(record hospital name)
.........................................
.........................................
.........................................
2. New malignancies including skin 
cancer?
No (skip to Q3)
Yes
|__|__|-|__|__|-|__|__|
  dd      mm     yy
No…..
Yes…
No
Yes: ..........................
(record hospital name)
.........................................
.........................................
.........................................
3. Exposure to possible therapeutic or 
environmental mutagenic agents 
including radiotherapy or 
chemotherapy?
No (skip to Q4)
Yes
|__|__|-|__|__|-|__|__|
  dd      mm     yy
No…..
Yes…
No
Yes: ..........................
(record hospital name)
.........................................
.........................................
.........................................
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Disease, condition or problem
Approximately 
when did they 
FIRST notice this 
condition?
Over the past 12 
months have they 
seen a health care 
provider for this 
condition?
Over the past 12 months, 
have they been 
hospitalized for this 
condition?
Study Physician’s 
Comments including 
Diagnosis
4. New or exacerbated immunologic/ 
rheumatologic disorder
No (skip to Q5)
Yes
|__|__|-|__|__|-|__|__|
dd      mm     yy
No…..
Yes…
No
Yes: ..........................
(record hospital name)
.........................................
.........................................
5. New or exacerbated neurologic 
disorder
No (skip to Q6)
Yes
|__|__|-|__|__|-|__|__|
  dd      mm     yy
No….
Yes…
No
Yes: ..........................
(record hospital name)
.........................................
.........................................
.........................................
6. Adverse Events other than covered 
above?
No (skip to PART B)
Yes (complete Q7)
|__|__|-|__|__|-|__|__|
dd      mm     yy
No….
Yes…
No
Yes: ..........................
(record hospital name)
.........................................
.........................................
.........................................
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Disease, condition or problem
Approximately 
when did they 
FIRST notice this 
condition?
Over the past 12 
months have they 
seen a health care 
provider for this 
condition?
Over the past 12 months, 
have they been 
hospitalized for this 
condition?
Study Physician’s 
Comments including 
Diagnosis
7. Was this adverse event serious?
No (skip to PART B)
Yes (complete Q8)
Physician must complete SAE 
Notification Form
|__|__|-|__|__|-|__|__|
  dd      mm     yy
No…..
Yes…
No
Yes: ..........................
(record hospital name)
.........................................
.........................................
.........................................
8. For any serious adverse events, list 
new medications or treatments etc
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PART B: Contact Information
1.
Please read subject current address and phone contact details. Is contact information correct?
Yes (skip to Q2)
No: Record updated contact details: ....................................................................................................................................................
........................................................................................................................................................................................................................................
........................................................................................................................................................................................................................................
2.
Please read name, address and phone contact details for subjects NOMINATED SECONDARY CONTACT PERSON. Is contact 
information correct?
Yes (skip to PART C)
No: Record updated contact details: ....................................................................................................................................................
........................................................................................................................................................................................................................................
........................................................................................................................................................................................................................................
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PART C: Further Follow-Up
1.
Do any findings noted during the interview warrant review of the subject's medical records?
No (skip to Q2)
Yes: specify details: .............................................................................................................................................................................
........................................................................................................................................................................................................................................
2.
Do any findings noted during the clinical history interview warrant further safety testing?
No (skip to Q3)
Yes: specify details: .............................................................................................................................................................................
........................................................................................................................................................................................................................................
3.
Is authorization for the release of medical records to be obtained?
No
Yes: specify details: .............................................................................................................................................................................
........................................................................................................................................................................................................................................
Investigator's Signature:______________________________
Date: |__|__|- |__|__|__|-|__|__
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Appendix 3:
PROTOCOL AMENDMENT HISTORY
Amendment 1; 23 June 2006
Applicable sections
Original Text
New/Revised Text
Description and Rationale
SYNOPSIS
OVERVIEW OF STUDY DESIGN:
This will be a follow-up study of patients who 
complete the OTH/OZ1-INT-1 trial.
OVERVIEW OF STUDY DESIGN:
This will be a follow-up study of patients previously enrolled in 
the OTH/OZ1-INT-1 trial. 
To include all patients 
‘enrolled’ in the trial, 
rather than only patients 
that ‘complete’ the trial.
SYNOPSIS
New text
POPULATION
Participants of the OTH/OZ1-INT-1 Phase II study entitled “A 
Randomized Phase II, double blind, controlled trial to evaluate the 
safety and efficacy of autologous CD34+ hematopoietic 
progenitor cells transduced with placebo or an anti-HIV-1 
ribozyme (OZ1) in patients with HIV-1 infection” will be asked to 
consent to continued safety monitoring and gene marking as 
described in this protocol.
To further clarify the trial 
population and the means 
by which they will enter 
this protocol.
SYNOPSIS
New text
DOSAGE AND ADMINISTRATION
All participants of the OTH/OZ1-INT-1 Phase II study received a 
single dose of transduced CD34+ cells.
To clarify that the dosage 
and administration of the 
transduced CD34+ cells 
relates to a separate 
protocol.
SYNOPSIS
EFFICACY EVALUATIONS:
In addition to safety evaluations, patients may elect 
to have ongoing analysis of quantitative marking 
and expression of the gene transfer product in 
peripheral blood mononuclear cells.
EFFICACY EVALUATIONS:
Ongoing analysis of quantitative marking of the gene transfer 
product (OZ1 and LNL6) in peripheral blood mononuclear cells 
will be performed as part of the testing of predominant integration 
sites. This marking data will also be analyzed independently of the 
integration analysis to detect changes in the number of cells 
carrying the gene transfer product. In addition to safety 
evaluations, patients may elect to have ongoing analysis of 
quantitative expression of the gene transfer product in peripheral 
blood mononuclear cells.
To specify the level of 
analysis to be undertaken 
of the quantitative 
marking of the gene 
transfer product in the 
peripheral blood 
mononuclear cells as part 
of integration.
SYNOPSIS
The Time and Events Schedule for this study is 
shown on the following page.
TIME AND EVENTS SCHEDULE:
Follow up visits may be part of routine clinic visits where 
possible, but must be performed as described in the Time & 
Events Schedule. Additional unscheduled visits will be made if 
clinical or biological findings, as described in this protocol, 
require additional evaluation or investigation.
Note: Time and Events Schedule inserted
To clarify procedures 
associated with visits, 
both scheduled and 
unscheduled.
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INTRODUCTION
1.2 Toxicology
New text
Viruses like LNL6 have been tested extensively in animal models. 
(Brenner et al., 1993; Dunbar et al, 1995; Economou et al., 1996; 
Emmons et al., 1997; Huhn et al., 1999). Leukemia has been 
reported in one bone marrow transplantation study (Li et al. 2002;
Baum et al., 2005) in mice where the blood progenitor cells were 
infected ex-vivo with a retrovirus containing the nerve growth 
factor receptor and then re-introduced to the same animal. No 
hematopoietic alterations were observed in the 5 mice so treated.
However, when bone marrow cells were later taken from these 
mice, pooled and transplanted into secondary irradiated mice, the 
cells gave rise to hematopoietic disorders in all 10 recipient 
animals (1 animal showed extramedullary hematopoiesis, 3 had 
pre-leukemia and 6 developed overt acute myeloid leukemia). The 
transformed cells of these animals were clonal and retroviral 
integration was found in a gene (ecotropic viral integration site-1, 
Evi-1) that may have cooperated with the nerve growth factor 
receptor to cause leukemia. Several subsequent bone marrow 
transplantation studies have shown co-operation between 
insertional mutagenesis of a host gene and a growth promoting 
gene introduced by the retroviral vector (Du et al., 2005a and b 
Modlich et al., 2005)
In another study one of seven rhesus macaque monkeys developed 
a solid tumor in the kidney approximately five years after 
transplantation with retrovirally transduced blood progenitor cells 
(Seggewiss et al., 2006). Insertional mutagenesis has not been
seen previously in approximately 80 large animals followed long-
term (Kiem et al., 2004; Seggewiss et al., 2006). Confounding 
factors in this monkey study include the relatively old age of the 
affected animal, and the fact that it had gone through multiple 
cycles of blood progenitor cell mobilization, progenitor cell 
growth outside the animal and in vivo drug selection of the 
transduced cells. In studies of bone marrow transplantation in 
mice and non-human primates predominant clones with vector 
insertions have been seen in genes apparently linked to enhanced 
hematopoietic cell proliferation, but have not resulted in 
disease(Seggewiss et al., 2006; Klein et al., 2004; Kusticova et 
al., 2005; Du et al., 2005; Nienhuis et al., 2006) and in the case of 
2 patients with Chronic Granulomatous Disease this enhanced 
expansion appeared to be therapeutic (Ott et al., 2006) 
Inclusion of new data.
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1.3 Clinical 
Experience
New text
Phase I CD4+ Cell Study
This 'proof of principle' study conducted at St. Vincent's Hospital, 
Sydney, Australia, involved identical twins discordant for HIV 
infection. Lymphocytes were collected by apheresis from the 
HIV-negative twin, purified by CD8+ depletion to yield CD4+ 
cells and stimulated to expand in cell culture with OKT3 and IL-2 
to in excess of 1 x 109 cells.  Approximately half of the cells were 
transduced with LNL6 and the other half with OZ1. 
Both batches of cells were mixed and infused into the HIV-
positive twin (Cooper et al., 1999). The aim of the study was to 
determine the feasibility and safety of transduction and infusion of 
LNL6- and OZ1-containing CD4+ cells and the length of time the 
cells were detectable thereafter. Preferential survival of OZ1-
transduced CD4+ cells was also assessed by semi-quantitative 
PCR assay.
Table 1 presents the cell number and transduction efficiency for 
the four patients in the CD4+ cell trial. All patients were receiving 
combination ART while on study. The gene transfer approach was 
shown to be feasible and safe. The number of transduced CD4+ 
cells detected post-infusion was very low, < 0.01%, but marked 
cells are persisting in the peripheral blood at 3.5 years (latest time 
point censored to date) and continue to express the gene constructs 
(Cooper et al., unpublished data). No preferential survival for OZ1 
transduced cells is evident. 
All four patients have been followed for up to 6.5 years.  None of 
the patients experienced any Serious Adverse Events (SAEs) 
related to the gene transfer procedure either during the 6 months 
study period or, to date, in the long-term follow-up. Patient R0005 
died 5.7 years post infusion due to CMV related pneumonia due to
progression of HIV infection. There was no report of malignancy 
at the time of death. Patient R003 developed an SAE, a basal cell 
carcinoma, unrelated to the gene transfer product, during the 
follow up period of the study.
(Table 1 inserted)
There were no gene transfer–related adverse events reported. 
Importantly, there was no evidence of transmission of any 
infection from donor to recipient. The infusion of CD4+ cells was 
associated with some minimal light-headedness, headache and 
pruritus. There was no evidence of graft versus host disease. The 
changes in plasma HIV RNA (viral load) and CD4+ cell counts 
To provide background 
on other OZ1 Phase I 
studies.
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are consistent with those for HIV-infected patients on ART. 
Replication competent retrovirus (RCR) polymerase chain 
reaction (PCR) assay of patient samples showed no detectable 
RCR.
Phase I CD34+ Cell Study
This Phase I study was conducted at the University of California 
Los Angeles (UCLA), California, USA, in 10 patients, using 
autologous CD34+ cells collected from HIV-1 infected patients. 
Patients were not myeloablated. Following G-CSF mobilization 
and apheresis, the CD34+ cells were purified using a CD34+ 
specific antibody. The CD34+ cells were then introduced into 
culture with the growth factors Stem Cell Factor (SCF) and 
Megakaryocyte Growth and Development Factor. Approximately 
half the cells were transduced with LNL6 and half with OZ1. Both 
batches of cells were mixed and re-infused. Table 2 presents the 
purity, total number CD34+ infused (number/kg body weight), 
percent transduction and number of transduced (LNL6 + OZ1) 
cells. The first three patients treated received between 0.4%-4% 
mixture of LNL6- and OZ1-transduced cells. A modification to 
the transduction procedure was introduced, and retronectin (RN –
a recombinant cell adhesion protein) was used to enhance 
transduction efficiency. The remaining seven patients received 
cells with transduction efficiencies ranging between 7 - 57 %.
(Table 2 inserted)
Patients were recruited over the period February 1998 to January 
2000. The last three patients were enrolled substantially later 
(November 1999 to January 2000) than the first seven (February 
1998 to October 1998). The time period since infusion for all ten 
patients ranges from approximately 4 to 6 years. Six patients 
completed the 3-year study period and 8 patients are participating 
in long-term follow up. Results to date show gene marking in 
bone marrow and peripheral blood mononuclear cells, 
specifically, purified T-cells, monocytes and granulocytes, and in 
purified naïve and memory CD4+ and CD8+ cells (Amado et al., 
2004). The presence of gene marked cells with the naïve 
phenotype (CD45RA+/CD62L+) is direct evidence for the 
production of mature T-cells from the infused CD34+ cells 
(Amado et al., 2004, Tough et al., 1995; Aguila et al., 1997; 
McFarland et al., 2000). Thus, the transduced CD34+ cells have 
contributed to relevant hematopoietic lineages. 
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The factors that affected the degree of cell marking in the ten 
patients in this study were:
The percentage of CD34+ cell transduction
Number of transduced CD34+ cells infused
Total number of CD34+ cells infused
No gene transfer-related SAEs were reported for any of the treated 
patients. One patient developed Kaposi’s sarcoma, an Adverse 
Event (AE) reported to be related to the underlying Acquired 
Immunodeficiency Syndrome (AIDS) rather than the gene transfer 
product. There were five patients who experienced AEs definitely 
or possibly related to the G-CSF mobilization procedure. There 
were two cases of severe bone pain, one case of headache, one of 
moderate back pain, and one of mild bone pain with mild myalgia 
and chest pain. In addition, 3 patients experienced a transient mild 
thrombocytopenia, on or after the infusion procedure; however, 
only one was reported as related to the G-CSF treatment. There 
was one report of moderate anxiety related to the apheresis 
procedure. Only three AEs were possibly related to the re-infusion 
of the CD34+ cells; one patient developed sweating and one 
reported nausea, and a third patient developed hypotension during 
the infusion. All three were categorized as mild. No RCR has been 
detected by PCR. Long-term follow up and collection of archival 
samples is ongoing as per the current FDA/CBER 
recommendations.
1.4 Clinical 
Toxicology
To date, LNL6 or similar retroviral vectors have 
been used in more than 1800 patients in 254 gene 
transfer clinical trials worldwide 
(www.wiley.co.uk/genmed). Serious Adverse 
Events (SAEs) reported in a gene transfer study for 
X-linked Severe Combined Immunodeficiency 
(SCID-X1) have led to specific changes to the long 
term monitoring protocols for recipients of 
retroviral gene transfer products. In the study of 
patients with SCID-X1 in whom the gamma 
common chain gene is absent or defective, eleven 
children received autologous CD34+ cells 
transduced with Moloney-derived retroviral vector 
containing the gamma common chain gene. A 
clinical response was evident in nine children, two 
of whom developed T cell leukemia at 
To date, LNL6 or similar retroviral vectors have been used in 
more than 1800 patients in 250 gene transfer clinical trials 
worldwide (www.wiley.co.uk/genmed).The neoR gene product, 
neomycin phosphotransferase, has not been shown to be antigenic 
in humans (Riddell et al., 1996). There may be a greater potential 
risk of an antigenic response in the OZ1 group in the current study 
because the number of transduced cells will be greater than in the 
Phase I trials. Therefore blood samples will be analyzed for 
cytotoxic T-lymphocyte response to neomycin phosphotransferase 
(neoR specific CTLs). Any patient who develops a CTL response 
to the neoR gene product may be ineligible to receive future 
infusions of any gene transfer products that express neomycin 
phosphotransferase.
SAEs reported in a gene transfer study for X-linked Severe 
Combined Immunodeficiency (SCID-X1) have led to specific 
Inclusion of new safety 
data.
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approximately 3 years after infusion of the 
transduced CD34+ cells (Baum et al., 2003; 
Buckley et al., 2002; Cavazzana-Calvo et al., 2000 
& 2004; Check  2003; Dave et al., 2004; Fischer 
2000; Hacein-Bey-Abina et al., 2002 & 2003; 
Kaiser 2003; Williams & Baum 2003).
The leukemic clones in both children, contained a 
single copy of the intact retroviral vector near or 
within the LMO2 gene. The LMO2 protein is 
known from previous work (primarily in mice) to 
act as a bridge molecule in transcriptional factor 
complexes. Abnormal expression of the LMO2 
gene appears to increase susceptibility to leukemia 
by blocking T cell differentiation (Drynan et al.,
2001; McCormack and Rabbitts 2004; Orkin 1995; 
Rabbitts 2001). Retroviral insertion into LMO2 
has been found in a third patient from the same 
study. This patient, who has not shown any signs 
of leukemia, is being monitored closely 
(McCormack and Rabbitts 2004). 
Expression of the introduced gamma common 
chain is essential to the T cell reconstitution in 
these children but also may be a factor in the 
development of the leukemias. The rapid increase 
in T cells that results from expression of the 
introduced gamma common chain gene does not 
occur normally in embryonal and early childhood 
hematopoiesis. Thus it has been speculated that the 
dysregulated hematopoiesis associated with 
abnormal expression of LMO2 and the 
considerable survival advantage conferred by the 
introduced gamma common chain gene to cells in 
the T lymphocyte lineage are the main factors that 
contributed to the development of leukemias.
(Baum et al., 2003; Buckley et al., 2002; 
Cavazano-Calvo et al., 2004; Dave et al., 2004; 
Hacein-Bey-Abina et al., 2003; Kaiser .2003; 
Leonard 2000; McCormack and Rabbitts 2004; 
Williams & Baum 2003;). 
Other possible contributing factors to the 
changes to the long term monitoring protocols for recipients of 
retroviral gene transfer products. In that study, eleven children 
with SCID-X1 received autologous CD34+ cells transduced with 
Moloney-derived retroviral vector containing the cytokine gamma 
common chain gene. A clinical response was evident in nine 
children. In 2002 two of the children, both who of whom had 
responded well to the procedure, developed T cell leukemia 
approximately 3 years after infusion of the transduced CD34+ 
cells (Baum et al., 2003; Buckley et al., 2002; Cavazzana-Calvo et 
al., 2000 & 2004; Check. 2003; Dave et al., 2004; Fischer 2000; 
Hacein-Bey-Abina et al., 2002 & 2003 Kaiser 2003; Williams & 
Baum 2003). One of the children with leukemia died in October 
2004, but the other child continues to respond to treatment.
The leukemic clones in all three of the children contained a copy 
of the intact retroviral vector near or within the LMO2 gene 
(Frederickson, 2005). The LMO2 protein is known from previous 
work (primarily in mice) to act as a bridge molecule in 
transcriptional factor complexes. Abnormal expression of the 
LMO2 gene appears to increase susceptibility to leukemia by 
blocking T cell differentiation (Drynan et al. 2001; McCormack 
and Rabbitts 2004; Orkin 1995; Rabbitts 2001). (). The relevant 
regulatory agencies continue to monitor these studies closely. 
Expression of the introduced gamma common chain is essential to 
the T cell reconstitution in these children but also may be a factor 
in the development of the leukemias. The rapid increase in T cells 
that results from expression of the introduced gamma common 
chain gene does not occur normally in embryonal and early 
childhood hematopoiesis. Thus it has been speculated that the 
dysregulated hematopoiesis associated with abnormal expression 
of LMO2 and the considerable survival advantage conferred by 
the introduced gamma common chain gene to cells in the T 
lymphocyte lineage are the main factors that contributed to the 
development of leukemias. (Baum et al., 2003; Buckley et al.,
2002; Cavazzana-Calvo et al., 2004; Dave et al., 2004; Hacein-
Bey-Abina et al., 2003; Kaiser .2003; Leonard 2000; McCormack 
and Rabbitts 2004; Williams & Baum 2003). Investigations in 
mice have indicated an apparent cooperation between LMO2 and 
the gamma common chain gene (Berns, 2004; Woods et al., 2006) 
Other possible factors contributing to the development of 
leukemia are the disease background including the unusual 
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development of leukemia in these children are the 
disease background including the unusual 
properties of the bone marrow derived CD34+ 
cells in young children and the high numbers of 
CD34+ cells that were transduced and infused 
(approximately 2 x 107 cells/kg) (Cavazano-Calvo 
et al., 2004; Dave et al., 2004; Hacein-Bey-Abina 
et al., 2003; McCormack and Rabbitts 2004; 
Williams & Baum 2003).
The two cases of insertional oncogenesis led to the 
FDA/CBER requirements to include the number 
and any clonality of vector integration sites in 
peripheral blood mononuclear cells (Schmidt et al., 
2001 & 2002). If a predominant integration site is 
detected, a second test will be conducted within 3 
months to determine if it persists. If so, the site of 
integration of OZ1 will be sequenced and mapped 
to the human genome to determine any association 
with a known human oncogene. In all instances 
that a predominant integration site is confirmed, 
and particularly when there is expansion of a 
cellular clone, the patient will be monitored closely 
for signs of oncogenesis, so that treatment can be 
initiated as early as possible.
properties of the bone marrow derived CD34+ cells in young 
children and the high numbers of CD34+ cells that were 
transduced and infused (approximately 2 x 107 cells/kg) 
(Cavazzana-Calvo et al., 2004; Dave et al., 2004; Hacein-Bey-
Abina et al., 2003; McCormack and Rabbitts 2004; Williams & 
Baum 2003). 
In contrast to the studies by Fischer and colleagues, a similar trial 
for SCID-X1 by Thrasher and colleagues in the United Kingdom 
have not shown these SAEs (Gaspar et al., 2004; Gaspar and 
Thrasher, 2005).
The initial two cases of insertional oncogenesis led to the 
FDA/CBER requirements to extend the monitoring for patients in 
this study to include the number and any clonality of vector 
integration sites in peripheral blood mononuclear cells (Schmidt et 
al., 2001 & 2002). If a predominant integration site is detected, a 
second test will be conducted within 3 months to determine if it 
persists. If so, the site of integration of OZ1 will be sequenced and 
mapped to the human genome to determine any association with a 
known human oncogene. In all instances that a predominant 
integration site is confirmed, and particularly when there is 
expansion of a cellular clone, the patient will be monitored closely 
for signs of oncogenesis, so that treatment can be initiated as early 
as possible. This recommendation was not modified by the third 
case (Baum, 2005; Check, 2005).
2. OBJECTIVES
1.To undertake long term safety monitoring for 
any development of:
a. Replication Competent Retrovirus (RCR)
b. Clonal expansion of cells with a predominant 
OZ1 or LNL6 vector insertion site
c. Insertional oncogenesis
2. To assess quantitative marking and expression 
of the gene transfer product in peripheral blood 
mononuclear cells over time.
1. To undertake long term safety monitoring for any development 
of:
a. Replication Competent Retrovirus (RCR)
b. Clonal expansion of cells with a predominant OZ1 or LNL6 
vector insertion site
c. Insertional oncogenesis
2. To archive/store plasma and PBMC samples for other safety 
testing as maybe required.
3. To assess quantitative marking and expression of the gene 
transfer product in peripheral blood mononuclear cells over time.
To define the use of 
stored samples, should 
additional safety testing 
be required.
3. OVERVIEW 
OF STUDY 
DESIGN
New text
The patients who were enrolled in the OTH/OZ1-INT-1 trial 
entitled “A randomized Phase II, double blind, controlled trial to 
evaluate the safety and efficacy of autologous CD34+ 
hematopoietic cells transduced with placebo or an anti-HIV-1 
ribozyme (OZ1) in patients with HIV-1 infection” will continue to 
To further clarify the trial 
population and the means 
by which they will enter 
this protocol.
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be assessed under this Long Term Follow-Up Protocol. Where 
possible follow up visits will coincide with routine clinic visits.
4. 
COMPLIANCE
New text
1.The semi-annual visit interval is 6 months 6 weeks (for years 
2.5-5). The annual visit interval is 12 months 12 weeks (year 
6+).
2.CBC/Differential data will be obtained specifically as part of the 
follow up procedures for a total of fifteen (15) years following the 
time of the infusion in the original phase II study. After this date, 
CBC/Differential data obtained as part of routine clinic 
assessments will be collected in the study CRF on an unscheduled 
basis (as per the unscheduled visit in the Time & Events 
Schedule). Failure to obtain this data will not be considered 
protocol non-compliance.
3.In the event that a Recipient dies, irrespective of cause of death 
or time after the gene transfer procedure, a request will be made 
by the Principal Investigator to the next of kin for an autopsy to 
assess for the presence of 1) RCR and 2) LNL6 or OZ1 containing 
cells. If efforts to obtain permission for an autopsy are 
unsuccessful or not practicable, it will not be considered as 
protocol non-compliance. If an autopsy is performed, a copy of 
the autopsy report will be obtained and the cause of death and any 
significant observations noted in the Serious Adverse Event 
report.
4. In the event that the Recipient undergoes a biopsy or surgical 
removal of a tumor, an attempt will be made by the Principal 
Investigator to obtain a sample of tissue for the assessment of the 
presence of 1) RCR and 2) LNL6 or OZ1 containing cells. If 
efforts to obtain a tissue sample are unsuccessful or not 
practicable, it will not be considered as protocol non-compliance.
To be consistent with the 
other OZ1 long-term 
follow-up protocols.
6. 
CONCOMITANT 
THERAPY AND 
ACTIVITIES
Information regarding medications (prescriptions 
and/or over-the-counter) or therapies being taken 
or administered will be collected if the subject has 
a serious adverse event.
Information on current medications or other therapies will not be 
collected, unless required for submission of a Serious Adverse 
Event report.
To further define which 
concomitant medications 
will be collected.
7. STUDY 
EVALUATIONS
The Time and Events Schedule included in the 
Synopsis summarizes the frequency and timing of 
the various efficacy and safety measurements.
Visit schedules are fixed from the day of the 
original infusion of autologous CD34+ cells as per 
the OTH/OZ-1-INT-1 protocol.
Allowed Visit Intervals
The Time and Events Schedule included in the Synopsis 
summarizes the frequency and timing of the various efficacy and 
safety measurements.
Visit schedules are fixed from the day of the original infusion of 
autologous CD34+ cells as per the OTH/OZ-1-INT-1 protocol.
Allowed Visit Intervals
Visit interval: 6 months
A breakdown of years 2-
5, 5-15, 15+ and 
unscheduled visits has 
been included.
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Visit interval: 6 months
Allowed window:
6
months + 6 weeks
Visit interval: 12 months
Allowed window:
12 months + 612 weeks.
The following assessments and evaluations will 
be completed as described in the Time & Events 
Schedule during the various phases of the 
study:
Complete Blood Count (CBC), differential and 
platelet count.
Archival storage of plasma and PBMC samples.
PCR analysis of PBMCs for the presence of 
Replication-Competent Retrovirus (RCR) using 
primers specific for amphotropic env retroviral 
gene sequences.
Optional quantitative analysis of OZ1 DNA (PCR) 
in total PBMC
Optional quantitative analysis of OZ1 RNA (RT-
PCR) in total PBMC if OZ1 DNA is detected
Testing for clonality of OZ1 integration in PBMC 
samples (PCR).
Recording of serious adverse events (SAEs).
2 to 5 years post-Infusion
Visits will be at six monthly intervals from year 2 
to year 5 post-infusion. 
The Long Term Follow-up visits at Year 2.5, 3.5 
and Year 4.5 post-infusion, will have the following 
assessments :
CBC, differential and platelet count.
Testing for clonality of OZ1 integration sites in 
PBMC samples (PCR).
Recording of Serious Adverse Events (SAEs).
The Long Term Follow-up visits at Year 3, 4 and 
5 post-infusion the following assessments will be 
completed:
CBC, differential and platelet count. 
Testing for clonality of OZ1 integration sites in 
Allowed window:
6 months + 6 weeks
Visit interval: 12 months
Allowed window:
12 months + 12 weeks.
The following assessments and evaluations will be completed 
as described in the Time & Events Schedule during the 
various phases of the study:
2 to 5 years post-Infusion
Visits will be at six monthly intervals from year 2 to year 5 post-
infusion. 
The Long Term Follow-up visits at Year 2.5, 3.5 and Year 4.5 
post-infusion, will have the following assessments:
Clinical History and Physical Examination including a detailed 
record of:
-exposure to possible mutagenic agents eg radiotherapy or 
chemotherapeutic agents
-new malignancies 
-new or exacerbated preexisting neurologic, autoimmune and 
hematologic disorders.
Complete Blood Count (CBC), differential and platelet count.
Testing for clonality of OZ1/LNL6 integration in PBMC samples 
(PCR) including gene marking (quantitative OZ1 DNA-PCR).
Recording of adverse events (AEs).
The Long Term Follow-up visits at Year 3, 4 and 5 post-infusion 
the following assessments will be completed:
Clinical History and Physical Examination including a detailed 
record of:
-exposure to possible mutagenic agents eg radiotherapy or 
chemotherapeutic agents
-new malignancies 
-new or exacerbated preexisting neurologic, autoimmune and 
hematologic disorders.
Complete Blood Count (CBC), differential and platelet count.
Archival storage of plasma and PBMC samples for Replication-
Competent Retrovirus (RCR) and other safety testing as required
Testing for clonality of OZ1/LNL6 integration in PBMC samples 
(PCR) including gene marking (quantitative OZ1 DNA-PCR).
Quantitative analysis of PBMC sample for OZ1 RNA (RT PCR) if 
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PBMC samples (PCR).
Archival storage of plasma and PBMC samples.
PBMC archive for PCR analysis for the presence 
of Replication-Competent Retrovirus (RCR) using 
primers specific for amphotropic env retroviral 
gene sequences. Both PBMC cell pellets and 
cryopreserved cells are required for archive.
Recording of SAEs
Year 5+
Annual Visits 
Annual visits will include all assessments listed in 
the 2-5 year annual visits above.
If the full blood count/differential and clonality of 
OZ1 integration in PBMC show no significant 
abnormality during the first 15 years post-infusion 
for patients receiving OZ1, these tests will no 
longer be performed for the remaining Long Term 
Follow-up Protocol. It is currently required that all 
other assessments continue for the lifetime of the 
patient.
OZ1 DNA is detected.
Recording of adverse events (AEs).
Annual Visits Year 5-15 post infusion
Clinical History and Physical Examination including a detailed 
record of:
-exposure to possible mutagenic agents eg radiotherapy or 
chemotherapeutic agents
-new malignancies 
-new or exacerbated preexisting neurologic, autoimmune and 
hematologic disorders.
Complete Blood Count (CBC), differential and platelet count.
Archival storage of plasma and PBMC samples for Replication-
Competent Retrovirus (RCR) and other safety testing as required
Testing for clonality of OZ1/LNL6 integration in PBMC samples 
(PCR) including gene marking (quantitative OZ1 DNA-PCR).
Quantitative analysis of PBMC sample for OZ1 RNA (RT PCR) if 
OZ1 DNA is detected.
Recording of adverse events (AEs).
Annual Visits Year 15+ post infusion
Clinical History and Physical Examination including a detailed 
record of:
-exposure to possible mutagenic agents eg radiotherapy or 
chemotherapeutic agents
-new malignancies 
-new or exacerbated preexisting neurologic, autoimmune and 
hematologic disorders.
Archival storage of plasma and PBMC samples for Replication-
Competent Retrovirus (RCR) and other safety testing as required
Recording of adverse events (AEs).
If the full blood count/differential and platelet count and the 
clonality of OZ1 integration in PBMC show no significant 
abnormality during the first 15 years post-infusion these tests will 
no longer be performed for the remaining Long Term Follow-up 
Protocol. It is currently required that all other assessments 
continue for the lifetime of the patient.
Unscheduled Assessments
In addition to the annual follow up visit, unscheduled procedures 
may be performed in the event of an adverse event.
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7.2 Optional 
Efficacy 
Evaluation
Patients will have the option of consenting to the 
collection of additional blood samples for the 
ongoing assessment of OZ1. The following 
efficacy assessments will continue as detailed in 
the Time & Events Schedule:
Quantitative analysis of PBMC sample for OZ1 
DNA (PCR) and OZ1 RNA (RT PCR)
Patients will have the option of consenting to the collection of 
additional blood samples for the ongoing assessment of OZ1 
expression (OZ1 RNA- RTPCR).
Specific efficacy 
assessments included.
7.3 Safety 
Evaluations
Gene Transfer Product Safety Testing
Testing for clonality of OZ1 integration in PBMC 
using PCR. 
If a predominant integration site is detected, the 
patient will be retested within three months to 
determine if it persists. If so, the site of integration 
of OZ1 will be sequenced and mapped to the 
human genome to determine any association with a 
known human oncogene. In all instances that a 
dominant integration site is present and, 
particularly when there is expansion of a cellular 
clone, the patient will be monitored closely for 
signs of cancer, so that any potential treatment can 
be initiated as early as possible.
Any confirmed finding of a predominant 
integration site will be reported as a serious 
adverse event (SAE).
“Predominant integration site” is defined as an 
integration site which has a density of at least 50% 
of the total signal detected by PCR.
Gene Transfer Product Safety Testing
Testing for clonality of OZ1 integration in PBMC using PCR. 
If a predominant integration site is detected, the patient will be 
retested within three months to determine if it persists. If so, the 
site of integration of OZ1 will be sequenced and mapped to the 
human genome to determine any association with a known human 
oncogene. In all instances that a dominant integration site is 
present and, particularly when there is expansion of a cellular 
clone, the patient will be monitored closely for signs of cancer, so 
that any potential treatment can be initiated as early as possible. 
Predominant integration site” is defined as an integration site 
which has a density of at least 50% of the total signal detected by 
PCR, when the % of cells marked by the vector (quantitative OZ1 
DNA PCR) is >1% of the test cell population.
Any confirmed finding of a predominant integration site i.e. 
present on at least two consecutive samples will be reported as a 
serious adverse event (SAE)
General rewording.
Specify additional SAE 
reporting requirements.
9.1 Efficacy 
Evaluation
There will be ongoing assessment of quantitative 
marking and expression of the gene transfer 
product in PBMC
Ongoing analysis of quantitative marking of the gene transfer 
product (OZ1 and LNL6) in peripheral blood mononuclear cells 
will be performed as part of the testing of OZ1 or LNL6 vector 
integration sites. This data will be used to independently assess 
changes in the number of peripheral blood mononuclear cells that 
carry the gene transfer product over time. Patients will have the 
option of consenting to the collection of additional blood samples 
for the ongoing assessment of OZ1 expression (OZ1 RNA-
RTPCR).
To clarify the use of the 
data obtained from this 
analysis.
9.2 Safety 
Evaluations
Serious Adverse Event data 
will be assigned a body system and preferred term 
using the MedDRA coding dictionary, Version 6.0. 
All Serious Adverse Events (SAEs) will be 
Serious Adverse Event data will be assigned a body system and 
preferred term using the current MedDRA coding dictionary. All 
Serious Adverse Events (SAEs) will be recorded with respect to 
severity as per the ACTG 285 Toxicity Table (See Appendix 1). 
The current version of the 
MedDRA dictionary will 
be used.
Description of safety 
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recorded with respect to severity as per the ACTG 
285 Toxicity Table (See Appendix 1). 
Serious Adverse Events will be summarized either 
in a tabular form, or via data listings. Data will be 
summarized annually for regulatory reporting.
Serious Adverse Events will be summarized either in a tabular 
form, or via data listings. Data will be summarized annually for 
regulatory reporting.
evaluations expanded to 
include all clinical 
observations.
10.2 Procedures
Serious 
Adverse Events
Only Serious Adverse Events (SAEs) that are 
“possibly”, “probably” or “very likely” related to 
the study drug that occur from two years after 
infusion will be reported on a SAE form by the 
Investigator. Death or malignancies (except Basal 
Cell or Squamous Cell Carcinomas) should be 
reported, regardless of causality assessment. All 
other SAEs (unrelated to the drug) will be recorded 
in the CRF as a summary of the event. SAEs may 
be reported by the patient to the site at the 6 
monthly or annual follow up visits or via 
spontaneous reporting between follow up visits. 
For each serious adverse event reported, the 
Investigator should obtain all the information 
required to complete the Serious Adverse Event 
Form (if applicable), in accordance with the 
guidelines that accompany it. All measures 
required for serious adverse event management 
must be recorded in the source document and 
reported according to Sponsor instructions.
Patients (or their designee, if appropriate) must be 
provided with a “trial card” indicating the name of 
the investigational product, the trial number, the 
Investigator’s name and a 24-hour emergency 
contact number.
All serious adverse events occurring during 
clinical trials must be reported to the appropriate 
Sponsor contact person by investigational staff 
within 24 hours of their knowledge of the event.
Information regarding serious adverse events will 
be transmitted to JJR using the Serious Adverse 
Event Form, which must be signed by a member of 
the investigational staff. The initial report of a 
serious adverse event may be made by telephone 
or facsimile (FAX). A telephone report of a serious 
Only Serious Adverse Events (SAEs) that are “possibly”, 
“probably” or “very likely” related to the study drug that occur 
from two years after infusion will be reported on a SAE form by 
the Investigator. Death or malignancies (except Basal Cell or 
Squamous Cell Carcinomas) should be reported, regardless of 
causality assessment. All other SAEs (unrelated to the drug) will 
be recorded in the CRF as a summary of the event. SAEs may be 
reported by the patient to the site at the follow up visits or via 
spontaneous reporting between follow up visits. 
For each serious adverse event reported, the investigational staff 
should obtain all the information required to complete the Serious 
Adverse Event Form (if applicable), in accordance with the 
guidelines. All measures required for serious adverse event 
management must be recorded in the source document and 
reported according to Sponsor instructions.
All reportable serious adverse events must be reported to the 
appropriate Sponsor contact person by investigational staff within 
24 hours of their knowledge of the event.
If the SAE is a death or a life threatening event the Investigator 
must notify the Sponsor immediately by both telephone and FAX. 
The completed SAE form must be transmitted by FAX to JJR 
within 24 hours of knowledge of the event. The Investigator must 
provide the following minimal information: Protocol number, 
patient’s initials and date of birth, patient number or medication 
code number, date of treatment, nature of the adverse event and 
Investigator’s attribution.
All serious adverse events must be followed until any of the 
following occurs:
the event resolves;
the event stabilizes;
the event returns to baseline, if a baseline value is available; or
the event can be attributed to agents other than the study drug or 
to factors unrelated to study conduct.
The cause of death of a patient in a clinical trial, whether the event 
is expected or associated with the investigational agent, is 
To define specific SAE 
and pregnancy reporting 
responsibilities.
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adverse event must be followed by a completed 
Serious Adverse Event Form from the 
investigational staff within one working day. The 
Investigator must provide the following minimal 
information: Protocol number, patient’s initials and 
date of birth, patient number or medication code 
number, period of intake, nature of the adverse 
event and Investigator’s attribution.
All serious adverse events must be followed until 
any of the following occurs:
the event resolves;
the event stabilizes;
the event returns to baseline, if a baseline value is 
available; or
the event can be attributed to agents other than the 
study drug or to factors unrelated to study conduct.
The cause of death of a patient in a clinical trial, 
whether the event is expected or associated with 
the investigational agent, is considered a serious 
adverse event.
If there is evidence of leukemia (proven or strong 
clinical suspicion), RCR or a predominant 
integration site the Sponsor assumes responsibility 
for reporting these serious adverse events to the 
relevant regulatory authorities in an expedited 
manner. 
The Sponsor will also report to the Investigator all 
serious adverse events that are unlisted and 
associated with the use of the drug. The 
Investigator must report these events to the 
appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) 
in accordance with local regulations.
Any event requiring hospitalisation (or 
prolongation of hospitalisation) that occurs during 
the course of a patient’s participation in a clinical 
study must be reported as a serious adverse event, 
except hospitalisations for:
social reasons in absence of an adverse event;
surgery or procedure planned prior to entry into the 
considered a reportable serious adverse event.
If there is evidence of leukemia (proven or strong clinical 
suspicion), RCR or a predominant integration site the Sponsor 
assumes responsibility for reporting these serious adverse events 
to the relevant regulatory authorities in an expedited manner. 
The Sponsor will also report to the Investigator all serious adverse 
events that are unlisted and associated with the use of the drug. 
The Investigator must report these events to the appropriate 
Independent Ethics Committee/Institutional Review Board 
(IEC/IRB) in accordance with local regulations.
Any event requiring hospitalisation (or prolongation of 
hospitalisation) that occurs during the course of a patient’s 
participation in a clinical study is a serious adverse event, except 
hospitalisations for:
social reasons in absence of an adverse event;
surgery or procedure planned prior to entry into the study.
Pregnancy
Pregnancy must be reported by the investigational staff within 24 
hours of their knowledge of the event using the JJR SAE 
Notification Form. Follow-up information regarding the outcome 
of the pregnancy and any postnatal sequelae in the infant will be 
required. 
In the event that, while enrolled in the trial, a male patient 
impregnates his partner, the Sponsor should be notified by 
completion of a Pregnancy Notification Form faxed to the 
Sponsor. The outcome of the pregnancy and any postnatal 
sequelae in the infant should also be required.
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study.
PREGNANCY
Any pregnancy occurring during clinical studies 
must be reported by the investigational staff within 
1 working day of their knowledge of the event 
using the Pregnancy Notification Form. Follow-up 
information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant 
will be required. 
In the event that, while enrolled in the trial, a male 
patient impregnates his partner, the Sponsor should 
be notified by completion of a Pregnancy 
Notification Form faxed to the Sponsor. The 
outcome of the pregnancy should also be reported.
12.9 Use of 
Information and 
Publication
All information concerning placebo and OZ1, JJR 
operations, patent application, formulas, 
manufacturing processes, basic scientific data, and 
formulation information, supplied by the Sponsor 
to the Investigator and not previously published, is 
considered confidential and remains the sole 
property of JJR. The Investigator agrees to use this 
information only to accomplish this study and will 
not use it for other purposes without the Sponsor’s 
written consent.
The Investigator understands that the information 
developed in the clinical study will be used by JJR 
in connection with the continued development of 
OZ1, and thus may be disclosed as required to 
other clinical Investigators or government 
regulatory agencies. To permit the information 
derived from the clinical studies to be used, the 
Investigator is obligated to provide the Sponsor 
with all data obtained in the study.
Guidelines regarding publication and presentation 
of study data are outlined in the study Investigator 
Agreement.
All information concerning placebo and OZ1, JJR operations, 
patent application, formulas, manufacturing processes, basic 
scientific data, and formulation information, supplied by the 
Sponsor to the Investigator and not previously published, is 
considered confidential and remains the sole property of JJR. The 
Investigator agrees to use this information only to accomplish this 
study and will not use it for other purposes without the Sponsor’s 
written consent.
The Investigator understands that the information developed in the 
clinical study will be used by JJR in connection with the 
continued development of OZ1, and thus may be disclosed as 
required to other clinical Investigators or government regulatory 
agencies. To permit the information derived from the clinical 
studies to be used, the Investigator is obligated to provide the 
Sponsor with all data obtained in the study.
Guidelines regarding 
publication and 
presentation of study data 
have been provided 
elsewhere in study 
documentation.
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13. 
REFERENCES
16.REFERENCES
Bahner, I., C. Zhou, X. J., 
Yu, Q. L. Hao, J. C. 
Guatelli and D. B. Kohn. 
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clonal hematopoiesis or 
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MP, Arndt AJ, Todd AV, 
Fanning GC, Ely JA, 
Elliott F, Knop A, 
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May;7(5):552-64.
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C.E. and Sorrentino, B.P. 
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news tempered by bad 
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differentiation potential 
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S., Adler, R.M., Guenaga, 
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Donahue, R.E., Von Kalle, 
Raponi M, Murray J, 
Gerlach W, Sun LQ, 
Penny R, Symonds GP, 
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May;7(5):552-64.
Nienhuis, A.W., Dunbar, 
C.E. and Sorrentino, B.P. 
Genotoxicity of 
retroviral integration in 
hematopietic cells. 
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13 (6): 1031-1049.
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H.L. Gene therapy for 
immune disorders: Good 
news tempered by bad 
news. J Allergy Clin 
Immunol, 2006; 117: 
865-869.
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Bey-Abina, S., Wissler, 
M., Carlier, F., Lim, A., 
Prinz, C., Glimm, H., 
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Deist, F., Lagresle, C., 
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Calvo, M. and Von 
Kalle, C. Clonal 
evidence for the 
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cells with 
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3865-3867.
Shearer, W.T. and Fischer, 
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Therapeutic gene causing 
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2005; 105 (7): 2699-
2706.
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Amendment 2; 28 August 2007
Applicable 
sections
Original Text
New/Revised Text
Description and Rationale
SYNOPSIS
It is currently a requirement of the United States Food and 
Drug Administration (FDA) that all individuals receiving 
retroviral gene transfer products are followed indefinitely.
It is currently a requirement of the United States Food and Drug 
Administration (FDA) that all individuals receiving retroviral gene 
transfer products are followed for the life.
Clarification regarding the 
lifetime follow-up of 
individuals receiving 
retroviral gene transfer 
products
Time and Events 
Schedule
New Text
Contact details updated for subject and nominated secondary 
contact
If the percentage of cells marked by the vector (quantitative 
OZ1 DNA-PCR) is less than 1% of the test cell population, 
the site of integration will not be investigated.
Addition of scheduled 
review of contact details to 
facilitate long term follow-
up
Clarification regarding the 
analysis of the site of 
integration 
2. Objectives
a. Replication Competent Retrovirus
Deleted
RCR assessment 
undertaken as safety testing 
under item 2.
7. STUDY 
EVALUATIONS 
7.1 Study 
Procedures by 
Visit
New Text
new or exacerbated preexisting neurologic, 
autoimmune and hematologic disorders
In the event that a subject is unable to attend the clinic 
within the allowed visit window, a telephone interview can 
be conducted to collect information on important medical 
events since the last study visit (or telephone interview). 
Refer to Appendix 2 for the interview questionnaire.
new or exacerbated preexisting neurologic, rheumatologic, 
autoimmune and hematologic disorders
Addition of a Telephone 
Questionnaire to facilitate 
long term follow up
Addition of 
“rheumatologic”.
7.3 Safety 
Evaluations
Gene Transfer 
Product Safety 
Testing
New Text
Testing for clonality of OZ1/LNL6 integration in PBMC 
samples (PCR) will proceed if the percentage of cells 
marked by the vector (quantitative OZ1 DNA-PCR) is 
greater than or equal to 1% of the test cell population.
Clarification regarding the 
analysis of the site of 
integration
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9. STATISTICAL 
METHODS
Statistical analysis of data collected during the Long 
Term Follow-up Trial will be performed annually.
Statistical analysis of data collected during the Long Term 
Follow-up Trial will be performed every 5 years. 
Clinical history, physical examination findings, CBC and 
AEs will be listed and summarized in a tabular form. AE 
data will be summarized annually for regulatory reporting.
Interval between statistical 
analyses increased to allow 
the accumulation of 
sufficient data
Description of safety 
evaluations expanded to 
include all clinical 
observations.
9.2 Safety 
Evaluations
Serious Adverse Event data will be assigned a body 
system and preferred term using the current MedDRA
coding dictionary. All Serious Adverse Events (SAEs) 
will be recorded with respect to severity as per the 
ACTG 285 Toxicity Table (See Appendix 1). 
Serious Adverse Events will be summarized either in a 
tabular form, or via data listings. Data will be 
summarized annually for regulatory reporting.
All AE data will be coded to a body system and preferred 
term using the current MedDRA coding dictionary. 
Clinical history, physical examination findings, CBC and 
AEs will be listed and summarized in a tabular form. AE 
data will be summarized annually for regulatory reporting.
Description of safety 
evaluations expanded to 
include all clinical 
observations.
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10. ADVERSE 
EVENT 
REPORTING 
10.2 
PROCEDURES 
ADVERSE 
EVENTS
Only Serious Adverse Events (SAEs) that are 
“possibly”, “probably” or “very likely” related to the 
study drug that occur from two years after infusion will 
be reported on a SAE form by the Investigator. Death 
or malignancies (except Basal Cell or Squamous Cell 
Carcinomas) should be reported, regardless of 
causality assessment. All other SAEs (unrelated to the 
drug) will be recorded in the CRF as a summary of the 
event. SAEs may be reported by the patient to the site 
at the follow up visits or via spontaneous reporting 
between follow up visits. 
For each serious adverse event reported, the 
investigational staff should obtain all the information 
required to complete the Serious Adverse Event Form 
(if applicable), in accordance with the guidelines. All 
measures required for serious adverse event 
management must be recorded in the source document 
and reported according to Sponsor instructions.
All reportable serious adverse events must be reported 
to the appropriate Sponsor contact person by 
investigational staff within 24 hours of their 
knowledge of the event.
If the SAE is a death or a life threatening event the 
Investigator must notify the Sponsor immediately by 
both telephone and FAX. The completed SAE form 
must be transmitted by FAX to JJR within 24 hours of 
knowledge of the event. The Investigator must provide 
the following minimal information: Protocol number, 
patient’s initials and date of birth, patient number or 
medication code number, date of treatment, nature of 
the adverse event and Investigator’s attribution.
All serious adverse events must be followed until any 
of the following occurs:
the event resolves;
the event stabilizes;
the event returns to baseline, if a baseline value is 
Non-Serious Adverse Events
Non-serious adverse events must be recorded using medical 
terminology in the source document and in the case report 
form if they have a possible, probable or very likely suspect 
association to the study drug.
Serious Adverse Events
All adverse events meeting the definition of serious, 
regardless of severity or presumed relationship, must be 
recorded using medical terminology in the source document 
and in the case report form. Only SAEs that are “possibly”, 
“probably” or “very likely” related to the study drug must be 
reported using the Sponsor Serious Adverse Event Form 
within 24 hours of knowledge of the event. Exceptions to 
this include:
Death, regardless of the cause, is considered a reportable 
SAE;
Malignancy (except Basal Cell or Squamous Cell 
Carcinomas), regardless of causality, is considered a 
reportable SAE.
Whenever possible, diagnoses should be given when signs 
and symptoms are due to a common etiology (e.g., cough, 
runny nose, sneezing, sore throat, and head congestion 
should be reported as “upper respiratory infection”). 
Investigators must record in the CRF their opinion 
concerning the relationship of the SAE to study therapy. All 
measures required for serious adverse event management 
must be recorded in the source document.
Subjects (or their designees, if appropriate) must be 
provided with a “study card” indicating the name of the 
investigational product, the study number, the investigator’s 
name, and a 24-hour emergency contact number.
All reportable SAEs occurring during the study period must 
be reported to the appropriate sponsor contact person by 
investigational staff within 24 hours of their knowledge of 
the event. If the SAE is a death or a life threatening event the 
Investigator must notify the Sponsor immediately by both 
telephone and FAX.
Change to reflect updates to 
company safety reporting 
requirements clarify 
reporting requirements and 
expand safety reporting 
requirements to include 
non-serious, associated 
adverse events.
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available; or
the event can be attributed to agents other than the 
study drug or to factors unrelated to study conduct.
The cause of death of a patient in a clinical trial, 
whether the event is expected or associated with the 
investigational agent, is considered a reportable serious 
adverse event.
If there is evidence of leukemia (proven or strong 
clinical suspicion), RCR or a predominant integration 
site the Sponsor assumes responsibility for reporting 
these serious adverse events to the relevant regulatory 
authorities in an expedited manner. 
The Sponsor will also report to the Investigator all 
serious adverse events that are unlisted and associated 
with the use of the drug. The Investigator must report 
these events to the appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) in 
accordance with local regulations.
Any event requiring hospitalisation (or prolongation of 
hospitalisation) that occurs during the course of a 
patient’s participation in a clinical study is a serious 
adverse event, except hospitalisations for:
social reasons in absence of an adverse event;
surgery or procedure planned prior to entry into the 
study.
Information regarding serious adverse events will be 
transmitted to the sponsor using the Sponsor Serious 
Adverse Event Form, which must be signed by a member of 
the investigational staff. The initial report of a serious 
adverse event may be made by facsimile (fax) or telephone. 
It is preferable that serious adverse events be reported via 
fax. Subsequent to a telephone report of a serious adverse 
event, a Serious Adverse Event Form must be completed by 
the investigational staff and transmitted to the sponsor 
within 1 working day.
All SAEs must be followed until any of the following 
occurs:
the event resolves;
the event stabilizes;
the event returns to baseline, if a baseline value is available;
the event can be attributed to agents other than the study 
drug or to factors unrelated to study conduct; or
when it becomes unlikely that any additional information 
can be obtained (subject or health care practitioner refusal 
to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts)
The sponsor assumes responsibility for appropriate reporting 
of serious adverse events to the regulatory authorities. This 
includes expedited reporting of leukemia (proven or strong 
clinical suspicion), confirmed positive RCR or predominant 
integration site. The sponsor will also report to the 
investigator all serious adverse events that are unlisted and 
associated with the use of the drug. The investigator (or 
sponsor where required) must report these events to the 
appropriate Independent Ethics Committee/Institutional 
Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB.
The sponsor will evaluate any safety information that is 
spontaneously reported by a subject outside their 
participation in the formal study program.
Pregnancy
The investigational staff must report pregnancy within 24 
hours of their knowledge of the event using the Sponsor 
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Benefit Risk Management Pregnancy Notification Form. 
Follow-up information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant will be 
required, and is to be reporting using the Sponsor follow up 
collection Forms A & B.
Because the study drug may have an effect on sperm, 
pregnancies in partners of male subjects included in the 
study will be reported by the investigational staff in the same 
manner as above. The outcome of the pregnancy and any 
postnatal sequelae in the infant is also to be reported using 
the Sponsor pregnancy notification and follow up forms.
Any pregnancy abnormal outcomes (eg, spontaneous 
abortion, fetal demise, stillbirth, congenital abnormality, 
ectopic pregnancy) or pregnancy associated adverse events 
must be reported as SAE’s, as per SAE reporting procedures 
described above.
12. 
ADMINISTRATIVE
REQUIREMENTS
12.4 Record 
Retention
If the responsible Investigator retires, relocates, or for 
other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred 
to a person who will accept the responsibility.
If an Investigator retires, relocates, or for other reasons 
withdraws from the responsibility of keeping the study 
records, the Institution with which the Investigator is 
associated must transfer the responsibility to another person 
within the Institution.
Clarification of 
responsibilities in the event 
that an Investigator is no 
longer involved with the 
study.
Appendix 2
New Text
See Questionnaire
Addition of a Telephone 
Questionnaire to facilitate 
long term follow up
Amendment 3; 15 October 2008
Applicable 
sections
Original Text
New/Revised Text
Description and Rationale
Global change
Johnson & Johnson Research
JJR
Janssen Cilag Pty Ltd
JC
Change to indicate change in 
Sponsor, effective 01/01/09
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SYNOPSIS
Efficacy 
evaluations
Ongoing analysis of quantitative marking of the gene 
transfer product (OZ1 and LNL6) in peripheral blood 
mononuclear cells (PBMC) will be performed as part 
of the testing of predominant integration sites. These 
marking data will also be analyzed independently of 
the integration analysis to detect changes in the number 
of cells carrying the gene transfer product. In addition 
to safety evaluations, patients may elect to have 
ongoing analysis of quantitative expression of the gene 
transfer product in peripheral blood mononuclear cells 
on an annual basis.
Ongoing analysis of quantitative marking of the gene 
transfer product (OZ1 and LNL6) in peripheral blood 
mononuclear cells (PBMC) will be performed as part of the 
testing of predominant integration sites. These marking data 
will also be analyzed independently of the integration 
analysis to detect changes in the number of cells carrying the 
gene transfer product.
Removal of OZ1 
expressions analysis as the 
assay no longer available. 
TIME & 
EVENTS 
SCHEDULE
Table
Footnotes
Table – row deleted
Footnotes – amended to remove footnote 3
Removal of OZ1 
expressions analysis as the 
assay no longer available. 
Update numbering of 
footnotes.
1. INTRODUCTION 1.1 Background
1.2 Toxicology
1.3 Clinical Experience
1.4 Rationale for Study
1.1 Background
1.2 Rationale for Study
Sections 1.2 (Toxicology) and 
1.3 (Clinical Experience) 
removed as they are covered 
more fully in the Investigators 
Brochure.
Section 1.4 renumbered to 1.2
OBJECTIVES
3. To assess quantitative marking and expression of the 
gene transfer product in PBMCs over time.
3. To assess quantitative marking of the gene transfer 
product in PBMCs over time.
Removal of OZ1 
expressions analysis as the 
assay no longer available.
STUDY 
EVALUATIONS
2 to 5 years post-
Infusion
Annual Visits 
Year 5-15 post 
infusion
Quantitative analysis of PBMC sample for OZ1 RNA 
(RT PCR). 
Quantitative analysis of PBMC sample for OZ1 RNA 
(RT PCR).
Deleted
Deleted
Removal of OZ1 
expressions analysis as the 
assay no longer available.
7.2 Optional 
Efficacy 
Patients will have the option of consenting to the 
collection of additional blood samples for the ongoing 
Deleted section
Removal of OZ1 
expressions analysis as the 
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Evaluation
assessment of OZ1 expression (OZ1 RNA- RTPCR).
assay no longer available.
7.2 Safety 
Evaluation
7.3 Safety Evaluations
7.2 Safety Evaluations
Renumbered section in line 
with above deletion
STATISTICAL 
METHODS
9.1 Efficacy 
Evaluation
Ongoing analysis of quantitative marking of the gene 
transfer product (OZ1 and LNL6) in peripheral blood 
mononuclear cells will be performed as part of the 
testing of OZ1 or LNL6 vector integration sites until 
year 15 post infusion. These data will be used to 
independently assess changes in the number of 
peripheral blood mononuclear cells that carry the gene 
transfer product over time. Patients will have the 
option of consenting to the collection of additional 
blood samples for the ongoing assessment of OZ1 
expression (OZ1 RNA- RTPCR).
Ongoing analysis of quantitative marking of the gene 
transfer product (OZ1 and LNL6) in peripheral blood 
mononuclear cells will be performed as part of the testing of 
OZ1 or LNL6 vector integration sites until year 15 post 
infusion. These data will be used to independently assess 
changes in the number of peripheral blood mononuclear 
cells that carry the gene transfer product over time.
Removal of OZ1 
expressions analysis as the 
assay no longer available.
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Amendment 4; 07 June 2017
Applicable sections
Original Text
New/Revised Text
Description and Rationale
CONTACT 
INFORMATION
Contact details for the sponsor, serious 
adverse event reporting, and appropriate 
sponsor contact personnel.
For the Sponsor: address was updated, central 
emergency number was changed to general 
contact number and a fax number was included. 
For serious adverse event reporting: the office 
phone number and e-mail were updated. For 
appropriate sponsor contact personnel: the 
project physician’s phone number was deleted 
and fax number was updated. The project 
manager’s name and contact details were 
updated.
Updated appropriate details to reflect the 
current contact information 
PROTOCOL 
VERSION 
INFORMATION
Sections of this protocol have been revised. 
Sections marked “” were revised as 
Amendment 1, 23 June 2006. Sections 
marked “#” were revised as Amendment 2, 
28 August 2007. Sections marked “” were 
revised as Amendment 3; 15 October 2008. 
Please refer to Appendix 3 – Protocol 
Amendment History for a detailed 
description of the specific changes.
Sections of this protocol have been revised. 
Amendment 1 was issued on 23 June 2006. 
Amendment 2 was issued on 28 August 2007. 
Amendment 3 was issued on 15 October 2008. 
Sections marked “†” have been revised as 
Amendment 4; 07 June 2017. Please refer to 
Appendix 3 – Protocol Amendment History for 
a detailed description of the specific changes.
The identifiers “”, “#”, and “” for the first 
three protocol amendments were removed 
throughout the text of the protocol 
amendment for improving readability.
SYNOPSIS
Objective
The objective of this study is to evaluate the 
long-term safety of a cell-delivered 
ribozyme gene transfer product (OZ1) in 
patients infected with HIV-1. OZ1 
comprises a Moloney Murine Leukemia 
Virus based retroviral vector (LNL6) 
containing a gene that encodes an anti-HIV 
ribozyme. It is currently a requirement of 
the United States Food and Drug 
Administration (FDA) that all individuals 
receiving retroviral gene transfer products 
are followed for life.
The objective of this study is to evaluate the 
long-term safety of a cell-delivered ribozyme 
gene transfer product (OZ1) in patients infected 
with HIV-1. OZ1 comprises a Moloney Murine 
Leukemia Virus based retroviral vector (LNL6) 
containing a gene that encodes an anti-HIV 
ribozyme. It is currently a recommendation of 
the United States Food and Drug Administration 
(FDA) and Australian Therapeutic Goods 
Administration (TGA) that all individuals 
receiving retroviral gene transfer products are 
followed to collect data on delayed adverse 
events.
This follow up protocol is to monitor the 
long-term safety of OZ1/LNL6 gene transfer 
product in patients who were enrolled in the 
OTH/OZ1-INT-1 study. Based on the 
integrated safety analysis of observations of 
up to 10 years in this LTFU study, up to 15 
years with the same OZ1/LNL6 gene transfer 
product in 2 Phase 1 LTFU studies (OZ1-
HV1-101 and OZ1-HV1-102), and published 
reports of adverse events observed with gene 
therapeutic products using the same type of 
retroviral vector, the sponsor has determined 
that the risk of OZ1/LNL6 gene transfer 
product to patients beyond 10 years post-
infusion is minimal. Accordingly, this long 
term follow up study will conclude by 
30 November 2017.
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SYNOPSIS
Overview of Study 
Design
This will be a follow-up study of patients 
previously enrolled in the OTH/OZ1-INT-1 
trial. All patients in this protocol will be 
reviewed at six monthly intervals until year 
5 post infusion. Thereafter all patients will 
be reviewed annually, on the anniversary of 
the infusion. Patients who were enrolled in 
the placebo arm will be discontinued after 
OTH/OZ1-INT-1 has been unblinded.
This will be a follow-up study of patients 
previously enrolled in the OTH/OZ1-INT-1 
trial. All patients in this protocol will be 
reviewed at six monthly intervals until year 5 
post infusion. Thereafter all patients will be 
reviewed annually, on the anniversary of the 
infusion until withdrawal or study completion. 
Patients who were enrolled in the placebo arm 
will be discontinued after OTH/OZ1-INT-1 has 
been unblinded.
Reference to study completion and 
withdrawal added
SYNOPSIS
Safety Evaluations
Follow-up will be conducted as per 
FDA/Center for Biologics Evaluation and 
Research (CBER) recommendations. 
Evaluations will include monitoring for 
related adverse events such as the 
development of replication competent 
retrovirus (RCR), predominant integration 
sites and insertional oncogenesis. Blood 
samples will be collected for archival 
storage for assessment of replication 
competent retrovirus (RCR) and other 
safety testing as necessary.
Follow-up will be conducted as per current 
FDA/Center for Biologics Evaluation and 
Research (CBER) recommendations. 
Evaluations will include monitoring for related 
adverse events such as the development of 
replication competent retrovirus (RCR), 
predominant integration sites and insertional 
oncogenesis. Blood samples will be collected 
for archival storage for assessment of 
replication competent retrovirus (RCR) and 
other safety testing as necessary.
Specifically mentioned the use of ‘current’ 
FDA recommendations.
TIME & EVENTS 
SCHEDULE
Removed the column “Annual Visit Yr 15+” as 
it is no longer applicable.
Amended to be consistent with modified 
rationale for study section.
Column Heading “Annual Visit Yr 5-15”
Changed to “Annual Yr 5+/End-of-Study
Added footnote 4
End-of-Study assessments will be performed 
after all ongoing patients have been followed up 
for least 10 years post-infusion. End-of-Study 
visits will be completed by 30 November 2017. 
In the event that a patient cannot attend a site 
visit, telephonic follow-up will be an acceptable 
alternative.
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INVESTIGATOR 
AGREEMENT
Replaced the old investigator agreement page 
with a new one.
1. 
INTRODUCTION
1.1 Background
Updated reference citations
1. 
INTRODUCTION
1.2 Rationale for 
Study
Currently FDA/CBER requires lifetime 
follow-up 
of 
participants 
in 
gene 
therapy/transfer studies. The safety of 
patients 
who 
were 
enrolled 
in 
the 
OTH/OZ1-INT-1 study will continue to be 
assessed under this long term follow-up 
protocol.
Food and Drug Administration (FDA)/Center 
for Biologics Evaluation and Research (CBER) 
recommends a 15-year time-period for follow-
up observations. However, CBER also 
recognizes that assessment of risk is a 
continuous process, and the nature and duration 
of follow up observations may be revised 
accordingly.4 This follow up protocol is to 
assess the long-term safety of OZ1/LNL6 gene 
transfer product in patients who were enrolled 
in the OTH/OZ1-INT-1 study. Based on the 
integrated safety analysis of observations up to 
10 years in this LFTU study, up to 15 years with 
the same OZ1/LNL6 gene transfer product in 2 
Phase 1 LTFU studies (OZ1-HV1-101 and 
OZ1-HV1-102), and published reports of 
adverse events observed with gene therapeutic 
products using the same type of retroviral 
vector,2,3,5,6,7,8,10,11,12 the sponsor has determined 
that the risk to OZ1/LNL6 gene transfer product 
to recipients beyond 10 years post-infusion is 
minimal. Accordingly, this long term follow up 
study will conclude by 30 November 2017. This 
completion date represents a minimum of 10 
years follow up following the receipt of 
OZ1/LNL6-modified CD34+ cells.
Amended the duration of follow-up in 
individuals receiving O1/LNL6 gene 
modified products with current FDA 
Guidance dated Nov 2006. “Guidance for 
Industry: Gene Therapy Clinical Trials -
Observing Subjects for Delayed Adverse 
Events”.
Current recommendation is for a 15-year 
time period for follow-up observations. 
However, shorter periods of observation may 
be appropriate in individual trials based on 
supporting evidence. The complete rationale 
for the shortened follow up period is 
provided by FDA in a separate document 
(Gene Therapy Clinical Trials - Observing 
Subjects for Delayed Adverse Events; 
November 2006)
4. COMPLIANCE
1. The semi-annual visit interval is 6 
months 6 weeks (for years 2.5-5). The 
annual visit interval is 12 months 12 
weeks (year 6+).
2. Complete Blood Count/Differential data 
will be obtained specifically as part of the 
follow up procedures for a total of fifteen 
(15) years following the time of the infusion 
in the original phase II study. After this 
1. The semi-annual visit interval is 6 months 6 
weeks (for years 2.5-5). The annual visit 
interval is 12 months 12 weeks (year 5+) 
except the End-of-Study visit. End-of-Study 
assessments will be performed after all ongoing 
patients have been followed up for least 10 
years post-infusion. End-of-Study visits will be 
completed by 30 November 2017. In the event 
that a recipient cannot attend a site visit, a 
Point #1 and Point #2 were amended to 
reflect that the study will complete up to 
fifteen (15) years post-infusion, or 
30 November 2017, whichever occurs first.
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date, complete blood count/differential data 
obtained as part of routine clinic 
assessments will be collected in the study 
CRF on an unscheduled basis. Failure to 
obtain these data will not be considered 
protocol non-compliance.
telephonic follow-up will be an acceptable 
alternative.
2. Complete Blood Count/Differential data will 
be obtained specifically as part of the follow up 
procedures.
7. STUDY 
EVALUATIONS
7.1 Study 
Procedures by Visit
Table 3: Long term follow-up allowed visit 
intervals.
The following footnote was added: Except the 
End-of-Study visit, which will be scheduled at a 
date no later than 30 November 2017.
To keep consistency within the protocol.
In the event that a subject is unable to 
attend the clinic within the allowed visit 
window, a telephone interview can be 
conducted to collect information on 
important medical events since the last 
study visit (or telephone interview). Refer 
to Appendix 2 for the interview 
questionnaire. If the clinical trial site is 
unable to contact the patient directly a 
nominated secondary contact will be 
contacted. A lost or withdrawn patient may 
re-enter this long term follow-up protocol at 
any stage in the future.
In the event that a subject is unable to attend the 
clinic within the allowed visit window, a 
telephone interview can be conducted to collect 
information on important medical events since 
the last study visit (or telephone interview). 
Refer to Appendix 2 for the interview 
questionnaire. If the clinical trial site is unable 
to contact the patient directly a nominated 
secondary contact will be contacted. A patient 
will be considered to be lost-to-follow-up, at 
any stage of the clinical trial, after three failed 
documented attempts (telephone calls, certified 
letters, e-mail requests) to contact either the 
patient or a nominated secondary contact. A lost 
or withdrawn patient may re-enter this long 
term follow-up protocol at any stage up until 
30 November 2017.
Text included to explain when a patient 
would be considered to be lost-to-follow-up.
2 to 5 years post-Infusion
Visits will be at six monthly intervals from 
year 2 to year 5 post-infusion
Annual Visits Year 5+ post infusion and 
End-of-Study visit
Clinical History and Physical 
Examination including a detailed record 
of:
o exposure to possible mutagenic agents 
e.g. radiotherapy or chemotherapeutic 
agents
2.5 to 5.0 years post-infusion
Visits will be at six monthly intervals from year 
2.5 to year 5.0 post-infusion.
Annual Visits Year 5+ post infusion and End-
of-Study visit
Clinical History and Physical Examination 
including a detailed record of:
o exposure to possible mutagenic agents e.g. 
radiotherapy or chemotherapeutic agents
o new malignancies
o new or exacerbated preexisting neurologic, 
LTFU visit headings corrected within the 
subsection-‘Study procedures by visit’. 
Addition of a telephonic follow-up as an 
acceptable End-of study criterion.
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o new malignancies
o new 
or 
exacerbated 
preexisting 
neurologic, rheumatologic, autoimmune 
and hematologic disorders
Complete 
Blood 
Count 
(CBC), 
differential and platelet count.
Archival storage of plasma and PBMC 
samples for safety testing including 
Replication-Competent Retrovirus (RCR) 
as required.
Testing for clonality of OZ1/LNL6 
integration in PBMC samples (PCR) if 
the percentage of cells marked by the 
vector (quantitative OZ1/LNL6 DNA-
PCR) is greater than or equal to 1% of the 
test cell population.
Analysis of quantitative marking of the 
gene transfer product (OZ1 and LNL6) in 
peripheral 
blood 
mononuclear 
cells 
(PBMC) will be performed as part of the 
testing of predominant integration sites. 
These marking data will also be analyzed 
independently of the integration analysis 
to detect changes in the number of cells 
carrying the gene transfer product.
Recording of AEs.
Contact details updated for subject and 
nominated secondary contact.
rheumatologic, autoimmune and hematologic 
disorders
Complete Blood Count (CBC), differential 
and platelet count.
Archival storage of plasma and PBMC 
samples 
for 
safety 
testing 
including 
Replication-Competent Retrovirus (RCR) as 
required.
Testing for clonality of OZ1/LNL6 integration 
in PBMC samples (PCR) if the percentage of 
cells marked by the vector
(quantitative 
OZ1/LNL6 DNA-PCR) is greater than or 
equal to 1% of the test cell population.
Analysis of quantitative marking of the gene 
transfer 
product 
(OZ1 
and 
LNL6) 
in 
peripheral blood mononuclear cells (PBMC) 
will be performed as part of the testing of 
predominant integration sites. These marking 
data will also be analyzed independently of 
the integration analysis to detect changes in 
the number of cells carrying the gene transfer 
product.
Recording of AEs.
Contact details updated for subject and 
nominated secondary contact.
In the event that a recipient does not report for 
an in-person End-of-Study visit, a telephonic 
follow-up will be an acceptable alternative.
Annual Visits Year 5-15 post infusion
Annual Visits Year 5+ post infusion and End-of 
Study visit
Annual Visits Year 15+ post infusion
Deleted
Removed the heading ‘Annual Visits Year 
15+ post infusion’ within the subsection-
‘Study procedures by visit’ as it is not
applicable.
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7. STUDY 
EVALUATIONS
7.2 Safety 
Evaluations
Autopsy
As per the FDA/CBER guidelines or gene 
transfer studies, when a patient dies during 
the long-term follow up, an autopsy will be 
requested to determine the extent of gene 
transfer into bone marrow, spleen, lymph 
nodes and gonadal tissue, as well as any 
potentially transformed tissues (e.g. 
lymphomas, leukemia). A separate 
informed consent for autopsy will be 
requested. Patients may sign the consent for 
autopsy at the time of enrollment. Autopsy 
will not be required for patients randomized 
to placebo (after unblinding of the 
OTH/OZ1-INT-1 trial).
If a patient dies during the long-term follow up, 
an autopsy will be requested to determine the 
extent of gene transfer into bone marrow, 
spleen, lymph nodes and gonadal tissue, as well 
as any potentially transformed tissues (e.g. 
lymphomas, leukemia). A separate informed 
consent for autopsy will be requested. Patients 
may sign the consent for autopsy at the time of 
enrollment. Autopsy will not be required for 
patients randomized to placebo (after 
unblinding of the OTH/OZ1-INT-1 trial).
Request for autopsy will remain, but current 
FDA guidance (Considerations for the 
Design of Early-Phase Clinical Trials of 
Cellular and Gene Therapy Products; June 
2015) does not specify this.
8. PATIENT 
COMPLETION
It is an FDA requirement that individuals 
receiving retroviral gene transfer products 
are followed for life.
Patients must be withdrawn from the study 
if:
They received placebo in the OTH/OZ1-
INT-1 trial. This will only become known 
when the OTH/OZ1-INT-1 study has 
been unblinded. 
They withdraw their consent.
If a patient withdraws, the reason for 
withdrawal is to be documented on the CRF 
and in the source document. A withdrawn 
patient or a patient who was lost to follow-
up can re-enter this long term follow-up 
protocol at any time.
Patients will complete long term follow up with 
an End-of-Study visit to be completed by 
30 November 2017.
Patients must be withdrawn from the study if:
They received placebo in the OTH/OZ1-INT-
1 trial. This will only become known when 
the 
OTH/OZ1-INT-1 
study 
has 
been 
unblinded. 
They withdraw their consent.
If a patient withdraws, the reason for 
withdrawal is to be documented on the CRF and 
in the source document. A withdrawn patient or 
a patient who was lost to follow-up can re-enter 
this long term follow-up protocol at any time up 
until 30 November 2017.
Amended the description of patient 
completion possibilities in accordance with 
the modified Rationale for Study section
9. STATISTICAL 
METHODS
Statistical analysis of data collected during 
the long term follow-up study will be 
performed every 5 years. The primary focus 
of analysis will be descriptive summarizing 
changes over time. Patterns over time will 
be analysed using appropriate techniques. 
Statistical analysis of data collected during the 
long term follow-up study will be performed 
every 5 years. After patients complete an End-of 
Study visit, the final analysis of data will be 
done. The primary focus of analysis will be 
descriptive summarizing changes over time. 
Text highlighting the timing of final analysis 
included.
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Factors associated with quantitative 
changes may be assessed.
Patterns over time will be analysed using 
appropriate techniques. Factors associated with 
quantitative changes may be assessed.
9. STATISTICAL 
METHODS
9.1 Efficacy 
Evaluation
Ongoing analysis of quantitative marking of 
the gene transfer product (OZ1 and LNL6) 
in peripheral blood mononuclear cells will 
be performed as part of the testing of OZ1 
or LNL6 vector integration sites until year 
15 post infusion. These data will be used to 
independently assess changes in the number 
of peripheral blood mononuclear cells that 
carry the gene transfer product over time.
Ongoing analysis of quantitative marking of the 
gene transfer product (OZ1 and LNL6) in 
peripheral blood mononuclear cells will be 
performed as part of the testing of OZ1 or 
LNL6 vector integration sites. These data will 
be used to independently assess changes in the 
number of peripheral blood mononuclear cells 
that carry the gene transfer product over time.
Amended to be consistent with modified 
rationale for study section.
10. ADVERSE 
EVENT 
REPORTING
10.1 Adverse Event 
Definitions and 
Classifications
Adverse Event
An adverse event is any untoward medical 
occurrence in a clinical study subject 
administered a pharmaceutical product. An 
adverse event does not necessarily have a
causal relationship with the treatment. An 
adverse event can therefore be any 
unfavorable and unintended sign (including 
an abnormal finding), symptom, or disease 
temporally associated with the use of a 
medicinal (investigational) product, 
whether or not related to the medicinal 
(investigational) product. (Definition per 
International Conference on Harmonisation 
[ICH]). This includes any occurrence that is 
new in onset or aggravated in severity or 
frequency from the baseline condition, or 
abnormal results of diagnostic procedures, 
including laboratory test abnormalities.
Note: The sponsor collects adverse events 
starting with the signing of the informed 
consent
Adverse Event
An adverse event is any untoward medical 
occurrence in a clinical study subject 
administered a pharmaceutical product. An 
adverse event does not necessarily have a causal 
relationship with the treatment. An adverse 
event can therefore be any unfavorable and 
unintended sign (including an abnormal 
finding), symptom, or disease temporally 
associated with the use of a medicinal 
(investigational) product, whether or not related 
to the medicinal (investigational) product. 
(Definition per International Conference on 
Harmonisation [ICH]). This includes any 
occurrence that is new in onset or aggravated in 
severity or frequency from the baseline 
condition, or abnormal results of diagnostic 
procedures, including laboratory test 
abnormalities.
Note: The sponsor collects adverse events 
starting with the signing of the informed 
consent until completion of the subject’s last 
study related procedure.
The note was amended to be consistent with 
modified rationale for study section.
13. REFERENCES
Updated reference list.
Deleted references that are no longer cited.
Added references: # 2, 3, 4, 5, 6, 7, 8, 9, 10, 
11, and 12
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References are alphabetically ordered and 
renumbered
Appendix 2
Telephone follow-up 
questionnaire
For semi-annual or annual review of 
clinical history
For semi-annual, annual, or end-of-study review 
of clinical history
Added end-of-study to the telephone follow-
up questionnaire title to be consistent.
NCT01177059