A Randomized, Double-Blind, Sham-Controlled Study to Evaluate the Safety and Tolerability of Glutamic Acid Decarboxylase Gene Transfer to the Subthalamic Nuclei in Participants With Parkinson's Disease
Phase: PHASE1
Conditions: Parkinson's Disease
Sponsor: MeiraGTx, LLC

CLINICAL STUDY PROTOCOL
A Randomized, Double-Blind, Sham-Controlled Study to Evaluate 
the Safety and Tolerability of Glutamic Acid Decarboxylase Gene 
Transfer to the Subthalamic Nuclei in Participants with Parkinson’s 
Disease 
Investigational product:
Two recombinant adeno-associated virus (AAV) serotype 2-
glutamic acid decarboxylase (GAD) vectors, GAD65 and 
GAD67, mixed in a 1:1 ratio (AAV-GAD) 
Protocol number:
MGT-GAD-025 
IND number
28482 
Sponsor:
MeiraGTx, LLC
450 East 29th Street
14th Floor 
New York, NY 10016 USA 
Version - date of protocol: v6.0 - 22 Sep 2023 
GCP statement:
This study is to be performed in full compliance with 
International Council for Harmonisation (ICH) of Technical 
Requirements for Pharmaceuticals for Human Use and all 
applicable local Good Clinical Practice (GCP) guidelines and 
regulations. All required study documentation will be archived 
as required by regulatory authorities. 
Confidentiality 
statement:
This document is confidential. It contains proprietary 
information of MeiraGTx (the sponsor). Any viewing or 
disclosure of such information that is not authorized in writing 
by the sponsor is strictly prohibited. Such information may be 
used solely for the purpose of reviewing or performing this 
study. 

AAV-GAD
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CHANGES COMPARED TO PREVIOUS VERSION(S) 
Protocol v6.0 (22 September 2023)  
The changes between protocol Version 6.0 (dated 22 September 2023) and protocol Version 5.0 (dated 
18 July 2023) are highlighted below.  
Version n° and date were adapted throughout the document (including headers and footers). The List of 
Abbreviations was updated and the Section “Changes Compared to Previous Version(s)” was completed. 
Section
Change/Rationale
Section 4.2
Removed exclusion criterion 22, which excluded individuals with poorly controlled 
diabetes (as evidenced by HbA1c >7%). Medically and surgically, these individuals do 
not need to be excluded from this study. 
Protocol v5.0 (18 July 2023)  
The changes between protocol Version 5.0 (dated 18 July 2023) and protocol Version 4.0 (dated 18 January 
2023) are highlighted below.  
Version n° and date were adapted throughout the document (including headers and footers). The Table of 
Contents was updated and the Section “Changes Compared to Previous Version(s)” was completed. 
Section 
Change/Rationale 
Synopsis and 
Section 3.1 
Clarified that the study will be carried out at approximately 5 sites in the United States. 
Schedule of Activities, 
Section 5.5.3, 
Section 5.5.4, 
Section 5.5.6.2, and 
Section 8.8 
The cranial anchor kit will not be removed after completing the infusion. 
Consequently, specific MRI conditions are to be taken into account for post-surgical 
MRI scans and participants are to be provided with a patient implant card.   
Section 4.2 
Exclusion criterion 11 updated to clarify that evidence of lesions or other significant 
abnormalities on cranial neuroimaging suggesting findings compatible with a probable 
diagnosis other than Parkinson’s disease is exclusionary. 
Section 8.2.8
Updated the safety contact information (contact details for reporting of SAEs and 
pregnancies). 
Protocol v4.0 (18 January 2023) 
The changes between protocol Version 4.0 (dated 18 January 2023) and protocol Version 3.0 (dated 
21 September 2022) are highlighted below.  
Version n° and date were adapted throughout the document (including headers and footers). The Table of 
Contents and the List of Abbreviations was updated and the Section “Changes Compared to Previous Version(s)” 
was completed. 
Section 
Change/Rationale 
Synopsis, Section 3.1, 
Section 5.1, Section 5.2, 
Section 5.3, 
Section 5.5.1.1, 
Section 5.5.3, 
Updated to reflect that a total of 14 participants will be randomized to receive either 
AAV-GAD at a dose of 3.5 × 1010 vg/STN (5 participants), AAVGAD at a dose of 
10.45 × 1010 vg/STN (5 participants) or sham surgery (4 participants). The rationale for 
adding a higher dose group is provided in Section 5.2. 

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Section 5.5.4, and 
Section 10.1.6 
Synopsis, Section 2, 
Section 10.1.4.1 
Updated wording on the planned statistical analyses and the endpoints to account for 
the additional dose group. 
Schedule of Activities, 
Section 6.2 
Clarified that during visits that include the MDS-UPDRS assessment, the MDS-
UPDRS Part 3 “off” state assessment should preferably be performed before any other 
assessments or questionnaires. 
Schedule of Activities, 
Section 5.5.5, 
Section 8.5 
To avoid accidental unblinding, the text has been updated to specify all timepoints for 
vital signs assessments in relation to the start of the infusion. Also, the actual volume 
infused will no longer be collected in the CRF. 
Section 1.1, 
Section 1.2, and 
Section 1.3 
Included additional information related to the doses used in the previous clinical 
studies and the doses that will be used in this study. 
Section 4
Clarified that individuals who have not completed the screening assessments within the 
specified time period may be rescreened, after discussion with the Sponsor 
Section 5.6.1 
Text updated to align with the language in the exclusion criteria 
Section 8.2.6.4 
Clarified that the Sponsor will report all information related to serious and unexpected 
adverse reactions to all relevant Competent Authorities 
Section 8.2.8 
Updated the safety contact information. 
Section 12.4 
Clarified that protocol amendments must be submitted to the relevant Competent 
Authorities in accordance with regulatory requirements. 
Protocol v3.0 (21 September 2022)  
The changes between protocol Version 3.0 (dated 21 September 2022) and protocol Version 2.0 (dated 
23 August 2022) are highlighted below.  
Version n° and date were adapted throughout the document (including headers and footers). The Table of 
Contents was updated and the Section “Changes Compared to Previous Version(s)” was completed. 
Section 
Change/Rationale 
Schedule of 
Activities and 
Section 7.3 
Updated to specify that the Hauser Patient Diary should be completed twice per week 
(on 2 non-sequential days) for 3 consecutive weeks prior to the second screening visit 
(Day -7 to Day -3 visit) instead of prior to randomization. 
Section 1.4.2 
Text added to elaborate on the potential risks associated with the Acute Delivery System 
and how they have been mitigated. 
Section 5.5.6.2 
Updated to reflect that following implant and administration of AAV-GAD, all 
components of the Acute Delivery System are to be packaged in a sealed biohazard bag 
and stored until the end of the study when they will either be returned to MeiraGTx or 
designee or allowed to be destroyed. 
Section 8.2.3 
The descriptions of the adverse event causality definitions in Table 3 have been 
corrected. 
Section 8.2.7 
Updated for clarity.  

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Protocol v2.0 (23 August 2022)  
The changes between protocol Version 2.0 (dated 23 August 2022) and protocol Version 1.0 (dated 9 May 
2022) are highlighted below.   
Version n° and date were adapted throughout the document (including headers and footers). The Table of 
Contents was updated and the Section “Changes Compared to Previous Version(s)” was added and completed. 
Section 
Change/Rationale 
Synopsis, Schedule 
of Activities 
To allow sufficient time for study materials to be delivered between randomization and 
the day of the surgery, the screening visit window has been adjusted from Day-40 to 
Day-14 to Day-40 to Day-8 and the window for randomization has been shifted from 
Day-7 to Day-3 to Day-40 to Day-8. Footnote q remains applicable: ‘Randomization will 
occur after all inclusion and exclusion criteria have been met and surgery is scheduled’. 
Schedule of Activities, 
Section 5.5.3, 
Section 5.5.4, 
Section 5.5.6.2, and 
Section 8.8 
The cranial anchor kit will be removed after completing the infusion. A commercially 
available burr hole cover may be used at the neurosurgeon’s discretion to cover the burr 
hole created for the procedure. Consequently, specific MRI conditions are no longer to 
be taken into account for post-surgical MRI scans and participants are no longer to be 
provided with a patient implant card.   
Section 5.5.3 
Wording is added to specify that the pump is to be at approximately the same level as the 
infusion site and is to be maintained at the same height for the duration of the infusion.  

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SYNOPSIS 
Title of study: A Randomized, Double-Blind, Sham-Controlled Study to Evaluate the Safety and 
Tolerability of Glutamic Acid Decarboxylase Gene Transfer to the Subthalamic Nuclei in Participants 
with Parkinson’s Disease 
Study short title: A double-blind study to evaluate the safety of Glutamic Acid Decarboxylase gene 
transfer in participants with Parkinson’s Disease 
Protocol number: MGT-GAD-025 
Study center(s): To be conducted at approximately 5 sites in the United States (US)
Phase of development: 1/2
Objectives:  
The primary objective of this study is to evaluate the safety and tolerability of AAV-GAD delivered 
bilaterally to the subthalamic nuclei (STN) in participants with Parkinson’s disease. 
Study design: Phase 1/2, randomized, double-blind, sham-controlled, safety and tolerability   
Methodology:  
This study is designed to evaluate the safety and tolerability of AAV-GAD administered bilaterally into 
the STN in participants with Parkinson’s disease not adequately controlled with appropriate anti-
Parkinsonian medications.  
The study will be carried out in the US at approximately 5 sites with established and highly experienced 
surgical programs for deep brain stimulation (DBS) treatment of Parkinson’s disease. The principal 
investigators will be neurosurgeons or neurologists with expertise in the assessment and treatment of 
participants with Parkinson’s disease and with strong backgrounds in clinical research. Each site will also 
have support personnel knowledgeable in the care of participants with this disorder. 
After discussion of the study risks and possible benefits with the Investigator, participants will provide 
written informed consent and be considered eligible for the study if they satisfy all inclusion and exclusion 
criteria. Approximately 14 participants will be randomized to receive 1 of 2 doses of AAV-GAD infused 
bilaterally into the STN (5 participants per dose group) or sham surgery (bilateral, partial-thickness, burr 
hole procedure with saline administration; 4 participants) and followed for 6 months. Day 1 will be 
defined as the day of AAV-GAD or sham treatment.  
Safety and tolerability of AAV-GAD gene transfer will be assessed by adverse events (AEs), vital sign 
measurements, neurological examinations, physical examinations, radiographic imaging of the head 
(computed tomography [CT] and magnetic resonance imaging [MRI]), clinical laboratory evaluations, 
electrocardiograms (ECGs), immune response, and the Columbia-Suicide Severity Rating Scale.  
A Data and Safety Monitoring Board (DSMB) will be established for this study to provide expert input on 
safety of the investigational product, surgical procedure, and related issues. 
Participants also will be assessed for potential clinical responses to AAV-GAD on Parkinson’s disease 
signs, symptoms, and disabilities using assessments widely used in Parkinson’s disease research for 
evaluating new medications and surgical procedures.  
Upon completion of this study, participants randomized to receive AAV-GAD treatment will be asked to 
enter a long-term (4.5 year) safety follow-up study (MGT-GAD-026) in accordance with applicable 
regulatory agency guidance for surveillance of participants who receive gene therapy. Participants 
randomized to the sham group in this study will be offered bilateral, open-label treatment with AAV-GAD 

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as part of the long-term follow-up study (pending regulatory approval) and will be followed for 5 years of 
assessments consistent with those participants who received AAV-GAD in study MGT-GAD-025.
Number of participants (planned): Approximately 14 
Diagnosis and main criteria for inclusion: 
The study population will consist of participants with Parkinson’s disease not adequately controlled with 
appropriate anti-Parkinsonian medications. Participants must meet established clinical criteria for 
Parkinson’s disease and meet 18F-deoxyglucose (FDG)-positron emission tomography (PET) criteria for 
idiopathic Parkinson’s disease; have a history of having experienced levodopa responsiveness for at least 
12 months; and 
the MDS-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part 3 (motor examination) while in 
the “off” state (without the benefit of medication).  
In order to qualify for entry into the study, eligible participants must be willing to not receive DBS (or 
initiate other anti-PD treatments) for the 6-month duration of the study.  
Duration of participation: 
After informed consent is obtained, screening assessments should be conducted within the 40 days 
preceding surgery (AAV-GAD treatment or sham). After surgery, participants will be followed for 
6 months in this study. The duration of individual participation will be approximately 7 months. 
Investigational product, dosage and mode of administration:  
AAV-GAD will be administered bilaterally via stereotactic infusion into each STN (1 infusion per 
hemisphere: 2 infusions in total). Each STN will be infused with either 
 × 1012 vg/mL AAV-
GAD, for a dose of 3.5 × 1010 vg/STN or 50 
 of 2.09 × 1012 vg/mL AAV-GAD, for a dose of 
10.45 × 1010 vg/STN. The total dose per participant will be 7.0 × 1010 vg or 20.9 × 1010 vg. AAV-GAD 
 
AAV-GAD is formulated in a buffered solution of KH2PO4, Na2HPO4, NaCl, and MgCl2, with pH 7.4.
The AAV-GAD formulation will be diluted to a concentration of 1x1012 vg/mL (low dose) or used at the 
undiluted concentration of 2.09 x 1012 vg/mL (high dose). 
Reference therapy, dosage and mode of administration:   
Sham surgery. 
Partial-thickness burr holes will be generated to eliminate the risk of intracranial hemorrhage, followed by 
sham physiological mapping of the STN and then saline infusion through catheters inserted into each 
partial-thickness burr hole (no brain infusion). The volume of saline 
 
Criteria for evaluation: 
Safety: 
Safety will be evaluated by vital signs, neurological examinations, physical examinations, 
electrocardiograms, radiographic imaging of the head (CT and MRI), clinical laboratory evaluations, 
descriptive analysis of AEs (including incidence, severity, seriousness, and relatedness), immune 
response, and the Columbia-Suicide Severity Rating Scale over the duration of the study. 
Exploratory activity assessments: 
Assessments of potential activity of AAV-GAD will include the MDS-UPDRS, Parkinson’s disease-
related pattern (PDRP), glutamic acid decarboxylase-related pattern (GADRP), MDS-Unified Dyskinesia 
Rating Scale, Montreal Cognitive Assessment, Parkinson’s Disease Sleep Scale-2, Hauser Patient Diary, 

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TABLE OF CONTENTS 
SPONSOR SIGNATURE ............................................................................................................... 2
INVESTIGATOR’S AGREEMENT .............................................................................................. 2
CHANGES COMPARED TO PREVIOUS VERSION(S) ............................................................ 3
SYNOPSIS ...................................................................................................................................... 6
SCHEDULE OF ACTIVITIES....................................................................................................... 9
TABLE OF CONTENTS .............................................................................................................. 12
List of Tables ................................................................................................................................ 15
List of Abbreviations and Definition of Terms............................................................................. 16
1
INTRODUCTION AND BACKGROUND INFORMATION .............................................. 18
1.1 
Overview of Nonclinical Studies .................................................................................. 19
1.2 
Overview of Clinical Studies ........................................................................................ 19
1.3 
Study Rationale ............................................................................................................. 21
1.3.1
18FDG-PET as a Potential Biomarker of AAV-GAD Treatment Effect ........... 21
1.4 
Benefit/Risk ................................................................................................................... 22
1.4.1
Potential Benefits of AAV-GAD ...................................................................... 22
1.4.2
Potential Risks of AAV-GAD ........................................................................... 23
2
STUDY OBJECTIVES ........................................................................................................... 25
3
STUDY DESCRIPTION ........................................................................................................ 27
3.1 
Summary of Study Design ............................................................................................ 27
4
SELECTION AND WITHDRAWAL OF PARTICIPANTS ................................................. 28
4.1 
Inclusion Criteria ........................................................................................................... 28
4.2 
Exclusion Criteria .......................................................................................................... 29
4.3 
Withdrawal Criteria ....................................................................................................... 31
4.4 
End of Study .................................................................................................................. 31
5
STUDY TREATMENTS ........................................................................................................ 32
5.1 
Treatment Groups .......................................................................................................... 32
5.2 
Rationale for Dosing ..................................................................................................... 32
5.3 
Randomization and Blinding ......................................................................................... 34
5.4 
Breaking the Blind ........................................................................................................ 34
5.5 
Treatment Supplies ........................................................................................................ 35

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5.5.1
AAV-GAD ........................................................................................................ 35
5.5.2
Acute Delivery System ...................................................................................... 35
5.5.3
AAV-GAD Administration and Surgery Procedure ......................................... 36
5.5.4
Saline Administration and Sham Surgery Procedure ........................................ 37
5.5.5
Treatment Compliance ...................................................................................... 38
5.5.6
Labeling, Storage, and Accountability .............................................................. 38
5.6
Prior and Concomitant Medications and/or Procedures ................................................ 39
5.6.1
Excluded Medications and/or Procedures ......................................................... 39
5.6.2
Restricted Medications and/or Procedures ........................................................ 39
5.6.3
Allowed Medications and/or Procedures .......................................................... 40
5.6.4
Documentation of Prior and Concomitant Medication Use .............................. 40
6
STUDY PROCEDURES AND VISITS ................................................................................. 41
6.1 
Informed Consent .......................................................................................................... 41
6.2 
Study Procedures ........................................................................................................... 41
6.3 
Early Termination Visit and Withdrawal Procedures ................................................... 42
7
EFFICACY ASSESSMENTS ................................................................................................ 43
7.1 
18FDG-PET .................................................................................................................... 43
7.2 
Questionnaires and Scales ............................................................................................. 43
7.3 
Hauser Patient Diary ..................................................................................................... 45
8
SAFETY ASSESSMENTS ..................................................................................................... 47
8.1 
Data and Safety Monitoring Board ............................................................................... 47
8.2 
Adverse Events .............................................................................................................. 47
8.2.1
Seriousness Assessment .................................................................................... 48
8.2.2
Assessment of Severity ..................................................................................... 48
8.2.3
Assessment of Causality .................................................................................... 48
8.2.4
Assessment of Expectedness ............................................................................. 49
8.2.5
Clinical Laboratory Abnormalities .................................................................... 49
8.2.6
Safety Reporting Requirements ........................................................................ 50
8.2.7
Special Situation Reports .................................................................................. 52
8.2.8
Safety Contact Information ............................................................................... 53
8.3 
Physical and Neurological Examinations ...................................................................... 53
8.4 
Clinical Safety Laboratory Evaluations ........................................................................ 53

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8.5 
Vital Sign Measurements .............................................................................................. 54
8.6 
Electrocardiogram ......................................................................................................... 54
8.7
Immune Response ......................................................................................................... 54
8.8
Radiographic Imaging ................................................................................................... 55
8.9 
Blood Volume ............................................................................................................... 55
9
DATA COLLECTION AND MANAGEMENT .................................................................... 56
9.1
Data Collection, Management and Entry ...................................................................... 56
10 STATISTICAL ANALYSES ................................................................................................. 57
10.1 Statistical Methods ........................................................................................................ 57
10.1.1 General Considerations ..................................................................................... 57
10.1.2 Analysis Populations ......................................................................................... 57
10.1.3 Analysis of Safety ............................................................................................. 57
10.1.4 Analysis of Efficacy .......................................................................................... 58
10.1.5 Interim Analysis ................................................................................................ 58
10.1.6 Sample Size Determination ............................................................................... 58
11 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ..................................................... 60
11.1 Study Monitoring .......................................................................................................... 60
11.2 Audits and Inspections .................................................................................................. 60
11.3 Direct Access to Participant Records ............................................................................ 61
11.4 Institutional Review Board/Independent Ethics Committee ......................................... 61
11.5 Trial Oversight .............................................................................................................. 61
12 ETHICS................................................................................................................................... 62
12.1 Ethical Conduct of the Study ........................................................................................ 62
12.2 Written Informed Consent ............................................................................................. 62
12.3 Confidentiality ............................................................................................................... 62
12.4 Protocol Amendments ................................................................................................... 62
13 DATA HANDLING AND RECORDKEEPING ................................................................... 63
13.1 Inspection of Records .................................................................................................... 63
13.2 Retention of Records ..................................................................................................... 63
13.3 Publication of Study Data ............................................................................................. 63
14 REFERENCES ....................................................................................................................... 65
Appendix: Guidance on Study Conduct during the COVID-19 Pandemic .................................. 66

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LIST OF TABLES 
Table 1:
Schedule of Activities ................................................................................................... 9
Table 2: 
Adverse Event Definitions .......................................................................................... 47
Table 3: 
Adverse Event Causality Definitions .......................................................................... 49
Table 4:
Clinical and Safety Related Laboratory Tests ............................................................ 53
Table 5:
Approximate Volume of Blood to be Collected ......................................................... 55
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
AAV 
adeno-associated virus
AAV2 
adeno-associated virus serotype 2 
AAV-GAD
The investigational product: Two recombinant adeno-associated virus (AAV) 
serotype 2-glutamic acid decarboxylase (GAD) vectors, GAD65 and GAD67, 
mixed in a 1:1 ratio (AAV-GAD) 
ADL 
activities of daily living 
ADR
adverse drug/device reaction
AE
adverse event
AR 
Adverse Reaction
CI 
confidence interval
CMO 
Contract Manufacturing Organization
CNS 
central nervous system 
COVID-19 
Coronavirus Disease 2019
CRO 
Contract Research Organization 
CT 
computed tomography 
DBS 
deep brain stimulation
DKEFS 
Delis–Kaplan Executive Function System
DNA 
deoxyribonucleic acid
DSMB
Data and Safety Monitoring Board
ECG 
Electrocardiogram
eCRF
electronic case report form
EDC 
electronic data capture
EW
early withdrawal
FDA 
Food and Drug Administration
FDG 
18fluorodeoxyglucose
GABA
gamma-aminobutyric acid 
GAD 
glutamic acid decarboxylase
GADRP 
glutamic acid decarboxylase-related pattern 
GCP 
Good Clinical Practice
GPi 
globus pallidus internal segment 
HVLT-R 
Revised Hopkins Verbal Learning Test 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH
International Council for Harmonisation
IFU
Instructions for Use
IND 
Investigational New Drug

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Abbreviation 
Definition 
INR
international normalized ratio
IRB/IEC
institutional review board/independent ethics committee
ITT
Intention-to-Treat
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed model for repeated measures 
MoCA 
Montreal Cognitive Assessment 
MP 
Monitoring Plan
MPTP
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
MRI
magnetic resonance imaging
MSA
multiple system atrophy
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHP 
nonhuman primate 
NOAEL 
No Observed Adverse Effect Level
PDRP 
Parkinson's disease-related pattern 
PET 
positron emission tomography 
PSP 
progressive supranuclear palsy
PTT 
partial thromboplastin time
RSI 
Reference Safety Information
SAE 
serious adverse event
SAP
Statistical Analysis Plan 
SAR 
serious adverse reaction (device or drug)
SNpc
substantia nigra pars compacta
SNr
substantia nigra pars reticulata
SoA 
Schedule of Activities
STN 
subthalamic nuclei(us)
SUSAR
suspected unexpected serious adverse reaction
TMT
Trail Making Test
UK
United Kingdom
ULN 
upper limit of normal
UPDRS
Unified Parkinson’s Disease Rating Scale 
MDS-UPDRS 
Movement Disorder Society-Sponsored Revision of the UPDRS 
US 
United States 
UV
Unscheduled visit
WOCBP 
women of childbearing potential 

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1
INTRODUCTION AND BACKGROUND INFORMATION  
This is a Phase 1/2, randomized, double-blind, sham-controlled study to evaluate the safety and 
tolerability of AAV-GAD delivered bilaterally to the subthalamic nucleus (STN) in participants
with Parkinson’s disease.  
Parkinson’s disease is a neurodegenerative disorder with characteristic impairments of motor 
function such as slowed movement, impaired dexterity, gait disturbance, tremors, and rigidity of 
muscles. These clinical features are associated with progressive loss of neurons in the midbrain, 
particularly the substantia nigra pars compacta (SNpc). The net effect is a disruption of basal 
ganglia activity and downstream brain networks that control movement and possibly other 
neurological functions, including cognitive function and autonomic regulation.   
The loss of dopamine signaling in Parkinson’s disease leads to dysregulation of the STN due to a 
reduction in GABA inputs to this structure, resulting in excessive STN mediated activation of 
GPi/SNpr outflow, which increases the inhibitory brake on the thalamus. Loss of dopamine also 
leads to a decrease in GABA-mediated inhibition of GPi/SNr, further exacerbating the excessive 
basal ganglia outflow inhibition of the thalamus. This inhibition of the thalamus underlies the 
motor symptoms characteristic of Parkinson’s disease. 
Early in the course of Parkinson’s disease, dopaminergic replacement therapy and other 
medications are sufficient for marked symptomatic improvement of the motor deficits, which are 
the major source of disability for these patients. Facilitation of dopaminergic neurotransmission 
benefits most patients early in the disease, but generally requires both increasing drug doses and a 
move to more complex polytherapy, yet still targeting the dopaminergic pathway. As the disorder 
advances and brain physiology changes in response to chronic medication exposure, drug-related 
complications develop and often cause significant disability, such as disabling dyskinesias and 
motor fluctuations. Thus, almost all Parkinson’s disease patients reach a stage sometime after the 
initiation of treatment where their symptoms cannot be adequately controlled with current therapy.  
The development of these complications, among other factors, are among the primary reasons why 
patients with moderate to advanced Parkinson’s disease and their physicians consider surgical 
intervention to reduce symptoms and improve function.  
Gene therapy, consisting of the adeno-associated virus (AAV)-mediated delivery of the glutamic 
acid decarboxylase (GAD) 65/67 complementary DNAs into the intrinsic neurons of the STN, 
provides a therapeutic strategy to restore normal outflow of the basal ganglia to improve motor 
function. Glutamic acid decarboxylase is the rate-limiting enzyme for GABA production with 
inhibitory neurons expressing both GAD65 and GAD67 isoforms that serve complementary and 
synergistic roles in regulation of brain excitability. AAV-GAD comprises 2 recombinant 
AAV-GAD vectors, GAD65 and GAD67, mixed in a 1:1 ratio. 
AAV-GAD drives expression of GAD in the transduced cells of the STN, which catalyzes the 
enzymatic conversion of glutamate to GABA. This restores the more normal glutamate/GABA 
balance in both the STN and its efferent targets, the GPi/SNr. Nonclinical evidence suggests that 

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increased STN activity (more abnormal activity) leads to increased GABA release to regulate this 
circuitry. As a result, the activity of downstream thalamocortical networks is normalized in an 
autoregulatory fashion, leading to improved motor function. 
1.1 
OVERVIEW OF NONCLINICAL STUDIES 
Pharmacology 
and 
toxicology 
studies 
utilizing 
behavioral, 
electrophysiological, 
immunohistochemical, and imaging endpoints demonstrated that AAV-GAD injections into the 
STN of both rats and rhesus monkeys provided benefit in traditional Parkinson’s disease models, 
consistent with the proposed mechanism of action. The original development and characterization 
of AAV-GAD in nonclinical models was carried out in 6-hydroxydopamine–lesioned 
Parkinsonian rats and demonstrated both phenotypic correction of motor deficits and 
neuroprotection of dopamine neurons (Luo et al. 2002). This study also demonstrated that more 
abnormally increased STN activity resulted in increased GABA release to the basal ganglia 
outflow nuclei, suggesting an autoregulatory component to this gene therapy. The approach was 
then generalized to a study in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated 
Parkinsonian nonhuman primates (NHPs), i.e., rhesus monkeys (Emborg et al. 2007), that provided 
further proof of concept and supported clinical translation. These MPTP-treated Parkinsonian 
NHPs received 20 L of 6×1012 vg/mL AAV-GAD into the STN. This dose represents, based on 
the relative STN neuronal numbers in rhesus monkeys (approximately 150,000 neurons) versus 
the human STN (560,000 neurons) (Hamani et al. 2004), a 12-fold multiple of the dose used in the 
subsequent Phase 2 study discussed below, and a 12-fold or 4-fold multiple of the low and high
doses to be administered in this study, respectively. This dose was well tolerated, and no acute or 
long-term toxicity was observed. The monkeys remained in good health throughout the 12-month 
duration of the study, and there was no evidence of any inflammatory responses on postmortem 
analysis. 
1.2
OVERVIEW OF CLINICAL STUDIES
Following the successful proof of concept of STN administration of AAV-GAD in the nonclinical 
models, a Phase 1, first-in-human, unilateral treatment, dose escalation study was conducted 
(Kaplitt et al. 2007). In this open-label study, 12 participants with advanced Parkinson’s disease
had AAV-GAD in a final volume of 50 
delivered to one STN. This allowed the untreated side 
to serve as a control. Participants were divided into 3 equal groups, with the low dose group 
receiving a total of 3.5x109 vg, the middle dose group receiving 1.05x1010 vg and the high dose 
group receiving 3.5x1010 vg. Data from this Phase 1 study showed treatment with AAV-GAD to 
be well tolerated and safe, with improved motor function contralateral to the treated hemisphere. 
18F-deoxyglucose-positron emission tomography (18FDG-PET), performed by an Investigator 
blinded to the side that was treated, demonstrated improvement in abnormal thalamic metabolism 
only in the treated hemisphere, thereby providing objective biological support for the clinical 
efficacy observations (Feigin et al. 2007). 

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Following completion of the Phase 1 study, a randomized, double-blinded, sham surgery, 
controlled, multicenter, Phase 2 study was conducted. In this study, 22 participants were 
randomized to 
-GAD (1×1012 vg/mL concentration) per hemisphere for 
a dose of 3.5×1010 vg (7.0×1010 vg total dose to the participant), and 23 participants were 
randomized to a sham surgery procedure. Of the 23 sham participants, 14 participants subsequently 
received AAV-GAD in the open-label phase of the study prior to premature discontinuation of the 
study and IND inactivation (LeWitt et al. 2011).  
Data from the Phase 1 and 2 studies confirmed that treatment with AAV-GAD was both well 
tolerated and safe, with no serious adverse events (SAEs) related to the gene transfer or to the 
surgical procedure (Kaplitt et al. 2007, LeWitt et al. 2011, Niethammer et al. 2017).  
In both the Phase 1 and Phase 2 studies, treatment with AAV-GAD led to statistically significant 
improvements in the primary efficacy endpoint, the Unified Parkinson’s Disease Rating Scale 
(UPDRS) Part 3 (motor examination) score in the “off” state. Improvement was observed at 
3 months and continued for the duration of the study (12 months). In the Phase 2 study, the mean 
improvement in the “off” state UPDRS Part 3 (motor examination) scores was statistically 
significantly greater than that achieved in the sham surgery group at the primary blinded endpoint 
of 6 months and continued through 12 months (LeWitt et al. 2011, Niethammer et al. 2017). There 
was also a significantly greater percentage of clinically meaningful responders, defined as 9 points 
or greater in UPDRS Part 3 improvement, in the AAV-GAD group compared with the sham group 
at both 6 and 12 months (Niethammer et al. 2017). The Phase 2 study also noted improvements in 
the amount of time spent dyskinetic as well as ON time per day throughout the 12-month follow-
up (Niethammer et al. 2017).  
The Phase 2 study further identified a unique 18FDG-PET brain network pattern associated with 
response to AAV-GAD therapy, involving the generation of new polysynaptic functional pathways 
linking the STN to the motor cortical regions (Niethammer et al. 2018). This new 18FDG-PET 
metabolic network is termed the GAD-related pattern (GADRP) and is quantified using a z-scale 
unit score. This network was defined in an unbiased fashion while the data were blinded, using 
mathematical modeling to identify patterns which might distinguish AAV-GAD from sham. While 
AAV-GAD-treated participants showed significant and substantial changes in the GADRP at both 
6 and 12 months, the sham-treated participants showed no significant changes in GADRP at either 
timepoint. Additionally, there was a strong positive correlation between the change in UPDRS 
Part 3 score and the change in GADRP. These data indicate that GADRP is an objective biomarker
of Parkinson’s disease brain network changes that is both specific to AAV-GAD-treated 
participants and reflective of clinical improvement.  
Following identification of the GADRP in the Phase 2 study imaging data, the GADRP was also 
retrospectively quantified using the 18FDG-PET data from the Phase 1 study, blinded to treatment 
dose. The 18FDG-PET pattern unique to AAV-GAD treatment in the Phase 2 study was confirmed 
in the Phase 1 high-dose participants (same dose used in each STN in the Phase 2 study) but not 
in the lower-dose cohorts. These results help to both confirm the validity of the GADRP, since it 

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was found to be present in Phase 1 participants treated long before the GADRP was first identified, 
and demonstrates the robustness of the GADRP, since it was present in 2 different clinical studies 
of AAV-GAD performed years apart at different clinical centers using different stocks of 
AAV-GAD.  
In summary, Phase 1 and Phase 2 clinical studies have demonstrated safety and efficacy of 
AAV-GAD treatment in participants with Parkinson’s disease (Feigin et al. 2007, Kaplitt et al. 
2007, LeWitt et al. 2011, Niethammer et al. 2017). Efficacy was determined by a significant 
reduction in the UPDRS Part 3 (motor examination) score in the “off” state. In addition, treatment 
with AAV-GAD therapy was associated with a unique brain network defined by 18FDG-PET 
(Niethammer et al. 2018). There was a strongly positive correlation between the change in UPDRS 
score and the change in this AAV-GAD -induced 18FDG-PET pattern (GADRP). This pattern was 
not observed in the sham surgery control group.  
1.3
STUDY RATIONALE 
Based on the encouraging findings from nonclinical and Phase 1 and 2 clinical 
studies, MeiraGTx is proposing to conduct a new Phase 1/2 clinical study (MGT-GAD-025) of 
AAV-GAD infusion into human Parkinson’s disease participants with inadequate medication 
responses. This study will use AAV-GAD manufactured using new optimized processes that meet 
current FDA standards. As a result, it is necessary to first evaluate the safety and tolerability of 
AAV-GAD produced with this new method prior to conducting any further studies. This new 
process will use the same vector used in the prior Phase 1 and 2 studies and participants treated 
with the low dose will receive the same dose used in the prior Phase 2 study. Data from NHPs and 
other nonclinical toxicology studies established a no observed adverse effect level (NOAEL) with 
a safety margin of >4 to 5-fold the high dose in this current MGT-GAD-025 study.     
1.3.1 
18FDG-PET as a Potential Biomarker of AAV-GAD Treatment Effect
18FDG-PET will be used in the screening process to exclude participants with atypical forms of 
Parkinson’s disease most commonly misdiagnosed as idiopathic Parkinson’s disease, i.e., those 
with multiple system atrophy (MSA) or progressive supranuclear palsy (PSP) (Tang et al. 2010). 
18FDG-PET measures the uptake of radiolabeled, peripherally administered glucose in brain tissue, 
providing an index of the relative activity of neurons within a region or in a network of regions. 
Therefore, the abnormalities in brain network activity can be evaluated with this imaging 
technique, and biological changes in brain function can be objectively measured following 
interventions.  
Baseline 18FDG-PET scans will be assessed using an automated differential diagnosis algorithm 
based on previously identified disease-specific brain networks diagnostic of idiopathic PD to 
exclude participants with “lookalike” disorders such as multiple system atrophy and progressive 
supranuclear palsy (Tang et al. 2010, Tripathi et al. 2016, Rus et al. 2020). Scans will also be 
evaluated for GADRP in a double-blind fashion at baseline and at 6 months after study drug 
administration as an exploratory evaluation for potential correlates of efficacy.  

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1.4
BENEFIT/RISK
1.4.1 
Potential Benefits of AAV-GAD
Early in the course of Parkinson’s disease, medications enhancing dopaminergic 
neurotransmission are sufficient for achieving symptomatic improvement of most clinical features. 
Facilitation of dopaminergic signaling continues to benefit most patients, but as the disorder 
advances, higher and/or more frequent doses of dopaminergic drugs are required, as well as 
increased numbers of medications, and there is an increasing chance for patients to develop drug-
related complications such as involuntary movements (dyskinesias), increased off times and motor 
fluctuations. As a result, Parkinson’s disease usually progresses, and patients typically worsen and 
become less responsive to dopaminergic medication while developing adverse effects of medical 
therapy. When patients have disabling motor symptoms that no longer respond adequately to 
medical therapy and/or have complications of medical therapy, such as dyskinesias or motor 
fluctuations, medical options are limited. 
Surgical options for these more advanced patients include destructive lesioning of the STN (i.e., 
subthalamotomy) or deep brain stimulation (DBS) of the STN to reduce excessive excitatory 
glutamatergic drive from STN projection neurons. However, subthalamotomy is permanent and 
can adversely affect critical nearby white matter connections. It is often not well tolerated when 
administered bilaterally, which is usually required for most patients. Deep brain stimulation is 
better tolerated than subthalamotomy as it modulates STN activity rather than destroying STN 
neurons. However, electrical stimulation from DBS is not specific to STN neurons and can also 
influence nearby white matter connections, leading to dose-limiting adverse effects such as speech 
and swallowing problems, sensory changes, and gait dysfunction.  
Although DBS is effective and the current standard of care for patients who do not respond 
adequately to medications, the procedure has many limitations which complicate the patient’s 
experience and limit access to therapy. Since DBS requires installation of electrodes into the brain 
and an implanted electrical stimulator, there is risk of inflammation, hardware-related infections, 
wound breakdown or skin erosion and pain from scarring, or skin sensitivity from the subcutaneous 
hardware. Patients must undergo 2 surgeries, the first to implant the brain electrode and a second 
to implant the pulse generator, with the second procedure usually performed under general 
anesthesia to facilitate tunneling of lead extensions. Patients must live in reasonable proximity to 
a DBS center, since most require frequent visits to reprogram and optimize DBS therapy for several 
months after surgery and periodic follow-ups indefinitely after the initial programming period. The 
DBS pulse generators also have a limited life span and must be replaced after some time. Finally, 
DBS is a local therapy that is designed to influence only the target structure and does not directly 
influence the basal ganglia circuitry, which controls movement beyond local effects on the STN. 
The AAV-GAD gene therapy described in this protocol offers a method to increase GAD activity 
in the STN, enhance GABA production within the STN to reduce abnormal activity and release 
GABA downstream through STN projections to GPi/SNr. This improves the neurochemistry and 

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neuronal activity of all these structures, normalizing basal ganglia outflow and restoring motor 
function. Furthermore, AAV-GAD has the potential to overcome many of the limitations of DBS. 
Unlike DBS, AAV-GAD treatment requires only one routine stereotactic surgery, carried out 
under local anesthesia with no need for general anesthesia. No equipment is required to be 
permanently implanted in the brain, and there is no need for burdensome and lengthy post-surgical 
optimization of therapy. AAV-GAD treatment therefore avoids the potential risk of indwelling 
hardware-related infections. In both the Phase 1 and 2 studies, AAV-GAD led to clinical benefits 
in motor function without the need for ongoing management or adjustment of the therapy, and it 
was confirmed that AAV-GAD was both well tolerated and safe, with no SAEs related to the gene 
transfer. AAV-GAD is also infused into the STN, which is the most common target for Parkinson’s 
disease surgery, so the procedure to identify and insert an infusion catheter into the STN is standard 
and has been utilized for decades in surgery for Parkinson’s disease.  
1.4.2 
Potential Risks of AAV-GAD
Most of the participants in this study will be candidates for bilateral STN DBS. The bilateral 
administration of AAV-GAD into the STN is not expected to preclude any other Parkinson’s 
disease treatment option if it fails to achieve clinically meaningful improvements. Yet it is 
theoretically possible that the passage of the infusion catheter into the STN could induce scar tissue 
that could jeopardize future DBS electrode positioning in that structure. However, there is prior 
experience of carrying out repeated DBS electrode placement in the same location. For example, 
a DBS system is sometimes removed due to refractory infection and reinserted several months 
later, after the infection clears. This is analogous to removal of the catheter followed by 
implantation of a DBS system in the future. The results from these experiences do not indicate that 
the second procedure poses an increased risk of complications. Three of 12 participants in the 
Phase 1 study experienced suboptimal long-term responses to unilateral gene therapy and 
progression of disease in the untreated hemisphere and subsequently underwent bilateral DBS-
STN approximately 18 months later with no reported adverse events (AEs). 
The risks associated with placement of the infusion catheter are similar to those that occur with 
the placement of depth electrodes for DBS. Implanting the infusion catheter carries the following 
risks also associated with other brain surgery procedures: paralysis, coma, and/or death; stroke; 
cerebrospinal fluid leakage; seizures; allergic response to implanted materials; reaction to 
anesthetic agents; nausea and/or vomiting; temporary or permanent neurological complications; 
confusion or attention deficits; pain or swelling at surgical sites; and headache/migraine. The DBS 
technique has a complication rate of approximately 1% for hemorrhage locally in the path of the 
electrodes. The risk for an operation-related infection is also possible; however, removal of all 
introduced equipment following gene therapy infusion is expected to reduce the possibility of 
hardware-related infections and other wound complications that occur with permanently implanted 
hardware.  The acute delivery system for infusion of AAV-GAD is investigational. There are 
potential risks of catheter migration leading to off-target infusion and pump or other unexpected 
system malfunction that could lead to delivery of less or more AAV-GAD than the intended 
delivery volume.  Appropriate risk control measures were implemented to mitigate these risks and 

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their effectiveness verified through engineering tests. These measures include the use of a 
breakaway connector to avoid accidental catheter movement and the use of a preset torque 
screwdriver to ensure a leak-free connection with the syringe. Patency checks are to be performed 
before and after each infusion to provide confirmation of the functionality of each infusion device 
that is used. 
Adverse events reported during the Phase 1 study included headache (4 participants), nausea 
(1 participant), fatigue (1 participant), pain at the site of incision (1 participant), and subdural fluid 
collection (1 participant). These AEs were reported as unrelated to AAV-GAD. There were no 
deaths in the study. Three participants had SAEs (i.e., a hospitalization for a freezing episode in 
acapone, a COPD exacerbation, and arthroscopic knee surgery), 
which were reported as unrelated to AAV-GAD or procedures and resolved. Additionally, there 
were no clinically significant laboratory abnormalities, and there were no measured changes in 
antibody titers to either the virus or transgene in any participant. 
Adverse events reported during the 12-month duration of the Phase 2 study included headache 
(7 AAV-GAD and 2 sham participants), nausea (6 AAV-GAD, 2 sham), depression 
(4 AAV-GAD, 2 sham), and worsening of Parkinsonism (8 sham participants). Other AEs reported 
in at least 2 participants in either group were influenza, sinusitis, incision site complication, 
muscular weakness, hypoesthesia, insomnia, and rash. The AEs were mostly mild and resolved. 
During the 6-month blinded phase of the study, 1 SAE was reported (i.e., bowel obstruction in a 
participant in the AAV-GAD treatment group). This event resolved and was classified as unrelated 
to AAV-GAD or the surgical procedure. 
Nonetheless, there remains the possibility of an unanticipated reaction to the vector produced using 
the new method despite all the prior human safety data, which is the justification for this new 
Phase 1/2 study. Similarly, even though AAV-GAD was well tolerated previously, there is still the 
possibility of an unanticipated response to GAD expression within the STN, which might be 
controlled by medication adjustment or, in an extreme situation, DBS or even subthalamotomy to 
remove the source of GAD production. It is possible that even these may not be fully effective at 
resolving any unexpected AE, particularly if this is due to an inadvertent off-target infusion of 
AAV-GAD. The risk of permanent complication from off-target surgery is common to any gene 
therapy, cell therapy, or lesioning procedure and is not unique to AAV-GAD, although in both 
animal and human studies, there has been no evidence of SAEs related to off-target infusion of 
AAV-GAD other than inadequate therapeutic responses.  

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STUDY DESCRIPTION 
3.1
SUMMARY OF STUDY DESIGN 
This is a Phase 1/2, randomized, double-blind, sham-controlled study designed to assess the safety 
and tolerability of AAV-GAD administered bilaterally into the STN in participants with 
Parkinson’s disease not adequately controlled with appropriate anti-Parkinsonian medications.  
The study will be carried out in the US at approximately 5 sites with established and highly 
experienced surgical programs for DBS treatment of Parkinson’s disease. The principal 
investigators will be neurosurgeons or neurologists with expertise in the assessment and treatment 
of participants with Parkinson’s disease and with strong backgrounds in clinical research. Each 
site will also have support personnel knowledgeable in the care of participants with this disorder. 
Approximately 14 eligible participants will be randomized to receive 1 of 2 doses of AAV-GAD 
infused bilaterally into the STN (5 participants per dose group) or sham surgery (bilateral partial-
thickness burr hole procedure) (4 participants) and followed for 6 months.  
After discussion of the study risks and possible benefits with the Investigator, participants will 
provide written informed consent and be considered eligible for the study if they satisfy all 
inclusion and exclusion criteria. Day 1 will be defined as the day of AAV-GAD or sham treatment.  
Safety and tolerability of AAV-GAD gene transfer will be assessed by AEs, vital sign 
measurements, neurological examinations, physical examinations, radiographic imaging of the 
head (computed tomography [CT] and magnetic resonance imaging [MRI]), clinical laboratory 
evaluations, electrocardiograms (ECGs), immune response, and the Columbia-Suicide Severity 
Rating Scale.  
A Data and Safety Monitoring Board (DSMB) will be established for this study to provide expert 
input on safety of the investigational product, surgical procedure, and related issues. 
Participants will also be assessed for potential clinical responses of AAV-GAD on Parkinson’s 
disease signs, symptoms, and disabilities using assessments widely used in Parkinson’s disease
research for evaluating new medications and surgical procedures.  
Upon completion of this study, participants randomized to receive AAV-GAD treatment will be 
asked to enter a long-term (4.5 year) safety follow-up study (MGT-GAD-026) in accordance with 
applicable regulatory agency guidance for surveillance of participants who receive gene therapy. 
Participants randomized to the sham group in this study will be offered bilateral, open-label 
AAV-GAD treatment as part of the long-term follow-up study (pending regulatory approval) and 
will be followed for 5 years of assessments consistent with those participants who received AAV-GAD 
in study MGT-GAD-025. 

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4
SELECTION AND WITHDRAWAL OF PARTICIPANTS
Participants who meet all inclusion criteria and none of the exclusion criteria will be eligible to 
participate in the study.  
Individuals who do not meet the criteria for participation in this study (screen failure) or 
individuals who have not completed the screening assessments within the specified time period 
may be rescreened, after discussion with the Sponsor. Rescreened participants will be assigned a 
new participant number. Those tests that require repetition will be repeated, as needed, upon the 
agreement of the Sponsor. 
4.1
INCLUSION CRITERIA 
1.
Male or female
2. 
Age 25 to 85 years, inclusive. 
3. 
Must sign an informed consent form (ICF) (or their legally acceptable representative must 
sign) indicating that he or she understands the purpose of, and procedures required for the 
study and is willing to participate in the study and consider participation in the long-term 
follow-up study.  
4. 
Diagnosis of probable idiopathic Parkinson’s disease by United Kingdom Parkinson’s 
Disease Society Brain Bank criteria and no evidence of another Parkinsonian disorder. 
5. 
Completed cranial MRI and 18FDG-PET during Screening. MRI and 18FDG-PET scans 
obtained during Screening will be used as baseline tests and will be reviewed to verify the 
diagnosis of Parkinson’s disease. 
6.
Presence of typical features of Parkinson’s disease and history of levodopa responsiveness 
demonstrated for at least 12 months prior to Screening. 
7. 
Progressive Parkinsonian disability with demonstrated response from continued use of 
levodopa (or from other Parkinson’s disease medications if part of the treatment regimen), 
but with insufficient response to medication (e.g., uncontrolled tremors, increased off-time, 
decreased on-time, motor fluctuations, dyskinesias, gait disturbance) or with intolerable 
side effects as judged by the Investigator. 
8. 
Severe disability, which includes a practically defined “off” state MDS-UPDRS Part 3 
(motor examination) score of 25 points after overnight omission of all Parkinson’s disease 
medications. 
9. 
Continued use of an unchanged stable anti-Parkinsonian drug regimen for 
 weeks prior 
to Screening. 
10. 
Willingness to not add any new treatments for Parkinson’s disease for the duration of the 
6-month study period. Adjustments in the dose of dopaminergic medications are permitted 
when medically indicated. 
11. 
Agrees not to participate in another interventional study until completion of this study and 
the long-term follow-up study.   

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12.
Willingness to not receive DBS or any other approved or experimental surgical therapy for 
PD during the 6-month study period. 
13. 
Receiving stable doses of other medications for any other underlying medical conditions
for 4 weeks prior to Screening. 
14.
Must demonstrate a full understanding of the Hauser Patient Diary rating criteria and 
demonstrate proficiency in completing the diary by reaching at least 66% of diary 
concordance with a site rater.
15.
A woman must be: 
a.
Not of childbearing potential or:
b. Of childbearing potential and 
o 
Practicing a highly effective method of contraception (failure rate of <1% per year 
when used consistently and correctly) and agrees to remain on a highly effective 
method for at least 6 months after receiving the last dose of study intervention. The 
Investigator should evaluate the potential for contraceptive method failure (e.g., 
noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Examples of highly effective methods of contraception are hormonal or 
barrier methods of contraceptive, or sexual abstinence. 
NOTE: Participants who are randomly assigned to sham surgery will also be required to 
adhere to this restriction to receive treatment in Study MGT-GAD-026. 
16.
If male, willing to use barrier and spermicide form of contraception or maintain sexual 
abstinence for at least 6 months following surgery.  
NOTE: Participants who are randomly assigned to sham surgery will also be required to 
adhere to this restriction to receive treatment in Study MGT-GAD-026. 
17.
Ability to discontinue use of aspirin, other antiplatelet drugs, or anti-coagulants at least 
1 week prior to surgery and for 1 week following surgery. 
4.2
EXCLUSION CRITERIA 
1.
Women who are pregnant or breastfeeding. Women of childbearing potential are required 
to have a negative serum pregnancy test at the Screening Visit and within approximately 
1 week prior to surgery on Day 1. Participants are considered not of childbearing potential 
if they are surgically sterile (i.e., they have undergone a hysterectomy or bilateral 
oophorectomy), or are postmenopausal. 
2. 
Any experimental therapy (drug or biologic) within 3 months prior to Screening. 
3.
Have a known allergy to any of the non-investigational drugs (e.g., antibiotics and local 
anesthesia) to be used in the study. 
4. 
Known allergies, hypersensitivity, or intolerance to AAV-GAD excipients. 
5.
Any prior history of brain surgery for Parkinson’s disease. 
6.
Ongoing treatment with dopamine receptor-blocking drugs. 

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7.
History of any serious cerebral insult, such as head injury, or central nervous system
infection, or uncontrolled seizures. 
8.
Mental retardation or impaired cognitive abilities, as judged by patient history or cognitive 
impairment as defined by Montreal Cognitive Assessment (MoCA) 20. 
9.
Focal or lateralized central nervous system (CNS) neurological deficits other than mild 
memory disturbance. 
10.
Neurological features suggestive of the diagnosis of a “Parkinson-plus” disorder (such as 
progressive supranuclear palsy, multiple system atrophy, corticobasal ganglionic 
degeneration, or “lower body” Parkinsonism) or normal pressure hydrocephalus. 
11.
Evidence of lesions or other significant abnormalities on cranial neuroimaging (either CT, 
MRI, or 18FDG-PET) suggesting findings compatible with a probable diagnosis other than 
Parkinson’s disease. 
12.
Alanine aminotransferase and/or aspartate aminotransferase >1.5 upper limit of normal 
(ULN) or alkaline phosphatase >1.5 ULN. 
13. 
Clinically relevant abnormality on 12-lead ECG. 
14. 
Administration of any live virus vaccine within 4 weeks of surgery. 
15. 
Evidence of other significant medical or psychiatric disorders, such as psychosis, frequent 
occurrence of hallucinations, severe depression, significant cognitive decline in recent 
months, systemic organ failure, or bleeding diathesis, not attributable to adverse effects of 
anti-Parkinsonian medications. 
16. 
Evidence of active impulse control disorder, or substance or alcohol abuse unrelated to use 
of dopaminergic medication. 
17.
Significant concurrent or recently diagnosed ( 2 months prior to the Screening Visit) 
medical condition that, in the opinion of the Investigator, could affect the participant’s 
ability to tolerate or complete the study. 
18. 
Current immunosuppressive therapy or underlying disorder associated with diminished 
immunocompetence. 
19. 
Serum platelet count of <80,000/mm3, international normalized ratio (INR) >1.3, or partial 
thromboplastin time (PTT) >40 seconds. 
20.
Score of 20 on the Beck Depression Inventory-II. 
21.
Acute or chronic systemic and/or local skin infections involving the scalp. 
22.
Criterion removed in protocol version 6.0. 
23.
Has any other condition that, at the consideration of the Investigator, makes them 
inappropriate for entry into the study. 
24.
Is an employee of MeiraGTx. 
25.
Is an employee of the Investigator or study site, with direct involvement in the proposed 
study or other studies under the direction of that Investigator or study site, as well as family 
members of the employees or the Investigator. 

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4.3
WITHDRAWAL CRITERIA 
Participation in this clinical study may be discontinued for any of the following reasons: 
 The participant withdraws consent or requests discontinuation from the study for any reason 
Occurrence of any medical condition or circumstance that exposes the participant to substantial 
risk and/or does not allow the participant to adhere to the requirements of the protocol 
Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, or 
other medical condition that indicates to the Investigator that continued participation is not in 
the best interest of the participant
Requirement of prohibited concomitant medication
Participant failure to comply with protocol requirements or study-related procedures
Termination of the study by the sponsor or the regulatory authority 
The reason for participant withdrawal must be documented in the electronic case report form 
(eCRF).
Participants who withdraw prior to surgery will be replaced. Participants who withdraw after
surgery will not be replaced. 
4.4
END OF STUDY 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last participant in the study. All participants
who receive AAV-GAD will be followed in a subsequent long-term study in accordance with 
applicable regulatory agency guidance for the follow-up of participants who receive gene therapy. 
Additionally, participants randomized to the sham surgery group in this study will be offered 
bilateral, open-label AAV-GAD treatment as part of the long-term follow-up study. 

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STUDY TREATMENTS  
5.1
TREATMENT GROUPS
Participants will be randomized to one of the three following groups:  
 AAV-GAD at a dose of 3.5×1010 vg/STN, low dose group 
 AAVGAD at a dose of 10.45×1010 vg/STN, high dose group 
Sham surgery
5.2
RATIONALE FOR DOSING
AAV-GAD will be administered bilaterally via stereotactic infusion into each STN (1 infusion per 
hemisphere: 2 infusions in total). Each STN will be infused with either 
1012 vg/mL 
AAV-GAD, for a dose of 3.5×1010 vg/STN (low dose group) or 50 
12 vg/mL 
AAV-GAD, for a dose of 10.45×1010 vg/STN (high dose group). The total dose per participant 
will be 7.0×1010 vg or 20.9×1010 vg, in the low and high dose groups, respectively. 
The doses are based on the safety demonstrated in MPTP-treated Parkinsonian NHPs and the prior 
Phase 1 and 2 studies, and safety data from other nonclinical studies evaluating AAV gene delivery 
into the brain. The high dose is >4-fold and the low dose is >12-fold less than the dose received 
by the NHPs (based on correcting for STN neuronal counts), which was well tolerated without any 
signs of toxicity (Hamani et al. 2004, Emborg et al. 2007).  
Data from the prior Phase 1 study showed treatment with AAV-GAD to be well tolerated and safe 
with improved motor function contralateral to the treated hemisphere and consistent with 
improvement in  thalamic metabolism based on 18FDG-PET (Feigin et al. 2007, Kaplitt et al. 2007). 
-GAD infused into the STN, with the highest 
dose cohort receiving 3.5 x1010 vg into the STN.    
In the subsequent Phase 2 study, participants randomized to active treatment received AAV-GAD 
at a dose of 35
L of 1 1012 vg/mL into each STN (i.e., the same total vg per STN as in the prior 
Phase 1 and the same as the low dose in the current study). The Phase 2 study confirmed that 
treatment with AAV-GAD was safe and well tolerated, and improved motor function.  
A nonclinical GLP study evaluating the same AAV-GAD manufactured using new optimized 
processes delivered to the STN in rodents established a safe NOAEL that is >5-fold and >16-fold 
(based on correcting for STN volume) the high and low dose in this current MGT-GAD-025 study, 
respectively. 
The safety and potential additional efficacy benefit of adding a higher dose group to this study are 
supported by previously observed safety as well as efficacy data.   
 In the previous Phase 2 study, the same dose was delivered to each STN as the low dose in this 
current study. In one participant, however, due to mistargeting, the contralateral catheter was 

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inadvertently placed across the midline into the same STN that received the first catheter
(LeWitt et al. 2011).  This led to two catheters delivering the total viral load into a single STN, 
resulting in a doubling of the volume and dose to that STN in the one hemisphere (to a total 
volume of 70 µL). No adverse events resulted from this surgical error. Also, both the volume 
and titer of virus delivered to the brain in this study is in most cases orders of magnitude below 
the majority of completed or active human gene therapy studies approved by the FDA using 
AAV in the brain for a variety of disorders. 
 While the safety data suggest that the higher dose would not be expected to pose an 
unacceptable risk, there is also justification for adding a higher dose based upon the potential 
for increasing efficacy of the gene therapy product.  The low dose of AAV-GAD has
demonstrated efficacy in previous Phase 1 and Phase 2 clinical studies conducted with AAV-
GAD produced with an earlier method. In the Phase 2 study, the participant who inadvertently 
received a double dose to a single STN not only had no adverse effects but appeared to have a 
roughly 50% improvement compared to baseline in the primary outcome measure, which was 
the off-medication UPDRS part 3 score, despite only receiving treatment to one STN. This 
was also approximately double the average improvement observed in that cohort (in which all 
other participants received the intended dose per STN and received bilateral treatment).  
 This suggestion of greater potential clinical improvement from a higher dose of AAV-GAD to 
the STN is also supported by functional imaging data.  In the Phase 2 study, FDG-PET was 
used to evaluate brain network changes before and after gene therapy. From that data, the novel 
network GADRP was identified, which indicated a reorganization of dysfunctional brain 
circuits into more therapeutically beneficial circuits in response to AAV-GAD. The data 
demonstrated a highly significant change in this GADRP in treated participants, which 
correlated with the degree of clinical improvement, while this was not observed in the sham 
surgery group (Niethammer et al. 2018). This pattern was unknown at the time of the prior 
Phase 1 study, yet FDG-PET scans were obtained as a part of that study, thus a retrospective 
analysis of that data could be performed. In the prior Phase 1 study, participants were treated 
in 1 of 3 dose cohorts that escalated by approximately 3-fold between cohorts. The high dose
in that Phase 1 study was equivalent to that used for the subsequent Phase 2 study on a per-
hemisphere basis (and is the same as the low dose in the current study). FDG-PET analysis 
demonstrated consistent changes in GADRP, similar to the Phase 2 study but of a lower 
magnitude, and only in the highest dose cohort. The lower magnitude was expected since 
participants in the prior Phase 1 study were only treated in one hemisphere compared to 
bilateral treatment delivered in the Phase 2 study. This suggests that the highest dose from the 
prior Phase 1 study was potentially just above a therapeutic threshold and that a higher dose 
might further enhance GADRP, which would be expected to improve clinical scores based 
upon the correlation between the two in the Phase 2 data. 
In summary, data from the previous Phase 1 and 2 studies demonstrated that treatment with the 
low dose that is included in the current study was safe and well tolerated, with no SAEs related to 
gene transfer, and with improvements in motor function. Clinical and functional imaging data 
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NHP study and other nonclinical toxicology studies established a NOAEL with safety margins of 
>4-fold to >5-fold the high dose in this current MGT-GAD-025 study.   
5.3 
RANDOMIZATION AND BLINDING 
Participants will be randomized to receive 1 of 2 doses of AAV-GAD (5 participants per dose 
group) or sham surgery (4 participants).  
Randomization will occur after all inclusion and exclusion criteria have been met and surgery is 
scheduled. 
Details of the randomization and randomization procedure will be provided in a randomization-
specification document. The actual date/time of the randomization will be collected in the eCRF.
This study will be performed in a double-blinded manner, with Investigators, study staff, and 
participants unaware of treatment assignment. However, due to the requirement for surgical 
delivery of ATIMP in the operating room, surgeons, surgical staff, the pharmacist and the 
radiologist will be aware of treatment status in accordance with site-specific blinding/unblinding 
procedures. The surgical staff will perform the surgery and provide postoperative care; they will 
play no role in the evaluation of study participants.  
5.4 
BREAKING THE BLIND 
After a participant completes the Week 26 Visit and that participant’s data are considered clean in 
the MGT-GAD-025 study database, that participant’s treatment assignment will be unblinded. 
Participants randomized to AAV-GAD treatment will be consented to enter the long-term 
follow-up study and participants randomized to sham surgery will be consented and offered 
AAV-GAD treatment in the long-term follow-up study (pending regulatory approval). 
Emergency unblinding procedure 
Code-breaking and unblinding in the event of medical emergencies can be done by the Investigator 
via physical code break envelopes stored at the site in accordance with the site’s 
blinding/unblinding procedures. 
Unblinding by the Investigator should occur only in the event of an AE/SAE for which it is 
necessary to know the treatment assignment to determine an appropriate course of therapy for the 
participant. The Investigator should first discuss options with the Sponsor, if possible, with due 
consideration of the safety of the participant.  
Participants for whom the code has been broken by the Investigator will be encouraged to attend 
all post-treatment visits as indicated in the Schedule of Activities. Code breaking will be 
documented in the eCRF. 

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5.5
TREATMENT SUPPLIES
5.5.1 
AAV-GAD  
5.5.1.1 
Formulation and Packaging 
AAV-GAD is formulated in a buffered solution of KH2PO4, Na2HPO4, NaCl, and MgCl2, with pH 
7.4. The AAV-GAD formulation will be diluted to a concentration of 1x1012 vg/mL (low dose) or 
used at the undiluted concentration of 2.09 × 1012 vg/mL (high dose), as specified in the Pharmacy 
Manual. 
The vehicle for the sham surgery procedure will be saline.  
5.5.1.2 
Study Drug Preparation and Dispensing
AAV-GAD will be supplied in vials with a coded label. The label will contain all information as 
per local requirements/regulations.  
5.5.2
Acute Delivery System 
Instructions for use (IFU) and maintenance of the Acute Delivery System will be provided to each 
site.
5.5.2.1 
Acute Delivery System Description
The following devices are used as part of the procedure: 
1. Infusion Catheter Kit: Sterile, disposable, single-patient, single-use infusion catheter 
system consisting of a parenchymal catheter and extension set (including a breakaway 
connector). 
2. Cranial Anchor Kit: Sterile, disposable, single-patient, single-use Cranial Anchor kit  
3. Transfer Guard and Syringe Kit: Sterile, disposable, single-patient, single-use syringe and 
sterile, disposable, single-patient, single-use syringe transfer guard  
4. Accessory kit  
5. Reusable pump 
These components facilitate infusion by connecting the syringe containing the therapeutic agent(s) 
to the parenchymal catheter via the extension set. This system includes a breakaway connector to 
preclude accidental movement of the parenchymal catheter during infusion. 
The infusion catheter kit, cranial anchor kit, transfer guard and syringe kit, and accessory kit will 
be manufactured by a qualified contract manufacturing organization (CMO). The pump is 
manufactured by Harvard Biosciences and the final product is provided to MeiraGTx for use in 
the clinical study. Neither MeiraGTx nor its qualified CMO will be reprocessing the syringe or the 
pump. Please refer to the IFU for further details. 

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All the components listed above will be provided by MeiraGTx to the site. 
5.5.2.2 
Device Packaging  
The single-use disposable infusion catheter kit, anchor kit, and transfer guard and syringe kit (1 per 
hemisphere for each kit) will each be packaged and distributed in sterile packaging. The reusable 
accessory kit will be packaged in sterile packaging. The pump will be distributed in the packaging 
provided by the manufacturer. 
5.5.3 
AAV-GAD Administration and Surgery Procedure 
On the day of AAV-GAD administration, participants will be taken to the operating room. 
Intravenous antibiotics will be given prior to skin incision. The neurosurgeon will make a frontal 
burr hole at a standard entry site normally used for the placement of STN DBS electrodes. Local 
anesthesia will be used unless general anesthesia is necessary for participant safety. This entry site 
is usually at or just anterior to the coronal suture in the mid-pupillary line; however, the entry site 
can be adjusted for optimal safety and accuracy depending upon the assessment of the participant’s 
presurgical CT or MRI. The brain parenchymal infusion catheters will be placed in each STN 
bilaterally using standard stereotactic procedures.  
Details of syringe and catheter infusion system preparation, insertion of the catheter, infusion, 
removal of the catheter, and intraoperative and post-operative imaging will be outlined in the IFU 
for the Acute Delivery System.  
Briefly, standard stereotactic systems for the insertion of STN DBS electrodes will be used to 
target each STN. After a plan is created for trajectories from the frontal burr hole to the STN target, 
a burr hole will be generated centered over the planned entry site. The base of a specially designed 
burr hole cover used to secure the catheter will then be fixed to the skull. The trajectory plan and/or 
coordinates are to be confirmed prior to insertion of the cannula guide for each catheter placement. 
The surgeon will read the settings of the stereotactic frame or the plan in a frameless system while 
an assistant confirms and documents in the source documents that these match the plan written 
prior to the start of surgery. Standard methods for localizing the STN at the site will then be 
performed to confirm the proper location of the center of the STN. Once the dorsal and ventral 
limits of the STN are mapped along an optimal trajectory, the rigid cannula guide will be inserted 
to a depth of 10 mm above the intended target. The intended target will be the middle of the STN 
(based upon the intraoperative mapping).  
Prior to thawing the study drug vial, the code will be confirmed to match the code provided by the 
sponsor. Prior to infusion, the vial will be thawed at room temperature and the AAV-GAD 
formulation will be prepared as specified in the Pharmacy Manual
AAV-GAD will be drawn into the infusion syringe under sterile conditions. The neurosurgeon will 
then connect the syringe to the infusion catheter. Prior to inserting the catheter, the neurosurgeon 
will take the sterile syringe filled with the AAV-GAD solution and will prime the catheter system 
with the solution to flush air and confirm flow.  

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The catheter will then be disconnected from the infusion system and will be inserted to a 
predetermined depth through the cannula guide to place the tip of the infusion catheter within the 
center of the STN. Confirmation of the location of the catheter tip will be obtained using standard 
procedures for localizing DBS electrodes at the site. The cannula guide will be partially withdrawn 
to expose the catheter, and then the second stage of the locking mechanism (cranial anchor disk) 
will be inserted securely into the cranial anchor base that was previously fixed to the skull. The 
ancillary surgical supplies, forceps and standard Rhoton dissector will be used to close the locking 
mechanism and secure the catheter. The catheter and the release ripcord for the locking cap will 
both be externalized through the skin flap by using an IV needle and the incision will then be 
sutured. The catheter will then be reattached to the infusion system.  
Prior to inserting the contralateral catheter, the surgeon will verbally confirm the coordinates or 
localization plan for the catheter tip in the contralateral hemisphere and this will be recorded in the 
source documents to document that they completed this prior to insertion of the contralateral 
cannula guide. The contralateral catheter will then be inserted in the same manner as the first 
catheter. Following completion of second catheter insertion, the infusion will commence, and the 
frame or fiducials will be removed. Confirmation of the location of this second catheter tip will be 
obtained using standard procedures for localizing DBS electrodes at the site. 
In preparation for the infusion, ensure that the pump (pump head and controller) is at 
approximately the same level as the infusion site.  Ensure that the pump is maintained at the same 
height for the duration of the infusion. To begin infusion, the syringe will be placed into the pump 
that will be programmed to infuse either 35 
or 50 
of AAV-GAD, depending upon the dose 
assignment, at a rate of approximately 
. After completion of AAV-GAD infusion, a 
non-contrast CT of the head will be performed to document the catheter position upon completion 
of the infusion. The catheter will then be removed in its entirety by removing the release ripcord 
to open the locking mechanism followed by withdrawal of the catheter. A non-contrast CT of the 
head will be performed within 24 hours following removal of the catheter to evaluate any new 
bleeding or retained catheter fragment.  
5.5.4 
Saline Administration and Sham Surgery Procedure 
The same surgical procedure described for AAV-GAD administration will occur for the 
participants randomized to sham surgery; however, the burr holes will be of partial-thickness and 
neither the inner table of the skull nor the dura will be penetrated, thereby minimizing the risk of 
intracranial injury, hemorrhage, or infection. Of note, surgeons need to carefully select where they 
create burr holes for the sham surgery, as these holes will be used for the administration of 
AAV-GAD in Study MGT-GAD-026. A sham procedure to simulate mapping of the STN will be 
performed per the site’s standard practice, with electrophysiological recordings made from a 
routine case played as part of a mock mapping procedure for sites using this method to target the 
STN. The distal ~10 cm of the catheter will be cut, unbeknownst to the participant, and the 
truncated catheter will be inserted into the partial-thickness burr hole and fixed in place with the 
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The release ripcord and catheter will be externalized in the same fashion as for AAV-GAD 
participants and then saline infusion will be performed through catheters inserted into each partial-
thickness burr hole (no brain infusion). The volume of saline 
). A sham non-contrast CT of the head will be performed within 24 hours following 
removal of the catheter.
5.5.5 
Treatment Compliance 
Study drug will be administered under the supervision of the treating neurosurgeon as outlined in 
the IFU manual. Administration of study drug will be recorded in the eCRF.  
5.5.6 
Labeling, Storage, and Accountability 
5.5.6.1 
AAV-GAD Study Drug 
The study drug will be labeled in accordance with the relevant current Good Clinical Practice 
(GCP) guidelines and MeiraGTx procedures and will include the statement “Caution: New Drug-
Limited by Federal (or United States) law to Investigational Use." The study drug should be stored 
-70oC as specified on the label. 
Health hazards related to the preparation and administration of AAV-GAD by health care workers 
are not anticipated. Recombinant AAV serotype 2 vectors, such as AAV-GAD, are considered to 
be the lowest risk group (Risk Group 1) for recombinant DNA agents and can be manipulated 
under the lowest biosafety level (Biosafety Level 1) according to the April 2019 National Institutes 
of Health Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules. 
Nevertheless, waste generated during the preparation and administration of AAV-GAD should be 
properly disposed of in accordance with applicable Federal, state, and institutional policies 
regarding disposal of hazardous biological materials and medical waste. 
All vials of study drug must be accounted for by the pharmacy. All used and unused vials will be 
destroyed at the site per institutional policies. Used vials are defined as the following: 1) vials that 
were thawed and product was infused, or 2) vials that were thawed and product was not infused. 
5.5.6.2 
Medical Devices 
The Investigator or designee will record the receipt and disposition of the infusion catheter kits, 
cranial anchor kits, transfer guard and syringe kits, accessory kits, and the pumps. As used in this 
study, the infusion catheter kits, cranial anchor kits, transfer guard and syringe kits, and accessory 
kits are investigational, and all medical devices must be tracked. Shipping receipts must be retained 
with the study records. Details (e.g., serial number, lot number) of implants and other devices used 
for the surgery will be documented in the eCRF. After completion of the study, any unused infusion 
catheter kits, cranial anchor kits, transfer guard and syringe kits (or parts of those devices), 
accessory kits, and pumps must be available to be returned to MeiraGTx or designee. Final 
accountability and reconciliation will be completed. 

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The infusion catheter kits, cranial anchor kits, transfer guard and syringe kits, and accessory kits, 
pump(s) must be kept in a storage area that is physically separate from commercial device 
inventory at the clinical site. The investigational medical devices should be stored according to 
their respective labeling. The investigational devices or their immediate package will bear a label 
with the following information: 
 The name and place of business of the manufacturer or distributor 
 The quantity of the contents, if appropriate 
The following statement: “CAUTION - Investigational Device. Limited by Federal (or United 
States) Law to Investigational Use.” 
Following implant and administration of AAV-GAD, the parenchymal catheter system, transfer 
guard and syringe kit components, and accessory kit should be packaged in a sealed biohazard bag 
and stored until the end of the study when they will either be returned to MeiraGTx or designee or 
allowed to be destroyed. 
All sterilized components must be used before the predetermined number of months from the date 
of sterilization as indicated by the “use by date” on the label. 
5.6 
PRIOR AND CONCOMITANT MEDICATIONS AND/OR PROCEDURES 
5.6.1 
Excluded Medications and/or Procedures 
The following medications and procedures will be prohibited: 
 Deep brain stimulation  
 Other brain surgery for Parkinson’s disease 
 Other experimental therapy (drug or biologic) within 3 months prior to Screening and 
throughout participation in the study 
 Dopamine receptor-blocking drugs 
 Live virus vaccine within 4 weeks of surgery 
 Immunosuppressive therapy 
 New treatment for Parkinson’s disease. 
Note:  Adjustments in the dose of dopaminergic medications are allowed when medically 
indicated. 
5.6.2 
Restricted Medications and/or Procedures 
The following medications and procedures will be restricted: 

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Aspirin, other antiplatelet drugs, or anticoagulants from 1 week prior to surgery through 
1 week following surgery 
Note: Participants receiving anticoagulation therapy must be able to maintain, with acceptable risk, 
a normal INR and PTT for at least 1 week prior to surgery and 1 week following surgery as 
determined by the participant’s primary care physician. 
5.6.3
Allowed Medications and/or Procedures 
Participants will continue to receive any medications that they were receiving at study entry for 
underlying medical conditions. Participants should be on an unchanged, stable anti-Parkinsonian 
drug regimen and on stable doses of medications for any other underlying medical conditions for 
4 weeks prior to Screening. 
5.6.4 
Documentation of Prior and Concomitant Medication Use 
All concomitant medications (including prescription medications and over-the-counter 
preparations) used by the participant from date of ICF signing, during the study, and at the final 
study visit will be documented and recorded in the eCRF. 

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6
STUDY PROCEDURES AND VISITS
6.1 
INFORMED CONSENT 
Written informed consent must be obtained from participants by the Investigator or delegated 
clinician/staff member before any study-specific procedures are performed. See Section 12.2 for 
details on consent. 
6.2 
STUDY PROCEDURES 
The Schedule of Activities (SoA) summarizes the frequency and timing of efficacy, safety, and 
immunogenicity assessments applicable to this study. 
The diagnosis of idiopathic PD will be made before any other screening procedure takes place. 
During screening, assessments that are not part of the study entry criteria will be performed after 
the participant has qualified to enroll in the study (as per footnote “p” of the SoA [Table 1]). 
All participants will be provided with an emergency card on enrollment to the study to enable 
24-hour contact with study Investigators. 
Participants randomly assigned to immediate treatment with AAV-GAD will be scheduled for 
surgery and complete the full battery of visits through the Week 26 visit (as described in the SoA), 
and then enter the long-term follow-up MGT-GAD-026 study. 
Participants randomly assigned to sham surgery will follow the same visit schedule during the first 
6 months, and then enroll in the long-term follow-up MGT-GAD-026 study, in which these 
participants will be offered treatment with AAV-GAD. The Week 26 visit of this study will serve 
as the Baseline visit of MGT-GAD-026. 
Any medical condition already present at Screening should be recorded as medical history and not 
be reported as an AE unless the medical condition or signs or symptoms present at screening
change in severity, frequency, or seriousness at any time during the study. In such a case, it should 
be reported as an AE.
The Week 19 visit is a telephone visit for assessment of AEs, changes in control of Parkinsonism, 
and other neurological events. The following actions must be taken if a participant fails to answer 
or return phone calls: 
 
The study-site personnel must attempt to contact the participant to reschedule the missed 
telephone visit as soon as possible. 
 
The Investigator or designee must make every reasonable effort to regain contact with the 
participant (where possible, 3 telephone calls, emails, fax).  
 
Should the participant continue to be unreachable, they will be considered to have missed the 
telephone visit. 

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During visits that include the UPDRS assessment, the MDS-UPDRS Part 3 “off” state assessment 
should preferably be performed before any other assessments or questionnaires. Site staff are to 
confirm that the last dose of dopaminergic medication(s) was taken by the participant at least 
12 hours before performing the MDS-UPDRS Part 3 “off” state assessment (also see Section 7.2). 
For the other assessment tools, the following order is recommended: 
1. HVLT-R (10 min + 20-25 min delay*) 
2. Trail Making Test (10 min) 
3. Color-word interference (10 min) 
4. Digit Span Test (5 min) 
5. *HVLT-R delayed memory (continued from 1, above, after planned delay) 
6. Verbal fluency test (10 min) 
7. All other questionnaires  
Additional serum or urine pregnancy tests may be performed, as determined necessary by the 
Investigator or required by local regulation, to establish the absence of pregnancy at any time 
during the participation in the study. Similarly, unscheduled clinical chemistry examinations will 
be permitted as required to manage emerging issues. 
6.3 
EARLY TERMINATION VISIT AND WITHDRAWAL PROCEDURES
The end-of-treatment visit for participants completing the study is the Week 26 visit.  
If a participant who received surgery withdraws early, they will be encouraged to maintain contact 
with the Investigator and allow reporting to the sponsor of follow-up MRI and clinical features 
related to Parkinson’s disease and other neurological problems. Every effort should be made to 
complete the full panel of assessments scheduled for the Week 26 Visit. 
If a participant discontinues (for any reason) the study after surgery on Day 1, all assessments 
scheduled for the Week 26 Visit should be completed.  
In the case of a participant lost to follow-up, attempts to contact the participant must be made and 
documented in the participant’s medical records. 

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7
EFFICACY ASSESSMENTS 
7.1
18FDG-PET 
18FDG-PET scans will be performed per site standards to assess patient’s eligibility and evaluate 
the abnormalities in brain network activity and biological changes in brain function.  
Scans will also be evaluated for PDRP and GADRP at baseline and at 6 months after study drug 
administration as an exploratory evaluation for potential correlates of activity.  
PDRP score is a z-scale unit score of 18FDG-PET brain network pattern. 
GADRP score is a z-scale unit score of 18FDG-PET brain network pattern associated with response 
to AAV-GAD therapy, involving the generation of new polysynaptic functional pathways linking 
the STN to the motor cortical regions. 
18FDG-PET scans will be collected for centralized reading by an independent specialist. 
7.2 
QUESTIONNAIRES AND SCALES 
The following assessment tools will be used in this study: 
 Columbia Suicide severity rating scale: a measure assessed by the Investigator or a qualified 
member of her/his team (e.g., a neurologist), used to identify and assess individuals at risk for 
suicide. 
 Beck Depression Inventory-II: a 21-item self-report inventory measuring the severity of 
depression in adolescents and adults 
Beck Anxiety Inventory: a 21-item self-report inventory measuring the severity of anxiety in 
adolescents and adults 
 Clinical Global Impression-Severity: a 7-point scale completed by the Investigator or a 
qualified member of her/his team (e.g., a neurologist), to rate the severity of the participant’s 
illness at the time of assessment, relative to her/his baseline state (prior to the surgery)  
 Clinical Global Impression-Improvement: a 7-point scale completed by the Investigator or a 
qualified member of her/his team (e.g., a neurologist) to assess how much the participant’s 
illness has improved or worsened relative to her/his baseline state (prior to the surgery) 
 EuroQol-5 Dimensions-5 Levels Survey comprises five dimensions: mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, 
slight problems, moderate problems, severe problems and extreme problems. The participant 
is asked to indicate his/her health state by ticking the box next to the most appropriate statement 
in each of the five dimensions. This decision results in a 1-digit number that expresses the level 
selected for that dimension. The digits for the five dimensions can be combined into a 5-digit 
number that describes the patient’s health state. 

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Montreal Cognitive Assessment: a brief cognitive screening task assessment administered by 
the Investigator or a qualified member of her/his team (e.g., a neuropsychologist) of different 
cognitive abilities such as visuospatial skills, executive function, memory, language and 
attention. 
Parkinson’s Disease Questionnaire-39 Scale: a 39-item questionnaire completed by 
participants that measures health status and quality of life 
Parkinson’s Disease Sleep Scale-2: a 15-item scale completed by participants to self-rate and 
quantify the level of sleep disruption being experienced 
Unified Dyskinesia Rating Scale: a scale formatted as a questionnaire for the participant and 
completed by the Investigator or a qualified member of her/his team (e.g., a neurologist), used 
to evaluate the involuntary movements that can be associated with long-term treatment with 
dopaminergic medication 
 MDS-Unified Parkinson’s Disease Rating Scale Part 1 (Non-Motor Experiences of Daily 
Living), Part 2 (motor experiences of daily living), Part 3 (motor examination) and Part 4 
(motor complications). Part 1 has two components: 1A concerns a number of behaviors that 
are assessed by the Investigator or a qualified member of her/his team (e.g., a neurologist) with 
all pertinent information from participants and caregivers, and 1B will be completed by the 
participant with or without the aid of the caregiver, but independently of the Investigator. Part 2 
is designed to be a self-administered questionnaire like Part 1B. Part 3 will be completed by 
the Investigator or a qualified member of her/his team (e.g., a neurologist) and has instructions 
for the Investigator to give or demonstrate to the participant. Part 4 integrates patient-derived 
information with the Investigator’s clinical observations and judgments and will be completed 
by the Investigator or a qualified member of her/his team (e.g., a neurologist). 
The MDS-UPDRS Part 3 will first be completed while in the “off” state. “Off” state scores 
will be obtained after at least 12 hours of holding dopaminergic medication. Once this 
assessment is completed, participants are to take their usual medications for Parkinson’s 
disease. “On” state evaluations will be assessed when participants and Investigators agree 
that the participant is in a typical “on” state (as a guidance, the “on” state is expected to be 
achieved approximately 2 hours after taking medication(s) for Parkinson’s disease). 
Participants may take additional levodopa (in addition to their usual dose) if needed to 
achieve the “on” state.  
 Revised Hopkins Verbal Learning Test (HVLT-R) is a test administered by the Investigator or 
a qualified member of her/his team (e.g., a neuropsychologist), assessing verbal memory. 
Participants are presented with a list of words over repeated learning trials and are required to 
recall words from the list immediately and after a delay of 20-25 minutes and complete a yes-
no delayed recognition task.  The HVLT-R also provides 6 alternate forms in order to reduce 
the effects of practice and will be administered during each session. 
 Stroop Color and Word Test (DKEFS version) is a test administered by the Investigator or a 
qualified member of her/his team (e.g., a neuropsychologist), measuring processing speed and 

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executive functioning. There are 4 parts. Participants are required to read printed color names 
as fast as possible (Part 1), and name color patches as fast as possible (Part 2). To assess 
executive functioning, and specifically cognitive inhibition, participants are then required to 
name the ink color of printed color names, avoiding the ‘read’ the printed work. In the 4th part, 
participants are required to do the same as in Part 3 unless the word is presented in a box, and 
in these instances, they must read the word instead of naming the color.   
 Trail Making Test (TMT) (DKEFS version) is a paper-and-pencil test administered by the 
Investigator or a qualified member of her/his team (e.g., a neuropsychologist), measuring 
processing speed and executive functioning. There are 4 trials to complete including a 
cancellation task (i.e., cross-out targets as fast as possible), simple tracking tasks requiring 
participants to connect numbers with a line as fast as possible, connect letters in order, and 
lastly, a more complex task requiring them to alternate between numbers and letters in 
sequences. 
 Verbal fluency Test (DKEFS version) is a verbal fluency test administered by the Investigator 
or a qualified member of her/his team (e.g., a neuropsychologist), measuring executive 
function and language abilities. Participants are required to generate as many words as possible 
aloud within a one-minute period following letter cues (3 trials) and category cues (3 trials). 
 Digit Span test (part of Weschler Memory and Weschler scales) is a test administered by the 
Investigator or a qualified member of her/his team (e.g., a neuropsychologist), measuring 
attention and working memory span. Participants are required to repeat strings of digits of 
increasing length in the same order as well as in reverse order. 
To the extent possible, all questionnaires to be used in repeated assessments should be 
administered by the same rater (Investigator, neuropsychologist, or neurologist, as applicable). 
7.3
HAUSER PATIENT DIARY 
The Hauser Patient Diary will be used to collect information on how much time a participant 
spends in the different Parkinson’s disease states: 
 ON - Good or practically normal mobility 
 ON with Troubling Dyskinesia – participant is troubled by involuntary twisting, turning 
movements. These movements are different from the rhythmic "tremor" which is a symptom 
of Parkinson's disease itself 
 OFF - stiffness, marked decrease in mobility, and/or immobility
 ASLEEP - time spent sleeping.   
The diary is divided into 30-minute sections starting at midnight and ending at 11:30 PM. 
Participation in the study requires that participants demonstrate full understanding of the rating 
criteria and proficiency in completing the diary. At the Screening Visit, participants will be taught 

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how to use the diary by a member of the study site staff. At the end of the training session, 
participants and a site staff rater will concurrently but separately complete diary entries for 3 half 
hour periods. Diary concordance of at least 66% will be required for the participant to qualify for 
the study. 
Participants are to complete this 24-hour diary of their Parkinson’s disease symptoms twice per 
week (on 2 nonsequential days) for 3 consecutive weeks prior to the second screening visit (i.e., 
the Day -7 to Day -3 visit) (baseline entries), and on 2 nonsequential days during the week prior 
to Day 15, and Weeks 12 and 26.  
The change from baseline in absolute number of daily hours in the “on without troublesome 
dyskinesias” state to the weeks prior to Day 15, Week 12 and Week 26 will be compared.  

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8
SAFETY ASSESSMENTS
Safety will be evaluated by vital signs, neurological examinations, physical examinations, ECGs, 
radiographic imaging (CT and MRI), clinical laboratory evaluations, descriptive analysis of AEs 
(including incidence, severity, seriousness, and relatedness), immune response, and the Columbia-
Suicide Severity Rating Scale over the 6-month duration of the study. Safety will continue to be
assessed within the proposed separate long-term follow-up study, assuming regulatory approval. 
8.1 
DATA AND SAFETY MONITORING BOARD 
A DSMB will be established to ensure the continuing safety of the participants enrolled in this 
study. This committee will consist of neurosurgeons and neurologists with expertise in the 
assessment and treatment of participants with Parkinson’s disease and with backgrounds in clinical 
research. The committee will meet at predefined timepoints, or on an ad hoc basis at the request 
of the sponsor to provide expert consultation on specific issues as described in the DSMB charter. 
8.2
ADVERSE EVENTS 
Adverse event definitions are provided in Table 2.
Table 2: Adverse Event Definitions
Adverse Event (AE) 
Any untoward medical occurrence in a clinical study participant 
administered a medicinal product and which does not necessarily have a 
causal relationship with this product. 
Adverse Drug Reaction 
(ADR)/Adverse Reaction 
(AR) 
Any untoward and unintended response to an investigational medicinal 
product related to any dose administered. 
Serious Adverse Event 
(SAE) or Serious 
Adverse Reaction (SAR) 
Any AE or AR that at any dose: 
 
Results in death  
 
Is life threateninga
 
Requires hospitalization or prolongs existing hospitalizationb
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
Or is another important medical conditionc
Unexpected Serious 
Adverse Drug Reaction 
A SAR whose nature, severity or outcome is not consistent with the 
reference safety information (RSI). As AAV-GAD is an investigational 
medicinal product, the RSI is included in the IB for this study. 
a:
Life threatening refers to an event in which the participant is at risk of death at the time of the event; it 
does not refer to an event that might hypothetically cause death if it was more severe (e.g., a silent 
myocardial infarction). 
b: 
Hospitalization is defined as an inpatient admission, regardless of length of stay. Hospitalization for an 
elective procedure for a pre-existing condition does not constitute an SAE. 
c: 
Medical judgment should be exercised in deciding whether an AE or ADR is serious in other situations. 
Important AEs or ARs that may not be immediately life threatening or result in death or hospitalization 
but may seriously jeopardize the participant by requiring intervention to prevent one of the other 
outcomes listed in the table (e.g., a secondary malignancy, an allergic bronchospasm requiring intensive 
emergency treatment, seizures or blood dyscrasias that do not require hospitalization, or development of 
drug dependency).

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Adverse events include: 
 An exacerbation of a pre-existing illness
An increase in the frequency or intensity of a pre-existing episodic event or condition 
A condition (regardless of whether PRESENT prior to the start of the study) that is 
DETECTED after study drug administration (or sham surgery). (This does not include pre-
existing conditions recorded as such at screening.) 
Continuous persistent disease or a symptom present at baseline that worsens following 
administration of study drug (or sham surgery) 
Overdose of study drug  
Adverse events do NOT include: 
Medical or surgical procedures: the condition that leads to the procedure is an AE
Pre-existing disease or a condition present before treatment that does not worsen 
 Hospitalization where no untoward or unintended response has occurred, e.g., elective 
cosmetic surgery
8.2.1
Seriousness Assessment  
When an AE or adverse drug/device reaction occurs, the Investigator responsible for the care of 
the participant must first assess whether the event is serious using the definition given in Table 2.
If the event is classified as ‘serious’ then the sponsor/designee must be notified within 24 hours as 
outlined in Section 8.2.6.
8.2.2
Assessment of Severity 
The Investigator will assess the severity of all AEs and/or adverse drug/device reactions (serious 
and nonserious) in this study as mild, moderate, or severe. 
8.2.3
Assessment of Causality
For all AEs, the relationship of the AE to the administration of the study drug, the surgical 
procedure, and the devices is to be assessed and captured in the study-specific eCRF.  
Relation to study drug is to be assessed according to the definitions in Table 3. 

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Table 3: Adverse Event Causality Definitions 
Related
Description
Event 
Type 
NO
(unrelated, unlikely 
to be related) 
The time course between the administration of study drug and the 
occurrence or worsening of the AE rules out a causal relationship 
or another cause (concomitant drugs, therapies, complications, etc.) 
is suspected. 
Unrelated 
AE or SAE 
YES 
(possibly, probably, 
or definitely related)
The time course between the administration of study drug and the 
occurrence or worsening of the AE is consistent with a causal 
relationship and no other cause (concomitant drugs, therapies, 
complications, etc.) is more likely. The definition implies a 
reasonable possibility of a causal relationship between the event 
and the study drug. This means that there are facts (evidence) or 
arguments to suggest a causal relationship. 
AR or SAR 
AE = adverse event; SAE = serious adverse event; AR= adverse reaction; SAR = serious adverse 
reaction.
8.2.4
Assessment of Expectedness 
8.2.4.1 
Unexpected Serious Adverse Reaction  
If there is at least a reasonable possibility of a causal relationship between the event and the study 
drug, the Sponsor must assess the expectedness of the event. An unexpected serious adverse 
reaction (SAR) is one that is not reported in the current IB, or one that is more frequently reported 
or more severe than previously reported. In view of the limited clinical experience with the study 
drug, there are at present no events considered as expected. Therefore, any SAE that is assessed as 
related to study drug (i.e., considered a SAR) will be deemed an unexpected serious adverse 
reaction) and safety reporting guidelines will apply (Section 8.2.6).
8.2.5
Clinical Laboratory Abnormalities 
It is the responsibility of the Investigator to assess the clinical significance of all abnormal 
laboratory values as defined by the appropriate reference range(s). All abnormal values assessed 
to be of clinical concern and at least possibly related to study drug or of uncertain causality should 
be repeated. Clinically significant abnormal laboratory values occurring during the clinical study 
are to be followed until repeat tests return to normal, stabilize, or are no longer clinically 
significant.
An abnormal laboratory value that is not already associated with an AE is to be recorded as an AE 
if intervention for management of the abnormality is required or at the discretion of the 
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8.2.6
Safety Reporting Requirements
All AEs, serious and non-serious, will be fully documented on the appropriate eCRF. For each AE, 
the Investigator must provide its duration (start and end dates or ongoing), severity, assessment of 
causality, and whether specific action or therapy was required.
All adverse events and special reporting situations, whether serious or non-serious, will be reported 
from the time a signed and dated ICF is obtained until the participant’s last study visit. 
8.2.6.1 
Investigator Responsibilities Relating to Safety Reporting 
The Investigator will assume overall responsibility for evaluating and reporting AEs. In urgent 
situations, a member of the study team may report on their behalf, while making every effort to 
discuss the event with them. All nonserious AEs and ARs, including all events observed following 
study drug administration, should be recorded in the participant’s medical notes, and in the eCRF. 
Serious Adverse Events and SARs should be reported to the Sponsor or designee immediately 
once the Investigator becomes aware of the event (in no circumstance should this notification take 
longer than 24 hours) (see Section 8.2.6.2). 
All AEs, which include clinical laboratory test results, that occur after the time of informed consent 
until the final visit are to be documented. Participants should be instructed to report any AE that 
they experience to the Investigator, whether or not they think the event is due to study drug. Once 
written informed consent is obtained, the Investigator should make an assessment for AEs at each 
visit and record the event on the appropriate AE eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate AE on the eCRF. Additionally, 
the condition that led to a medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, 
or transfusion) should be recorded as an AE, not the procedure itself.  
Clinically significant abnormal laboratory or other examination findings (e.g., ECG) that are 
detected during the study or significantly worsen during the study should be reported as AEs. The 
Investigator is to exercise their medical and scientific judgment in deciding whether an abnormal 
laboratory finding, or other abnormal assessment is clinically significant. Clinically significant 
abnormal laboratory values occurring during the clinical study are to be followed until repeat tests 
return to normal, stabilize, or are no longer clinically significant.
8.2.6.2 
Serious Adverse Event Reporting – Procedures for Investigators 
All adverse events are to be recorded in the participant’s medical notes and the CRF from the date 
of written informed consent until the last study visit. The Sponsor or designee must be notified of 
all SAEs within 24 hours of the Investigator becoming aware of the event during this period. The 
Investigator will respond to any SAE queries raised by the Sponsor or designee as soon as possible. 

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After the last visit, any SAE reported to the Investigator and considered causally related to study 
treatment should be reported as part of the follow-up study. 
The SAE form must be completed by the Investigator (i.e., the individual named on the delegation 
of responsibilities list who is responsible for the participant’s care) with attention paid to the 
severity, and causality of the event. In the absence of the Investigator, the SAE form should be 
completed and signed by a member of the site study team and emailed as appropriate within the
required timeframe. The Investigator should check the SAE form at the earliest opportunity, make 
any changes necessary, sign and then email to the Sponsor or designee (see Section 8.2.8). Systems 
will be in place at the site to enable the Investigator to check the form for clinical accuracy as soon 
as possible. 
The minimum components required for reporting a SAE are the patient ID and year of birth, name 
of reporting Investigator and sufficient information on the event to confirm seriousness. Any 
further information regarding the event that is unavailable at the time of the first report should be 
sent as soon as it becomes available. 
For information on code-breaking and unblinding in the event of medical emergencies, please refer 
to Section 5.4. 
Participants must be followed up until clinical recovery is complete and laboratory results have 
returned to normal or baseline values, or until the event has stabilized. Follow-up should continue 
after completion of the study if necessary. Follow-up SAE forms (clearly marked as follow-up) 
should be completed and emailed to the Sponsor or designee (see Section 8.2.8) as further 
information becomes available. Additional information and/or copies of test results, etc. may be 
provided separately. The participant’s name and full date of birth must not be used in any 
correspondence and must be blacked out and replaced with study identifiers on any test results, 
should they be provided. 
8.2.6.3 
Pregnancy Reporting 
If a participant becomes pregnant prior to receiving treatment, the participant should not receive 
treatment and will be replaced.  If a participant becomes pregnant after receiving treatment, the 
participant will continue the protocol-defined assessments. However, any assessment that in the 
opinion of the Investigator or primary physician would be deemed a risk to the pregnancy may be 
omitted or deferred. 
In case a pregnancy occurs after study treatment is administered, the participant’s general 
practitioner is to be notified that she is participating in a gene therapy study and that, although the 
risks involved are minimal, there is a chance of gene transfer to the unborn child.  
A pregnancy is not considered to be an AE or SAE; however, it must be reported to the Sponsor 
or designee using a pregnancy report form, within 24 hours of the Investigator becoming aware of 
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If the female partner of a male participant becomes pregnant while the participant is receiving 
study drug or within the safety follow-up period defined in the protocol, the Investigator should 
notify the Sponsor or designee as described above.  
After written informed consent is obtained from the female partner (via a pregnant partner consent 
form), the pregnancy should be followed until its outcome is known. Once the outcome of the 
pregnancy is known, the pregnancy report form should be completed and faxed/emailed to the 
Sponsor or designee (see Section 8.2.8). If the outcome of the pregnancy meets the criteria for 
immediate classification as an SAE (i.e., postpartum complication, spontaneous abortion, stillbirth, 
neonatal death, or congenital anomaly), the Investigator should follow the procedures for reporting 
an SAE. 
8.2.6.4 
Expedited Reporting  
The Sponsor or designee will report all relevant information about serious and unexpected adverse 
reactions that are fatal or life-threatening as soon as possible to the relevant Competent Authorities, 
and, in any case, no later than 7 days after knowledge by the Sponsor or designee of such a case. 
Relevant follow-up information is to be communicated within an additional 8 days.  
All other serious and unexpected adverse reactions will be reported to the relevant Competent 
Authorities as soon as possible but within a maximum of 15 days of first knowledge by the Sponsor 
or designee. 
The Sponsor or designee also will inform all Investigators of the SAE/SAR as required per local 
regulation.  
8.2.7
Special Situation Reports 
Special situation reports include reports of study treatment error and reports of adverse reactions 
associated with product complaints. 
 Study treatment error: Is any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product by a healthcare professional, participant, or consumer, 
respectively. The administration or consumption of the unassigned treatment, higher doses than 
planned and administration of an expired product are always reportable as study treatment 
errors. 
 Product complaint: Is defined as any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of a drug or device after it is released for distribution. A special situations report 
will only be completed if a complaint is associated with an adverse drug reaction. For more
information, please refer to the Pharmacy Manual. 
All special situation events as described above must be reported in the same time frame as SAEs 
(see Section 8.2.6.2). All AEs associated with these special situation reports should be reported as 

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AEs or SAEs as well as recorded on the AE eCRF and/or the SAE report form. Details of the 
symptoms and signs, clinical management, and outcome should be provided, when available. 
8.2.8
Safety Contact Information 
SAE forms must be scanned and sent by email to 
. 
8.3 
PHYSICAL AND NEUROLOGICAL EXAMINATIONS 
A standard/limited physical examination and neurological examination will be performed.  
8.4 
CLINICAL SAFETY LABORATORY EVALUATIONS 
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form.  
Refer to the SoA (Table 1) for the timing and frequency of all sample collections. 
Blood samples for hematology, chemistry, and coagulation panels and urine samples will be 
obtained for the tests outlined in Table 4, and testing will be performed at the participating 
institution.  
Note that a serum pregnancy test must be performed for women of childbearing potential at 
Screening and within 1 week prior to the surgery. 
Coronavirus Disease 2019 (COVID-19) testing and follow-up will be done as per institution 
protocol. 
Screening results will be assessed by the Investigator for inclusion of participants in the study. 
Additionally, unscheduled clinical laboratory tests may be obtained at any time during the study 
at the Investigator’s discretion. The diagnosis corresponding to any clinically significant 
abnormality or abnormality requiring treatment/intervention must be recorded as an AE. 
Table 4: Clinical and Safety Related Laboratory Tests 
Standard Safety Chemistry Panel 
Alanine aminotransferase
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Blood urea nitrogen
Calcium
Chloride 
Glucose 
Creatinine
Inorganic phosphorus
Lactate dehydrogenase
Magnesium 
Potassium 
Sodium
Total and direct bilirubin 
Total carbon dioxide 
Total protein
Uric acid 

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Hematology
Hematocrit 
Hemoglobin 
Mean corpuscular volume
Platelets
White blood cell count and differential [1]
Coagulation
Partial thromboplastin time
International normalized ratio
Prothrombin time
Urinalysis
Bilirubin
Glucose 
Hemoglobin
Ketones 
Microscopy [2] 
pH
Protein
Specific gravity
1. 
Manual microscopic review is performed only if white blood cell count and/or differential values are 
out of reference range.  
2.
Microscopy is performed only as needed based on positive dipstick test results.
8.5
VITAL SIGN MEASUREMENTS
Vital sign measurements include oral or tympanic temperature (Celsius), heart rate (beats per 
minute), respiratory rate (breaths per minute), and blood pressure (mmHg). In addition, height will 
be measured at screening, whereas weight will be measured at both screening and Week 26 visits. 
Note that on the day of surgery, temperature, heart rate, respiratory rate, and blood pressure are to 
be measured before surgery, approximately every 30 minutes for at least the first 4 hours after start 
of infusion (this can be prolonged in 30-minute intervals if the infusion takes longer than 4 hours), 
and then at approximately 8 and 12 hours after the start of infusion. Of note, the participant may
be transferred to an inpatient hospital service for the assessment of vital signs between 4 hours and 
12 hours after start of infusion. 
8.6
ELECTROCARDIOGRAM
Standard 12-lead ECGs (ventricular rate, PR interval, QRS duration, and QT interval) is to be 
performed with the participant in a supine position having rested in this position for at least 
5 minutes before each reading.  
8.7 
IMMUNE RESPONSE 
Immune responses against AAV2 viral capsids and/or the AAV-GAD product will be assessed. 
Blood samples will be obtained to evaluate for anti-GAD antibodies and anti-AAV2 antibodies.  
Instructions for the collection, handling, storage, and shipment of samples are found in the 
Laboratory Manual that will be provided. Collection, handling, storage, and shipment of samples 
must be under the specified conditions, and where applicable, controlled-temperature conditions 
as indicated in the Laboratory Manual. 
The immunological studies will be conducted at one or more central laboratories. 

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8.8
RADIOGRAPHIC IMAGING  
Radiographic imaging of the head (CT or MRI) will be performed per site standard for assessments 
pre-, intra-, and post-operatively.  
Due to the retention of the nylon/titanium cranial anchor base above the skull as a burr hole cover 
following removal of the infusion system, the specific MRI conditions detailed in the IFU must be 
taken into account for all post-surgical MRI scans. Participants will also be provided with a patient 
implant card (in addition to the emergency card), which will specify the need to perform MRI 
scans under specific conditions. 
8.9
BLOOD VOLUME 
The total blood volume collected for the study is approximately 58.5 mL (Table 5).
Table 5:
Approximate Volume of Blood to be Collected 
Type of Sample
Approximate 
Volume per Sample 
(mL)
No. of Samples 
per Participant
Approximate  
Total Volume of Blood (mL)a 
Hematology 
2.0 
7
14.mL
Serum chemistry
3.5 
7
24.5 mL
Coagulation (PT/PTT) 
2.0 
2
4 mL 
Immunogenicity 
4.0 
4
16 mL
Approximate Totalb,c
 
 
58.5 mL
a. Calculated as number of samples multiplied by amount of blood per sample.
b. Repeat or unscheduled samples may be taken for safety reasons or technical issues with the samples. 
c.  Please refer to the Laboratory Manual for Sample Collection requirements 

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DATA COLLECTION AND MANAGEMENT  
9.1
DATA COLLECTION, MANAGEMENT AND ENTRY  
Electronic case report forms will be completed for each study participant. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, legibility, and timeliness of the data reported 
in the participant’s eCRF. The eCRFs must be reviewed and electronically signed by the 
Investigator. Source documentation supporting the eCRF data should indicate the participant’s 
participation in the study and should document the dates and details of study procedures, AEs, and 
participant status.
The Investigator, or designated representative, should complete the eCRF pages as soon as possible 
after information is collected, preferably on the same day that a study participant is seen or spoken 
to. Any outstanding entries must be completed immediately after the final visit. An explanation 
should be given for all missing data. 

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STATISTICAL ANALYSES
10.1
STATISTICAL METHODS
10.1.1 
General Considerations
Details for all analyses will be described in a Statistical Analysis Plan (SAP). 
Descriptive statistical methods will be used to summarize the data from this study with formal 
hypothesis testing performed for MDS-UPDRS Part 3 and GADRP. The descriptive methods used 
to summarize continuous variables will include the number of participants, mean, median, standard 
deviation, minimum, maximum, and quartiles. The descriptive methods used to summarize 
categorical data will include counts and percentages. 
10.1.2 
Analysis Populations 
Safety analyses will be performed using the Safety Population, defined as all participants who are 
randomized and receive treatment (AAV-GAD or sham). 
Efficacy analysis will be performed using the Intention-to-Treat (ITT) Population, defined as all 
participants who are randomized. 
10.1.3 
Analysis of Safety 
10.1.3.1 
Adverse Events 
AEs will be summarized by the Medical Dictionary for Regulatory Activities (MedDRA; latest 
version) system organ classification and preferred term.  
10.1.3.2 
Clinical Laboratory Evaluations 
Descriptive summaries of clinical laboratory results, including changes from baseline, will be 
presented by study visit. Numbers and percentages of participants with abnormalities will be 
tabulated. 
10.1.3.3 
Vital Sign Measurements 
Descriptive summaries of vital signs, including changes from baseline, will be presented by study 
visit. Numbers and percentages of participants with abnormalities, according to predefined criteria, 
will be tabulated. 
10.1.3.4 
Electrocardiograms 
ECG results will be reviewed for clinically notable abnormalities according to predefined criteria.  

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10.1.3.5 
Immunogenicity 
The number of participants with a positive immune response will be summarized. 
10.1.3.6 
Columbia-Suicide Severity Rating Scale
Descriptive summaries of the Columbia-Suicide Severity Rating Scale will be presented by study 
visit. 
10.1.3.7 
Other 
Descriptive summaries of findings on physical examination, neurological examination, CT, and 
MRI will be presented by study visit. 
10.1.4 
Analysis of Efficacy 
10.1.4.1 
Exploratory Efficacy Endpoints
The exploratory efficacy analyses will be performed at Weeks 12 and 26. 
Descriptive statistics will be presented for efficacy endpoints. Differences between the individual 
and pooled (when appropriate) AAV-GAD groups and the sham group in mean change from 
baseline to Weeks 12 and 26 will be compared for each of the endpoints.   
 
Additional sensitivity analyses will be described in the SAP. 
  
10.1.5 
Interim Analysis 
There is no interim analysis planned for this study.  
10.1.6 
Sample Size Determination 
This is a Phase 1/2 study to assess safety and tolerability of AAV-GAD produced using an updated 
production methodology, therefore, no formal sample size calculation was performed. Based upon 
experience with and data from the prior Phase 1 and 2 studies, it is estimated that inclusion of 

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approximately 14 participants (5 participants receiving AAV-GAD at a dose of 3.5 × 1010 vg/STN, 
5 participants receiving AAV-GAD at a dose of 10.45 × 1010 vg/STN and 4 participants
undergoing sham surgery) will be sufficient to determine safety and tolerability of AAV-GAD. 

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DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
11.1
STUDY MONITORING
Monitoring and auditing procedures developed by MeiraGTx/designee will be implemented to 
ensure compliance with the protocol, Declaration of Helsinki, ICH GCP, Directive 2001/20/EC, 
and the applicable regulatory requirements.  
The frequency, type and intensity of routine and triggered on-site or central/remote monitoring 
will be detailed in the study Monitoring Plan (MP). The MP will also detail the procedures for 
review and sign-off of monitoring reports.  
The sponsor’s designated representative (the monitor) will contact the Investigator and conduct 
regular visits to the study site. The monitor will be expected and allowed to verify the 
Investigator’s qualifications, to review study site facilities, and to inspect study records, including 
proof of Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review, with the 
stipulation that participant confidentiality will be maintained in accordance with local and Federal 
regulations, including Health Insurance Portability and Accountability Act requirements. The 
monitor will also be responsible for confirming adherence to the study protocol, reviewing eCRFs 
and source documents, and ensuring the integrity of the data. eCRFs will be checked for accuracy, 
completeness, and clarity and will be cross-checked for consistency with source documents, 
including laboratory test reports and other participant records. Instances of missing or 
uninterpretable data will be resolved in coordination with the Investigator.  
The monitor will also follow up on any questions concerning adherence to regulatory 
requirements. Any administrative concerns will be clarified and followed. The monitor will 
maintain contact with the site through frequent direct communications with the study site by email, 
telephone, facsimile, and mail. The Investigator and all other site personnel agree to cooperate 
fully with the monitor and will work in good faith with the monitor to resolve all questions raised, 
and difficulties detected by the monitor. 
11.2 
AUDITS AND INSPECTIONS 
The Investigator understands that regulatory authorities, the IRB/IEC, and/or MeiraGTx Quality 
Assurance auditors or designees have the right to access all eCRFs, source documents, and other 
study documentation for on-site audit or inspection and will retain this right from the start of the 
study to at least 2 years after the last approval of a marketing application or for at least 2 years 
after clinical development of the study drug for the indication being studied has been discontinued. 
The Investigator is required to guarantee access to these documents and to cooperate with and 
support such audits and inspections. The Investigator and study-site personnel are responsible for 
being present and available for consultation during study-site audit visits conducted by the Sponsor 
or its designees. 

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In the event of a request for a study site inspection by any regulatory authority, MeiraGTx must 
be notified as soon as possible. 
11.3
DIRECT ACCESS TO PARTICIPANT RECORDS
Participating Investigators must agree to allow study related monitoring, including audits, IRB/IEC 
review and regulatory inspections, by providing access to source data and other study-related 
documentation as required. Participant consent for this must be obtained as part of the informed 
consent process for the study. 
11.4 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS 
COMMITTEE  
The IRB/IEC must be a properly constituted board or committee operating in accordance with 
21 CFR Part 56, “Institutional Review Boards.” This protocol, any protocol amendments, and the 
associated informed consent forms must be submitted to the IRB/IEC for review and approved 
before the enrollment of any participant in the study. The Investigator is responsible for sending a 
copy of the letter or certificate of approval from the IRB/IEC for the protocol and any protocol 
amendments to the sponsor. 
All types of participant recruitment or advertising information must be submitted to 
MeiraGTx/designee and to the IRB/IEC for review and approval prior to implementation. IRB/IEC 
approval of any protocol amendments must be received before any of the changes outlined in the 
amendments are put into effect, except when the amendment has been enacted to eliminate a 
potential hazard to study participants. In such cases, the chair of the IRB/IEC should be notified 
immediately, and the amendment forwarded to the IRB/IEC for review and approval. 
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, e.g., 
recruitment advertisements from the IRB/IEC. All correspondence with the IRB/IEC should be 
retained in the Investigator file. Copies of IRB/IEC approvals should be forwarded to 
MeiraGTx/designee.
11.5
TRIAL OVERSIGHT 
Trial oversight is intended to preserve the integrity of the study by independently verifying a 
variety of processes and prompting corrective action and preventative actions where necessary. 
The processes reviewed relate to participant enrollment, consent, eligibility, and allocation to study 
groups; adherence to study interventions and policies to protect participants, including reporting 
of harms; and completeness, accuracy, and timeliness of data collection.  
In multicenter studies, oversight is considered and described both overall and for each recruiting 
center by exploring the study dataset or performing site visits as described in the study Monitoring 
Plan.

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ETHICS
12.1
ETHICAL CONDUCT OF THE STUDY 
The Investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current International Council for Harmonisation (ICH) guidelines on Good Clinical 
Practice (GCP), and applicable regulatory and country-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve the participation of human participants. 
Compliance with this standard provides public assurance that the rights, safety, and well-being of 
study participants are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible. 
12.2
WRITTEN INFORMED CONSENT
Written informed consent will be obtained from each participant by the Investigator or delegated 
clinician/staff member following appropriate explanation of the aims, methods, possible benefits, 
and risks of the study, allowing sufficient time for the potential participant to ask all questions s/he 
may have about the study. The Investigator or designee will explain that the participants are under 
no obligation to enter the study and that they can withdraw at any time during the study, without 
having to give a reason, and without their clinical care being affected. No clinical study-specified 
procedure will be conducted prior to obtaining consent from the participant. 
If new safety information results in significant changes in the risk/benefit assessment, the ICF will 
be reviewed and updated if necessary, and participants will be re-consented as appropriate. 
12.3 
CONFIDENTIALITY 
The Investigator must ensure that the participant’s privacy is maintained. The study protocol, 
documentation, data, and all other information generated will be held in strict confidence. No 
information concerning the study or data will be released to any unauthorized third party without 
prior written approval of the sponsor. 
12.4 
PROTOCOL AMENDMENTS 
All amendments to the protocol must be documented in writing, reviewed, and approved by the 
Investigator and the sponsor, and submitted to the IRB/EC/CEC for approval prior to initiation, 
except in cases where required for participant safety. Protocol amendments must be submitted to 
the relevant Competent Authorities in accordance with regulatory requirements. If the protocol 
amendment substantially alters the study design or potential risk to the participant, a new written 
ICF for continued participation in the study must be obtained from each participant or their legal 
representative. 
 

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DATA HANDLING AND RECORDKEEPING
13.1
INSPECTION OF RECORDS
The Investigator shall permit authorized representatives of the sponsor, regulatory authorities, and 
IRB/IECs to review the portion of the participant’s medical record that is directly related to the 
study. As part of the required content of the ICF, the participant must be informed that their records 
will be reviewed in this manner.
13.2
RETENTION OF RECORDS 
In compliance with the ICH/GCP guidelines, the Investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents 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 after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. 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 the responsible Investigator retires, relocates, or for other reasons withdraws from the 
responsibility of retention of study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the Investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor. 
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the Investigator/institution must permit access to such reports.
13.3
PUBLICATION OF STUDY DATA
Following completion of the study, the data may be considered for publication in a scientific 
journal and/or for reporting at a scientific meeting by the Sponsor and/or Investigators. However, 
the Sponsor shall have the right to the first publication of the study data, including as part of a 
joint, multi-center publication (Sponsor in conjunction with Investigators from all appropriate sites 
contributing data, analysis and comments). For other publications, the Investigator must consult 
with the Sponsor before any study data are submitted for publication. The Sponsor reserves the 
right to delay publication until mutual agreement on the content, format, accuracy, interpretation 
of data in the manuscript, and journal selected for publication are achieved, as well as to protect 

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Sponsor’s interests in its intellectual property (the publication is to be in accordance with the terms 
of the clinical trial agreement).  
In addition, this clinical study must be registered with ClinicalTrials.gov, which will be done by 
the sponsor/designee. 

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REFERENCES 
Emborg, M. E., M. Carbon, J. E. Holden, M. J. During, Y. Ma, C. Tang, J. Moirano, H. Fitzsimons, 
B. Z. Roitberg, E. Tuccar, A. Roberts, M. G. Kaplitt and D. Eidelberg (2007). "Subthalamic 
glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism." J 
Cereb Blood Flow Metab 27(3): 501-509. 
Feigin, A., M. G. Kaplitt, C. Tang, T. Lin, P. Mattis, V. Dhawan, M. J. During and D. Eidelberg 
(2007). "Modulation of metabolic brain networks after subthalamic gene therapy for Parkinson's 
disease." Proc Natl Acad Sci U S A 104(49): 19559-19564. 
Hamani, C., J. A. Saint-Cyr, J. Fraser, M. Kaplitt and A. M. Lozano (2004). "The subthalamic 
nucleus in the context of movement disorders." Brain 127(Pt 1): 4-20. 
Kaplitt, M. G., A. Feigin, C. Tang, H. L. Fitzsimons, P. Mattis, P. A. Lawlor, R. J. Bland, D. 
Young, K. Strybing, D. Eidelberg and M. J. During (2007). "Safety and tolerability of gene therapy 
with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, 
phase I trial." Lancet 369(9579): 2097-2105. 
LeWitt, P. A., A. R. Rezai, M. A. Leehey, S. G. Ojemann, A. W. Flaherty, E. N. Eskandar, S. K. 
Kostyk, K. Thomas, A. Sarkar, M. S. Siddiqui, S. B. Tatter, J. M. Schwalb, K. L. Poston, J. M. 
Henderson, R. M. Kurlan, I. H. Richard, L. Van Meter, C. V. Sapan, M. J. During, M. G. Kaplitt 
and A. Feigin (2011). "AAV2-GAD gene therapy for advanced Parkinson's disease: a double-
blind, sham-surgery controlled, randomised trial." Lancet Neurol 10(4): 309-319. 
Luo, J., M. G. Kaplitt, H. L. Fitzsimons, D. S. Zuzga, Y. Liu, M. L. Oshinsky and M. J. During 
(2002). "Subthalamic GAD gene therapy in a Parkinson's disease rat model." Science 298(5592): 
425-429. 
Niethammer, M., C. C. Tang, P. A. LeWitt, A. R. Rezai, M. A. Leehey, S. G. Ojemann, A. W. 
Flaherty, E. N. Eskandar, S. K. Kostyk, A. Sarkar, M. S. Siddiqui, S. B. Tatter, J. M. Schwalb, K. 
L. Poston, J. M. Henderson, R. M. Kurlan, I. H. Richard, C. V. Sapan, D. Eidelberg, M. J. During, 
M. G. Kaplitt and A. Feigin (2017). "Long-term follow-up of a randomized AAV2-GAD gene 
therapy trial for Parkinson's disease." JCI Insight 2(7): e90133. 
Niethammer, M., C. C. Tang, A. Vo, N. Nguyen, P. Spetsieris, V. Dhawan, Y. Ma, M. Small, A. 
Feigin, M. J. During, M. G. Kaplitt and D. Eidelberg (2018). "Gene therapy reduces Parkinson's 
disease symptoms by reorganizing functional brain connectivity." Sci Transl Med 10(469). 
Rus, T., P. Tomse, L. Jensterle, M. Grmek, Z. Pirtosek, D. Eidelberg, C. Tang and M. Trost (2020). 
"Differential diagnosis of parkinsonian syndromes: a comparison of clinical and automated - 
metabolic brain patterns' based approach." Eur J Nucl Med Mol Imaging 47(12): 2901-2910. 
Tang, C. C., K. L. Poston, T. Eckert, A. Feigin, S. Frucht, M. Gudesblatt, V. Dhawan, M. Lesser, 
J. P. Vonsattel, S. Fahn and D. Eidelberg (2010). "Differential diagnosis of parkinsonism: a 
metabolic imaging study using pattern analysis." Lancet Neurol 9(2): 149-158. 
Tripathi, M., C. C. Tang, A. Feigin, I. De Lucia, A. Nazem, V. Dhawan and D. Eidelberg (2016). 
"Automated Differential Diagnosis of Early Parkinsonism Using Metabolic Brain Networks: A 
Validation Study." J Nucl Med 57(1): 60-66. 

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APPENDIX: 
GUIDANCE ON STUDY CONDUCT DURING THE 
COVID-19 PANDEMIC 
The measures outlined in this Appendix are temporary, while access to sites is restricted 
during the COVID-19 pandemic. As restrictions are lifted, the decision to revert back to 
the protocol in effect prior to the pandemic should be discussed and agreed with the 
sponsor.  
It is recognized that the Coronavirus Disease 2019 (COVID-19) pandemic may have an impact on 
the conduct of this clinical study due to, for example, self-isolation/quarantine by participants and 
study-site personnel; travel restrictions/limited access to public places, including hospitals; study 
site personnel being reassigned to critical tasks. 
In alignment with recent health authority guidance, the sponsor is providing options for study 
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgement of the 
Investigator to protect the health and well-being of participants and site staff.  
Every effort should be made to adhere to protocol-specified assessments for participants on study 
intervention, including follow-up. Modifications to protocol-required assessments may be 
permitted after consultation between the participant and Investigator, and with the agreement of 
the sponsor. Missed assessments/visits will be captured for protocol deviations. Discontinuations 
of study interventions and withdrawal from the study should be documented with the prefix 
“COVID-19-related” in the case report form.
Scheduled visits that cannot be conducted in person at the study site will be performed 
remotely/virtually, and site-based evaluations may be delayed until such time that on-site visits 
can be resumed. At each contact, participants will be interviewed to collect safety data. Key 
efficacy and safety endpoint assessments should be performed as feasible. Participants will also 
be questioned regarding general health status to fulfill any physical examination requirement.  
The sponsor will continue to monitor the conduct and progress of the clinical study and any 
changes (e.g., delay or discontinuation in recruitment, site monitoring and audits) will be 
communicated to the sites and health authorities according to local guidance. If a participant has 
tested positive for COVID 19, the Investigator should contact the sponsor’s responsible medical 
officer to discuss plans for study intervention and follow-up. Modifications made to the study 
conduct as a result of the COVID-19 pandemic should be summarized in the clinical study report.  
GUIDANCE SPECIFIC TO THIS PROTOCOL  
Each participant will be risk assessed on a case-by-case basis by the Investigator and his/her 
research team to decide the appropriate care for the participant.  
 

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Item 
no
Item
Management of Item
1  
Missed assessments
Missed assessments will be captured as a deviation 
with the prefix COVID-19 RELATED.  
2
Protocol Deviations   
Any deviations to the study protocol due to COVID-19 
pandemic will be captured with the prefix COVID-19 
RELATED.  
3
Participant missing any scheduled 
visits  
If scheduled visits cannot be conducted within the visit 
window, the site can schedule an additional visit at the 
earliest opportunity the participant is able to travel,
4  
Participants may be unable to attend 
study visit during visit window.
It is acknowledged that this is a global crisis 
and participants may be put at more risk attending 
hospital appointments due to route of travel to the
research facility. If appropriate, the sponsor will offer 
expenses for taxi fares to avoid busy train or bus 
routes.  
 
5  
Participants visits conducted outside of 
visit window  
Participants will be assessed individually by the sites 
on a case by case basis and phone interviews may be 
conducted by sites for all post-treatment visits up until 
-surgery.   
Participants undergoing telephone assessment will be 
asked to provide information on any adverse events or 
other safety concerns.
6  
Participants self-quarantined or 
government implemented quarantine.  
If participants and/or their caregivers are under 
quarantine and unable to leave home, their cases will be 
assessed by medical monitors and PI as to risk of 
delayed appointment. (e.g., ongoing AEs, date of last 
appointment, less than 3 months since intervention). 
7  
Potential lack of reporting of symptoms 
due to delayed visits  
  
Delayed reporting of SAEs, SARs & 
SUSARs- Potential for events to not be 
reported within 24 hours of occurrence
Delayed Participant reporting of 
Adverse Events
All participants are provided with emergency cards on 
enrollment to the study to enable 24-hour contact with 
study investigators. 
All serious adverse events should be reported by an 
Investigator (as assigned on the delegation log) or 
another member of the site team, in the Investigators 
event occurring.  
Reminder of importance to report any new 
AEs/symptoms to be communicated to participants by 
the sites during this time.  
8  
Emergencies during the study and the 
provision of emergency contact 
arrangements:  
  
If a participant encounters difficulties in contacting the 
Trial Team in the event of emergencies, s/he has been 
provided with an alert card to inform other healthcare 
providers of their participation in the gene therapy trial. 
The Trial card includes the 24 hour/7-day contact 
number, participant’s trial code, trial number, and brief 
details of the trial intervention.  

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Assessment results outside of window 
not true representation of protocol 
stated timepoints
Participant safety will be the most important factor to 
consider. Participants will complete visits as close to 
the visit window as possible and deviations will be
recorded where applicable.  
10
Clinician(s) and site research staff 
unavailable due to contraction of virus
Site to ensure appropriate staff are available and are 
documented on the delegation log to provide medical 
coverage if the Investigator is unavailable.
11  
Monitor may not be allowed on site or 
may be quarantined and unable to visit.
Monitors will be encouraged to attend the sites where 
and when possible. If they are unable to do so, they will 
conduct remote monitoring as much as possible and 
arrange as many visits as required to get back on track 
once the site re-opens.