A Randomised, Balanced, Double-blind Two-way Crossover Design Study to Evaluate the Effects of SRC Kinase Inhibitor, Saracatinib, on Brain Activity Associated With Visual Processing in Patients With Parkinson's Disease Psychosis.
Phase: EARLY_PHASE1
Conditions: Parkinson Disease Psychosis
Sponsor: King's College London

PROTOCOL SCRIPT  
 
 
 Protocol Version 2.2 23/08//2018 
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IRAS ID: 247303 
 
 
 
   
PROTOCOL FULL TITLE: A randomised, balanced, double-blind 
two-way crossover design study to evaluate the effects of SRC 
kinase inhibitor, Saracatinib, on brain activity associated with 
visual processing in patients with Parkinson’s disease 
Psychosis.  
 
Protocol Short Title/Acronym: SRC inhibition as a potential 
target for Parkinson’s disease psychosis- SCRIPT 
 
Trial Identifiers  
  
REC Number –  
 
[Awaiting further information] 
 
 
 
 Co-Sponsors: King’s College London & Kings College Hospital 
NHS trust 
 
Chief Investigator  
Name: Professor Mitul Mehta 
Address: Department of Neuroimaging, Institute of Psychology, Psychiatry and 
Neuroscience, King’s College London, London SE5 8AF 
Telephone: +44 (0) 2032283053 
Email: mitul.mehta@kcl.ac.uk 
 
 
 
Name and address of Co-Investigator(s), Statistician, 
Laboratories etc 
Name: Dr Dominic ffytche 
Address: Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and 
Neuroscience, King’s College London, London SE5 8AF 
Telephone:  
Fax: 

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IRAS ID: 247303 
 
 
 
Email: dominic.ffytche@kcl.ac.uk 
 
Name: Professor K Ray Chaudhuri 
Address: Dept. Basic and Clinical Neuroscience, The Maurice Wohl Clinical 
Neuroscience Institute, King's College London, Cutcombe Road, London SE5 9RT 
Telephone: 
Fax: 
Email: ray.chaudhuri@kcl.ac.uk 
 
Name: Professor Dag Aarsland 
Address: Department of Old Age Psychiatry, Institute of Psychiatry, Psychology and 
Neuroscience, King’s College London, London SE5 8AF 
Telephone: 
Fax: 
Email: dag.aarsland@kcl.ac.uk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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IRAS ID: 247303 
 
 
 
 
1. Study Synopsis 
 
Title of clinical trial 
A randomised, balanced, double-blind two-way crossover 
design study to evaluate the effects of SRC kinase inhibitor, 
Saracatinib, on brain activity associated with visual processing 
in patients with Parkinson’s disease Psychosis.  
 
 
 
 
 
Protocol Short Title/Acronym 
 
SRC inhibition as a potential target for Parkinson’s disease 
psychosis- SCRIPT 
 
Trial Phase if not mentioned in title 
 
 
 
Sponsor name 
 
King’s College London (KCL)/ King’s College Hospital (KCH) 
 
Chief Investigator 
 
Professor Mitul Mehta 
 
REC number 
 
 
 
Medical condition or disease under 
investigation 
Parkinson’s disease Psychosis  
 
Purpose of clinical trial 
 
To test the effects of Saracatinib on brain activity associated 
with visual processing in Parkinson’s disease psychosis. 
 
Primary objective 
 
To examine the effects of Saracatinib on brain activity 
associated with the visual recognition task in PD psychosis. 
 
Secondary objective (s) 
 
Secondary:  
• 
To examine the effects of Saracatinib on brain activity 
associated with visual processing in patients with PD psychosis. 
 
• 
To examine the effects of Saracatinib on brain 
connectivity within the default mode network in patients with 
PD psychosis. 
 
Exploratory:  
• 
To examine the effects of Saracatinib on brain 
connectivity with the inferotemporal cortex in patients with PD 
psychosis. 
 
• 
To examine the effects of Saracatinib on brain activity 
measured with EEG during a mismatch negativity paradigm in 
patients with PD psychosis. 
 
• 
To test a prediction error model for the effects of 
Saracatinib on brain activity measured with EEG during a 
mismatch negativity paradigm in patients with PD psychosis. 
 
• 
To examine the effects of Saracatinib on standard 
questionnaires of motor and non-motor experiences in patients 
with PD psychosis. 
 

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IRAS ID: 247303 
 
 
 
Trial Design  
 
A Randomised, balanced double blind two-way cross-over 
design.  
 
Endpoints 
 
Primary Endpoint:  
• 
Difference between study drug and placebo in BOLD 
activity in the ventral visual stream during visual 
recognition vs. the control task measure using fMRI.  
Secondary: 
• 
Difference between study drug and placebo in BOLD 
activity in the occipito-temporal region during the 
visual processing task (Kanisza illusion).  
• 
Change in Mismatch negativity (MMN) in microvolts 
(mV) and connectivity with the posterior cingulate hub 
of the default mode network. 
Exploratory:  
• 
Seed-based connectivity from the Regions Of Interest 
(ROI) within the inferotemporal cortex.  
• 
Difference between study drug and placebo in MMN 
amplitude at FZ on EEG.  
• 
Test a prediction error model for the effects of 
Saracatinib on brain activity during a mismatch 
negativity paradigm on the EEG.  
• 
Difference between study drug and placebo in Factor 
summary score on the scales for assessment of positive 
symptoms in Parkinson’s disease (SAPS-PD) and the 
Neuropsychiatric Inventory (NPI).  
 
 
Sample Size 
 
30 participants with PD psychosis to be enrolled for 26 
completers.   
 
Summary of eligibility criteria 
 
To be considered eligible for this study participants must:  
1. Understand the study procedures and agree to 
participate by providing written informed consent. 
2. Have a confirmed diagnosis of Parkinson’s disease 
using internationally accepted UK brain bank criteria. 
3. Be male or female 
4. Be right handed  
5. Aged 40 years or over 
6. Be judged to be in good health by the investigator, 
based on clinical evaluations including laboratory 
safety tests, medical history, physical examination, 12 
lead ECG and vital signs measurements performed at 
screening and prior to administration of the initial dose 
of study drug.  
7. Have a score of at least 22 in the Montreal Cognitive 
Assessment (MoCA). 
8. Have a diagnosis of idiopathic PD  
9. Have a combined score of at least 6 or an individual 
score of at least 4 on the neuropsychiatric inventory 
(NPI [20]) 23 items A (delusions) and/or B 
(hallucinations).     
 

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IRAS ID: 247303 
 
 
 
Study drug, dosage, and route of 
administration 
 
AZD0530 (saracatinib) oral dose 100mg administered as two 
50mg tablets 
 
Active comparator product(s) 
 
N/A 
 
Maximum duration of treatment of a 
 Subject 
 
 
14 days (+/- 2 days) 
 
Version and date of protocol amendments  V 2.2 23/08/18 
 

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2. Background & Rationale 
2.1 Parkinson’s disease psychosis and visual hallucinations 
Parkinson’s disease (PD) is a neurodegenerative condition which has a 1% prevalence in 
the over 60s and also affects young adults. As well as motor symptoms such as akinesia 
or rigidity, many patients also experience non-motor symptoms of which psychosis is the 
most common (Chang and Fox, 2016). Psychosis in Parkinson’s disease has been 
identified as a spectrum of illusions, visual hallucinations, auditory hallucinations and 
delusions that occur throughout the course of the disease (Ffytche et al., 2017). Current 
treatments for Parkinson’s disease psychosis include atypical antipsychotics such as 
quetiapine, clozapine and pimavanserin (a 5-HT2a inverse agonist). Pimavanserin has 
recently been approved in the USA as a PD psychosis treatment; it has been shown to 
have an overall effect on reducing hallucinations as a whole, but not on visual 
hallucinations specifically. Functional neuroimaging evidence confirms dysfunctional 
ventral visual pathway activity in PD psychosis with altered metabolism, blood flow and 
brain activation following visual stimulation (Chang and Fox, 2016). Outside of the 
ventral visual pathways, two imaging studies in PD patients with visual hallucinations 
have shown altered connectivity within the default mode network, a brain system 
implicated in many neuropsychiatric conditions, pointing to more widespread 
abnormalities (Chang and Fox, 2016). Structural imaging studies show some atrophy 
within the ventral visual pathways, but also implicates brain regions outside of visual 
processing areas, including parietal, frontal, and cerebellar and hippocampal regions 
(Ffytche et al., 2017). Some authors have argued that the atrophy is independent of the 
hallucinations (Meppelink et al., 2011). Together, these studies fit with previously 
proposed models of PD psychosis that suggest that it is caused by both disrupted bottom-
up processing of sensory information and dysfunctional top-down influences on 
perceptions.  
2.2 The Serotonergic system and current treatments  
Although many treatments for psychosis unrelated to Parkinson’s disease are centred on 
dopaminergic therapies, post-mortem and in-vivo human studies have shown loss of 
striatal and extra-striatal serotonin markers in the course of PD, suggesting the 
involvement of the serotonergic system in PD (Politis and Niccolini, 2015). Furthermore, 
the serotonin system has also been implicated in PD psychosis. In vivo, [18F]-setoperone 
PET studies showed increased 5-HT2a receptor binding in people with PD with visual 
hallucinations in the ventral visual pathway (Ballanger et al., 2010). A post-mortem study 
showed increased [3H]-ketanserin binding in the inferolateral temporal cortex in people 
with visual hallucinations compared to PD patients without visual hallucinations (Huot et 
al., 2010). Although pimavanserin has been shown to reduce hallucinations overall, it 
does not affect visual hallucinations specifically. Even though the serotoninergic 

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dysfunction underpinning Parkinson’s disease psychosis is not fully understood, animal 
studies with psychedelics have pointed to the dimerisation of the 5-HT2A and mGlu2 
receptors and the over recruitment of specific downstream signalling pathways. Src 
kinase inhibition is a potential mechanism for blocking the hallucinogenic effects of 5-
HT2A receptor agonism. Src kinase inhibitor, Saracatinib, has shown to reduce the 
intensity of the psychedelic effect induced by psilocybin (a naturally occurring 
psychedelic found in psilocybe mushrooms (Byock, 2018)) and attenuate social cognition 
and brain changes in healthy volunteers.  
We will test the effects of Saracatinib on brain activity associated with visual processing 
using a visual processing task, known to be sensitive to 5-HT2a receptor stimulation in 
previous studies with psilocybin (Carter et al., 2004), and a visual recognition task 
(Meppelink et al., 2009) with known sensitivity to PD psychosis, both scanned using the 
latest implementation of multi-echo blood oxygen level dependent (BOLD) functional 
Magnetic Resonance Imaging (fMRI). Resting state fMRI is a type of functional 
neuroimaging that allows the assessment of intrinsic correlations within known brain 
networks. Since alterations in resting state fMRI within the default mode network (a 
network of regions in the brain that have been demonstrated to have a role in image 
production (Catani et al., 2013)) have been shown in PD psychosis this will be an 
important tool to uncover potential ‘non-visual’ mechanisms modulated by Saracatinib. 
2.3 Rationale for the study design 
We aim to conduct a double-blind crossover design study, looking at the effects of 
Saracatinib and placebo treatment on 26 patients who have PD with psychosis. Existing 
data shows that 10 days of dosing with Saracatinib will achieve a steady state level that is 
known to be well tolerated in people with Alzheimer’s disease (Nygaard et al., 2015). 
Therefore, participants will be given an oral dose of 100mg of Saracatinib as two 50mg 
tablets to be taken once daily for 14 days. Participants will return to the clinic on day 14 
for their final dose of Saracatinib, fMRI and EEG scans, cognitive assessments (described 
in section 6.2), physical examination and blood screen. There will be a minimum 2-week 
washout between treatment arms to avoid potential carry over effects. A cross-over 
design was chosen for this study to minimize the potential impact of inter-subject 
variability on the ability to detect a treatment effect of Saracatinib, as each subject serves 
as his/her own comparator. A placebo control is standard in the evaluation of novel 
therapeutics for neuropsychiatric disorders.    
The aim of the current study is to use neuroimaging combined with psychopharmacology 
to provide evidence that a putative new treatment approach can modulate abnormal visual 
cortex activation in patients with PD psychosis. If positive, this proof of mechanism study 
would provide a strong platform to pursue symptom modification studies with 
Saracatinib. 

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Saracatinib is considered to be safe and well tolerated by healthy volunteers in doses up 
to and above the dose used in this study (100mg for 14 days (+/- 2 days)) this dose 
(100mg) is also well tolerated by patients with Alzheimer’s disease (Nygaard et al., 
2015). The most common side effects reported in multiple dose healthy volunteer studies 
in doses lower than 125mg were headache, papular rash, upper respiratory tract infection, 
loose stools, and myalgia.   
2.3.1 Dose justification 
An oral dose of 100mg of Saracatinib (two 50mg tablets) will be administered during the 
study period. Previous data from Nygaard et. al. in 2015 shows that doses between 50mg 
to 125mg are well tolerated in human participants with Alzheimer’s disease. 100mg was 
the lowest dose that inhibited src-kinase activity in the periphery and was clearly 
detectable in the CSF. The study states that substantial nervous system penetration with 
an oral dose is achieved between 100 to 125mg, although at 125mg there were some 
safety and tolerability issues (Nygaard et al., 2015). Therefore, we have selected 100mg 
given o.d. for 14 days (with or without food) to achieve steady state plasma levels. 
3. Trial Objectives and Design 
3.1. Trial Objectives 
 
Primary:  
• To examine the effects of Saracatinib on brain activity associated with the visual 
recognition task in patients with PD psychosis. 
 
Secondary:  
• To examine the effects of Saracatinib on brain activity associated with visual 
processing in patients with PD psychosis. 
 
• To examine the effects of Saracatinib on brain connectivity within the default 
mode network in patients with PD psychosis. 
 
Exploratory:  
• To examine the effects of Saracatinib on brain connectivity with the 
inferotemporal cortex in patients with PD psychosis. 
 
• To examine the effects of Saracatinib on brain activity measured with EEG during 
a mismatch negativity paradigm in patients with PD psychosis. 
 
• To test a prediction error model for the effects of Saracatinib on brain activity 
measured with EEG during a mismatch negativity paradigm in patients with PD 
psychosis. 

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• To examine the effects of Saracatinib on standard questionnaires of motor and 
non-motor experiences in patients with PD psychosis. 
 
3.1.1 Primary endpoints 
 
• 
Difference between study drug and placebo in BOLD activity in the ventral visual 
stream during visual recognition vs. the control task measure using fMRI.  
 
3.1.2 Secondary endpoints 
 
• Difference between study drug and placebo in BOLD activity in the occipito-
temporal region during the visual processing task (Kanisza illusion).  
• Change in Mismatch negativity (MMN) in microvolts (mV) and connectivity with 
the posterior cingulate hub of the default mode network. 
3.1.3 Exploratory endpoints 
 
• Seed-based connectivity from the Regions of Interest (ROI) within the 
inferotemporal cortex.  
• Difference between study drug and placebo in MMN amplitude at FZ on EEG.  
• Test a prediction error model for the effects of Saracatinib on brain activity during 
a mismatch negativity paradigm on the EEG.  
• Difference between study drug and placebo in Factor summary score on the scales 
for assessment of positive symptoms in Parkinson’s disease (SAPS-PD) and the 
Neuropsychiatric Inventory (NPI).  
3.2 Trial Design  
This will be a balanced double-blind two-way crossover design study looking at the 
effects of Saracatinib on brain activity associated with visual processing in patients with 
Parkinson’s disease psychosis. This study will be carried out at a single site in the UK.  
Approximately 30 patients for 26 completers with Parkinson’s disease psychosis will be 
required to attend the study site for 5 visits; the initial screening visit, and two visits for 
each of two study periods. On day 1 of each study period they will attend for baseline 
cognitive assessments to provide a profile for the patient and will receive their first dose 

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of study medication (Saracatinib/placebo). They will take a dose of the medication at 
home every morning for the following 12 days (Days 2-13) and return to the study site on 
day 14 (+/- 2 days) for dosing and have their day 14 assessments performed (fMRI, EEG, 
Kanisza task, Meppelink task, NPI, SAPS-PD and physical examination). The two study 
periods will be separated by a washout period of at least 2 weeks. Approximately 14 days 
after their day 14 visit for study period 2 they will receive a telephone follow up call.   
3.3 Trial Flowchart 
 
        Period 1- Saracatinib/Placebo                            Period 2- Saracatinib/Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
Baseline 
assessments 
(Day one) 
Final 
assessments
- Scanning 
(Day 
fourteen) 
Pre- dose 
assessments 
(Day one) 
Final 
assessments- 
Scanning 
(Day 
fourteen) 
Safety 
follow 
up phone 
call  
Minimum 14-
day washout 

Protocol Final v 3.1 19/04/2018             
 
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Study period 1 and 21 
 
Study days 
Screening 
Day 1- Baseline and Placebo/drug 
dose 
Day 
2-13 
Day 14- Scanning and assessment day 
Follow 
up 
Early 
termination 
visit2 
  
  
 
 
Hours 
  
Hours 
 
 
  
  
Pre-
Dose 
0 
1 
2 
3 
  
Pre-
Dose 
0 
1 
2 
3  
4 
 
 
Patient consent  
X 
 
 
  
  
  
  
 
 
  
  
  
  
 
 
Physical examination  
X 
X 
 
 
  
X 
 
 
  
  
X 
 
X 
Neurological examination  
X 
X 
 
 
  
X 
 
 
  
  
X 
 
X 
Vitals3 
X 
X 
 
X 
X 
X 
  
X 
 
 
  
  
X 
 
X 
12- lead ECG  
X 
X 
 
 
  
  
  
X 
 
 
  
  
  
 
X 
Oral dose of drug4 
  
 
X 
 
  
  
X 
 
X 
 
  
  
  
 
 
NPI5 
X 
X 
 
 
  
  
  
X 
 
 
  
  
  
 
 
MoCA 
X 
X 
 
 
  
  
  
X 
 
 
  
  
  
 
 
SAPS-PD 
X 
X 
 
 
  
  
  
X 
 
 
  
  
  
 
 
Lab safety blood and urine tests6 
X 
X 
 
 
  
  
  
 
 
 
  
X  
 
 
Hepatitis screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
Pharmacokinetic blood sample7 
X 
 
 
  
  
  
X 
 
 
 X 
X  
  
 
 
Non-motor symptoms8 
  
X 
 
 
  
  
  
  
 
 
  
  
  
 
 
SCOPA-MOTOR7 
  
X 
 
 
  
  
  
  
 
 
  
  
  
 
 
PD sleepiness scale7 
  
X 
 
 
  
  
  
X 
 
 
  
  
  
 
 
                                                          
1 There will be a minimum 14-day washout period between study periods 
2 This visit will only take place if a participant decides to discontinue study treatment 
3 Vitals will consist of semi recumbent blood pressure, heart rate, temperature, and respiratory rate.  
 
4 100mg of Saracatinib or placebo  
5 To ensure that the inclusion criteria have been met. Minimum combined score of 6 in hallucinations and delusions section.  
6 For females of child-bearing potential. 
7 To measure the levels of Saracatinib/Placebo in the blood at baseline and scanning day.  
8 Profiling assessments- only applicable to period one.  

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Word reading (WTAR)7 
  
X 
 
 
  
  
  
  
 
 
  
  
  
 
 
Verbal fluency8 
  
X 
 
 
  
  
  
  
 
 
  
  
  
 
 
Months reversed9 
  
X 
 
 
  
  
  
  
 
 
  
  
  
 
 
NEVHI8 
  
X 
 
 
  
  
  
X 
 
 
  
  
  
 
 
Clinical impression of severity index8 
  
X 
 
 
  
  
  
  
 
 
  
  
  
 
 
fMRI 
  
 
 
 
  
  
  
  
 
 
X 
  
  
 
 
EEG 
  
 
 
 
  
  
  
  
 
 
X  
  
 
 
Kanizsa illusion10 
  
 
 
 
  
  
  
  
 
 
X 
  
  
 
 
Meppelink task (visual pop-out)9 
  
 
 
 
  
  
  
  
 
 
X 
  
  
 
 
Visual Analogue scales  
  
 
 
 
  
  
  
X 
 
 
  
  
  
 
 
PDQ 
  
X 
 
 
  
  
  
  
 
 
  
X  
 
 
EQ 
  
X 
 
  
  
  
  
  
 
 
  
X  
 
 
Dispense study medication 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Telephone call 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Adverse event monitoring 
 
                                                          
9 Profiling assessments- only applicable to period one 
10 While in the MRI scanner. 

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4 Trial Medication 
4.1 Study drug 
Clinical study drug will be supplied by AstraZeneca.  
 
Saracatinib will be provided as 50mg pink film coated tablets in child resistant, tamper 
evident high density polyethene (HDPE) bottles for oral dosing. The bottles will contain 
32 tablets in total to cover a potential 16 days of dosing. 
 
Matching placebo tablets will also be provided.   
 
The study drug should be stored at the temperature and in the conditions described on the 
drug label.   
 
4.2 Dosing Regimen 
Participants will receive a daily oral dose of Saracatinib 100mg at one study period and 
matched placebo at the other study period. The order in which the participant received the 
medication will be randomised (see section 5.5.1).  
 
The study drug will be administered every morning for 14 days (+/- 2 days). 10 days of 
dosing with 100 mg Saracatinib will achieve a steady state level that is known to be well 
tolerated in patients with Alzheimer’s disease. 
An additional 2 days doses will be provided to accommodate any delays in scheduling of 
the Day 14 assessment visit, which may be caused by difficulty in attending the research 
facility, problems with the MRI scanner or other unforeseen circumstances.  
 
There will be a minimum 14-day washout period between the final dose of period one 
and the first dose of period 2.  
 
4.3 Study drug Risks  
Key findings from studies conducted by AstraZeneca show that Saracatinib is a potent 
inhibitor of specific downstream signalling pathways via Src-kinase. It is detectable in the 
brain of rats and the CSF of human volunteers when administered systemically and there 
is minimal metabolism of Saracatinib by human hepatocytes, based on in vitro studies. 
However, Saraccatinib is metabolised by CYP3A4 as well as being a moderate inhibitor 
of CYP3A4, so co-administration with moderate or potent CYP3A4 inhibitors or inducers 
or with medications that are metabolised by CYP3A4 (especially those with a narrow 
therapeutic index) should be avoided. Saracatinib has a high bioavailability and it is well-

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tolerated in single and multiple doses (50, 100 or 125mg per day (Nygaard et al., 2015)) 
in healthy volunteers, including the 14 days of dosing we propose to use here. The 
compound has been administered to over 235 healthy volunteers with the most common 
side effects being headache (31% (Nygaard et al., 2015)), diarrhoea (31% (Nygaard et al., 
2015) and 43% (Gubens et al., 2015)) and nausea (19% (Nygaard et al., 2015) and 62% 
(Gubens et al., 2015)). Symptoms characteristic of an influenza-like syndrome, such as 
fever, myalgia, pyrexia and raised C-reactive protein were evident in some volunteers 
receiving Saracatinib in doses of 125mg or more. More information can be found in the 
Investigators brochure.  
Participants will be observed at all times whilst in our clinical research facility. 
Participants will remain at the facility until discharged home or admittance to hospital for 
further assessment. Throughout the study the highest standards of care for the participants 
will be maintained. 
4.4 Drug Accountability 
The investigator or designee must ensure that the study medication is used in accordance 
with the approved protocol and is dispensed only to participants enrolled in the study. To 
document appropriate use of study medication, pharmacy (on behalf of the investigator) 
will maintain records of all study medication delivery to the site, site inventory, use by 
each subject, and returns to pharmacy and destruction. 
Upon receipt of study medication, pharmacy (on behalf of the investigator) will verify the 
contents of the shipments against the packing list. The verifier will ensure that the 
quantity is correct; the medication is received within the labelled storage conditions and 
is in good condition. If there are any discrepancies between the packing list versus the 
actual product received, AstraZeneca will be contacted to resolve the issue. The packing 
list will be filed in the pharmacy file at the investigator’s site. 
The investigator or his delegate must fully account for all study medication received and 
dispensed during his or her entire participation in the study. Proper drug accountability 
includes, but is not limited to: 
-Continuously monitoring expiration dates if expiry date is provided to the investigator. 
-Verifying that the log is completed for the drug lot used to prepare each dose. 
-Verifying that all study drug used are documented accurately on the log. 
-Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
The following information will be recorded at a minimum: protocol number and title, 
name of investigator, site identifier contacting number, description of study medication, 

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expiry date, date and amount dispensed, and the date and amount returned to the site by 
the subject, including the initials of the person dispensing and receiving the study 
medication. The log should include all required information as a separate entry for each 
subject to whom study medication is dispensed. 
The investigator will retain the original documentation regarding clinical study material 
accountability, return, and/or destruction. 
The investigator will be notified of any expiry date change of clinical study material 
during the study conduct by AstraZeneca.  
In the event of expiry date extension of supplies already at the study site, supplies may be 
relabelled with the new expiry date at that site. In such cases, AstraZeneca or its designee 
will prepare additional labels and all necessary documentation for completion of the 
procedure at the sites. 
4.5 Storage of study drug 
The study drug (Saracatinib) will be stored in the South London and Maudsley Pharmacy 
Department. The pharmacy will comply with all required storage conditions. If the 
storage conditions are not maintained, the pharmacy will quarantine the supplies and 
immediately report this to the CI who will confirm what action will be taken, following 
discussion with the supplies manufacturer.   
4.6 Subject Compliance. 
Participants will be telephoned on a daily basis after the initial dose visit to ensure that 
they are feeling well and have taken the drug. At the time of consent permission will be 
obtained from the participant to speak to their carer or support person, if they are not 
available, to ensure that the participant has taken the medication for the day. 
4.7 Concomitant Medication 
Participants in the study should not be on quetiapine. If patients are taking quetiapine, 
with permission of the treating physician and full, informed consent from the patient, they 
will be withdrawn from the medication for at least a month, after which they will be 
screened again to see if they still meet the criteria for the study. Over this month they will 
have regular contact with a clinician (including the drug helpline at the Maudsley 
Hospital) for clinical management of withdrawal symptoms and appropriate replacements 
will be provided depending on the symptom they are experiencing. There will be no 
changes to any dopaminergic medications being taken by the participant but they must be 
maintained on a stable dose throughout the course of the study.  
Any, and all, medications or vaccines including over-the-counter or prescription 
medicines, vitamins, and/or herbal supplements that the subject is receiving at the time of 
enrolment or receives during the study must be recorded in the CRF along with:  

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Reason for use 
Dates of administration including start and end dates 
Dosage information including dose and frequency 
4.7.1 Prohibited medication  
 
Saracatinib is metabolised by CYP3A4 as well as being a moderate inhibitor of CYP3A4, 
therefore, the following medications/class of drug should not be commenced in any 
subject for the duration of the study: 
 
• Moderate or potent CYP3A4 inducers or inhibitors 
• Medications that are metabolised by CYP3A4 (especially those with a narrow 
therapeutic index) 
• Quetiapine 
• Anti-cholinergic medications 
 
It is also recommended that Seville oranges, grapefruit and OTC remedies (including 
herbal) that interact with CYP3A4 should be avoided.  
5 Selection and Withdrawal of Subjects  
5.1 Inclusion Criteria  
To be eligible for participation in this study, the subject must:  
1. Understand the study procedures and agree to participate by providing written 
informed consent. 
2. Have a confirmed diagnosis of Parkinson’s disease using internationally accepted 
UK brain bank criteria.  
3. Be male or female 
4. Be right handed  
5. Aged 40 years or over 
6. Be judged to be in good health by the investigator, based on clinical evaluations 
including laboratory safety tests, medical history, physical examination, 12 lead 
ECG and vital signs measurements performed at screening and prior to 
administration of the initial dose of study drug.  
7. Have a score of at least 22 on the Montreal Cognitive Assessment (MoCA). 
8. Have a diagnosis of idiopathic PD with moderate severity  

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9. Have a combined score of at least 6 or an individual score of at least 4 on the 
neuropsychiatric inventory (NPI [20]) 23 items A (delusions) and/or B 
(hallucinations).    
5.2 Exclusion Criteria 
The subject must be excluded from participating in the study if the subject:  
1. Is a female of child bearing potential 
2. Is currently taking anticholinergic medication 
3. Is currently taking any medication known to be a moderate or potent CYP3A4 
inducer or inhibitor. 
4. Has an ongoing disability, medical or neurological history, cognitive impairment, or 
conditions that in the opinion of the investigator may interfere with study conduct or 
clinical assessments.  
5. Refuses to be withdrawn from quetiapine (see section 4.7).   
6. Has a family history of psychosis in a first degree relative  
7. Has poor peripheral arterial/venous access or recent wrist trauma that will restrict 
ability to gain venous access. 
8. Is currently using prescription or non-prescription drugs and herbal supplements, 
which are deemed to affect the integrity of the study, within 7 days or 5 half-lives 
(whichever is longer) prior to the first dose of trial medication. As an exception, 
paracetamol or acetaminophen may be used at doses of 1 g/day. 
9. Has a history of sensitivity to any of the study medications or any of the excipient 
constituents. 
10. Has a history of febrile illness within 5 days prior to the first dose 
11. Has a hairstyle which would affect EEG recording. 
12. Has any condition possibly affecting drug absorption (eg, gastrectomy). 
13. Has a history of regular alcohol consumption exceeding 14 units/week (6 glasses of 
13.0% wine (175ml), 6 pints of 4.0% lager or ale (568ml), 5 pints of 4.5% cider (568 
ml) or 14 glasses of 10.0% spirits (25ml)) within 6 months of screening.  
14. Uses tobacco- or nicotine-containing products in excess of the equivalent of 5 
cigarettes per day. 

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15. Uses caffeine containing products of the equivalence of 5 cups of regular filter coffee 
per day 
16. Has a positive urine drug screen on or after the screening visit during their active 
involvement in the study for opiates, methadone, cocaine, amphetamines (including 
MDMA), barbiturates, benzodiazepines and cannabinoids. 
17. Is unwilling or unable to comply with the Lifestyle guidelines. 
18. Has, in the opinion of the investigator, has any medical or psychological condition or 
social circumstances which would impair their ability to participate reliably in the 
study, or who may increase the risk to themselves or others by participating. 
19. Is male and is unwilling to follow the contraception guidance or has a female partner 
of child bearing potential who is unwilling to follow the contraception guidance 
throughout the study. 
20. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 x 
upper limit of normal (ULN) 
21. Total bilirubin > 1.25 x ULN 
22. Known congenital long QT syndrome  
23. Baseline resting QTcF > 470ms on 12 lead ECG 
24. Positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus 
core antibody at screening  
25. Known to have tested positive for human immunodeficiency virus.  
26. Participation in another clinical study with an investigational product administered in 
the last 3 months 
27.  Below the lower limit of normal Hb, total WBC and neutrophils on blood counts as 
per the reference ranges of the laboratory conducting the tests.   
5.3 Study restrictions 
If considered eligible for the study subjects will: 
1. Abstain from consuming alcohol from 24 hours before admission until 24 hours 
after discharge on day 1 and day 14 of each study period.  

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2. Abstain from the use of tobacco- or nicotine-containing products for 4 hours prior 
to admission until discharge on day 14 of each study period.  
3. Abstain from unaccustomed strenuous exercise (e.g., heavy lifting, weight 
training, and aerobics) from 48 hours prior to day 1 until discharge on day 14 of 
each study period.    
4. Be warned not to drive or operate machinery from the time of first dosing until 
24hrs post the first dose. Taxis will be provided to transport the participants to and 
from the study site.  
5.3.2 Reproductive restrictions 
 
Pre-clinical in vitro studies have shown that Saracatinib is not genotoxic, however 
reproductive toxicity studies in rats indicate that Saracatinib can induce effects on 
embryofoetal survival and foetal malformations. Conception must be avoided during 
maternal or paternal exposure to Saracatinib. Women of child bearing potential will not 
be included in the study. In addition, it is important that women of childbearing potential, 
who are the partners of male study subjects, do not become pregnant during the study and 
for a total period of 3 weeks after the male study subject has received his last dose of 
study drug (5 x elimination half-life plus 1 week). 
 
All male subjects should avoid fathering a child by either true abstinence or use together, 
with their female partner/spouse, of a highly effective method of contraception (see 
definition below), starting from the time of study drug administration until 3 weeks after 
the last dose of study drug. Male subjects whose partner is pregnant should use a condom 
for the duration of the study and for 3 weeks afterwards. 
 
Methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly are considered highly effective birth control methods.  Such methods 
include: 
 
• Combined (oestrogen and progesterone containing) hormonal contraception 
associated with inhibition of ovulation: 
- 
Oral 
- 
Intravaginal 
- 
transdermal 
• Progesterone-only hormonal contraception associated with inhibition of ovulation: 
- 
oral 

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- 
injectable 
- 
implantableIntrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion of female partner 
• Male vasectomy 
• True sexual abstinence 
 
True abstinence refers to: When this is in line with the preferred and usual lifestyle of the 
subject.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post ovulation 
methods), declaration of abstinence for the duration of a trial, and withdrawal are not 
acceptable methods of contraception. 
 
Sperm Donation 
 
Male study subjects should not donate sperm for the duration of the study and for at least 
3 weeks (5 x elimination half-life plus 1 week) after the study Follow up Visit. 
 
Pregnancy 
 
Male subjects will be instructed that if their partner becomes pregnant during the study 
this should be reported to the investigator.  The investigator should also be notified of 
pregnancy occurring during the study but confirmed after completion of the study.  In the 
event that a subject’s partner is subsequently found to be pregnant after the study subject 
is included in the study, then consent will be sought from the partner and if granted any 
pregnancy will be followed and the status of mother and/or child will be reported to the 
Sponsor after delivery. 
 
A pregnancy notification form and follow up will be completed. 
 
Definition of women NOT of child-bearing potential  
 
Women who are permanently or surgically sterilized or postmenopausal. Permanent 
sterilisation includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy but excludes bilateral tubal occlusion. Tubal occlusion is considered a 
highly effective method of birth control but does not absolutely exclude possibility of 
pregnancy. The term occlusion refers to both occluding and ligating techniques that do 
not physically remove the oviducts. 
 

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Definition of female post-menopausal state 
 
Women will be considered postmenopausal if they are amenorrhoeic for 12 months 
without an alternative medical cause. The following age-specific requirements apply: 
 
• Women under 50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatments AND with LH and FSH levels in the post-menopausal range. 
• Women over 50 years of age will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatments. 
5.4 Selection of Participants  
A group of 30 patients with 26 completers with PD psychosis will be recruited from a 
London-wide network of patients with non-motor symptoms through recruitment 
infrastructure of Professor Chaudhuri which include approx. 4000 patients. Within this 
network are a range of patients and we will have an extended patient identification period 
at the beginning of the study to maximise recruitment potential from this source. Patients 
will also be recruited from SHAPED, an NIHR-funded programme investigating patients 
with visual hallucinations with Parkinson’s disease, eye disease or dementia led by Dr 
ffytche. Finally, on-going referrals from the Movement Disorders Clinics of KHP will be 
assessed and screened for this study.  
To be included in the study participants must have a diagnosis of PD and be deemed to 
have psychosis (based on NPI scores- see section 5.1) which is of moderate severity to 
minimize alternative diagnoses (such as Lewy Body disease).  
5.5 Randomisation Procedure / Code Break 
5.5.1  Randomisation 
Simple crossover randomisation will be done using RNG in Matlab. The code will be 
done by CNS and ratified by pharmacy at King’s College Hospital. The pharmacist will 
be unblinded and independent of the data collection team and the blinding information 
will not be available to the study team. Subjects will be randomised into the trial provided 
they have satisfied all subject selection criteria.  
 
The plan is to recruit 30 participants with 26 completers and any dropouts will be 
replaced. That is the blind for 26 patients will be balanced and any replacement will have 
the same blinding as the dropout. Any unblinding of dropouts will be dealt with on a 
case-by-case basis, but typically only the medical cover will be unblinded and we have 

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sufficient cover to ensure they are not involved in the data collection of the replacement. 
The rest of the study team will always remain blinded. 
5.5.2 Emergency Code Break 
24hr Emergency Code Break and Medical Information will be provided by pharmacy 
unblinding service within pharmacy hours. A member of the clinical team will hold an 
envelope for out of hours. The pharmacy out of hours will be used as a back-up. Each 
randomised subject will be provided with a card detailing code break telephone numbers 
and emergency contact details. Subjects will be requested to carry this card with them at 
all times whilst participating in the trial. 
5.6 Withdrawal of Subjects  
The investigator may discontinue a subject’s study participation at any time during the 
study, if he/she feels that the subject’s continued participation is not in their best interests 
or if a subject deviates from the study criteria (e.g. positive DOA test) or lifestyle 
guidelines (e.g. reproductive restrictions, caffeine/nicotine intake). In addition, a subject 
may discontinue their participation without giving a reason at any time during the study.   
 
Should a subject’s participation be discontinued during a study visit after dosing, every 
effort should be made to perform all procedures scheduled for discharge. There is no 
requirement for an early termination visit in this study.  
 
At the investigator’s and sponsor’s discretion, additional subjects may be added to 
account for discontinued or withdrawn subjects. 
 
The investigator also has the right to withdraw patients from the study in the event of 
inter-current illness, AEs, SAE’s, SUSAR’s, protocol violations, administrative reasons, 
or other reasons.  It is understood by all concerned that an excessive rate of withdrawals 
can render the study un-interpretable; therefore, unnecessary withdrawal of patients 
should be avoided.  Should a patient decide to withdraw from the study, all efforts will be 
made to report the reason for withdrawal as thoroughly as possible.  Should a patient 
withdraw from study drug only, efforts will be made to continue to obtain follow-up data, 
with the permission of the patient.  
 
Participants who wish to withdraw from trial medication (IMP) will be asked to confirm 
whether they are still willing to provide the following.  
• trial specific data at visits 
• data collected as per routine clinical practice at visits  
 
Study drug must be discontinued if: 

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• 
The participant misses two or more doses of treatment.  
• 
The participant decides they no longer wish to continue. 
• 
The investigator recommends it. 
 
The reason for withdrawal will be recorded in the CRF.  
5.7 Expected Duration of Trial 
The end of the trial will be defined as last patient last visit; each individual subject will 
remain on the trial until they have completed all five visits and have had the final follow 
up phone call. 
6 Trial Procedures and assessments 
6.1 By Visit 
Pre-Screening  
The pre-screening procedure will involve reviewing notes and undertaking telephone 
interviews with the patients to evaluate whether they are suitable and interested in taking 
part in the study.  
Screening 
If the subject appears to be suitable and is interested in taking part in the study they will 
be provided with a patient information leaflet before they are invited to the clinic where 
they will have the opportunity to ask any questions or discuss the information leaflet with 
the Investigator or the study team. The investigator or a suitably qualified person 
designated by the investigator will obtain written informed consent from each subject or 
the subject's legally acceptable representative before any study-specific activity is 
performed. The investigator will retain the original of each subject's signed consent form, 
which will be stored in the Centre of neuroimaging sciences (CNS) in a locked cabinet 
and a copy will be provided to the patient. 
Following provision of informed consent, the subject will have a medical screening, 
physical and psychiatric examinations including completion of the NPI, MoCA and 
SAPS-PD, familiarisation, and tolerability check in the mock MRI scanner (to see how 
well participants can tolerate the scanner environment) and basic training on the visual 
processing tasks. Blood and urine samples will be taken for safety tests, drug screen and 
pregnancy testing (if applicable).  
Day 1- Baseline visit 
Patients will attend the clinic on the morning of study day 1. They will be checked to 
make sure that they continue to meet all inclusion criteria and none of the exclusion 
criteria and undergo physical and neurological examinations, including completion of the 
NPI, MoCA, SAPS-PD, PDQ and EQ. To build the patient profile at the start of the 

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study, baseline questionnaire and assessments will be carried out. These include the Non-
motor symptoms, SCOPA-MOTOR, PD sleepiness, WTAR, verbal fluency, months’ 
reversed, clinical impression of severity index and the NEVHI (assessments described in 
section 6.2). The recall period for each of the assessments will be adapted to when the 
visit is taking place. Following completion of the baseline assessments the participant 
will receive their first dose of study medication. Saracatinib/placebo will be administered 
followed by a 3 hour stay during which vitals will be assessed at regular intervals. A 
physical examination will take place prior to discharge. On discharge, medication will be 
provided to be taken for the following 12 days, confirmed by daily telephone contact. 
Days 2 to 13 
Patients will take a dose (two 50mg tablets) of study medication at home each morning. 
The study team will telephone the patient/their carer each day to confirm the medication 
has been taken and to assess for any adverse events.  
Day 14 Scanning visit  
On the 14th day participants will be asked to attend the research facility in the time 
window of 12-16 days after their first dose, given their last dose of the study medication 
and then at approximately 2 hours post dose will be scanned using BOLD fMRI whilst 
doing the Kanizsa task and the Meppelink task. After MRI scanning is complete 
participants will have mismatch negativity measured using EEG. They will also have the 
NPI, SAPD-PD, PD sleepiness scale, NEVHI, PDQ and EQ (details of the tasks and 
scans outlined in section 6.2 below).  
Following this, participants will undergo a physical examination and assessment by the 
study physician, and they will also have blood sampling for pharmacokinetic/drug 
exposure levels. Participants will then be discharged provided there are no concerns. 
There will then be a minimum 14-day washout (+/- 2 days), after which they will return 
for day 1 of the second study period. All study procedures (apart from the profiling 
assessments) on days 1 through 14 will be repeated for study period 2.  
Participants will be contacted by telephone between 10 and 14 days after their final visit 
to check for adverse events.  
Early termination visit 
If a participant decides to stop the study treatment they will be given a phone call by a 
study physician and may be invited for an early termination visit where participants will 
return any unused medication undergo a physical and neurological examination, vitals, 
and an ECG. 

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6.2 Assessments 
6.2.1 Profiling assessments 
 
North-East Visual Hallucinations Interview (NEVHI) 
 
The NEVHI is a visual complaints questionnaire that is used to assess the 
phenomenology of visual hallucinations (Urwyler et al., 2014). The participants will be 
given the NEVHI at the baseline visit to understand their hallucinations.   
 
Wechsler Test of Adult Reading (WTAR) 
 
The WTAR was developed to predict intellectual performance in adults and had shown to 
have a significant correlation with measures for intellectual functioning. It consists of 50 
words with irregular ‘grapheme to phoneme translation’ which the participant must read 
out loud (Whitney et al., 2010). The WTAR takes approximately 90 seconds to complete.  
Non-motor symptoms questionnaire 
A nine-domain questionnaire consisting of 30 questions designed to test the frequency 
and severity of the non-motor symptoms of Parkinson’s disease over the past month 
(Chaudhuri and Martinez-Martin, 2008). This questionnaire will take approximately 5 
minutes to complete.  
SCOPA-MOTOR scale 
A 21-question test on the severity of motor symptoms PD. The test consists of three 
components; evaluation of motor symptoms (10 items), activities of daily living (ADL 7 
items) and motor complications (4 items). All items are scored from 0 (normal) to 3 
(severe) on the questionnaire (Martinez-Martin et al., 2008). This will take approximately 
10 minutes to complete.  
Parkinson’s disease sleepiness scale 
The PDSS is a 15-item scale for the assessment of sleep disorders in Parkinson’s disease 
over the past week. The PDSS involves patients marking their response to each item on a 
10cm long visual analogue scale that goes from 0 (worst) to 10 (best). All of the items of 
the scale are focused on nocturnal sleep except item 15 which is about daytime 
sleepiness. The total score on the PDSS is the sum of all of the items with a maximum 
score of 150 (Martinez-Martin et al., 2008). 
Cognitive assessment 
A brief cognitive assessment consisting of two parts; Months reversed (saying the months 
of the year backwards from December in 90 seconds) and Lexical fluency (giving the 

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patient 1 minute to name as many words as they can beginning with a particular letter) 
(Dubois et al., 2007).  
Clinical impression of severity index  
An assessment for the clinical severity of motor symptoms in 4 domains: motor signs, 
disability, motor complication and cognitive status. Each are is scored from 0 (normal) to 
6 (very severe) and the global index from 0-24 points (Martinez-Martin et al., 2008).  
The Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease– Rating 
Scale (QUIP-RS) 
 
The QUIP-RS (Weintraub et al., 2012) is a self-report measure designed to assess the 
presence and the severity (on a scale from 0 to 4) of symptoms of impulse control 
disorders (compulsive gambling, buying, sexual behavior, and eating) and related 
disorders (including hobbyism, punding, and dopamine dysregulation syndrome). The 
questionnaire takes approximately 5 minutes to complete. 
 
6.2.2 Study Assessments 
 
Neuropsychiatric Inventory (NPI)  
 
The NPI is an informant-based scale that was developed to assess neuropsychiatric 
symptoms. It consists of 12 items, but section A and B are delusions and hallucinations 
respectively. If symptoms are present, then more information is obtained through 
questions about frequency (scale of 1-3) and severity (scale of 1-4). The total scores are 
added up to get the NPI total score (Ferreira et al., 2015). An inclusion criterion for this is 
included in section 5.1.  
 
Montreal Cognitive Assessment (MoCA)  
 
The MoCA is a one‐page 30‐point test administered in 10 minutes. The MoCA focuses 
on different aspects of cognitive abilities by testing various areas such as short‐term 
memory recall, visuospatial abilities, multiple aspects of executive functions such as 
attention, concentration, working memory and Language. The final questions test 
orientation to time and place (Nasreddine et al., 2005). Please see section 5.1 for the 
minimum cut off score for inclusion in this study.  
 
Scale for the Assessment of Positive Symptoms- Parkinson’s Disease (SAPS-PD) 
 

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The Scale for the Assessment of Positive Symptoms (SAPS) was originally designed for 
use in schizophrenia and was found to be a reliable tool for people with Parkinson’s 
disease (Fernandez et al., 2008). Therefore, the SAPS-PD compromises of the 9 items 
that were found to be most frequently reported in patients with PD psychosis. It 
compromises of questions about hallucinations and delusions and the severity of the 
symptoms (Voss et al., 2013).  
EEG 
MMN is an ERP evoked in response to unattended changes in background stimulation. 
MMN is believed to reflect an automatic process of detecting a mismatch between a 
deviant stimulus and a sensory-memory trace. Smaller amplitudes of MMN have been 
consistently identified in schizophrenia subjects, showing promise as a quantitative 
clinical biomarker of the disease. MMN amplitude is associated with ketamine-induced 
psychotic experiences. MMN has demonstrated stability in clinical populations with high 
test-retest reliability over 1 year. Hence, MMN represents a potentially informative probe 
of sensory processes relevant to hallucinations/psychosis for use in experimental 
medicine studies of novel therapeutics. The MMN test takes approximately 10 minutes 
with 25 minutes set up time. Further details will be provided in the study manual. 
MRI scan  
The scanning protocol will comprise a localiser to ensure a good positioning in the 
scanner, T1-weighted structural scan (to allow registration to a template), multi-echo 
resting state scan (for connectivity), Kanizsa illusion, the Meppelink task and a perfusion 
scan using pseudo-continuous ASL (to determine changes in neurovascular coupling 
caused by the drug). 
Kanizsa Illusion  
 
The Kanizsa task is a task that compromises of illusory contours which are perceived 
edges that ‘bridge gaps between aligned luminance edges’ but do not exist physically. 
The Kanizsa task is a task that used the perceived edges to give a direct comparison of the 
physiological response to illusory contours which may reveal information about object 
perception (Mendola et al., 1999). This task will take approximately 12 minutes.  
 
Visual pop-out task (Meppelink task)  
A visual task where objects, animals and people appear out of noise and participants must 
press a button when they recognise what it is. A previous study by Meppelink et. Al. 
reported that patients with visual hallucinations and Parkinson’s disease had decreased 
activation of the lateral occipital cortex several seconds before image recognition 
compared to patients with PD but no psychosis and healthy controls (Meppelink et al., 
2009). This task consists of 50 images appearing from noise and each video lasts for 30 
seconds. In total, the task will take approximately 20 minutes.  

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Visual analogue scales of physical fatigue, mental fatigue and overall health 
Visual scales ranging from 0-100 where the patient marks on the scale how they would 
rate their physical fatigue, mental fatigue, and overall health today.  
PDQ 
The Parkinson’s disease questionnaire is a quality of life questionnaire specific to 
Parkinson’s disease (Young et al., 2013). It is composed of 39 questions and participants 
are asked to read a statement and indicate on a scale of ‘Never’ to ‘Always or cannot do 
at all’ which applies best. The questionnaire assesses difficulties of daily living across 8 
dimensions. The scale can provide a single figure that can be used to assess the overall 
quality of life related to health.  
EQ-5D 
The European quality of life 5-dimension questionnaire is a standardized questionnaire 
for measuring health-related quality of life in 5 dimensions; mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression. Each dimension has 3 statements and 
participants are asked to tick which statement best describes their health today.  
6.3 Laboratory Tests 
PK and plasma exposure levels will be measured on days 1 and 14 (pre and post 
scanning) at approximately the same time of day to control for any bioanalytical timing 
effects.  
 
Haematology 
Haematology will consist of the following tests: 
Erythrocytes (red blood cells) 
Haemoglobin 
Haematocrit 
Platelets 
Leukocytes (white blood cells [WBCs]) 
with absolute differential 
 
 
Urinalysis 
Urinalysis will consist of the following tests: 
Protein 
Glucose 
Blood 
Nitrite 
 
Urine microscopy will be performed if urinalysis is abnormal. Microscopy consists of 
red blood cell/high-power field, white blood cell/high-power field, and casts. 

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Chemistry  
Chemistry evaluations will consist of the following standard chemistry panel: 
Albumin 
Alkaline phosphatase  
ALT 
AST 
Blood urea nitrogen  
Calcium 
Carbon dioxide 
Chloride 
Creatinine 
Glucose 
Gamma-glutamyl transferase  
Sodium 
Potassium 
Bilirubin (total), if above ULN total 
bilirubin will be fractionated 
Protein (total) 
 
Diagnostic Screening 
Serum 
Serum diagnostic evaluations will include the following tests: 
Hepatitis Screen (hepatitis A virus antibody, HBsAg, HCV antibody) 
FSH, LH (females of NCBP aged under 50 only) 
 
Urine 
A urine drug screen will include the following tests:  
Amphetamines 
3,4-methylenedioxy-methamphetamine  
Barbiturates 
Methadone / Metabolite 
Benzodiazepines 
Opiates 
Buprenorphine / Metabolite 
Cocaine / Metabolites 
Cannabinoids  
Phencyclidine 
 
 
 
 
 
7 Assessment of Efficacy  
This study is not powered for clinical efficacy, it is powered for proof of concept and 
mechanism of action (change in visual cortex fMRI signal). We nonetheless record 
symptoms and exploratory analyses will be conducted with these. In addition, we will 

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explore relationships between the neuroimaging and EEG endpoints and symptoms. The 
symptom scores will be:  
• Factor summary score on the Scale for the Assessment of Positive Symptoms in 
Parkinson’s disease (SAPS-PD) 
• Factor summary score on the Neuropsychiatric Inventory (NPI)  
8 Assessment of Safety  
8.1 Specification, Timing and Recording of Safety Parameters  
A trained medical doctor will be available/present at all times and on all study days and 
be responsible for confirmation of suitability to participate, dosing, reviewing AEs, 
management of any side effects or medical events and discharge. At each study visit the 
study physician or delegate will carry out a physical exam, vital signs (blood pressure, 
heart rate, body temperature and respiratory rate) and ECG which will be recorded at 
each visit.  
Participants will also be called daily to confirm they have taken the medication and for 
adverse event monitoring.  
8.2 Procedures for Recording and Reporting Adverse Events 
 
The Medicines for Human Use (Clinical Trials) Regulations 2004 and Amended 
Regulations 2006 gives the following definitions: 
Adverse Event (AE): Any untoward medical occurrence in a subject to whom a 
medicinal product has been administered including occurrences which are not necessarily 
caused by or related to that product. 
Adverse Reaction (AR): Any untoward and unintended response in a subject to an 
investigational medicinal product which is related to any dose administered to that 
subject. 
Unexpected Adverse Reaction (UAR): An adverse reaction the nature and severity of 
which is not consistent with the information about the medicinal product in question set 
out in: 
The Investigator's Brochure (IB) relating to the trial in question (for any other 
investigational product)  
 
Serious adverse Event (SAE), Serious Adverse Reaction (SAR) or Unexpected 
Serious Adverse Reaction (USAR): Any adverse event, adverse  reaction or unexpected 
adverse reaction, respectively, that 

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• 
Results in death; 
• 
Is life-threatening; 
• 
Required hospitalisation or prolongation of existing hospitalisation; 
• 
Results in persistent or significant disability or incapacity; 
• 
Consists of a congenital anomaly or birth defect. 
 
Important Medical Events (IME) & Pregnancy 
Events that may not be immediately life-threatening or result in death or hospitalisation 
but may jeopardise the patient or may require intervention to prevent one of the other 
outcomes listed in the definition above should also be considered serious. 
 
Although not a serious adverse event, any unplanned pregnancy will also be reported via 
the SAE reporting system and to Astrazeneca. As outlined in the exclusion criteria, 
females of child bearing potential will not be included in the study.  
Reporting Responsibilities  
King’s College London and King’s College Hospital have delegated the delivery of the 
Sponsor’s responsibility for Pharmacovigilance (as defined in Regulation 5 of the 
Medicines for Human Use (Clinical Trials) Regulations 2004 to the King’s Health 
Partners Clinical Trials Office (KHP-CTO).  
All SAEs, SARs and SUSARs (excepting those specified in this protocol as not requiring 
reporting) will be reported immediately by the Chief Investigator (and certainly no later 
than 24hrs) to the KHP-CTO in accordance with the current Pharmacovigilance Policy. 
In addition, all SAEs, SARs and SUSARs will be reported to AstraZeneca via Kinapse 
(astrazeneca@kinapse.com) according to the timelines outlined in Appendix A and to the 
research ethics committee (REC). 
Death as a result of disease progression and other events that are primary or secondary 
outcome measures are not considered to be SAEs and should be reported in the normal 
way, on the appropriate CRF. 
 
The KHP-CTO will report SUSARs to the regulatory authorities (REC, competent 
authorities of other EEA (European Economic Area) states in which the trial is taking 
place. 
The Chief Investigator will report to the relevant ethics committee. Reporting timelines 
are as follows: 
− SUSARs which are fatal or life-threatening must be reported not later than 7 days to 

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the sponsor and reported to Kinapse as they occur and within 24 hours of knowledge. 
SAEs will be reported to Kinapse on a quarterly basis. Any additional relevant 
information must be reported within a further 8 days. 
− SUSARs that are not fatal or life-threatening must be reported to Kinapse within 24 
hours of the sponsor first becoming aware of the reaction.   
− The Chief Investigator and KHP-CTO (on behalf of the co-sponsors), will submit a 
Development Safety Update Report (DSUR) relating to this trial study drug, to the 
REC annually.  
8.2.1 Adverse events that do not require reporting 
All reporting of adverse events will be as per usual standards. All adverse events will be 
reported, except for ongoing symptoms due to their illness. Any changes will be recorded 
as adverse events.  
 
8.3 Treatment Stopping Rules 
 
Subjects may be discontinued from the study drug in the following situations. Note that 
discontinuation from study treatment is NOT the same thing as a complete withdrawal from 
the study (i.e. data collected may still be used in data analysis). 
 
• 
Subject decision. The subject is at any time free to discontinue treatment, without 
prejudice to further treatment. In this case, the subject will have a follow up phone call 
and at the discretion of a study physician, will be invited for an early termination visit.   
• 
Adverse Event 
• 
Severe non-compliance with the Clinical Study Protocol 
• 
Safety reasons as judged by the investigator and/or sponsor and/or safety advisory 
committee where continued treatment may put patient at undue risk.  
8.3.1 Study termination  
A study advisory committee will be set-up including representatives from the study team, 
the clinical team, AZ and an independent chair. This committee will meet every six months 
to review all AE, SAE and SUSAR data as well as study progress. The committee can 
advise pausing or stopping the study. Any member of this committee will be able to call an 
ad-hoc meeting if deemed necessary based on the AE reporting for this or other studies 
using Saracatinib.  
 
If the trial is prematurely discontinued, active participants will be informed and no further 
participant data will be collected. The Competent Authority and Research Ethics 

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Committee will be informed within 15 days of the early termination of the trial. 
9 
Statistics 
9.1 Sample Size 
A group of approximately 30 with PD Psychosis will be enrolled in the study for 26 
completers. 
We used the results from (Meppelink et al., 2009), to estimate statistical power to detect 
the attenuation in the brain activity impairments prior to and during ‘pop-out’ recognition 
of degraded stimuli. This activity is reduced in those with PD psychosis with visual 
hallucinations compared to those without hallucinations. The signal reduction is greatest 
immediately before target detection or ‘pop-out’ in clusters with peaks in the occipital 
lobe and fusiform gyrus extending into the posterior lateral temporal lobes. The signal 
changes from the bilateral peaks in the fusiform gyrus were used for the power 
calculation. An effect size of 2/3 of that seen in Meppelink was used as a conservative 
estimate of the predicted change with Saracatinib (see below for justification of effect). 
For left fusiform prior to ‘pop-out’ the power calculation was for an effect size of 0.91 
(0.66 * 1.39) and SD of 0.048 on the mean difference of 0.0462 requiring 15 patients 
with a power of 0.9 and alpha of 0.05, or 20 patients with alpha=0.01. The same 
calculation for the right fusiform gyrus gives a sample size of 13 patients for an effect 
size of 1.26 and alpha=0.01 (or a difference of 0.0595 with an SD of the difference of 
0.046). Based on these calculations we propose to recruit 30 patients for at least 26 
completers, with a primary endpoint of change in activity in the fusiform/posterior lateral 
temporal lobes. Drop-outs may be replaced at the discretion of the investigator.  
 
For fMRI power calculations: A change in fMRI signal would indicate support for the 
modulation of the hypothesized mechanism. This is generally considered a valuable goal 
in proof of mechanism experimental studies. Understanding if the effect size of the fMRI 
signal change is clinically meaningful (i.e. likely to result in symptom improvement) 
would provide a stronger platform for translating findings for patient benefit and 
potentially aid outcome measure and dose selection. There are many examples of 
treatment studies in which fMRI changes are accompanied by symptomatic improvement. 
For example, in patients with psychosis (unrelated to Parkinson’s disease) and other 

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psychiatric disorders such as depression studies show that activation, connectivity and 
multivariate patterns can normalize with treatment effects [(Abbott et al., 2013), (Rubia et 
al., 2011)]. When studies have reported brain activation levels, existing treatments do not 
reverse, but instead reduce impairments. For example, responders to antidepressants show 
a 2/3 reduction in amygdala activation abnormality compared to no change in non-
responders (Williams et al., 2015) and frontal cortex impairments reduce by a similar 
amount after successful antipsychotic treatment in patients with schizophrenia (Snitz et 
al., 2005), leading to the hypothesis that a reduction of 2/3 impairment in brain activation 
is a valid target for predicting symptom improvement. 
 
9.2 Randomisation 
 
Subjects will be randomised into the trail on a 1:1 basis provided they have satisfied all 
subject selection criteria. Each subject will be assigned to a treatment arm by the means 
of a computer-generated pseudo code.  
 
9.3 Analysis 
A statistical analysis plan (SAP) will be prepared and finalised prior to un-blinding of 
treatment assignments. This document will provide further details regarding the definition 
of analysis variables and analysis methodology to address all study objectives.  
We will be running a mixed effect analysis for the primary endpoints. Dropouts or 
missing data will not be included in the final analysis. For each analysis statistical outliers 
(2 SDs from mean) will be removed. Analyses with and without outliers will be provided 
for transparency as will a mixed affects analysis with all the data. 
 
EEG data will be cleaned of artefacts and filtered before comparing N1 components of 
standard and deviant stimuli in an oddball paradigm. MRI data will go through standard 
pre-processing (i.e. movement correction and spatial normalisation) in SPM before fitting 
models of visual task events for each session (see below). These steps will occur at the 
single subject level and therefore will not require unblinding after this, single subject (or 
first level) analysis will be combined for group analysis. For the primary endpoints, the 
regions of interest data will be extracted and analysed using mixed effects models. 
 
ROI Analyses 
 
ROI endpoints will be calculated as the mean fit (beta) of the BOLD response to the task 
parameters within each hemisphere of the predefined brain region- inferior posterior 
aspect of the ventral visual system defined as a cluster peak in the fusiform gyrus extend 
into the lateral temporal cortex and occipital lobe. This data will be derived from 

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individual sessions and will be blinded to the treatment. Following unblinding, the 
primary comparison of interest will evaluate the effect of saracatinib in attenuating the 
reduced response on the visual recognition tasks, compared to placebo. The conditions to 
be compared are thus:  
• Saracatinib vs placebo: during visual processing task 
• Saracatinib vs placebo: during visual pop-out recognition 
In addition, placebo scans will be compared to patients with psychosis to confirm reginal 
brain differences.  
These comparisons will be made using mixed effects models (with unstructured 
covariance) with fixed factors of drug (saracatinib or placebo) and session number (first 
or second), and a random effect of subject.  
Pre-processing for ROI analysis will be identical to pre-processing for the image based 
analysis described below.  
 
Image-based analyses 
 
Image analysis will be analogous to the ROI approach, but to map at a higher spatial 
resolution, univariate effects. Pre-processing steps for the images will be conducted in a 
fixed, full-release version of SPM. 
1. 
Slice timing correction: For each volume of the time series, a correction is 
performed for the differences in acquisition time between the slices with the middle slice 
used as reference. 
2. 
Motion correction: For each time series, two-pass motion correction will be used. 
Total frame wise displacement (FD) will be calculated per volume and used to compare 
movement across sessions, and define movement spikes (>1mm) which will be used to 
derive a control regressor. If >10% of volumes are classified as spikes the particular 
fMRI time series will be excluded.  
3. 
Co-registration: All the fMRI time series are co-registered using affine 
transformation to the same individual’s T1-weighted scan.  
4. 
Spatial normalization: All images will be registered to the standard-space 
(Montreal Neurological Institute) reference image. Non-linear warping will be used as 
per current best-practice. 
5. 
Spatial smoothing: Data will be spatially smoothed with a Gaussian kernel 
(FWHM 6-8mm) to allow for gyral variability across subjects, improve the signal-to-
noise ratio and ensure that the data be consistent with the assumptions of Gaussian 
Random Field theory used for the multiple comparisons corrections in the parametric 
image analysis. 
 
Task based modelling 
 

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Onset times for events during each condition will be used to model the haemodynamic 
response using first level models of each session individually. For the Kanizsa task, the 
events are the presentation of each moving stimulus for each of the different conditions. 
For the visual pop-out task a finite impulse response function model will be used and will 
be time-locked to the detection point for the stimuli (the ‘pop-out’). The time just prior to 
the recognition will be used for the primary end-point analysis.  
 
EEG Data  
 
The MMN will be analysed using the ‘Neuroscan’ software. Pre-processing: The slow 
ocular artefacts will be removed by regression with eye channels, and the data will be re-
referenced to the average of the left and right Mastoids. After applying suitable filters 
(low pass and high pass), and rejecting any segments with gross artefact contamination, 
ERPs will be formed separately to the deviant/target and standard tones. The feature to be 
extracted for the MMN task is the magnitude in the most negative peak in the baseline 
corrected difference wave between the deviant and standard ERP. It is around 100 to 
200ms after the deviance in the stimuli. It will be determined at FZ.  
 
Behavioural data 
 
Behavioural data will be summarized as means and standard deviations per subject per 
session and tested for normality using Shapiro-Wilk test and resulting deviations will be 
corrected using logarithm or square root transformations as appropriate. If reaction time 
data deviates from normality after transformation medians will be used for all analyses. 
Differences between groups will be tested with ANOVA models and drug effects with 
mixed effects models with fixed factors of drug (saracatinib or placebo) and session 
number (first or second), and a random effect of subject. We will consider use of 
unstructured covariance if there are sufficient degrees of freedom. 
 
Pharmacokinetic Analyses 
 
The plasma concentration of saracatinib will be assayed using samples taken just prior to 
and following the fMRI and EEG assessments and regressed against the fMRI and EEG 
endpoints in an exploratory analysis.  
 
Safety Analyses  
Safety parameters that will be assessed include pathology laboratory parameters, vital 
signs and adverse events. The parameters will be listed and summarized using standard 
descriptive statistics (where appropriate).  
 

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Audit trail 
 
All recordings and processing steps will be logged and any scripts for the analyses will be 
saved.    
 
10 Direct Access to Source Data and Documents 
 
The Investigator(s) will permit trial-related monitoring, audits, REC review, and 
regulatory inspections by providing the Sponsor(s), Regulators and REC direct access to 
source data and other documents (e.g. patients’ case sheets, blood test reports, X-ray 
reports, histology reports etc.). 
 
11 Ethics & Regulatory Approvals 
The trial will be conducted in compliance with the principles of the Declaration of 
Helsinki (1996), the principles of GCP and in accordance with all applicable regulatory 
requirements including but not limited to the Research Governance Framework and the 
Medicines for Human Use (Clinical Trial) Regulations 2004, as amended in 2006 and any 
subsequent amendments. 
 
This protocol and related documents will be submitted for review to the Research Ethics 
Committee (REC), and to the Medicines and Healthcare products Regulatory Agency 
(MHRA) for Clinical Trial Authorisation 
 
The Chief Investigator will submit a final report at conclusion of the trial to the KHP-
CTO (on behalf of the Sponsor), the REC and the MHRA within the timelines defined in 
the Regulations.  
 
The investigator must ensure that each study subject, or his/her legally acceptable 
representative, is fully informed about the nature and objectives of the study and possible 
risks associated with participation. The investigator, or a person designated by the 
investigator, will obtain written informed consent from each subject or the subject’s 
legally acceptable representative before any study specific activity is performed. The 
informed consent form used in this study, and any changes made during the course of the 
study must be prospectively approved by the REC and HRA before use. The investigator 
will retain the original of each subjects’ signed consent form.  

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12 Quality Assurance 
Monitoring of this trial will be to ensure compliance with Good Clinical Practice and 
scientific integrity will be managed and oversight retained, by the KHP-CTO Quality 
Team.  
 
Data handling, record keeping, quality control and quality assurance will adhere to the 
procedures to be outlined in the documentation of the Neuropharmacology Section of the 
Department of Neuroimaging, IoPPN, KCL. These are available on request from 
mitul.mehta@kcl.ac.uk. 
 
13 Data Handling  
The Chief Investigator will act as custodian for the trial data. The following guidelines 
will be strictly adhered to: 
 
Patient data will be anonymised. 
• All anonymised data will be stored on a password protected computer. 
• All trial data will be stored in line with the Medicines for Human Use (Clinical 
Trials) Amended Regulations 2006 and the Data Protection Act and archived in 
line with the Medicines for Human Use (Clinical Trials) Amended Regulations 
2006 as defined in the Kings Health Partners Clinical Trials Office Archiving 
SOP. 
14 Data Management 
Electronic CRF will be used  
15 Publication Policy  
It is intended that the results of the study will be reported and disseminated at 
international conferences and in peer-reviewed scientific journals. Results will also be 
published on clinicaltrials.gov within one year of completion and in open access journals.  
 
16 Insurance / Indemnity  
[AWAITING FURTHER INFORMATION] 
17 Financial Aspects 
 
Funding to conduct the trial is provided by MRC 
 

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18 
Signatures 
 
 
______________________________________ 
 
 
_________________________ 
Chief Investigator 
 
 
 
 
 
Date 
Print name 
 
______________________________________ 
 
 
_________________________ 
Statistician (if applicable) 
 
 
 
 
 
 
Date 
Print name 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 References 
 

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RUSJAN, P. M., HOULE, S. & FOX, S. H. 2010. Serotonin 2A receptors and 
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MENDOLA, J. D., DALE, A. M., FISCHL, B., LIU, A. K. & TOOTELL, R. B. 1999. 
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MEPPELINK, A. M., DE JONG, B. M., RENKEN, R., LEENDERS, K. L., 
CORNELISSEN, F. W. & VAN LAAR, T. 2009. Impaired visual processing 
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Appendix A 
 
Safety Reporting Responsibilities 
  
 
 
Sponsor:   
 
Trial:  
                         
 
 
 
 
 
AstraZeneca Reference number:  
                 
Date:  
 
 
 
 
    
 
Sponsors and AstraZeneca will exchange safety information in accordance with the 
requirements set out in the summary table at the end of this document. 
 
The following information is required. 
 
 
Before the trial starts: 
 
 Sponsor will provide AstraZeneca with:  
• 
A copy of the format of the SAE report form including the AZ Reference number. 
 
• 
An example of the format by which SAEs (including SUSARS) will be reported from sponsor to 
AZ. This should include the format of any individual reports (this may be the same form used 
for reporting SAEs above) and/or the format of quarterly listings if appropriate. 
 
• 
The format by which site and patient ID will be presented in safety reports so that they can be 
entered in a consistent way on the AZ safety database. 
 
AstraZeneca will provide the sponsor with: 
• 
The current IB  
An adverse event should only be considered expected for an AstraZeneca Investigational 
Medicinal Product (IMP) if it is included in Section 5.4 of the IB.  
These will be available to access through ES2ROS – Externally Sponsored Scientific Research 
Operations System 
 
• 
The contact information for our safety reporting: astrazeneca@kinapse.com. All information that 
needs to be shared with AstraZeneca should be sent to Kinapse at the email address provided 
according to the guidelines set out in subsequent sections of this document. 
 
 
 

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During the Trial 
Sponsor will: 
• Report unblinded Suspected Unexpected Serious Adverse Reactions (SUSARs) to AstraZeneca 
(via Kinapse) as individual case reports as they occur  
• 
Report blinded listings of Serious Adverse Events (SAEs) and Suspected Serious Adverse 
Reactions (SSAR’s) to AstraZeneca on a quarterly basis.  
• Inform AstraZeneca within 24 hours of knowledge of the event of any emerging safety data or 
actions that the Sponsor is considering as a result of a safety signal with the IMP.  This includes 
but is not limited to:  
o Urgent safety measures to be implemented in the study 
o Safety amendments to protocol/patient information & informed consent 
o Open reports from Independent Data Monitoring Committees (IDMCs) excluding 
confidential reports to IDMC and minutes of IDMC meetings 
o Interactions with Regulatory Authorities (RA’s)/ Ethics Committees (EC’s) 
o Inform AZ on an ongoing basis of any new safety trends or signals observed 
during routine safety  surveillance activities 
 
• Include the following essential information in SUSAR, SSAR and SAE reports provided to 
AstraZeneca (initial and follow-up) :  
 
o AstraZeneca Reference number  
o Sponsor trial number 
o Centre number 
o Patient trial number 
o Year of birth or age 
o Sex 
o IMP(s) dose, start & stop date 
o SAE onset & stop date 
o Event term as reported by the investigator (and/or the CTCAE V4 term and 
grade) 
o Investigator’s assessment of seriousness (ICH definitions) 
o Investigator’s assessment of causality  
o SAE Outcome 
During the Trial 
 
AstraZeneca will:  
 
• Immediately inform the sponsor of any emerging safety data or actions that AstraZeneca is 
considering as a result of a safety signal with the IMP.  This includes but is not limited to: 
o New safety information which may alter the benefit risk assessment  
o Urgent safety measures to be implemented 
 
• 
Request follow-up information on an SAE that is of interest and is related to the IMP(s). 
• 
Provide the Sponsor with IB updates on an annual basis or as new safety information 

PROTOCOL SCRIPT  
 
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emerges.  
• 
Consult with the sponsor in the unlikely circumstance that code break information is 
required for an individual patient, should AstraZeneca need to expedite an SAE that has not 
been reported to RAs by the sponsor. 
• 
Provide SAE Line Listings of the IMP if required 
 
 
 
 
At the end of the Trial 
Sponsor will: 
• 
Provide safety listings (details are included in the summary table below) 
 

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Summary of Minimum Requirements for Exchange of Safety Data 
Sponsors will submit safety information in compliance with clinical trial regulations and the Standard Operating Procedures of their organisation including to: 
• 
Regulatory authorities 
• 
Ethics committees 
• 
Site investigators 
 
In addition, Sponsors will submit the following safety information to AstraZeneca: 
 
 
Category of Adverse Event/ 
Report 
Report Type 
When to send report 
to AZ 
 
Method of Submission 
 
 
Additional Information 
 
SUSARs 
 
Individual unblinded case 
reports 
(Initial and follow-up reports) 
 
Within one (1) 
business day of the 
reports being sent to 
the Regulatory 
Authority 
Email to: 
astrazeneca@kinapse.com 
 
Sponsor responsible for: 
• 
Expedited reporting of all SUSARs to the RA of 
participating countries in line with local 
requirements.  
• 
Compliance with local regulations of participating 
countries for reporting of SUSARs to 
investigational sites and EC’s. 
 
 AstraZeneca responsible for: 
• 
Reporting SUSARs to RA’s where AstraZeneca 
sponsored studies are being conducted with the 
IMP as appropriate. 
• 
Reporting SUSARs to investigators participating 
in any AstraZeneca sponsored studies with the 
IMP as required by RA’s. 
 
SAEs/ SSARs  
 
Summary Line Listings  
 
 
 
 
 
 
On a quarterly basis 
from the date of the 
first patient consent 
 
 
 
 
• 
SAEs and SSARs should be provided as blinded 
line listings. 
• 
Where possible the listing should include only 
events that are new or updated since the last 
report.  

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Category of Adverse Event/ 
Report 
Report Type 
When to send report 
to AZ 
 
Method of Submission 
 
 
 
Additional Information 
 
 
 
 
Annual DSUR – (EU only) 
 
 
 
 
Periodic safety reports 
(produced for external 
purposes e.g. EC or RA of 
participating countries) 
Only required if the 
DSUR is inconsistent 
with the IB. 
Contact your AZ 
operational representative 
• 
Ideally any findings in the DSUR that are 
inconsistent with the IB should be communicated 
to AZ during DSUR production but at the latest in 
parallel to the DSUR being sent to the RA/Ethics 
committee. If this situation arises contact your AZ 
operational representative. 
 
• 
The production of any DSUR with no new safety 
concerns should be confirmed in writing to your 
AZ operational representative.  
 
End of Study 
 
 
SAEs, SSARs & SUSARs 
(for entry onto AZ Patient 
Safety database) 
 
 
 
A cumulative final listing of 
all unblinded SAEs, SSAR’s 
& SUSARs 
At ‘clean file’  (when all 
study queries have 
been answered and 
the database is 
locked) at the following 
time points: 
1. At primary analysis  
2. After last patient 
has completed 
study treatment  
 
Email to: 
astrazeneca@kinapse.com 
and to AZ operational 
representative 
 
 
 
• 
For blinded studies AZ require an unblinded 
listing of SAEs and SSARs to enable unblinding 
of these events on the AZ safety database.  
 
• 
For convenience and completeness SUSARs 
should also be included and easily identifiable. 
 
 
 
 
 
AstraZeneca will submit the following safety information to trial Sponsors:  
 
Category of Adverse Event/ 
Report 
Report Type 
Frequency/ 
Timeframe 
Method of Submission 
 
Additional Information 
 
SUSARs  
 
Final CIOMS report of case 
(password protected) 
 
Within 15 days of 
initial receipt  
Email to Sponsor contact.  
• These may be provided whilst clinical studies 
(AZ-sponsored or externally-sponsored) are on-
going or until the IMP becomes marketed. 
• AstraZeneca will provide these over the time 
period stated in the bullet point above to 
investigators, EC’s and relevant RAs involved in 
AstraZeneca sponsored studies.  

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• Sponsor will distribute these to investigators and 
ECs in line with local requirements.  

Protocol Final v 3.1 19/04/2018             
 
Page 49 of 49 
 
Contact Details 
 
 
AstraZeneca: 
 
Emerging safety data or actions: 
 
Email to: astrazeneca@kinapse.com 
 
 
General enquiries to AZ: 
 
 
 
AZ Operational or Scientific Representative 
 
The AstraZeneca Reference number and IMP name(s) should be included in email 
headers and emails should be sent in an encrypted file e.g. WinZip  
 
 
 
Sponsor responsibility:  
 
Periodic line listings notification:  
Name of Trial Coordinator of Study: 
 
 
Address:      
  
 
SAE follow-up queries: 
Name: 
 
 
Email:  
 
 
Telephone:      
  
 
Unblinded Request:  
Name: 
 
 
Email:  
 
 
Telephone:      
 
  
 
 
Only organisational emails may be used