Clinical trial NCT02578940
Conditions: Cancer of the Prostate
Sponsor: Blue Earth Diagnostics
Start date: 2015-11-01; Completion date: 2018-06-22
Enrollment: 104 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main aim is to assess the impact of using 18F-fluciclovine (as a PET imaging radiotracer) on the clinical and treatment decision required for managing patients with biochemically recurrent prostate cancer (BCR) who are being considered for salvage treatment with the intention of providing disease cure. Also, this study will consolidate the information regarding diagnostic performance of fluciclovine PET/CT in a large number of prospectively followed patients at several centres in the UK and assess the effect of PSA level on the likelihood of detecting cancer lesions by 18F-fluciclovine

Detailed description:
Proposed Research In the setting of growing single-centre evidence of superior diagnostic performance of 18F-fluciclovine PET/CT in BCR, our primary aim is to assess its clinical impact on treatment decisions in a multi-centre study in patients with BCR being considered for radical salvage treatment (with curative intent). In addition, we aim to further characterise its diagnostic performance, afforded by larger numbers of patients from multi-centre recruitment. We also aim to assess the effect of PSA level on probability of lesion detection by 18F-fluciclovine.

Arms: arm 1: Single intravenous administration of 18F-Fluciclovine for PET Scan
Interventions: intervention 1: 18F-Fluciclovine PET CT
Intervention descriptions: intervention 1: Radioligand for PET CT scanning

Protocol documents:
Prot_000.pdf: 
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FALCON 
(Short title: Fluciclovine (18F) PET/CT in biochemicAL reCurrence Of prostate caNcer) 
 
A phase 3, open-label study to assess the clinical utility of  
Fluciclovine (18F) PET/CT in patients with prostate cancer with 
biochemical recurrence after radical treatment 
 
Protocol No: BED-004 EudraCT number: 2015-000625-37 
Date and Version No: Amendment 4   4 June 2018   V5.0 
 
 
Chief Investigators: 
Professor Fergus Gleeson 
 
Co-ordinating Investigator:  Dr. Eugene Teoh 
Investigators:  
Complete list of collaborators and participating site contact details on file 
Sponsor:  
Blue Earth Diagnostics Ltd 
Funder: 
Innovate UK 
 
Confidentiality Statement 
This document contains confidential information that must not be disclosed to anyone other than the Sponsor, the 
Investigator Team, host organisation, and members of the Research Ethics Committee, unless authorised to do so. 
Conflicts of Interest 
Blue Earth Diagnostics Ltd is responsible for the manufacture of fluciclovine (18F). 




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Blue Earth Diagnostics  
Clinical Research Protocol 
Protocol Number: 
Fluciclovine (18F) - BED - 004 
Version / Date: 
V5.0 4 June 2018 
Investigational Product: 
Fluciclovine (18F) 
EUDRACT/IND Number: 
2015-000625-37 
Sponsor: 
Blue Earth Diagnostics  
Medical Monitor: 
Name:  Dr Daniel Stevens,  
Medical Director,  
Blue Earth Diagnostics 
Robert Robinson Avenue 
Oxford OX4 4GA 
Telephone: +44 (0)1865 784 186 
Mobile: +44 (0)7412 467 852 
E-mail: d.stevens@blueearthDx.com 
 
 
Approval: 
 
 
 
Sponsor Signature (Dr Peter Gardiner, Chief Medical Officer)  
 
Date 
 
 
Signature:
Email:
Peter Gardiner (Jul 26, 2018)
Peter Gardiner
p.gardiner@blueearthdx.com


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Study Management Group 
 
 
 
Chief Investigator 
Professor Fergus Gleeson 
Consultant Radiologist 
Department of Radiology 
Churchill Hospital 
Old Road 
Oxford OX3 7LE 
fergus.gleeson@oncology.ox.ac.uk 
 
 
Co-ordinating Investigator 
Dr Eugene Teoh 
Clinical Research Fellow 
Department of Radiology 
Churchill Hospital 
Old Road 
Oxford OX3 7LE 
eugene.teoh@oncology.ox.ac.uk 
 
Medical Monitor 
Dr Daniel Stevens 
Blue Earth Diagnostics Ltd 
Magdalen Centre 
Robert Robinson Avenue 
Oxford OX4 4AG 
 
Statistician 
Mr Albert Chau 
Blue Earth Diagnostics Ltd 
Unit F14 Oxford Science Park 
Magdalen Centre 
Robert Robinson Avenue 
Oxford OX4 4AG 
 
Pharmacovigilance 
Blue Earth Diagnostics SAE 
PharSafer House 
White Hart Meadows 
Ripley 
Surrey GU23 6ND 
drugsafety@pharsafer.com 
 
Funding 
Innovate UK 
North Star House 
North Star Avenue  
Swindon SN2 1UE 
 
Sponsor 
Blue Earth Diagnostics Ltd 
Unit F14 Oxford Science Park 
Magdalen Centre 
Robert Robinson Avenue 
Oxford OX4 4AG 
 


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TABLE OF CONTENTS 
 
1. 
SYNOPSIS ............................................................................................................................................... 7 
2. 
ABBREVIATIONS ..................................................................................................................................... 9 
3. 
BACKGROUND AND RATIONALE .......................................................................................................... 10 
4. 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS ........................................................................ 15 
5. 
STUDY DESIGN ..................................................................................................................................... 15 
6. 
PARTICIPANT IDENTIFICATION ............................................................................................................ 18 
6.1. 
Study Participants ........................................................................................................................ 18 
6.2. 
Inclusion Criteria .......................................................................................................................... 18 
6.3. 
Exclusion Criteria ......................................................................................................................... 19 
7. 
STUDY PROCEDURES ........................................................................................................................... 19 
7.1. 
Recruitment ................................................................................................................................. 19 
7.2. 
Informed Consent ........................................................................................................................ 20 
7.3. 
Screening and Eligibility Assessment ........................................................................................... 20 
7.4. 
Randomisation, blinding and code-breaking ............................................................................... 20 
7.5. 
Baseline Assessments .................................................................................................................. 21 
7.6. 
Fluciclovine (18F) PET/CT .............................................................................................................. 22 
7.7. 
Subsequent Visits ........................................................................................................................ 23 
7.8. 
Procedure for centres which perform choline PET as standard of care ...................................... 25 
7.9. 
Discontinuation/Withdrawal of Participants from Study ............................................................ 26 
7.10. 
Definition of End of Study ....................................................................................................... 26 
8. 
Risks and Benefits to Trial Participants ............................................................................................... 27 
8.1. 
Benefits ........................................................................................................................................ 27 
8.2. 
Risks ............................................................................................................................................. 27 
9. 
Intervention ......................................................................................................................................... 27 
9.1. 
Investigational Medicinal Product ............................................................................................... 27 
10. 
SAFETY REPORTING ......................................................................................................................... 31 
10.1. 
Definitions ............................................................................................................................... 31 
10.2. 
Clinical laboratory abnormalities and other abnormal assessments as AEs and SAEs ........... 32 
10.3. 
Causality .................................................................................................................................. 33 
10.4. 
Procedures for Recording Adverse Events .............................................................................. 33 
10.5. 
Reporting Procedures for Serious Adverse Events .................................................................. 35 
10.6. 
SUSAR Reporting ..................................................................................................................... 35 


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10.7. 
Safety Monitoring Committee ................................................................................................. 35 
10.8. 
Development Safety Update Reports (DSURs) ........................................................................ 36 
11. 
STATISTICS AND ANALYSIS ............................................................................................................... 36 
11.1. 
Sample size .............................................................................................................................. 36 
11.2. 
Analysis of Outcome Measures/Endpoints ............................................................................. 36 
11.3. 
Interim Analysis ....................................................................................................................... 37 
12. 
DATA MANAGEMENT ...................................................................................................................... 38 
12.1. 
Access to Data ......................................................................................................................... 38 
12.2. 
Data Recording and Record Keeping ....................................................................................... 38 
13. 
QUALITY ASSURANCE PROCEDURES ............................................................................................... 39 
13.1. 
Site Monitoring ........................................................................................................................ 39 
13.2. 
Central Monitoring .................................................................................................................. 39 
13.3. 
Audit and Regulatory Inspection ............................................................................................. 39 
13.4. 
Contracts / Agreements .......................................................................................................... 39 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................................................... 39 
14.1. 
Ethical Conduct of the trial and ethics approval ..................................................................... 40 
14.2. 
Regulatory Authority approval ................................................................................................ 40 
14.3. 
Subject identification ............................................................................................................... 40 
14.4. 
Early termination or temporary halt on urgent safety grounds .............................................. 40 
14.5. 
Expenses and benefits ............................................................................................................. 40 
14.6. 
Protocol Amendments ............................................................................................................. 40 
14.7. 
Urgent safety measures .......................................................................................................... 41 
14.8. 
Temporary halt ........................................................................................................................ 41 
14.9. 
Serious Breaches ..................................................................................................................... 42 
14.10. 
Approvals ................................................................................................................................. 42 
14.11. 
Reporting ................................................................................................................................. 42 
14.12. 
Participant Confidentiality ....................................................................................................... 42 
15. 
FINANCE AND INSURANCE .............................................................................................................. 42 
15.1. 
Funding .................................................................................................................................... 42 
15.2. 
Insurance ................................................................................................................................. 43 
16. 
PUBLICATION POLICY ....................................................................................................................... 43 
17. 
REFERENCES .................................................................................................................................... 43 
18. 
APPENDIX A:  SCHEDULE OF STUDY PROCEDURES .......................................................................... 48 
19. 
APPENDIX B: Oxford site sub-study ................................................................................................. 49 


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1. SYNOPSIS 
 
Study Title 
A phase 3, open-label study to assess the clinical utility of fluciclovine (18F) 
PET/CT in patients with prostate cancer with biochemical recurrence  (BCR) 
after initial treatment 
Internal ref. no. / short 
title 
Fluciclovine (18F) PET/CT in biochemicAL reCurrence Of prostate caNcer 
(FALCON); BED-004 
Study Design 
This is a phase 3, open-label study to confirm the clinical benefit of 
fluciclovine (18F) PET/CT in patients with biochemical recurrence of prostate 
cancer (BCR). 
Study Participants 
Patients with BCR being considered for radical salvage treatment (with 
curative intent), having had primary radical curative therapy performed at 
least 3 months before enrolment. 
Planned Sample Size 
Recruitment of 180 patients with anticipation of 171 patients completing 
the trial. 
Planned Study Period 
Patients will be followed up for treatment outcome and standard of care 
investigation results for up to 7-8 months after completion of treatment 
plan. Duration on study will be up to 7-8 months after completion of 
treatment plan. 
 
Objectives 
Endpoints 
Primary 
 
To assess the clinical impact of 
fluciclovine (18F) PET/CT in affecting 
management decisions in patients 
with BCR being considered for radical 
salvage treatment (with curative 
intent). 
The record of the revised 
management plan post fluciclovine 
(18F) PET/CT scan in comparison to 
the pre-scan intended 
management plan. 
Secondary 
 
1. To assess possible improvement in 
outcome of radical salvage 
treatment based on fluciclovine 
(18F) PET/CT being included in the 
assessment. 
2. To assess the prostate specific 
antigen (PSA) threshold for 
positive lesion detection by 
fluciclovine (18F) PET/CT in BCR 
3. To assess the safety of fluciclovine 
(18F) injection in patients 
undergoing PET/CT 
 
1. The proportion of patients 
who have a sustained response 
to radical salvage therapy. 
2. PSA levels in relation to scan 
positivity will be analysed to 
determine the optimal PSA 
threshold for detecting 
recurrent PCa by fluciclovine 
(18F) PET/CT. 
3. Safety will be assessed from 
data on the occurrence of 
adverse events (AEs) and 
changes in clinical laboratory 
tests, vital signs, injection-site 
status, and physical 
examination findings from the 


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time of administration of 
fluciclovine (18F) injection 
throughout the study period. 
 
 


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2. ABBREVIATIONS 
 
AE 
Adverse Event 
CI 
Chief Investigator 
C.I. 
Confidence Interval 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonisation 
MRI 
Magnetic Resonance Imaging 
NHS 
National Health Service 
NRES 
National Research Ethics Service 
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
PIL 
Participant/ Patient Information Leaflet 
R&D 
NHS Trust R&D Department 
REC 
Research Ethics Committee 
SOP 
Standard Operating Procedure 
SPECT 
Single Photon Emission Computed Tomography 
US 
Ultrasound 
 


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3. BACKGROUND AND RATIONALE 
 
Prostate cancer (PCa) is the commonest cancer in males in the UK, accounting for 25.9% of total 
malignancies in men in 2012, with an age-standardised incidence of 174.7 per 100,000 males [1]. It is the 
second commonest cause of male cancer deaths [2] with a recurrence rate of 20-30% in patients who 
have received primary radical treatment [3].  
The diagnosis of PCa is often made following the detection of elevated prostate-specific antigen (PSA) 
and / or an abnormal digital rectal examination, with confirmation of diagnosis by prostate biopsy. PSA is 
used as a tumour marker and its levels are positively correlated with the risk of metastatic disease or 
subsequent disease progression. 
The primary treatment of PCa can be divided into radical and non-radical treatment, the former 
applicable to patients with localised non-invasive disease. Radical primary treatment options include 
radical prostatectomy (RP), radical external beam radiotherapy (RRT) and brachytherapy. Following 
radical treatment, patients undergo surveillance via PSA measurement. Detection of PSA post radical 
therapy (at least 6 weeks post treatment in the case of RP), or an initially falling and then rising PSA are 
evidence of biochemical disease relapse, BCR. Depending on clinical factors and local practice, patients 
may undergo imaging, usually a bone scan and or pelvic MRI, to confirm the sites and extent of disease 
relapse.  
 
3.1 Conventional Imaging in BCR 
Standard imaging investigations are an isotope bone scan to evaluate for bony metastatic disease [4] and 
MRI / CT to assess for local / nodal recurrence [5]. However, BCR after RP or RRT precedes clinical 
metastases by 7-8 years on average, rendering the diagnostic yield low in asymptomatic patients [6]. EAU 
guidelines recommend these tests only be performed in patients with BCR who have a high baseline PSA 
(> 10 ng/mL) or a high PSA velocity (> 0.5 ng/mL/month) or in patients with symptoms of bone disease. 
The positive detection rate of these investigations are poor below these thresholds  [7, 8]. In BCR 
patients with PSA ≤ 10 ng/ml, Dotan et al  [9], only 4% of patients had positive bone scans. Studies have 
shown CT to be positive in only 11–14% of men with BCR after RP  [8, 10]. The diagnosis of nodal 
involvement on conventional cross-sectional imaging (CT / MRI) is based primarily on nodal size, which is 
known to be inaccurate, with pooled sensitivities of 39% and 42% for MRI and CT respectively and 
pooled specificities of 82% in both modalities [11]. As such, the utility of imaging and type of 
investigation in BCR varies across the UK. 
 
3.2 FDG PET-CT Imaging in BCR 
The uptake of FDG is low in prostate cancer and its use as an imaging agent in PET-CT in prostate cancer 
has been shown to be of limited value  [12, 13].  Several radionuclide tracers have been developed for 
clinical use in prostate cancer. The most well-established tracers in clinical use within Europe are choline-
based PET radiotracers.  
 


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3.3 Choline PET/CT 
The concept of using radiolabelled choline in the imaging of prostate cancer is based on the 
overexpression of choline kinase by prostate cancer cells, a property shared with other tumour types  
[14]. Two different forms of radiolabelled choline are in current use, 11C-choline and 18F-fluorocholine. 
With the latter, two chemically variant compounds are commercially available, 18F-fluoromethylcholine 
and 18F-fluoroethylcholine. No in vivo studies directly comparing the different forms of radiolabelled 
choline have been published. 
Choline PET/CT has better diagnostic performance in detecting sites of recurrent prostate cancer than 
conventional imaging and 18F-FDG PET/CT. Evangelista et al  [15] pooled data from 2 studies (n=89) 
comparing 11C-choline to 18F-FDG PET/CT in detecting prostate cancer metastases. In 11C-choline and 18F-
FDG PET/CT scans respectively, they reported pooled sensitivities of 65.1 % (95% C.I. 53.8–75.2 %) and 
39.8 % (95% C.I. 29.2–51.1 %), and pooled specificities of 83.3 % (35.9–99.6 %) and 83.3 % (35.9–99.6 %). 
Von Eyben et al  [16] pooled data from 7 studies (n=280) comparing choline PET/CT to bone scintigraphy. 
Choline PET/CT yielded positive results for more patients [127 (45%) vs. 46 (16%), odds ratio (OR) 2.8, 
95% C.I. 1.9–4.1]. In a cohort of 109 BCR patients with negative conventional imaging (transrectal US, 
MRI, abdominopelvic CT, bone scintigraphy), Giovacchini et al reported positive 11C-choline PET/CTs in 
11%  [17].  
The adoption of choline PET/CT has also been shown to have clinical impact. In a recent retrospective 
multicenter study, Ceci et al  [18]reported 11C-choline PET/CT led to a major clinical impact change in 
management in 18% of patients, with an overall management change in 46.7%. Von Eyben et al 2014 
pooled data from 15 studies (n=938) evaluating the impact of choline PET/CT on changing treatment in 
prostate cancer  [16]. They reported 41% of patients undergoing a change in treatment. Based on a 
secondary pooled analysis restricting this cohort to patients with BCR [19-22], 40% underwent a change 
in treatment. Furthermore, patients with negative choline PET/CT results had better BCR-free, disease-
free and treatment-free survival rates than those with positive findings. Choline PET/CT 
positivity/negativity was the only significant predictor of treatment-free survival. 
In the same meta-analysis, PSA response following a change in treatment based on choline PET/CT 
results was evaluated using pooled data from 10 studies (n=404)  [16]. This demonstrated 25% of 
patients having a complete PSA response. Treatments included salvage lymphadenectomy (LND) and 
pelvic radiotherapy. 
Despite better diagnostic performance compared to conventional imaging, choline PET/CT still suffers 
from suboptimal sensitivity. Whenever choline-PET/CT identifies a suspected lesion, almost twice as 
many metastases are present [23], an observation reflected in data from recent meta-analyses. Von 
Eyben et al  [16] pooled data from 11 studies (n=609) evaluating the performance of choline in detecting 
lymph node metastases in BCR – with histological correlation. Pooled sensitivity was 59% (51%–66%) and 
specificity was 92% (89%–94%). Hence, choline cannot adequately characterise the extent of nodal 
disease in BCR. 
In the context of primary prostate cancer, Evangelista et al [24] pooled data from 10 studies (n=441) 
evaluating the performance of choline in detecting lymph node involvement. This also yielded a 
relatively poor pooled sensitivity of 49.2% (95% C.I., 39.9-58.4%), with a higher specificity of 95% (95% 
C.I., 92-97.1%). 


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While it performs better than conventional imaging counterparts, the detection rate of choline PET/CT 
remains poor in the setting of relatively low PSA and slow PSA kinetics. Husarik et al and Castellucci et al 
reported a moderate and low detection rate in case of PSA value <2 ng/mL and <1.5 ng/mL (71.4% and 
28%), respectively  [25, 26]. The detection rate of metastases has been described to range between 20% 
and 36% in patients with PSA <1 ng/mL, compared to 63%-83% where PSA levels exceed 3 ng/mL  [27-
29]. In a cohort of 109 BCR patients with negative conventional imaging (TRUS, MR, abdominopelvic CT, 
bone scintigraphy), Giovacchini et al reported a higher rate of positive 11C-choline PET/CTs with higher 
PSA [17]. Imaging was positive in 3 of 65 (5%), 4 of 26 (15%) and 5 of 18 patients (28%) with PSA between 
0.2 and 1, between 1 and 2, and greater than 2 ng/ml, respectively. 
 
As with other diagnostic tests, choline PET/CT is liable to produce false positive findings. This is reflected 
in the aforementioned diagnostic performance parameters and has been described in a number of 
entities. These included increased choline uptake within: the prostate in benign prostatic hypertrophy 
(BPH)  [30], lymph nodes due to inflammation  [31, 32], the prostate bed due to post-surgical scarring 
and inflammation post-RP/RRT  [33], bones due to degenerative change or recent fractures  [34]. 
The two different forms of radiolabelled choline, 11C-choline and 18F-fluorocholine, have individual 
drawbacks. 11C-choline exhibits early accumulation in small bowel limiting pelvic analysis [35]. The short 
20-minute half-life of 11C limits the use of 11C-choline to centres with an on-site cyclotron and 
radiopharmacy facilities. Its short half-life also limits the scope for obtaining delayed acquisitions to 
improve tumour-to-background ratio. The latter can be performed with 18F-fluorocholine, which has a 
longer half-life of 110 minutes. This also makes it a more widely distributable tracer. However, high 
urinary tract uptake and excretion of 18F-fluorocholine into the urinary bladder limits assessment of the 
prostate bed  [36]. 
 
3.4 Conventional and Emerging Radical Salvage Options in BCR 
The options for radical salvage therapy (with curative intent) in BCR remain controversial  [5]. In the 
context of prior RP, the main option is salvage radiotherapy (SRT) to the prostate bed. In patients with 
intact prostates, having had prior primary RRT or brachytherapy, a wider range of options for salvage 
therapy with curative intent are available. These include salvage radical prostatectomy, salvage 
cryotherapy, salvage brachytherapy and salvage HIFU [5]. 
The described therapies are local treatments, directed at the prostate / prostate bed. Based on current 
mainstream practice, the presence of disease outside the prostate bed precludes radical salvage therapy. 
Paradoxically, current NICE guidelines recommend against the use of conventional imaging in patients 
being considered for radical salvage therapy [37], unless symptomatic. This may be rationalised by the 
observation of more favorable outcomes from radical salvage therapy at low PSA levels, particularly SRT 
[38], and foreknowledge of the poor diagnostic performance of conventional imaging at such PSA levels. 
While this in itself underpins the need for an imaging test to accurately detect extra-prostatic disease 
and thus prevent unnecessary radical salvage treatment, there is an emerging role for salvage treatment 
of limited nodal disease, with several reports of promising clinical endpoints based on early results. This 
has been described in the form of salvage pelvic lymphadenectomy (LND) or targeted pelvic 
radiotherapy, the latter afforded by the advent of more sophisticated techniques, namely intensity 
modulated radiotherapy (IMRT) and stereotactic beam radiotherapy (SBRT).  


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Rigatti et al  [39] evaluated the effect of salvage LND in 72 patients with BCR post-RP, who had choline-
positive lymph nodes on PET/CT. They reported a complete PSA response in 56.9% of patients and 5-year 
recurrence-free and cancer-specific survival of 24% and 75% respectively. The mean PSA in this cohort 
was 1.5 ng/ml. In 47 patients with BCR and a history of RP or RRT and choline-positive nodal disease, Jilg 
et al  [40] evaluated the impact of salvage LND (with adjuvant radiotherapy in a subset). Similar 
outcomes were reported, a complete PSA response in 46% and 5-year recurrence-free and cancer-
specific survival of 25.6% and 77.7% respectively. 
Alongi et al  [41] described an overall response rate of 82% (over a median follow-up of 195 days) to 
SBRT of isolated lymph node metastases in 34 patients with previously radically treated PCa. In a cohort 
of 24 patients with BCR and up to 3 synchronous bone or nodal metastases treated with SBRT, Berkovic 
et al  [42] reported a median delay in commencing ADT of 38 months (95% C.I. 18–58 months). In 
another cohort of 34 patients with BCR and isolated disease recurrence (in various sites) on imaging, 
robotic SBRT resulted in a progression-free survival of over 40% at 30 months, and complete PSA 
response in over 60% treated with SBRT alone  [43]. 
3.5 Rationale for accurate imaging in BCR 
As mentioned previously, the presence of disease outside the prostate bed precludes radical salvage 
therapy based on mainstream practice. In addition, more favorable outcomes from salvage therapy are 
observed at low PSA levels  [38], when the diagnostic performance of current imaging options is poor. 
Conversely, the presence of a high PSA is associated with an increased risk of metastatic disease  [44], 
the presence of which precludes the option of radical salvage therapy. Herein lies the ongoing need for 
an imaging test to detect sites of recurrent disease earlier and with greater accuracy, to aid clinical 
management in patients with BCR. 
 
3.6 Fluciclovine (18F) PET/CT 
Fluciclovine (18F) is a synthetic amino acid ([18F]1-amino-3-fluorocyclobutane 1-carboxylic acid) 
developed by Shoup et al as a PET radiotracer for visualising malignant tumours  [45]. The concept of 
using radiolabeled amino acids for the imaging of cancer is based on the increased metabolic demand of 
tumour cells, with enhanced channelling of amino acids into select metabolic pathways and increased 
expression of amino acid transporters to acquire these substrates. It is thought to be taken up by PCa 
cells via the ASCT2 and LAT1 amino acid transporters, and is not metabolised upon internalisation  [46]. 
In 2007, Schuster et al first described the use of fluciclovine (18F) PET/CT in PCa in 15 patients with either 
primary disease or BCR  [47]. This yielded promising findings of accurate nodal staging and identification 
of disease sites in patients with proven recurrence. This group have gone on to expand their work in a 
single centre study, evaluating the diagnostic performance of fluciclovine (18F) PET/CT compared to that 
of 111In-capromab pendetide SPECT/CT in BCR. The latter is a radionuclide tracer licenced and established 
as standard of care for PCa imaging in the USA, but has been shown to have low sensitivities, with dismal 
detection of bone metastases  [48]. Based on their latest published results in May 2014 from a cohort of 
93 patients [49], fluciclovine (18F) PET/CT demonstrated a significantly higher accuracy, detecting more 
prostatic and extra-prostatic disease, and effectively up-staging 25.7% of cases. With specific regards to 
extra-prostatic disease (n=70), fluciclovine (18F) PET/CT detected disease in 18 more patients compared 
to 111In-capromab pendetide (22 vs 4). Fluciclovine (18F) PET/CT had 55.0% sensitivity, 96.7% specificity, 


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72.9% accuracy, 95.7% positive predictive value (PPV) and 61.7% negative predictive value (NPV) 
compared to 111In-capromab pendetide with 10.0%, 86.7%, 42.9%, 50.0% and 41.9%, respectively. 
Histological proof was obtained for majority (96.1%) of the lesions which had fluciclovine (18F) positivity. 
In the largest cohort to date of intra-individual comparison of fluciclovine (18F) to 11C-choline PET/CT, 
Nanni et al compared diagnostic performance between the two tracers in 28 patients with BCR after RP, 
in a single-centre study  [50]. In the setting of relatively low PSA levels (mean 2.9 ng/mL, range 0.2- 14.6), 
the positive detection rate was found to be higher in fluciclovine (18F) compared to 11C-choline PET/CT 
(35.7% vs 17.8%). Specifically, the detection rate was higher at PSA levels ≤ 1 ng/mL and > 2 ng/mL, and 
similar at levels between 1 – 2 ng/mL. All choline-positive lesions were also fluciclovine-positive. 
Fluciclovine (18F) PET/CT was positive in an additional 5 patients who had negative 11C-choline PET/CTs. 
The tumour-to-background ratio (TBR) of fluciclovine (18F) was greater than 11C-choline in 83.3% of 
lesions. There were also fewer false positive findings on fluciclovine (18F) PET/CT. Increased choline 
uptake by liver angiomatosis and several inflammatory inguinal lymph nodes were fluciclovine-negative. 
The same trend of higher detection rates across all PSA levels, and higher TBR in fluciclovine (18F) PET/CT  
compared to 11C-choline PET/CT in a larger cohort of 50 patients was more recently presented by the 
same group [51].  
Compared to its radiolabelled choline counterparts, fluciclovine (18F) also has a more favourable 
biodistribution. It has minimal renal excretion and associated bladder activity, and low homogeneous 
activity in the bowel  [52]. Furthermore, being an 18F labelled tracer, it is a distributable product which 
does not have to be manufactured on-site. 
With a high positive predictive value (95.7%) for extra-prostatic disease, almost entirely confirmed by 
histology, and a higher detection rate than choline, fluciclovine (18F) bears hallmarks of a competitively 
diagnostic agent in BCR. The impact of fluciclovine (18F) PET/CT on clinical management of patients with 
BCR remains to be defined, as is the PSA level associated with probability of a positive scan. 
Furthermore, the encouraging results on diagnostic performance observed at two expert centres need to 
be corroborated with larger multi-centre data, in order to formally validate its clinical utility for medical 
practice. 
 
3.7 Proposed Research 
In the setting of growing single-centre evidence of superior diagnostic performance of fluciclovine (18F) 
PET/CT in BCR, our primary aim is to assess its clinical impact on treatment decisions in a multi-centre 
study in patients with BCR being considered for radical salvage treatment (with curative intent). In 
addition, we aim to further characterise its diagnostic performance, afforded by larger numbers of 
patients from multi-centre recruitment. We also aim to assess the effect of PSA level on probability of 
lesion detection by fluciclovine (18F). 


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4. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
 
Objectives 
Outcome Measures/Endpoints  
Primary Objective 
To confirm the clinical benefit of fluciclovine (18F) 
PET/CT in affecting management decisions in 
patients with BCR being considered for radical 
salvage treatment (with curative intent). 
The record of the revised management plan post 
fluciclovine (18F) PET/CT scan in comparison to 
the pre-scan intended management plan. 
Secondary Objectives 
1. To assess possible improvement in outcome 
of radical salvage treatment based on 
fluciclovine (18F) PET/CT being included in the 
assessment. 
2. To assess the prostate specific antigen (PSA) 
threshold for positive lesion detection by 
fluciclovine (18F) PET/CT in BCR 
3. To assess the safety of fluciclovine (18F) 
injection in patients undergoing PET/CT 
4.  
1. The proportion of patients who have a 
sustained response to radical salvage 
therapy. 
2. PSA levels in relation to scan positivity will be 
analysed to determine the optimal PSA 
threshold for detecting recurrent PCa by 
fluciclovine (18F) PET/CT. 
3. Safety will be assessed from data on the 
occurrence of adverse events (AEs) and 
changes in clinical laboratory tests, vital 
signs, injection-site status, and physical 
examination findings from the time of 
administration of fluciclovine (18F) injection 
throughout the study period. 
4. . 
 
5. STUDY DESIGN 
 
5.1 Summary of Study Design 
This will be an open-labelled, multi-centred study in the UK. The study group will include up to 180 
patients with a diagnosis of BCR of previous radically treated PCa, and who are being considered for 
radical salvage therapy. Patients will have a fluciclovine (18F) PET/CT scan in addition to standard work-up 
for radical salvage therapy. The clinical utility of fluciclovine (18F) PET/CT will be assessed by recording 
changes to the recommended management plan influenced by the scan result.  
Eligible patients who have expressed interest in the study will be provided detailed information about 
the study to consider participation, and means to communicate with the study team to discuss and raise 
any queries regarding participation. If the patient would like to take part, an enrolment visit (Visit 1) will 
be organised. Written informed consent, study registration and screening (including baseline blood tests 
and electrocardiogram [ECG]) will be performed on the same visit. The visit is also a further opportunity 
to ensure all queries about the study have been addressed. 
At the baseline imaging visit (Visit 2), participants will undergo routine medical screening approximately 
1 hour prior to receiving fluciclovine (18F) injection and undergoing PET/CT imaging. Vital signs and the 


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injection site will be monitored regularly for 2 hours after administration of fluciclovine (18F). In the 
absence of AEs, patients may be discharged 2 hours after administration. Participants will receive a 
telephone consultation 24 -72rs after completion of fluciclovine (18F) PET/CT to review any AEs that have 
occurred in the interim following discharge (Telephone Visit 3). Furthermore, participants will attend a 
subsequent hospital outpatient appointment (Visit 4) after the scan to discuss their test results and 
treatment options, and undergo post-imaging blood tests and ECG, during which they will have a further 
opportunity to report any AEs. Participants will receive a second telephone consultation 1 month after 
completion of fluciclovine (18F) PET/CT to review any AEs that have occurred in the interim (Telephone 
Visit 5). Subsequent hospital visits for treatment and assessing response to treatment will be performed 
as part of routine standard of care. 
Participation in Visit 1 should take 30 minutes to 1 hour. Visit 2 will take approximately 3 hours from the 
point of commencing medical screening to being discharged. Visit 4 will take approximately 30 minutes 
and may vary depending on practice of the participant’s clinical team. Telephone consultations will take 
approximately 15 minutes. 
In patients who receive radical salvage therapy (regardless of fluciclovine (18F) PET/CT result), PSA should 
be assessed a maximum of 31 days before therapy and at least once between 7-8 months after 
treatment completion. Where possible, this should be arranged to coincide with treatment-associated 
hospital visits as per standard of care. If these cannot be incorporated into the hospital visits, a minimum 
of one, maximum of two extra visits will be required for these PSA tests. 


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5.2 Summary Flow Chart of Study Design 
   


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6. PARTICIPANT IDENTIFICATION 
6.1. Study Participants 
 
Participants with a diagnosis of BCR of previous radically treated PCa, aged ≥18 years old, being 
considered for radical salvage therapy (with curative intent). 
6.2. Inclusion Criteria  
 
(1) The subject is a male ≥18 years old. 
(2) The subject has had an original diagnosis of PCa and underwent radical curative therapy at least 
3 months before enrolment, and has been diagnosed with BCR on the basis of: 
a. Post RRT / brachytherapy: Increase in PSA level ≥2.0 ng/mL above the nadir level after 
radiotherapy (RT) or brachytherapy (ASTRO-Phoenix criteria)  [53], or 
b. Post RP: EITHER two consecutive rises in PSA and final PSA >0.1ng/ml OR three 
consecutive rises in PSA. This definition is also applicable to subjects with PSA 
persistence post RP (where the PSA fails to fall to undetectable levels). 
i. In addition, the subject post RP, should have a PSA doubling time of ≤15 months 
OR PSA level ≥1.0 ng/mL at time of recruitment. The PSA doubling time will be 
calculated using the Memorial Sloan Kettering Cancer Center nomogram 
(http://www.mskcc.org/nomograms/prostate/psa-doubling-time), based on a 
minimum of two PSA levels within 12 months of screening, taken after the last 
recorded nadir PSA available at time of screening. 
(3) The subject has not had previous recurrences of PCa, i.e. this is the first diagnosis of BCR. 
(4) The subject is being considered for radical salvage therapy. 
(5) The subject is able and willing to comply with study procedures, and signed, dated and timed 
informed consent is obtained before any study-related procedure is performed. 
(6) The subject’s Eastern Cooperative Oncology Group [ECOG] performance status 0-2. 
(7) The subject should not have received androgen-deprivation therapy within 3 months of 
screening. 
(8) The subject has a normal or clinically acceptable medical history and vital signs findings at 
screening (up to 14 days before administration of study drug). 
 


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6.3. Exclusion Criteria 
 
(1) The subject has been previously included in this study. 
(2) The subject has received, or is scheduled to receive, another investigational medicinal product 
(IMP) from 1 month before to 1 week after administration of fluciclovine (18F) injection. 
(3) The subject has known hypersensitivity to fluciclovine (18F) injection or any of its constituents. 
(4) The subject has had a choline PET/CT scan within 3 months of the screening visit. 
(5) The subject has bilateral hip prostheses. 
 
7. STUDY PROCEDURES 
7.1. Recruitment 
 
The trial will be advertised in the clinical centres participating in the study using REC approved 
advertising materials explaining the study and providing contact information for the local study team. In 
addition, potential participants will be identified from their local urology MDT meeting and during 
outpatient oncology or urology appointments. They will be approached by a member of their clinical 
team within the hospital setting and be informed of the trial, or be sent information, the patient 
information sheet (PIS) by post. The PIS will also provide contact details for the study team should the 
potential participant wish to initiate contact. 
If a patient expresses an interest in the study to their clinical team within the hospital setting, they will 
be given a PIS and will be asked to give their permission to be contacted by the study team. If this 
permission is given, the referring clinical team member will complete a referral form to the study team 
with the patient’s contact details.  
Upon establishing contact with the study team to indicate interest in the study, a concise explanation of 
the study will be provided to the patient (as detailed in section 7.2). Patients will be encouraged to raise 
any queries they have about the study to aid their decision regarding participation. They will be allowed 
as much time as wished to consider the information, and the opportunity to question the Investigator, 
their GP or other independent parties to decide whether they will participate in the study. This may 
involve more than one contact with the study team. When the patient has decided to participate in the 
study, an enrolment visit (Visit 1) will be arranged. Enrolment will involve checking that the patient is 
eligible for the study, completion of informed consent, study registration and screening. The patient’s 
hospital notes will be made available for screening purposes. The visit is also a further opportunity to 
ensure all queries about the study have been addressed. 


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7.2. Informed Consent 
 
The participant must personally sign and date the REC approved version of the Informed Consent form 
before any study specific procedures are performed. If an amendment is made to the informed consent 
document during the study, patients still being followed up in the study will be informed of the changes 
made to the document and will be asked to consent to continued participation in the trial. 
Written and verbal versions of the Participant Information and Informed Consent will be presented to 
the participants detailing no less than: the exact nature of the study; what it will involve for the 
participant; the implications and constraints of the protocol; the known side effects and any risks 
involved in taking part. It will be clearly stated that the participant is free to withdraw from the study at 
any time for any reason without prejudice to future care, and with no obligation to give the reason for 
withdrawal. 
The participant will be allowed as much time as wished to consider the information, and the opportunity 
to question the Investigator, their GP or other independent parties to decide whether they will 
participate in the study. Written Informed Consent will then be obtained by means of participant dated 
signature and dated signature of the person who presented and obtained the Informed Consent. The 
person who obtained the consent must be suitably qualified and experienced, trained in GCP and 
informed consent procedures, and have been authorised to do so by the Chief/Principal Investigator. A 
copy of the signed Informed Consent will be given to the participant. The original signed form will be 
retained at the study site. 
7.3. Screening and Eligibility Assessment 
 
Prior to registration or any study measures being undertaken, eligibility will be checked as detailed in 
section 7.1 and documented informed consent will be completed as detailed in section 7.2.  
All participants will undergo clinical assessment including medical history and baseline study measures 
(section 7.5) over Visits 1-2 as outlined below and in Appendix A (Schedule of Study Procedures): - 
 
7.4. Randomisation, blinding and code-breaking 
 
All participants will receive fluciclovine (18F) injection. 


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7.5. Baseline Assessments 
 
Visit 1 (after successful screening and patient informed consent obtained) 
Demographics 
The participant’s age will be recorded.  
Medical History 
This forms part of the participant’s routine clinical care, consisting of significant past medical history and 
drug history including known drug allergies.  
PSA level 
The dates and levels of the participant’s PSA from the date of radical therapy will be recorded. These 
values will be obtained from the participant’s hospital records. A repeat PSA level will be measured at 
time of screening at the same time as the clinical laboratory tests are taken.  
PCa treatment history 
Specific details on the treatment history for PCa will be recorded. This will include the date of initial PCa 
diagnosis, initial tumour stage and Gleason score, dates of radical treatment and adjuvant treatment (if 
given), date of BCR diagnosis. This information will be obtained from the participant’s hospital records. 
Imaging history 
The nature, date and outcome of imaging examinations performed up to 3 months before screening will 
be recorded. This information will be obtained from the participant’s hospital records.  
Intended management plan 
The management plan, based on pre-existing clinical information including results of conventional 
imaging, will be recorded. This information will be obtained from the participant’s hospital records or 
MDT records. 
ECG 
An ECG will be performed. 
Vital Signs 
Sitting blood pressure and heart rate will be recorded. 
Urine  
Patients will be asked to provide a mid-stream specimen of urine to be tested with urine dipstick 
(leucocytes, nitrites, pH, protein, ketones, glucose, bilirubin, blood, urobilinogen). If the sample is 
positive for leucocytes or nitrites, the sample should be sent for urine microscopy and culture and if the 


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patient has symptoms of a urinary tract infection, this should be treated according to local guidelines 
prior to PET/CT. Fluciclovine (18F) PET/CT can be performed during such treatment. 
Clinical laboratory tests 
Blood samples for clinical laboratory tests will be taken and sent for analysis at the local hospital. This 
will consist of haematology (red blood cell count, haemoglobin, white blood cell count with automated 
differential count, platelet count and haematocrit), biochemistry (electrolytes (sodium, potassium, 
calcium, chloride), urea, creatinine, total bilirubin alkaline phosphatase (AP), aspartate aminotransferase 
(AST), alanine transaminase (ALT), creatine kinase (CK), lactate dehydrogenase (LDH), albumin, total 
protein).  
 
Visit 2 (day of Fluciclovine (18F) PET/CT) 
Vital signs 
The sitting blood pressure and resting heart rate of the participant will be recorded.  
Height and weight 
The participant’s height and weight will be measured. 
Post-screening pre-administration events 
A review of the participant’s medical history will be performed to check for new health-related events 
and changes to concomitant medications since the screening visit.  
7.6. Fluciclovine (18F) PET/CT 
 
The PET/CT will be acquired on the highest quality scanner available in the participating institution. The 
participant will be required to fast for at least 4 hours prior to the scan, drinking only sips of water within 
4 hours of the scan if needed for administration of medications, and not exercise from the day before the 
scan through to the time of the scan. The participant will be cannulated, preferably in the right arm, and 
receive one dose of fluciclovine (18F) diluted up to 10 mL injected by intravenous push (5-10 seconds) via 
the cannula with arms down followed by ≥ 10mL flush   [54].  The participant will be scanned in the 
supine position in the direction of mid-thigh to skull base, with the arms positioned overhead following 
the dose and flush. The uptake time should be 3 to 5 minutes with a goal of 4 minutes from the end of 
the dose. For the PET acquisition, participants will be imaged for approximately 25 minutes. For the CT 
parameters, a high-quality unenhanced CT will be employed. Further details on the PET/CT acquisition 
will be given in the Study Imaging Manual. 
Vital signs, examination of the injection site and review of AE/SAEs will be performed immediately post 
scan and at 60(±5) minutes, 90(±5)  minutes and 120(±5)  minutes post-injection. All images obtained 
during the trial will be retained for use in this research and may be used for future approved research 
studies. 


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Analysis 
Image interpretation will be based on guidelines derived from an international fluciclovine (18F) reader 
consensus meeting held in June 2014 [54]. All readers will undergo training in interpretation of 
fluciclovine (18F) scans, and will have a training set available for reference.  
Primary evaluation and reporting of the PET/CT scan will be site-based (as per standard of care). The 
clinical team should make the revised treatment decision on the site-based report.  
The fluciclovine (18F) PET/CT scan will be centrally reported at the end of the study, blinded to the 
original report. Copies of the fluciclovine (18F) PET/CT will be transferred from the host site for this 
purpose. Copies of the original report will also be transferred, as this data will be used to determine 
inter-reader agreement. 
Prospective central review of scans will also be permitted where a second opinion is sought by a reader 
prior to issuing the report. This can be arranged ad hoc by contacting the co-ordinating investigator, 
sponsor or chief investigator. 
7.7. Subsequent Visits 
 
At each subsequent visit for the first 4 weeks following fluciclovine (18F) PET/CT, study patients will be 
asked whether they have had any:  
• 
Hospitalisations 
• 
Consultations with other medical practitioners 
• 
Disability or incapacity or other adverse event that has occurred since their last visit 
24 (+ 4)-72 hours after fluciclovine (18F) PET/CT (Telephone Visit 3) 
A review of AE/SAEs will be performed via telephone consultation. 
Outpatient appointment to review fluciclovine (18F) PET/CT and revise management (Visit 4) 
It is recommended that this outpatient appointment is scheduled approximately 2 weeks after the 
fluciclovine (18F) PET/CT scan (Visit 2), although a window of 0-6 weeks is permitted depending on local 
clinical practice. The clinical team will then record whether the pre-scan management plan will be 
unchanged or altered based on the new information provided by the fluciclovine (18F) PET/CT, and the 
reason for the decision. It is recognised that the revised management plan may be decided on before the 
outpatient appointment and this is permitted.  
Examples of a change in proposed management plan include changing of treatment types and/or 
approaches (including change to radiotherapy plans), and recruitment into another clinical trial. The 
patient may enter another clinical trial as part of the management plan influenced by the PET/CT 
findings. Where an additional diagnostic procedure (e.g. imaging or biopsy) is performed in light of the 
PET/CT findings, the results of these should be considered prior to recording the revised management 


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plan, and this should be recorded on the CRF. The exception to this is where choline PET is performed in 
addition to fluciclovine (18F) PET/CT (see section 7.7). 
The revised management plan will be discussed between the clinical team and participant, and the 
agreed management decision recorded. If the revised management plan and agreed management 
decision are different, the reason for the decision, including the influence of other standard of care 
assessments performed outside the trial protocol, will be documented.  
The participant will also have an opportunity to report any AEs. A repeat set of clinical laboratory tests, 
urine dipstick analysis and ECG will also be performed during Visit 4 as part of a review for AEs. 
1 month (+7 days) after fluciclovine (18F) PET/CT (Telephone Visit 5) 
A review of AE/SAEs will be performed via telephone consultation. 
First day of new management plan (Visit 6) 
This will be performed as per standard of care and may be the same date as Visit 4, if the new 
management plan is commenced on the same day as the agreed treatment decision. During this visit, the 
investigator will record the date of management starting (to determine when follow-up information 
should be collected as detailed in the next heading “Clinical follow-up”).  
Where patients are commencing radical salvage therapy, the investigator will also ensure that a pre-
treatment PSA has been measured and recorded up to 31 days before this date. 
All patients who receive radical salvage therapy 
In this patient group, PSA will be measured a maximum of 31 days before therapy and at least once 
between 7-8 months after treatment completion. Where possible, this should be arranged to coincide 
with treatment-associated hospital visits as per standard of care. If these cannot be incorporated into 
the hospital visits, a minimum of one, maximum of two extra visits will be required for these PSA tests.  
If the actual treatment received by the subject differs to the plan agreed at Visit 4, then this will be 
recorded on the “End of study” CRF (see the next section “Clinical follow-up”), along with the reason.  
Clinical follow-up 
Following instigation of their management plan, patients will be seen for follow-up at intervals as per 
standard of care and have imaging tests as clinically appropriate and per standard of care. 
At the end of specified follow-up windows, follow-up information will be obtained by the local study 
team via attendance for imaging tests and via the GP or hospital medical care team as appropriate and 
entered on the “End of study” CRF. The patient will not be required to make a dedicated visit for this.  
The follow-up window is dependent on the type of management: 
1. Radical salvage therapy: Up to the date of post-treatment PSA level check  (7-8 months after 
completion of treatment). 
2. Non-salvage management: Up to 6 months after Visit 6 (instigation of management plan).  


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In the event where radical salvage therapy is stopped prematurely or deemed by the clinical team to be 
sub-optimally delivered, the follow-up window should apply as for non-salvage management (up to 6 
months from instigation of the initial management plan). The reasons for this should be recorded on the 
CRF as described in the prior section “All patients who receive radical salvage therapy”. 
The following information will be collected for all patients: 
1. Copies of imaging tests and reports, and histopathological reports for relevant endpoint analyses 
2. PSA levels 
3. Mortality (if applicable) 
a. Date of death 
b. Causes of death 
c. Other significant conditions contributing to death 
d. Source of report 
e. Whether the death was expected 
f. Whether a causal relationship to the study IMP is suspected 
g. Name of the investigator responsible for assessing expectedness and causality (if the 
patient died prior to the last research scan or as a result of an ongoing reportable AE) 
 
In addition, the following information on effect of management will be collected:  
Radical salvage therapy 
Non-salvage management 
Effect of radical salvage therapy: 
a. Treatment response 
I. 
≥50% decline in PSA  [5] ± 
II. 
Radiological response 
b. Treatment failure 
I. 
Increase or <50% decline in PSA ± 
II. 
Radiological progression 
 
Effect of management as assessed by the clinical 
team: 
a. Response  
I. 
≥50% decline in PSA ± 
II. 
Radiological response 
b. Stable 
c. Progressed 
I. 
PSA progression and/or 
II. 
Radiological progression 
d. Not assessed 
 
 
7.8. Procedure for centres which perform choline PET as standard of care 


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In these participating centres, where the clinical team decides to investigate the subject with choline PET 
in addition to fluciclovine (18F) PET/CT, this will be performed only after the fluciclovine (18F) PET/CT 
report has been issued by the site, considered to formulate a revised management plan, and 
documented onto the appropriate CRF. 
7.9. Discontinuation/Withdrawal of Participants from Study 
Each participant has the right to withdraw from the study at any time.  In addition, the Investigator may 
discontinue a participant from the study at any time if the Investigator considers it necessary for any 
reason including: 
• 
Ineligibility (either arising during the study or retrospectively having been overlooked at 
screening) 
• 
Significant protocol deviation 
• 
Significant non-compliance with study requirements 
• 
Withdrawal of consent 
• 
Loss to follow up 
Withdrawal from the study will not result in exclusion of the data for that participant from analysis 
provided all baseline study measures have been completed. 
The reason for withdrawal will be recorded in the CRF. If the participant is withdrawn due to an AE/SAE, 
the Investigator will arrange for follow-up visits or telephone calls until the AE/SAE has resolved or 
stabilised. 
7.10. 
Definition of End of Study 
 
The fluciclovine (18F) injection administration will be followed by a follow-up period which will continue 
for 6 months after instigation of management plan.  
The end of the trial for an individual patient is defined as 6 months after instigation of their management 
plan. In patients who receive radical salvage therapy, the end of the trial is defined as the date of post-
treatment PSA level. 
The end of the study is defined as the date of database lock for data analysis, which is anticipated to 
occur within 12 weeks after the last patient has completed the 6 months post treatment follow up. 


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8. Risks and Benefits to Trial Participants 
8.1. Benefits 
 
The research scans may provide further clinical information regarding the patient’s disease status that 
may not have been appreciated by other standard of care tests. If such information arises, this will be 
reported back to the responsible clinician to help direct the patient’s further management. This may 
provide a direct benefit to the subject 
8.2. Risks 
 
The risks from the imaging studies to subjects mainly relate to the intravenous injection and the 
radiation emitted by the radiopharmaceutical.  Intravenous injection carries a small risk of infection and 
haematoma.  
Assuming an average annual background radiation exposure of 2.6mSv [ARSAC 2006], the radiation 
exposure from an individual administration of fluciclovine (18F) Injection would be equivalent to 3.2 years 
of background radiation, and the associated CT transmission scans would be equivalent to about 2.7 
years of background radiation. 
The above estimations are based on a mean effective dose per unit administered activity of 
22.1µSv/MBq [55]. An administered activity of 370 MBq will result in an effective dose of 8.2mSv. A 
maximum effective dose of 7 mSv would be expected due to the CT transmission scan depending on the 
scanner (details of scanner-specific CT effective doses will be given in the Study Imaging Manual).  The 
effective dose due to the helical CT acquisition will be in accordance with ALARA (As Low As Reasonably 
Achievable).  
The total dose of 15.2mSv would be equivalent to 5.8 years of background radiation. This level of 
radiation exposure is in line with other common nuclear medicine procedures. 
9. Intervention 
9.1. Investigational Medicinal Product 
 
The IMP is fluciclovine (18F) injection and consists of the radiolabelled compound fluciclovine (18F) 
together with excipients. Fluciclovine (18F) is a radiolabelled synthetic amino acid. The radioactive isotope 
18F decays with a half-life of approximately 110 minutes.  
Chemical formula 
C5H818FNO2 
Chemical structure 


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Chemical name 
(anti)-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid. 
Physiological effects 
Biodistribution and radiation dosimetry studies have demonstrated physiological uptake of fluciclovine 
(18F) to be highest in the liver and pancreas, with rapid biological clearance [56]. There is low albeit 
prolonged uptake in skeletal muscle and bone marrow, with clearance dominated by the tracer half-life 
[56]. A 370-MBq injection of fluciclovine (18F) results in an effective dose of 8.2 mSv. 
Side effects 
To date, fluciclovine (18F) has been found to be well-tolerated, with all treatment emergent AEs reported 
during clinical studies in humans to be mild in intensity, none requiring treatment [57]. AEs reported that 
were considered possibly related to receipt of fluciclovine (18F) include injection site reactions (redness, 
pain, bruising), dysgeusia and headache [57].  
Safety considerations 
All participants will be carefully observed and monitored throughout the study. A panel of blood tests 
comprising of serum biochemistry and haematology, and an electrocardiogram (ECG), will be performed 
during screening and at outpatient follow-up after the PET/CT scan.  
On the day of scan, there will be a minimum number of two people in attendance.  This will include a 
doctor or allied health care professional such as a nurse or radiographer, who is solely responsible for 
patient monitoring, safety and well-being.  They will be aware of potential risks of fluciclovine (18F) 
injection, and appropriately trained in how to respond to any adverse sequelae arising.  The second 
person in attendance will be a technician/ radiologist responsible for acquiring images.  In the event of 
any untoward medical event occurring mid-scan, staff can reach the patient immediately. As in all clinical 
areas throughout the participating institutions, emergency drugs and equipment are readily available 
and staff are trained in their use.  This includes supplementary oxygen and resuscitation equipment.  
Visual monitoring of the injection site and monitoring of blood pressure and heart rate will be 
undertaken at intervals for up to 2 hours after injection prior to discharge. After the scan, the 
participants will be allowed to leave the PET/CT department but remain within the host site in between 
the monitoring intervals. Participants will receive a telephone consultation 24 -72 hours after completion 
of fluciclovine (18F) PET/CT to review any AEs that have occurred in the interim following discharge. 
Furthermore, participants will have further opportunity to report any AEs during their outpatient follow-
up appointment 14 days later and at a telephone call 1 month post scan. 
Participants will be recommended not to have close contact with pregnant women or young children for 
6 hours after the injection, and to drink plenty of fluids for at least 5 days after the scan to aid urinary 


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clearance of the tracer. These guidelines are considered as the standard of care following injection of 
other 18F labelled tracers. 
IMP preparation 
The sponsor will provide fluciclovine (18F) injection as a sterile solution for injection. The fluciclovine (18F) 
injection will be manufactured to Good Manufacturing Practice (GMP) at a qualified facility. 
Before approval of the batch by the Qualified Person, the suitability of each preparation will be assessed 
by tests including radioactivity, HPLC, and pH quality control methods, against the drug product 
specification according to approved standard operating procedures (SOPs) of the GMP manufacturing 
site. 
Supply and packaging 
Sites will be provided with instructions for ordering the fluciclovine (18F) injection for use in the study. 
The site must keep records of all shipments of IMP received, dispensing and disposal/destruction 
performed on site. The IMP will be delivered to the site by courier from the manufacturing facility as is 
appropriate to each facility. Information will be provided on each shielded container giving the batch 
number, radioactive concentration of injection (MBq/mL) at a stated time and date, and shelf life 
information. To ensure timely delivery, product may be dispatched from the manufacturing site before it 
has been approved for use by the Qualified Person. A written agreement will be required between the 
investigation site and the manufacturing site in which the investigation site undertakes not to administer 
the drug product until it has received written confirmation from the manufacturing site that the batch 
has been approved by the Qualified Person. Such confirmation will be provided, for example, by fax or e-
mail.  
The IMP is supplied as a solution for injection, 200 MBq/ml at the reference date and time in a vial from 
the GMP-validated manufacturing facility. Each vial is supplied in a container providing appropriate 
radiation shielding. The subject dose will be drawn just before administration. The radiochemical purity 
of fluciclovine (18F) injection is not less than 95% during the shelf life of the product. 
Stability and storage 
The in-use shelf life of fluciclovine (18F) injection is 10 hours from the end of synthesis and must not be 
used beyond this limit. The expiry date and time is included on the product label. Fluciclovine (18F) 
injection must be kept in a locked, restricted access area when not in use. Fluciclovine (18F) injection 
should be stored at room temperature in a shielded container and in accordance with national 
regulations for radioactive materials. The precautions normally taken when handling radioactive 
materials should be observed. All non-radioactive IMP shielded containers must be returned to the 
sponsor/manufacturing site. Vials that are radioactive, or contained radioactive products must be 
destroyed at the PET centre after the study and after overall drug accountability have been completed by 
the sponsor or its representative. A list of IMP doses and other materials that were returned, or 
destroyed, must be prepared and signed by the principal investigator. An overall accountability form of 
the IMP will be prepared and supplied by the sponsor and completed properly. An explanation for any 
discrepancy must be provided. 


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Waste must be disposed of according to national regulations for radioactive material. The shielded 
container and transport case that the product is delivered in are the property of the manufacturing site. 
After use of the product, they must be stored securely and made available for collection on the 
reasonable notice of BED or the manufacturer. 
IMP administration 
Each individual drawn subject dose will only be administered to the subject assigned to it. No patient is 
to receive more than 5ml of the undiluted product. 
Since the drug product vial could contain more radioactivity than is required for a 1-subject dose at the 
time of administration, the correct volume needs to be calculated before administration. The volume to 
be withdrawn and injected must be calculated from the required dose, the radioactive concentration and 
the reference date and time, and documented (must not exceed 5ml). After the dose has been given, 
subsequent doses may be withdrawn for additional subjects. When the study site receives the dose in a 
vial and prior to administration, the activity in the vial containing the IMP will be measured in a dose 
calibrator. The required dose will then be drawn into a syringe, with the activity confirmed using the 
same dose calibrator. Post injection, remaining activity within the syringe would be measured and the 
difference of pre- and post-injection syringe activities, accounting for physical decay, would be used to 
calculate the actual activity administered into the cannula. Appropriate dose calibrator scale factors for 
18F (as per manufacturer’s specifications) should be applied to ensure accuracy of all activity 
measurements and be documented. Aseptic conditions must be observed during withdrawal of a dose 
from the vial, including microbial decontamination of the rubber stopper with a suitable disinfectant 
before removal of a dose.  
Prior to PET/CT, 370 ± 20% MBq of fluciclovine (18F) (not more than 5ml of product) diluted up to 10 ml 
with saline (sodium chloride IV infusion 0.9% w/v) will be administered. The administration will be by 
intravenous push (5-10 seconds) followed by a 10 ml saline flush. Fluciclovine (18F) will be injected 
through a cannula (or indwelling catheter) with the subject lying in a supine position and in an 
antecubital vein or another vein that will provide access. The administration site will be evaluated pre- 
and post administration for any reaction (e.g. bleeding, haematoma, redness, or infection). 
Documentation of the IMP administered to a subject will be recorded according to standard of care and 
on the appropriate CRF, including date, vial number, total volume, total radioactivity, start/stop time of 
administration, and injection site. 
Compliance with trial treatment 
Participants will receive the fluciclovine (18F) injection under direct supervision of study personnel. Each 
administration volume and total radioactivity injected will be checked. The label on the IMP container 
will include the batch number, expiry date/time activity in MBq, reference date/time, and volume. The 
batch number and volume per administration will be recorded in each subject’s CRF/source document. 
Concomitant medication 
In general, concomitant medications and therapies deemed necessary for the supportive care and safety 
of the subject are allowed, provided their use is documented in the participant’s records and on the 
appropriate CRF. Participants should be maintained on the same medications throughout the study 
period, if medically feasible. 


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10. SAFETY REPORTING  
10.1. 
Definitions 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a medicinal 
product has been administered, including occurrences which are not 
necessarily caused by or related to that product. 
Adverse Reaction (AR) 
 
An untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose 
administered to that participant. 
The phrase "response to an investigational medicinal product" means 
that a causal relationship between a trial medication and an AE is at 
least a reasonable possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified professional 
or the Sponsor as having a reasonable suspected causal relationship to 
the trial medication qualify as adverse reactions. 
Serious Adverse Event 
(SAE) 
A serious adverse event is any untoward medical occurrence that: 
• 
results in death 
• 
is life-threatening 
• 
requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
• 
results in persistent or significant disability/incapacity 
• 
consists of a congenital anomaly or birth defect. 
Other ‘important medical events’ may also be considered serious if 
they jeopardise the participant or require an intervention to prevent 
one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
Serious Adverse Reaction 
(SAR) 
An adverse event that is both serious and, in the opinion of the 
reporting Investigator, believed with reasonable probability to be due 
to one of the trial treatments, based on the information provided. 
Suspected Unexpected 
A serious adverse reaction, the nature and severity of which is not 


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Serious Adverse Reaction 
(SUSAR) 
consistent with the information about the medicinal product in 
question set out: 
• 
in the case of a product with a marketing authorisation, in the 
summary of product characteristics (SmPC) for that product 
• 
in the case of any other investigational medicinal product, in 
the investigator’s brochure (IB) relating to the trial in question. 
 
NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and “severe”, 
the following note of clarification is provided: “Severe” is often used to describe intensity of a specific 
event, which may be of relatively minor medical significance. “Seriousness” is the regulatory definition 
supplied above. 
10.2. 
Clinical laboratory abnormalities and other abnormal assessments as AEs and 
SAEs 
 
Abnormal laboratory findings or other abnormal assessments (e.g. injection site) that are judged by the 
investigator as clinically significant will be recorded as AEs or SAEs if they meet the definitions given 
above. By definition, all CTCAE v4.0 Grade 3 and or 4 laboratory abnormalities should be reported as 
SAEs (unless specified otherwise below). 
Clinically significant abnormal laboratory findings or other abnormal assessments that are detected 
during the study or are present at baseline and significantly worsen following the start of the study will 
be reported as AEs or SAEs.  However, clinically significant abnormal laboratory findings or other 
abnormal assessments that are associated with the disease being studied, unless judged by the 
investigator as more severe than expected for the patient’s condition, or that are present or detected at 
the start of the study and do not worsen, will not be reported as AEs or SAEs.  The investigator will 
exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding 
or other abnormal assessment is clinically significant. 
Incidental synchronous cancers findings noted on fluciclovine (18F) PET/CT images will be reported as 
medical events, and qualify for reporting as AEs due to their temporal relationship to fluciclovine (18F) 
administration. 
 


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10.3. 
Causality 
 
The relationship of each adverse event to the trial medication must be determined by a medically 
qualified individual according to the following definitions: 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected 
response pattern to the suspected drug; that is confirmed by stopping or reducing 
the dosage of the drug; and that is not explained by any other reasonable 
hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to the suspected drug; 
that is confirmed by stopping or reducing the dosage of the drug; and that is 
unlikely to be explained by the known characteristics of the subject’s clinical state 
or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the 
drug; that follows a known or expected response pattern to that suspected drug; 
but that could readily have been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship to the study 
drug. 
 
10.4. 
Procedures for Recording Adverse Events 
 
All AEs observed by the investigator or reported by the patient up to 1 month after fluciclovine (18F) 
PET/CT are reported on the case report forms. A member of the research team will contact the 
participant by telephone 24 -72 hours and 1 month after completion of fluciclovine (18F) PET/CT to record 
any AEs that may have occurred after leaving the hospital. Patients will also attend a clinic visit 14 days 
post scan. All AEs reported by the patient will be clearly documented on the patient CRFs. The following 
information will be recorded: description, date of onset and end date, severity, investigator assessment 
of relatedness to fluciclovine (18F) injection, other suspect drug or device and action taken.  Follow-up 
information should be provided as necessary. 
AE severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 
(June 14, 2010) will be used to assess and grade event severity, including laboratory abnormalities 
judged to be clinically significant. The severity grading is provided below (Table 1).   


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Table 1.  CTCAE (V4.03) AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; 
limiting age-appropriate instrumental ADL.* 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation of hospitalization indicated; disabling; 
limiting self care ADL**. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
** Self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.   
If the experience is not covered in the modified criteria, the guidelines shown in Table 2 below will be 
used to grade severity.  It should be pointed out that the term “severe” is a measure of intensity and that 
a severe event is not necessarily serious. 
Table 2.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the 
sign or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
Death (5) 
Death related to AE 
 


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AEs considered related to fluciclovine (18F) injection as judged by a medically qualified investigator or the 
Sponsor will be followed either until resolution, or the event is considered stable. 
It will be left to the investigator’s clinical judgment whether or not an AE/ AR is of sufficient severity to 
require the patient’s removal from PET/CT scanning.  A participant may also voluntarily withdraw from 
study procedures if they tolerate it poorly.  Further details of withdrawal are presented in Section 7.7.   
In the event of symptoms arising, participants will be given appropriate care and medical supervision 
until symptoms resolve, or the condition becomes stable.  Every effort will be made to gather outcome 
data on patients through study follow-up, or general practitioner/ hospital staff unless the participant 
has specifically withdrawn consent to such efforts. 
10.5. 
Reporting Procedures for Serious Adverse Events 
 
All SAEs following fluciclovine (18F) PET/CT must be reported on the SAE reporting form within 24 hours 
of the Site Study Team becoming aware of the event. All SAE information must be recorded on an SAE 
form and faxed, or scanned and emailed to:  
Blue Earth Diagnostics SAE E mail: Drugsafety@pharsafer.com 
Tel: +44 (0) 1483 212155 
Fax: +44 (0) 1483 212178 
Additional and further requested information (follow-up or corrections to the original case) will be 
detailed on a new SAE Report Form and faxed/emailed to the same address. 
10.6. 
SUSAR Reporting 
 
Blue Earth Diagnostics will be responsible for reporting of all SUSARs to the relevant Competent 
Authority (MHRA in the UK) and to the REC and other parties as applicable. For fatal and life-threatening 
SUSARS, this will be done no later than 7 calendar days after the Sponsor or delegate is first aware of the 
reaction. Any additional relevant information will be reported within 8 calendar days of the initial report. 
All other SUSARs will be reported within 15 calendar days. 
Principal Investigators will be informed of all SUSARs for the relevant IMP for all studies with the same 
Sponsor, whether or not the event occurred in the current study. 
10.7. 
Safety Monitoring Committee 
 
The Sponsor will conduct a review of all SAEs for the trial reported during the quarter and cumulatively. 
The aims of this committee include: 
• 
To pick up any trends, such as increases in un/expected events, and take appropriate action 


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• 
To seek additional advice or information from investigators where required 
• 
To evaluate the risk of the trial continuing and take appropriate action where necessary 
10.8. 
Development Safety Update Reports (DSURs) 
 
In addition to the expedited reporting above Blue Earth Diagnostics will submit DSURs once a year 
throughout the clinical trial, or on request, to the Competent Authority (MHRA in the UK), to the Chief 
Investigator and to the Co-Investigator at each site. The CI is responsible for submitting these to the 
Ethics Committee and the Host NHS Trust. 
 
11. STATISTICS AND ANALYSIS 
Prior to the conduct of the planned interim analysis, a detailed Statistical Analysis Plan (SAP) will be 
written describing all analyses that will be performed for both the interim analysis and the final analysis 
of all study data.  
11.1. 
Sample size 
 
For the primary objective of treatment change evaluation, a minimum of 171 patients with complete 
primary endpoint data will be required to allow for a width of +/-6% in a two-sided 95% C.I. This is based 
on the conservative assumption that 20% of patients will have a treatment change, as fluciclovine (18F) 
PET/CT has been shown to upstage 25.7% of patients with recurrent prostate cancer [49], and also based 
on the management change studies reported on choline PET/CT (section 3). The aim is to recruit 180 
patients for this trial, based on an anticipated primary endpoint drop-out rate of 5%.  
11.2. 
Analysis of Outcome Measures/Endpoints 
 
Evaluable patients are those that have had all baseline study measures recorded, including having had a 
fluciclovine (18F) PET/CT scan.  
Evaluation of fluciclovine (18F) PET/CT 
Evaluation of the fluciclovine (18F) PET/CT images will be primarily reviewed by site-based investigator(s) 
(as per standard of care). Image interpretation will be based on guidelines derived from an international 
fluciclovine (18F) reader consensus meeting held in June 2014. All readers will undergo training in 
interpretation of fluciclovine (18F) scans, and will have a training set available for reference. The 
investigators will have access to all the conventional imaging and medical record information. 
The summary of findings will be documented on the appropriate CRF, in addition to a conventional 
imaging report issued as per standard of care in the respective institution. 


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Primary endpoint 
The primary endpoint of clinical impact of fluciclovine (18F) in affecting treatment decisions will be 
assessed by record of the revised treatment plan post fluciclovine (18F) PET/CT scan in comparison to the 
pre-scan intended treatment plan.  
 
Secondary endpoints 
Improvement in outcome of radical salvage treatment based on fluciclovine (18F) PET/CT being included 
in the assessment. 
This will be assessed as the proportion of these patients who have a treatment response or treatment 
failure, using the following definitions: 
1. Treatment response  
a. ≥50% decline in PSA  [5] ± 
b. Radiological response 
2. Treatment failure 
a. Increase or <50% decline in PSA ± 
b. Radiological progression 
 
PSA threshold 
The positive detection rate will be calculated for the overall cohort and across a range of PSA values, to 
determine the optimum PSA threshold for lesion detection. 
Safety assessment 
Safety will be assessed from data on the occurrence of adverse events (AEs) and changes in clinical 
laboratory tests, vital signs, injection-site status, and physical examination findings from the time of 
administration of fluciclovine (18F) injection throughout the study period. This has been described in 
detail in Section 9. 
11.3. 
Interim Analysis 
 
A single interim analysis of the primary endpoint was performed in the first 85 evaluable patients. The 
number of treatment changes was greater than 45 (52.9%, with a 97.5% two-sided C.I. of 40.3%-62.3%, 
so the lower limit is over 40%), the trial recruitment was terminated early due to overwhelming 
effectiveness. If the number of treatment changes would have been 8 or fewer (9.4%, with a 97.5% two-
sided C.I. of 3.6%-18.9%, so the upper limit in this population would have been below the 20% of the null 
hypothesis), the trial would have been terminated early due to futility. 
 


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12. DATA MANAGEMENT 
12.1. 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor or host institution for 
monitoring and/or audit of the study to ensure compliance with regulations. 
12.2. 
Data Recording and Record Keeping 
 
Database considerations 
Data collection will be done using a web-based eCRF and Data management will be managed by a 
contracted Clinical Research Organisation. The Chief Investigator will act as Data Custodian for the trial. 
Case report forms 
Data collected on each subject will be recorded by the research team as accurately and completely as 
possible.  The Investigator will be responsible for the timeliness, completeness, legibility and accuracy of 
the CRFs.  Each patient enrolled into the study must have the correct CRFs completed and signed by the 
Principal Investigator (or designee). This also applies to those patients who have been withdrawn early. 
Please ensure that all data submitted on CRFs are verifiable in the source documentation or the 
discrepancies explained. 
Records retention and archiving 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate 
records to enable the conduct of a clinical trial and the quality of the research data to be evaluated and 
verified.  These essential documents (as detailed in Section 8 of the ICH GCP Guidelines) must be stored 
in such a way that ensures that they are readily available, upon request for the minimum period required 
by national legislation or for longer if needed.  The medical files of trial subjects shall be retained in 
accordance with national legislation and in accordance with the host institution policy.  Data entered 
onto the eCRFs will be returned to the sites in CD format and must be checked for accuracy and then 
held with the study files. Data will be retained on site for a minimum of 5 years. Retention and storage of 
scanning records for clinical scans must also follow these guidelines. 
Imaging data for central review 
Copies of the fluciclovine (18F) PET/CT scan and PET/CT report will be made for central review and 
analysis. Retention and archiving of this data will be performed according to the guidelines stipulated in 
this section. 


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13. QUALITY ASSURANCE PROCEDURES 
13.1. 
Site Monitoring 
Regular monitoring will be performed according to a Sponsor approved monitoring plan. Data will be 
evaluated for compliance with the protocol and accuracy in relation to source documents. Monitoring 
visit reports will be sent to the site. 
13.2. 
Central Monitoring 
The study site will be monitored centrally by checking incoming forms for compliance with the protocol, 
data consistency, missing data and timing. All changes to data that could influence the outcome will be 
queried with and approved by the study site in a timely manner. For all other data, where there is no 
doubt about the source of any errors, clear changes to data will be made internally without referring 
back to the study site staff. The trial office will be in regular contact with site personnel to check on 
progress and deal with any queries that they may have including those arising from data queries. 
13.3. 
Audit and Regulatory Inspection 
All aspects of the study conduct may be subject to internal or external quality assurance audit to ensure 
compliance with the protocol, GCP requirements and other applicable regulation or standards. It may 
also be subject to a regulatory inspection. Such audits or inspections may occur at any time during or 
after the completion of the study. Investigators and their host Institution(s) should understand that it is 
necessary to allow auditors/inspectors direct access to all relevant documents, study facilities and to 
allocate their time and the time of their staff to facilitate the audit or inspection visit. Anyone receiving 
notification of a Regulatory Inspection that will (or is likely to) involve this trial must inform the trial 
office without delay. 
13.4. 
Contracts / Agreements  
This trial is subject to the Sponsors policy requiring that written contracts/agreements are agreed 
formally by the participating bodies as appropriate.  
14. ETHICAL AND REGULATORY CONSIDERATIONS 
 
The Sponsor and Investigators will ensure that this protocol will be conducted in compliance with the UK 
Clinical Trials Regulations1, the ICH guidelines of Good Clinical Practice (GCP)2 and the applicable policies 
of the sponsoring organisation. Together, these implement the ethical principles of the Declaration of 
Helsinki (1996) and the regulatory requirements for clinical trials of an investigational medicinal product 
under the European Union Clinical Trials Directive. 
                                                          
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Tripartite Guideline with Integrated Addendum E6(R2): Note for Guidance on Good Clinical 
Practice (CPMP/ICH/135/95) Step 4, adopted by CPMP 9 Nov 2016. 


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14.1. 
Ethical Conduct of the trial and ethics approval 
The protocol, patient information sheet, consent form and any other information that will be presented 
to potential trial patients (e.g. advertisements or information that supports or supplements the informed 
consent) will be reviewed and approved by an appropriately constituted, independent Research Ethics 
Committee (REC). 
14.2. 
Regulatory Authority approval  
This study will be conducted under a UK Medicines and Healthcare Products Regulatory Agency (MHRA) 
Clinical Trials Authorisation (CTA). Approval to conduct the study will be obtained from the Responsible 
Authority prior to initiating the study.  
14.3. 
Subject identification 
The study staff will ensure that the participants’ anonymity is maintained.  The participants will be 
identified only by a participants ID number on the CRF and any electronic database.  All documents will 
be stored securely and only accessible by study staff and authorised personnel. The study will comply 
with the Data Protection act which requires data to be anonymised as soon as practical.. 
14.4. 
Early termination or temporary halt on urgent safety grounds 
In cases of early termination or a temporary halt of the study due to toxicity or other safety grounds, the 
Chief Investigator will notify the Sponsor and Main REC within 15 calendar days of the decision giving a 
written explanation for the decision.  In this instance, the study will not be restarted until REC & MHRA 
approval has been obtained for a substantial amendment. 
14.5. 
Expenses and benefits 
Reasonable travel expenses for any visits additional to normal care will be reimbursed on production of 
receipts or a mileage allowance provided as appropriate. 
14.6. 
Protocol Amendments 
Amendments are changes made to the research following initial approval. A ‘substantial amendment’ is 
an amendment to the terms of the MHRA CTA authorisation, the REC application, or to the protocol or 
any other supporting documentation, that is likely to affect to a significant degree: 
• 
the safety or physical or mental integrity of the subjects of the trial; 
• 
the scientific value of the trial; 
• 
the conduct or management of the trial; or 
• 
the quality or safety of the investigational medicinal product used in the trial. 
Non-substantial amendments are those where the change(s) involve only minor logistical or 
administrative aspects of the study. 


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Amendments will be generated and managed according to the trial office standard operating procedures 
to ensure compliance with applicable regulation and policies. Substantial Amendments will be sent to 
Blue Earth Diagnostics Ltd for review prior to submission. Written confirmation of all applicable REC, 
regulatory, funder and local approvals must be in place prior to implementation by Investigators. The 
only exceptions are for changes necessary to eliminate an immediate hazard to study patients (see 
below). It is the Investigator’s responsibility to update patients (or their authorised representatives, if 
applicable) whenever new information (in nature or severity) becomes available that might affect the 
patient’s willingness to continue in the trial.  The Investigator must ensure this is documented in the 
patient’s medical notes and the patient is re-consented if appropriate. 
14.7. 
Urgent safety measures 
The sponsor or Investigator may take appropriate urgent safety measures to protect trial participants 
from any immediate hazard to their health or safety. Urgent safety measures may be taken without prior 
authorisation. The trial may continue with the urgent safety measures in place. The Investigator must 
inform the trial office IMMEDIATELY if the study site initiates an urgent safety measure: 
• 
Date of the urgent safety measure; 
• 
Who took the decision; and 
• 
Why the action was taken. 
The Investigator will provide any other information that may be requested by the trial office. The trial 
office will ensure that the urgent safety measure is reported in accordance with the current regulatory, 
ethical and sponsor requirements for expedited reporting and close out. 
14.8. 
Temporary halt 
The sponsor and Investigators reserve the right to place recruitment to this protocol on hold for short 
periods for administrative reasons or to declare a temporary halt where necessary. For this protocol, a 
temporary halt is defined a formal decision to: 
• 
interrupt the treatment of subjects already in the trial for safety reasons; 
• 
stop recruitment on safety grounds; or 
• 
stop recruitment for any other reason(s) considered to meet the substantial amendment criteria, 
including possible impact on the feasibility of completing the trial in a timely manner. 
 
The trial office will report the temporary halt via an expedited substantial amendment procedure. The 
trial may not restart after a temporary halt until a further substantial amendment to re-open is in place.  
If it is decided not to restart the trial this will be reported as an early termination. 


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14.9. 
Serious Breaches 
The Medicines for Human Use (Clinical Trials) Regulations require the Sponsor to notify any "serious 
breaches" to the MHRA within 7 days of the sponsor becoming aware of the breach. A serious breach is 
defined as “A breach of GCP or the trial protocol which is likely to effect to a significant degree:  
• 
the safety or physical or mental integrity of the subjects of the trial; or 
• 
the scientific value of the trial 
Investigators must notify the trials office at once if any serious breach of GCP is suspected. 
14.10. 
Approvals 
 
The protocol, informed consent form, participant information sheet and any proposed advertising 
material will be submitted to an appropriate Research Ethics Committee (REC), and host institution(s) for 
written approval. 
The Investigator will submit and, where necessary, obtain approval from the above parties for all 
substantial amendments to the original approved documents. 
14.11. 
Reporting 
The CI shall submit once a year throughout the study, or on request, an Annual Progress report to the 
REC Committee, host organisation and Sponsor.  In addition, an End of Study notification and final report 
will be submitted to the same parties. 
14.12. 
Participant Confidentiality 
 
The personal data recorded on all documents will be regarded as confidential, and to preserve each 
patient’s anonymity, only their participant ID number will be recorded on the CRFs. The Investigator site 
must maintain the patient’s anonymity in all communications and reports related to the research. The 
Investigator site team must keep a separate log of enrolled patients’ personal identification details as 
necessary to enable them to be tracked. These documents must be retained securely, in strict 
confidence. They form part of the Investigator Site File and are not to be released externally. 
15. FINANCE AND INSURANCE 
15.1. 
Funding 
 
This study is jointly funded by Blue Earth Diagnostics Ltd (Unit 14, Magdalen Centre, Robert Robinson 
Avenue, Oxford Science Park, Oxford OX4 4GA) and Innovate UK (an executive non-departmental public 
body, sponsored by the Department for Business, Innovation & Skills of the UK Government). 


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15.2. 
Insurance 
Blue Earth Diagnostics Ltd has insurance cover for this study and will compensate patients who suffer 
harm from participation in the study in accordance with the ABPI guidelines. A Certificate of Insurance 
can be provided upon request. 
16. PUBLICATION POLICY 
The results of the study are intended for submitted to peer-reviewed journals such as the Journal of 
Nuclear Medicine, European Journal of Nuclear Medicine and Molecular Imaging and Journal of Urology 
with findings presented at such annual society meetings as the SNMMI, EANM, RSNA, or ASTRO. All 
publications will include a list of all participating PIs. The support obtained from the main research 
funding bodies and Sponsor will be acknowledged in any publication. No subgroup analysis can be 
published before the publication of the entire study. The Investigator will ensure that patients taking 
part in the study who are interested to learn the study findings are informed appropriately. In addition, 
the Sponsor will be free to use the study results, in compliance with applicable regulations and the terms 
of the trial agreement, to assemble supplements, amendments or other documentation required by 
regulatory authorities, and for other marketing or development purposes. 
17. REFERENCES 
 
1. Office for National Statistics. Cancer Registration Statistics, England, 2012. 2014. 
2. Cancer Research UK. Cancer Stats report - Prostate Cancer. 2014. 
3. Punnen S, Cooperberg MR, D'Amico AV et al. Management of biochemical recurrence after primary 
treatment of prostate cancer: a systematic review of the literature. Eur Urol 2013;64:905-915. 
4. National Institute for Health and Care Excellence. Prostate cancer: diagnosis and treatment. 2014. 
5. Heidenreich A, Bastian PJ, Bellmunt J et al. EAU guidelines on prostate cancer. Part II: Treatment of 
advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2014;65:467-479. 
6. Rouviere O, Vitry T and Lyonnet D. Imaging of prostate cancer local recurrences: why and how? Eur 
Radiol 2010;20:1254-1266. 
7. Beresford MJ, Gillatt D, Benson RJ and Ajithkumar T. A systematic review of the role of imaging before 
salvage radiotherapy for post-prostatectomy biochemical recurrence. Clin Oncol (R Coll Radiol) 
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8. Kane CJ, Amling CL, Johnstone PA et al. Limited value of bone scintigraphy and computed tomography 
in assessing biochemical failure after radical prostatectomy. Urology 2003;61:607-611. 
9. Dotan ZA, Bianco FJ,Jr, Rabbani F et al. Pattern of prostate-specific antigen (PSA) failure dictates the 
probability of a positive bone scan in patients with an increasing PSA after radical prostatectomy. J Clin 
Oncol 2005;23:1962-1968. 


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10. Johnstone PA, Tarman GJ, Riffenburgh R et al. Yield of imaging and scintigraphy assessing biochemical 
failure in prostate cancer patients. Urol Oncol 1997;3:108-112. 
11. Hovels AM, Heesakkers RA, Adang EM et al. The diagnostic accuracy of CT and MRI in the staging of 
pelvic lymph nodes in patients with prostate cancer: a meta-analysis. Clin Radiol 2008;63:387-395. 
12. Powles T, Murray I, Brock C et al. Molecular positron emission tomography and PET/CT imaging in 
urological malignancies. Eur Urol 2007;51:1511-20; discussion 1520-1. 
13. Effert PJ, Bares R, Handt S et al. Metabolic imaging of untreated prostate cancer by positron emission 
tomography with 18fluorine-labeled deoxyglucose. J Urol 1996;155:994-998. 
14. Ramirez de Molina A, Rodriguez-Gonzalez A, Gutierrez R et al. Overexpression of choline kinase is a 
frequent feature in human tumor-derived cell lines and in lung, prostate, and colorectal human cancers. 
Biochem Biophys Res Commun 2002;296:580-583. 
15. Evangelista L, Cervino A, Burei M et al. Comparative studies of radiolabeled choline positron emission 
tomography, histology of primary tumor and other imaging modalities in prostate cancer: a systematic 
review and meta-analysis. 2013;1:99-109. 
16. von Eyben FE and Kairemo K. Meta-analysis of (11)C-choline and (18)F-choline PET/CT for 
management of patients with prostate cancer. Nucl Med Commun 2014;35:221-230. 
17. Giovacchini G, Picchio M, Briganti A et al. 11C]choline positron emission tomography/computerized 
tomography to restage prostate cancer cases with biochemical failure after radical prostatectomy and no 
disease evidence on conventional imaging. J Urol 2010;184:938-943. 
18. Ceci F, Herrmann K, Castellucci P et al. Impact of (11)C-choline PET/CT on clinical decision making in 
recurrent prostate cancer: results from a retrospective two-centre trial. Eur J Nucl Med Mol Imaging 
2014;41:2222-2231. 
19. Mitchell CR, Lowe VJ, Rangel LJ et al. Operational characteristics of (11)c-choline positron emission 
tomography/computerized tomography for prostate cancer with biochemical recurrence after initial 
treatment. J Urol 2013;189:1308-1313. 
20. Souvatzoglou M, Krause BJ, Purschel A et al. Influence of (11)C-choline PET/CT on the treatment 
planning for salvage radiation therapy in patients with biochemical recurrence of prostate cancer. 
Radiother Oncol 2011;99:193-200. 
21. Soyka JD, Muster MA, Schmid DT et al. Clinical impact of 18F-choline PET/CT in patients with 
recurrent prostate cancer. Eur J Nucl Med Mol Imaging 2012;39:936-943. 
22. Ceci F, Herrmann K, Castellucci P et al. Impact of C-choline PET/CT on clinical decision making in 
recurrent prostate cancer: results from a retrospective two-centre trial. Eur J Nucl Med Mol Imaging 
2014. 
23. Schiavina R and Martorana G. The promise of choline-PET/CT in the detection of recurrent prostate 
cancer: what are the limits of our investigation? Eur Urol 2013;63:797-799. 


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24. Evangelista L, Guttilla A, Zattoni F et al. Utility of choline positron emission tomography/computed 
tomography for lymph node involvement identification in intermediate- to high-risk prostate cancer: a 
systematic literature review and meta-analysis. Eur Urol 2013;63:1040-1048. 
25. Husarik DB, Miralbell R, Dubs M et al. Evaluation of [(18)F]-choline PET/CT for staging and restaging 
of prostate cancer. Eur J Nucl Med Mol Imaging 2008;35:253-263. 
26. Castellucci P, Fuccio C, Rubello D et al. Is there a role for (1)(1)C-choline PET/CT in the early detection 
of metastatic disease in surgically treated prostate cancer patients with a mild PSA increase <1.5 ng/ml? 
Eur J Nucl Med Mol Imaging 2011;38:55-63. 
27. Rinnab L, Mottaghy FM, Simon J et al. 11C]Choline PET/CT for targeted salvage lymph node dissection 
in patients with biochemical recurrence after primary curative therapy for prostate cancer. Preliminary 
results of a prospective study. Urol Int 2008;81:191-197. 
28. Castellucci P, Fuccio C, Nanni C et al. Influence of trigger PSA and PSA kinetics on 11C-Choline PET/CT 
detection rate in patients with biochemical relapse after radical prostatectomy. J Nucl Med 
2009;50:1394-1400. 
29. Krause BJ, Souvatzoglou M, Tuncel M et al. The detection rate of [11C]choline-PET/CT depends on the 
serum PSA-value in patients with biochemical recurrence of prostate cancer. Eur J Nucl Med Mol Imaging 
2008;35:18-23. 
30. Sutinen E, Nurmi M, Roivainen A et al. Kinetics of [(11)C]choline uptake in prostate cancer: a PET 
study. Eur J Nucl Med Mol Imaging 2004;31:317-324. 
31. Schiavina R, Scattoni V, Castellucci P et al. 11C-choline positron emission tomography/computerized 
tomography for preoperative lymph-node staging in intermediate-risk and high-risk prostate cancer: 
comparison with clinical staging nomograms. Eur Urol 2008;54:392-401. 
32. Beheshti M, Imamovic L, Broinger G et al. 18F choline PET/CT in the preoperative staging of prostate 
cancer in patients with intermediate or high risk of extracapsular disease: a prospective study of 130 
patients. Radiology 2010;254:925-933. 
33. Juweid ME and Cheson BD. Positron-emission tomography and assessment of cancer therapy. N Engl 
J Med 2006;354:496-507. 
34. Beheshti M, Vali R, Waldenberger P et al. The use of F-18 choline PET in the assessment of bone 
metastases in prostate cancer: correlation with morphological changes on CT. Mol Imaging Biol 
2009;11:446-454. 
35. Murphy RC, Kawashima A and Peller PJ. The utility of 11C-choline PET/CT for imaging prostate cancer: 
a pictorial guide. AJR Am J Roentgenol 2011;196:1390-1398. 
36. Schillaci O, Calabria F, Tavolozza M et al. 18F-choline PET/CT physiological distribution and pitfalls in 
image interpretation: experience in 80 patients with prostate cancer. Nucl Med Commun 2010;31:39-45. 
37. National Institute for Clinical Excellence. Prostate cancer: diagnosis and treatment. NICE clinical 
guideline 175. 2014. 


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38. Stephenson AJ, Scardino PT, Kattan MW et al. Predicting the outcome of salvage radiation therapy for 
recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25:2035-2041. 
39. Rigatti P, Suardi N, Briganti A et al. Pelvic/retroperitoneal salvage lymph node dissection for patients 
treated with radical prostatectomy with biochemical recurrence and nodal recurrence detected by 
[11C]choline positron emission tomography/computed tomography. Eur Urol 2011;60:935-943. 
40. Jilg CA, Rischke HC, Reske SN et al. Salvage Lymph Node Dissection with Adjuvant Radiotherapy for 
Nodal Recurrence of Prostate Cancer. J Urol;188:2190-2197. 
41. Alongi F, Fogliata A, Clerici E et al. Volumetric modulated arc therapy with flattening filter free beams 
for isolated abdominal/pelvic lymph nodes: report of dosimetric and early clinical results in 
oligometastatic patients. Radiat Oncol 2012;7:204-717X-7-204. 
42. Berkovic P, De Meerleer G, Delrue L et al. Salvage stereotactic body radiotherapy for patients with 
limited prostate cancer metastases: deferring androgen deprivation therapy. Clin Genitourin Cancer 
2013;11:27-32. 
43. Jereczek-Fossa BA, Beltramo G, Fariselli L et al. Robotic image-guided stereotactic radiotherapy, for 
isolated recurrent primary, lymph node or metastatic prostate cancer. Int J Radiat Oncol Biol Phys 
2012;82:889-897. 
44. Petrylak DP. Risk Factors for the Development of Bone Metastases in Prostate Cancer. 2007;6:677-
682. 
45. Shoup TM, Olson J, Hoffman JM et al. Synthesis and evaluation of [18F]1-amino-3-fluorocyclobutane-
1-carboxylic acid to image brain tumors. J Nucl Med 1999;40:331-338. 
46. Okudaira H, Shikano N, Nishii R et al. Putative transport mechanism and intracellular fate of trans-1-
amino-3-18F-fluorocyclobutanecarboxylic acid in human prostate cancer. J Nucl Med 2011;52:822-829. 
47. Schuster DM, Votaw JR, Nieh PT et al. Initial experience with the radiotracer anti-1-amino-3-18F-
fluorocyclobutane-1-carboxylic acid with PET/CT in prostate carcinoma. J Nucl Med 2007;48:56-63. 
48. Osborne JR, Akhtar NH, Vallabhajosula S et al. Prostate-specific membrane antigen-based imaging. 
Urol Oncol 2013;31:144-154. 
49. Schuster DM, Nieh PT, Jani AB et al. Anti-3-[(18)F]FACBC positron emission tomography-
computerized tomography and (111)In-capromab pendetide single photon emission computerized 
tomography-computerized tomography for recurrent prostate carcinoma: results of a prospective clinical 
trial. J Urol 2014;191:1446-1453. 
50. Nanni C, Schiavina R, Brunocilla E et al. 18F-FACBC compared with 11C-choline PET/CT in patients 
with biochemical relapse after radical prostatectomy: a prospective study in 28 patients. Clin Genitourin 
Cancer 2014;12:106-110. 
51. Zanoni L, Nanni C, Schiavina R et al. OP344: 18F-FACBC PET/CT FOR THE DETECTION OF PROSTATE 
CANCER RELAPSE: A COMPARISON TO 11C-CHOLINE PET/CT. Eur J Nucl Med Mol Imaging 2014;41 Suppl 
2:151-705. 


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52. Sorensen J, Owenius R, Lax M and Johansson S. Regional distribution and kinetics of [18F]fluciclovine 
(anti-[18F]FACBC), a tracer of amino acid transport, in subjects with primary prostate cancer. Eur J Nucl 
Med Mol Imaging 2013;40:394-402. 
53. Roach M,3rd, Hanks G, Thames H,Jr et al. Defining biochemical failure following radiotherapy with or 
without hormonal therapy in men with clinically localized prostate cancer: recommendations of the 
RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006;65:965-974. 
54. Anonymous SNMMI NMCTG Fluciclovine (18F) Consensus Reader Meeting Report. 2014. 
55. McParland BJ, Wall A, Johansson S and Sorensen J. The clinical safety, biodistribution and internal 
radiation dosimetry of [(1)(8)F]fluciclovine in healthy adult volunteers. Eur J Nucl Med Mol Imaging 
2013;40:1256-1264. 
56. Nye JA, Schuster DM, Yu W et al. Biodistribution and radiation dosimetry of the synthetic 
nonmetabolized amino acid analogue anti-18F-FACBC in humans. J Nucl Med 2007;48:1017-1020. 
57. Blue Earth Diagnostics Ltd.  Fluciclovine (18 F) Investigator’s Brochure (Version 5.1). 2018. 
 


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18. APPENDIX A:  SCHEDULE OF STUDY PROCEDURES 
Variables 
Visit 1 
(Screening, 
up to 14 
days before 
Visit 2) 
Visit 2  
(Day of 
fluciclovine 
(18F) injection 
and PET/CT) 
Post-administration 
Phone 
Visit 3 
(24 -72 (+ 
4) hours 
after 
dose) 
Visit 4 
(Manag
ement 
plan 
decision
) 
Phone 
Visit 5 (1 
month +7 
days 
after 
dose) 
Visit 6 
(First day of 
management 
plan, may be 
same date as 
Visit 4) 
Standard of care 
clinical follow-up 
(data entry at 6 
months after 
starting 
management plan ) 
Patients who have radical 
salvage therapy 
Dose 
 
Immediately 
post scan 
60 
(±5)  
min 
90 
(±5) 
min 
120 
(±5) 
min 
 
 
 
 
 
Pre-treatment 
PSA level (<31 
days pre-therapy) 
7-8 months 
after 
completing 
therapy 
Inclusion / exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height, weight 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Measure PSA level 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Record prior PSA levels  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
PCa treatment history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Imaging history (3 months before 
to 6 months after PET/CT) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Intended management plan 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication and 
allergies 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood test 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
ECG 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Post-screening pre-
administration events 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs (heart rate and blood 
pressure) 
X 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Injection site monitoring 
 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Imaging 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AE monitoring 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Revised management plan 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Agreed management plan 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Date of starting treatment 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Deviation from agreed 
management plan (if any) 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Treatment response assessment 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 


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19. APPENDIX B: Oxford site sub-study 
Evaluation and optimisation of Bayesian penalised likelihood PET 
reconstruction for Fluciclovine (18F) whole body imaging 
FALCON trial Oxford site sub-study 
 
Dr. Eugene Teoh, Daniel McGowan, Prof. Fergus Gleeson and Oxford FALCON trial 
investigators. 
 
Background 
We have recently investigated and reported on the optimisation of Bayesian penalised likelihood 
(BPL) reconstruction for 18F-FDG whole body oncological PET [1], and its effect on evaluating 
various clinical entities on 18F-FDG PET/CT [2-4]. BPL includes point spread function modeling 
while controlling noise through the use of a penalty term (β) [1]. One pertinent observation from 
our work has been of how BPL improves signal-to-noise in areas of increased tracer uptake on 
clinical scans, particularly in subcentimetre abnormalities [2]. This is corroborated by phantom 
data [1]. Our institution currently uses BPL reconstructed images (β=400) [1] for the clinical 
interpretation of all 18F-FDG whole body oncological PET/CT studies. 
We propose to investigate the use of BPL reconstruction for Fluciclovine (18F) whole body PET, 
using scan data acquired in Oxford for the FALCON trial. This will be wholly performed using 
pre-existing scan data, so participants will not be required to make extra visits or subjected to 
additional study procedures. 
Rationale 
Currently OSEM reconstructions are standard of care worldwide, and BPL reconstruction is used 
with more modern PET/CT scanner reconstruction, it is important to determine if BPL improves 
detection. This study will address this issue. 
Aims 
Primary Objective 
Endpoints/ Outcome measures 
To evaluate the difference in image quality between 
BPL 
and 
standard 
PET 
reconstructions 
of 
Fluciclovine (18F) whole body PET images. 
Signal-to-noise (SNR) of background structures 
and areas of pathological uptake on both 
reconstructions. 
Secondary Objectives 
Endpoints 
To determine the optimum penalisation factor (β) 
for Fluciclovine (18F) whole body PET BPL 
reconstruction. 
SNR of background structures and areas of 
pathological uptake on BPL reconstructions 
using different β values. 
To determine the difference in positive detection 
rates between BPL and OSEM reconstructions. 
Record 
of 
fluciclovine 
(18F) 
positive 
abnormalities on both reconstructions. 


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Tertiary/Exploratory Objectives 
Endpoints 
Future study of other PET reconstruction methods 
(e.g. new / in development) for Fluciclovine (18F) 
PET imaging 
 
 
Methodology 
Optimum β 
The scan data (sinograms) acquired for FALCON will be reconstructed with BPL using a range 
of β values. Parameters measuring the degree of tracer uptake (standardised uptake value – 
SUV) for background structures (blood pool, marrow and liver) and areas of pathological uptake 
will be measured. The SNR will be calculated using these parameters and compared between 
the reconstructions.  
This range of reconstructions will also be visually scored by readers for image quality using 
previously described methodology and criteria to determine the optimum  for Fluciclovine [1].  
Image quality evaluation 
SUV parameters described in the former section (“Optimum β”) will be measured in the OSEM 
reconstruction (current trial standard), and compared with those measured on BPL 
reconstruction.  
Positive detection 
The OSEM reconstructed images will be interpreted on day of scan, and fluciclovine (18F) 
positive abnormalities recorded. The BPL reconstructed images will then be reviewed by the 
same reader(s). Any new / change in fluciclovine (18F) positive abnormalities will be recorded 
and compared. This will be performed prospectively after REC and R&D approval have been 
obtained. Retrospective image review will be performed for all scans acquired before this time. 
Receiver operating characteristic analysis will be considered to compare the two reconstructions 
depending on the number of cases where diagnostic performance (as laid out in the FALCON 
trial protocol) can be assessed. 
The prospective nature of this component is partly necessitated by the use of BPL reconstruction 
in our routine clinical practice. As such, the BPL images will be reconstructed using a β of 400, 
as is used for whole body 18F-FDG and 18F-ethylcholine PET/CT scans in our institution. All 
readers will have the same baseline degree of competency and experience in interpreting 
Fluciclovine (18F) whole body PET/CT. 
Where there is a change in findings, a consensus on whether this is clinically significant in such a way that 
would influence the patient’s management, will be reached between the reader(s), the principal 
investigator (or a nominated investigator), and the referring investigator responsible for the patient’s 
clinical management.  
In the rare event that this is deemed to be significant, it has been agreed with the trial sponsor and Chief 
Investigator that: 


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1. the Revised Management Plan recorded at Visit 4 would be based on findings made on the trial 
standard reconstruction ie OSEM. 
2. the Agreed Management Plan recorded at Visit 4 would be based on findings made on the BPL 
reconstruction.  
As BPL is used as standard of care in our institution, the change in findings will be reflected in the clinical 
report if deemed to be clinically significant.  
 
References 
1. 
Teoh, E.J., et al., Phantom and Clinical Evaluation of the Bayesian Penalized Likelihood 
Reconstruction Algorithm Q.Clear on an LYSO PET/CT System. J Nucl Med, 2015. 
56(9): p. 1447-52. 
2. 
Teoh, E.J., et al., Novel penalised likelihood reconstruction of PET in the assessment of 
histologically verified small pulmonary nodules. Eur Radiol, 2016. 26(2): p. 576-84. 
3. 
Teoh, E.J., et al., 18F-FDG PET/CT assessment of histopathologically confirmed 
mediastinal lymph nodes in non-small cell lung cancer using a penalised likelihood 
reconstruction. Eur Radiol, 2016. DOI: 10.1007/s00330-016-4253-2 
4. 
Parvizi, N., et al., Does a novel penalized likelihood reconstruction of 18F-FDG PET-CT 
improve signal-to-background in colorectal liver metastases? Eur J Radiol, 2015. 84(10): 
p. 1873-8. 
 

SAP_001.pdf: 
Date: 10OCT2018  
Page 1 of 22 
Version: Amendment 1 Final 
ST/form/010/6 
A Phase 3, Open-label Study to Assess the Clinical Utility 
of Fluciclovine (18F) PET/CT in Patients with Prostate 
Cancer with Biochemical Recurrence after Radical 
Treatment 
Blue Earth Diagnostics Study No: BED-004 
Syne qua non Ltd Study No: BLS14004 
Statistical Analysis Plan 
Version: Amendment 1 Final 
Date:  10th October 2018 
For Syne qua non Ltd  Lead Statistician 
Sig1sig 
For Blue Earth Diagnostics 
Sig2sig 
DocuSign Envelope ID: 93B644B8-A891-4520-914F-18451BC4D479


Syne qua non study no: BLS14004 
 
Blue Earth Diagnostics study no: BED-004 
 
Date: 10OCT2018  
 
Page 2 of 22 
Version: Amendment 1 Final 
ST/form/010/6 
 
Contents 
 
1 
INTRODUCTION ............................................................................................................................. 5 
2 
GENERAL PRINCIPLES ................................................................................................................. 5 
3 
STUDY OBJECTIVES AND DESIGN ............................................................................................. 5 
3.1 
Study Objectives ......................................................................................................................... 5 
3.2 
Study Design ............................................................................................................................... 6 
3.3 
Visit Structure .............................................................................................................................. 6 
3.4 
Sample Size ................................................................................................................................ 7 
3.5 
Changes from the Protocol Planned Analysis ............................................................................ 7 
4 
STUDY SUBJECTS ........................................................................................................................ 7 
4.1 
Analysis sets ............................................................................................................................... 7 
4.2 
Disposition of Subjects ............................................................................................................... 7 
4.3 
Protocol Deviations ..................................................................................................................... 8 
4.4 
Background and Demographic Characteristics .......................................................................... 8 
4.4.1 
Demographic and Baseline Characteristics............................................................................. 8 
4.4.2 
Medical History ........................................................................................................................ 8 
4.4.3 
Prostate Cancer History........................................................................................................... 8 
4.4.4 
Cancer Therapies for Prostate Cancer .................................................................................... 9 
4.4.5 
Prior and Concomitant Medications ....................................................................................... 10 
4.5 
Administration of Investigational Product ................................................................................. 10 
5 
EFFICACY EVALUATION ............................................................................................................. 10 
5.1 
Primary Efficacy Variable .......................................................................................................... 11 
5.2 
Secondary Efficacy Variables ................................................................................................... 11 
5.3 
Definition of Region Levels ....................................................................................................... 11 
5.4 
Statistical Analysis .................................................................................................................... 14 
5.4.1 
Primary Efficacy Analysis ...................................................................................................... 14 
5.4.2 
Secondary Efficacy Analyses ................................................................................................ 18 
5.4.3 
Handling of Dropouts or Missing Data ................................................................................... 19 
5.4.4 
Interim Analyses and Data Monitoring ................................................................................... 19 
5.4.5 
Examination of Subgroups .................................................................................................... 19 
5.4.6 
Site Specific Sub-study .......................................................................................................... 19 
6 
SAFETY EVALUATION ................................................................................................................ 19 
6.1 
Adverse Events ......................................................................................................................... 20 
6.2 
Clinical Laboratory Evaluation .................................................................................................. 21 
6.2.1 
Haematology .......................................................................................................................... 21 
6.2.2 
Biochemistry .......................................................................................................................... 21 
6.2.3 
Urinalysis dipstick .................................................................................................................. 21 
6.2.4 
Urine microscopy ................................................................................................................... 21 
6.3 
Vital Signs ................................................................................................................................. 21 
6.4 
Electrocardiography .................................................................................................................. 21 
7 
References .................................................................................................................................... 22 
 
 
 
 
DocuSign Envelope ID: 93B644B8-A891-4520-914F-18451BC4D479


Syne qua non study no: BLS14004 
 
Blue Earth Diagnostics study no: BED-004 
 
Date: 10OCT2018  
 
Page 3 of 22 
Version: Amendment 1 Final 
ST/form/010/6 
ABBREVIATIONS 
 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BCR 
Biochemical recurrence 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CrCl 
Creatinine clearance 
CRF 
Case report form 
CT 
Computerised Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
EAS 
Evaluable analysis set 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
LDH 
Lactate dehydrogenase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
ms 
Milliseconds 
PCa 
Prostate cancer 
PET 
Positron emission tomography 
PPS 
Per protocol set 
PSA 
Prostate specific antigen 
PT 
Preferred term 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
RP 
Radical prostatectomy 
RRT 
Radical external beam radiotherapy 
RT 
Radiotherapy 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
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SOC 
System organ class 
TEAE 
Treatment emergent adverse event 
TNM 
TNM classification of malignant tumours 
WBC 
White blood cell 
WHO 
World Health Organization  
WHO DDE 
WHO Drug Dictionary Enhanced 
 
 
 
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1 INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the final protocol version dated 24th 
March 2015 and amendments 1-4 dated 30th November 2015, 5th April 2016, 2nd 
March 2017 and 4th June 2018. 
The SAP describes the tables, listings and figures which will be provided upon 
completion of the study. The SAP will be finalised before locking the database. 
The table, listing and figure shells will be supplied in a separate document. 
2 GENERAL PRINCIPLES 
The analysis and statistical reporting will be conducted at Syne qua non using SAS 
version 9.2 or higher. 
All listings will be based on all enrolled subjects unless specified otherwise.  All 
tables will be presented by site and overall for the appropriate analysis population. 
Descriptive summary statistics for continuous variables will include number of 
subjects (n), mean, standard deviation (SD), minimum, median, and maximum, 
unless specified otherwise. The precision of these summary statistics is defined in 
the table, figure and listing shells document. 
Descriptive summary statistics for categorical variables will include frequency counts 
and percentages [n (%)]. Unless stated otherwise, the denominator for percentage 
calculations will be the number of subjects in the analysis set. 
For treatment response baseline prostate specific antigen (PSA) is the most recent 
PSA measurement prior to salvage therapy for subjects who had salvage treatment 
and the most recent PSA measurement prior to the 18F-fluciclovine positron 
emission tomography/computerised tomography (PET/CT) for non-salvage subjects. 
If no PSA measurement is available just prior to salvage therapy, baseline will be 
defined as the most recent PSA measurement prior to fluciclovine (18F) scan.  For all 
other variables, and for baseline PSA other than for treatment response, baseline is 
defined as the most recent value prior to fluciclovine (18F) administration.  
In general, there will be no imputation of missing data, however where dates are 
partially missing dates may be imputed for calculation purposes, details are given 
under relevant section. 
3 STUDY OBJECTIVES AND DESIGN 
3.1 Study Objectives 
The primary objective of the study is to confirm the clinical benefit of fluciclovine (18F) 
PET/CT in affecting management decisions in subjects with biochemical recurrence 
(BCR) being considered for radical salvage treatment (with curative intent). 
The secondary objectives of the study are 
 To assess possible improvement in outcome of radical salvage treatment 
based on fluciclovine (18F) PET/CT being included in the assessment 
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 To assess the PSA threshold for positive lesion detection by fluciclovine (18F) 
PET/CT in BCR  
 To assess the safety of fluciclovine (18F) injection in subjects undergoing 
PET/CT  
3.2 Study Design 
This will be an open-labelled, multi-centred study in the United Kingdom.  
The study group will include up to 180 subjects with a diagnosis of BCR of previous 
radically treated prostate cancer (PCa), and who are being considered for radical 
salvage therapy.  
Subjects will have a fluciclovine (18F) PET/CT scan in addition to standard work-up 
for radical salvage therapy. The clinical utility of fluciclovine (18F) PET/CT will be 
assessed by recording changes to the recommended management plan influenced 
by the scan result.  
The summary flow chart of the study design is as follows: 
 
3.3 Visit Structure 
The visit structure and scheduled assessments are detailed in Appendix A: Schedule 
of study procedures of the protocol. 
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3.4 Sample Size 
For the primary objective of treatment change evaluation, a minimum of 171 subjects 
with complete primary endpoint data will be required to allow for a width of +/-6% in a 
two-sided 95% confidence interval (CI). This is based on the conservative 
assumption that 20% of subjects will have a treatment change, as fluciclovine (18F) 
PET/CT has been shown to upstage 25.7% of subjects with recurrent prostate 
cancer, and also based on the management change studies reported on choline 
PET/CT. The aim is to recruit 180 subjects for this trial, based on an anticipated 
primary endpoint drop-out rate of 5%.  
3.5 Changes from the Protocol Planned Analysis 
Improvement in outcome of radical salvage treatment based 
on fluciclovine (18F) PET/CT being included in the assessment
endpoint.   This was to be assessed based on PSA and radiological response.  Due 
to lack of data being recorded for radiological response this definition was not used, 
treatment response was instead assessed using PSA only (see section 5.4.2.1.). 
4 STUDY SUBJECTS 
4.1 Analysis sets 
The list of subjects to be included in each of the analysis set is to be agreed between 
the Syne qua non statistician and Blue Earth Diagnostics once all study data are 
available and prior to database lock. 
Enrolled Set:  All subjects who entered screening. 
Safety Analysis Set (SAF): All subjects who have been included in the database 
and have been administered fluciclovine (18F) will be included in the Safety Analysis 
Set (SAF). 
Full Analysis Set (FAS): All subjects enrolled who have had a fluciclovine (18F) 
PET/CT scan will be included in the Full Analysis Set (FAS). 
Evaluable Analysis Set (EAS): All subjects from the FAS who have an intended 
treatment management plan completed and a revised management plan page 
completed will be included in the Evaluable Analysis Set (EAS). 
Per Protocol Set (PPS): All subjects in the EAS without major significant deviation 
following review of the protocol deviation list.  
4.2 Disposition of Subjects 
The number and percentage of all subjects enrolled, included in each analysis set, 
who completed the study and who prematurely withdrew, including a breakdown of 
the primary reasons for withdrawal, will be presented. 
All enrolled subjects will be listed indicating their membership to the evaluable 
analysis set along with the reason for exclusion. 
Completion and withdrawal information will be listed, including individual reasons for 
withdrawal. 
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4.3 Protocol Deviations 
Failed inclusion criteria and failed exclusion criteria will be listed for screening 
failures. 
The number and percentage of subjects within each deviation category will be 
presented by deviation type (Major Significant, Major or Minor) and by site and 
overall. The deviation category and type will be provided by Blue Earth Diagnostics. 
All protocol deviations will be listed. 
4.4 Background and Demographic Characteristics 
4.4.1 
Demographic and Baseline Characteristics 
Demographic characteristics (age, ethnic origin and race collected at Screening), 
body measurements (height, weight collected, and BMI derived at Visit 2) will be 
summarised for the enrolled set, FAS, EAS and PPS populations. 
Body mass index (BMI) is calculated as (weight (kg)/height (m)²). 
Individual demographic characteristics and body measurements data will be listed. 
4.4.2 
Medical History 
Medical history events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.1. 
The number and percentage of subjects from the FAS with previous medical history 
and current events will be tabulated by system organ class (SOC), preferred term 
(PT). SOCs will be ordered in decreasing frequency of the total number of subjects 
with medical history events reported in each SOC and PTs will be ordered within a 
SOC in decreasing frequency of the total number of subjects with each medical 
history event.  This table will be repeated for all events, regardless of whether 
previous or current events. 
All medical history events will be listed. 
4.4.3 
Prostate Cancer History 
Details of prostate cancer history will be summarised for subjects from the FAS, and 
will consist of: 
 Time since initial diagnosis (months), calculated as [12*(date of informed 
consent  date of initial prostate cancer diagnosis + 1)/365.25] 
 TNM stage: Pathological TNM stage if available, otherwise Clinical TNM 
stage.  A summary for T1 total, T2 total and T3 total will be provided as the 
sum of the number of subjects in each of the subgroups plus any subjects 
where only T1, T2 or T3 was recorded. 
 Gleason total score: Gleason total score from surgery if available, otherwise 
Gleason total score from biopsy 
 Time since adjuvant treatment (months), calculated as [12*(date of informed 
consent  stop date of adjuvant treatment + 1)/365.25] 
 Duration of adjuvant treatment (months), calculated as [12*(stop date of 
adjuvant treatment  start date of adjuvant treatment + 1)/365.25] 
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 Time since diagnosis of biochemical recurrence (days), calculated as (date of 
informed consent  date of diagnosis of biochemical recurrence + 1).  Time 
since diagnosis of BCR may be derived in months if more appropriate. 
 Baseline PSA value 
 Baseline PSA category (0  0.2, >0.2  0.5, >0.5  1, >1  2, >2  5, >5  10 
and >10) 
In addition, summary table to summarise baseline Prostate Specific Antigen (PSA) by 
Prior Radical Prostatectomy status (Prior Radical Prostatectomy vs No Prior Radical 
Prostatectomy) using descriptive statistics (number of subjects (n), mean, standard 
deviation (SD), minimum, median, and maximum), will be produced.   
Details of prostate cancer history will be listed.  
Date imputation for incomplete dates: 
 If day part missing, put 15th of the month 
 If day and month parts missing, put 01 July 
4.4.4 
Cancer Therapies for Prostate Cancer 
Cancer therapies for prostate cancer will be coded according to the World Health 
Organization Drug Dictionary Enhanced (WHO DDE) (Enhanced) version Sep 2015.  
Cancer therapies will be categorised as follows: 
Subjects with radical prostatectomy: 
 Radiotherapy 
 No radiotherapy 
Subjects without radical prostatectomy: 
 Radiotherapy only 
o EBRT only 
o Brachytherapy only 
o EBRT and brachytherapy 
 Radiotherapy and other therapies 
o EBRT and other therapies 
o Brachytherapy and other therapies 
 Other therapies 
Prior cancer therapies for prostate cancer are defined as those for which the end 
date is prior to the date of injection of fluciclovine (18F). 
Concomitant/post-scan cancer therapies for prostate cancer are defined as those 
with a start date on or after the injection date of fluciclovine (18F), or those with a start 
date before the injection date of fluciclovine (18F) but which continued with a stop on 
or after the injection date of fluciclovine (18F).  Summaries for subjects with prior and 
post-scan radical prostatectomy will be presented separately. 
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Summary table to summarise time from 18F-fluciclovine PET/CT to first post-18F-
fluciclovine treatment in days using descriptive statistics (number of subjects (n), 
mean, SD, minimum, median, and maximum) will be provided. 
If cancer therapy dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.   
The number and percentage of subjects per category of prostate cancer therapy will 
be presented for all subjects from the SAF, separately for subjects with and without 
radical prostatectomy.  This summary will be repeated for prior and concomitant 
cancer therapies. 
All therapies for prostate cancer will be listed including type of therapy, reported 
therapy name, medication class, standardised medication name, dose, dose unit, 
   
4.4.5 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded according to the World Health 
Organization Drug Dictionary Enhanced (WHO DDE) (Enhanced) version Sep 2015. 
Prior medications are defined as those for which the end date is prior to the date of 
injection of fluciclovine (18F). 
Concomitant medications are defined as those with a start date on or after the 
injection date of fluciclovine (18F), or those with a start date before the injection date 
of fluciclovine (18F) but which continued with a stop date on or after the injection date 
of fluciclovine (18F). 
If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.   
The number and percentage of subjects who took any medications will be presented 
by centre and overall by medication class, standardised medication names sorted 
alphabetically for all subjects from the SAF, separately for prior medications and 
concomitant medications. 
All prior and concomitant medications will be listed including reported name, 
medication class, standardised medication name, indication, dose, dose unit, 
   
4.5 Administration of Investigational Product 
The volume of undiluted fluciclovine, activity of fluciclovine and injection site reaction 
during and following fluciclovine administration will be summarised for subjects in the 
SAF. 
5 EFFICACY EVALUATION 
All listings will be based on the FAS unless specified otherwise.  The primary efficacy 
analysis will be based on the EAS and will be repeated on the PPS as a secondary 
analysis.  The secondary efficacy analyses will be based on the FAS. 
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5.1 Primary Efficacy Variable 
The primary efficacy variable is the record of the revised management plan post 
fluciclovine (18F) PET/CT scan in comparison to the pre-scan intended management 
plan. 
5.2 Secondary Efficacy Variables 
The secondary efficacy variables are: 
 The proportion of subjects who have a sustained response to radical salvage 
therapy.  
 PSA levels in relation to scan positivity will be analysed to determine the 
optimal PSA threshold for detecting recurrent PCa by fluciclovine (18F) 
PET/CT.  
5.3 Definition of Region Levels 
Two main regions will be analysed, the prostate and prostate bed and the extra-
prostatic region. 
The prostate and prostate bed include the following lesion locations: 
 Prostate bed left 
 Prostate bed right 
 Peripheral zone left 
 Peripheral zone right 
 Central gland left 
 Central gland right 
 Left seminal vesicle 
 Right seminal vesicle 
The extra-prostatic regions include the following lesion locations 
 Lymph nodes 
o Pelvic lymph nodes 
 Common iliac left 
 Common iliac right 
 Internal iliac left 
 Internal iliac right 
 External iliac left 
 External iliac right 
 Obturator left 
 Obturator right 
 Pre-sacral left 
 Pre-sacral right 
 Peri-rectal anterior 
 Peri-rectal 
posterior 
 Peri-rectal left 
 Peri-rectal right 
 Inguinal left 
 Inguinal right 
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o Retroperitoneal lymph nodes 
 Para-aortic 
 Retro-aortic 
 Para-caval 
 Retro-caval 
 Aorto-caval 
 Retrocrural left 
 Retrocrural right 
o Other lymph nodes 
 Intra-peritoneal 
 Mediastinal left 
 Mediastinal right 
 Axillary left 
 Axillary right 
 Cervical left 
 Cervical right 
 Soft tissues/parenchyma 
o Lung upper lobe left 
o Lung upper lobe right 
o Lung middle lobe right 
o Lung lower lobe left 
o Lung lower lobe right 
o Brain left 
o Brain right 
o Liver left 
o Liver right 
o Spleen 
o Subcutaneous/cutaneous 
o Muscle 
o Bowel 
 Bones 
o Skull 
 Skull base/maxilla left 
 Skull base/maxilla right 
 Mandible left 
 Mandible right 
o Vertebra 
 Vertebra C1  
 Vertebra C2 
 Vertebra C3 
 Vertebra C4  
 Vertebra C5 
 Vertebra C6 
 Vertebra C7  
 Vertebra T1 
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 Vertebra T2 
 Vertebra T3  
 Vertebra T4 
 Vertebra T5 
 Vertebra T6 
 Vertebra T7  
 Vertebra T8 
 Vertebra T9 
 Vertebra T10 
 Vertebra T11 
 Vertebra T12 
 Vertebra L1  
 Vertebra L2  
 Vertebra L3  
 Vertebra L4  
 Vertebra L5  
 Sacrum left 
 Sacrum right 
 Sacrum central 
o Chest  
 1st rib left 
 1st rib right 
 2nd rib left 
 2nd rib right 
 3rd rib left 
 3rd rib right 
 4th rib left 
 4th rib right 
 5th rib left 
 5th rib right 
 6th rib left 
 6th rib right 
 7th rib left 
 7th rib right 
 8th rib left 
 8th rib right 
 9th rib left 
 9th rib right 
 10th rib left 
 10th rib right 
 11th rib left 
 11th rib right 
 12th rib left 
 12th rib right 
 Sternum 
 Clavicle left 
 Clavicle right 
 Scapula left 
 Scapula right 
o Pelvis 
 Ilium left 
 Ilium right 
 Superior pubic 
ramus left 
 Superior pubic 
ramus right 
 Inferior pubic 
ramus left 
 Inferior pubic 
ramus right 
 Pubic body left 
 Pubic body right 
 Ischium left 
 Ischium right 
 
 
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o Appendicular 
 Proximal humerus left 
 Proximal humerus right 
 Proximal femur left 
 Proximal femur right 
5.4 Statistical Analysis 
5.4.1 
Primary Efficacy Analysis 
The analysis of the primary outcome will be performed on the EAS as the primary 
analysis and will be repeated on the PPS as a secondary analysis.  Comparisons 
between the original treatment plan and the revised treatment plan will be 
categorised as no change, major change or other change.  The definitions of the 
change categories are listed below. 
 No change: the original treatment plan is the same as the revised treatment 
plan 
 Major change: the original treatment plan is not the same as the revised 
treatment plan and the grouping for the original treatment plan is not the same 
as the grouping for the revised treatment plan 
These will be further split and presented according to the following categories: 
- Salvage or Non-curative systemic therapy to Watchful waiting 
- Salvage therapy to Non-curative systemic therapy 
- Non-curative systemic therapy to Salvage therapy 
- Alternative Major change   
 Other change: the original treatment plan is not the same as the revised 
treatment plan but the grouping for the original treatment plan is the same as 
the grouping for the revised treatment plan 
These will be further split and presented according to the following categories: 
- Modified RT field plan 
- Modified androgen-deprivation regimen 
- Alternative Other change 
Groupings of treatment plans are detailed in the following table: 
 
 
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Original Treatment 
Plan 
Grouping for 
Original Tx Plan 
Revised Treatment 
Plan 
Grouping for 
Revised Tx Plan 
Was 
androgen 
deprivation therapy 
planned 
Androgen 
Deprivation 
Therapy 
Androgen 
deprivation therapy 
Androgen 
deprivation therapy 
 
 
Watch and wait 
Watch and wait 
 
 
Chemotherapy 
Chemotherapy 
Salvage 
radiotherapy to the 
prostate bed 
Salvage 
Radiotherapy 
 
Salvage 
radiotherapy to the 
prostate bed 
Salvage 
Radiotherapy 
Salvage 
radiotherapy to the 
prostate bed, with 
boost 
to 
areas 
guided 
by 
conventional 
imaging 
Salvage 
radiotherapy to the 
prostate bed, with 
boost 
to 
areas 
guided 
by 
conventional 
imaging 
 
Salvage 
radiotherapy to the 
prostate bed with 
boost 
to 
areas 
guided 
by 
fluciclovine 
(18F) 
PET/CT 
Salvage 
radiotherapy to the 
prostate bed and 
whole pelvis 
Salvage 
Radiotherapy 
Salvage 
radiotherapy to the 
prostate bed and 
whole pelvis 
Salvage 
Radiotherapy 
Salvage 
radiotherapy to the 
prostate bed and 
whole pelvis, with 
boost 
to 
areas 
guided 
by 
conventional 
imaging 
Salvage 
radiotherapy to the 
prostate bed and 
whole pelvis, with 
boost 
to 
areas 
guided 
by 
conventional 
imaging 
 
Salvage 
radiotherapy to the 
prostate bed and 
whole pelvis with 
boost 
to 
areas 
guided 
by 
fluciclovine 
(18F) 
PET/CT 
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Original Treatment 
Plan 
Grouping for 
Original Tx Plan 
Revised Treatment 
Plan 
Grouping for 
Revised Tx Plan 
Salvage 
cryotherapy 
Salvage 
Cryotherapy 
Salvage 
cryotherapy 
Salvage 
Cryotherapy 
 
Salvage 
cryotherapy 
with 
boost 
to 
areas 
guided 
by 
fluciclovine 
(18F) 
PET/CT 
Salvage 
brachytherapy 
Salvage 
Brachytherapy 
Salvage 
brachytherapy 
Salvage 
Brachytherapy 
 
Salvage 
brachytherapy with 
boost 
to 
areas 
guided 
by 
fluciclovine 
(18F) 
PET/CT 
 
Salvage 
brachytherapy with 
treatment 
plan 
guided 
by 
fluciclovine 
(18F) 
PET/CT 
Salvage HIFU 
Salvage HIFU 
Salvage HIFU 
Salvage HIFU 
 
Salvage HIFU with 
treatment 
plan 
guided 
by 
fluciclovine 
(18F) 
PET/CT 
Salvage 
prostatectomy 
Salvage 
Prostatectomy 
Salvage 
prostatectomy 
Salvage 
Prostatectomy 
 
Salvage 
prostatectomy with 
targeted resection / 
sampling 
of 
fluciclovine 
(18F) 
positive 
areas 
outside 
conventional 
surgical field 
Salvage 
prostatectomy and 
limited lymph node 
dissection 
Salvage 
prostatectomy and 
limited lymph node 
dissection 
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Original Treatment 
Plan 
Grouping for 
Original Tx Plan 
Revised Treatment 
Plan 
Grouping for 
Revised Tx Plan 
 
Salvage 
prostatectomy and 
limited lymph node 
dissection 
with 
targeted resection / 
sampling 
of 
fluciclovine 
(18F) 
positive 
areas 
outside surgical field
Salvage 
prostatectomy and 
extended 
lymph 
node 
dissection 
(including 
internal 
and external iliac, 
and 
obturator 
nodes) 
Salvage 
prostatectomy and 
extended 
lymph 
node 
dissection 
(including 
internal 
and external iliac, 
and 
obturator 
nodes) 
 
Salvage 
prostatectomy and 
extended 
lymph 
node 
dissection 
(including 
internal 
and external iliac, 
and 
obturator 
nodes) with targeted 
resection / sampling 
of fluciclovine (18F) 
positive 
areas 
outside surgical field
 
 
Targeted 
salvage 
treatment 
of 
fluciclovine 
(18F) 
positive extra-pelvic 
/ bony areas 
Targeted salvage 
treatment 
 
 
Other 
Other 
The classification and sub-classification of change in treatment management plan 
will be agreed prior to data base lock.  
The number, percentage and exact 95% CI of subjects with and without a change in 
management plan after the fluciclovine (18F) scan results become available will be 
presented.  In addition, the number and percentage of subjects with changes 
categorised as major or other will be presented.  These summaries will be repeated 
separately for subjects with a positive and a negative fluciclovine (18F) scan and for 
subjects without prostatectomy and with prostatectomy.  
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The number, percentage and 95% CI of subjects who agreed to the revised 
management plan after fluciclovine (18F) scan results become available will be 
presented. 
Details of the intended management plan, revised management plan and agreed 
management plan will be listed. 
5.4.2 
Secondary Efficacy Analyses 
5.4.2.1 Treatment response as assessed by change in PSA 
An assessment of treatment response, which is based on the percentage change in 
PSA from baseline to the last value reported, is defined as: 
 >=30% decrease in PSA will be considered to be a response to treatment 
 <25% increase or <30% decrease will be classified as stable disease 
 >=25% increase in PSA will be classified as disease progression 
See section 2 General Principles for baseline definition. 
The number, percentage and exact 95% CI of subjects having a treatment response, 
stable disease and disease progression, as assessed by change in PSA, will be 
presented overall and separately for subjects in the FAS who had salvage treatment, 
for subjects who had non-salvage treatment, for those with a change in management 
plan and for subjects with no change in management plan following the 18F-
fluciclovine PET/CT scan.  In addition, treatment response assessed by change in 
PSA will be summarised by disease location (local disease versus extra-prostatic 
disease) and treatment administered. 
The percentage change in PSA from baseline to the last value reported will be 
summarised overall and by subjects who had a change in management plan versus 
those who did not have a change in management plan following the 18F-fluciclovine 
PET/CT scan, disease location and treatment administered.   
Finally, a waterfall plot of the maximum percentage reduction in PSA during the 4-8 
month window will be presented on the y-axis and each subject will be represented by 
a bar on the x-axis.  The bars will be ordered in descending order of the magnitude of 
the percentage change in PSA value. 
Treatment response and the factors used to assess the response will be listed in full. 
5.4.2.2 PSA threshold 
The detection rate (DR) will be calculated as number of positive fluciclovine (18F) 
scan results/total number of scans. 
 
 
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The point estimate (expressed in percentage) of the DR will be presented at the 
region level and at the subject level. These rates will be presented for all subjects 
from the FAS and PPS, overall and across a range of baseline PSA values: 
 0  0.2 
 >0.2  0.5 
 >0.5  1.0 
 >1.0  2.0 
 >2.0  5.0 
 >5.0  10.0 
 >10.0 
to determine the optimum PSA threshold for lesion detection.   See section 2 
General Principles for baseline definition. 
The detection rates will also be summarised across the following baseline Gleason 
score categories: <=6, 7, 8 and >=9. 
All fluciclovine (18F) and other imaging results will be listed. 
5.4.3 
Handling of Dropouts or Missing Data 
Subjects who withdrew from the study prior to completion will be summarised. 
Withdrawn subjects will not be directly replaced and no imputation of missing data 
will be conducted. 
5.4.4 
Interim Analyses and Data Monitoring 
A single interim analysis of the primary endpoint will be performed in the first 85 
evaluable subjects. If the number of treatment changes is greater than 45 (52.9%, 
with a 97.5% two-sided CI of 40.3%-62.3%, so the lower limit is over 40%), the trial 
will be terminated early due to overwhelming effectiveness. If the number of 
treatment changes is 8 or fewer (9.4%, with a 97.5% two-sided CI of 3.6%-18.9%, so 
the upper limit in this population is below the 20% of the null hypothesis), the trial will 
be terminated early due to futility.  
5.4.5 
Examination of Subgroups 
No subgroup analyses will be conducted during the study. 
5.4.6 
Site Specific Sub-study 
A site specific sub-study will be conducted in order to compare the ordered subset 
expectation maximisation (OSEM) standard of care method of reconstructing 
PET/CT images with that of the Bayesian penalised likelihood method of PET/CT 
image reconstruction.  The analysis of the sub-study results is beyond the scope of 
this SAP. 
6 SAFETY EVALUATION 
All safety evaluations will be performed on the safety analysis set (SAF) unless 
specified otherwise. 
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All safety tables will be presented by centre and overall. 
Subjects will be included and counted in summary tables only if they have available 
data. 
6.1 Adverse Events 
Adverse events (AE) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 17.1. 
A treatment-emergent adverse event (TEAE) is defined as an AE with start date/time 
on or after the start/time of fluciclovine (18F) administration, or AEs with worsening 
intensity on or after the start date/time of fluciclovine (18F) administration.   
AEs with unknown start date/time will be assumed to be treatment-emergent unless 
the end date/time is known to be before the fluciclovine (18F) administration. 
Summary tables will be produced for all TEAEs occurring up to 42 days (i.e. 
occurring between day 1 and day 43) after the fluciclovine (18F) administration. 
An overall summary of TEAEs will be created including: 
 number of TEAEs and number of subjects with TEAEs,  
 number of TEAEs and number of subjects with TEAEs associated with the 
injection site,  
 number of serious TEAEs and number of subjects with serious TEAEs,  
 number of subjects with TEAEs by CTCAE grade (Grade 1 to Grade 5),  
 number of subjects with TEAEs by relationship to fluciclovine (unrelated, 
possibly related, probably related, definitely related and related, where related 
adverse events are those classified as possibly, probably and definitely 
related to fluciclovine 18F)  
The number and percentage of subjects experiencing TEAEs will be presented by 
system organ class (SOC) and preferred term (PT).  System organ class and 
preferred term will be presented in decreasing frequency of the total number of 
subjects with TEAEs.  If a subject experienced more than one treatment-emergent 
adverse event, the subject will be counted once for each system organ class and 
once for each preferred term. 
The number and percentage of subjects experiencing TEAEs will be presented by 
SOC, PT and CTCAE grade.  SOC and PT will be presented in decreasing 
frequency of the total number of subjects with TEAEs. If a subject experienced more 
than one TEAE, the subject will be counted once for each SOC and once for each 
PT at the worst severity. 
The number and percentage of subjects experiencing TEAEs will be presented by 
SOC, PT and relationship to study drug. SOC and PT will be presented in 
decreasing frequency of the total number of subjects with TEAEs. If a subject 
experienced more than one TEAE, the subject will be counted once for each SOC 
and once for each PT at the closest relationship to study drug. 
All adverse events will be listed and TEAEs will be identified.  AEs occurring up to 42 
days after fluciclovine (18F) administration will be flagged.   All SAEs will be listed 
separately. 
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6.2 Clinical Laboratory Evaluation 
6.2.1 Haematology 
Haematology values will be summarised by parameter and visit, and also for change 
from baseline (last pre-scan value vs first post-scan value). 
All haematology values will be listed showing reference ranges (flagging abnormal 
findings). 
6.2.2 Biochemistry 
Biochemistry values will be summarised by parameter and visit, and also for change 
from baseline (last pre-scan value vs first post-scan value). 
Additionally, from the serum creatinine levels (mg/dL), creatinine clearance (CrCl) 
will be derived using the Cockcroft Gault formula (Cockroft DW, 1976)  and the 
glomerular filtration rate (GFR) will be derived using the MDRD formula (Levey AS, 
2006) as follows: 
 Cockcroft-Gault formula: CrCl (mL/min) = [(140 - age) * (Weight in kg) * (0.85 
if female)] / (72 * Creatinine) 
 MDRD formula: GFR (mL/min) = 175 * Creatinine-1.154 * age-0.203 * (1.212 if 
subject is black) * (0.742 if female) 
/min, >30 - 
- 
summarised by time window, and the shift table of baseline status against the worst 
status on or after fluciclovine (18F) administration will be presented. 
All biochemistry values will be listed showing reference ranges and flagging 
abnormal findings. 
6.2.3 Urinalysis dipstick 
All urinalysis results will be listed. 
6.2.4 Urine microscopy 
All urine microscopy results will be listed. 
6.3 Vital Signs 
Vital signs include pulse rate, systolic and diastolic blood pressure. 
Vital sign values will be summarised by parameter and time point, and also for 
change from baseline. 
Details of vital signs data will be listed. 
6.4 Electrocardiography 
Electrocardiogram (ECG) interpretation is recorded at screening and visit 4. 
ECG interpretations will be summarised by shift tables highlighting any changes 
between screening and visit 4. 
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7 REFERENCES 
Cockroft DW, G. M. (1976). Prediction of creatinine clearance from serum creatinine. 
Nephron, 31-41. 
Levey AS, C. J. (2006). Using standardized serum creatinine values in the modification 
of diet in renal disease study equation for estimating glomerular filtration rate. 
Ann Intern Med, 247-254. 
 
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Date: 10OCT2018  
 
Page 1 of 22 
Version: Amendment 1 Final 
ST/form/010/6 
 
 
A Phase 3, Open-label Study to Assess the Clinical Utility 
of Fluciclovine (18F) PET/CT in Patients with Prostate 
Cancer with Biochemical Recurrence after Radical 
Treatment 
 
Blue Earth Diagnostics Study No: BED-004 
Syne qua non Ltd Study No: BLS14004 
 
 
Statistical Analysis Plan  
 
 
Version: Amendment 1 Final 
Date:  10th October 2018 
 
 
 
 
For Syne qua non Ltd  Lead Statistician 
Sig1sig 
 
For Blue Earth Diagnostics 
 
Sig2sig 
 
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Contents 
 
1 
INTRODUCTION ............................................................................................................................. 5 
2 
GENERAL PRINCIPLES ................................................................................................................. 5 
3 
STUDY OBJECTIVES AND DESIGN ............................................................................................. 5 
3.1 
Study Objectives ......................................................................................................................... 5 
3.2 
Study Design ............................................................................................................................... 6 
3.3 
Visit Structure .............................................................................................................................. 6 
3.4 
Sample Size ................................................................................................................................ 7 
3.5 
Changes from the Protocol Planned Analysis ............................................................................ 7 
4 
STUDY SUBJECTS ........................................................................................................................ 7 
4.1 
Analysis sets ............................................................................................................................... 7 
4.2 
Disposition of Subjects ............................................................................................................... 7 
4.3 
Protocol Deviations ..................................................................................................................... 8 
4.4 
Background and Demographic Characteristics .......................................................................... 8 
4.4.1 
Demographic and Baseline Characteristics............................................................................. 8 
4.4.2 
Medical History ........................................................................................................................ 8 
4.4.3 
Prostate Cancer History........................................................................................................... 8 
4.4.4 
Cancer Therapies for Prostate Cancer .................................................................................... 9 
4.4.5 
Prior and Concomitant Medications ....................................................................................... 10 
4.5 
Administration of Investigational Product ................................................................................. 10 
5 
EFFICACY EVALUATION ............................................................................................................. 10 
5.1 
Primary Efficacy Variable .......................................................................................................... 11 
5.2 
Secondary Efficacy Variables ................................................................................................... 11 
5.3 
Definition of Region Levels ....................................................................................................... 11 
5.4 
Statistical Analysis .................................................................................................................... 14 
5.4.1 
Primary Efficacy Analysis ...................................................................................................... 14 
5.4.2 
Secondary Efficacy Analyses ................................................................................................ 18 
5.4.3 
Handling of Dropouts or Missing Data ................................................................................... 19 
5.4.4 
Interim Analyses and Data Monitoring ................................................................................... 19 
5.4.5 
Examination of Subgroups .................................................................................................... 19 
5.4.6 
Site Specific Sub-study .......................................................................................................... 19 
6 
SAFETY EVALUATION ................................................................................................................ 19 
6.1 
Adverse Events ......................................................................................................................... 20 
6.2 
Clinical Laboratory Evaluation .................................................................................................. 21 
6.2.1 
Haematology .......................................................................................................................... 21 
6.2.2 
Biochemistry .......................................................................................................................... 21 
6.2.3 
Urinalysis dipstick .................................................................................................................. 21 
6.2.4 
Urine microscopy ................................................................................................................... 21 
6.3 
Vital Signs ................................................................................................................................. 21 
6.4 
Electrocardiography .................................................................................................................. 21 
7 
References .................................................................................................................................... 22 
 
 
 
 
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ABBREVIATIONS 
 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BCR 
Biochemical recurrence 
BMI 
Body mass index 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CrCl 
Creatinine clearance 
CRF 
Case report form 
CT 
Computerised Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
EAS 
Evaluable analysis set 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
GFR 
Glomerular filtration rate 
GGT 
Gamma glutamyl transferase 
LDH 
Lactate dehydrogenase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
ms 
Milliseconds 
PCa 
Prostate cancer 
PET 
Positron emission tomography 
PPS 
Per protocol set 
PSA 
Prostate specific antigen 
PT 
Preferred term 
RBC 
Red blood cell 
RDW 
Red cell distribution width 
RP 
Radical prostatectomy 
RRT 
Radical external beam radiotherapy 
RT 
Radiotherapy 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
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SOC 
System organ class 
TEAE 
Treatment emergent adverse event 
TNM 
TNM classification of malignant tumours 
WBC 
White blood cell 
WHO 
World Health Organization  
WHO DDE 
WHO Drug Dictionary Enhanced 
 
 
 
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1 INTRODUCTION 
This Statistical Analysis Plan (SAP) is based on the final protocol version dated 24th 
March 2015 and amendments 1-4 dated 30th November 2015, 5th April 2016, 2nd 
March 2017 and 4th June 2018. 
The SAP describes the tables, listings and figures which will be provided upon 
completion of the study. The SAP will be finalised before locking the database. 
The table, listing and figure shells will be supplied in a separate document. 
2 GENERAL PRINCIPLES 
The analysis and statistical reporting will be conducted at Syne qua non using SAS 
version 9.2 or higher. 
All listings will be based on all enrolled subjects unless specified otherwise.  All 
tables will be presented by site and overall for the appropriate analysis population. 
Descriptive summary statistics for continuous variables will include number of 
subjects (n), mean, standard deviation (SD), minimum, median, and maximum, 
unless specified otherwise. The precision of these summary statistics is defined in 
the table, figure and listing shells document. 
Descriptive summary statistics for categorical variables will include frequency counts 
and percentages [n (%)]. Unless stated otherwise, the denominator for percentage 
calculations will be the number of subjects in the analysis set. 
For treatment response baseline prostate specific antigen (PSA) is the most recent 
PSA measurement prior to salvage therapy for subjects who had salvage treatment 
and the most recent PSA measurement prior to the 18F-fluciclovine positron 
emission tomography/computerised tomography (PET/CT) for non-salvage subjects. 
If no PSA measurement is available just prior to salvage therapy, baseline will be 
defined as the most recent PSA measurement prior to fluciclovine (18F) scan.  For all 
other variables, and for baseline PSA other than for treatment response, baseline is 
defined as the most recent value prior to fluciclovine (18F) administration.  
In general, there will be no imputation of missing data, however where dates are 
partially missing dates may be imputed for calculation purposes, details are given 
under relevant section. 
3 STUDY OBJECTIVES AND DESIGN 
3.1 Study Objectives 
The primary objective of the study is to confirm the clinical benefit of fluciclovine (18F) 
PET/CT in affecting management decisions in subjects with biochemical recurrence 
(BCR) being considered for radical salvage treatment (with curative intent). 
The secondary objectives of the study are 
 To assess possible improvement in outcome of radical salvage treatment 
based on fluciclovine (18F) PET/CT being included in the assessment 
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 To assess the PSA threshold for positive lesion detection by fluciclovine (18F) 
PET/CT in BCR  
 To assess the safety of fluciclovine (18F) injection in subjects undergoing 
PET/CT  
3.2 Study Design 
This will be an open-labelled, multi-centred study in the United Kingdom.  
The study group will include up to 180 subjects with a diagnosis of BCR of previous 
radically treated prostate cancer (PCa), and who are being considered for radical 
salvage therapy.  
Subjects will have a fluciclovine (18F) PET/CT scan in addition to standard work-up 
for radical salvage therapy. The clinical utility of fluciclovine (18F) PET/CT will be 
assessed by recording changes to the recommended management plan influenced 
by the scan result.  
The summary flow chart of the study design is as follows: 
 
3.3 Visit Structure 
The visit structure and scheduled assessments are detailed in Appendix A: Schedule 
of study procedures of the protocol. 
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3.4 Sample Size 
For the primary objective of treatment change evaluation, a minimum of 171 subjects 
with complete primary endpoint data will be required to allow for a width of +/-6% in a 
two-sided 95% confidence interval (CI). This is based on the conservative 
assumption that 20% of subjects will have a treatment change, as fluciclovine (18F) 
PET/CT has been shown to upstage 25.7% of subjects with recurrent prostate 
cancer, and also based on the management change studies reported on choline 
PET/CT. The aim is to recruit 180 subjects for this trial, based on an anticipated 
primary endpoint drop-out rate of 5%.  
3.5 Changes from the Protocol Planned Analysis 
Improvement in outcome of radical salvage treatment based 
on fluciclovine (18F) PET/CT being included in the assessment
endpoint.   This was to be assessed based on PSA and radiological response.  Due 
to lack of data being recorded for radiological response this definition was not used, 
treatment response was instead assessed using PSA only (see section 5.4.2.1.). 
4 STUDY SUBJECTS 
4.1 Analysis sets 
The list of subjects to be included in each of the analysis set is to be agreed between 
the Syne qua non statistician and Blue Earth Diagnostics once all study data are 
available and prior to database lock. 
Enrolled Set:  All subjects who entered screening. 
Safety Analysis Set (SAF): All subjects who have been included in the database 
and have been administered fluciclovine (18F) will be included in the Safety Analysis 
Set (SAF). 
Full Analysis Set (FAS): All subjects enrolled who have had a fluciclovine (18F) 
PET/CT scan will be included in the Full Analysis Set (FAS). 
Evaluable Analysis Set (EAS): All subjects from the FAS who have an intended 
treatment management plan completed and a revised management plan page 
completed will be included in the Evaluable Analysis Set (EAS). 
Per Protocol Set (PPS): All subjects in the EAS without major significant deviation 
following review of the protocol deviation list.  
4.2 Disposition of Subjects 
The number and percentage of all subjects enrolled, included in each analysis set, 
who completed the study and who prematurely withdrew, including a breakdown of 
the primary reasons for withdrawal, will be presented. 
All enrolled subjects will be listed indicating their membership to the evaluable 
analysis set along with the reason for exclusion. 
Completion and withdrawal information will be listed, including individual reasons for 
withdrawal. 
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4.3 Protocol Deviations 
Failed inclusion criteria and failed exclusion criteria will be listed for screening 
failures. 
The number and percentage of subjects within each deviation category will be 
presented by deviation type (Major Significant, Major or Minor) and by site and 
overall. The deviation category and type will be provided by Blue Earth Diagnostics. 
All protocol deviations will be listed. 
4.4 Background and Demographic Characteristics 
4.4.1 
Demographic and Baseline Characteristics 
Demographic characteristics (age, ethnic origin and race collected at Screening), 
body measurements (height, weight collected, and BMI derived at Visit 2) will be 
summarised for the enrolled set, FAS, EAS and PPS populations. 
Body mass index (BMI) is calculated as (weight (kg)/height (m)²). 
Individual demographic characteristics and body measurements data will be listed. 
4.4.2 
Medical History 
Medical history events will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 18.1. 
The number and percentage of subjects from the FAS with previous medical history 
and current events will be tabulated by system organ class (SOC), preferred term 
(PT). SOCs will be ordered in decreasing frequency of the total number of subjects 
with medical history events reported in each SOC and PTs will be ordered within a 
SOC in decreasing frequency of the total number of subjects with each medical 
history event.  This table will be repeated for all events, regardless of whether 
previous or current events. 
All medical history events will be listed. 
4.4.3 
Prostate Cancer History 
Details of prostate cancer history will be summarised for subjects from the FAS, and 
will consist of: 
 Time since initial diagnosis (months), calculated as [12*(date of informed 
consent  date of initial prostate cancer diagnosis + 1)/365.25] 
 TNM stage: Pathological TNM stage if available, otherwise Clinical TNM 
stage.  A summary for T1 total, T2 total and T3 total will be provided as the 
sum of the number of subjects in each of the subgroups plus any subjects 
where only T1, T2 or T3 was recorded. 
 Gleason total score: Gleason total score from surgery if available, otherwise 
Gleason total score from biopsy 
 Time since adjuvant treatment (months), calculated as [12*(date of informed 
consent  stop date of adjuvant treatment + 1)/365.25] 
 Duration of adjuvant treatment (months), calculated as [12*(stop date of 
adjuvant treatment  start date of adjuvant treatment + 1)/365.25] 
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 Time since diagnosis of biochemical recurrence (days), calculated as (date of 
informed consent  date of diagnosis of biochemical recurrence + 1).  Time 
since diagnosis of BCR may be derived in months if more appropriate. 
 Baseline PSA value 
 Baseline PSA category (0  0.2, >0.2  0.5, >0.5  1, >1  2, >2  5, >5  10 
and >10) 
In addition, summary table to summarise baseline Prostate Specific Antigen (PSA) by 
Prior Radical Prostatectomy status (Prior Radical Prostatectomy vs No Prior Radical 
Prostatectomy) using descriptive statistics (number of subjects (n), mean, standard 
deviation (SD), minimum, median, and maximum), will be produced.   
Details of prostate cancer history will be listed.  
Date imputation for incomplete dates: 
 If day part missing, put 15th of the month 
 If day and month parts missing, put 01 July 
4.4.4 
Cancer Therapies for Prostate Cancer 
Cancer therapies for prostate cancer will be coded according to the World Health 
Organization Drug Dictionary Enhanced (WHO DDE) (Enhanced) version Sep 2015.  
Cancer therapies will be categorised as follows: 
Subjects with radical prostatectomy: 
 Radiotherapy 
 No radiotherapy 
Subjects without radical prostatectomy: 
 Radiotherapy only 
o EBRT only 
o Brachytherapy only 
o EBRT and brachytherapy 
 Radiotherapy and other therapies 
o EBRT and other therapies 
o Brachytherapy and other therapies 
 Other therapies 
Prior cancer therapies for prostate cancer are defined as those for which the end 
date is prior to the date of injection of fluciclovine (18F). 
Concomitant/post-scan cancer therapies for prostate cancer are defined as those 
with a start date on or after the injection date of fluciclovine (18F), or those with a start 
date before the injection date of fluciclovine (18F) but which continued with a stop on 
or after the injection date of fluciclovine (18F).  Summaries for subjects with prior and 
post-scan radical prostatectomy will be presented separately. 
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Summary table to summarise time from 18F-fluciclovine PET/CT to first post-18F-
fluciclovine treatment in days using descriptive statistics (number of subjects (n), 
mean, SD, minimum, median, and maximum) will be provided. 
If cancer therapy dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.   
The number and percentage of subjects per category of prostate cancer therapy will 
be presented for all subjects from the SAF, separately for subjects with and without 
radical prostatectomy.  This summary will be repeated for prior and concomitant 
cancer therapies. 
All therapies for prostate cancer will be listed including type of therapy, reported 
therapy name, medication class, standardised medication name, dose, dose unit, 
   
4.4.5 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded according to the World Health 
Organization Drug Dictionary Enhanced (WHO DDE) (Enhanced) version Sep 2015. 
Prior medications are defined as those for which the end date is prior to the date of 
injection of fluciclovine (18F). 
Concomitant medications are defined as those with a start date on or after the 
injection date of fluciclovine (18F), or those with a start date before the injection date 
of fluciclovine (18F) but which continued with a stop date on or after the injection date 
of fluciclovine (18F). 
If medication dates are incomplete and it is not clear whether the medication was 
concomitant, it will be assumed to be concomitant.   
The number and percentage of subjects who took any medications will be presented 
by centre and overall by medication class, standardised medication names sorted 
alphabetically for all subjects from the SAF, separately for prior medications and 
concomitant medications. 
All prior and concomitant medications will be listed including reported name, 
medication class, standardised medication name, indication, dose, dose unit, 
   
4.5 Administration of Investigational Product 
The volume of undiluted fluciclovine, activity of fluciclovine and injection site reaction 
during and following fluciclovine administration will be summarised for subjects in the 
SAF. 
5 EFFICACY EVALUATION 
All listings will be based on the FAS unless specified otherwise.  The primary efficacy 
analysis will be based on the EAS and will be repeated on the PPS as a secondary 
analysis.  The secondary efficacy analyses will be based on the FAS. 
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5.1 Primary Efficacy Variable 
The primary efficacy variable is the record of the revised management plan post 
fluciclovine (18F) PET/CT scan in comparison to the pre-scan intended management 
plan. 
5.2 Secondary Efficacy Variables 
The secondary efficacy variables are: 
 The proportion of subjects who have a sustained response to radical salvage 
therapy.  
 PSA levels in relation to scan positivity will be analysed to determine the 
optimal PSA threshold for detecting recurrent PCa by fluciclovine (18F) 
PET/CT.  
5.3 Definition of Region Levels 
Two main regions will be analysed, the prostate and prostate bed and the extra-
prostatic region. 
The prostate and prostate bed include the following lesion locations: 
 Prostate bed left 
 Prostate bed right 
 Peripheral zone left 
 Peripheral zone right 
 Central gland left 
 Central gland right 
 Left seminal vesicle 
 Right seminal vesicle 
The extra-prostatic regions include the following lesion locations 
 Lymph nodes 
o Pelvic lymph nodes 
 Common iliac left 
 Common iliac right 
 Internal iliac left 
 Internal iliac right 
 External iliac left 
 External iliac right 
 Obturator left 
 Obturator right 
 Pre-sacral left 
 Pre-sacral right 
 Peri-rectal anterior 
 Peri-rectal 
posterior 
 Peri-rectal left 
 Peri-rectal right 
 Inguinal left 
 Inguinal right 
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o Retroperitoneal lymph nodes 
 Para-aortic 
 Retro-aortic 
 Para-caval 
 Retro-caval 
 Aorto-caval 
 Retrocrural left 
 Retrocrural right 
o Other lymph nodes 
 Intra-peritoneal 
 Mediastinal left 
 Mediastinal right 
 Axillary left 
 Axillary right 
 Cervical left 
 Cervical right 
 Soft tissues/parenchyma 
o Lung upper lobe left 
o Lung upper lobe right 
o Lung middle lobe right 
o Lung lower lobe left 
o Lung lower lobe right 
o Brain left 
o Brain right 
o Liver left 
o Liver right 
o Spleen 
o Subcutaneous/cutaneous 
o Muscle 
o Bowel 
 Bones 
o Skull 
 Skull base/maxilla left 
 Skull base/maxilla right 
 Mandible left 
 Mandible right 
o Vertebra 
 Vertebra C1  
 Vertebra C2 
 Vertebra C3 
 Vertebra C4  
 Vertebra C5 
 Vertebra C6 
 Vertebra C7  
 Vertebra T1 
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 Vertebra T2 
 Vertebra T3  
 Vertebra T4 
 Vertebra T5 
 Vertebra T6 
 Vertebra T7  
 Vertebra T8 
 Vertebra T9 
 Vertebra T10 
 Vertebra T11 
 Vertebra T12 
 Vertebra L1  
 Vertebra L2  
 Vertebra L3  
 Vertebra L4  
 Vertebra L5  
 Sacrum left 
 Sacrum right 
 Sacrum central 
o Chest  
 1st rib left 
 1st rib right 
 2nd rib left 
 2nd rib right 
 3rd rib left 
 3rd rib right 
 4th rib left 
 4th rib right 
 5th rib left 
 5th rib right 
 6th rib left 
 6th rib right 
 7th rib left 
 7th rib right 
 8th rib left 
 8th rib right 
 9th rib left 
 9th rib right 
 10th rib left 
 10th rib right 
 11th rib left 
 11th rib right 
 12th rib left 
 12th rib right 
 Sternum 
 Clavicle left 
 Clavicle right 
 Scapula left 
 Scapula right 
o Pelvis 
 Ilium left 
 Ilium right 
 Superior pubic 
ramus left 
 Superior pubic 
ramus right 
 Inferior pubic 
ramus left 
 Inferior pubic 
ramus right 
 Pubic body left 
 Pubic body right 
 Ischium left 
 Ischium right 
 
 
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o Appendicular 
 Proximal humerus left 
 Proximal humerus right 
 Proximal femur left 
 Proximal femur right 
5.4 Statistical Analysis 
5.4.1 
Primary Efficacy Analysis 
The analysis of the primary outcome will be performed on the EAS as the primary 
analysis and will be repeated on the PPS as a secondary analysis.  Comparisons 
between the original treatment plan and the revised treatment plan will be 
categorised as no change, major change or other change.  The definitions of the 
change categories are listed below. 
 No change: the original treatment plan is the same as the revised treatment 
plan 
 Major change: the original treatment plan is not the same as the revised 
treatment plan and the grouping for the original treatment plan is not the same 
as the grouping for the revised treatment plan 
These will be further split and presented according to the following categories: 
- Salvage or Non-curative systemic therapy to Watchful waiting 
- Salvage therapy to Non-curative systemic therapy 
- Non-curative systemic therapy to Salvage therapy 
- Alternative Major change   
 Other change: the original treatment plan is not the same as the revised 
treatment plan but the grouping for the original treatment plan is the same as 
the grouping for the revised treatment plan 
These will be further split and presented according to the following categories: 
- Modified RT field plan 
- Modified androgen-deprivation regimen 
- Alternative Other change 
Groupings of treatment plans are detailed in the following table: 
 
 
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Original Treatment 
Plan 
Grouping for 
Original Tx Plan 
Revised Treatment 
Plan 
Grouping for 
Revised Tx Plan 
Was 
androgen 
deprivation therapy 
planned 
Androgen 
Deprivation 
Therapy 
Androgen 
deprivation therapy 
Androgen 
deprivation therapy 
 
 
Watch and wait 
Watch and wait 
 
 
Chemotherapy 
Chemotherapy 
Salvage 
radiotherapy to the 
prostate bed 
Salvage 
Radiotherapy 
 
Salvage 
radiotherapy to the 
prostate bed 
Salvage 
Radiotherapy 
Salvage 
radiotherapy to the 
prostate bed, with 
boost 
to 
areas 
guided 
by 
conventional 
imaging 
Salvage 
radiotherapy to the 
prostate bed, with 
boost 
to 
areas 
guided 
by 
conventional 
imaging 
 
Salvage 
radiotherapy to the 
prostate bed with 
boost 
to 
areas 
guided 
by 
fluciclovine 
(18F) 
PET/CT 
Salvage 
radiotherapy to the 
prostate bed and 
whole pelvis 
Salvage 
Radiotherapy 
Salvage 
radiotherapy to the 
prostate bed and 
whole pelvis 
Salvage 
Radiotherapy 
Salvage 
radiotherapy to the 
prostate bed and 
whole pelvis, with 
boost 
to 
areas 
guided 
by 
conventional 
imaging 
Salvage 
radiotherapy to the 
prostate bed and 
whole pelvis, with 
boost 
to 
areas 
guided 
by 
conventional 
imaging 
 
Salvage 
radiotherapy to the 
prostate bed and 
whole pelvis with 
boost 
to 
areas 
guided 
by 
fluciclovine 
(18F) 
PET/CT 
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Original Treatment 
Plan 
Grouping for 
Original Tx Plan 
Revised Treatment 
Plan 
Grouping for 
Revised Tx Plan 
Salvage 
cryotherapy 
Salvage 
Cryotherapy 
Salvage 
cryotherapy 
Salvage 
Cryotherapy 
 
Salvage 
cryotherapy 
with 
boost 
to 
areas 
guided 
by 
fluciclovine 
(18F) 
PET/CT 
Salvage 
brachytherapy 
Salvage 
Brachytherapy 
Salvage 
brachytherapy 
Salvage 
Brachytherapy 
 
Salvage 
brachytherapy with 
boost 
to 
areas 
guided 
by 
fluciclovine 
(18F) 
PET/CT 
 
Salvage 
brachytherapy with 
treatment 
plan 
guided 
by 
fluciclovine 
(18F) 
PET/CT 
Salvage HIFU 
Salvage HIFU 
Salvage HIFU 
Salvage HIFU 
 
Salvage HIFU with 
treatment 
plan 
guided 
by 
fluciclovine 
(18F) 
PET/CT 
Salvage 
prostatectomy 
Salvage 
Prostatectomy 
Salvage 
prostatectomy 
Salvage 
Prostatectomy 
 
Salvage 
prostatectomy with 
targeted resection / 
sampling 
of 
fluciclovine 
(18F) 
positive 
areas 
outside 
conventional 
surgical field 
Salvage 
prostatectomy and 
limited lymph node 
dissection 
Salvage 
prostatectomy and 
limited lymph node 
dissection 
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Original Treatment 
Plan 
Grouping for 
Original Tx Plan 
Revised Treatment 
Plan 
Grouping for 
Revised Tx Plan 
 
Salvage 
prostatectomy and 
limited lymph node 
dissection 
with 
targeted resection / 
sampling 
of 
fluciclovine 
(18F) 
positive 
areas 
outside surgical field
Salvage 
prostatectomy and 
extended 
lymph 
node 
dissection 
(including 
internal 
and external iliac, 
and 
obturator 
nodes) 
Salvage 
prostatectomy and 
extended 
lymph 
node 
dissection 
(including 
internal 
and external iliac, 
and 
obturator 
nodes) 
 
Salvage 
prostatectomy and 
extended 
lymph 
node 
dissection 
(including 
internal 
and external iliac, 
and 
obturator 
nodes) with targeted 
resection / sampling 
of fluciclovine (18F) 
positive 
areas 
outside surgical field
 
 
Targeted 
salvage 
treatment 
of 
fluciclovine 
(18F) 
positive extra-pelvic 
/ bony areas 
Targeted salvage 
treatment 
 
 
Other 
Other 
The classification and sub-classification of change in treatment management plan 
will be agreed prior to data base lock.  
The number, percentage and exact 95% CI of subjects with and without a change in 
management plan after the fluciclovine (18F) scan results become available will be 
presented.  In addition, the number and percentage of subjects with changes 
categorised as major or other will be presented.  These summaries will be repeated 
separately for subjects with a positive and a negative fluciclovine (18F) scan and for 
subjects without prostatectomy and with prostatectomy.  
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The number, percentage and 95% CI of subjects who agreed to the revised 
management plan after fluciclovine (18F) scan results become available will be 
presented. 
Details of the intended management plan, revised management plan and agreed 
management plan will be listed. 
5.4.2 
Secondary Efficacy Analyses 
5.4.2.1 Treatment response as assessed by change in PSA 
An assessment of treatment response, which is based on the percentage change in 
PSA from baseline to the last value reported, is defined as: 
 >=30% decrease in PSA will be considered to be a response to treatment 
 <25% increase or <30% decrease will be classified as stable disease 
 >=25% increase in PSA will be classified as disease progression 
See section 2 General Principles for baseline definition. 
The number, percentage and exact 95% CI of subjects having a treatment response, 
stable disease and disease progression, as assessed by change in PSA, will be 
presented overall and separately for subjects in the FAS who had salvage treatment, 
for subjects who had non-salvage treatment, for those with a change in management 
plan and for subjects with no change in management plan following the 18F-
fluciclovine PET/CT scan.  In addition, treatment response assessed by change in 
PSA will be summarised by disease location (local disease versus extra-prostatic 
disease) and treatment administered. 
The percentage change in PSA from baseline to the last value reported will be 
summarised overall and by subjects who had a change in management plan versus 
those who did not have a change in management plan following the 18F-fluciclovine 
PET/CT scan, disease location and treatment administered.   
Finally, a waterfall plot of the maximum percentage reduction in PSA during the 4-8 
month window will be presented on the y-axis and each subject will be represented by 
a bar on the x-axis.  The bars will be ordered in descending order of the magnitude of 
the percentage change in PSA value. 
Treatment response and the factors used to assess the response will be listed in full. 
5.4.2.2 PSA threshold 
The detection rate (DR) will be calculated as number of positive fluciclovine (18F) 
scan results/total number of scans. 
 
 
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The point estimate (expressed in percentage) of the DR will be presented at the 
region level and at the subject level. These rates will be presented for all subjects 
from the FAS and PPS, overall and across a range of baseline PSA values: 
 0  0.2 
 >0.2  0.5 
 >0.5  1.0 
 >1.0  2.0 
 >2.0  5.0 
 >5.0  10.0 
 >10.0 
to determine the optimum PSA threshold for lesion detection.   See section 2 
General Principles for baseline definition. 
The detection rates will also be summarised across the following baseline Gleason 
score categories: <=6, 7, 8 and >=9. 
All fluciclovine (18F) and other imaging results will be listed. 
5.4.3 
Handling of Dropouts or Missing Data 
Subjects who withdrew from the study prior to completion will be summarised. 
Withdrawn subjects will not be directly replaced and no imputation of missing data 
will be conducted. 
5.4.4 
Interim Analyses and Data Monitoring 
A single interim analysis of the primary endpoint will be performed in the first 85 
evaluable subjects. If the number of treatment changes is greater than 45 (52.9%, 
with a 97.5% two-sided CI of 40.3%-62.3%, so the lower limit is over 40%), the trial 
will be terminated early due to overwhelming effectiveness. If the number of 
treatment changes is 8 or fewer (9.4%, with a 97.5% two-sided CI of 3.6%-18.9%, so 
the upper limit in this population is below the 20% of the null hypothesis), the trial will 
be terminated early due to futility.  
5.4.5 
Examination of Subgroups 
No subgroup analyses will be conducted during the study. 
5.4.6 
Site Specific Sub-study 
A site specific sub-study will be conducted in order to compare the ordered subset 
expectation maximisation (OSEM) standard of care method of reconstructing 
PET/CT images with that of the Bayesian penalised likelihood method of PET/CT 
image reconstruction.  The analysis of the sub-study results is beyond the scope of 
this SAP. 
6 SAFETY EVALUATION 
All safety evaluations will be performed on the safety analysis set (SAF) unless 
specified otherwise. 
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All safety tables will be presented by centre and overall. 
Subjects will be included and counted in summary tables only if they have available 
data. 
6.1 Adverse Events 
Adverse events (AE) will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) version 17.1. 
A treatment-emergent adverse event (TEAE) is defined as an AE with start date/time 
on or after the start/time of fluciclovine (18F) administration, or AEs with worsening 
intensity on or after the start date/time of fluciclovine (18F) administration.   
AEs with unknown start date/time will be assumed to be treatment-emergent unless 
the end date/time is known to be before the fluciclovine (18F) administration. 
Summary tables will be produced for all TEAEs occurring up to 42 days (i.e. 
occurring between day 1 and day 43) after the fluciclovine (18F) administration. 
An overall summary of TEAEs will be created including: 
 number of TEAEs and number of subjects with TEAEs,  
 number of TEAEs and number of subjects with TEAEs associated with the 
injection site,  
 number of serious TEAEs and number of subjects with serious TEAEs,  
 number of subjects with TEAEs by CTCAE grade (Grade 1 to Grade 5),  
 number of subjects with TEAEs by relationship to fluciclovine (unrelated, 
possibly related, probably related, definitely related and related, where related 
adverse events are those classified as possibly, probably and definitely 
related to fluciclovine 18F)  
The number and percentage of subjects experiencing TEAEs will be presented by 
system organ class (SOC) and preferred term (PT).  System organ class and 
preferred term will be presented in decreasing frequency of the total number of 
subjects with TEAEs.  If a subject experienced more than one treatment-emergent 
adverse event, the subject will be counted once for each system organ class and 
once for each preferred term. 
The number and percentage of subjects experiencing TEAEs will be presented by 
SOC, PT and CTCAE grade.  SOC and PT will be presented in decreasing 
frequency of the total number of subjects with TEAEs. If a subject experienced more 
than one TEAE, the subject will be counted once for each SOC and once for each 
PT at the worst severity. 
The number and percentage of subjects experiencing TEAEs will be presented by 
SOC, PT and relationship to study drug. SOC and PT will be presented in 
decreasing frequency of the total number of subjects with TEAEs. If a subject 
experienced more than one TEAE, the subject will be counted once for each SOC 
and once for each PT at the closest relationship to study drug. 
All adverse events will be listed and TEAEs will be identified.  AEs occurring up to 42 
days after fluciclovine (18F) administration will be flagged.   All SAEs will be listed 
separately. 
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6.2 Clinical Laboratory Evaluation 
6.2.1 Haematology 
Haematology values will be summarised by parameter and visit, and also for change 
from baseline (last pre-scan value vs first post-scan value). 
All haematology values will be listed showing reference ranges (flagging abnormal 
findings). 
6.2.2 Biochemistry 
Biochemistry values will be summarised by parameter and visit, and also for change 
from baseline (last pre-scan value vs first post-scan value). 
Additionally, from the serum creatinine levels (mg/dL), creatinine clearance (CrCl) 
will be derived using the Cockcroft Gault formula (Cockroft DW, 1976)  and the 
glomerular filtration rate (GFR) will be derived using the MDRD formula (Levey AS, 
2006) as follows: 
 Cockcroft-Gault formula: CrCl (mL/min) = [(140 - age) * (Weight in kg) * (0.85 
if female)] / (72 * Creatinine) 
 MDRD formula: GFR (mL/min) = 175 * Creatinine-1.154 * age-0.203 * (1.212 if 
subject is black) * (0.742 if female) 
/min, >30 - 
- 
summarised by time window, and the shift table of baseline status against the worst 
status on or after fluciclovine (18F) administration will be presented. 
All biochemistry values will be listed showing reference ranges and flagging 
abnormal findings. 
6.2.3 Urinalysis dipstick 
All urinalysis results will be listed. 
6.2.4 Urine microscopy 
All urine microscopy results will be listed. 
6.3 Vital Signs 
Vital signs include pulse rate, systolic and diastolic blood pressure. 
Vital sign values will be summarised by parameter and time point, and also for 
change from baseline. 
Details of vital signs data will be listed. 
6.4 Electrocardiography 
Electrocardiogram (ECG) interpretation is recorded at screening and visit 4. 
ECG interpretations will be summarised by shift tables highlighting any changes 
between screening and visit 4. 
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7 REFERENCES 
Cockroft DW, G. M. (1976). Prediction of creatinine clearance from serum creatinine. 
Nephron, 31-41. 
Levey AS, C. J. (2006). Using standardized serum creatinine values in the modification 
of diet in renal disease study equation for estimating glomerular filtration rate. 
Ann Intern Med, 247-254. 
 
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Syne qua non study no: BLS14004 
 
Blue Earth Diagnostics study no: BED004 
 
Date: 08MAR2019 
Page 1 of 5 
Version: Addendum 2 Final 
ST/form/038/1 
 
 
 
 
 
 
A Phase 3, Open-label Study to Assess the Clinical Utility 
of Fluciclovine (18F) PET/CT in Patients with Prostate 
Cancer with Biochemical Recurrence after Radical 
Treatment 
 
Blue Earth Diagnostics Study No : BED-004 
Syne qua non Ltd Study No : BLS14004 
 
 
Statistical Analysis Plan Addendum 2 
 
 
Version: Final 
Date: 08 March 2019 
 
 
 
For Syne qua non Ltd  Lead Statistician 
Sig1sig 
 
For Blue Earth Diagnostics 
 
Sig2sig 
 
 
DocuSign Envelope ID: 5BE13F32-F6D6-4C38-B852-1A3A0545F67E


Syne qua non study no: BLS14004 
 
Blue Earth Diagnostics study no: BED004 
 
Date: 08MAR2019 
Page 2 of 5 
Version: Addendum 2 Final 
ST/form/038/1 
 
 
Contents 
 
1 
INTRODUCTION ............................................................................................................................. 4 
2 
CHANGES TO the FINAL SAP ....................................................................................................... 4 
2.1 
Change 1 .................................................................................................................................... 4 
2.2 
Change 2 .................................................................................................................................... 4 
 
 
DocuSign Envelope ID: 5BE13F32-F6D6-4C38-B852-1A3A0545F67E


Syne qua non study no: BLS14004 
 
Blue Earth Diagnostics study no: BED004 
 
Date: 08MAR2019 
Page 3 of 5 
Version: Addendum 2 Final 
ST/form/038/1 
 
LIST OF ABBREVIATIONS 
 
PSA 
Prostate specific antigen 
SAP 
Statistical analysis plan 
 
 
 
 
 
 
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Syne qua non study no: BLS14004 
 
Blue Earth Diagnostics study no: BED004 
 
Date: 08MAR2019 
Page 4 of 5 
Version: Addendum 2 Final 
ST/form/038/1 
 
1 INTRODUCTION 
This the second addendum to the final statistical analysis plan (SAP) Amendment 1 
dated 10th October 2018, documenting additional analyses following database lock. 
Full details of the changes are detailed below. 
2 CHANGES TO THE FINAL SAP 
2.1 Change 1 
Section 5.4.2.1 Treatment response as assessed by change in PSA 
The number, percentage and exact 95% CI of subjects having a treatment response, 
stable disease and disease progression, as assessed by change in PSA, will be 
presented for subjects in the FAS who had salvage therapy.  The summary will 
include an overall summary and separate summaries for subjects who had therapy 
guided by fluciclovine and for subjects whose therapy was not guided by fluciclovine. 
This additional table will be of the same format as Table 14.2.2.1 Treatment 
Response Assessment as Assessed by PSA - by Disease Location, with the 
 and 
-
 A
Therapy Not 
 respectively.  
This description is considered sufficient and a shell is not required. The title will be 
Table 14.2.2.5 Treatment Response Assessment as Assessed by PSA in Subjects 
with Salvage Therapy - by Guided by/Not Guided by Fluciclovine . 
Subjects will be determined to have a therapy guided by fluciclovine if they have an 
agreed therapy which contains the text string 
 
Reason for the change 
To assess possible improvement in outcome of radical salvage treatment based on 
18F fluciclovine PET/CT being included in the assessment. 
2.2 Change 2 
Section 5.4.2.3 Summary of disease location in subjects who had a change in 
management plan from salvage therapy to non-salvage therapy 
The number and percentage of subjects who had positive extra-prostatic findings 
and negative extra-prostatic findings will be presented for subjects who had a 
change in management plan from salvage therapy to non-salvage therapy. 
Subjects who had a change in management plan from salvage therapy to non-
salvage therapy will be identified where the change of management plan is 
-
. 
Positive/negative extra-prostatic findings will be determined from the imaging results. 
This description is considered sufficient and a shell is not required. The title will be 
Table 14.2.2.6 Presence of Extra-prostatic Disease in Subjects with Change of 
Management Plan from Salvage Therapy to Non-salvage Therapy
 
DocuSign Envelope ID: 5BE13F32-F6D6-4C38-B852-1A3A0545F67E


Syne qua non study no: BLS14004 
 
Blue Earth Diagnostics study no: BED004 
 
Date: 08MAR2019 
Page 5 of 5 
Version: Addendum 2 Final 
ST/form/038/1 
 
Reason for the change 
This is an exploratory descriptive analysis to aid interpretation of the change in 
management plan data. 
 
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Elizabeth Gardener
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