Clinical trial NCT04193527
Conditions: Parkinsonian Syndrome Parkinson Disease(PD) Multiple System Atrophy (MSA) Progressive Supranuclear Palsy (PSP) Essential Tremor
Sponsor: GE Healthcare
Start date: 2020-06-28; Completion date: 2021-12-20
Enrollment: 172 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter, open-label, non-controlled, non-randomized, phase 3 clinical study to compare the SPECT findings after a single IV administration of DaTSCAN™ ioflupane (123I) injection for patients with a clinical diagnosis of Parkinsonian syndrome (PS) involving striatal dopaminergic deficit (SDD; specifically, Parkinson's disease \[PD\] \[SDD\], multiple system atrophy \[MSA\] \[SDD\] or or progressive supranuclear palsy \[PSP\] \[SDD\]) as compared with patients with a clinical diagnosis of essential tremor (ET) (no SDD) and age-matched healthy controls.

Detailed description:

Arms: arm 1: Participants with Parkinsonian Syndrome (PS), Essential Tremor (ET), and Healthy Volunteers (HV) received a single dose of DaTSCAN™ ioflupane (123I) injection. Single photon emission computed tomography (SPECT) imaging was performed between 3 to 6 hours post-injection and lasted approximately 20 minutes to 1 hour.
Interventions: intervention 1: DaTSCAN™ Ioflupane (123I) Injection
Intervention descriptions: intervention 1: All participants (Participants with PS, ET, and HV) received a single dose of DaTSCAN™ ioflupane (123I) injection within the range of 111 to 185 megabecquerel (MBq) (3 to 5 millicurie \[mCi\]) per participant at a maximum volume of 5 milliliter \[mL\]) intravenously on Day 1.

Protocol documents:
Prot_000.pdf: 
GE Confidential 
Page 1 of 75 
Clinical Study Protocol 
GE Healthcare 
GE-001-024 
Title: A multicentre, phase 3, clinical study to compare the striatal uptake of a dopamine 
transporter radioligand, DaTSCAN™ ioflupane (123I) injection, after intravenous 
administration to Chinese patients with a diagnosis of Parkinson’s disease, multiple system 
atrophy, progressive supranuclear palsy, or essential tremor and to healthy controls 
REVISED TO INCORPORATE AMENDMENT A03 
Sponsor 
GE Healthcare Ltd. and its Affiliates (hereinafter referred to as the “sponsor”) 
Pollards Wood 
Nightingales Lane 
Chalfont St Giles 
HP8 4SP 
United Kingdom 
Medical Director 
 
GE Healthcare 
Pollards Wood 
Nightingales Lane 
Chalfont St Giles 
Buckinghamshire 
HP8 4SP United Kingdom 
 
 
Confidentiality Statement 
This protocol is provided for conducting a clinical research study. The information contained in 
this document is confidential and, except to the extent necessary to obtain informed consent or 
IEC/IRB approval, cannot be disclosed unless required by governmental regulation. Persons to 
whom any portion of the contents of this document is disclosed must be informed that the 
information is confidential and may not be further disclosed by them. 
GE-001-024 Protocol Am
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Investigators' Signature Page 
I have read this protocol and all associated case report forms and agree to conduct this study in 
full accordance with the stipulations of the protocol described herein. 
 
 
 
Signature 
 
 
 
Date 
Print Name 
 
 
 
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1 
SYNOPSIS 
Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
DaTSCAN™ ioflupane (123I) 
injection 
Name of Active Ingredient: 
[123I]Ioflupane  
Title of Study: A multicentre, phase 3, clinical study to compare the striatal uptake of a dopamine 
transporter radioligand, DaTSCAN™ ioflupane (123I) injection, after intravenous administration to Chinese 
patients with a diagnosis of Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, or 
essential tremor and to healthy controls 
Protocol Number: GE-001-024 
Investigators and Study Centres: Approximately 10 centres in the People's Republic of China 
Phase of Development: Phase 3 
Objectives:  
Primary Objective: 
• To determine the sensitivity and specificity of a measure of striatal uptake of [123I]ioflupane as visualised 
in single photon emission computed tomography (SPECT) images taken 3 to 6 hours after a single 
intravenous (IV) administration of DaTSCAN™ ioflupane (123I) injection (111 to 185 MBq [3 to 5 mCi]) 
for the diagnosis of Parkinsonian syndrome (PS) involving striatal dopaminergic deficit (SDD; 
specifically, Parkinson’s disease [PD], multiple system atrophy [MSA], or progressive supranuclear palsy 
[PSP]) as opposed to essential tremor (ET; no SDD) or no neurologic disease (healthy volunteers [HVs]) 
in Chinese subjects.  
Secondary Objectives: 
• To assess the striatal uptake of [123I]ioflupane in healthy Chinese volunteers (no SDD). 
• To assess safety parameters (haematology, biochemistry and urinalysis, and vital signs) and the adverse 
event (AE) profile in Chinese patients/HVs after a single IV administration of DaTSCAN™ ioflupane 
(123I) injection. 
Study Design  
This is a multicentre, open-label, non-controlled, non-randomised clinical study to compare the SPECT 
findings after a single IV administration of DaTSCAN™ ioflupane (123I) injection for patients with a clinical 
diagnosis of PS (SDD; specifically, patients with PD [SDD], MSA [SDD] or PSP [SDD]) as compared with 
patients with a clinical diagnosis of ET (no SDD) and age-matched healthy controls. 
Selection of Subjects:  
Inclusion Criteria: 
For all subjects: 
1. 
Chinese male or female, aged 40 to 80 years, has agreed to sign and date the written informed consent 
form. 
For HVs:  
2. 
Non-patient volunteers with good age-appropriate health as established by clinical examination during 
screening and no evidence of movement disorder by complete neurological evaluation. 
For patients with PD: 
3. 
A diagnosis of clinically established or clinically probable PD in accordance with the MDS Clinical 
Diagnostic Criteria for Parkinson’s Disease [Postuma et al. 2015]. 
For patients with MSA (SDD): 
4. 
A diagnosis of probable or possible MSA in accordance with the Second Consensus Statement on the 
Diagnosis of MSA [Gilman et al. 2008].  
For patients with PSP (SDD): 
5. 
A diagnosis of probable or possible PSP in accordance with the Clinical Criteria for the Diagnosis of 
Progressive Supranuclear Palsy National Institute for Neurological Disorders and Society for PSP 
(NINDS-SPSP) [Litvan et al. 1996]. 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
DaTSCAN™ ioflupane (123I) 
injection 
Name of Active Ingredient: 
[123I]Ioflupane  
For patients with ET (no SDD) 
6. 
A diagnosis of definite or probable ET in accordance with the Washington Heights-Inwood Genetic 
Study of Essential Tremor (WHIGET) diagnostic criteria for ET (no SDD) [Louis et al. 1997]. 
Exclusion Criteria 
1. 
The subject is lactating. 
2. 
The subject is pregnant as detected by a β-human chorionic gonadotropin (β-hCG) pregnancy test. 
3. 
A cerebral structural vascular abnormality indicative of at least 1 infarction in the region of the basal 
ganglia (including the internal capsule) ≥5 mm has been confirmed, preferably by magnetic resonance 
imaging (MRI) performed within 6 months of screening. If an MRI is not clinically feasible, cerebral 
CT imaging within 6 months is also acceptable. 
4. 
The subject is diagnosed with major neurocognitive disorder by the Diagnostic and Statistical Manual 
of Mental Disorders (DSM) 5 criteria, or Mini-Mental State Examination total score is <24. 
5. 
Subject is being investigated for or has been diagnosed and/or is being treated for repeated stroke with 
stepwise progression of Parkinson features. 
6. 
History of repeated head injury (≥3 concussions, or history of professional sports with repeated head 
trauma [e.g., boxing]). 
7. 
History of definite encephalitis (≥1 episode of confirmed encephalitis with objective residual 
neurologic deficit). 
8. 
The subject is using or has insufficient washout from medication known or suspected to interact with 
striatal uptake through direct competition with binding of DaTSCAN™ to the dopamine transporters 
(i.e., amphetamine, benztropine, bupropion, cocaine, mazindol, methylphenidate, phentermine, 
sertraline, selective serotonin reuptake inhibitors) before the imaging visit. 
9. 
The patient is using Chinese traditional medicine for PD treatment, which cannot be safely withdrawn 
for at least 1 week (7 days) before the imaging visit. 
10. The subject has a moderate to severe renal impairment (i.e., serum creatinine 1.5 upper limit of 
normal [ULN], or blood urea nitrogen [BUN] 30 mg/dL). 
11. The subject has a moderate to severe hepatic impairment (bilirubin 2 ULN and alanine 
aminotransferase (ALT) or aspartate aminotransferase (AST) 3 ULN). 
12. The subject has a history of current abuse of drugs and/or alcohol (for the previous 12 months before 
trial enrolment). 
13. The subject has a history of occupational exposure to any radiation >50 mSv/year. 
14. The subject has been previously enrolled in this study or participated in a clinical study involving an 
investigational pharmaceutical product within 30 days prior to screening and/or any 
radiopharmaceutical within a minimum of 5 radioactive half-lives prior to screening. 
15. The subject presents with symptoms suggestive of corticobasal degeneration or Huntington’s disease. 
16. The subject has known allergies to the investigational medicinal product (IMP). 
17. The subject presents with any clinically active, serious, life-threatening disease with a life expectancy 
of less than 12 months.  
18. Any laboratory value(s) exceeding the limits of normality if deemed to be clinically relevant by the 
investigator. 
19. The subject complains of claustrophobia. 
20. The subject has a moderate to severe thyroid disease (thyroid stimulating hormone exceeding the limits 
of normality by more than 10%), if deemed to be clinically relevant by the investigator. 
For patients with ET:  
21. The patient has at least 1 first-degree relative diagnosed with PD. 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
DaTSCAN™ ioflupane (123I) 
injection 
Name of Active Ingredient: 
[123I]Ioflupane  
For HVs: 
22. History of psychiatric illness. 
For all subjects: 
23. It is the physician’s best judgment not to include the patient in the trial. 
Number of Subjects/Centres Planned:  It is expected that 150 patients with movement disorders (with and 
without SDD) and 22 HVs will be needed to provide 140 evaluable subjects (60 with movement disorder and 
SDD, 60 with movement disorder but without SDD, 20 HVs) at approximately 10 centres in China. 
Treatment of Subjects: 
Investigational Medicinal Product: DaTSCAN™, a single IV injection containing 111 to 185 MBq (3 to 
5 mCi).  
Control: None. 
Comparator: None. 
Standard of Truth: Clinical diagnosis as established at entry (baseline visit) in specialised medical centres. 
Adjunctive Drugs: None. 
Duration of Treatment: 1 day for injection and scanning and 3 (±1) days post-injection for a final follow-up 
visit.  
Efficacy and Safety Variables 
Primary Endpoint:  
• Assessment of DaTSCAN™ SPECT images by 3 independent blinded readers to compare specific striatal 
uptake with the clinical diagnosis.  
Secondary Endpoints: 
• Central read (by semi-quantitative assessment by use of DaTQUANT™) of DaTSCANTM SPECT images 
to compare specific uptake with clinical diagnosis. 
• Comparison and assessment of safety parameters and AEs reported by all study participants. 
Standard of Truth:  
The clinical diagnosis as established by the investigator at the recruiting centres according to internationally 
accepted diagnostic criteria and based on a standardised and comprehensive clinical and neuropsychiatric 
assessment will be the standard of truth used for determining sensitivity and specificity.  
Safety: 
Imaging visit: DaTSCAN™-emergent AEs, injection site monitoring, and vital signs (blood pressure, heart 
rate). 
3 (±1) days post-injection: AEs, physical examination, neurological examination, vital signs (blood pressure 
and heart rate), clinical laboratory evaluations (haematology, serum biochemistry, and urinalysis), and 
concomitant medications. 
Statistical Methods and Planned Analysis:  
Primary Efficacy Analysis:  
The sensitivity and specificity of the blinded independent read of DaTSCAN™ SPECT images in detecting 
or excluding SDD, when the clinical diagnosis as established by the investigator is used as the standard of 
truth, will be summarised with both by-reader and majority-read analyses. For each summary, the computed 
value and the 95% 2-sided confidence interval will be presented for both sensitivity and specificity. In this 
study, sensitivity will be defined as positive percentage agreement, and specificity will be defined as negative 
percentage agreement. For the specificity analysis, only subjects with a clinical diagnosis of ET will be 
included; the HVs will be excluded from this analysis.  Accuracy will be calculated, and a 2-sided binomial 
confidence interval constructed around it. 
 
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
DaTSCAN™ ioflupane (123I) 
injection 
Name of Active Ingredient: 
[123I]Ioflupane  
Secondary Efficacy Analyses: 
A semi-quantitative analysis of the striatal uptake ratios in specific regions of interest (ROIs; i.e., left and 
right striatum, caudate, and putamen) of DaTSCAN™ SPECT images will be performed with DaTQUANT™. 
To account for nonspecific binding, the DaTSCAN™ uptake in the ROI will be normalised to DaTSCAN™ 
uptake in the subject's occipital cortex. The normalised DaTSCAN™ uptake values for each ROI will be 
summarised with descriptive statistics for each category of subjects with SDD (PD, MSA, or PSP) and each 
category of subjects without SDD (ET and HVs). For all striatal uptake ratios, an analysis of variance 
(ANOVA) will be carried out to test for differences in the striatal uptake ratios among the clinical diagnosis 
groups.   
Safety Analyses: 
All safety data will be listed by subject group, subject number, and time point (if applicable). No inferential 
testing will be performed for safety parameters. 
• An overall summary of AEs and DaTSCAN™-emergent AEs will be presented, coded with Medical 
Dictionary for Regulatory Activities (MedDRA) and summarised by MedDRA system-organ class and 
preferred term.  
• Observations and changes from baseline in the results of the physical examination (including vital signs), 
neurological examination, injection site monitoring, and clinical laboratory evaluations (haematology, 
serum biochemistry, and urinalysis) will be summarised.  
Study Populations 
The efficacy analysis will be performed for the full analysis set (FAS), which will consist of all subjects who 
have both a DaTSCAN™ image set and a clinical diagnosis made by the investigator. 
The per-protocol (PP) population will include all subjects who meet the inclusion/exclusion criteria and did 
not withdraw informed consent (if applicable), and who have DaTSCAN™ image sets that are considered 
evaluable by at least 2 of the 3 blinded readers. Subjects considered for PP population include subjects in the 
FAS with no major protocol violations. Subjects with protocol violations will be excluded from the PP 
population but will be included in the FAS.  
All subjects who receive an injection of IMP will be included in the safety population. 
Sample Size Estimation: 
Although the primary efficacy analysis is not inferentially based, sample size calculations are based on 
hypothesis testing separately for sensitivity and specificity, assuming 1-sided alpha of 0.05, statistical power 
of 80%, and assumed sensitivity and specificity of 95%. 
The null hypothesis tests are given as H0: p ≤ p0 where p0 is the specified threshold. The alternate hypothesis 
is given by Ha: p>p0. The parameter p represents the sensitivity/specificity of the blinded independent read of 
DaTSCAN™ SPECT images in detecting or excluding SDD, using the clinical diagnosis as established by 
the investigator as the standard of truth.  
An exact binomial test with a nominal 0.05 1-sided significance level will have 80% power to detect the 
difference between the null hypothesis diagnostic sensitivity threshold of 0.85 and the assumed alternative 
proportion of 0.95 when the sample size is 59 subjects with SDD present. 
An exact binomial test with a nominal 0.05 1-sided significance level will have 80% power to detect the 
difference between the null hypothesis diagnostic specificity threshold of 0.85 and the assumed alternative 
proportion of 0.95 when the sample size is 59 subjects with SDD absent.  
An extensive set of values for the specified threshold, p0, and the resultant sample size (for either sensitivity 
or specificity) are as follows: P0 = 0.89: n=128; P0 = 0.88: n=107; P0 = 0.87: n= 89; P0 = 0.86: n= 73; P0 = 
0.85: n= 59; P0 = 0.84: n= 55; P0 = 0.83: n= 44; P0 = 0.82: n= 41; P0 = 0.81: n= 39; P0 = 0.80: n=30.  
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Name of Sponsor/Company: 
GE Healthcare Ltd. and its 
Affiliates 
Individual Study Table 
Referring to Part of Dossier in 
Which the Individual Study or 
Study Table is Presented: 
 
Volume: 
 
Reference: 
 
(For National Authority Use 
Only) 
 
Name of Finished Product: 
DaTSCAN™ ioflupane (123I) 
injection 
Name of Active Ingredient: 
[123I]Ioflupane  
However, according to regulatory guidelines sample size for a new product with more than 1 indication 
(which is the case for DaTSCAN) requires a minimum of 60 pairs of cases. Therefore, the final number of 
evaluable diseased individuals will be 60 in each group (SDD present and absent). 
In addition to the 120 evaluable subjects (subjects with movement disorder), each centre will be requested to 
recruit 2 to 4 HVs (subjects without movement disorder) for the sole purpose of the creation of a normal 
database. A total of 20 HVs will be recruited across the centres. These subjects will also be included in the 
safety analysis. 
On the basis of a previous study (DP008-003), it is projected that evaluable results will be obtained from 
80% of diseased individuals and 90% of HVs. After adjustment for losses, it is therefore expected that 150 
patients with movement disorders (with and without SDD) and 22 HVs will be needed to provide at least the 
minimum required number of evaluable patients. 
 
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2 
TABLE OF CONTENTS 
2.1 
Overall Table of Contents 
Page Number 
1 
SYNOPSIS ..................................................................................................................... 3 
2 
TABLE OF CONTENTS ............................................................................................... 8 
2.1 
Overall Table of Contents .................................................................................. 8 
2.2 
List of Tables .................................................................................................... 11 
2.3 
List of Figures ................................................................................................... 11 
3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 12 
4 
BACKGROUND INFORMATION ............................................................................. 14 
5 
STUDY OBJECTIVES AND PURPOSE .................................................................... 15 
6 
STUDY DESIGN ......................................................................................................... 16 
6.1 
Overall Study Design and Plan ......................................................................... 16 
6.2 
Study Rationale ................................................................................................ 19 
6.2.1 
Justification for the efficacy analysis of diagnosis of PS ............... 19 
6.2.2 
Justification for dose and volume ................................................... 19 
6.2.3 
Justification for prohibited and permitted medication .................... 19 
6.2.4 
Justification of safety plan .............................................................. 20 
6.3 
Study Timeframe .............................................................................................. 20 
6.4 
Risks and Benefits to Subjects.......................................................................... 20 
7 
SELECTION AND WITHDRAWAL OF SUBJECTS................................................ 22 
7.1 
Procedures for Enrolment ................................................................................. 22 
7.2 
Inclusion Criteria .............................................................................................. 22 
7.3 
Exclusion Criteria ............................................................................................. 23 
7.4 
Withdrawal and Termination Criteria............................................................... 25 
7.4.1 
Subject withdrawal ......................................................................... 25 
7.4.2 
Study or site termination ................................................................ 25 
8 
TREATMENT OF SUBJECTS .................................................................................... 26 
8.1 
Description of Medicinal Products ................................................................... 26 
8.1.1 
Investigational medicinal product: DaTSCAN™ ioflupane (123I) 
injection .......................................................................................... 26 
8.1.2 
IMP accountability ......................................................................... 26 
8.1.3 
Registration of investigational medicinal product(s) complaints ... 27 
8.1.4 
Other medicinal products: Thyroid-blocking treatment ................. 27 
8.2 
Method of Numbering Subjects and Assigning Subjects to Treatment Groups27 
8.3 
Selection of Doses and Timing ......................................................................... 28 
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8.4 
Blinding ............................................................................................................ 28 
8.5 
Prior and Concurrent Therapy .......................................................................... 28 
8.5.1 
Permitted concomitant medications................................................ 29 
8.6 
Treatment Compliance ..................................................................................... 29 
9 
STUDY PROCEDURES .............................................................................................. 30 
9.1 
Screening Visit ................................................................................................. 32 
9.2 
Baseline Visit .................................................................................................... 33 
9.3 
Imaging Visit .................................................................................................... 33 
9.4 
Follow-up Visit (3 [±1] days after injection).................................................... 34 
9.5 
Unscheduled Visits ........................................................................................... 34 
10 
EFFICACY, SAFETY, AND OTHER VARIABLES ................................................. 35 
10.1 
Efficacy Assessments ....................................................................................... 35 
10.1.1 
Primary endpoint ............................................................................ 35 
10.1.2 
Secondary endpoints ....................................................................... 35 
10.2 
Technical Requirements for DaTSCAN™ SPECT Image Acquisition ........... 35 
10.2.1 
Image acquisition ............................................................................ 35 
10.2.2 
Standard of truth ............................................................................. 35 
10.2.3 
Image interpretation and correlation with standard of truth ........... 36 
10.3 
Safety Assessments .......................................................................................... 37 
10.3.1 
Physical examinations .................................................................... 37 
10.3.2 
Vital signs ....................................................................................... 38 
10.3.3 
Clinical laboratory evaluation ........................................................ 39 
10.3.4 
Injection site monitoring ................................................................. 40 
10.3.5 
Adverse events ................................................................................ 40 
10.3.6 
Other significant adverse events ..................................................... 42 
10.3.7 
Adverse event and serious adverse event reporting........................ 42 
10.3.8 
Urgent safety measures ................................................................... 43 
10.4 
Other Variables ................................................................................................. 44 
10.4.1 
Demographic data ........................................................................... 44 
10.4.2 
Medical and surgical history........................................................... 44 
10.4.3 
Prior and concomitant medication .................................................. 44 
10.4.4 
Drug and alcohol screening ............................................................ 44 
10.4.5 
Neuropsychiatric assessments ........................................................ 45 
10.4.6 
Investigator’s clinical diagnosis ..................................................... 45 
10.5 
Appropriateness of Measurements ................................................................... 46 
11 
DATA HANDLING AND QUALITY ASSURANCE ................................................ 47 
11.1 
Completing and Signing Case Report Forms ................................................... 47 
11.2 
Clinical Data Management ............................................................................... 47 
11.3 
Archiving .......................................................................................................... 47 
12 
STATISTICAL METHODS AND PLANNED ANALYSIS ...................................... 48 
12.1 
General Statistical Considerations .................................................................... 48 
12.2 
Populations for Analysis ................................................................................... 48 
12.2.1 
Full analysis set (FAS) ................................................................... 48 
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12.2.2 
Per-protocol (PP) population .......................................................... 48 
12.2.3 
Safety population ............................................................................ 49 
12.3 
Subject Demographics/Other Baseline Characteristics .................................... 49 
12.3.1 
Subject disposition .......................................................................... 49 
12.3.2 
Demographic data ........................................................................... 49 
12.3.3 
Risk factors and medical history .................................................... 49 
12.3.4 
Clinical diagnosis ........................................................................... 49 
12.4 
Study Treatments .............................................................................................. 49 
12.4.1 
Previous and concurrent medication............................................... 49 
12.4.2 
Exposure to IMP ............................................................................. 50 
12.4.3 
Thyroid blockade ............................................................................ 50 
12.4.4 
Handling of uninterpretable images as determined by the BIE ...... 50 
12.4.5 
Handling of uninterpretable images ............................................... 50 
12.4.6 
Reader difference ............................................................................ 50 
12.5 
Efficacy Analysis .............................................................................................. 50 
12.5.1 
Primary efficacy analysis................................................................ 51 
12.5.2 
Secondary efficacy analyses ........................................................... 51 
12.6 
Safety Analyses ................................................................................................ 52 
12.6.1 
Safety variables and analyses ......................................................... 52 
12.7 
Sample Size Calculation ................................................................................... 53 
12.8 
Power for Analysis of Critical Secondary Variables ........................................ 54 
12.9 
Procedures for Missing, Unused and Spurious Data ........................................ 54 
12.10 Rules for Excluding Subjects from Analysis .................................................... 54 
12.11 Procedures for Reporting Deviations from Original Statistical Plan ............... 55 
13 
SPECIAL REQUIREMENTS AND PROCEDURES ................................................. 56 
13.1 
Regulatory, Institutional and Ethical Review ................................................... 56 
13.2 
Investigator’s Responsibilities .......................................................................... 56 
13.2.1 
Overall responsibilities ................................................................... 56 
13.2.2 
Subject informed consent ............................................................... 56 
13.2.3 
Direct access to source data/documents ......................................... 57 
13.2.4 
Confidentiality regarding study subjects ........................................ 57 
13.3 
Protocol Deviations .......................................................................................... 57 
13.4 
Study Monitoring .............................................................................................. 57 
13.5 
Audit and Inspection ......................................................................................... 57 
13.6 
Radioactive Licence Requirements .................................................................. 58 
13.7 
Insurance ........................................................................................................... 58 
13.8 
Publication Policy ............................................................................................. 58 
14 
REFERENCES ............................................................................................................. 59 
15 
APPENDICES .............................................................................................................. 62 
15.1 
Clinical Diagnostic Criteria .............................................................................. 62 
15.1.1 
MDS Clinical Diagnostic Criteria for Parkinson’s Disease 
[Postuma et al. 2015] ...................................................................... 62 
15.1.2 
Second Consensus Statement on the Diagnosis of Multiple 
System Atrophy [Gilman et al. 2008] ............................................. 64 
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15.1.3 
Clinical Criteria for the Diagnosis of Progressive Supranuclear 
Palsy National Institute for Neurological Disorders and Society 
for PSP (NINDS-SPSP) [Litvan et al. 1996] .................................. 66 
15.1.4 
Washington Heights-Inwood Genetic Study of Essential Tremor 
(WHIGET) diagnostic criteria for ET (no SDD) [Louis et al. 
1997] ............................................................................................... 67 
15.1.5 
UPDRS (Unified Parkinson's Disease Rating Scale) Part III—
Motor Examination ......................................................................... 69 
15.1.6 
DSM-5 Diagnostic Criteria for Major Neurocognitive Disorder 
[Hugo and Ganguli 2014] ............................................................... 70 
15.1.7 
H & Y (Modified Hoehn and Yahr) staging ................................... 70 
15.2 
Radiation dosimetry data .................................................................................. 71 
16 
CLINICAL PROTOCOL AMENDMENT SUMMARIES .......................................... 73 
16.1 
Amendment A01 .............................................................................................. 73 
16.1.1 
Reasons for Amendment ................................................................ 73 
16.1.2 
Summary of Key Changes .............................................................. 73 
16.2 
Amendment A02 .............................................................................................. 74 
16.2.1 
Reasons for Amendment ................................................................ 74 
16.2.2 
Summary of Key Changes .............................................................. 74 
16.3 
Amendment A03 .............................................................................................. 74 
16.3.1 
Reasons for Amendment ................................................................ 74 
16.3.2 
Summary of Key Changes .............................................................. 75 
2.2 
List of Tables 
Table 1 
Study Schedule of Events ......................................................................................... 31 
Table 2 
Laboratory Measurements ........................................................................................ 39 
Table 3 
Modified Hoehn and Yahr Staging ........................................................................... 70 
Table 4 
Estimated Absorbed Radiation Doses to an Average Adult Patient ......................... 71 
 
2.3 
List of Figures 
Figure 1 
Study Flow Chart ...................................................................................................... 18 
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3 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
AE 
adverse event 
ATC 
Anatomic Therapeutic Chemical 
β-hCG 
β-human chorionic gonadotropin 
BIE 
blinded image evaluation 
BUN 
blood urea nitrogen 
CRF 
case report form 
CRO 
contract research organisation 
CT 
computed tomography 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
ET 
essential tremor 
DaT 
dopamine transporters 
FAS 
full analysis set 
FDG-PET 
[18F]fluorodeoxyglucose positron emission tomography 
FN 
false negatives 
FP 
false positives 
GCP 
Good Clinical Practice 
HV 
healthy volunteer 
H&Y 
Hoehn and Yahr 
IB 
investigator brochure 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IV 
intravenous 
IRB 
Institutional/Independent Review Board 
MDS-UPDRS 
Movement Disorder Society United Parkinson’s Disease Rating 
Scale 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Examination 
MRI 
magnetic resonance imaging 
MSA 
multiple system atrophy 
MSA-C 
multiple system atrophy with predominant cerebellar ataxia 
MSA-P 
multiple system atrophy with predominant parkinsonism 
NINDS-SPSP 
National Institute of Neurological Disorders and Stroke and Society 
for Progressive Supranuclear Palsy  
PD 
Parkinson’s disease 
PP 
per-protocol 
PSP 
progressive supranuclear palsy 
SAE 
serious adverse event 
SDD 
striatal dopaminergic deficit 
SmPC 
summary of product characteristics 
SOPs 
standard operating procedures 
SPECT 
single photon emission computed tomography 
TN 
true negatives 
TP 
true positives 
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ULN 
upper limit of normal 
UPDRS  
United Parkinson's Disease Rating Scale 
WHIGET 
Washington Heights-Inwood Genetic Study of Essential Tremor 
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4 
BACKGROUND INFORMATION 
Parkinson’s disease (PD) is a slowly progressing neurodegenerative disease with a variable 
prevalence in the People’s Republic of China. Since 1985, many PD prevalence studies have 
been conducted in China, covering 9 provinces [Li et al. 2019]. Based on published data, the 
average prevalence of PD in China was approximately 3.8756% (≥50 years old) in the Han 
population, 1.234% in Uygur ethnicity, 1.208% in Kazak, and 1.224% in Hui ethnicity, 
respectively [Liu et al. 2010] [Jianlong et al. 2013] [Yang et al. 2015] [Li et al. 2019]. 
Regarding incidence of PD in China, 1 study, which was performed in IIan country of Taiwan, 
showed the incidence was 10.4 per 100,000 with a slightly higher rate in men compared to 
women (11.1 per 100,000 vs. 9.8 per 100,000 in women) [Chen et al. 2001]. 
The prevalence of PD increases with age. A recent multicentre, cross-sectional study using a 
stratified cluster sampling approach showed that the prevalence in Chinese veterans is 
comparable to that in other countries and regions and suggested a gradual increase tendency in 
the oldest old population. The estimated number of cases of PD in China was 1.72 to 1.99 
million in 2005. The number is projected to increase to 4.95 million (approximately half of the 
global disease burden) in 2030 [Zhou et al. 2014].  
The diagnosis of PD is based mostly on clinical symptoms and a favourable response to 
levodopa therapy. However, patients manifest symptoms only when 50% to 80% of the 
nigrostriatal neurons are lost. Clinical methods cannot provide an early diagnosis before a 
significant loss of dopamine neurons has occurred. Additionally, some authors have indicated 
that almost 25% of patients with an ante-mortem clinical diagnosis may not have PD in 
clinical-pathological studies [Wu et al. 2014]. It is therefore clear that new tests that can 
improve/or accelerate diagnosis of PD are needed to assist with the clinical assessment.  
The hallmark of this disease is a slow, progressive degeneration of the nigrostriatal 
dopaminergic system, which can be visualised in vivo by using various probes (i.e., 
radiotracers that can bind to different receptors in the dopaminergic system) [Wang et al. 
2012].  
DaTSCAN™ is an intravenously administered single-dose radiopharmaceutical that allows 
single photon emission computed tomography (SPECT) imaging of dopamine transporters 
(DaT) in the striata of the brain. The information provided by DaTSCAN™ SPECT images 
may assist in the diagnostic assessment of subjects with suspected movement disorders such as 
Parkinsonian syndromes (PS) involving striatal dopaminergic deficit (SDD). These disorders 
encompass PD, multiple system atrophy (MSA), and progressive supranuclear palsy (PSP). In 
contrast, essential tremor (ET) does not involve SDD [DaTSCAN™ Product Information].  
DaTSCAN™ ioflupane (123I) injection has been extensively studied in Europe and the United 
States for diagnostic imaging in suspected cases of PD [O'Brien et al. 2014]. The information 
derived from a DaTSCAN™ SPECT image has prognostic value and can be used to guide 
treatment decisions [Bajaj et al. 2013]. 
 
 
 
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5 
STUDY OBJECTIVES AND PURPOSE 
Primary Objective 
• 
To determine the sensitivity and specificity of a measure of striatal uptake of 
[123I]ioflupane as visualised in SPECT images taken 3 to 6 hours after a single 
intravenous (IV) administration of DaTSCAN™ ioflupane (123I) injection (111 to 185 
MBq [3 to 5 mCi]) for the diagnosis of PS involving SDD (specifically, PD, MSA, or 
PSP) as opposed to ET (no SDD) or no neurologic disease (healthy volunteers [HVs]) 
in Chinese subjects.  
Secondary Objectives 
• 
To assess the striatal uptake of [123I]ioflupane in healthy Chinese volunteers (no SDD). 
• 
To assess safety parameters (haematology, biochemistry and urinalysis, and vital signs) 
and the adverse event (AE) profile in Chinese patients/HVs after a single IV 
administration of DaTSCAN™ ioflupane (123I) injection. 
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6 
STUDY DESIGN 
6.1 
Overall Study Design and Plan 
This is a multicentre, open-label, non-controlled, non-randomised clinical study to compare the 
SPECT findings after a single IV administration of DaTSCAN™ ioflupane (123I) injection for 
patients with a clinical diagnosis of PS (SDD; specifically, patients with PD [SDD], MSA 
[SDD] or PSP [SDD]) as compared with patients with a clinical diagnosis of ET (no SDD) and 
age-matched healthy controls. 
This study will be conducted at approximately 10 centres in China. The planned sample size 
for this clinical investigation will be 140 evaluable subjects (60 with movement disorder and 
SDD, 60 with movement disorder but without SDD, 20 HVs). On the basis of a previous study 
(DP008-003), it is projected that evaluable results will be obtained from 80% of diseased 
individuals and 90% of HVs. After adjustment for losses, it is therefore expected that 150 
patients with movement disorders (with and without SDD) and 22 HVs will be needed to 
provide the minimum required number of evaluable patients.  
Each subject will be required to visit the study centre for a screening visit, baseline visit, 
DaTSCAN™ imaging visit, and 1 follow-up visit. In order to prevent misinterpretations of the 
DaTSCAN™ SPECT images by the independent blinded readers (who will not be supplied 
with clinical data), the absence of structural abnormalities in the basal ganglia must be ruled 
out by a magnetic resonance imaging (MRI) scan performed within 6 months prior to 
inclusion. If an MRI scan is not clinically feasible, cerebral computed tomography (CT) image 
findings will also be accepted. If the subject does not have an MRI scan, one will be offered 
(provided no contraindications are met). If an MRI is not feasible, the investigator will consider 
offering a CT scan. 
During the baseline visit, safety assessments and an extensive neurologic examination will be 
performed. At that visit, each subject will receive a clinical diagnosis (e.g., PD or ET or no 
neurologic disease). 
The dose of DaTSCAN™ to be used in this study is within the range of 111 to 185 MBq (3 to 
5 mCi) per subject in a maximum volume of 5 mL (see Sections 6.2.2 and 8.3). The selected 
dose is within the range used in previous phase 3 studies and in current clinical practice in 
Europe and the United States. To minimise thyroid uptake of radioactive iodine, subjects 
should undergo appropriate thyroid blocking treatment prior to and/or after injection according 
to local practices. 
During the DaTSCAN™ imaging visit, all subjects will receive a single IV injection of 
DaTSCAN™ ioflupane (123I) injection. SPECT imaging will be performed between 3 to 6 
hours post-injection and will last approximately 20 minutes to 1 hour, depending on type of 
SPECT camera. The DaTSCAN™ imaging visit may occur as soon as possible after the 
baseline visit but no later than 28 days after baseline. Each subject will be asked to return for a 
final follow-up visit at 3 (±1) days after the administration of DaTSCAN™ ioflupane (123I) 
injection. 
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Subjects will receive the investigational medicinal product (IMP) under direct supervision of 
hospital personnel. Each administration dose in MBq will be checked, and the vial code, dose, 
volume per administration will be recorded in each subject’s case report form (CRF). 
Safety will be assessed from the rates of AEs, changes in vital signs, changes in physical 
examination findings, changes in clinical laboratory findings, changes in injection site 
monitoring, and changes in neurologic examination. 
Subjects will return to the study centre for a follow-up visit at 3 (±1) days after DaTSCAN™ 
injection for a safety assessment. To rule out any metabolic disturbances that may underlie 
changes in neuropsychiatric state, routine laboratory parameters, including glucose and those 
reflecting hepatic and renal function, will also be assessed. 
For further details, refer to Table 1 (Study Schedule of Events) and Figure 1 (Study Flow 
Chart). 
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Figure 1 Study Flow Chart 
Within 28 days 
before imaging visit 
Screening Visit 
• 
Informed consent 
• 
Assign subject number 
• 
Inclusion/exclusion criteria 
• 
Demographic information 
• 
Medical and surgical history 
• 
Neuropsychiatric history (including dementia history) 
• 
Safety assessments (vital signs) 
• 
Neurological examination 
• 
Neuropsychiatric examination (Section 9.1) 
• 
Prior and concomitant medications 
• 
Pregnancy test (serum ß-hCG test for women of child-bearing potential) 
• 
Laboratory tests (Section 9.1) 
• 
Adverse events 
 
 
Within 28 days 
before imaging visit 
Baseline Visit 
• 
Concomitant medication 
• 
Adverse events 
• 
Physical examination 
• 
Neurological examination 
• 
Neuropsychiatric examination 
• 
Investigator’s clinical diagnosis 
• 
Eligibility check 
 
 
 
Imaging Visit 
• 
Concomitant medication 
• 
Pregnancy test (hCG urine test; if appropriate) 
• 
Final eligibility check 
• 
Administer thyroid blocking drug (see Section 8.1.4) according to local practice 
• 
Safety assessments (vital signs; pre- and post-injection) 
• 
Injection site monitoring (pre- and post-injection) 
• 
DaTSCAN™ injection 
• 
SPECT Imaging (must be performed within 3 to 6 hours after injection) 
• 
Adverse events 
 
 
3 (±1) days after 
injection 
Follow-up Visit 
• 
Concomitant medications 
• 
Laboratory tests (haematology, serum biochemistry, and urinalysis) 
• 
Safety assessments (vital signs) 
• 
Neurological examination 
• 
Physical examination 
• 
Adverse events 
 
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6.2 
Study Rationale 
6.2.1 
Justification for the efficacy analysis of diagnosis of PS 
PD is characterised by the progressive degeneration of the dopamine-producing neurons in the 
substantia nigra pars compacta, and the ventral tegmental area [Gibb and Lees 1991], 
[Bernheimer et al. 1973]. As a result of this neuronal loss, a marked decrease of striatal 
dopamine content can be detected [Hornykiewicz and Kish 1986]. The dopaminergic 
nigrostriatal neuron bundle is crucial in the function of the neostriatum (caudate nucleus and 
putamen) and its control of movement. MSA and PSP also involve progressive degeneration of 
dopaminergic nigrostriatal neurons that may produce a DaTSCAN™ image that is 
indistinguishable from that of a patient with PD. In contrast, the dopaminergic nigrostriatal 
bundle is not involved in the aetiology of ET. Nevertheless, patients with ET have often been 
given a misdiagnosis of PD [Guberman 1994]. 
The reliability of the clinical diagnosis of PD is approximately 76% [Hughes et al. 1993], 
[Meara et al. 1999]. Clinical studies have shown that visual assessment of DaTSCAN™ 
SPECT images permits detection of loss of functional dopaminergic nigrostriatal neurons and 
confirm that DaTSCAN™ imaging can discriminate PS from ET. However, it cannot 
differentiate the different PS subtypes: PD, MS, and PSP.  
Longitudinal studies have shown an average age-related decline in DAT availability of 5.5 % 
per decade both sexes [Varrone et al. 2013], justifying the addition of a group of age-matched 
controls who will be expected to show some decline in the uptake of DaTSCAN™ with no 
movement disorders. 
6.2.2 
Justification for dose and volume 
Pilot and pivotal clinical studies have demonstrated that visual assessment of DaTSCAN™ 
SPECT images permits detection of any nigrostriatal disorder and confirms that DaTSCAN™ 
can discriminate Parkinson’s symptoms from ET. 
 
 The results of several 
studies have validated the efficacy of DaTSCAN™ within the currently approved dose range 
and in accordance with the Summary of Product Characteristics (SmPC) and Package Insert.  
DaTSCAN™ with extended shelf-life (370 MBq [10 mCi] in 5 mL at reference time) will be 
supplied to allow administration of radioactivity within the required dose range of 111 to 185 
MBq (3 to 5 mCi). 
6.2.3 
Justification for prohibited and permitted medication 
Agents with high affinity for DAT, such as amphetamine, benztropine, bupropion, cocaine, 
mazindol, methylphenidate, phentermine, sertraline, and selective serotonin reuptake 
inhibitors, are identified as having interaction potential with DaTSCAN™ and are, therefore, 
prohibited in the study. Additionally, it is uncertain how traditional Chinese medicines 
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prescribed to treat PD may affect the DAT. Therefore, if the medication cannot be safely 
withdrawn at least 1 week before DaTSCAN™ SPECT is performed these patients will also be 
excluded.   
Drugs shown during clinical trials not to interfere with DaTSCAN™ imaging include 
amantadine, benzhexol, budipine, levodopa, metoprolol, primidone, propranolol, and 
selegiline. Dopamine agonists and antagonists acting on the postsynaptic dopamine receptors 
are not expected to interfere with DaTSCAN™ imaging and can therefore be continued if 
desired. Drugs shown in animal studies not to interfere with DaTSCAN™ imaging include 
pergolide. 
6.2.4 
Justification of safety plan 
This study’s safety monitoring plan is justifiable and adequate from a safety standpoint in view 
of the following: 
• 
The design of the safety plan permits an appropriate and adequate evaluation of the 
safety response to DaTSCAN™ under baseline and post-study drug injection conditions 
in the same subject. 
• 
The design of the safety plan allows a comparison of this study’s safety data set with 
other phase 3 studies.  
• 
The measures used to assess safety are well defined and reliable within the context of 
the SPECT imaging environment, and the proposed safety analyses are adequate to 
assess the effects of DaTSCAN™. 
• 
The safety plan aims to restrict the collection of data up to and including 4 days, based 
on the pharmacokinetic characteristics of DaTSCAN™ and the absence of any study 
procedures beyond the follow-up visit taking place at 3 (±1) days post administration. 
6.3 
Study Timeframe 
The recruitment period will be approximately 18 months, with an approximate 1 month of 
study participation per subject.  The overall study duration is approximately 18 months from 
First Patient First Visit to Last Patient Last Visit. 
6.4 
Risks and Benefits to Subjects 
The SPECT images that will be produced in this study can provide diagnostic information that 
could help to differentiate PS from ET. Thus, subjects with a movement disorder could benefit 
if the results of the study are used to guide treatment decisions. The HVs are not expected to 
have a direct benefit. 
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DaTSCAN™ is a radiopharmaceutical and as such involves exposure to ionising radiation. The 
maximal effective dose (i.e., the one corresponding to an injection of 185 MBq) is 4.35 mSv 
for a 70 kg individual, which represents approximately twice the annual average dose to 
inhabitants in China [Pan et al. 1994] and falls within the limits of other commonly performed 
diagnostic tests in nuclear medicine and radiology [Health Physics Society]. 
No serious AEs (SAEs) related to DaTSCAN™ administration have been reported. Commonly 
reported AEs (not believed to be related to DaTSCAN™) are headache, nausea, dizziness, 
nasopharyngitis, vertigo, increased appetite, and formication. Intense pain on injection has 
been reported uncommonly following administration into small veins. 
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7 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1 
Procedures for Enrolment 
Subjects will be recruited by means accepted by the respective regulatory bodies/local health 
authority (in accordance with local regulations) and the local independent ethics committee 
(IEC). 
The study population will consist of subjects with a clinical diagnosis of PS, subjects with a 
clinical diagnosis of ET, and HVs. The subjects will be recruited from movement disorder 
clinics and general neurology clinics.  
Each potential subject will attend the centre for a screening visit. Only the individuals who 
fulfil all of the inclusion criteria (Section 7.2) and none of the exclusion criteria (Section 7.3) 
will be recruited for the study. Written, dated, and witnessed informed consent will be obtained 
from all subjects or their legally acceptable representatives prior to study entry and prior to any 
protocol-specific procedures. 
Sufficient subjects will be recruited to obtain the required number of evaluable subjects. The 
distribution will be assessed on an ongoing basis during the trial using an Interactive Web 
Response System. Subjects will be assigned a unique identification number during the 
screening visit, after the informed consent document has been signed and dated. 
7.2 
Inclusion Criteria 
For all subjects:  
1. 
Chinese male or female, aged 40 to 80 years, has agreed to sign and date the written 
informed consent form. 
For HVs:  
2. 
Non-patient volunteers with good age-appropriate health as established by clinical 
examination during screening and no evidence of movement disorder by complete 
neurological evaluation. 
For patients with PD: 
3. 
A diagnosis of clinically established or clinically probable PD in accordance with the 
MDS Clinical Diagnostic Criteria for Parkinson’s Disease [Postuma et al. 2015], 
Appendix 15.1.1. 
For patients with MSA (SDD): 
4. 
A diagnosis of probable or possible MSA in accordance with the Second Consensus 
Statement on the Diagnosis of MSA [Gilman et al. 2008], Appendix 15.1.2.  
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For patients with PSP (SDD): 
5. 
A diagnosis of probable or possible PSP in accordance with the Clinical Criteria for the 
Diagnosis of Progressive Supranuclear Palsy National Institute for Neurological 
Disorders and Society for PSP (NINDS-SPSP) [Litvan et al. 1996], Appendix 15.1.3.  
For patients with ET (no SDD) 
6. 
A diagnosis of definite or probable ET in accordance with the Washington Heights-
Inwood Genetic Study of Essential Tremor (WHIGET) diagnostic criteria for ET (no 
SDD) [Louis et al. 1997], Appendix 15.1.4. 
7.3 
Exclusion Criteria 
1. 
The subject is lactating. 
2. 
The subject is pregnant as detected by a β-human chorionic gonadotropin (-hCG) 
pregnancy test. 
3. 
A cerebral structural vascular abnormality indicative of at least 1 infarction in the 
region of the basal ganglia (including the internal capsule) ≥5 mm has been confirmed, 
preferably by MRI performed within 6 months of screening. If an MRI is not clinically 
feasible, cerebral CT imaging within 6 months is also acceptable. 
4. 
The subject is diagnosed with major neurocognitive disorder by the Diagnostic and 
Statistical Manual of Mental Disorders (DSM) 5 criteria, or Mini-Mental State 
Examination total score is <24. 
5. 
Subject is being investigated for or has been diagnosed and/or is being treated for 
repeated stroke with stepwise progression of Parkinson features. 
6. 
History of repeated head injury (≥3 concussions, or history or professional sports with 
repeated head trauma [e.g., boxing]). 
7. 
History of definite encephalitis (≥1 episode of confirmed encephalitis with objective 
residual neurologic deficit). 
8. 
The subject is using or has insufficient washout from medication known or suspected to 
interact with striatal uptake through direct competition with binding of DaTSCAN™ to 
the DaT (i.e., amphetamine, benztropine, bupropion, cocaine, mazindol, 
methylphenidate, phentermine, sertraline, selective serotonin reuptake inhibitors) before 
the imaging visit.  
9. 
The patient is using Chinese traditional medicine for PD treatment, which cannot be 
safely withdrawn for at least 1 week (7 days) before the imaging visit. 
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10. 
The subject has a moderate to severe renal impairment (i.e., serum creatinine 1.5 
upper limit normal [ULN], or blood urea nitrogen [BUN] >30 mg/dL). 
11. 
The subject has a moderate to severe hepatic impairment (bilirubin 2 ULN and 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST)  3 ULN). 
12. 
The subject has a history of current abuse of drugs and/or alcohol (for the previous 
12 months before trial enrolment). 
13. 
The subject has a history of occupational exposure to any radiation >50 mSv/year. 
14. 
The subject has been previously enrolled in this study or participated in a clinical study 
involving an investigational pharmaceutical product within 30 days prior to screening 
and/or any radiopharmaceutical within a minimum of 5 radioactive half-lives prior to 
screening. 
15. 
The subject presents with symptoms suggestive of corticobasal degeneration or 
Huntington’s disease. 
16. 
The subject has known allergies to the IMP. 
17. 
The subject presents with any clinically active, serious, life-threatening disease with a 
life expectancy of less than 12 months.  
18. 
Any laboratory value(s) exceeding the limits of normality if deemed to be clinically 
relevant by the investigator. 
19. 
The subject complains of claustrophobia. 
20. 
The subject has a moderate to severe thyroid disease (thyroid stimulating hormone 
exceeding the limits of normality by more than 10%), if deemed to be clinically 
relevant by the investigator. 
For patients with ET:  
21. 
The patient has at least 1 first-degree relative diagnosed with PD. 
For HVs: 
22. 
History of psychiatric illness. 
For all subjects: 
23. 
It is the physician’s best judgement not to include the patient in the trial. 
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7.4 
Withdrawal and Termination Criteria 
7.4.1 
Subject withdrawal 
There are no formal withdrawal criteria for this study. During the conduct of the study, the 
sponsor will review the safety data for trends and signals that would indicate the need for 
withdrawal of a subject. 
In accordance with the Declaration of Helsinki, each subject is free to withdraw from the study 
at any time. Investigator(s) also have the right to withdraw subjects from the study in the event 
of illness, AEs, or other reasons concerning the health or well-being of the subject, or in the 
case of lack of co-operation. 
Should a subject decide to withdraw after administration of the IMP(s), or should the 
investigator(s) decide to withdraw the subject, all efforts will be made to complete and report 
the observations up to the time of withdrawal as thoroughly as possible. A complete final 
evaluation at the time of the subject’s withdrawal should be made and an explanation given of 
why the subject is withdrawing or being withdrawn from the study.  
The reason for withdrawal must be noted in the CRF. If the reason for withdrawal is a clinical 
AE, monitoring will continue until the outcome is evident. The specific event or test result(s) 
must be recorded in the CRF.  
7.4.2 
Study or site termination 
Both the sponsor and principal investigator reserve the right to terminate the study at the 
respective centre at any time. Before terminating the study, the sponsor and investigator will 
ensure that a careful review of the overall risk/benefit analysis confirms the balance to be no 
longer acceptable. Should termination be necessary, both parties will arrange the procedures 
after review and agreement with the IEC. In terminating the study, the sponsor and investigator 
will assure that adequate consideration is given to the protection of all the subjects having been 
recruited. 
Study enrolment will be stopped when the planned number of evaluable subjects has been 
enrolled. The sponsor or the health authorities may terminate an investigator centre if serious 
protocol violations occur. 
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8 
TREATMENT OF SUBJECTS 
8.1 
Description of Medicinal Products 
8.1.1 
Investigational medicinal product: DaTSCAN™ ioflupane (123I) injection 
In this study, each subject will receive 1 dose of the IMP in this study, DaTSCAN™ ioflupane 
(123I) injection, during the imaging visit. Each patient will receive a dose of 111 to 185 MBq in 
a maximum volume of 5 mL. To minimise pain upon injection, the dose will be delivered by a 
slow IV injection (not less than 15 to 20 seconds) into an arm vein. 
DaTSCAN™ ioflupane (123I) injection is a sterile, pyrogen-free radiopharmaceutical for IV 
injection. The clear and colourless solution is supplied in single-use vials in which each 
millilitre contains 0.07 to 0.13 µg ioflupane, 74 MBq (2 mCi) of iodine 123 (as ioflupane [123I]) 
at calibration time, 5.7 mg acetic acid, 7.8 mg sodium acetate, and 0.05 mL (5%) ethanol. The 
pH of the solution is between 4.2 and 5.2. 
Iodine 123 is a cyclotron-produced radionuclide that decays to tellurium 123 by electron 
capture and has a physical half-life of 13.2 hours. The principal radiation emitted by 123I is  
radiation (159 keV).  
Only personnel authorised by Chinese regulations to handle radioactive materials will be 
allowed to handle DaTSCAN™.  
DaTSCAN™ (Ioflupane (123I) Injection) preparations will not be used after the expiration date 
and time stated on the label. 
Appropriate radiation precautions should be observed during the preparation and storage of the 
agent. Aseptic technique with sterile syringes and needles should be used. 
8.1.2 
IMP accountability 
Each investigator is responsible for ensuring that deliveries of IMP(s) and other study materials 
from the sponsor are correctly received, recorded, handled, and stored safely and properly in 
accordance with all applicable regulatory guidelines, and used in accordance with this protocol. 
All IMP containers (opened, unopened, or empty) must be destroyed on site after the study and 
overall drug accountability have been completed by the representative. A list of IMP(s) and 
other materials that were destroyed, must be prepared and signed by the principal investigator 
or designee. If there are any discrepancies, an explanation for these should also be provided. 
Any package inserts, SmPCs, or other safety documents for IMPs or adjunctive study materials 
will be supplied to the site.  
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8.1.3 
Registration of investigational medicinal product(s) complaints 
In the event of an IMP complaint (e.g., breakage, leakage, particulate matter, discoloration), the 
investigator or recipient of the IMP is requested to report the problem on the IMP shipping 
documentation (e.g., ‘Delivery Note for Product’, Drug Shipping and Receiving Form, or 
equivalent form). This documentation should be promptly forwarded to the person indicated on 
the shipping documentation. Once the complaint is received, the Clinical Supplies Manager 
will register the complaint and determine, according to sponsor procedures, if the complaint is 
minor or significant. All complaints will be followed up, and the appropriate action will be 
implemented according to sponsor procedures. 
8.1.4 
Other medicinal products: Thyroid-blocking treatment 
To minimise thyroid uptake of radioactive iodine, subjects must undergo appropriate thyroid 
blocking treatment prior to and/or after injection according to local practice. The thyroid 
blocking agent will be preferably sourced locally by the hospital. If it is not available in the 
hospital, then sponsor should source it. The administered time, date and dose will be captured 
on the concomitant medication page. 
8.2 
Method of Numbering Subjects and Assigning Subjects to 
Treatment Groups 
In this open-label study, all subjects will undergo the same procedure: diagnostic imaging with 
DaTSCAN™ ioflupane (123I) injection.  
Each subject will be given a unique identification number. The identification number will be 
assigned to the subject during the screening visit, after the informed consent document has 
been signed and dated.  Once an identification number has been assigned, it cannot be 
reassigned, even if the subject is deemed ineligible or withdraws consent.  No subject may 
enter the study more than once.  Nor may a subject be re-screened for the study after having 
failed to meet the inclusion/exclusion criteria.  If the investigator has any question about any 
subject’s eligibility to participate in the study, the investigator or study personnel should 
contact the sponsor to discuss the subject’s eligibility. 
Each subject’s identification number will consist of a 3-digit site code plus a 4-digit 
consecutive number.  For example, site “999” will assign the number “999-0001” to its first 
subject, “999-0002” to its second subject, and so on. To preserve the integrity of the study, it is 
crucial that these numbers be assigned in consecutive numerical order.  
All subjects will receive the same treatment. Therefore, there will be no assignment to 
treatment groups.  
No randomisation will take place in this study. For analysis, the subjects will be assigned to 
diagnostic categories according to their clinical diagnosis (e.g., PD, MSA, PSP, ET, or HV). 
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8.3 
Selection of Doses and Timing 
The dose of DaTSCAN™ ioflupane (123I) injection to be used in this study is based on the dose 
that has been approved by the regulatory authorities in Europe and in the United States.  
The dose of this radiopharmaceutical is calculated in terms of radioactivity. Clinical efficacy 
has been demonstrated across the range 111 to 185 MBq. The dose should not exceed 
185 MBq, and the product should not be used when the activity is below 111 MBq. Because of 
the short half-life of 123I, the dose to be administered to the subject is calculated in relation to 
the reference time on the label.  
DaTSCAN™ is a 5% (v/v) ethanolic solution for IV injection and should be used without 
dilution. To minimise the potential for pain at the injection site during administration, a slow 
IV injection (not less than 15 to 20 seconds) via an arm vein is recommended. 
SPECT imaging should take place between 3 and 6 hours after the administration of 
DaTSCAN™ ioflupane (123I) injection. 
8.4 
Blinding 
This is an open label study where all individuals will receive a dose of DaTSCAN™ and no 
blinding of the IMP will be performed.   
A blinded image evaluation (BIE) will be performed as described in Section 10.2.3.  
8.5 
Prior and Concurrent Therapy 
If a subject is taking a prohibited medication that cannot be withdrawn, the subject must be 
excluded from participation in the study. If during the pre-treatment and treatment phases of 
the study the use of any prohibited medication becomes necessary for medical reasons, the 
subject will be withdrawn from further participation in the study. 
The investigator should avoid the concomitant administration of any medication that is known 
or suspected of negative interaction with DaTSCAN™. The minimum washout period for all 
generally prohibited concomitant medications is 5 half-lives prior to imaging. If the patient is 
using Chinese traditional medicine for PD treatment, the minimum washout period required to 
enter the study is 1 week (7 days). 
The following list of prohibited concomitant medications does not represent a complete list, 
and as such should only be used as a guide for the investigator: psychostimulants (e.g., 
amphetamine), benztropine, bupropion, cocaine, mazindol, methylphenidate, phentermine, 
sertraline. Selective serotonin reuptake inhibitors (paroxetine and citalopram) may increase or 
decrease ioflupane binding to the DaT. Updated information on concomitant therapy, if any, 
will be provided in the DaTSCAN™ investigator brochure (IB).  
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Before one of the above-prohibited medications is withdrawn from a subject to satisfy 
inclusion/exclusion criteria, the investigator will seek the subject's agreement on the informed 
consent form as well as the agreement of the referring physician and document it in the 
subject’s medical notes. The investigator will then implement and oversee an appropriate drug-
withdrawal regimen. 
8.5.1 
Permitted concomitant medications 
Clinical trials have shown that the following drugs do not interfere with DaTSCAN™ imaging: 
amantadine, benzhexol, budipine, levodopa, metoprolol, primidone, propranolol, and 
selegiline. Dopamine agonists and antagonists acting on the postsynaptic dopamine receptors 
are not expected to interfere with DaTSCAN™ imaging and can therefore be continued if 
desired. In preclinical studies, pergolide did not interfere with DaTSCAN™ imaging. 
The sponsor will encode all therapy and medication according to a World Health Organization 
preferred term dictionary of medical codes (see Section 12.4.1). 
8.6 
Treatment Compliance 
The IMP will be administered by study personnel. Each administration volume and the total 
radioactivity injected will be checked and the vial code, dose, volume per administration will 
be recorded in each subject’s CRF. Doses administered outside of specific dose requirements 
or defined range must be reported as protocol deviations (see Section 13.3). 
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9 
STUDY PROCEDURES 
All efficacy and safety measurements obtained during the course of the study are summarised 
in the Study Schedule of Events (Table 1). 
 
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Table 1 
Study Schedule of Events 
 
Screening 
Visit a 
Treatment  
Follow-up 
Baseline Visit a 
Imaging Visit 
Pre-injection 
0 
Post-injection 
Within 28 
days prior to 
imaging visit 
Within 28 days 
prior to imaging 
visit 
Within 1 to 4 
hours prior 
to injection 
Within 30 min 
prior to injection 
10 min 
3 to 6 
hours 
3 (±1) days b 
Informed consent 
X 
 
 
 
 
 
 
 
Subject number assignment 
X 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
Neuropsychiatric history (including dementia history) 
X 
 
 
 
 
 
 
 
Neurological examination 
X 
X 
 
 
 
 
 
X 
Pregnancy test (if applicable) 
X 
 
X 
 
 
 
 
 
Prior and concomitant medication 
X--------------------------------------------------------------------------------------------------------------------------------------X 
Laboratory tests c 
X 
 
 
 
 
 
 
X 
Physical examination 
 
X 
 
 
 
 
 
X 
Neuropsychiatric examination (Section 9.1) d 
X 
X 
 
 
 
 
 
 
Clinical diagnosis  
 
X 
 
 
 
 
 
 
Vital signs (blood pressure, heart rate) 
X 
 
 
X 
 
 
X 
X 
Thyroid blocking 
 
 
Xe 
 
 
 
Xe 
 
Injection site monitoring 
 
 
 
X 
X 
X 
X 
 
DaTSCAN™ injection  
 
 
 
 
X 
 
 
 
SPECT imaging 
 
 
 
 
 
 
Xf 
 
Adverse events 
X---------------------------------------------------------------------------------------------------------------------------------------X 
a The screening visit and baseline visit may be combined and conducted on the same day. 
b Performed at 3 (±1) days after injection of DaTSCAN™ 
c Some tests will only be performed at screening (refer to Section 10.3.3, Table 2) 
d Mini Mental State Examination, UPDRS-III, United Parkinson's Disease Rating Scale Part III; H&Y, Hoehn and Yahr and WHIGET assessment 
e The dosage and timing of administration will be based on investigator’s discretion according to local practice of each site (e.g., to be administered within 1 to 4 hours prior to and 12 
to 24 hours after injection of DaTSCANTM are just for reference) 
f Performed 3 to 6 hours after injection of DaTSCAN™ 
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9.1 
Screening Visit 
At the screening visit (within 28 days prior to the imaging visit), the following will be 
performed/recorded: 
• 
Signed and dated informed consent 
• 
Assign subject number 
• 
Inclusion criteria and exclusion criteria (listed in Sections 7.2 and 7.3) 
• 
Demographic information 
• 
Medical and surgical history 
• 
Neuropsychiatric history (including dementia history) 
• 
Neurological examination 
• 
Neuropsychiatric examination: 
- 
Mini-Mental State Examination 
- 
United Parkinson's Disease Rating Scale (UPDRS) Part III assessment 
- 
Hoehn and Yahr Scale for PD 
- 
WHIGET assessment for ET 
• 
Vital signs (blood pressure, heart rate)  
• 
Pregnancy test (serum ß-hCG test; if applicable) 
• 
Prior and concomitant medications 
• 
Blood and urine samples for laboratory testing (see Table 2). 
• 
AEs 
The screening visit and baseline visit may be combined and conducted on the same day. All 
procedures for both visits have to be completed at this combined visit.  Laboratory results for 
the subject must be available and assessed by investigators before the imaging visit is 
scheduled.  
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9.2 
Baseline Visit 
At the baseline visit (within 28 days prior to the imaging visit) the following will be 
performed/recorded: 
• 
Physical examination 
• 
Neurological examination 
• 
Neuropsychiatric examination 
• 
Concomitant medication 
• 
Investigator's clinical diagnosis  
• 
Eligibility check 
• 
AEs 
9.3 
Imaging Visit 
The imaging visit will take place as soon as possible but within 28 days after the baseline visit 
(Table 1).  
The following will be performed 1 to 4 hours before administration of IMP: 
• 
Concomitant medication 
• 
Pregnancy test (hCG urine test; if applicable)  
• 
Final eligibility check 
• 
Administer thyroid blocking drug (see Section 8.1.4) according to local practice 
• 
AEs 
Within 30 minutes prior to the injection of IMP, the following will be performed/recorded: 
• 
Vital signs 
• 
Injection site examination  
• 
AEs 
The subject will then receive a dose of IMP as described in Sections 8.1 and 8.3.  
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Post-IMP injection, the following will be performed/recorded: 
• 
Injection site examination: 10 minutes and 3 to 6 hours post-IMP injection 
• 
Imaging: 3 to 6 hours post-IMP injection(see Section 10.2 and the Imaging Manual) 
• 
Vital signs: 3 to 6 hours post-IMP injection 
• 
AEs 
• 
Administer thyroid blocking drug (see Section 8.1.4) according to local practice 
9.4 
Follow-up Visit (3 [±1] days after injection) 
At the follow-up visit scheduled for 2 to 4 days after injection, the following will be 
performed/recorded (Table 1): 
• 
Neurological examination 
• 
Concomitant medications 
• 
Clinical laboratory tests 
• 
Physical examination 
• 
Vital signs 
• 
AEs 
9.5 
Unscheduled Visits 
An unscheduled visit can be arranged at the discretion of the investigator. At a minimum, the 
date and reason for the visit will be captured. Any procedures performed will also be captured 
in the CRF. 
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10 
EFFICACY, SAFETY, AND OTHER VARIABLES 
10.1 
Efficacy Assessments 
10.1.1 
Primary endpoint 
• 
Assessment of DaTSCAN™ SPECT images by 3 independent blinded readers to 
compare specific striatal uptake with the clinical diagnosis. 
10.1.2 
Secondary endpoints 
• 
Central read (by semi-quantitative assessment by use of DaTQUANT™) of 
DaTSCAN™ SPECT images to compare specific uptake with clinical diagnosis. 
• 
Comparison and assessment of safety parameters and AEs reported by all study 
participants. 
10.2 
Technical Requirements for DaTSCAN™ SPECT Image 
Acquisition 
10.2.1 
Image acquisition 
Images will be acquired within the pre-specified time window and without any interference in 
appropriate medical care; the latter will take priority. Acquired image data will be anonymised 
and all Personal Health Information will be removed at site before electronic transmission to 
the Sponsor for the BIE. The sponsor will prepare and distribute an Imaging Manual that 
describes all image acquisition and transmittal procedures.  
Prior to the first DaTSCAN™ image acquisition, equipment will be checked to ensure 
compliance with the requirements for DaTSCAN™ image acquisition and data transfer.  
Details of SPECT hardware qualification requirements are presented in the Imaging Manual. 
10.2.2 
Standard of truth 
The clinical diagnosis as established by the investigator at baseline at the recruiting centres 
according to internationally accepted diagnostic criteria and based on a standardised and 
comprehensive clinical and neuropsychiatric assessment will be the standard of truth used for 
determining sensitivity and specificity.  
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10.2.3 
Image interpretation and correlation with standard of truth 
Anonymised DaTSCAN™ SPECT images will be presented in randomized order to 3 
independent readers. Each blinded image reviewer will determine if the image is of sufficient 
quality to be interpretable. If the image is not interpretable, the blinded image reviewer will be 
required to specify the reason why on the CRF. If the image is considered evaluable by the 
reader, then the reader will be required to record his/her assessment of the subject’s image in 
terms of a normal pattern of tracer uptake (negative image interpretation) or an abnormal 
pattern of tracer uptake (positive image interpretation). If the image is classified as abnormal, 
he/she will be asked to further classify the image as typical SDD or atypical SDD. 
The BIE readers will evaluate the DaTSCAN™ SPECT images according to the following 
classification: 
1. 
Normal DaTSCAN™ SPECT images: 2 symmetric comma- or crescent-shaped focal 
regions of activity mirrored about the median plane. Striatal activity is distinct, relative 
to surrounding brain tissue 
2. 
Abnormal DaTSCAN™ SPECT image type 1: Activity is asymmetric (i.e., activity in 
the region of the putamen of 1 hemisphere is absent or greatly reduced with respect to 
the other). Activity is still visible in the caudate nuclei of both hemispheres, resulting in 
a comma or crescent shape in 1 and a circular or oval focus in the other. There may be 
reduced activity between ≥1 striatum and surrounding tissues 
3. 
Abnormal DaTSCAN™ SPECT image type 2: Activity is absent in the putamen of both 
hemispheres and confined to the caudate nuclei. Activity is relatively symmetric and 
forms 2 roughly circular or oval foci. Activity of one or both is generally reduced. 
4. 
Abnormal DaTSCAN™ SPECT image type 3: Activity is absent in the putamen of both 
hemispheres and greatly reduced in one or both caudate nuclei. Activity of the striata 
with respect to the background is reduced. 
5. 
Other: Abnormal pattern, not conforming to any of the patterns above, to be specified 
by the reviewer (e.g., ‘punched-out’ lesion such as caused by an ischaemic stroke) or if 
the image cannot be interpreted. 
Where an image cannot be assigned to one of the categories 1) to 5) a reason must be specified 
in the CRF. 
The readers will be blinded to subject Personal Health Information, details of the originating 
institution, and all other clinical information except for the subject’s age. Because of an overall 
decrease in cerebral circulatory capacity with increasing age, the specific nigrostriatal 
DaTSCAN™ uptake decreases and the non-specific uptake increases. Thus, knowledge of the 
subject’s age is required for appropriate evaluation of the SPECT images. 
The BIE will be conducted in accordance with the study Independent Review Charter prepared 
by the sponsor. 
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10.3 
Safety Assessments 
The following safety data will be collected and evaluated, as detailed in Table 1: 
• 
Physical examination 
• 
Neurological examination 
• 
Vital signs: blood pressure, heart rate 
• 
Laboratory tests for haematology, serum biochemistry (including vitamin B12, folic 
acid, thyroid function, and C-reactive protein), tests for syphilis, and urinalysis (refer to 
Table 2) 
• 
AEs 
• 
Injection site monitoring 
10.3.1 
Physical examinations 
A physical examination will be conducted at baseline and at a follow-up visit at 3 (±1) days 
post-injection (see Table 1). 
A licensed physician will conduct the physical examinations. If possible, the same physician 
should conduct the physical exam at both time points. 
A physical examination will include an assessment for the presence of abnormalities in: 
• 
General appearance 
• 
Lungs 
• 
Cardiovascular system 
• 
Abdomen 
A neurological examination will include an assessment for the presence of abnormalities of the 
following:  
• 
Level of consciousness 
• 
Cranial nerves (II-XII) 
• 
Motor function 
• 
Sensory function 
• 
Proprioception/position sense of extremities 
• 
Reflexes (biceps, triceps, patellar, ankle) 
• 
Mood and affect 
• 
Cognitive function 
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• 
Cerebellar 
• 
Speech 
• 
Orientation 
• 
Memory 
• 
Gait 
In the event that “new” or “worsening” abnormal physical examination findings are 
encountered during the study, these terms are defined as follows: 
• 
A “new” abnormal physical examination finding is defined as one that occurs when a 
subject's normal baseline physical examination becomes abnormal post-baseline, based 
on clinical grounds. 
• 
A “worsening” abnormal physical examination finding is defined as one that occurs 
when a subject's abnormal baseline physical examination becomes worse post-baseline, 
also based on clinical grounds. 
New and worsening abnormal physical examination findings qualify as AEs.  
10.3.2 
Vital signs 
Vital signs variables will include measurements of systolic and diastolic blood pressure and 
heart rate. Blood pressure and heart rate measurements will be obtained at screening, within 30 
minutes prior to injection, within 3 to 6 hours and at 3 (±1) days post-injection (see Table 1). 
All blood pressure measurements will be taken on the arm contralateral to the site of 
DaTSCAN™ injection. Before vital signs are measured, the subject should be resting for at 
least 5 minutes. The same position will be used each time vital signs are measured for a given 
subject. 
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10.3.3 
Clinical laboratory evaluation 
10.3.3.1 
Measurements 
Laboratory measurements to be assessed in this study are displayed in Table 2. 
Table 2 
Laboratory Measurements 
Serum Biochemistry 
Haematology 
Urinalysis (Dipstick) 
Creatinine 
Urea nitrogen 
Bilirubin (total) 
Albumin 
Aspartate aminotransferase 
Alanine aminotransferase 
Alkaline phosphatase 
-Glutamyl transferase 
Sodium 
Potassium 
Lactate dehydrogenase 
Creatine phosphokinase 
Vitamin B12 (at screening only) 
Folic acid (at screening only) 
Calcium 
Phosphate 
Glucose 
Thyroid function (at screening only) 
C-reactive protein (at screening only) 
Haematocrit 
Haemoglobin 
Red blood cell (RBC) count 
White blood cell (WBC) count 
WBC Differential 
Platelet count 
 
 
Tests for 
Syphilis (at screening only) 
 
Bilirubin 
Protein 
Urobilinogen 
Glucose 
Ketone 
Occult blood 
Specific gravity 
Leukocytes 
pH 
 
Laboratory measurements will be examined for clinically notable values according to central 
laboratory reference ranges and clinically notable criteria.  
The signed and interpreted laboratory results will be kept together with the subject’s CRF as 
supplemental pages, both centrally and at the site. 
10.3.3.2 
Blood sampling 
Clinical laboratory tests to be evaluated in this study include haematology, serum biochemistry 
(including vitamin B12, folic acid, thyroid function, and C-reactive protein), and tests for 
syphilis. Tests for vitamin B12, folic acid, thyroid function, C-reactive protein, and syphilis are 
to be performed only at screening. Blood samples will be collected at screening (within 28 days 
prior to injection) and at the follow-up visit at 3 (±1) days post-injection. All samples will be 
analysed at a central laboratory. 
10.3.3.3 
Urinalysis 
Urinalysis will be performed at screening (within 28 days prior to injection) and at 3 (±1) days 
post-injection (Follow-up Visit). The time of void will be documented on the CRF. Midstream 
urine will be collected. Urine voided will be tested at the investigator site using urinary 
dipstick. Any patients with positive protein and/or blood in urinalysis at screening will be 
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further investigated for urinary tract infection and adequately treated by the investigator prior 
to study entry. 
10.3.4 
Injection site monitoring 
The injection site will be evaluated for physical evidence of local/regional adverse outcomes at 
the following time points: within 30 minutes prior to injection, during injection, at 10 minutes 
post-injection, and 3 to 6 hours post-injection (see Table 1). The abnormal injection site 
findings include, but are not limited to, radiopharmaceutical extravasation, bleeding, 
haematoma, redness, and infection. 
Any abnormal finding that is new or represents a worsening from baseline is an AE. 
10.3.5 
Adverse events 
All AEs/SAEs that occur after informed consent shall be recorded in the AE/SAE report form 
(see the Study Schedule of Events, Table 1). 
Study personnel must remain vigilant for the occurrence of AEs after administration of IMP, 
particularly those that may be life threatening. Personnel who are trained in the acute 
management of anaphylaxis and other emergencies and who have access to appropriate clinical 
supplies must be immediately available for 1 hour after dosing. Treatment of SAEs should be 
primarily supportive of vital functions.  
AE and DaTSCAN™-emergent AE definition: An AE is defined as any untoward medical 
occurrence or an already present event that worsens either in intensity or frequency. A 
DaTSCAN™-emergent AE is defined as an AE that starts on or after the time of the injection 
of DaTSCAN™ until the follow-up visit at 3 (±1) days later. The DaTSCAN™-emergent AE 
does not necessarily have to have a causal relationship with exposure to the investigational 
agent. A DaTSCAN™-emergent AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with 
the exposure to the IMP, whether or not considered related to that product.  
The subjects will be closely observed and questioned for any kind of AE during the study 
procedures and throughout the study period with non-leading questioning (e.g., “How do you 
feel?”). The subjects will be instructed to immediately report any symptoms and signs to the 
study staff (i.e., between formal observations). 
If an AE has already been reported it is not necessary to report each individual sign and 
symptom of that AE as a separate AE. For example, if myocardial infarction is reported as an 
AE, there is no need to report an elevated creatine phosphokinase, abnormal ECG, or other 
related signs, symptoms, or laboratory values as separate AEs. 
All AEs/SAEs and all DaTSCAN™-emergent AEs/SAEs shall be collected up to the time 
point of finalisation of the last safety examination during the follow-up performed at 3 (±1) 
days post-injection.  
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Causal relationship 
Both the investigator(s) and Sponsor/contract research organisation (CRO) will perform a 
causality assessment on any AE, to assess whether or not there is a reasonable possibility 
(evidence to suggest) that the IMP caused the event. 
The relationship of an AE with DaTSCANTM will be assessed and reported by the investigator 
as: 
• 
Reasonably related to study drug (“Reasonable cause”): - A causal relationship between 
DaTSCANTM and an AE is at least a reasonable possibility, i.e., the relationship cannot 
be ruled out. 
• 
Not reasonably related to study drug (“Not reasonable cause”): - A causal relationship 
between DaTSCANTM and an AE is not a reasonable possibility. 
Suspected Adverse Reaction: A suspected adverse reaction is an AE where reasonable 
possibility exists for causality between DaTSCANTM and the AE. 
Expectedness 
All DaTSCANTM-emergent AEs will be assessed, by the sponsor (or CRO on behalf of 
sponsor), as to whether they were expected to occur or unexpected, meaning not anticipated 
based on current knowledge found in the applicable safety information included in the 
reference safety information in the IB for DaTSCANTM. 
Unexpected: An unexpected DaTSCANTM-emergent AE is a reaction, for which the nature, 
seriousness, severity or outcome is not consistent with the applicable safety 
information included in the IB. 
Expected: 
An expected DaTSCANTM-emergent AE is a reaction which is consistent with 
the applicable safety information included in the IB. 
10.3.5.1 
Serious adverse events 
An SAE is defined as any AE that: 
• 
Results in death. 
• 
Is immediately life-threatening. 
• 
Requires inpatient hospitalisation or prolongation of existing hospitalisation. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect. 
• 
Is another important medical event.* 
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*Other important medical events are those that may not result in death, be life-threatening, or 
require hospitalisation, but may be considered a SAE when, based upon appropriate medical 
judgement, they may jeopardise the subject and may require medical intervention to prevent 1 
of the outcomes listed in this definition. 
10.3.6 
Other significant adverse events 
Clinically notable results from vital signs, clinical laboratory, and injection site findings should 
be reported as AEs, where applicable. 
10.3.7 
Adverse event and serious adverse event reporting 
All AEs shall be recorded in the AE/SAE report form using acceptable diagnoses, if possible.  
If an AE has already been reported (by the investigator to the sponsor/CRO) it is not necessary 
to report each individual sign and symptom of that AE as a separate AE.  For example, if 
myocardial infarction is reported as an AE, there is no need to report elevated creatine kinase 
and abnormal ECG, or other related signs, symptoms, or laboratory values as separate AEs.  
However, if both occurred in isolation and myocardial infarction was not diagnosed, then each 
event would be reported as an AE. 
The intensity of all AEs will be graded as mild, moderate, or severe using the following 
definitions: 
Mild: 
Tolerable. 
Moderate: 
Interferes with normal activity. 
Severe: 
Incapacitating (causes inability to perform usual activity or work).  The 
investigator will be instructed to closely monitor each patient who 
experiences an AE (whether ascribed to DaTSCAN™ or not) until the 
outcome of the AE has been determined. 
In addition to the investigator’s own description of the AEs, each AE will be encoded by the 
sponsor/CRO according to a well-recognised dictionary of medical codes (Medical Dictionary 
for Regulatory Activities [MedDRA]). 
All serious and non-serious AEs must be followed for a final outcome until the end of the 
follow-up period.  An outcome of “unknown” is not considered to be an acceptable final 
outcome.  An outcome of “not yet resolved” is an acceptable final outcome for non-serious 
AEs at the end of a patient’s participation in a study, and for SAEs at database lock. 
Study centres are instructed to report all SAEs (including DaTSCAN™-emergent SAEs), 
together with a causality assessment, to the sponsor (or a service provider/CRO acting on 
behalf of the sponsor) within 24 hours. The Sponsor will review SAEs as they are 
received, and report to Health Authority as per local regulation. 
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All AEs and SAEs are reported in the AE form of the CRF. Detailed information about 
management of AE information will be provided, e.g., in a Safety Management Plan or 
equivalent document. 
10.3.8 
Urgent safety measures 
In accordance with the principles of Good Clinical Practice (GCP) as laid out in International 
Conference on Harmonisation (ICH) E6, the investigator(s) has/have primary responsibility for 
assuring subject safety throughout the performance of study procedures. An urgent safety 
measure is defined as any measure which an investigator may need to implement which is a 
deviation from, or a change in, the protocol to eliminate an immediate hazard(s) to trial 
subjects without prior favourable opinion from the IEC or institutional review board (IRB). 
The investigator may take appropriate urgent safety measures in order to protect the subjects of 
a clinical trial against any immediate hazards to their health or safety. However, the 
investigator must inform the sponsor/CRO within 24 hours of having taken such measures. 
The sponsor in turn shall immediately and in any event no later than 3 days from the date the 
measures are taken, give written notice to the licensing authority and the relevant IEC/IRB of 
the measures taken and the circumstances giving rise to those measures. 
All urgent safety measures must be reported to the sponsor/CRO using the SAE contact 
numbers provided in a separate document (as stipulated in in Section 10.3.7) within 24 hours of 
having to take such a measure(s). Such reports can be initiated by telephone but must be 
officially documented by the investigator (by email or fax) and must include details of what 
measures were taken and the circumstances giving rise to those measures. 
10.3.8.1 
Pregnancy reporting 
This process is aimed at ensuring the appropriate monitoring of the potential risk related to 
IMP exposure of pregnant women and/or foetuses as well as the risks associated with exposure 
of a father, regarding congenital abnormalities or birth defects in their offspring. It also ensures 
compliance with applicable international and local regulations. 
The requirements are applicable to all subjects following exposure to IMP. 
Female trial subjects: The study patient must be advised by the investigator to inform him/her 
immediately if she suspects she may be pregnant and believes conception occurred within 
72 hours of DaTSCANTM administration 
Male trial subjects: The study patient must be advised by the investigator to inform him/her 
immediately if he suspects his partner became pregnant within 72 hours after DaTSCANTM 
administration.  
When a trial subject reports a pregnancy (post-IMP administration) to the investigator, a 
pregnancy test should be arranged for the trial subject (or their partner) by the investigator 
within 7 days of the pregnancy being reported. 
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The investigator must inform the sponsor/CRO within 24 hours of receiving positive pregnancy 
test results using either a copy of the relevant CRF page (demography or AE) or via e-mail. 
The investigator should include an estimated date of conception when communicating with the 
sponsor/CRO. 
10.4 
Other Variables 
10.4.1 
Demographic data 
The following demographic data will be collected at the screening visit 
• Age 
• Gender 
• Weight 
• Height 
• Race 
• Level of education 
10.4.2 
Medical and surgical history 
The medical and surgical history will be recorded at the baseline visit.  
10.4.3 
Prior and concomitant medication 
The subjects will be asked about prior and concomitant medications at the screening visit 
(within 28 days prior to the screening visit), at the baseline (from screening visit to baseline 
visit), at the imaging visit (from baseline visit to imaging visit), and at the follow-up visit (from 
imaging visit to follow-up visit). History of treatment response to medications used to treat PD, 
MSA, PSP and ET will be recorded. At the imaging visit, the investigator will review the list of 
medications to determine whether sufficient washout from any prohibited medication and from 
traditional Chinese medication has been achieved to determine final eligibility.  
At the baseline visit, the date and time of the last dose of PD treatments prior to UPDRS Part 
III will be recorded as part of UPDRS Part III.   
10.4.4 
Drug and alcohol screening 
At the screening visit, subjects will be asked about a history of drug or alcohol abuse.  
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10.4.5 
Neuropsychiatric assessments 
At the screening and baseline visit, the following assessments will be performed: 
• 
Mini-Mental State Examination (MMSE): The MMSE is a simplified, cognitive mental 
status examination focusing on the cognitive aspect of mental function. It is an 
examiner-led evaluation and consists of 11 questions [Folstein et al. 1975]. 
• 
Movement Disorder Society United Parkinson’s Disease Rating Scale (MDS-UPDRS) 
Part III assessment: MDS-UPDRS Part III [Goetz et al. 2008] will be used to assess any 
presence of motor symptoms of parkinsonism. Examiners should complete online 
training for the MDS-UPDRS Part III examination. Results will be captured in the 
CRF. 
• 
Modified Hoehn and Yahr (H&Y) Scale for Parkinson’s Disease: The 8-point Modified 
H&Y scale will be used. 
• 
WHIGET assessment for ET:  The WHIGET Tremor Rating Scale (version 1) was 
developed for the purpose of identifying patients with ET in population studies.  This 
version, published in 1997 [Louis et al. 1997], has inclusion and exclusion criteria for 
distinguishing ET from other forms of action tremor.  It is a 10-minute tremor 
examination designed to elicit rest tremor, rest tremor and kinetic tremor.  Postural and 
kinetic tremors elicited from a battery of tasks are rated from 0 to 3 [Elble et al. 2013]. 
Results of these assessments, together with medical and medication history will be used to 
determine the clinical diagnosis at the baseline visit. 
10.4.6 
Investigator’s clinical diagnosis 
The investigator will establish clinical diagnosis of the subject at the baseline visit. Diagnosis 
will be made by using the following internationally accepted diagnostic criteria: 
• 
MDS Clinical Diagnostic Criteria for Parkinson’s Disease 
• 
Second Consensus Statement on the Diagnosis of MSA 
• 
Clinical Criteria for the Diagnosis of Progressive Supranuclear Palsy National Institute 
for Neurological Disorders and Society for PSP 
• 
WHIGET diagnostic criteria for ET (no SDD) 
All available data at the site will be used to establish the diagnosis, including medical records, 
comprehensive medical history, clinical examination, neuropsychiatric assessment and 
laboratory results collected at screening and baseline visit. 
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10.5 
Appropriateness of Measurements 
All assessments and measurements are appropriate and generally regarded as standard medical 
practice.  
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11 
DATA HANDLING AND QUALITY ASSURANCE 
11.1 
Completing and Signing Case Report Forms 
For electronic CRFs, data will be entered by trained site personnel. Any errors should be 
corrected within the electronic system. The audit trail will record all changes made, the date 
and time of the correction, and the person correcting the error. The appropriate electronic 
signature will be provided. 
11.2 
Clinical Data Management 
The sponsor or CRO will be responsible for the processing and quality control of the data. Data 
management will be carried out by the CRO. The handling of data, including data quality 
control, will comply with all applicable regulatory guidelines. 
11.3 
Archiving 
All study documentation at the investigator site and sponsor site will be archived in accordance 
with ICH E6-GCP and the GE Healthcare's quality standards and standard operating 
procedures (SOPs). 
All study documentation at the Investigator site and sponsor site will be archived as required 
by local regulatory legislation following completion or discontinuation of the study, unless 
notified otherwise by the sponsor. The Investigator must request written agreement from the 
sponsor before destruction of archived study documentation. 
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12 
STATISTICAL METHODS AND PLANNED ANALYSIS 
The data will be analysed by the sponsor and/or designated CRO. Any data analysis carried out 
independently by the investigator should be submitted to the sponsor before publication or 
presentation. 
Data from participating centres in this protocol will be combined so that an adequate number of 
subjects will be available for analysis. The data will be summarised with respect to 
demographic and baseline characteristics, efficacy observations and measurements, and safety 
observations and measurements. 
12.1 
General Statistical Considerations 
Tabulations of summary statistics, graphical presentations, and statistical analyses will be 
performed with SAS software, Version 9.2 or higher. Descriptive statistics for continuous 
data in summary tables will include the number of subjects in the analysis (n), mean, standard 
deviation, median, and range (minimum, maximum). Descriptive statistics for categorical data 
in summary tables will include counts and percentages. The last observation prior to 
administration of IMP will be used as the baseline value for calculating changes from baseline 
after administration of IMP. All data recorded on the CRF and entered into the database will be 
provided in separate data listings showing individual subject values. All summary tables and 
data listings will be separated by baseline diagnosis. The planning and reporting of statistical 
analysis will be carried out as described in the sponsor and/or CRO’s SOPs governing clinical 
studies. 
12.2 
Populations for Analysis 
12.2.1 
Full analysis set (FAS) 
The efficacy analysis will be performed for the full analysis set (FAS), which will consist of all 
subjects who have both a DaTSCAN™ image set and a clinical diagnosis made by the 
investigator. 
12.2.2 
Per-protocol (PP) population  
The per-protocol (PP) population will include all subjects who meet the inclusion/exclusion 
criteria and did not withdraw informed consent (if applicable), and who have DaTSCAN™ 
image sets that are considered evaluable by at least 2 of the 3 blinded readers. Subjects 
considered for PP population include subjects in the FAS with no major protocol violations.  
Subjects with protocol violations will be excluded from the PP population but will be included 
in the FAS. Subjects with protocol violations will be identified in the study report. 
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12.2.3 
Safety population 
All subjects who receive an injection of IMP will be included in the safety population. 
12.3 
Subject Demographics/Other Baseline Characteristics 
12.3.1 
Subject disposition 
A table will be provided with the following information: 
• 
Number of subjects enrolled. 
• 
Number of subjects included in the efficacy analysis. 
• 
Number of subjects included in the safety analysis. 
• 
Number of subjects withdrawn from the study and the reason for withdrawal. 
12.3.2 
Demographic data 
Demographic information (age, height, weight, and body mass index) will be summarised by 
using descriptive statistics. Sex and race will be summarised by counts and percentages. 
12.3.3 
Risk factors and medical history 
Pregnancy information, medical/surgical history, and history of any disease classification will 
be summarised by counts and percentages. 
12.3.4 
Clinical diagnosis  
The clinical diagnosis of PS (SDD; specifically, PD, MSA, or PSP) or no SDD (ET or healthy 
controls) as determined by the investigator at entry will be summarised by counts and 
percentages. 
12.4 
Study Treatments 
12.4.1 
Previous and concurrent medication 
Any prior and concurrent therapy or medication (and the indication for the treatment) given to 
a subject from 28 days prior to IMP administration and throughout the follow-up period after 
IMP administration will be tabulated by counts and percentages. The World Health 
Organization Drug Global Dictionary, Version September 1, 2018 or later, using Anatomic 
Therapeutic Chemical (ATC) and Herbal ATC Code Level 3, and preferred name will be used.   
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12.4.2 
Exposure to IMP 
The following information will be recorded and summarised with descriptive statistics: 
• 
The radioactivity (in megabecquerels) of the syringe before injection. 
• 
The volume (in millilitres) of IMP administered.  
• 
The total radioactivity administered.  
• 
The duration of injection. 
• 
The saline flush volume.  
12.4.3 
Thyroid blockade 
The amount and type of medication used for thyroid blockade for each subject will be 
summarised.   
12.4.4 
Handling of uninterpretable images as determined by the BIE 
Subjects with image(s) that cannot be interpreted from the BIE will be excluded from the 
primary analysis but will be included to determine the sensitivity of results. 
12.4.5 
Handling of uninterpretable images 
Uninterpretable images will be excluded from the efficacy analysis. All data from all subjects 
dosed in the study will be included in all listings, plots, summary tables, and statistical analyses 
when appropriate. The number and proportion of images that are uninterpretable will be 
displayed in tables. 
12.4.6 
Reader difference 
Intra-reader (within-reader) agreement of blinded visual image assessment will be measured by 
percentage agreement. This will be based on a random selection of 10% of the subjects having 
re-read images. A percentage agreement with an exact 95% confidence interval will be 
determined for each reader comparison and all readers for subjects with re-reads of images. 
In cases where images are re-read, it is the result of the first read that is to be included in the 
efficacy analysis. 
12.5 
Efficacy Analysis 
Efficacy analyses will be performed on both the FAS and PP populations defined in 
Section 12.3. 
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12.5.1 
Primary efficacy analysis 
The sensitivity and specificity of the blinded independent read of DaTSCAN™ SPECT images 
in detecting or excluding SDD, when the clinical diagnosis as established by the investigator is 
used as the standard of truth, will be summarised with both by-reader and majority-read 
analyses. For each summary, the computed value and the 95% 2-sided binomial confidence 
interval will be presented for both sensitivity and specificity.  
12.5.1.1 
Sensitivity 
In this study, sensitivity will be defined as positive percentage agreement. Sensitivity will be 
calculated as the number of true positives (TP) / (number of TP + number of false negatives 
[FN]): TP/(TP + FN), and a 2-sided 95% binomial confidence interval constructed around it.   
12.5.1.2 
Specificity 
In this study, specificity will be defined as negative percentage agreement. Specificity will be 
calculated as the number of true negatives (TN) / (number of TN + number of false positives 
[FP]): TN/(TN + FP), and a 2-sided 95% binomial confidence interval constructed around it.  
For the specificity analysis, only subjects with a clinical diagnosis of ET will be included; the 
HVs will be excluded from this analysis.   
12.5.1.3 
Accuracy 
Accuracy will be calculated as (TP + TN) / (TP + FN + TN + FP), and a 2-sided 95% binomial 
confidence interval constructed around it.   
12.5.2 
Secondary efficacy analyses 
12.5.2.1 
Semi-quantitative analysis 
A semi-quantitative analysis of the striatal uptake ratios in specific regions of interest (ROIs; 
i.e., left and right striatum, caudate, and putamen) of DaTSCAN™ SPECT images will be 
performed with DaTQUANT™. To account for nonspecific binding, the DaTSCAN™ uptake 
in the ROI will be normalised to DaTSCAN™ uptake in the subject's occipital cortex. The 
normalised DaTSCAN™ uptake values for each ROI will be summarised with descriptive 
statistics for each category of subjects with SDD (PD, MSA, or PSP) and each category of 
subjects without SDD (ET and HVs). For all striatal uptake ratios, an analysis of variance 
(ANOVA) will be carried out to test for differences in the striatal uptake ratios among the 
clinical diagnosis groups.  
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12.6 
Safety Analyses 
12.6.1 
Safety variables and analyses 
All safety data will be listed by subject group, subject number, and time point (if applicable). 
No inferential testing will be performed for safety parameters. 
• 
An overall summary of AEs and DaTSCAN™-emergent AEs will be presented, coded 
with MedDRA and summarised by MedDRA system organ class and preferred term.  
• 
Observations and changes from baseline in the results of the physical examination 
(including vital signs), neurologic examination, injection site monitoring, and clinical 
laboratory evaluation (haematology, serum biochemistry, and urinalysis) will be 
summarised (see Table 1). 
12.6.1.1 
Clinical laboratory evaluation 
Descriptive statistics will be displayed for the observed values and changes from baseline. In 
addition, for each clinical laboratory variable and each time point, the following safety 
endpoints will be summarised by counts and percentages for the overall safety population and 
for each diagnostic group subset: 
• 
The occurrence of 1 or more changes from baseline, at each post-administration time 
point, greater than 40% and 80% of the span of the normal limits (not applicable to 
qualitative parameters). 
• 
The occurrence of post-administration values outside the normal limits (not applicable 
to qualitative parameters). Shift tables based on the normal range will be prepared.  
12.6.1.2 
Vital signs 
Descriptive statistics will be displayed for the observed values and changes from baseline. For 
each vital-sign variable and each time point, the following safety endpoints will be summarised 
by counts and percentages for the overall safety population and for each subject group: 
• 
The occurrence of 1 or more changes from baseline, at each post-administration time 
point, greater than a pre-specified magnitude (20 mm Hg for systolic blood pressure, 
10 mm Hg for diastolic blood pressure, 10 beats per minute for heart rate). 
• 
The occurrence of post-administration values outside the normal limits. Shift tables 
based on the normal range will be prepared.  
12.6.1.3 
Physical examination 
Baseline findings and the number and percentage of subjects with changes in physical 
examination status from normal at baseline to abnormal at each post-administration time point 
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(and vice versa) will be presented for the safety population and for each subject group. Shift 
tables based on normal vs abnormal results will be prepared.  
12.6.1.4 
Neurological examination 
Baseline findings and the number and percentage of subjects with changes in neurological 
examination status from normal at baseline to abnormal at each post-administration time point 
(and vice versa) will be presented for the safety population and for each subject group. Shift 
tables based on normal vs abnormal results will be prepared. 
12.6.1.5 
Injection site monitoring 
Injection site findings will be summarised by time point for the safety population and for each 
subject group. 
12.6.1.6 
Adverse events 
An overall summary of AEs and DaTSCAN™-emergent AEs will be presented, coded with 
MedDRA and summarised by MedDRA system organ class and preferred term for the safety 
population and for each subject group.  Summaries will also be presented by AE intensity and 
judged relationship to IMP.   
SAEs will be separately presented for the safety population and for each subject group.   
Other significant AEs, defined as laboratory abnormalities that qualify as AEs (other than those 
meeting the definition for serious) and any events that led to an intervention (including 
premature discontinuation of IMP, dose reduction, or significant additional concomitant 
therapy), in addition to those reported as SAEs, will be summarised for the safety population 
and for each subject group. 
12.7 
Sample Size Calculation 
Although the primary efficacy analysis is not inferentially based, sample size calculations are 
based on hypothesis testing separately for sensitivity and specificity, assuming 1-sided alpha of 
0.05, statistical power of 80%, and assumed sensitivity and specificity of 95%.  
The null hypothesis tests are given as H0: p ≤ p0 where p0 is the specified threshold. The 
alternate hypothesis is given by Ha: p>p0. The parameter p represents the sensitivity/specificity 
of the blinded independent read of DaTSCAN™ SPECT images in detecting or excluding 
SDD, using the clinical diagnosis as established by the investigator as the standard of truth.  
An exact binomial test with a nominal 0.05 1-sided significance level will have 80% power to 
detect the difference between the null hypothesis diagnostic sensitivity threshold of 0.85 and 
the assumed alternative proportion of 0.95 when the sample size is 59 subjects with SDD 
present.  
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An exact binomial test with a nominal 0.05 1-sided significance level will have 80% power to 
detect the difference between the null hypothesis diagnostic specificity threshold of 0.85 and 
the assumed alternative proportion of 0.95 when the sample size is 59 subjects with SDD 
absent.  
An extensive set of values for the specified threshold, p0, and the resultant sample size (for 
either sensitivity or specificity) are as follows: P0 = 0.89: n=128; P0 = 0.88: n=107; P0 = 0.87: 
n= 89; P0 = 0.86: n= 73; P0 = 0.85: n= 59; P0 = 0.84: n= 55; P0 = 0.83: n= 44; P0 = 0.82: n= 41; 
P0 = 0.81: n= 39; P0 = 0.80: n=30.  
However, according to regulatory guidelines sample size for a new product with more than 1 
indication (which is the case for DaTSCAN™) requires a minimum of 60 pairs of cases. 
Therefore, the final number of evaluable diseased individuals will be 60 in each group (SDD 
present and absent). 
In addition to the 120 evaluable subjects (subjects with movement disorder), each centre will 
be requested to recruit 2 to 4 HVs (subjects without movement disorder) for the sole purpose of 
the creation of a normal database. A total of 20 HVs will be recruited across the centres. These 
subjects will also be included in the safety analysis. 
On the basis of a previous study (DP008-003), it is projected that evaluable results will be 
obtained for 80% of diseased individuals and 90% of HVs. After adjustment for losses, it is 
therefore expected that 150 patients with movement disorders (with or without SDD) and 22 
HVs will be needed to provide at least the minimum required number of evaluable subjects. 
12.8 
Power for Analysis of Critical Secondary Variables 
No power analysis was performed on any of the secondary variables.   
12.9 
Procedures for Missing, Unused and Spurious Data 
Missing values will not be substituted by estimated values but treated as missing in the 
statistical evaluation. All data from all subjects dosed in the study will be included in all 
listings, plots, summary tables, and statistical analyses when appropriate.  
12.10 
Rules for Excluding Subjects from Analysis 
All dosed subjects will be included in the analyses unless otherwise specified. The sponsor will 
make any decisions regarding whether any subjects or any individual values belonging to a 
subject will be excluded from the statistical evaluation (tables, plots, and analyses). Apart from 
the conditions on excluding subjects from the efficacy population stated in Section 12.2, 
subjects will only be excluded from the evaluations when a protocol violation is considered to 
imperil the scientific aspects and interpretation of the study results. If the subject has received 
any IMP, all available safety data will be used. The reason(s) for any exclusion will be 
described in the report. 
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12.11 
Procedures for Reporting Deviations from Original Statistical Plan 
Any deviations from the statistical analysis outlined in this protocol will be described, and 
reasons for the deviations listed, in the final Clinical Study Report. 
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13 
SPECIAL REQUIREMENTS AND PROCEDURES 
13.1 
Regulatory, Institutional and Ethical Review 
Before this study is started, the protocol (authorized by the sponsor) will be submitted to the 
regulatory bodies/local health authorities (in accordance with local regulations) and to the 
IEC/IRB for evaluation. The protocol will also be signed by the principal investigator before 
submission to the IEC/IRB. The study will not start before the IEC/IRB gives written approval 
or a favourable opinion in accordance with ICH E6-GCP and all applicable regulatory 
bodies/local health authorities give approval or a favourable opinion as required. 
No changes from the final approved (authorized) protocol will be initiated without the 
IEC’s/IRB’s prior written approval or favourable opinion of a written amendment, except when 
necessary to eliminate immediate hazards to the subjects or when the change involves only 
logistics or administration. The sponsor will authorize and the principal investigator(s) will 
sign the protocol amendment prior to submission to the IEC/IRB. Protocol amendments should 
be submitted to the IEC/IRB without delay.  
13.2 
Investigator’s Responsibilities 
13.2.1 
Overall responsibilities 
The investigator(s) is/are responsible for conducting the study in full accordance with the 
Protocol and the Declaration of Helsinki, the Good Clinical Practice: Consolidated Guideline, 
approved by the ICH, and any applicable national and local laws and regulations. Information 
regarding any investigational centres participating in this study that cannot comply with these 
standards will be documented. 
13.2.2 
Subject informed consent 
Written and oral information about the study in a language understandable by the subject 
and/or their legally acceptable representative will be given to all subjects and/or their legally 
acceptable representatives. Each subject’s willingness to participate in the study will be 
documented in a signed and dated informed consent form before any procedures or 
assessments are done and after the aims, methods, anticipated benefits, potential hazards, and 
insurance arrangements in force are explained. It will also be explained to the subjects and/or 
their legally acceptable representatives that they are free to refuse entry into the study and free 
to withdraw from the study at any time without prejudice to future treatment. The informed 
consent process will be documented in the subject's medical record and the investigator will 
sign, date the informed consent form after the subject and/or their legally acceptable 
representative has signed and dated the document. The investigator(s) will keep the original 
consent forms and copies will be given to the subjects and/or their legally acceptable 
representatives. 
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13.2.3 
Direct access to source data/documents 
The monitor(s), auditor(s), authorized personnel of the sponsor/CRO, health authority 
inspector(s) or their agents, and authorized members of IECs/IRBs will be given direct access 
to source data and documentation (e.g., medical charts/records, laboratory results, printouts, 
videotapes, etc.) for source data verification, provided that subject confidentiality is maintained 
in accordance with local requirements. 
13.2.4 
Confidentiality regarding study subjects 
The investigator(s) must assure that the privacy of the subjects, including their personal 
identity and all other personal medical information, will be maintained at all times. In CRFs 
and other documents or image material (including materials from all examinations, e.g., MRI, 
SPECT examinations) submitted to the sponsor/CRO, subjects will not be identified by their 
names, but by an identification code (e.g., study subject number). 
Personal medical information may be scrutinized for the purpose of verifying data recorded in 
the CRF. This may be done by the monitor(s), properly authorized persons on behalf of the 
sponsor, the quality assurance unit, or regulatory authorities. Personal medical information will 
always be treated as confidential. 
13.3 
Protocol Deviations 
Any deviation from the protocol when no approved amendment exists must be documented as 
a protocol deviation and reported according to local requirements. If appropriate, corrective 
and preventative action must be implemented to avoid repetition. Protocol deviations and any 
potential impact on the study results will be discussed during the reporting of the study. 
Waivers or protocol exceptions will not be granted prospectively by the sponsor under 
any circumstances. Any exceptions to protocol specified requirements will be considered 
as protocol deviations. 
13.4 
Study Monitoring 
Study monitoring will be performed in accordance with ICH E6-GCP, the Sponsor/CRO SOPs, 
the protocol, and applicable local regulations. 
13.5 
Audit and Inspection 
According to ICH E6-GCP, the sponsor or regulatory authorities may audit the investigational 
site. The sponsor’s Quality Assurance Unit, independent of the Clinical Research and 
Development Department, is responsible for auditing the study. 
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The investigator(s) must accept that regulatory authorities may conduct an inspection to verify 
compliance of the study with GCP. 
13.6 
Radioactive Licence Requirements 
The investigators must have the appropriate license (Nuclear Regulatory Commission By-
product Material Site License) for any procedure involving the administration of radioactive 
substances supplied by the sponsor. If radiolabelled materials will be shipped from the sponsor 
to the study site, a copy of the clinical site’s Nuclear Regulatory Commission license must be 
provided to the sponsor and archived in the Trial Master File before the radiolabelled material 
can be shipped. 
13.7 
Insurance 
This study is covered under the sponsor’s Liability Insurance Policy (under General Electric 
Insurance Company and/or a company designated by the study Sponsor). A Certificate of 
Insurance and/or an information leaflet containing essential information about the insurance 
coverage can be provided upon request. 
13.8 
Publication Policy 
The investigator and/or Institution shall have the right to publish the results of their work 
conducted under this protocol, subject to providing the sponsor with the opportunity to review 
the contents of any proposed abstract or publication concerning the work, including any results 
of the study, in advance of publication and if necessary to delay publication for a limited time 
not to exceed 60 days in order to protect the confidentiality or proprietary nature of any 
information contained therein. The sponsor will make every reasonable effort to consider and 
release each proposed publication within 30 days, or proposed abstract within 15 days, of 
submission. 
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14 
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Parkinson’s disease. Age Ageing 1999; 28:99-102. 
[O'Brien et al. 2014] 
O'Brien JT, Oertel WH, McKeith IG, Grosset DG, Walker Z, Tatsch K, et al. Is ioflupane I123 
injection diagnostically effective in patients with movement disorders and dementia? Pooled 
analysis of four clinical trials. BMJ Open 2014;4:3005122. 
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[Pan et al. 1994] 
Pan Z, He Z, Yang Y, Guo M. Natural background radiation and population dose in China. 
Radioprotection 1994;29(1):69-80. 
[Postuma et al. 2015] 
Postuma RB, Berg D, Stern M, Poewe W, Olanow CW, Oertel W, et al. MDS Clinical 
Diagnostic Criteria for Parkinson’s Disease. Movement Disorders. 2015;30(12):1591-1599. 
[Varrone et al. 2013] 
Varrone A, Dickson JC, Tossici-Bolt L, Sera T, Asenbaum S, Booij J, et al. European 
multicentre database of healthy controls for [123I]FP-CIT SPECT (ENC-DAT): age-related 
effects, gender differences and evaluation of different methods of analysis. Eur J Nucl Med 
Mol Imaging. 2013;40(2):213-27. 
[Wang et al. 2012] 
Wang L, Zhang Q, Li H, Zhang H. SPECT molecular imaging in Parkinson's disease. H 
Biomed Biotechnol. 2012;2012:412486. 
[Wu et al. 2014] 
Wu X, Cai H, Ge R, Li L, Jia Z. Recent progress of imaging agents for Parkinson's disease. 
Curr Neuropharmacol 2014;12:551-563. 
[Yang et al. 2015] 
Yang XL, et al. Related factors and prevalence of Parkinson’s disease among Uygur residents 
in Hetian, Xinjiang Uygur autonomous region. Genet Mol Res. 2015;14(3):8539–46. 
[Zhou et al. 2014] 
Zhou YM, Tan JP, Li N, Yang JS, Yu BC, Yu JM, et al. The prevalence of Parkinson's disease 
continues to rise after 80 years of age: a cross-sectional study of Chinese veterans. Eur Rev 
Med Pharmacol Sci. 2014;18:3908-3915. 
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15 
APPENDICES 
15.1 
Clinical Diagnostic Criteria 
15.1.1 
MDS Clinical Diagnostic Criteria for Parkinson’s Disease [Postuma et al. 2015] 
The first essential criterion is parkinsonism, which is defined as bradykinesia, in combination with at 
least 1 of rest tremor or rigidity. Examination of all cardinal manifestations should be carried out as 
described in the MDS-Unified Parkinson Disease Rating Scale. Once parkinsonism has been diagnosed: 
Diagnosis of Clinically Established PD requires: 
1. Absence of absolute exclusion criteria 
2. At least two supportive criteria, and 
3. No red flags 
Diagnosis of Clinically Probable PD requires: 
1. Absence of absolute exclusion criteria 
2. Presence of red flags counterbalanced by supportive criteria 
If 1 red flag is present, there must also be at least 1 supportive criterion 
If 2 red flags, at least 2 supportive criteria are needed 
No more than 2 red flags are allowed for this category 
Supportive criteria 
(Check box if criteria met) 
☐ 1. Clear and dramatic beneficial response to dopaminergic therapy. During initial treatment, patient 
returned to normal or near-normal level of function. In the absence of clear documentation of 
initial response, a dramatic response can be classified as: 
a) Marked improvement with dose increases or marked worsening with dose decreases. Mild 
changes do not qualify. Document this either objectively (>30% in UPDRS III with change in 
treatment), or subjectively (clearly-documented history of marked changes from a reliable 
patient or caregiver). 
b) Unequivocal and marked on/off fluctuations, which must have at some point included 
predictable end-of-dose wearing off. 
☐ 2. Presence of levodopa-induced dyskinesia 
☐ 3. Rest tremor of a limb, documented on clinical examination (in past, or on current examination) 
☐ 4. The presence of either olfactory loss or cardiac sympathetic denervation on MIBG scintigraphy 
Absolute exclusion criteria: The presence of any of these features rules out PD: 
☐ 1. Unequivocal cerebellar abnormalities, such as cerebellar gait, limb ataxia, or cerebellar 
oculomotor abnormalities (eg, sustained gaze evoked nystagmus, macro square wave jerks, 
hypermetric saccades) 
☐ 2. Downward vertical supranuclear gaze palsy, or selective slowing of downward vertical saccades 
☐ 3. Diagnosis of probable behavioral variant frontotemporal dementia or primary progressive 
aphasia, defined according to consensus criteria31 within the first 5 y of disease 
☐ 4. Parkinsonian features restricted to the lower limbs for more than 3 y 
☐ 5. Treatment with a dopamine receptor blocker or a dopamine-depleting agent in a dose and time-
course consistent with drug-induced parkinsonism 
☐ 6. Absence of observable response to high-dose levodopa despite at least moderate severity of 
disease 
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☐ 7. Unequivocal cortical sensory loss (ie, graphesthesia, stereognosis with intact primary sensory 
modalities), clear limb ideomotor apraxia, or progressive aphasia 
☐ 8. Normal functional neuroimaging of the presynaptic dopaminergic system 
☐ 9. Documentation of an alternative condition known to produce parkinsonism and plausibly 
connected to the patient’s symptoms, or, the expert evaluating physician, based on the full 
diagnostic assessment feels that an alternative syndrome is more likely than PD 
Red flags 
☐ 1. Rapid progression of gait impairment requiring regular use of wheelchair within 5 y of onset 
☐ 2. A complete absence of progression of motor symptoms or signs over 5 or more y unless stability 
is related to treatment 
☐ 3. Early bulbar dysfunction: severe dysphonia or dysarthria (speech unintelligible most of the time) 
or severe dysphagia (requiring soft food, NG tube, or gastrostomy feeding) within first 5 y 
☐ 4. Inspiratory respiratory dysfunction: either diurnal or nocturnal inspiratory stridor or frequent 
inspiratory sighs 
☐ 5. Severe autonomic failure in the first 5 y of disease. This can include: 
a) Orthostatic hypotension32—orthostatic decrease of blood pressure within 3 min of standing by 
at least 30 mm Hg systolic or 15 mm Hg diastolic, in the absence of dehydration, medication, or 
other diseases that could plausibly explain autonomic dysfunction, or 
b) Severe urinary retention or urinary incontinence in the first 5 y of disease (excluding long-
standing or small amount stress incontinence in women), that is not simply functional 
incontinence. In men, urinary retention must not be attributable to prostate disease, and must be 
associated with erectile dysfunction 
☐ 6. Recurrent (>1/y) falls because of impaired balance within 3 y of onset 
☐ 7. Disproportionate anterocollis (dystonic) or contractures of hand or feet within the first 10 y 
☐ 8. Absence of any of the common nonmotor features of disease despite 5 y disease duration. These 
include sleep dysfunction (sleep-maintenance insomnia, excessive daytime somnolence, 
symptoms of REM sleep behavior disorder), autonomic dysfunction (constipation, daytime 
urinary urgency, symptomatic orthostasis), hyposmia, or psychiatric dysfunction (depression, 
anxiety, or hallucinations) 
☐ 9. Otherwise-unexplained pyramidal tract signs, defined as pyramidal weakness or clear pathologic 
hyperreflexia (excluding mild reflex asymmetry and isolated extensor plantar response) 
☐ 10. Bilateral symmetric parkinsonism. The patient or caregiver reports bilateral symptom onset with 
no side predominance, and no side predominance is observed on objective examination 
Criteria Application: 
1. Does the patient have parkinsonism, as defined by the MDS criteria?   
 
 
Yes ☐  No ☐ 
If no, neither probable PD nor clinically established PD can be diagnosed. If yes: 
2. Are any absolute exclusion criteria present?   
 
 
 
 
 
 
 
 
 
Yes ☐  No ☐ 
If “yes,” neither probable PD nor clinically established PD can be diagnosed. If no: 
3. Number of red flags present ____ 
4. Number of supportive criteria present ____ 
5. Are there at least 2 supportive criteria and no red flags?   
 
 
 
 
 
 
Yes ☐  No ☐ 
If yes, patient meets criteria for clinically established PD. If no: 
6. Are there more than 2 red flags?   
 
 
 
 
 
 
 
 
 
 
 
 
 
Yes ☐  No ☐ 
If “yes,” probable PD cannot be diagnosed. If no: 
7. Is the number of red flags equal to, or less than, the number of supportive criteria? Yes ☐ No ☐ 
If yes, patient meets criteria for probable PD 
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15.1.2 
Second Consensus Statement on the Diagnosis of Multiple System Atrophy 
[Gilman et al. 2008] 
Criteria for the diagnosis of probable MSA 
• 
A sporadic, progressive, adult (>30 year)-onset disease characterized by  
• 
Autonomic failure involving urinary incontinence (inability to control the release of 
urine from the bladder, with erectile dysfunction in males) or an orthostatic decrease of 
blood pressure within 3 minutes of standing by at least 30 mm Hg systolic or 15 mm 
Hg diastolic and 
• 
Poorly levodopa-responsive parkinsonism (bradykinesia with rigidity, tremor, or 
postural instability) or 
• 
A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar 
oculomotor dysfunction). 
Criteria for possible MSA 
• 
A sporadic, progressive, adult (>30 year)-onset disease characterized by  
• 
Parkinsonism (bradykinesia with rigidity, tremor, or postural instability) or 
• 
A cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar 
oculomotor dysfunction) and  
• 
At least one feature suggesting autonomic dysfunction (otherwise unexplained urinary 
urgency, frequency, or incomplete bladder emptying, erectile dysfunction in males, or 
significant orthostatic blood pressure decline that does not meet the level required in 
probable MSA) and 
• 
At least one of the additional features of possible MSA. 
Additional features of possible MSA 
Possible MSA with predominant parkinsonism (MSA-P) or with predominant cerebellar 
ataxia (MSA-C) 
• 
Babinski sign with hyperreflexia. 
• 
Stridor. 
Possible MSA-P 
• 
Rapidly progressive parkinsonism. 
• 
Poor response to levodopa. 
• 
Postural instability within 3 years of motor onset. 
• 
Gait ataxia, cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction. 
• 
Dysphagia within 5 years of motor onset. 
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• 
Atrophy on MRI of putamen, middle cerebellar peduncle, pons, or cerebellum. 
• 
Hypometabolism on [18F]fluorodeoxyglucose positron emission tomography (FDG-
PET) in putamen, brainstem, or cerebellum. 
Possible MSA-C 
• 
Parkinsonism (bradykinesia and rigidity). 
• 
Atrophy on MRI of putamen, middle cerebellar peduncle, or pons. 
• 
Hypometabolism on FDG-PET in putamen. 
• 
Presynaptic nigrostriatal dopaminergic denervation on SPECT or PET. 
Features supporting (red flags) and not supporting a diagnosis of MSA 
Supporting features 
• 
Orofacial dystonia. 
• 
Disproportionate antecollis. 
• 
Camptocormia (severe anterior flexion of the spine) and/or Pisa syndrome (severe 
lateral flexion of the spine). 
• 
Contractures of hands or feet. 
• 
Inspiratory sighs. 
• 
Severe dysphonia. 
• 
Severe dysarthria. 
• 
New or increased snoring. 
• 
Cold hands and feet. 
• 
Pathologic laughter or crying. 
• 
Jerky, myoclonic postural/action tremor. 
Non-supporting features 
• 
Classic pill-rolling rest tremor. 
• 
Clinically significant neuropathy. 
• 
Hallucinations not induced by drugs. 
• 
Onset after age 75 years. 
• 
Family history of ataxia or parkinsonism. 
• 
Dementia (on DSM-IV). 
• 
White matter lesions suggesting multiple sclerosis. 
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15.1.3 
Clinical Criteria for the Diagnosis of Progressive Supranuclear Palsy National 
Institute for Neurological Disorders and Society for PSP (NINDS-SPSP) 
[Litvan et al. 1996] 
Mandatory Inclusion Criteria 
PSP Possible 
• 
Gradually progressive disorder. 
• 
Onset at age 40 years or later. 
• 
Either vertical (upward or downward gaze) supranuclear palsya or both slowing of 
vertical saccades and prominent postural instability with tendency to fallb in the first 
year of disease onset. 
• 
No evidence of other diseases that could explain the foregoing features, as indicated by 
mandatory exclusion criteria. 
PSP Probable 
• 
Gradually progressive disorder. 
• 
Onset at age 40 years or later. 
• 
Vertical (upward or downward gaze) supranuclear palsya and prominent postural 
instability with tendency to fallb in the first year of disease onset. 
• 
No evidence of other diseases that could explain the foregoing features, as indicated by 
mandatory exclusion criteria. 
Definite PSPc 
• 
Clinically probable or possible PSP and histopathologic evidence of typical PSP 
Mandatory exclusion criteria 
• 
Recent history of encephalitis 
• 
Alien limb syndrome, cortical sensory deficits, focal frontal or temporoparietal atrophy 
• 
Hallucinations or delusions unrelated to dopaminergic therapy. 
• 
Cortical dementia of Alzheimer's type (severe amnesia and aphasia or agnosia, 
according to NINCDS-ADRDA criteria). 
• 
Prominent, early cerebellar symptoms or prominent, early unexplained dysautonomia 
(marked hypotension and urinary disturbances). 
• 
Severe asymmetric parkinsonian signs (i.e., bradykinesia). 
• 
Neuroradiologic evidence of relevant structural abnormality (i.e., basal ganglia or 
brainstem infarcts, lobar atrophy). 
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• 
Whipple's disease, confirmed by polymerase chain reaction, if indicated. 
Supportive criteria 
• 
Symmetric akinesia or rigidity, proximal more than distal. 
• 
Abnormal neck posture, especially retrocollis. 
• 
Poor or absent response of parkinsonism to levodopa therapy. 
• 
Early dysphagia and dysarthria. 
• 
Early onset of cognitive impairment including at least 2 of the following: apathy, 
impairment in abstract thought, decreased verbal fluency, utilization or imitation 
behaviour, or frontal release signs. 
aUpward gaze is considered abnormal when pursuit or voluntary gaze, or both, have a 
restriction of at least 50% of the normal range. 
bTendency to fall is not the same as actual falls, as some patients have caregivers who 
accompany or catch them, and patients may also be more cautious (I. Litvan, personal 
communication, July 25, 2012). 
cDefinite PSP is a clinicopathologic diagnosis. 
15.1.4 
Washington Heights-Inwood Genetic Study of Essential Tremor (WHIGET) 
diagnostic criteria for ET (no SDD) [Louis et al. 1997] 
Protocol for Tremor Examination 
While subject is seated: 
(1) 
Hands resting in lap for 15 seconds 
(2) 
Arms held at 90o for 15 seconds (arm sustension) 
(3) 
Arms held in wing position for 15 seconds 
(4) 
Pouring water from one cup to another (cups should be standard size and at least three 
quarters filled; 8 transfers) 
(5) 
Bringing a spoon of water from lap level up to mouth and back again; repeat 7 
additional times 
(6) 
Drinking water from a full glass; repeat 7 times with each hand 
(7) 
Finger-nose-finger on right 8 times 
(8) 
Finger-nose-finger on left 8 times 
(9) 
Open and close right hand 10 times 
(10) 
Open and close left hand 10 times 
(11) 
Alternatively pronate and supinate right hand 10 times 
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(12) 
Alternatively pronate and supinate left hand 10 times 
(13) 
Tap right foot 10 times 
(14) 
Tap left foot 10 times 
(15) 
Jaw at rest for 5 seconds 
(16) 
Mouth open for 5 seconds 
(17) 
Sustained phonation: first ‘AAA’ for 10 seconds, then ‘EEE’ 
(18) 
Head while patient is seated for 10 seconds 
(19) 
The examiner will test the passive tone of each arm and leg and comment on this. 
(20) 
Drawing 2 Archimedes spirals with each hand (subject should make at least 6 full 
circular motions) 
While subject is standing: 
(21) 
Hands hanging at sides for 10 seconds; assess legs too 
(22) 
Walking 20 feet and turning 
(23) 
Tandem gait for 10 steps 
Assessment Scale 
Criteria for definite ET (all 5 must be true) 
1. On examination, a +2 postural tremor of at least 1 arm (a head tremor may also be 
present, but is not sufficient for the diagnosis). 
2. On examination, there must be 
a. A +2 kinetic tremor during at least 4 tasks or 
b. a +2 kinetic tremor on 1 task and a +3 kinetic tremor on a second task; tasks 
include pouring water, using a spoon to drink water, drinking water, finger-to-
nose, and drawing a spiral. 
3. If on examination, the tremor is present in the dominant hand, then by report, it must 
interfere with at least 1 activity of daily living (eating, drinking, writing, or using the 
hands). If on examination, the tremor is not present in the dominant hand, then this 
criterion is irrelevant. 
4. Medications, alcohol, parkinsonism, dystonia, other basal ganglionic disorders, and 
hyperthyroidism are not potential etiologic factors. 
5. Not psychogenic (bizarre features, inconsistent in character, changing, subject is 
distractable, or other psychiatric features on examination. 
Criteria for probable ET (1 and 3 to 5 must be true; also, either 2a or 2b must be true) 
1. On examination, a +2 postural tremor of arms may or may not be present. 
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2.  (a) Same as 2 above (see definite ET). 
 (b) Head tremor is present on examination. 
3. Tremor in dominant hand may or may not interfere with at least 1 daily activity.  
4. Medications, hyperthyroidism, dystonia, or alcohol are not potential etiologic factors. 
5. Not psychogenic. 
Criteria for possible ET 
1. On examination, a +2 kinetic tremor must be present on 3 tasks. 
2. No other stipulations. 
0-+3 Tremor ratings 
0, No visible tremor. 
+1, Low amplitude, barely perceivable tremor, or intermittent tremor. 
+2, Tremor is of moderate amplitude (1 to 2 cm) and usually present. It is clearly oscillatory. 
+3, Large amplitude (>2 cm), violent, jerky tremor resulting in difficulty completing the task 
due to spilling or inability to hold a pen to paper. 
15.1.5 
UPDRS (Unified Parkinson's Disease Rating Scale) Part III—Motor 
Examination 
PART III: MOTOR EXAMINATION 
MDS-UPDRS Part III [Goetz et al. 2008] will be used to assess any presence of motor 
symptoms of parkinsonism.   
https://www.movementdisorders.org/MDS/Education/Rating-Scales.htm 
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15.1.6 
DSM-5 Diagnostic Criteria for Major Neurocognitive Disorder [Hugo and 
Ganguli 2014] 
Major Neurocognitive Disorders as Diagnosed in DSM-5 
Diagnostic 
Criteria 
Major Neurocognitive Disorder 
A 
Significant cognitive decline in one or more cognitive domains, based on: 
 
1. 
Concern about significant decline, expressed by individual or reliable informant, or 
observed by clinician. 
 
 
2. 
Substantial impairment, documented by objective cognitive assessment. 
 
 
B 
Interference with independence in everyday activities. 
 
C 
Not exclusively during delirium. 
D 
Not better explained by another mental disorder. 
E 
Specify one or more etiologic subtypes, “due to” 
• 
Alzheimer’s disease 
• 
Cerebrovascular disease (vascular neurocognitive disorder) 
• 
Frontotemporal lobar degeneration (frontotemporal neurocognitive disorder) 
• 
Dementia with Lewy bodies (neurocognitive disorder with Lewy Bodies) 
• 
Parkinson’s disease 
• 
Huntington’s disease 
• 
Traumatic brain injury 
• 
HIV infection 
• 
Prion disease 
• 
Another medical condition 
• 
Multiple aetiologies 
From[Hugo and Ganguli 2014]. Adapted from: American Psychiatric Association: Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition. Arlington, VA, American Psychiatric Association; 2013. 
 
15.1.7 
H & Y (Modified Hoehn and Yahr) staging 
Table 3 
Modified Hoehn and Yahr Staging 
Stage 0: 
No signs of disease 
Stage 1: 
Unilateral disease 
Stage 1.5: 
Unilateral plus axial involvement 
Stage 2: 
Bilateral disease, without impairment of balance 
Stage 2.5:  
Mild bilateral disease, with recovery on pull test 
Stage 3: 
Mild to moderate bilateral disease, some postural instability; physically 
independent 
Stage 4: 
Severe disability; still able to walk or stand unassisted. 
Stage 5: 
Wheelchair bound or bedridden unless aided. 
 
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15.2 
Radiation dosimetry data 
[123I] has a physical half-life of 13.2 hours. As it decays, it emits gamma radiation with 
predominant energy of 159 keV and x-rays of 27 keV. 
The estimated absorbed radiation doses to an average adult subject (70 kg) from IV injection of 
ioflupane [123I] is listed below. The values are calculated assuming urinary bladder emptying at 
4.8-hour intervals and appropriate thyroid blocking ([123I] is a known Auger electron emitter). 
Frequent bladder emptying should be encouraged after dosing to minimise radiation exposure. 
Estimated absorbed radiation dose is shown in Table 4. 
Table 4 
Estimated Absorbed Radiation Doses to an Average Adult Patient 
Target Organ 
Absorbed radiation dose 
Gy/MBq 
Adrenals 
17.0 
Bone surface 
15.0 
Brain 
16.0 
Breast 
7.3 
Gallbladder wall 
44.0 
Gastrointestinal tract 
 
 
Stomach wall 
12.0 
 
Small intestine wall 
26.0 
 
Colon wall 
59.0 
 
(Upper large intestine wall 
57.0) 
 
(Lower large intestine wall 
62.0) 
Heart wall 
32.0 
Kidneys 
13.0 
Liver 
85.0 
Lungs 
42.0 
Muscles 
8.9 
Oesophagus 
9.4 
Ovaries 
18.0 
Pancreas 
17.0 
Red marrow 
9.3 
Salivary glands 
41.0 
Skin 
5.2 
Spleen 
26.0 
Testes 
6.3 
Thymus 
9.4 
Thyroid 
6.7 
Urinary bladder wall 
35.0 
Uterus 
14.0 
Remaining organs 
10.0 
Effective Dose (µSv/MBq) 
25.0 
Ref.: Publication 128 of the Annals of ICRP (Radiation dose to Patients from Radiopharmaceuticals: A 
Compendium of Current Information Related to Frequently Used Substances, 2015) 
 
The effective dose (E) resulting from administration of 185 MBq of DaTSCAN™ injection is 
4.63 mSv (per 70 kg individual).  The above data are valid in normal pharmacokinetic 
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behaviour.  When renal or hepatic function is impaired, the effective dose and the radiation 
dose delivered to organs might be increased. 
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16 
CLINICAL PROTOCOL AMENDMENT SUMMARIES 
16.1 
Amendment A01 
16.1.1 
Reasons for Amendment 
The China Center for Drug Evaluation requested that GE Healthcare evaluate the Study 
GE-001-024 protocol according to the ICH E5 requirement. As a result, changes have been 
incorporated to provide better characterisation of DaTSCAN™ in the Chinese population and 
improve clarity of study procedures.  Some procedures have been moved between the baseline 
and screening visits to ensure data required to make a clinical diagnosis will be available at the 
baseline visit. Protocol wording has been updated using the current GE Healthcare template. 
16.1.2 
Summary of Key Changes 
The following key changes have been made throughout the protocol: 
• 
Medical director details updated. 
• 
Diagnostic criteria for PD updated to MDS Clinical Diagnostic Criteria for Parkinson’s 
Disease following adoption in the China national guidelines and on the advice of the 
co-ordinating investigator. This reflects current medical practice in China and provides 
better scientific value to the study. 
• 
Removed requirement for ECG assessment. 
• 
Clarified that the DaTSCAN™ product will be supplied in a 5-mL vial.   
• 
Laboratory testing moved from baseline to screening to allow sufficient time for 
processing of samples. 
• 
Recruitment period corrected. 
• 
Subject numbering system clarified. 
• 
AE reporting updated in line with current standards. 
• 
Clarification that AEs are to be recorded from time of informed consent. 
• 
Text referring to paper CRFs deleted; electronic CRFs will be used. 
 
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16.2 
Amendment A02 
16.2.1 
Reasons for Amendment 
The Amendment is to provide further explanation and clarification to certain items in the 
protocol, to avoid potential ambiguity of interpretation, and ensure consistence of conduct 
between sites. Meanwhile, some wordings are revised according to idiomatic expression. 
16.2.2 
Summary of Key Changes 
The following key changes have been made throughout the protocol: 
• 
The GE Healthcare UK address and Medical Director details were updated. 
• 
Prevalence and incidence of Parkinson’s disease cited in this protocol were updated. 
• 
Thyroid blocking treatment was updated to add clarification on timing of administration 
for before and/or after injection, the example was removed, and how to handle sourcing 
was updated. 
• 
The final follow-up visit timing was changed from 48 (+48) hours to 72 (±24) hours. 
• 
DSM-5 criteria were updated for use in inclusion/exclusion criteria. The term 
“dementia” was changed to “major neurocognitive disorder”. 
• 
Added Mini-Mental State Examination total score <24 requirement in the exclusion 
criteria. 
• 
Changed classifying images “typical or atypical of PD” to “typical or atypical of SDD”. 
• 
Updated when prior medication needs to be collected. 
16.3 
Amendment A03 
16.3.1 
Reasons for Amendment 
The main purpose of the Amendment is to update the timing of recruitment, overall study 
duration, and study visits. 
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16.3.2 
Summary of Key Changes 
The following key changes have been made throughout the protocol: 
• 
The screening and baseline visits are to be performed within 28 days prior to the 
imaging visit. 
• 
The follow-up visit changed from 72 (±24) hours to 3 (±1) days. 
• 
Clarified the timing for performing injection site monitoring. 
• 
Changed the number of centres from approximately 8 to approximately 10. 
• 
Updated the recruitment period from approximately 9 months to approximately 18 
months. 
• 
Updated the overall study duration from approximately 10 months to approximately 18 
months from First Patient First Visit to Last Patient Last Visit. 
• 
Removed funduscopy. 
• 
Updated the Medical Director on the title page. 
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6,*1$785(3$*(
Date / Name
Justification / Role
Signed By: 
Date of signature: 25-Nov-2020 14:32:03 GMT+0000
Justification: Approved
Role: Head of Clinical Development
Signed By: 
Date of signature: 25-Nov-2020 15:28:18 GMT+0000
Justification: Approved
Role: Head of Biometrics
Signed By: 
Date of signature: 25-Nov-2020 15:42:28 GMT+0000
Justification: Approved
Role: Head of Imaging Technology
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SAP_001.pdf: 
Statistical Analysis Plan. Protocol GE-001-024 
GE Healthcare Ltd. 
Confidential and Proprietary 
1 
STATISTICAL ANALYSIS PLAN 
A multicentre, phase 3, clinical study to compare the striatal 
uptake of a dopamine transporter radioligand, DaTSCAN™ 
ioflupane (123I) injection, after intravenous administration to 
Chinese patients with a diagnosis of Parkinson’s disease, 
multiple system atrophy, progressive supranuclear palsy, or 
essential tremor and to healthy controls 
STUDY DRUG: 
DaTSCAN™ ioflupane (123I) injection 
PROTOCOL NUMBER: 
GE-001-024 
VERSION/ 
: 
1.0/
 
Prepared by: PPD Inc., on behalf of 
GE Healthcare Ltd. and its Affiliates 
Pollards Wood 
Nightingales Lane 
Chalfont St Giles 
HP8 4SP 
United Kingdom 
CONFIDENTIAL 
The information contained in this document is regarded as confidential 
and, except to the extent necessary to obtain informed consent, may not be 
disclosed to another party unless such disclosure is required by law or 
regulations.  Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them. 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................4 
1. 
INTRODUCTION ........................................................................................................5 
2. 
OBJECTIVES ...............................................................................................................6 
2.1. 
Primary Objective .........................................................................................................6 
2.2. 
Secondary Objectives ...................................................................................................6 
3. 
INVESTIGATIONAL PLAN .......................................................................................7 
3.1. 
Overall Study Design and Plan .....................................................................................7 
3.2. 
Study Endpoints ............................................................................................................7 
3.2.1. 
Primary Endpoint ..........................................................................................................7 
3.2.2. 
Secondary Endpoints ....................................................................................................7 
3.3. 
Treatments ....................................................................................................................7 
3.4. 
Dose Adjustment/Modification ....................................................................................8 
4. 
GENERAL STATISTICAL CONSIDERATIONS ......................................................9 
4.1. 
Reporting Conventions .................................................................................................9 
4.2. 
Baseline and Standard of Truth Definition ...................................................................9 
4.3. 
Sample Size Determination ..........................................................................................9 
4.4. 
Imputation of Incomplete Data ...................................................................................10 
4.5. 
Randomization ............................................................................................................11 
4.6. 
Analysis Sets ...............................................................................................................11 
5. 
SUBJECT DISPOSITION ..........................................................................................12 
5.1. 
Disposition ..................................................................................................................12 
5.2. 
Protocol Deviations/Violations ...................................................................................12 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .................................13 
6.1. 
Demographics .............................................................................................................13 
6.2. 
Inclusion/Exclusion Criteria .......................................................................................13 
6.3. 
Baseline Characteristics ..............................................................................................13 
6.3.1. 
Medical History and Pregnancy Test ..........................................................................13 
6.3.2. 
DSM-5 Diagnostic and Neuropsychiatric Examination .............................................13 
6.3.3. 
Clinical Diagnosis .......................................................................................................13 
7. 
TREATMENTS AND MEDICATIONS ....................................................................14 
7.1. 
Prior and Concomitant Medications ...........................................................................14 
7.2. 
Thyroid Blockade .......................................................................................................14 
7.3. 
Study Treatments ........................................................................................................14 
7.4. 
Handling of Uninterpretable Images ..........................................................................14 
7.5. 
Reader Difference .......................................................................................................14 
8. 
EFFICACY ANALYSIS ............................................................................................15 
8.1. 
Primary Efficacy Analysis ..........................................................................................15 
8.2. 
Secondary Efficacy Analysis ......................................................................................15 
9. 
SAFETY ANALYSIS ................................................................................................16 
9.1. 
Adverse Events ...........................................................................................................16 
9.2. 
Clinical Laboratory Evaluations .................................................................................16 
9.3. 
Vital Sign ....................................................................................................................17 
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9.4. 
Physical Examination .................................................................................................17 
9.5. 
Neurological Examination ..........................................................................................17 
9.6. 
Injection Site Monitoring ............................................................................................17 
10. 
INTERIM ANALYSES ..............................................................................................18 
11. 
CHANGES TO THE PLANNED ANALYSIS ..........................................................19 
12. 
REFERENCES ...........................................................................................................20 
13. 
APPENDICES ............................................................................................................21 
13.1. 
Study Schedule of Events ...........................................................................................21 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE  
adverse event 
BIE 
blinded image evaluation 
CRF 
case report form 
CT 
computed tomography 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
ET 
essential tremor 
FAS 
full analysis set 
FN 
false negatives 
FP 
false positives 
HV 
healthy volunteer 
H&Y 
Hoehn and Yahr 
IMP 
investigational medicinal product 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMSE 
Mini-Mental State Examination 
MSA 
multiple system atrophy 
PD 
Parkinson’s disease 
PP 
per-protocol 
PSP 
progressive supranuclear palsy 
PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDD 
striatal dopaminergic deficit 
SOC 
system organ class 
SPECT 
single photon emission computed tomography 
TEAE 
treatment-emergent adverse event 
TN 
true negatives 
TP 
true positives 
UPDRS 
United Parkinson's Disease Rating Scale 
WHIGET 
Washington Heights-Inwood Genetic Study of Essential Tremor 
WHO Drug 
World Health Organization Drug Directory 
 
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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the analyses and data presentations for GE 
Healthcare’s protocol GE-001-024 “A multicentre, phase 3, clinical study to compare the striatal 
uptake of a dopamine transporter radioligand, DaTSCAN™ ioflupane (123I) injection, after 
intravenous administration to Chinese patients with a diagnosis of Parkinson’s disease (PD), 
multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or essential tremor (ET) 
and to healthy controls” which was issued and finalized as protocol amendment A03, version 1.0 
approved on 25 Nov 2020. It contains definition of analysis populations, derived variables and 
statistical methods for analysis of safety and efficacy of DaTSCAN™ ioflupane (123I) injection, 
which will determine the sensitivity and specificity of a measure of striatal uptake of 
[123I]ioflupane as visualized in single photon emission computed tomography (SPECT) images 
taken 3 to 6 hours after a single intravenous (IV) administration of DaTSCAN™ ioflupane (123I) 
injection (111 to 185 MBq [3 to 5 mCi]) for the diagnosis of Parkinsonian syndrome (PS) 
involving striatal dopaminergic deficit (SDD; specifically, PD, MSA, or PSP) as opposed to ET 
(no SDD) or no neurologic disease (healthy volunteers [HVs]) in Chinese subjects. 
The purpose of the SAP is to ensure the credibility of the study findings by pre-specifying the 
statistical approaches to the analysis of study data. All statistical analyses detailed in this SAP 
will be conducted using SAS® version 9.3 or later (SAS Institute Inc., Cary, North Carolina). The 
SAP will be finalized and signed prior to the clinical database lock for the final analysis. 
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2. 
OBJECTIVES 
2.1. 
Primary Objective 
• To determine the sensitivity and specificity of a measure of striatal uptake of 
[123I]ioflupane as visualized in SPECT images taken 3 to 6 hours after a single IV 
administration of DaTSCAN™ ioflupane (123I) injection (111 to 185 MBq [3 to 5 mCi]) 
for the diagnosis of PS involving SDD (specifically, PD, MSA, or PSP) as opposed to ET 
(no SDD) or no neurologic disease (HVs) in Chinese subjects.  
2.2. 
Secondary Objectives 
• To assess the striatal uptake of [123I]ioflupane in healthy Chinese volunteers (no SDD). 
• To assess safety parameters (haematology, biochemistry and urinalysis, and vital signs) 
and the adverse event (AE) profile in Chinese patients/HVs after a single IV 
administration of DaTSCAN™ ioflupane (123I) injection. 
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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study Design and Plan 
This study is a multicentre, open-label, non-controlled, non-randomised clinical study to 
compare the SPECT findings after a single IV administration of DaTSCAN™ ioflupane (123I) 
injection for subjects with a clinical diagnosis of PS (SDD; specifically, subjects with PD [SDD], 
MSA [SDD] or PSP [SDD]) as compared with subjects with a clinical diagnosis of ET (no SDD) 
and age-matched healthy controls. The study will be conducted at approximately 10 centres in 
China. The planned sample size for this clinical investigation will be 140 evaluable subjects (60 
with movement disorder and SDD, 60 with movement disorder but without SDD, 20 HVs). After 
adjustment for losses, 150 subjects with movement disorders (with and without SDD) and 22 
HVs will need to be enrolled. Each subject will be required to visit the study centre for a 
screening visit, baseline visit, DaTSCAN™ imaging visit, and 1 follow-up visit. 
In order to prevent misinterpretations of the DaTSCAN™ SPECT images by the independent 
blinded readers (who will not be supplied with clinical data), the absence of structural 
abnormalities in the basal ganglia must be ruled out by a magnetic resonance imaging scan or 
cerebral computed tomography (CT) image findings performed within 6 months prior to 
inclusion. During the baseline visit, safety assessments and an extensive neurologic examination 
will be performed. At that visit, each subject will receive a clinical diagnosis (e.g., PD or ET or 
no neurologic disease). The dose of DaTSCAN™ to be used in this study is within the range of 
111 to 185 MBq (3 to 5 mCi) per subject in a maximum volume of 5 mL. Subjects should 
undergo appropriate thyroid blocking treatment prior to and/or after injection according to local 
practices in order to minimise thyroid uptake of radioactive iodine. During the DaTSCAN™ 
imaging visit, all subjects will receive a single IV injection of DaTSCAN™ ioflupane (123I) 
injection. SPECT imaging will be performed between 3 to 6 hours post-injection and will last 
approximately 20 minutes to 1 hour, depending on type of SPECT camera. The DaTSCAN™ 
imaging visit may occur as soon as possible after the baseline visit but no later than 28 days after 
baseline. Each subject will be asked to return for a final follow-up visit at 3 (±1) days after the 
administration of DaTSCAN™ injection for a safety assessment. Safety will be assessed from 
the rates of AEs, changes in vital signs, changes in physical examination findings, changes in 
clinical laboratory findings, changes in injection site monitoring, and changes in neurologic 
examination. To rule out any metabolic disturbances that may underlie changes in 
neuropsychiatric state, routine laboratory parameters, including glucose and those reflecting 
hepatic and renal function, will also be assessed. 
3.2. 
Study Endpoints 
3.2.1. 
Primary Endpoint 
• 
Assessment of DaTSCAN™ SPECT images by 3 independent blinded readers to 
compare specific striatal uptake with the clinical diagnosis. 
3.2.2. 
Secondary Endpoints 
• Central read (by semi-quantitative assessment by use of DaTQUANT™) of DaTSCAN™ 
SPECT images to compare specific uptake with clinical diagnosis. 
• Comparison and assessment of safety parameters and AEs reported by all study 
participants. 
3.3. 
Treatments 
In this open-label study, each subject will receive 1 dose of the investigational medicinal product 
(IMP), DaTSCAN™ ioflupane (123I) injection, during the imaging visit. Each subject will 
undergo appropriate thyroid blocking treatment prior to and/or after injection and receive a dose 
of 111 to 185 MBq DaTSCAN™ in a maximum volume of 5 mL. To minimise pain upon 
injection, the dose will be delivered by a slow IV injection (not less than 15 to 20 seconds) into 
an arm vein. SPECT imaging should take place between 3 and 6 hours after injection. Details of 
IMP and procedures are outlined in the protocol Sections 8 and 9.  
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3.4. 
Dose Adjustment/Modification 
All subjects will be administered the IMP by study personnel. No dose adjustment/ modification 
is allowed under normal circumstances. Doses administered outside of specific dose 
requirements or defined range must be reported as protocol deviations. 
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4. 
GENERAL STATISTICAL CONSIDERATIONS 
4.1. 
Reporting Conventions 
Continuous data (absolute values and change from baseline values) will be described using 
descriptive statistics (i.e. n, mean, standard deviation (SD), median, minimum, and maximum). 
Categorical data will be described using frequency count and percentage in each category. For 
the summary statistics of all numerical variables, unless otherwise specified, minimum and 
maximum will be displayed to the same level of precision as reported. Mean and median will be 
displayed to one level of precision greater than the data collected. SD/ standard error will be 
displayed to two levels of precision greater than the data collected. For the summary statistics of 
categorical variables, all percentages will be rounded to one decimal place. Number and 
percentage values will be presented as xx (xx.x). If the percentage is 100, no decimal is required. 
P-values will be rounded to three decimal places. If a p-value is less than 0.001 it will be 
reported as “<0.001.” If a p-value is greater than 0.999 it will be reported as “>0.999.” All 
general and safety analysis and summary tables will have the population sample size in the 
column headers in the form of N=XXX for the single diagnostic category according to subjects’ 
clinical diagnosis (PS (including PD, MSA, PSP), ET, HV, and all subjects) performed at 
baseline visit, and the efficacy analysis group for sensitivity, specificity and accuracy are 
specified in section 8. All enrolled subject data recorded on the case report form (CRF) and 
entered into the database will be provided in separate data listings showing individual subject 
values. Data will be displayed in all listings sorted by baseline clinical diagnosis, subject number 
and visit (time point, if applicable). 
All laboratory data will be reported using international system of units (SI). 
When count data are presented, the percentage will be suppressed when the count is zero in order 
to draw attention to the non-zero counts. A row denoted “Missing” will be included in count 
tabulations where specified on the shells to account for dropouts and missing values. The 
denominator for all percentages will be the number of subjects in that clinical diagnosis category 
within the analysis set of interest, unless otherwise specified. 
4.2. 
Baseline and Standard of Truth Definition 
The last observation prior to administration of IMP will be used as the baseline value for 
calculating changes from baseline after administration of IMP. 
The clinical diagnosis as established by the investigator at baseline at the recruiting centres 
according to internationally accepted diagnostic criteria and based on a standardized and 
comprehensive clinical and neuropsychiatric assessment will be the standard of truth used for 
determining sensitivity and specificity. 
The study day/time will be calculated as assessment date/time – date/time of injection + 1 if the 
presented date is on or after the date/time of injection. Otherwise, the study day/time will be 
calculated as assessment date/time – date/time of injection. 
4.3. 
Sample Size Determination 
The null hypothesis tests are given as H0: p ≤ p0 where p0 is the specified threshold. The alternate 
hypothesis is given by Ha: p>p0. The parameter p represents the sensitivity/specificity of the 
blinded independent read of DaTSCAN™ SPECT images in detecting or excluding SDD, using 
the clinical diagnosis as established by the investigator as the standard of truth. 
An exact binomial test with a nominal 0.05 1-sided significance level will have 80% power to 
detect the difference between the null hypothesis diagnostic sensitivity threshold of 0.85 and the 
assumed alternative proportion of 0.95 when the sample size is 59 subjects with SDD present. 
An exact binomial test with a nominal 0.05 1-sided significance level will have 80% power to 
detect the difference between the null hypothesis diagnostic specificity threshold of 0.85 and the 
assumed alternative proportion of 0.95 when the sample size is 59 subjects with SDD absent. 
An extensive set of values for the specified threshold, p0, and the resultant sample size (for either 
sensitivity or specificity) are as follows: P0 = 0.89: n=128; P0 = 0.88: n=107; P0 = 0.87: n= 89; 
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P0 = 0.86: n= 73; P0 = 0.85: n= 59; P0 = 0.84: n= 55; P0 = 0.83: n= 44; P0 = 0.82: n= 41; 
P0 = 0.81: n= 39; P0 = 0.80: n=30. 
However, according to regulatory guidelines sample size for a new product with more than 1 
indication (which is the case for DaTSCANTM) requires a minimum of 60 pairs of cases. 
Therefore, the final number of evaluable diseased individuals will be 60 in each group (SDD 
present and absent). 
In addition to the 120 evaluable subjects (subjects with movement disorder), each centre will be 
requested to recruit 2 to 4 HVs (subjects without movement disorder) for the sole purpose of the 
creation of a normal database. A total of 20 HVs will be recruited across the centres. These 
subjects will also be included in the safety analysis. 
On the basis of a previous study (DP008-003), it is projected that evaluable results will be 
obtained for 80% of diseased individuals and 90% of HVs. After adjustment for losses, it is 
therefore expected that 150 subjects with movement disorders (with or without SDD) and 22 
HVs will be needed to provide at least the minimum required number of evaluable subjects. 
4.4. 
Imputation of Incomplete Data 
Generally, missing values will not be substituted by estimated values but treated as missing in 
the statistical evaluation. Available data analysis will be applied to this study. All observed data 
from all subjects dosed in the study will be included in all listings, plots, summary tables, and 
statistical analyses when appropriate. Missing and incomplete data for AEs, medical/surgical 
history, prior and concomitant medication will be specifically imputed according to the 
following rules for analysis. 
Adverse Event  
• If onset date is completely missing, then onset date is set to date of IMP injection. 
• If onset date’s (year is present and month and day are missing) or (year and day are 
present and month is missing): 
o If year = year of IMP injection, then set onset month and day to month and day of 
IMP injection 
o If year < year of IMP injection, then set onset month and day to December 31st. 
o If year > year of IMP injection, then set onset month and day to January 1st. 
• If onset date’s month and year are present and day is missing: 
o If year=year of IMP injection and 
▪ If month = month of IMP injection then set day to day of IMP injection 
date 
▪ If month < month of IMP injection then set day to last day of month 
▪ If month > month of IMP injection then set day to 1st day of month 
o If year < year of IMP injection then set day to last day of month 
o If year > year of IMP injection then set day to 1st day of month 
• For all other cases, set onset date to date of IMP injection 
• If relationship to IMP is missing, AE will be reported separately and the relationship will 
be evaluated based on AE onset date compared with date of study procedures. 
• If Intensity is missing, it will be imputed as Severe. 
Medical and Surgical History 
• If start date is completely missing then start date will not be imputed. 
• If (start year is present and start month and start day are missing) or (start year and start 
day are present and start month is missing) then set start month and start day to January 1. 
• If start year and start month are present and start day is missing then set start day to 1st 
day of month. 
• If end date is completely missing then end date will not be imputed. 
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• If (end year is present and end month and end day are missing) or (end year and end day 
are present and end month is missing) then set end month and end day to December 31. 
• If end year and end month are present and end day is missing then set end day to last day 
of the month. 
Prior and Concomitant Medications 
• If start date is completely missing then start date will not be imputed. 
• If (start year is present and start month and start day are missing) or (start year and start 
day are present and start month is missing) then set start month and start day to January 1. 
• If start year and start month are present and start day is missing then set start day to 1st 
day of month. 
• If end date is completely missing then end date will not be imputed. 
• If (end year is present and end month and end day are missing) or (end year and end day 
are present and end month is missing) then set end month and end day to December 31. 
• If end year and end month are present and end day is missing then set end day to last day 
of the month. 
4.5. 
Randomization 
No randomization will take place in this open-label study.  
4.6. 
Analysis Sets 
The Enrolled population for this study includes all subjects enrolled, i.e., who meet the 
inclusion/exclusion criteria and are dosed with DaTSCAN™ ioflupane (123I). 
The following analysis sets will be used in the statistical analyses. 
Full-analysis set (FAS): The efficacy analysis will be performed for the FAS, which will consist 
of all subjects who have both a DaTSCAN™ image set and a clinical diagnosis made by the 
investigator. 
Per-protocol (PP) population: The PP population will include subjects in the FAS who comply 
with the following conditions: 
• Meet the inclusion/exclusion criteria, and did not withdraw informed consent (if 
applicable) 
• Have DaTSCAN™ image sets that are considered evaluable by at least 2 of the 3 blinded 
readers 
• No major protocol violations 
Safety population: All subjects who receive an injection of IMP will be included in the safety 
population. 
For this study, efficacy analyses will be performed on both the FAS and PP populations, and 
safety analyses will be performed on the safety population. 
 
 
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5. 
SUBJECT DISPOSITION 
5.1. 
Disposition 
Subject disposition will be summarized for all screened and enrolled subjects and will include 
the number and percentage of subjects in the FAS, PP and safety populations, the number and 
percentage of subjects who have completed or discontinued the study, as well as reasons for 
withdrawal/ discontinuation.  
Reasons for withdrawal/discontinuation will be collected on the CRF and will be summarized for 
subjects who withdrew/discontinued from study with the following categories: 
• Adverse event 
• Subject voluntarily withdrew consent 
• Technical problems 
• Lost to follow-up 
• Investigator decision 
• Death 
• Other 
5.2. 
Protocol Deviations/Violations 
A deviation from the protocol is an unintended or unanticipated departure from the procedures or 
processes approved by the Sponsor and the independent ethics committee and agreed to by the 
investigator. According to the protocol, doses administered outside of specific dose requirements 
or defined range must be reported as protocol deviations. 
All protocol deviations (significant or not) will be reviewed by the study team and sponsor prior 
to the database lock, to identify major protocol deviations that would potentially exclude a 
subject from the PP population. 
A by-subject listing of protocol deviations/violations in all subjects will be provided. 
 
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6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
6.1. 
Demographics 
Baseline demographics will be summarized for all subjects in the safety population. Subjects’ 
age (years), height (cm), weight (kg), and body mass index (kg/m2) at screening will be 
summarized using descriptive statistics; gender, race, ethnicity, and level of education will be 
summarized by counts and percentages. Subject demographics will be presented in a listing. 
6.2. 
Inclusion/Exclusion Criteria 
The criteria number will be listed for screened subjects who did not satisfy the 
inclusion/exclusion criteria.  
6.3. 
Baseline Characteristics 
6.3.1. 
Medical History and Pregnancy Test 
General medical/surgical history and neuropsychiatric history (including dementia history) will 
be presented in a data listing based on the safety population. A summary table by counts and 
percentages of medical/surgical history and neuropsychiatric history by system organ class 
(SOC) and preferred term (PT) will also be provided for all subjects in the safety population 
using version 22.0 or later of the Medical Dictionary for Regulatory Activities (MedDRA). 
Pregnancy test information at the screening and imaging visits will be presented in a data listing 
for each female subject in the safety population. Descriptive statistics will be applied to 
summarize observed values for all subjects in the safety population. 
6.3.2. 
DSM-5 Diagnostic and Neuropsychiatric Examination 
Information on DSM-5 diagnostic and neuropsychiatric examinations (including Mini-Mental 
State Examination (MMSE), United Parkinson’s Disease Rating Scale (UPDRS) Part III 
assessment, Hoehn and Yahr (H&Y) Scale for Parkinson’s disease, and Washington Heights-
Inwood Genetic Study of Essential Tremor (WHIGET) for ET) will be presented in a data listing.  
6.3.3. 
Clinical Diagnosis 
The clinical diagnosis of PS (SDD; specifically, PD, MSA, or PSP) or no SDD (ET or healthy 
controls) as determined by the investigator at baseline for enrolled subjects will be summarized 
by counts and percentages in the disposition table and will be presented in a data listing.  
 
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7. 
TREATMENTS AND MEDICATIONS 
7.1. 
Prior and Concomitant Medications 
Any prior and concurrent therapy or medication (and the indication for the treatment) given to a 
subject from 28 days prior to screening visit and throughout the follow-up period after IMP 
administration will be recorded in EDC. If a medication ended before IMP administration, this 
medication will be categorized as prior medication; if a medication started or continued to be 
used after the time of IMP administration, it will be categorized as concomitant medication. All 
medications will be mapped to PTs according to the World Health Organization (WHO) drug 
dictionary September 1, 2018 or later. The number and percentage of all subjects in the safety 
population having prior medications or concomitant medications will be tabulated by Anatomical 
Therapeutic Chemical Code Level 3 classification system and WHO drug PT. At each level of 
summarization, a subject is counted only once if she/he reported one or more medication. Prior 
medications and procedures, concomitant medications, and concomitant procedures will be 
presented in by-subject listings. If the start or end date of concomitant medications is missing, it 
will be imputed as shown in Section 4.4. 
7.2. 
Thyroid Blockade 
The amount and type of medication used for thyroid blockade for each subject will be 
summarized for all subjects in the safety population. All thyroid-blocking treatment will be 
included and presented in prior and concomitant medication listings. 
7.3. 
Study Treatments 
Exposure to IMP will be summarized for all subjects in the safety population. The radioactivity 
(in megabecquerels) of the syringe before and after injection, volume (in millilitres) of IMP 
administered, total radioactivity (in megabecquerels), duration of injection (seconds), and saline 
flush volume (in millilitres) administered will be summarized using descriptive statistics. IMP 
administration information recorded in EDC will be presented in a listing. 
7.4. 
Handling of Uninterpretable Images 
The image interpretation by 3 independent readers (including 10% re-read assessments) will be 
presented in a data listing. The image will be classified as SDD if blinded image evaluation 
(BIE) readers assess the image as abnormal with typical or atypical SDD, and it will be classified 
as no SDD if BIE readers assess the image as normal. If BIE readers determine the image is 
technically not adequate for interpretation or abnormal but cannot be assigned to typical and 
atypical SDD, the image will be defined as an uninterpretable image. The number and proportion 
of images that are uninterpretable will be displayed in table for all subjects by reader in FAS.  
7.5. 
Reader Difference 
Subjects having DaTSCANTM assessment as SDD and no SDD will be categorized as SDD 
positive and negative, respectively. Intra-reader (within-reader) agreement of blinded visual 
image assessment will be measured by overall percentage agreement, which is calculated as the 
total number of subjects who have a consistent assessment on the two reads divided by the total 
number of all re-read subjects. This will be based on a random selection of 10% of the subjects 
having re-read images. An overall percentage agreement with an exact 95% confidence interval 
will be determined for each reader comparison and all readers for subjects with re-reads of 
images. 
 
 
 
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8. 
EFFICACY ANALYSIS 
Efficacy analyses will be performed on both the FAS and PP populations defined in Section 4.6. 
Uninterpretable images will be excluded from the efficacy analysis. In cases where images are 
re-read, the result of the first read will be included in the efficacy analysis. 
8.1. 
Primary Efficacy Analysis 
The sensitivity and specificity of the blinded independent read of DaTSCAN™ SPECT images 
in detecting or excluding SDD, when the clinical diagnosis as established by the investigator is 
used as the standard of truth, will be summarized with both by-reader and majority-read 
analyses. Generally, True Positives (TP) include subjects with a clinical diagnosis of PS and 
having DatSCANTM assessment as SDD positive. False Negatives (FN) include subjects with a 
clinical diagnosis of PS but having DatSCANTM assessment as SDD negative. True negatives 
(TN) include subjects with a clinical diagnosis of ET or HV and having DatSCANTM assessment 
as SDD negative. False Positives (FP) include subjects with a clinical diagnosis of ET or HV but 
having DatSCANTM assessment as SDD positive. The efficacy will be measured by the following 
and presented by timepoint in the following summary tables:  
• Sensitivity: Subjects with a clinical diagnosis of PS will be included. It will be defined as 
positive percentage agreement and calculated as the number of TP / (number of TP + 
number of FN): TP/(TP + FN), and a 2-sided 95% binomial confidence interval 
constructed around it. 
• Specificity: Only subjects with a clinical diagnosis of ET will be included, which means 
that the HVs will be excluded from this analysis. It will be defined as negative percentage 
agreement and calculated as the number of TN / (number of TN + number of FP): 
TN/(TN + FP), and a 2-sided 95% binomial confidence interval constructed around it. 
• Accuracy: Subjects with clinical diagnosis of PS, ET, and HV will be included. It will be 
calculated as overall percentage agreement and calculated as (TP + TN) / (TP + FN + TN 
+ FP), and a 2-sided 95% binomial confidence interval constructed around it. 
The two primary hypotheses and alternative hypotheses are: 
• Sensitivity ≤ 85% vs Sensitivity >0.85 
• Specificity ≤ 85% vs Specificity >0.85 
The sensitivity will be successfully established for a reader if the lower bound of the 1-sided 
95% confidence interval of the sensitivity for this reader is > 85%.  The sensitivity will be 
successfully established for the study, only if the sensitivity is successfully established for at 
least two readers.  The specificity will be similarly analyzed.   
Additional sensitivity and specificity analyses will be performed based on the outcome from the 
majority read as supportive analyses.  In these analyses, only data with valid majority outcomes 
will be included (i.e., records with a three-way tie will not be included in this analysis.). 
8.2. 
Secondary Efficacy Analysis 
A semi-quantitative analysis of the striatal uptake ratios in specific regions of interest (ROIs; 
including left and right striatum, caudate, and putamen) of DaTSCAN™ SPECT images will be 
performed with DaTQUANT™. To account for nonspecific binding, the DaTSCAN™ uptake in 
the ROI will be normalised to DaTSCAN™ uptake in the subject's occipital cortex. The 
normalised DaTSCAN™ uptake values for each ROI will be summarized with descriptive 
statistics for each category of subjects with SDD, ET, and HV. For all striatal uptake ratios, an 
analysis of variance (ANOVA) will be carried out to test for differences in the striatal uptake 
ratios among the clinical diagnosis groups. A by-subject listing of DaTSCAN™ uptake values 
for each ROI will be provided. 
  
 
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9. 
SAFETY ANALYSIS 
Safety analyses will be performed on the safety population defined in Section 4.6. For each of 
the safety parameters, a summary statistic will be provided overall and by clinical diagnosis 
groups and no inferential testing will be performed. 
9.1. 
Adverse Events 
An AE is defined as any untoward medical occurrence or an already present event that worsens 
either in intensity or frequency. A DaTSCAN™-emergent AE, globally defined as treatment-
emergent AE (TEAE), is defined as an AE that starts on or after the time of the injection of 
DaTSCAN™ until the follow-up visit at 3 (±1) days later regardless of its causal relationship to 
investigational agent, therefore it can be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the exposure to 
the IMP, whether or not considered related to that product. A serious adverse event (SAE) is 
defined as any event that results in death, is immediately life threatening, requires inpatient 
hospitalization or prolongation of existing hospitalization, results in persistent or significant 
disability/incapacity, is a congenital anomaly/birth defect, or is another important medical event 
defined in protocol Section 10.3.5.1. Other significant AEs are defined as laboratory 
abnormalities that qualify as AEs (other than those meeting the definition for serious) and any 
events that lead to an intervention (including premature discontinuation of IMP, dose reduction, 
or significant additional concomitant therapy). 
AE terms recorded by the clinical site will be mapped to SOC and PT using MedDRA version 
22.0 or later. If the start date, end date, severity, or relationship of AE is missing, it will be 
imputed as shown in Section 4.4. 
The following summaries of AEs by SOC and PT will be provided: 
• All AEs 
• All TEAEs 
• All SAEs 
• All treatment-emergent SAEs 
• All TEAEs resulting in study treatment discontinuation 
• All related TEAEs 
• All related treatment-emergent SAEs 
• All other significant AEs 
• All TEAEs by intensity 
• All treatment-emergent SAEs by intensity 
• All most common AEs (defined as AEs reported by at least 5% of the subjects). 
If a subject experiences the same AE more than once with different intensity (mild, moderate, 
and severe), then the event with the highest intensity will be tabulated in “by intensity” tables. If 
a subject experiences multiple TEAEs under the same PT (or SOC), then the subject will be 
counted only once for that PT (or SOC). 
In summary tables, AEs are sorted by alphabetical order of SOC, and then descending 
frequencies of PT. 
Data listings will be provided for all AEs. The incidence of deaths and the primary cause of death 
will be displayed in a listing.  
9.2. 
Clinical Laboratory Evaluations 
Haematology, serum biochemistry, and urinalysis results will be summarized with descriptive 
statistics at each time point. Numeric haematology and serum biochemistry results will be 
summarized by actual result and change from baseline. Summaries by timepoint will include data 
from scheduled assessments only. 
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The occurrence of 1 or more changes from baseline, at each post-administration time point, 
greater than 40% and 80% of the span of the normal limits (not applicable to qualitative 
parameters), will be summarized by counts and percentages for haematology and serum 
biochemistry tests for the overall safety population and for each diagnostic group subset. 
A shift table representing the shift from baseline category (High, Normal, and Low) to each post-
baseline visit for haematology and serum biochemistry tests will be provided by counts and 
percentages for the overall safety population and for each diagnostic group subset.  
All laboratory results will be displayed in separate data listings. 
9.3. 
Vital Sign 
Vital sign measurements include systolic and diastolic blood pressure, and heart rate. Descriptive 
statistics of observations and changes from baseline in results for vital signs will be summarized 
by timepoint. Summaries by timepoint will include data from scheduled assessments only. 
The occurrence of 1 or more changes from baseline, at each post-administration time point, 
greater than a pre-specified magnitude (20 mm Hg for systolic blood pressure, 10 mm Hg for 
diastolic blood pressure, 10 beats per minute for heart rate) will be summarized by counts and 
percentages for the overall safety population and for each diagnostic group subset. 
Shifts from baseline during the treatment based on below, within, and above the normal ranges 
will be summarized by visit for the overall safety population and for each diagnostic group 
subset. Data from both scheduled and unscheduled assessments will be included for analysis of 
minimum and maximum post-baseline values in the shift table. 
Vital Sign Parameter 
Normal Range 
Low 
High 
Systolic BP (mmHg) 
85 
139 
Diastolic BP (mmHg) 
60 
89 
Heart Rate (beats/minute) 
60 
100 
 Vital signs results at all time points will be displayed in a listing. 
9.4. 
Physical Examination 
Physical examination will include recording an assessment for the presence of abnormalities of 
the following: general appearance, lungs, cardiovascular system, and abdomen. 
Descriptive statistics will be applied to summarize observed values at each time point. Shift table 
representing the shift from baseline status (Normal, Abnormal) to each post-administration time 
point will be prepared for the overall safety population and each diagnostic group subset. 
Physical examination results will be displayed in a data listing. 
9.5. 
Neurological Examination 
Neurological examination will include recording an assessment for the presence of abnormalities 
of the following: level of consciousness, cranial nerves (II-XII), motor function, sensory function, 
proprioception/position sense of extremities, reflexes (biceps, triceps, patellar, ankle), mood and 
affect, cognitive function, cerebellar, speech, orientation, memory, and gait. 
Descriptive statistics will be applied to summarize observed values at each time point. Shift table 
representing the shift from baseline status (Normal, Abnormal) to each post-administration time 
point will be prepared for the overall safety population and each diagnostic group subset. 
Neurological examination results will be displayed in a data listing. 
9.6. 
Injection Site Monitoring 
Injection site findings will be summarized by time point for the overall safety population and 
each diagnostic group subset. Shift table representing the shift from baseline status (Normal, 
Abnormal) to each post-administration time point will be prepared as well for the overall safety 
population and each diagnostic group subset. All injection site monitoring results will be 
displayed in a data listing. 
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10. 
INTERIM ANALYSES 
No formal interim analysis is planned in this study. 
 
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11. 
CHANGES TO THE PLANNED ANALYSIS 
No changes to the statistical analyses section of the protocol are made in this SAP. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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12. 
REFERENCES 
GE Healthcare Ltd. and its Affiliates GE-001-024 Protocol Amendment A03: A multicentre, 
phase 3, clinical study to compare the striatal uptake of a dopamine transporter radioligand, 
DaTSCAN™ ioflupane (123I) injection, after intravenous administration to Chinese patients with 
a diagnosis of Parkinson’s disease, multiple system atrophy, progressive supranuclear palsy, or 
essential tremor and to healthy controls.  
 
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13. 
APPENDICES  
13.1. 
Study Schedule of Events 
 
Screening 
Visit a 
Treatment  
Follow-up 
Baseline Visit a 
Imaging Visit 
Pre-injection 
0 
Post-injection 
Within 28 
days prior to 
imaging visit 
Within 28 days 
prior to imaging 
visit 
Within 1 to 4 
hours prior 
to injection 
Within 30 min 
prior to injection 
10 min 
3 to 6 
hours 
3 (±1) days b 
Informed consent 
X 
 
 
 
 
 
 
 
Subject number assignment 
X 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
Neuropsychiatric history (including dementia history) 
X 
 
 
 
 
 
 
 
Neurological examination 
X 
X 
 
 
 
 
 
X 
Pregnancy test (if applicable) 
X 
 
X 
 
 
 
 
 
Prior and concomitant medication 
X--------------------------------------------------------------------------------------------------------------------------------------X 
Laboratory tests c 
X 
 
 
 
 
 
 
X 
Physical examination 
 
X 
 
 
 
 
 
X 
Neuropsychiatric examination d 
X 
X 
 
 
 
 
 
 
Clinical diagnosis  
 
X 
 
 
 
 
 
 
Vital signs (blood pressure, heart rate) 
X 
 
 
X 
 
 
X 
X 
Thyroid blocking 
 
 
Xe 
 
 
 
Xe 
 
Injection site monitoring 
 
 
 
X 
X 
X 
X 
 
DaTSCAN™ injection  
 
 
 
 
X 
 
 
 
SPECT imaging 
 
 
 
 
 
 
Xf 
 
Adverse events 
X---------------------------------------------------------------------------------------------------------------------------------------X 
a The screening visit and baseline visit may be combined and conducted on the same day. 
b Performed at 3 (±1) days after injection of DaTSCAN™ 
c Some tests will only be performed at screening 
d Mini Mental State Examination, UPDRS-III, United Parkinson's Disease Rating Scale Part III; H&Y, Hoehn and Yahr and WHIGET assessment 
e The dosage and timing of administration will be based on investigator’s discretion according to local practice of each site (e.g., to be administered within 1 to 4 hours prior to and 12 
to 24 hours after injection of DaTSCANTM are just for reference) 
f Performed 3 to 6 hours after injection of DaTSCAN™ 
 
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6,*1$785(3$*(
Date / Name
Justification / Role
Signed By: 
Date of signature: 21-Oct-2021 14:39:55 GMT+0000
Justification: Approved
Role: Head of Biometrics
Signed By: 
Date of signature: 21-Oct-2021 14:54:45 GMT+0000
Justification: Approved
Role: Head of Clinical Development
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