Conditions: Prostate Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 221
Healthy volunteers: no

Brief summary:
This prospective study will enroll up to 330 men with PSA-persistent or PSA-recurrent prostate cancer after curative-intent primary therapy and negative or equivocal findings on standard-of-care imaging. Consenting participants will be imaged with 18F-fluciclovine PET/CT. Site clinicians will manage study subjects per standard practices and will document any change in treatment based on review of 18F-fluciclovine PET/CT findings. All participants will be followed for up to 6 months, with clinical data collected for this study. An interdisciplinary panel will provide expert guidance to local readers on request. The final reporting of the PET/CT scan will be a single report by the local reader following any such discussion.

Detailed description:

Arms:
arm 1: Single intravenous administration of 18F-fluciclovine PET CT.

Interventions: intervention 1: 18F-fluciclovine PET CT
Intervention descriptions: intervention 1: Subjects will undergo a fluciclovine F18 PET/CT scan in addition to standard of care monitoring. The results of this scan may influence further treatment

Protocol document:
Prot_000.pdf: 
LOCATE 
1 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LOCATE 
 
PROTOCOL NUMBER: BED003 
Version 4.0 Date: 07 June 2017 
 
 
The Impact of 18F-fluciclovine (FACBC) PET/CT on 
Management of Patients with Rising PSA after Initial 
Prostate Cancer Treatment 
 
PHASE IIIb 
 
 
IND Number : 107707 
Sponsor: Blue Earth Diagnostics 
 
 
 
 
Confidential 
This document is the property of Blue Earth Diagnostics and may not – in full or in part – 
be passed on, reproduced, published or otherwise used without the express permission of 
Blue Earth Diagnostics. 
 
 


LOCATE 
2 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
Blue Earth Diagnostics 
 
 
Clinical Research Protocol 
The Impact of 18F-fluciclovine (FACBC) PET/CT on Management of Patients with Rising PSA after 
Initial Prostate Cancer Treatment 
 
 
Protocol Number: 
BED003 
Version / Date: 
3.0/ May 23rd 2016 
Investigational Product: 
Fluciclovine (18F) [referred to as 18F-fluciclovine in this protocol] 
EUDRACT/IND Number: 
Development Phase: 
Phase IIIb 
Sponsor: 
Blue Earth Diagnostics Ltd 
Unit F14 Oxford Science Park 
Magdalen Centre 
Robert Robinson Avenue 
Oxford OX4 4AG 
UK 
Tel: +44 1865 784186 
Funding Organization: 
Blue Earth Diagnostics 
Study Chair: 
Umar Mahmood, MD, PhD 
Professor of Radiology, 
Harvard Medical School 
Director, Precision Medicine, Martinos Center for Biomedical 
Imaging 
Massachusetts General Hospital 
149 13th St, 2301 
Charlestown, MA 02129 
Phone: 617-726-6477 
Fax: 617-726-7422 
Email: umahmood@mgh.harvard.edu 
BED Medical Monitor: 
Peter Gardiner MB ChB, MRCP, FFPM 
Blue Earth Inc 
25 Burlington Mall Road 
Suite 404 
Burlington MA USA 01803 
Telephone: +1-978-502-9098 
E-mail: p.gardiner@blueearthdx.com 


LOCATE 
3 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
 
BED Study Statistician 
Albert Chau 
Blue Earth Diagnostics Ltd 
Oxford Science Park 
Magdalen Centre 
Robert Robinson Avenue 
Oxford OX4 4AG 


LOCATE 
4 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
Study Co-chairs 
David Mankoff, MD, PhD 
Professor of Radiology 
Chief, Nuclear Medicine & Clinical Molecular Imaging 
University of Pennsylvania 
116 Donner Building 
Philadelphia, PA 19104-4283 
Phone: 215-615-3687 
Fax: 215-349-5843 
Email:  david.mankoff@uphs.upenn.edu 
 
Jonathan McConathy, MD, PhD  
University of Alabama - Birmingham 
Director, Division of Molecular Imaging and Therapeutics 
Associate Professor, Division of Molecular Imaging and Therapeutics 
Email: jmcconathy@uabmc.edu 
Phone 205-996-7115 
 
 
 
Philip J. Saylor, MD 
Massachusetts General Hospital 
Assistant Professor, Medicine 
55 Fruit Street, Yawkey 7E 
Boston, MA 02114-2696 
Phone: 617-643-1763 
Fax: 617-726-8685 
Email: psaylor@partners.org 
 
David Schuster, MD 
Associate Professor 
Director, Division of Nuclear Medicine and Molecular Imaging 
Emory University Hospital 
1364 Clifton Road NE, Room E152 
Atlanta, GA 30322 
Phone: 404-712-4859 
Email: dschust@emory.edu 
 
Barry A. Siegel, MD 
Professor, Radiology and Medicine 
Chief, Division of Nuclear Medicine 
Washington University School of Medicine 
510 South Kingshighway Boulevard 
St. Louis, MO 63110 
Phone: 314- 362-2809 




LOCATE 
6 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
PROTOCOL AGREEMENT 
 
 
I have read the protocol specified below. In my formal capacity as Investigator, my duties include 
providing Blue Earth Diagnostics with the information, as outlined in the protocol. It is understood that 
all information pertaining to the study will be held strictly confidential and that this confidentiality 
requirement applies to all study staff at this site. Furthermore, on behalf of the study staff and myself, I 
agree to maintain the procedures required to carry out the study in accordance with accepted GCP 
principles and to abide by the terms of this protocol. 
 
 
Protocol Number:          BED003 Version 4.0 
 
 
Protocol Title: 
The Impact of 18F-fluciclovine (FACBC) PET/CT on Management of Patients 
with Rising PSA after Initial Prostate Cancer Treatment 
 
 
Protocol Date: 
07 June 2017 
 
 
 
 
 
____-
  
 
Investigator Signature 
Date 
 
 
 
 
 
Print Name and Title 
 
Site # 
 
 
 
Site Name 
 
 
 
Address 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phone Number 
 
 


LOCATE 
7 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
CONTENTS 
LIST OF ABBREVIATIONS ...........................................................................................................................10 
PROTOCOL SYNOPSIS ........................................................................................................................... 12 
1 
BACKGROUND ...................................................................................................................................... 17 
1.1 
Overview of Clinical Studies ........................................................................................................... 17 
2 
STUDY RATIONALE ............................................................................................................................. 18 
2.1 
Risk-Benefit Assessment.................................................................................................................. 19 
3 
STUDY OBJECTIVES ............................................................................................................................ 19 
3.1 
Primary Objective ....................................................................................................................... 19 
3.2 
Secondary Objectives ....................................................................................................................... 20 
4 
STUDY DESIGN ............................................................................................................................... 20 
4.1 
Study Overview .......................................................................................................................... 20 
5 
CRITERIA FOR EVALUATION ........................................................................................................... 20 
5.1 
Primary Efficacy Endpoint .......................................................................................................... 20 
5.2 
Secondary Efficacy Endpoints .................................................................................................... 20 
5.3 
Safety Evaluations ...................................................................................................................... 21 
6 
SUBJECT SELECTION ..................................................................................................................... 21 
6.1 
Study Population ......................................................................................................................... 21 
6.2 
Inclusion Criteria ........................................................................................................................ 21 
6.3 
Exclusion Criteria ....................................................................................................................... 22 
7 
CONCURRENT MEDICATIONS .......................................................................................................... 22 
7.1 
Allowed Medications and Treatments ......................................................................................... 22 
7.2 
Prohibited Medications and Treatments .......................................................................................... 22 
8 
STUDY TREATMENTS .................................................................................................................... 22 
8.1 
Formulation of Test Product ....................................................................................................... 22 
8.2 
Packaging and Labeling .............................................................................................................. 23 
8.3 
Supply of Study Drug at the Site................................................................................................. 23 
8.4 
Dispensing .................................................................................................................................. 23 
8.5 
Administration Instructions ..........................................................................................................23 
8.6 
Study Drug Accountability ..........................................................................................................23 
9 
STUDY PROCEDURES AND GUIDELINES ...................................................................................... 24 
9.1 
Informed Consent ....................................................................................................................... 24 
9.2 
Clinical Assessments ........................................................................................................................ 24 


LOCATE 
8 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
10 
EVALUATIONS BY VISIT .................................................................................................................26 
10.1 
Visit 1 - Screening .......................................................................................................................26 
10.2 
Enrollment and PET/CT Preparation ...........................................................................................26 
10.3 
Visit 2 – 18F-fluciclovine PET-CT ...............................................................................................27 
10.4 
Visit 3 - Telephone Consultation at 24 +/- 4 hours after dosing...................................................27 
10.5 
Documentation of Management plan revision post 18F-fluciclovine PET/CT Scan (2-22 days 
following the scan) ..................................................................................................................................27 
10.6 
End of Study (26+/-4 weeks post scan) ........................................................................................28 
10.7 
Off Study Criteria ........................................................................................................................28 
10.8 
Discontinuation/Withdrawal of Subjects......................................................................................28 
10.9 
Replacement of Subjects ............................................................................................................. 28 
11 
IMAGING PROTOCOL ................................................................................................................. 29 
11.1 
PET/CT Scanner ............................................................................................................................... 29 
11.2 
18F-fluciclovine injection administration ......................................................................................29 
11.3 
18F-fluciclovine PET/CT acquisition ............................................................................................29 
11.4 
Image Transfer .............................................................................................................................29 
11.5 
18F-fluciclovine image analysis .........................................................................................................29 
12 
ADVERSE EVENT REPORTING AND DOCUMENTATION .......................................................29 
12.1 
Adverse Events ..................................................................................................................................29 
12.2 
Serious Adverse Event (SAE) ......................................................................................................31 
12.3 
Medical Monitoring .................................................................................................................... 32 
13 
PROTOCOL VIOLATIONS ............................................................................................................... 32 
14 
STATISTICAL METHODS AND CONSIDERATIONS ................................................................. 32 
14.1 
Analysis of Primary Endpoint ......................................................................................................... 32 
14.2 
Analysis of Secondary Endpoints ............................................................................................... 33 
14.3 
Interim Analysis .......................................................................................................................... 33 
14.4 
Sample Size and Randomization ..................................................................................................33 
15 
DATA COLLECTION, RETENTION AND MONITORING ...........................................................34 
15.1 
Data Collection Instruments.........................................................................................................34 
15.2 
Data Management Procedures .....................................................................................................34 
15.3 
Data Quality Control and Reporting ........................................................................................... 34 
15.4 
Archiving of Data ....................................................................................................................... 34 
15.5 
Availability and Retention of Investigational Records ................................................................... 35 


LOCATE 
9 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
15.6 
Monitoring and Auditing .............................................................................................................35 
15.7 
Subject Confidentiality ................................................................................................................35 
16 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ....................................35 
16.1 
Protocol Amendments .......................................................................................................................35 
16.2 
Institutional Review Boards and Independent Ethics Committees ..............................................35 
16.3 
Informed Consent Form ...............................................................................................................36 
16.4 
Publications..................................................................................................................................36 
16.5 
Investigator Responsibilities .............................................................................................................36 
17 
REFERENCES ................................................................................................................................38 


LOCATE 
10 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
LIST OF ABBREVIATIONS 
 
ACRIN 
American College of Radiology Imaging Network 
AAT 
Amino acid transporters 
AE 
Adverse event 
ADT 
Androgen Deprivation Therapy 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BED 
Blue Earth Diagnostics 
BUN 
Blood urea nitrogen 
CFR 
Code of Federal Regulations 
C.I. 
Confidence Interval 
CRF 
Case report form 
CT 
Computerized Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Management Center 
DR 
Detection Rate 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FACBC 
Fluciclovine (18F) [referred to as 18F-fluciclovine in this protocol] 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
MEq 
Milliequivalent 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 


LOCATE 
11 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
mCi 
Millicurie 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic resonance imaging 
mSv 
Millisieverts 
NPV 
Negative predictive value 
PET 
Positron Emission Tomography 
PET/CT 
Positron Emission Tomography with Computerized Tomography 
PI 
Principal Investigator 
PPV 
Positive Predictive Value 
PK 
Pharmacokinetic 
PSA 
Prostate Specific Antigen 
PSADT 
Prostate Specific Antigen Doubling Time 
SAE 
Serious Adverse Experience 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SOP 
Standard Operating Procedure 
SPECT 
Single Photon Emission Computed Tomography 
TNM 
TNM Classification of Malignant Tumors 
US 
Ultrasonograph 


LOCATE 
12 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
PROTOCOL SYNOPSIS 
 
 
 
TITLE 
The Impact of 18F-fluciclovine (FACBC) PET/CT on Management of 
Patients with Rising PSA after Initial Prostate Cancer Treatment 
SPONSOR 
Blue Earth Diagnostics 
FUNDING 
ORGANIZATION 
Blue Earth Diagnostics 
NUMBER OF SITES 
20 
RATIONALE 
18F-fluciclovine  PET/CT  has  the potential  to  improve  medical  care and 
quality of life among men with prostate cancer in several ways. First, 
identification of disease in the prostate bed and/or regional nodes would 
provide evidence in support of salvage radiation treatment, and help to plan 
radiotherapy. In addition, the absence of distant disease by 18F-fluciclovine 
PET/CT in patients would preserve salvage local therapy as a clinical option 
beyond the time typically offered. Second, identification of distant disease at 
the time of consideration of salvage radiation therapy would allow patients 
to forego radiation that would ultimately be futile. This would spare those 
patients radiation-induced side effects such as impaired recovery of 
continence, impaired recovery of erectile function, and diarrhea. Finally, the 
absence of disease detection on a sensitive imaging modality in patients with 
a rising PSA would have the potential to delay initiation of systemic 
androgen deprivation therapy, a treatment strategy that causes a number of 
morbid side effects that are detrimental to quality of life. 
STUDY DESIGN 
This is a prospective phase IIIb study to assess the impact on patient 
management of 18F-fluciclovine PET/CT in patients with rising prostate 
specific antigen (PSA) after initial prostate cancer treatment. 
PRIMARY OBJECTIVE 
To measure the fraction of patients for whom 18F-fluciclovine PET/CT alters 
intended management through detection of disease after curative-intent 
treatment in a population of men with elevated PSA levels indicative of 
persistent or recurrent prostate cancer and negative or equivocal findings on 
standard-of-care diagnostic imaging tests. 


LOCATE 
13 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
SECONDARY 
OBJECTIVES 
1. To measure the fraction of patients for whom 18F-fluciclovine 
PET/CT leads to a change of actual management by comparison 
with intended management plan before 18F-fluciclovine PET/CT. 
2. To estimate the fraction of patients in whom 18F-fluciclovine 
PET/CT yields evidence of recurrent disease on the basis of imaging 
results. 
3. To estimate 1) the rates of detecting regionally recurrent disease 
(i.e., prostatic bed-only and/or pelvic disease outside of the bed) and 
2) the rate of detecting distant metastases (i.e., bone metastases, 
visceral metastases, or non-regional nodal metastases) with 18F- 
fluciclovine PET/CT in the study population. 
4.  To determine 1) the Positive Predictive Value (PPV) of 18F- 
fluciclovine PET/CT to detect regionally recurrent disease and 2) the 
PPV of 18F-fluciclovine PET/CT to detect distant metastases in the 
study population in patients who undergo optional biopsy of 18F- 
fluciclovine PET/CT findings or have documentation of disease 
status based on other imaging and/or follow-up data. 
5.   To explore differences in estimated cost of treatment plans 
determined prior to and following 18F-fluciclovine PET/CT 
NUMBER OF 
SUBJECTS 
330 patients 
SUBJECT SELECTION 
CRITERIA 
Study Population 
Patients with suspicion of recurrent prostate carcinoma after presumed 
definitive therapy for primary disease 
Inclusion Criteria: 
 
History of histologically confirmed adenocarcinoma of the prostate 
post curative-intent local treatment (radical prostatectomy, local 
radiotherapy, brachytherapy). 
 
Suspicion of recurrent prostate carcinoma after previous presumed 
definitive therapy for primary disease defined as : 
o Post-prostatectomy (with/without adjuvant RT): Detectable 
or rising PSA level that is >0.2 ng/mL with a second 
confirmatory level of   >0.2 ng/mL 
o Post radiotherapy (without RP): PSA rise ≥2ng/mL over 
nadir 
 
Negative or equivocal findings on standard-of-care imaging for 
restaging of disease in the previous 60 days: Standard-of care 
imaging is defined as: 


LOCATE 
14 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
o Whole-body 99mTc-MDP bone scintigraphy or NaF PET-CT 
(dependent on standard of care at the institution)  and 
o Either CT or MRI of the pelvis (or the abdomen and pelvis). 
 
Being considered for salvage therapy 
 
Any non-surgical local treatment such as previous cryotherapy, 
external beam radiation, or HiFU must have occurred at least 1 year 
in the past. 
 
Previous brachytherapy treatment will have occurred at least 2 years 
in the past 
 
Ability to understand and the willingness to sign a written informed 
consent 
Exclusion Criteria: 
 
Ongoing treatment with any systemic therapy intended for the 
treatment of prostate cancer (e.g., antiandrogen or LHRH agonist or 
antagonist) 
 
Androgen deprivation therapy (ADT) in the past 3 months 
 
History of bilateral orchidectomy 

Inability to tolerate 18F-fluciclovine PET/CT
TEST PRODUCT, 
DOSE, AND ROUTE OF 
ADMINISTRATION 
All subjects will receive a single intravenous dose of 10mCi (370MBq) 
+20%18F-fluciclovine immediately prior to PET scan. 
There will be no repeat dosing 
DURATION OF SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
Patients will be imaged with 18F-fluciclovine PET/CT prior to planned 
treatment. Follow-up for treatment outcome and results of standard-of-care 
investigations for up to 6 months after 18F-fluciclovine PET/CT. 
CONCOMITANT 
MEDICATIONS 
Allowed: 
All treatments except for those specifically prohibited 
Prohibited: 
Ongoing treatment with any systemic therapy intended for the treatment of 
prostate cancer (e.g., antiandrogen or LHRH agonist or antagonist), 
including bilateral orchiectomy at time of screening or scanning 
Efficacy Evaluations 
Primary endpoint 
Change to management plan assessed by comparing Pre-18F-fluciclovine 
PET/CT management plan with Post-18F-fluciclovine PET/CT management 
plan. 
Secondary endpoint 
1.   Per-patient impact (yes/no) of 18F-fluciclovine PET/CT on pre-PET 
intended versus post-PET actual patient management. 


LOCATE 
15 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
2. The rate of detection of any disease site by 18F-fluciclovine PET/CT 
in the study population. 
3. The rate of detection of 1) prostatic bed and other pelvic disease and 
2) distant metastases (i.e., bone metastases, visceral metastases, or 
non-regional nodal metastases) with 18F-fluciclovine PET/CT in the 
study population. 
4. The PPV of 18F-fluciclovine PET/CT to detect regionally recurrent 
disease compared to biopsy in those patients who undergo a regional 
disease biopsy on the basis of a 18F-fluciclovine PET/CT finding or 
in case of bony disease a correlation with MRI or biopsy. 
5. The PPV of 18F-fluciclovine PET/CT to detect distant disease 
compared to biopsy in those patients who undergo a distant disease 
biopsy on the basis of a 18F-fluciclovine PET/CT finding or in case 
of bony disease a correlation with MRI or biopsy. 
An independent adjudication panel will review and adjudicate 18F- 
fluciclovine PET/CT lesions with biopsy or MRI during follow-up to 
assess the PPV and, where possible, NPV, sensitivity and specificity. 
Rates of disease detection (radiographic only and confirmed by 
pathology or MRI) will be described 
Safety Evaluations 
Monitoring for adverse events, change in EKGs and routine hematology and 
biochemistry evaluations taken prior to and following receipt of 18F- 
fluciclovine 
Planned Interim Analyses 
An interim analysis of a subset of study results on all enrolled subjects may 
be submtted for potential public presentation prior to completion of all data 
collection and analyses. As trial design will not be modified as a result of this 
interim analysis, no adjustment to the type I error is required. 
STATISTICS 
Primary Analysis Plan 
For the evaluation of the primary endpoint (i.e., impact on therapy), 
questionnaires obtained pre- and post- 18F-fluciclovine PET/CT will be 
compared to calculate the fraction of cases with a change in management 
(versus no change in planned management). The 95% confidence interval 
will be calculated using the Exact method for a binomial distribution. 
Rationale for Number of 
Subjects 
Assuming a  prevalence rate of positive 18F-fluciclovine PET/CT of 
approximately 40%, of which 30% will be expected to change the 
physician’s intended management plan and binding of the 95% CI width at 
0.20 (i.e., half –length at 0.10), 89 18F-fluciclovine positive patients will be 
needed for the assessment of our primary aim. After taking into account the 
random nature of the observed numbers of patients meeting the clinical 
criteria in a prospective study, and potential data loss, provide a 90% 
probability of yielding the required number of patients for the primary 
comparison it is planned to enroll at least 292 and up to 330 patients into the 
study in order to obtain 89 evaluable patients. 


LOCATE 
16 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
STUDY SCHEMA 
Optional
biopsy 
of 
positive (+) 
18F- fluciclovine
sites (as 
clinically 
indicated) 
Adult Males 
Suspicion of
recurrent prostate
carcinoma after
presumed
definitive therapy
for primary 
disease (adapted
from AUA 2013 and
NCCN 1.2016): 

Post- 
prostatectomy:
Detectable PSA
to ≥0.2 ng/ml 
(confirmed) 

Radiotherapy:
PSA rise by ≥ 2.0 
ng/ml over 
nadir. 
 
18F-fluciclovine 
 
Imaging 
Questionnaire on 
planned treatment 
PRE-18F- 
FLUCICLOVINE 
PET/CT 
Questionnaire on 
planned treatment 
POST-18F 
FLUCICLOVINE 
PET/CT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6-month Follow-up 
SCREENING/REGISTRATION 


LOCATE 
17 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
1 
BACKGROUND 
 
Biochemically recurrent prostate cancer is a common clinical problem. Optimal strategies for detection of 
persistent or recurrent disease and for management of such patients are not currently well defined. Radical 
therapy for prostate cancer patients without pre-treatment evidence of distant disease using standard-of- 
care diagnostic imaging studies improves disease-specific survival and overall survival, (1) but relapse 
remains a significant problem. Biochemical failure rates despite optimal therapy can be as high as 30% 
with intermediate-risk disease (2) and 50% with high-risk disease. (3) Some of these relapses are 
attributable to distant metastases not detected by standard imaging modalities. Others are attributable to 
locally persistent disease in the region of the prostate or proximate nodes. Management of recurrent 
disease after curative-intent local therapy optimally requires disease localization. 
Standard-of-care staging imaging for prostate cancer as recommended by the current National 
Comprehensive Cancer Network guidelines includes 99mTc-MDP bone scintigraphy and pelvic imaging 
with CT or MRI. (4) In the setting of early biochemical relapse after prostatectomy, although used to help 
define the extent of disease, these studies are generally uninformative. As a result, clinicians must often 
decide for or against further local therapy (e.g., salvage external beam radiation therapy for biochemical 
recurrence after prostatectomy) as guided by nomogram-based probabilities rather than anatomic 
localization. A more sensitive imaging modality that could offer anatomic localization within the clinical 
setting of early PSA relapse would better inform treatment decisions and improve the management of 
patients with apparent recurrence based on PSA levels. 
Prostate cancer functional imaging with PET is presently used on a limited basis. Widely available, PET 
or PET/CT with 18F-fluorodeoxyglucose (FDG) is not standard as FDG uptake is usually low in prostate 
cancer prior to the development of castration-resistant disease. 18F-sodium fluoride PET is more sensitive 
than standard 99mTc-MDP bone scintigraphy, but both methods are non-specific and do not image cancer 
outside of the skeleton. Acetate- and choline-based PET tracers have been the subject of study but are not 
broadly approved and available. PET or PET/CT with the experimental L-leucine analog 18F-fluciclovine 
has demonstrated promise and is the subject of this experimental protocol. 
 
 
1.1 
Overview of Clinical Studies 
Published data from single-institution studies of 18F-fluciclovine PET have preliminarily demonstrated its 
operating characteristics in over one hundred study subjects with recurrent prostate cancer after curative- 
attempt primary therapy (see Figure) (5,6,7). Dosimetry has previously been described and is notable for a 
favorable pelvic imaging profile because of low levels of uptake within the urinary bladder. 18F- 
fluciclovine PET/CT has demonstrated approximately 90% sensitivity and 40-67% specificity for 
detection of cancer in the prostate bed. It has demonstrated 55-100% sensitivity and more than 95% 
specificity for the detection of disease outside of the prostate bed. Multi-center study is needed to 
determine the clinical impact of localization of suspected prostate cancer recurrence by 18F-fluciclovine 
PET/CT, specifically the impact on patient management. 


LOCATE 
18 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
 
 
 
The goal of the proposed study is to further evaluate the impact of 18F-fluciclovine PET/CT of prostate 
cancer in a multi-institution study. We hypothesize that by identifying disease in or outside of the prostate 
bed—either in regional lymph nodes or distant disease sites, 18F-fluciclovine PET/CT will impact the 
approach to patient management. This typically involves prostate bed irradiation in patients with prior 
prostatectomy, and a combination of additional focal therapy such as radiotherapy, cryotherapy, and/or 
systemic therapy in patients treated initially with local radiotherapy or brachytherapy. We propose a study 
of men who have undergone definitive treatment of localized prostate cancer (e.g. by prostatectomy, local 
radiotherapy, brachytherapy) and are presenting with rising PSA levels indicative of recurrent or persistent 
disease. We have chosen to study patients without evidence o f  disease (or with equivocal findings) 
by standard imaging (bone scintigraphy and CT or MRI) and with PSA levels in the range where 
imaging findings outside the prostatic bed would be expected to have a significant impact on treatment. 
Study participants with negative or equivocal conventional staging studies (99mTc-MDP bone scintigraphy 
/NaF PET-CT (dependent on standard of care at the institution) and abdominal-pelvic CT or MRI) will undergo 
18F-fluciclovine PET/CT. 
 
 
2 
STUDY RATIONALE 
 
This study has the potential to improve management of a common disease state (biochemically recurrent 
prostate cancer) within the most common cancer among men. If successful, it will establish an imaging 
strategy that is demonstrated to appropriately modify care compared to current standard imaging 
approaches. Single center experience of a similar study was reported at the SNMMI meeting in 2015 (11). 
They reported initial findings from an ongoing randomized study in which 24/54 patients with rising PSA 
and negative pelvic MRI and 99mTc-MDP bone scan were randomized to receive 18F-fluciclovine PET/CT 
before definitive treatment. In these patients 6/23 had changes made to their radiation fields as a result of 
the PET/CT; 1 had the offer of radiotherapy withdrawn. Overall in these early results 7/24 patients 
(29.2%) had the radiotherapy decision modified by the results of the PET/CT scan. If these results can be 
confirmed in a multi-center study there is the potential to improve medical care and quality of life among 
men with prostate cancer in several ways. First, identification of disease in the prostate bed and/or 
regional nodes would provide evidence in support of salvage radiation treatment, and help to plan 
radiotherapy. In addition, the absence of distant disease by 18F-fluciclovine PET/CT in patients with a 
PSA ≥ 1 ng/mL would preserve salvage local therapy as a clinical option beyond the time typically 
offered. Second, identification of distant disease at the time of consideration of salvage radiation therapy 
would allow patients to forego radiation that would ultimately be futile. This would spare those patients 


LOCATE 
19 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
radiation-induced side effects such as impaired recovery of continence, impaired recovery of erectile 
function, and diarrhea. Finally, the absence of disease detection using a sensitive imaging modality in 
patients with a rising PSA would have the potential to delay initiation of systemic androgen deprivation 
therapy, a treatment strategy that causes a number of morbid side effects that are detrimental to quality of 
life. 
This prospective study will enroll up to 330 men with PSA-persistent or PSA-recurrent prostate cancer 
after curative-intent primary therapy and negative or equivocal findings on standard-of-care imaging (see 
enrolment criteria for details of eligibility). Consenting participants will be imaged with 18F-fluciclovine 
PET/CT. Site clinicians will manage study subjects per standard practices and will document any change 
in treatment based on review of 18F-fluciclovine PET/CT findings. Rates of disease detection 
(radiographic-only, and pathologically confirmed) will be described. 
 
 
2.1 
Risk-Benefit Assessment 
Benefits 
The research scans may provide further clinical information regarding the patient’s disease status that 
may not have been appreciated using 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. 
Risks 
The risks from the imaging studies to subjects mainly relate to the intravenous injection and the radiation 
emitted by the radiopharmaceutical and CT.  Intravenous injection carries a small risk of infection and 
hematoma. 
 
The mean effective dose per unit administered activity of 18F-fluciclovine is 22.1µSv/MBq (8). An 
administered activity of 10mCi (370 MBq) will result in an effective dose of 8.2mSv. The maximum 
effective dose due to the CT transmission scan will vary from site to site, but as a guide a dose of 7 mSv 
would be expected (details of scanner-specific CT effective doses will be given in the Study Imaging 
Manual).  The effective dose due to the CT acquisition will be in accordance with ALARA (As Low As 
Reasonably Achievable) principles. The total dose of 15.2mSv is in line with other common nuclear 
medicine procedures. 
 
As with all imaging techniques there is the risk that the PET/CT scan may provide a false positive image 
(giving the appearance of cancer) in sites where it is not present, due to other events in the body such as 
inflammation or false negative (failing to detect a nidus of cancer). Thus patients should continue to be 
reviewed and may require other investigations, including biopsy, to confirm scan findings. 
 
3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to measure the fraction of patients for whom 18F-fluciclovine PET/CT alters 
patient treatment through detection of disease after curative-intent treatment in a population of men with 
elevated PSA levels indicative of persistent or recurrent prostate cancer and negative or equivocal findings 
on standard-of-care diagnostic imaging tests. 


LOCATE 
20 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
3.2 
Secondary Objectives 
1. To measure the fraction of patients for whom 18F-fluciclovine PET/CT leads to a change of actual 
management by comparison with the intended management plan before 18F-fluciclovine PET/CT. 
2. To estimate the fraction of patients in whom 18F-fluciclovine PET/CT yields evidence of recurrent 
disease on the basis of imaging results. 
3. To estimate 1) the rates of detecting regionally recurrent disease (i.e., prostatic bed-only and/or pelvic 
disease outside of the bed) and 2) the rate of detecting distant metastases (i.e., bone metastases, 
visceral metastases, or non-regional nodal metastases) with 18F-fluciclovine PET/CT in the study 
population. 
4. To determine 1) the PPV of 18F-fluciclovine PET/CT to detect regionally recurrent disease and 2) the 
PPV of 18F-fluciclovine PET/CT to detect distant metastases in the study population in patients who 
undergo optional biopsy of 18F-fluciclovine PET/CT findings or have documentation of disease status 
based on other imaging and/or follow-up data. For soft tissue disease these calculations will be 
limited to those patients who undergo a confirmatory biopsy and for bone disease those with 
confirmatory findings on MRI any time during the 6-month follow up. The denominator for the 
analysis will be [lesions biopsied + bone lesions]. 
5. To explore differences in estimated cost of treatment plans determined prior to and following 18F- 
fluciclovine PET/CT. 
 
4 
STUDY DESIGN 
 
4.1 
Study Overview 
This prospective study will enroll up to 330 men with PSA-persistent or PSA-recurrent prostate cancer 
after curative-intent primary therapy and negative or equivocal findings on standard-of-care imaging (see 
enrolment criteria for details of eligibility). Consenting participants will be imaged with 18F-fluciclovine 
PET/CT. Site clinicians will manage study subjects per standard practices and will document any change 
in treatment based on review of 18F-fluciclovine PET/CT findings. Additionally, as clinically indicated, 
optional biopsy will be performed. All participants will be followed for up to 6 months, with clinical data 
collected for this study: PSA measurement from scan for 6 months. An expert reader will provide 
guidance to local readers on request. The final reporting of the PET/CT scan will be a single report by the 
local reader following any such discussion. 
 
 
5 
CRITERIA FOR EVALUATION 
 
5.1 
Primary Efficacy Endpoint 
For the primary objective, the change of management will be based on referring physician questionnaires 
completed pre- and post- 18F-fluciclovine PET/CT (Intended v Revised  Management  Plans). Management 
options on referral will include prostatic bed radiotherapy (±hormone treatment), prostatic bed plus 
regional radiotherapy, cryoablation, surgery. Post PET/CT scan additional options include, inter alia no 
therapy, treatment of oligometastatic disease, hormonal and other systemic therapies). 
 
5.2 
Secondary Efficacy Endpoints 
1. Per-patient impact (yes/no) of 18F-fluciclovine PET/CT on pre-PET intended versus post-PET actual 
patient management (assessed at 6 months post scan) 


LOCATE 
21 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
2. The rate of detection of any disease site by 18F-fluciclovine PET/CT in the study population; 
3. The rate of detection of 1) prostatic bed and other pelvic disease and 2) distant metastases (i.e., bone 
metastases, visceral metastases, or non-regional nodal metastases) with 18F-fluciclovine PET/CT in 
the study population; 
4. The PPV of 18F-fluciclovine PET/CT to detect regionally recurrent disease compared to biopsy in 
those patients who undergo a regional disease biopsy on the basis of a 18F-fluciclovine PET/CT 
finding or in case of bony disease a correlation with MRI or biopsy. 
5. The PPV of 18F-fluciclovine PET/CT to detect distant disease compared to biopsy in those patients 
who undergo a distant disease biopsy on the basis of a 18F-fluciclovine PET/CT finding or in case of 
bony disease a correlation with MRI or biopsy. 
 
5.3 
Safety Evaluations 
1. Change from baseline QTc intervals and any clinically significant alterations in EKG after 18F- 
fluciclovine PET/CT scanning 
2. Change from baseline values in hematology and biochemistry profiles after 18F-fluciclovine PET/CT 
scanning 
3. Incidence of adverse events occurring after the 18F-fluciclovine injection 
 
 
6 
SUBJECT SELECTION 
 
6.1 
Study Population 
Eligible patients that  meet  inclusion and exclusion criteria  will have suspicion of recurrent prostate 
carcinoma after presumed definitive therapy for primary disease. 
 
6.2 
Inclusion Criteria 
1. History of histologically confirmed adenocarcinoma of the prostate post curative-intent local 
treatment (radical prostatectomy, local radiotherapy, brachytherapy) 
2. Suspicion of recurrent prostate carcinoma after presumed definitive therapy for primary 
disease, defined as 
a. Post-prostatectomy (with/without adjuvant RT): Detectable or rising PSA level that is 
>0.2 ng/mL with a second confirmatory level of   >0.2 ng/mL 
b. Post radiotherapy (without RP): PSA rise ≥2ng/mL over nadir 
3. Negative or equivocal findings on standard-of-care imaging for restaging of disease in the 
previous 60 days consisting of: 
a. Whole-body 99mTc-MDP bone scintigraphy  or NaF PET-CT (dependent on standard of care 
at the institution) and 
b. Either CT or MRI of the pelvis (or the abdomen and pelvis). 
4. Being considered for salvage therapy 
5. Previous cryotherapy, external beam radiation, or HiFU must have occurred at least one year in 
the past. 
6. Previous brachytherapy treatment will have occurred at least 2 years in the past 


LOCATE 
22 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
7. Ability to understand and the willingness to sign a written informed consent 
 
6.3 
Exclusion Criteria 
1. Ongoing treatment with any systemic therapy intended for the treatment of prostate cancer (e.g., 
antiandrogen or LHRH agonist or antagonist) 
2. Androgen deprivation therapy (ADT) in the past 3 months. 
3. History of bilateral orchiectomy. 
4. Inability to tolerate 18F-fluciclovine PET/CT. 
 
7 
CONCURRENT MEDICATIONS 
 
7.1 
Allowed Medications and Treatments 
All standard and approved treatments are permitted except for those specifically prohibited in section 7.2. 
 
7.2 
Prohibited Medications and Treatments 
The following medications and treatments are prohibited prior to the 18F-fluciclovine PET/CT. Any 
administration of 18F-fluciclovine during treatment with these will be considered a protocol violation. 
 
Treatment with any systemic therapy intended for the treatment of prostate cancer (e.g., 
antiandrogen or LHRH agonist or antagonist) 
 
Bilateral orchiectomy 
 
8 
STUDY TREATMENTS 
 
8.1 
Formulation of Test Product 
18F-fluciclovine is a radiolabelled synthetic amino acid. The radioactive isotope 18F decays with a half-life 
of approximately 110 minutes. 
 
 
Chemical formula 
 
18 
C5H8 FNO2 
 
 
 
 
 
 
Chemical structure 
 
 
H 
NH2 
 
 
18F 
COOH 
 
Chemical name 


LOCATE 
23 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
(anti)-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid. 
 
 
Physiological effects 
Biodistribution and radiation dosimetry studies have demonstrated physiological uptake of 18F- 
fluciclovine to be highest in the liver and pancreas, with rapid biological clearance. (9) There is low albeit 
prolonged uptake in skeletal muscle and bone marrow, with clearance dominated by the tracer half-life. 
(9) 
 
8.2 
Packaging and Labeling 
The investigational agent is supplied as a unit dose for injection in a syringe with a radioactive 
concentration at a reference date and time that is stated on the container label.  Each syringe is supplied in 
a container providing appropriate radiation shielding. Information will be provided with the shipment 
giving the confirmation number, radioactive concentration of injection (mCi/mL) at a stated time and 
date, shelf life information, protocol number and a unique prescription number. The radiochemical purity 
of 18F-fluciclovine injection is not less than 95% during the shelf life of the product 
 
8.3 
Supply of Study Drug at the Site 
Sites will be provided with instructions for ordering the 18F-fluciclovine injections for use in the study. 
The order for a specific patient to be scanned at a specific date and time must be made to PETNET 
Solutions Centralized Scheduling Team (Tel: 1 877 473 8638). The 18F-fluciclovine will be delivered 
from the radiopharmacy to the imaging site by courier. Each syringe is supplied in a container providing 
appropriate radiation shielding. The site must keep records of all shipments of 18F-fluciclovine received, 
dispensing and disposal/destruction performed on site as is appropriate to each facility. 
 
8.4 
Dispensing 
When the study site receives the dose and prior to administration, the activity in the syringe will be 
measured in a dose calibrator. Should the activity be less than 8mCi or the volume required exceed 5 mL 
undiluted material or the administration be more than 10 hours from manufacture the scan should not be 
performed. 
 
8.5 
Administration Instructions 
Prior to PET/CT, 10mCi ±20% of 18F-fluciclovine will be administered as an IV bolus injection 
followed by a 10 mL saline flush. 18F-fluciclovine 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, hematoma, redness, or infection). Documentation of administration to a subject will be 
recorded according to standard of care and on the appropriate eCRF, including date, prescription number, 
total volume, start/stop time of administration, and injection site. 
 
8.6 
Study Drug Accountability 
An accurate and current accounting of the dispensing and disposal of 18F-fluciclovine for each subject 
will be recorded on the Investigational Drug Accountability Record. The study monitor will verify this 
document throughout the course of the study. 


LOCATE 
24 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
9 
STUDY PROCEDURES AND GUIDELINES 
 
A Schedule of Events representing the required testing procedures to be performed for the duration of the 
study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent and the Health Insurance 
Portability and Accountability Act (HIPAA) authorization must be signed and dated by the subject. 
 
9.1 
Informed Consent 
The participant must sign and date the local site IRB-approved version of the Informed Consent form 
before any study-specific procedures are performed. 
Written and oral 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, his referring physician or other independent parties to decide whether he will 
participate in the study. Written Informed Consent will then be obtained by means of the participant’s 
dated signature and the 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. A copy of the signed Informed Consent will be given to the participant. The 
original signed form will be retained at the study site. 
 
 
9.2 
Clinical Assessments 
Data from the following assessments and procedures should be documented in the Subject’s medical 
records and recorded in the eCRF 
1. Concomitant Medications 
All concomitant medication and concurrent therapies will be documented at Screening and at all 
Visits and at End of Follow up. Dose, route, unit frequency of administration, and indication for 
administration and dates of medication will be captured. 
2. Demographics 
Demographic information will include age, gender, race and ethnicity. 
3. Medical History 
Include history of prostate cancer and prostate cancer treatments, and other clinically significant 
diagnoses. Prostate cancer history should include the date of initial diagnosis, initial tumor stage and 
Gleason score, dates of definitive therapy and adjuvant treatment (if given), and date of diagnosis of 
biochemical recurrence. 
4. Imaging Studies 
Imaging data will include all imaging results (including relevant bone scans, CT etc) from 60 days 
before screening so the final follow-up and all prostate cancer imaging results available from the 
Subject’s file 


LOCATE 
25 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
5. Vital Signs 
Blood pressure and pulse rate will be performed after resting for 5 minutes. 
6. 12 lead Electrocardiogram (EKG) 
EKG will be recorded as indicated in Section 10. Original EKGs are to be anonymized and forwarded 
to Clinical Research, Blue Earth Diagnostics, Magdalen Centre, Oxford Science Park, Oxford OX4 
4GA, United Kingdom and copies maintained in the Subject’s medical record. 
7. PSA Levels 
PSA levels will be recorded from the Subjects medical records 
8. Management Plan 
The Intended Management Plan. The treating physician will complete the Management Plan 
Questionnaire to document his/her intended treatment including planned radiation fields, intended 
resection limits of surgery, use of brachytherapy, cryotherapy or HiFU, intended use of adjuvant 
therapy. 
The Revised Management Plan. 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 plan. Any such diagnostic procedures do not qualify as a “change” to clinical 
management. The treating physician will complete the Management Plan Questionnaire to document 
changes to the Pre-scan Management Plan. Changes include such responses as change to radiation or 
surgical fields. The patient may enter another clinical trial as part of the Revised Management Plan. 
Actual Management Plan. At the final follow up visit any deviations or changes to the Revised 
Management Plan will be documented 
9. Biopsy 
Biopsy is not required by the protocol; however patients with PET/CT positive findings in soft-tissue 
supported by anatomical abnormalities on CT or MRI may have a biopsy performed per standard 
practice where the procedure is deemed clinically feasible and safe. Biopsies completed within 4 
months after imaging will contribute to the aim of the study. 
1. Biopsy results of suspected bone metastases conducted per standard practice will also be 
collected. Bone lesions may be followed up through imaging where biopsy is not practical. 
2. Based on local-radiologist/nuclear medicine physicians assessment of 18F-fluciclovine PET/CT- 
positive findings supported by anatomic abnormalities, conduct imaging-guided biopsy of soft- 
tissue 18F-fluciclovine -enhancement region per institutional standard of care; 
3. Submit pathology report(s) to the ACR Core Laboratory. The address is given in the Imaging 
Manual. 
10. Blood Chemistry Profile 
Blood will be obtained and sent to each site’s clinical chemistry lab for determination of serum 
sodium, potassium, calcium, chloride, BUN, creatinine, glutamic oxaloacetic transaminase 
(SGOT/AST), glutamic-pyruvic transaminase (SGPT/ALT), alkaline phosphatase, creatine kinase 
(CK), lactate dehydrogenase (LDH), albumin, total protein, total bilirubin. 
11. Hematology 
Blood will be obtained and sent to each site’s clinical hematology lab for a complete blood count 
(hemoglobin, hematocrit, red blood cell count, white blood cell count, white blood cell differential, 
and platelet count determinations). 


LOCATE 
26 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
12. Urinalysis 
Prior to the 18F-fluciclovine dosing a midstream sample of urine will be obtained and tested by 
dipstick for leukocytes, nitrite, pH, protein, ketones, glucose, bilirubin, urobilinogen, and blood. This 
will not be repeated following scanning unless clinically indicated. 
13. Adverse Events 
See Section 12. 
 
10 
EVALUATIONS BY VISIT 
 
A Schedule of Events representing the required testing procedures to be performed for the duration of the 
study is given in Appendix 1 
 
10.1 Visit 1 - Screening 
1. Review the study with the subject and obtain written informed consent and HIPAA authorization 
2. Record demographics data and current medication being taken. 
3. Obtain medical history including treatment history. 
4. Confirm negative or equivocal findings on baseline imaging studies (note: baseline imaging 
studies must be within 60 days prior Visit 1). 
5. Measure vital signs 
6. Obtain blood sample for: 
o PSA testing 
o Hematology 
o Biochemistry evaluations 
7. Obtain 12-lead EKG 
8. Obtain urine sample for dipstick urinalysis (may be collected and tested at any time between 
screening and the scan date) 
 
10.2 Enrollment and PET/CT Preparation 
Subjects who have provided informed consent and who meet all eligibility criteria will be enrolled into 
the study.  At the time the Subject is determined to be eligible, the following activities will be performed: 
1. Register the Subject via eCRF 
2. Schedule the 18F-fluciclovine PET/CT imaging study within 30 days of Visit 1 
3. The treating physician must complete the Management Plan Questionnaire. A copy of the 
Questionnaire must be maintained in the Subject’s medical record. 
4. PET/CT Preparation: 
Subjects 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. Optionally, if it is the standard practice at the 
site, one hour prior to scanning, the patient may drink 500 mL of oral contrast (e.g. 1.2%, Readi- 
Cat) over 1 hour to maximize conspicuity of abdomen and pelvic structures. No IV CT contrast 
will be used. 


LOCATE 
27 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
10.3 Visit 2 – 18F-fluciclovine PET-CT 
Prior to the dose of 18F-fluciclovine and the PET/CT scan, the following assessments will be performed: 
1. Review and update the Subject’s medical history to check for new health-related events and 
changes to concomitant medications since the Screening visit. 
2. Ensure treatment plan has been documented prior to 18F-fluciclovine PET/CT; 
3. Obtain vital signs. 
4. Obtain blood sample for: 
 
) 
o Hematology 
 
) 
Biochemistry 
 
)  Unless obtained at screening 
5. 12-lead EKG 
 
) 
6. Obtain a urine sample and perform dipstick analysis. 
) 
o If the results are abnormal these are to be recorded and the Subject is to proceed to having the 
fluciclovine PET/CT 
Dosing and PET/CT Procedure: A venous cannula will be inserted and the Subject will receive one 
dose of 18F-fluciclovine. Subjects will be imaged starting 4 minutes after injection from proximal- 
thigh to skull base. The duration of the scan is approximately 25 minutes on the PET/CT scanner. 
Following the scan, Subjects will be encouraged to drink water to encourage hydration and frequent 
voiding to reduce radiation dose from 18F-fluciclovine excretion. The following assessments will be 
performed 
1. Obtain blood sample for: 
) 
a. Hematology 
) 
b. Biochemistry 
)  Unless to be obtained in the next 7 days 
2. 12-lead EKG 
) 
3. Obtain vital signs immediately post scan and at 60 (± 5) minutes, and 120 (±5) minutes post-
injection. 
4. Assess the Subject for adverse events at 30 minutes, 60 minutes, and 120 minutes post-injection. 
10.4 Visit 3 - Telephone Consultation at 24 - 72 ( +/- 4) hours after dosing 
An  adverse  event  evaluation  will  be  performed  at  24 - 72  hours  (+  4  hours)  after  18F-
fluciclovine administration via telephone consultation. 
 
10.5 Documentation of Management plan revision post 18F-fluciclovine PET/CT Scan (2- 
22 days following the scan) 
The treating physician will complete the Management Plan Questionnaire to document changes to the 
Pre-Scan Management Plan. A copy of the Questionnaire must be maintained in the Subject’s medical 
record. 


LOCATE 
28 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
10.6 End of Study (26+/-4 weeks post scan) 
The  treating  physician  will  complete  the  Management  Plan  Questionnaire  to  document  the  actual 
treatment given, including any changes to radiation, surgery, or medications given. 
The following data from Visit 2 through to 6 months after the 18F-fluciclovine PET/CT will be abstracted 
from the Subject’s medical record: 
1. All PSA results. 
2. All biopsy results and reports. 
3. Restaging procedure results (e.g. bone scan or CT/MRI scans). 
4. Current prostate cancer status and date of recurrence if applicable. 
5. Adverse events reported by the patient  
6. Date and cause of death if applicable. 
 
10.7 Off Study Criteria 
Subjects will not continue with the study based on the following criteria: 
 
Subject withdraws consent. 
 
Subject does not complete 18F-fluciclovine PET/CT imaging 
 
10.8 Discontinuation/Withdrawal of Subjects 
Each Subject has the right to withdraw from the study at any time without giving a reason and without 
prejudice. In addition, a Subject may be discontinued from the study at any time for any of the following 
reasons: 
 
Ineligibility (recognized/arising after registration and prior to 18F-fluciclovine administration) 
 
Significant protocol deviation 
 
Significant non-compliance with study requirements 
 
Withdrawal of consent 
 
Loss to follow up 
 
Investigator discretion 
Withdrawal from the study will not result in exclusion of the data for that Subject from analysis provided 
all baseline study measures have been completed. 
The reason for withdrawal, if known, will be recorded in the eCRF. 
 
10.9 Replacement of Subjects 
Subjects who withdraw from the study treatment will not be replaced 


LOCATE 
29 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
11 
IMAGING PROTOCOL 
 
11.1 PET/CT Scanner 
A dedicated hybrid PET/CT scanner is mandatory. The selected PET/CT scanner must be qualified by the 
study management team and be capable of performing both emission and CT transmission images in 
order to allow for attenuation-corrected PET/CT images. The ability to calculate SUVs is also mandatory. 
PET/MR scanners are not approved for use on this study. 
 
11.2 18F-fluciclovine injection administration 
A venous cannula will be inserted, preferably in the right arm, and the participant will receive 10 mCi 
±20% 18F-fluciclovine injection diluted up to 10mL injected via the cannula with arms down, as an IV 
bolus injection followed by 10mL flush with normal saline solution. The participant will then be 
positioned supine in the scanner, with the arms above the head (if possible), and will be scanned in the 
direction of proximal-thigh to skull base. The time from end of injection of 18F-fluciclovine injection to 
the start of imaging should be 3 to 5 minutes with a goal of 4 minutes. 
 
11.3 18F-fluciclovine PET/CT acquisition 
For the PET acquisition, participants will be imaged for approximately 25 minutes. For the CT acquisition, 
an unenhanced (no IV contrast) CT will be employed. Further details on the PET/CT acquisition are given 
in the Study Imaging Manual. 
 
11.4 Image Transfer 
Following the completion of PET/CT imaging at the study site, the scan data will be sent to the ACR 
Imaging Core Laboratory using either the ACR TRIAD software, by uploading anonymized files via an 
sFTP server, or on physical media by courier. Full details are in the Study Imaging Manual. 
 
11.5 18F-fluciclovine image analysis 
Image interpretation will be based on guidelines derived from an international 18F-fluciclovine Reader 
Consensus Meeting held in June 2014 (10). All readers will undergo training in interpretation of 18F- 
fluciclovine PET/CT 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). Support 
for the local reader can be provided on request by contacting the Study Chair or Co-Chairs as listed in the 
protocol. The report provided to the treating physician and recorded in the eCRF will be that of the Site 
Investigator. The revised treatment decision will be made on the report of the Nuclear Medicine physician. 
 
 
12 
ADVERSE EVENT REPORTING AND DOCUMENTATION 
 
12.1 
Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered a pharmaceutical product and that does not necessarily have a causal relationship with the 
treatment. An AE is therefore any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the administration of an investigational product, 
whether or not related to that investigational product.  An unexpected AE is one of a type not identified in 


LOCATE 
30 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
nature, severity, or frequency in the current Investigator’s Brochure or of greater severity or frequency 
than expected based on the information in the Investigator’s Brochure. 
The Investigator will probe, via discussion with the subject, for the occurrence of AEs during each subject 
visit and record the information in the site’s source documents. Adverse events will be recorded in the 
patient eCRF. Adverse events will be described by duration (start and stop dates and times), severity, 
outcome, treatment and relation to study drug, or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.3 (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). 
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 daily activities. * 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care. ** 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE 
*Daily activities refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc. 
** Self-care refers 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. 


LOCATE 
31 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
 
 
Adverse Event Relationship to Study Drug 
The relationship of an AE to study drug will be assessed using the following guidelines in Table 
3. 
Table 3.  AE Relationship to Study Drug 
 
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. 
 
12.2 
Serious Adverse Event (SAE) 
An SAE is defined as any adverse event occurring at any dose that results in any of the following 
outcomes: 
 
death 
 
a life-threatening adverse experience 
 
inpatient hospitalization or prolongation of existing hospitalization 
 
a persistent or significant disability/incapacity 
 
a congenital anomaly/birth defect 
Other important medical events may also be considered an SAE when, based on appropriate medical 
judgment, they jeopardize the subject or require intervention to prevent one of the outcomes listed. 
 
 
Serious Adverse Event Reporting 
Study sites will document all SAEs that occur (whether or not related to study drug) on an SAE Report 
Form. The collection period for all SAEs will begin after informed consent is obtained and end after 
procedures for the final study visit have been completed. 
Death (5) 
Death related to AE 


LOCATE 
32 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
All SAEs following 18F-fluciclovine 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. 
In accordance with the standard operating procedures and policies of the local Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs to the IRB/IEC. 
12.3 Medical Monitoring 
Dr Peter Gardiner MB ChB, MRCP, FFPM should be contacted directly at these numbers to report 
medical concerns or questions regarding safety. 
Phone: +1-978-502-9098 
E-mail: p.gardiner@blueearthdx.com 
 
13 
PROTOCOL VIOLATIONS 
A protocol violation occurs when the subject, investigator, or Sponsor fails to adhere to significant 
protocol requirements affecting the inclusion, exclusion, subject safety and primary endpoint criteria. 
Protocol violations for this study include, but are not limited to, the following: 
 
Failure to meet inclusion/exclusion criteria 
 
Use of a prohibited concomitant medication 
 
Use of a camera which is not validated for the study or using an imaging technique different to that 
described in Section 11 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol violation. 
The Sponsor will determine if a protocol violation will result in withdrawal of a subject. 
When a protocol violation occurs, it will be discussed with the investigator and a Protocol Violation Form 
detailing the violation will be generated. This form will be signed by a Sponsor representative and the 
Investigator. A copy of the form will be filed in the site’s regulatory binder and in the Sponsor’s files. 
 
 
14 
STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be written 
describing all analyses that will be performed. The SAP will contain any modifications to the analysis 
plan described below. 
 
Adverse event rates will be coded by body system and MedDra classification term. Adverse events will 
be tabulated and will include the number of patients for whom the event occurred, the rate of occurrence, 
and the severity and relationship to study drug. 
 
14.1 Analysis of Primary Endpoint 
For the evaluation of the primary endpoint (i.e., impact on therapy), questionnaires obtained pre- and 
post-18F-fluciclovine PET/CT  will be compared to  calculate the fraction  of  cases  with a  change in 
management (versus no change in planned management). The 95% confidence interval will be calculated 
using the Exact method for a binomial distribution. 
 
 


LOCATE 
33 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
14.2 Analysis of Secondary Endpoints 
For the evaluation of the secondary endpoint examining actual impact on therapy, questionnaires obtained 
pre-FACBC will be compared to treatment executed post-18F-fluciclovine PET/CT to calculate  the fraction 
of cases with a change in management (versus no change in planned management). For the estimation 
of detection rate, the proportion of the 18F-fluciclovine -PET/CT positive results, 95% confidence interval 
will be calculated using the Exact method for a binomial distribution. 
 
For each patient a comparison will be made of the results of the 18F-fluciclovine PET/CT results, any 
histopathology results, results of any other imaging and also for the clinical response to treatment(s) 
(standard of truth) by an Adjudication Panel. The PPV, NPV, sensitivity and specificity will be calculated, 
where possible, at lesion or regional or patient level. The PPV will be calculated separately for patients 
undergoing optional biopsy for (1) regional disease and (2) distant disease. The 95% confidence interval 
will be calculated using the Exact method for a binomial distribution. The Adjudication Panel will 
follow the Adjudication Manual that will prospectively document the processes to be used to determine 
a decision concerning the result of the 18F-fluciclovine PET/CT scan vs standard of truth. 
 
Rates of disease detection (radiographic only and confirmed by pathology or MRI) will be described 
 
14.3 Interim Analysis 
When the study recruits the required number of 18F-fluciclovine -PET/CT  positive patients, accrual will be 
stopped.  A corresponding interim analysis for the primary aim will be planned and the study results will be 
submitted for potential public presentation prior to completion of all data collection and analyses.  As 
subject recruitment will have been completed and the trial design will not be modified as a result of this 
interim analysis, no adjustment to the type I error is required. 
 
14.4 Sample Size and Randomization 
The primary objective of this study is to measure the fraction of patients for whom 18F-fluciclovine - 
PET/CT alters intended management plan. The sample size consideration will be primarily based on 
binding the width of its 95% confidence interval, i.e., precision analysis. The prevalence rate of positive 
18F-fluciclovine -PET/CT findings in this population is assumed to be approximately 40%. About 30% of 
positive scans will be expected to change the physician’s intended management plan. (11). The goal is to 
accurately assess the fraction of change in intended management in these FACBC positive patients. The 
table below lists the calculated sample sizes with respect to binding different 95% CI widths at the 
proportion of 30%. The Clopper-Pearson Exact method was used in PASS 12 (Hintze, J. (2013). PASS 
12. NCSS, LLC. Kaysville, Utah, USA. www.ncss.com). 
 
Confidence 
Sample 
Size 
Target 
Actual 
Proportion 
Lower 
Upper 
Width if 
Level 
(N) 
Width 
Width 
(P) 
Limit 
Limit 
P = 0.5 
0.950 
341 
0.100 
0.100 
0.300 
0.252 
0.352 
0.109 
0.950 
89 
0.200 
0.199 
0.300 
0.207 
0.406 
0.216 
0.950 
40 
0.300 
0.300 
0.300 
0.166 
0.465 
0.324 
 
If the goal is to bind the 95% CI width at 0.20 (i.e., half –length at 0.10), then 89 FACBC positive 
patients will be needed for the assessment of our primary aim. Since the positivity rate is assumed to be 
around 40% in the study population, we need to enroll 223 patients. Due to the random nature of the 
observed numbers of patients meeting the clinical criteria in a prospective study, a sample size correction 
technique attributed to (12) was applied. Our calculation shows that after adding 25 extra patients (i.e., 
248 in total), we can be 90% sure to yield the required numbers of patients meeting the criteria. After 
taking 15% of potential data loss into consideration, we will need 292 patients in this study.  This number 


LOCATE 
34 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
will be 1,059 for binding the 95% CI width at 0.10, and 138 for binding the 95% CI width at 0.30. If the 
bandwidth of 95% CI remains at 0.20, but the prevalence rate of positive 18F-fluciclovine scans is lower 
than 0.40, it is estimated that we may need to enrol up to 330 patients into the study in order to obtain 89 
evaluable patients. 
 
 
 
 
15 
DATA COLLECTION, RETENTION AND MONITORING 
 
15.1 Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to record all 
observations and other pertinent data for each subject treated with the study drug. 
Study personnel at each site will enter data from source documents corresponding to a subject’s visit into 
the protocol-specific electronic Case Report Form (eCRF) when the information corresponding to that 
visit is available. Subjects will not be identified by name in the study database or on any study 
documents to be collected by the Sponsor (or designee), but will be identified by a site number, subject 
number and initials. 
 
If a correction is required for an eCRF, the time and date stamp tracks the person entering or updating 
eCRF data and creates an electronic audit trail. The Investigator is responsible for all information collected 
on subjects enrolled in this study. All data collected during the course of this study must be reviewed 
and verified for completeness and accuracy by the Investigator. A copy of the CRF will be provided to 
the Investigator’s site at the completion of the study. 
 
15.2 Data Management Procedures 
The data will be entered into a validated database. The Data Management group will be responsible for 
data processing, in accordance with procedural documentation. Database lock will occur once quality 
assurance procedures have been completed. 
 
All procedures for the handling and analysis of data will be conducted using good computing practices 
meeting FDA guidelines for the handling and analysis of data for clinical trials. 
 
15.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation checks 
will be implemented and applied to the database on a regular basis. Queries are entered, tracked, and 
resolved through the EDC system directly. The study database will be updated in accordance with the 
resolved queries.  All changes to the study database will be documented. 
 
15.4 Archiving of Data 
The database is safeguarded against unauthorized access by established security procedures; appropriate 
backup copies of the database and related software files will be maintained. Databases are backed up by 
the database administrator in conjunction with any updates or changes to the database. 
 
At critical junctures of the protocol (e.g., production of interim reports and final reports), data for analysis 
is locked and cleaned per established procedures. 


LOCATE 
35 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
15.5 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized representatives of the 
Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., FDA) inspectors upon request.  A file for 
each subject must be maintained that includes the signed Informed Consent, HIPAA Authorization and 
Assent Form and copies of all source documentation related to that subject.  The Investigator must ensure 
the reliability and availability of source documents from which the information on the CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, Study File Notebook, 
etc.) must be kept secured for a period of two years following marketing of the investigational product or 
for two years after centers have been notified that the IND has been discontinued.  There may be other 
circumstances for which the Sponsor is required to maintain study records and, therefore, the Sponsor 
should be contacted prior to removing study records for any reason. 
 
15.6 Monitoring and Auditing 
Monitoring visits will be conducted by representatives of the Sponsor according to the U.S. CFR Title 21 
Parts 50, 56, and 312 and ICH Guidelines for GCP (E6). By signing this protocol, the Investigator 
grants permission to the Sponsor (or designee), and appropriate regulatory authorities to conduct on-site 
monitoring and/or auditing of all appropriate study documentation. 
 
15.7 Subject Confidentiality 
In order to maintain subject confidentiality, only a site number, subject number and subject initials will 
identify all study subjects on CRFs and other documentation submitted to the Sponsor. Additional 
subject confidentiality issues (if applicable) are covered in the Clinical Study Agreement. 
 
16 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human Volunteers 
(21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical Investigators (21 
CFR 312). 
 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records will be 
identified by a coded number and initials only. All study records will be kept in a locked file cabinet and 
code sheets linking a patient’s name to a patient identification number will be stored separately in another 
locked file cabinet. 
 
Clinical information will not be released without written permission of the subject, except as necessary 
for monitoring by the FDA. The Investigator must also comply with all applicable privacy regulations 
(e.g., Health Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 
95/46/EC). 
 
16.1 
Protocol Amendments 
Any amendment to the protocol will be written by the Sponsor. Protocol amendments cannot be 
implemented without prior written IRB/IEC approval except as necessary to eliminate immediate safety 
hazards to patients. A protocol amendment intended to eliminate an apparent immediate hazard to 
patients may be implemented immediately, provided the IRBs are notified within five working days. 
 
16.2 
Institutional Review Boards and Independent Ethics Committees 
The protocol and consent form will be reviewed and approved by the IRB/IEC of each participating 
center prior to study initiation. Serious adverse experiences regardless of causality will be reported to the 
IRB/IEC in accordance with the standard operating procedures and policies of the IRB/IEC, and the 
Investigator will keep the IRB/IEC informed as to the progress of the study. The Investigator will obtain 
assurance of IRB/IEC compliance with regulations. 


LOCATE 
36 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
 
Any documents that the IRB/IEC may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning patient recruitment, 
payment or compensation procedures, or other pertinent information) will be submitted to the IRB/IEC. 
The IRB/IECs written unconditional approval of the study protocol and the informed consent form will be 
in the possession of the Investigator before the study is initiated. The IRB/IECs unconditional approval 
statement will be transmitted by the Investigator to Blue Earth Diagnostics Ltd prior to the shipment of 
study supplies to the site. This approval must refer to the study by exact protocol title and number and 
should identify the documents reviewed and the date of review. 
 
Protocol and/or informed consent modifications or changes may not be initiated without prior written 
IRB/IEC approval except when necessary to eliminate immediate hazards to the patients or when the 
change(s) involves only logistical or administrative aspects of the study. Such modifications will be 
submitted to the IRB/IEC and written verification that the modification was submitted and subsequently 
approved should be obtained. 
 
The IRB/IEC must be informed of revisions to other documents originally submitted for review; serious 
and/or unexpected adverse experiences occurring during the study in accordance with the standard 
operating procedures and policies of the IRB; new information that may affect adversely the safety of the 
patients of the conduct of the study; an annual update and/or request for re-approval; and when the study 
has been completed. 
 
16.3 
Informed Consent Form 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US Code of 
Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, and CFR Part 56, 
Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, if applicable), and local 
regulations. 
 
The Investigator will prepare the informed consent form, assent and HIPAA authorization and provide the 
documents to the Sponsor or designee for approval prior to submission to the IRB/IEC. The consent form 
generated by the Investigator must be acceptable to the Sponsor and be approved by the IRB/IEC. The 
written consent document will embody the elements of informed consent as described in the International 
Conference on Harmonization and will also comply with local regulations. The Investigator will send an 
IRB/IEC-approved copy of the Informed Consent Form to the Sponsor (or designee) for the study file. 
A properly executed, written, informed consent will be obtained from each subject prior to entering the 
subject into the trial. Information should be given in both oral and written form and subjects must be 
given ample opportunity to inquire about details of the study. A copy of the signed consent form (and 
assent) will be given to the subject or legal representative of the subject and the original will be 
maintained with the subject’s records. 
 
16.4 
Publications 
The preparation and submittal for publication of manuscripts containing the study results shall be 
in accordance with a process determined by mutual written agreement among the study Sponsor 
and participating institutions. The publication or presentation of any study results shall comply 
with all applicable privacy laws, including, but not limited to, the Health Insurance Portability 
and Accountability Act of 1996. 
 
16.5 
Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 


LOCATE 
37 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
1. 
Conduct the study in accordance with the protocol and only make changes after notifying the 
Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2. 
Personally conduct or supervise the study (or investigation). 
3. 
Ensure that the requirements relating to obtaining informed consent and IRB review and approval 
meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. 
Report to the Sponsor or designee any AEs that occur in the course of the study, in accordance with 
§21 CFR 312.64. 
5. 
Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. 
Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make those 
records available for inspection with the Sponsor (or designee). 
7. 
Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be responsible for 
initial and continuing review and approval of the clinical study. 
8. 
Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity and all 
unanticipated problems involving risks to subjects or others (to include amendments and IND safety 
reports). 
9. 
Seek IRB approval before any changes are made in the research study, except when necessary to 
eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all other 
pertinent requirements listed in § 21 CFR part 312. 


LOCATE 
38 of 39 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 
 
 
 
 
 
17 
REFERENCES 
 
1. Bill-Axelson A, Holmberg L, Ruutu M, Garmo H, Stark JR, Busch C, et al. Radical 
prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 
2011;364(18):1708-17. PUBMED ID: 21542742 
2. Jones CU, Hunt D, McGowan DG, Amin MB, Chetner MP, Bruner DW, et al. Radiotherapy and 
short-term androgen deprivation for localized prostate cancer. N Engl J Med 2011;365(2):107-18. 
PUBMED ID: 21751904 
3. Horwitz EM, Bae K, Hanks GE, Porter A, Grignon DJ, Brereton HD, et al. Ten-year follow-up of 
radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective 
androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008;26(15):2497-504. 
PUBMED ID: 18413638 
4. NCCN. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: 
Prostate Cancer. In; 2012. 
(http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site) 
5. Schuster DM, Savir-Baruch B, Nieh PT, Master VA, Halkar RK, Rossi PJ, et al. Detection of 
recurrent prostate carcinoma with anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid 
PET/CT and 111In-capromab pendetide SPECT/CT. Radiology 2011;259(3):852-61. PUBMED 
ID: 21493787 
6. Schuster DM, Votaw JR, Nieh PT, Yu W, Nye JA, Master V, 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(1):56-63. PUBMED ID: 17204699 
7. Schuster DM, Nieh PT, Jani AB, Amzat R, DuBois Bowman F, Halkar RK, Master VA, Nye JA, 
Odewole OA, Osunkoya AO, Savir-Baruch B, Alaei-Taleghani P, Goodman MM. Anti-3- 
[18F]FACBC positron emission tomography-computerized tomography and 111In-capromab- 
pendetide single photon emission computerized tomography-computerized tomography in 
recurrent prostate carcinoma: results of a prospective clinical trial. J Urology 2014; 191(5):1446- 
1453. 
8. McParland BJ, Wall A, Johansson S and Sorensen J. The clinical safety, biodistribution and 
internal radiation dosimetry of [(18)F]fluciclovine in healthy adult volunteers. Eur J Nucl Med 
Mol Imaging 2013;40:1256-1264. 
9. 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. 
10. SNMMI NMCTG Fluciclovine (18F) Consensus Reader Meeting Report. 2014. 
11. Odewole OA, Jani AB, Tade F, Nieh PT, Master VA, Bellamy LM, Goodman MM, Raghuveer 
H, and Schuster DM. Change in salvage radiotherapy management based on guidance with anti- 
3-[18F] FACBC PET-CT in recurrent prostate cancer patients post-prostatectomy. In Society of 
Nuclear Medicine Annual Meeting Abstracts, vol. 56, Supplement 3, p. 457. 2015. 
12. Pepe, MS. The Statistical Evaluation of Medical Tests for Classification and Prediction. Oxford 
University Press. 2003. 


LOCATE 
39 of 39 
 
 
 
Appendix 1: Schedule of Events 
 
Visit 1 - 
Screen 
up to 30 
days before 
Visit 2 
Document 
Initial 
Management 
Plan 
Visit 2 - Day of 18F-fluciclovine PET/CT 
Visit 3 
Document 
Post  18F- 
Fluciclovine 
PET/CT 
Management 
Plan 
End of Study 
Pre-dose/ 
pre-scan 
Immed. 
post scan 
60 min 
post dose 
120 min 
post dose 
Study Day 
-30 to Visit 2 
Prior to Visit 2 
1 
2 
2-22 
180 ± 28 days 
Visit Location/Type 
Treating 
Physician 
Office 
NA 
PET/CT Imaging Center 
Phone 
Call 
NA 
NA 
Assessments/Procedures 
Informed consent 
X 
Inclusion/ exclusion criteria 
X 
X 
Medical history 
X 
X 
PCa history, including treatment 
X 
Record PSA levels 1 
X 
X 
Record imaging studies 2 
X 
X 
Vital signs (heart rate and blood 
pressure) 
X 
X 
X 
X 
X 
Height, weight 
X 
Serum chemistry and hematology 
X 
X 3 
Serum PSA 
X 
Urinalysis, dipstick 
X4 
 
EKG 
X 
X 3 
Record biopsy results, if applicable 
X 
Injection site assessment 
X 
X 
X 
X 
X 
AE assessment 
X 
X 
X 
X 
X 
Concomitant medication assessment 
X 
X 
X 
Document management/plan 
Plan 
Revised 
Actual 
Treatment response assessment 
X 
1 - Record all available PSA levels obtained prior to Visit 1 through End of Study; for non-prostectomy subjects, the PSA nadir and 2 times over nadir result must be documented in the record.  
2 - Record all available imaging studies performed prior to Visit 1 through End of Study; negative or equivocal imaging within 60 days of Visit 1. 
3 - Post-dose blood tests and EKG may be performed at the Imaging Center or within 7 days of the scan at another laboratory/site. 4May be collected and tested at any time between screening and scan date 
 
 
 
 
 
 
CONFIDENTIAL Blue Earth Diagnostics Protocol BED003 Version 4.0 Version Date: 07 June 2017 

SAP_001.pdf: 

'DWH0$5

3DJH1 RI24 
9HUVLRQ$PHQGPHQW)LQDO
67IRUP


7KH,PSDFWRI)IOXFLFORYLQH)$&%&3(7&7RQ
0DQDJHPHQWRI3DWLHQWVZLWK5LVLQJ36$DIWHU,QLWLDO
3URVWDWH&DQFHU7UHDWPHQW

%OXH(DUWK'LDJQRVWLFV6WXG\1R%('
6\QHTXDQRQ/WG6WXG\1R%/6


6WDWLVWLFDO$QDO\VLV3ODQ


9HUVLRQ$PHQGPHQW'UDIW)LQDO
'DWHWK0DUFK




)RU6\QHTXDQRQ/WG–/HDG6WDWLVWLFLDQ
6LJVLJ

)RU%OXH(DUWK'LDJQRVWLFV

6LJVLJ

'RFX6LJQ(QYHORSH,'(%)'($
6L
6 JVLV J
6L
6L
6 JVLV J


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH2 RI24 
9HUVLRQ$PHQGPHQW)LQDO
67IRUP

&RQWHQWV


,1752'8&7,21 

*(1(5$/35,1&,3/(6 

678'<2%-(&7,9(6$1''(6,*1 

6WXG\2EMHFWLYHV 

6WXG\'HVLJQ 

9LVLW6WUXFWXUH 

6DPSOH6L]H 

&KDQJHVIURPWKH3URWRFRO3ODQQHG$QDO\VLV 

678'<68%-(&76 

$QDO\VLVVHWV 

'LVSRVLWLRQRI6XEMHFWV 

3URWRFRO'HYLDWLRQV 

%DFNJURXQGDQG'HPRJUDSKLF&KDUDFWHULVWLFV 

'HPRJUDSKLFDQG%DVHOLQH&KDUDFWHULVWLFV 

0HGLFDO+LVWRU\ 

3URVWDWH&DQFHU+LVWRU\ 

&DQFHU7KHUDSLHVIRU3URVWDWH&DQFHU 

3ULRUDQG&RQFRPLWDQW0HGLFDWLRQV 

2WKHU6XEMHFW&KDUDFWHULVWLFV 

$GPLQLVWUDWLRQRI,QYHVWLJDWLRQDO3URGXFW 

()),&$&<(9$/8$7,21 

3ULPDU\(IILFDF\9DULDEOH 

6HFRQGDU\(IILFDF\9DULDEOHV 

'HILQLWLRQRI5HJLRQ/HYHOV 

6WDWLVWLFDO$QDO\VLV 

3ULPDU\(IILFDF\$QDO\VLV 

6HFRQGDU\(IILFDF\$QDO\VHV 

+DQGOLQJRI'URSRXWVRU0LVVLQJ'DWD 

,QWHULP$QDO\VHVDQG'DWD0RQLWRULQJ 

([DPLQDWLRQRI6XEJURXSV 

6$)(7<(9$/8$7,21 

$GYHUVH(YHQWV 

&OLQLFDO/DERUDWRU\(YDOXDWLRQ 

+HPDWRORJ\ 

%LRFKHPLVWU\ 

8ULQDO\VLVGLSVWLFN 

9LWDO6LJQV 

(OHFWURFDUGLRJUDSK\ 

5HIHUHQFHV 




'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH3 RI24 
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
$%%5(9,$7,216

$EEUHYLDWLRQ
7HUP
$(
$GYHUVH(YHQW
%&5
%LRFKHPLFDOUHFXUUHQFH
%0,
%RG\0DVV,QGH[
&,
&RQILGHQFH,QWHUYDO
&U&O
&UHDWLQLQHFOHDUDQFH
&5)
&DVH5HSRUW)RUP
&7
&RPSXWHULVHG7RPRJUDSK\
&7&$(
&RPPRQ7HUPLQRORJ\&ULWHULDIRU$GYHUVH(YHQWV
($6
(IIHFWLYHQHVV$QDO\VLV6HW
(.*
(OHFWURFDUGLRJUDP
)$6
)XOO$QDO\VLV6HW
)1
)DOVH1HJDWLYH
)3
)DOVH3RVLWLYH
*)5
*ORPHUXODU)LOWUDWLRQ5DWH
0'5'
0RGLILFDWLRQRI'LHWLQ5HQDO'LVHDVH
0HG'5$
0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV
05,
0DJQHWLF5HVRQDQFH,PDJLQJ
PV
0LOOLVHFRQGV
139
1HJDWLYH3UHGLFWLYH9DOXH
3&D
3URVWDWH&DQFHU
3(7
3RVLWURQ(PLVVLRQ7RPRJUDSK\
336
3HU3URWRFRO6HW
339
3RVLWLYH3UHGLFWLYH9DOXH
36$
3URVWDWH6SHFLILF$QWLJHQ
37
3UHIHUUHG7HUP
6$(
6HULRXV$GYHUVH(YHQW
6$)
6DIHW\$QDO\VLV6HW
6$3
6WDWLVWLFDO$QDO\VLV3ODQ
6'
6WDQGDUG'HYLDWLRQ
62&
6\VWHP2UJDQ&ODVV
7($(
7UHDWPHQW(PHUJHQW$GYHUVH(YHQW
71
7UXH1HJDWLYH
710
710&ODVVLILFDWLRQRI0DOLJQDQW7XPRXUV
73
7UXH3RVLWLYH
:+2
:RUOG+HDOWK2UJDQL]DWLRQ
:+2''(
:+2'UXJ'LFWLRQDU\(QKDQFHG

'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH4 RI24 
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
 ,1752'8&7,21
7KLV6WDWLVWLFDO$QDO\VLV3ODQ6$3LVEDVHGRQSURWRFROYHUVLRQGDWHGWK-XQH

7KH6$3GHVFULEHVWKHWDEOHVOLVWLQJVDQGILJXUHVZKLFKZLOOEHSURYLGHGXSRQ
FRPSOHWLRQRIWKHVWXG\7KH6$3ZLOOEHILQDOLVHGEHIRUHORFNLQJWKHGDWDEDVH
7KHWDEOHOLVWLQJDQGILJXUHVKHOOVZLOOEHVXSSOLHGLQDVHSDUDWHGRFXPHQW
The analyses relating to the fifth secondary objective “To explore differences in 
HVWLPDWHGFRVWRIWUHDWPHQWSODQVGHWHUPLQHGSULRUWRDQGIROORZLQJ)IOXFLFORYLQH
PET/CT” will be reported separately and are not covered in this SAP. 
 *(1(5$/35,1&,3/(6
7KHDQDO\VLVDQGVWDWLVWLFDOUHSRUWLQJZLOOEHFRQGXFWHGDW6\QHTXDQRQXVLQJ6$6
YHUVLRQRUKLJKHU
$OOOLVWLQJVZLOOEHEDVHGRQDOOHQUROOHGVXEMHFWVXQOHVVVSHFLILHGRWKHUZLVH$OO
WDEOHVZLOOEHSUHVHQWHGE\VLWHDQGRYHUDOOIRUWKHDSSURSULDWHDQDO\VLVSRSXODWLRQ
'HVFULSWLYHVXPPDU\VWDWLVWLFVIRUFRQWLQXRXVYDULDEOHVZLOOLQFOXGHQXPEHURI
VXEMHFWVQPHDQVWDQGDUGGHYLDWLRQ6'PLQLPXPPHGLDQDQGPD[LPXP
XQOHVVVSHFLILHGRWKHUZLVH7KHSUHFLVLRQRIWKHVHVXPPDU\VWDWLVWLFVLVGHILQHGLQ
WKHWDEOHILJXUHDQGOLVWLQJVKHOOVGRFXPHQW
'HVFULSWLYHVXPPDU\VWDWLVWLFVIRUFDWHJRULFDOYDULDEOHVZLOOLQFOXGHIUHTXHQF\FRXQWV
DQGSHUFHQWDJHV>1@8QOHVVVWDWHGRWKHUZLVHWKHGHQRPLQDWRUIRUSHUFHQWDJH
FDOFXODWLRQVZLOOEHWKHQXPEHURIVXEMHFWVLQWKHDQDO\VLVVHW
7KHUHZLOOEHQRLPSXWDWLRQRIPLVVLQJGDWD
 678'<2%-(&7,9(6$1''(6,*1
 6WXG\2EMHFWLYHV
7KHSULPDU\REMHFWLYHRIWKHVWXG\LVWRPHDVXUHWKHIUDFWLRQRIVXEMHFWVIRUZKRP
)IOXFLFORYLQH3(7&7DOWHUVLQWHQGHGPDQDJHPHQWWKURXJKGHWHFWLRQRIGLVHDVH
DIWHUFXUDWLYHLQWHQWWUHDWPHQWLQDSRSXODWLRQRIPHQZLWKHOHYDWHGSURVWDWLFVSHFLILF
DQWLJHQ36$OHYHOVLQGLFDWLYHRISHUVLVWHQWRUUHFXUUHQWSURVWDWHFDQFHUDQG
QHJDWLYHRUHTXLYRFDOILQGLQJVRQVWDQGDUGRIFDUHGLDJQRVWLFLPDJLQJWHVWV
7KHVHFRQGDU\REMHFWLYHVRIWKHVWXG\DUH
x 7RPHDVXUHWKHIUDFWLRQRIVXEMHFWVIRUZKRP)IOXFLFORYLQH3(7&7OHDGVWR
DFKDQJHLQDFWXDOPDQDJHPHQWE\FRPSDULVRQZLWKWKHLQWHQGHG
PDQDJHPHQWSODQEHIRUH)IOXFLFORYLQH3(7&7
x 7RHVWLPDWHWKHIUDFWLRQRIVXEMHFWVLQZKRP)IOXFLFORYLQH3(7&7\LHOGV
HYLGHQFHRIUHFXUUHQWGLVHDVHRQWKHEDVLVRILPDJLQJUHVXOWV
x 7RHVWLPDWH
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH5 RI24 
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
o WKHUDWHVRIGHWHFWLQJUHJLRQDOO\UHFXUUHQWGLVHDVHLHSURVWDWLFEHG
RQO\DQGRUSHOYLFGLVHDVHRXWVLGHRIWKHEHG
o WKHUDWHRIGHWHFWLQJGLVWDQWPHWDVWDVHVLHERQHPHWDVWDVHVYLVFHUDO
PHWDVWDVHVRUQRQUHJLRQDOQRGDOPHWDVWDVHV

ZLWK)IOXFLFORYLQH3(7&7LQWKHVWXG\SRSXODWLRQ
x 7RGHWHUPLQH
o WKHSRVLWLYHSUHGLFWLYHYDOXH339RI)IOXFLFORYLQH3(7&7WRGHWHFW
UHJLRQDOO\UHFXUUHQWGLVHDVH
o WKH339RI)IOXFLFORYLQH3(7&7WRGHWHFWGLVWDQWPHWDVWDVHVLQWKH
VWXG\SRSXODWLRQLQVXEMHFWVZKRXQGHUJRRSWLRQDOELRSV\RI)
IOXFLFORYLQH3(7&7ILQGLQJVRUKDYHGRFXPHQWDWLRQRIGLVHDVHVWDWXV
EDVHGRQRWKHULPDJLQJDQGRUIROORZXSGDWD
x 7RH[SORUHGLIIHUHQFHVLQHVWLPDWHGFRVWRIWUHDWPHQWSODQVGHWHUPLQHGSULRU
WRDQGIROORZLQJ)IOXFLFORYLQH3(7&7
 6WXG\'HVLJQ
7KLVLVDSKDVH,,,ERSHQODEHOOHGPXOWLFHQWUHGVWXG\WRDVVHVVWKHLPSDFWRQ
VXEMHFWPDQDJHPHQWRI)IOXFLFORYLQH3(7&7LQVXEMHFWVZLWKULVLQJSURVWDWH
VSHFLILFDQWLJHQ36$DIWHULQLWLDOFDQFHUWUHDWPHQW
7KHSURVSHFWLYHVWXG\ZLOOHQUROXSWRPHQZLWK36$UHFXUUHQWSURVWDWHFDQFHU
DIWHUFXUDWLYHLQWHQWSULPDU\WKHUDS\DQGQHJDWLYHRUHTXLYRFDOILQGLQJVRQVWDQGDUG
RIFDUHLPDJLQJ&RQVHQWLQJSDUWLFLSDQWVZLOOEHLPDJHGZLWK)IOXFLFORYLQH
3(7&76LWHFOLQLFLDQVZLOOPDQDJHVWXG\VXEMHFWVSHUVWDQGDUGSUDFWLFHVDQGZLOO
GRFXPHQWDQ\FKDQJHLQWUHDWPHQWEDVHGRQUHYLHZRIWKH)IOXFLFORYLQH3(7&7
ILQGLQJV$GGLWLRQDOO\DVFOLQLFDOO\LQGLFDWHGRSWLRQDOELRSV\ZLOOEHSHUIRUPHG$OO
SDUWLFLSDQWVZLOOEHIROORZHGIRUXSWRPRQWKVZLWKFOLQLFDOGDWDFROOHFWHGIRUWKLV
VWXG\36$PHDVXUHPHQWIURPVFDQIRUPRQWKV7UHDWPHQWUHVSRQVHZLOOEH
DVVHVVHGPRQWKVSRVWVFDQ
7KHVXPPDU\IORZFKDUWRIWKHVWXG\GHVLJQLVDVIROORZV


'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6
%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH6 RI24 
9HUVLRQ$PHQGPHQW)LQDO
67IRUP








STUDY SCHEMA
2SWLRQDO
ELRSV\RI
SRVLWLYH
)
IOXFLFORYLQH
VLWHVDV
FOLQLFDOO\
LQGLFDWHG
Adult Males 
Suspicion of 
recurrent prostate 
carcinoma after 
presumed 
definitive therapy 
for primary 
disease (adapted 
from AUA 2013 and 
NCCN 1.2016):

x Post- 
prostatectomy: 
Detectable PSA to 
ш0.2 ng/ml 
(confirmed)
x Radiotherapy: PSA 
rise by ш 2.0 ng/ml 
over nadir
18F
fluciclovine 
Imaging
4XHVWLRQQDLUH
RQSODQQHG
WUHDWPHQW
35()
)/8&,&/29,1(
3(7&7
4XHVWLRQQDLUHRQ
SODQQHG
WUHDWPHQW
3267)
)/8&,&/29,1(
3(7&7
6 month follow up
SCREENING/REGISTRATION
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH7 RI24 
9HUVLRQ$PHQGPHQW)LQDO
67IRUP


 9LVLW6WUXFWXUH
7KHYLVLWVWUXFWXUHDQGVFKHGXOHGDVVHVVPHQWVDUHGHWDLOHGLQ$SSHQGL[6FKHGXOH
RI(YHQWVRIWKHSURWRFRO
 6DPSOH6L]H
7KHSULPDU\REMHFWLYHRIWKLVVWXG\LVWRPHDVXUHWKHIUDFWLRQRIVXEMHFWVIRUZKRP
)IOXFLFORYLQH3(7&7DOWHUVWKHLQWHQGHGPDQDJHPHQWSODQ7KHVDPSOHVL]H
FRQVLGHUDWLRQLVSULPDULO\EDVHGRQWKHELQGLQJZLGWKRILWVFRQILGHQFHLQWHUYDO
LHSUHFLVLRQDQDO\VLV7KHSUHYDOHQFHRISRVLWLYH)IOXFLFORYLQH3(7&7ILQGLQJVLQ
WKLVSRSXODWLRQLVDVVXPHGWREHDSSUR[LPDWHO\$ERXWRIWKHSRVLWLYH
VFDQVare expected to change the physician’s intended management pODQ7KHJRDO
LVWRDFFXUDWHO\DVVHVVWKHIUDFWLRQRIFKDQJHLQLQWHQGHGPDQDJHPHQWLQWKHVH
VXEMHFWV7KHWDEOHEHORZOLVWVWKHFDOFXODWHGVDPSOHVL]HVZLWKUHVSHFWWRELQGLQJ
GLIIHUHQW&,ZLGWKVDWWKHSURSRUWLRQRI7KH&ORSSHU3HDUVRQ([DFW
PHWKRGZDVXVHGLQ3$66+LQW]H

&RQILGHQFH
/HYHO
6DPSOH
6L]H
1
7DUJHW
:LGWK
$FWXDO
:LGWK
3URSRUWLRQ
3
/RZHU
/LPLW
8SSSHU
/LPLW
:LGWK
,I
3 

























,IWKHJRDOLVWRELQGWKH&,ZLGWKDWWKHQ)$&%&SRVLWLYHVXEMHFWVZLOO
EHQHHGHGIRUWKHDVVHVVPHQWRIWKHSULPDU\DLP6LQFHWKHSRVLWLYLW\UDWHLV
DVVXPHGWREHDSSUR[LPDWHO\LQWKHVWXG\SRSXODWLRQVXEMHFWVQHHGWREH
HQUROOHG$IWHUDFFRXQWLQJIRUWKHUDQGRPQDWXUHRIWKHREVHUYHGQXPEHUVRI
VXEMHFWVPHHWLQJWKHFOLQLFDOFULWHULDLQDSURVSHFWLYHVWXG\DQGSRWHQWLDOGDWDORVVLW
LVSODQQHGWRHQURODWOHDVWDQGXSWRVXEMHFWVLQRUGHUWRREWDLQ
HYDOXDEOHVXEMHFWV
 &KDQJHVIURPWKH3URWRFRO3ODQQHG$QDO\VLV
339HIILFDF\YDULDEOHVHFWLRQZLOOEHGHWHUPLQHGXVLQJDGMXGLFDWLRQSDQHO
GHFLVLRQUDWKHUWKDQRQO\XVLQJELRSV\RUELRSV\05,GDWD7KLVLVFRQVLVWHQWZLWK
WKHVWXG\REMHFWLYHV
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH8 RI24 
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
 678'<68%-(&76
 $QDO\VLVVHWV
7KHOLVWRIVXEMHFWVWREHLQFOXGHGLQHDFKRIWKHDQDO\VLVVHWVLVWREHDJUHHG
EHWZHHQWKH6\QHTXDQRQVWDWLVWLFLDQDQG%OXH(DUWK'LDJQRVWLFVRQFHDOOVWXG\
GDWDDUHDYDLODEOHDQGSULRUWRGDWDEDVHORFN
(QUROOHG6HW$OOVXEMHFWVZKRHQWHUHGVFUHHQLQJ
6DIHW\$QDO\VLV6HW6$)$OOVXEMHFWVZKRKDYHEHHQLQFOXGHGLQWKHGDWDEDVH
DQGKDYHEHHQDGPLQLVWHUHG)IOXFLFORYLQHZLOOEHLQFOXGHGLQWKH6DIHW\$QDO\VLV
6HW6$)
)XOO$QDO\VLV6HW)$6$OOVXEMHFWVHQUROOHGZKRKDYHKDGDQ)IOXFLFORYLQH
3(7&7VFDQZLOOEHLQFOXGHGLQWKH)XOO$QDO\VLV6HW)$6
(YDOXDEOH$QDO\VLV6HW($6$OOVXEMHFWVIURPWKH)$6ZKRKDYHDQLQWHQGHG
WUHDWPHQWPDQDJHPHQWSODQFRPSOHWHGDQGDUHYLVHGPDQDJHPHQWSODQSDJH
FRPSOHWHGZLOOEHLQFOXGHGLQWKH(YDOXDEOH$QDO\VLV6HW($6
3HU3URWRFRO6HW336$OOVXEMHFWVLQWKH($6ZKRPHHWWKHVHFRQGDQGWKLUG
SURWRFROLQFOXVLRQFULWHULDVHHSURWRFROVHFWLRQDQGDQ\RWKHUVXEMHFWZLWKRXW
PDMRUVLJQLILFDQWGHYLDWLRQIROORZLQJUHYLHZRIWKHSURWRFROGHYLDWLRQOLVW
 'LVSRVLWLRQRI6XEMHFWV
7KHQXPEHUDQGSHUFHQWDJHRIDOOVXEMHFWVHQUROOHGLQFOXGHGLQHDFKDQDO\VLVVHW
ZKRFRPSOHWHGWKHVWXG\DQGZKRSUHPDWXUHO\ZLWKGUHZLQFOXGLQJDEUHDNGRZQRI
WKHSULPDU\UHDVRQVIRUZLWKGUDZDOZLOOEHSUHVHQWHG
$OOHQUROOHGVXEMHFWVZLOOEHOLVWHGLQGLFDWLQJWKHLUPHPEHUVKLSWRWKHHYDOXDEOH
DQDO\VLVVHWDORQJZLWKWKHUHDVRQIRUH[FOXVLRQ
&RPSOHWLRQDQGZLWKGUDZDOLQIRUPDWLRQZLOOEHOLVWHGLQFOXGLQJLQGLYLGXDOUHDVRQVIRU
ZLWKGUDZDO
 3URWRFRO'HYLDWLRQV
)DLOHGLQFOXVLRQFULWHULDDQGIDLOHGH[FOXVLRQFULWHULDZLOOEHOLVWHGIRUVFUHHQLQJ
IDLOXUHV
7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVZLWKLQHDFKGHYLDWLRQFDWHJRU\ZLOOEH
SUHVHQWHGE\GHYLDWLRQW\SH0DMRU6LJQLILFDQW0DMRURU0LQRUDQGE\VLWHDQG
RYHUDOO7KHGHYLDWLRQFDWHJRU\DQGW\SHZLOOEHSURYLGHGE\%OXH(DUWK'LDJQRVWLFV
$OOSURWRFROGHYLDWLRQVZLOOEHOLVWHG
 %DFNJURXQGDQG'HPRJUDSKLF&KDUDFWHULVWLFV

'HPRJUDSKLFDQG%DVHOLQH&KDUDFWHULVWLFV
'HPRJUDSKLFFKDUDFWHULVWLFVDJHHWKQLFRULJLQDQGUDFHFROOHFWHGDW6FUHHQLQJ
ERG\PHDVXUHPHQWVKHLJKWZHLJKWFROOHFWHGDQG%0,GHULYHGDW9LVLWZLOOEH
VXPPDULVHGIRUWKHHQUROOHGVHW)$6($6DQG336SRSXODWLRQV
%RG\PDVVLQGH[%0,LVFDOFXODWHGDVZHLJKWNJKHLJKWPð
,QGLYLGXDOGHPRJUDSKLFFKDUDFWHULVWLFVDQGERG\PHDVXUHPHQWVGDWDZLOOEHOLVWHG
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH9 RI24 
9HUVLRQ$PHQGPHQW)LQDO
67IRUP

0HGLFDO+LVWRU\
0HGLFDOKLVWRU\HYHQWVZLOOEHFRGHGXVLQJWKHODWHVWYHUVLRQRIWKH0HGLFDO
'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV0HG'5$
7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVIURPWKH)$6ZLWKSUHYLRXVPHGLFDOKLVWRU\
DQGFXUUHQWHYHQWVZLOOEHWDEXODWHGE\V\VWHPRUJDQFODVV62&SUHIHUUHGWHUP
3762&VZLOOEHRUGHUHGLQGHFUHDVLQJIUHTXHQF\RIWKHWRWDOQXPEHURIVXEMHFWV
ZLWKPHGLFDOKLVWRU\HYHQWVUHSRUWHGLQHDFK62&DQG37VZLOOEHRUGHUHGZLWKLQD
62&LQGHFUHDVLQJIUHTXHQF\RIWKHWRWDOQXPEHURIVXEMHFWVZLWKHDFKPHGLFDO
KLVWRU\HYHQW
$OOPHGLFDOKLVWRU\HYHQWVZLOOEHOLVWHG

3URVWDWH&DQFHU+LVWRU\
'HWDLOVRISURVWDWHFDQFHUKLVWRU\ZLOOEHVXPPDULVHGIRUVXEMHFWVIURPWKH)$6DQG
ZLOOFRQVLVWRI
x 7LPHVLQFHLQLWLDOGLDJQRVLVPRQWKVFDOFXODWHGDV>GDWHRILQIRUPHG
FRQVHQW–GDWHRILQLWLDOSURVWDWHFDQFHUGLDJQRVLV@
x 710VWDJH3DWKRORJLFDO710VWDJHLIDYDLODEOHRWKHUZLVH&OLQLFDO710VWDJH
x *OHDVRQWRWDOVFRUH*OHDVRQWRWDOVFRUHIURPVXUJHU\LIDYDLODEOHRWKHUZLVH
*OHDVRQWRWDOVFRUHIURPELRSV\
x 7LPHVLQFHDGMXYDQWWUHDWPHQWPRQWKVFDOFXODWHGDV>GDWHRILQIRUPHG
FRQVHQW–VWRSGDWHRIDGMXYDQWWUHDWPHQW@
x 'XUDWLRQRIDGMXYDQWWUHDWPHQWPRQWKVFDOFXODWHGDV>VWRSGDWHRI
DGMXYDQWWUHDWPHQW–VWDUWGDWHRIDGMXYDQWWUHDWPHQW@
x 7LPHVLQFHGLDJQRVLVRIELRFKHPLFDOUHFXUUHQFH%&5LQGD\VFDOFXODWHGDV
GDWHRILQIRUPHGFRQVHQW–GDWHRIGLDJQRVLVRIELRFKHPLFDOUHFXUUHQFH
7LPHVLQFHGLDJQRVLVRI%&5PD\EHGHULYHGLQPRQWKVLIPRUHDSSURSULDWH
x %DVHOLQH36$YDOXHEDVHOLQHEHLQJGHILQHGDVWKHODVWYDOXHSULRUWR
IOXFLFORYLQH)DGPLQLVWUDWLRQ
'HWDLOVRISURVWDWHFDQFHUKLVWRU\ZLOOEHOLVWHG
'DWHLPSXWDWLRQIRULQFRPSOHWHGDWHV
x ,IGD\SDUWPLVVLQJXVHWKRIWKHPRQWK
x ,IGD\DQGPRQWKSDUWVPLVVLQJXVH-XO\

&DQFHU7KHUDSLHVIRU3URVWDWH&DQFHU
&DQFHUWKHUDSLHVIRUSURVWDWHFDQFHUZLOOEHFRGHGDFFRUGLQJWRWKHODWHVWYHUVLRQRI
WKH:RUOG+HDOWK2UJDQL]DWLRQ'UXJ'LFWLRQDU\(QKDQFHG:+2''(
&DQFHUWKHUDSLHVZLOOEHFDWHJRULVHGDVIROORZV
6XEMHFWVZLWKUDGLFDOSURVWDWHFWRP\
x 5DGLRWKHUDS\
x 1RUDGLRWKHUDS\
6XEMHFWVZLWKRXWUDGLFDOSURVWDWHFWRP\
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH10 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
x 5DGLRWKHUDS\RQO\
o (%57RQO\
o %UDFK\WKHUDS\RQO\
o (%57DQGEUDFK\WKHUDS\
x 5DGLRWKHUDS\DQGRWKHUWKHUDSLHV
o (%57DQGRWKHUWKHUDSLHV
o %UDFK\WKHUDS\DQGRWKHUWKHUDSLHV
x 2WKHUWKHUDSLHV
3ULRUFDQFHUWKHUDSLHVIRUSURVWDWHFDQFHUDUHGHILQHGDVWKRVHIRUZKLFKWKHHQG
GDWHLVSULRUWRWKHGDWHRILQMHFWLRQRI)IOXFLFORYLQH
&RQFRPLWDQWFDQFHUWKHUDSLHVIRUSURVWDWHFDQFHUDUHGHILQHGDVWKRVHZLWKDVWDUW
GDWHRQRUDIWHUWKHLQMHFWLRQGDWHRI)IOXFLFORYLQHRUWKRVHZLWKDVWDUWGDWHEHIRUH
WKHLQMHFWLRQGDWHRI)IOXFLFORYLQHEXWZKLFKFRQWLQXHGZLWKDVWRSGDWHRQRUDIWHU
WKHLQMHFWLRQGDWHRI)IOXFLFORYLQH
,IFDQFHUWKHUDS\GDWHVDUHLQFRPSOHWHDQGLWLVQRWFOHDUZKHWKHUWKHPHGLFDWLRQZDV
FRQFRPLWDQWLWZLOOEHDVVXPHGWREHFRQFRPLWDQW
7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVSHUFDWHJRU\RISURVWDWHFDQFHUWKHUDS\ZLOO
EHSUHVHQWHGIRUDOOVXEMHFWVIURPWKH6$)VHSDUDWHO\IRUVXEMHFWVZLWKDQGZLWKRXW
UDGLFDOSURVWDWHFWRP\7KLVVXPPDU\ZLOOEHUHSHDWHGIRUSULRUDQGFRQFRPLWDQW
FDQFHUWKHUDSLHV
$OOWKHUDSLHVIRUSURVWDWHFDQFHUZLOOEHOLVWHGLQFOXGLQJW\SHRIWKHUDS\UHSRUWHG
WKHUDS\QDPHPHGLFDWLRQFODVVVWDQGDUGLVHGPHGLFDWLRQQDPHGRVHGRVHXQLW
route of administration, start date and end date or ‘ongoing’ flag, therapy comments.

3ULRUDQG&RQFRPLWDQW0HGLFDWLRQV
3ULRUDQGFRQFRPLWDQWPHGLFDWLRQVZLOOEHFRGHGDFFRUGLQJWRWKHODWHVWYHUVLRQRI
WKH:+2''(
3ULRUPHGLFDWLRQVDUHGHILQHGDVWKRVHIRUZKLFKWKHHQGGDWHLVSULRUWRWKHGDWHRI
LQMHFWLRQRI)IOXFLFORYLQH
&RQFRPLWDQWPHGLFDWLRQVDUHGHILQHGDVWKRVHZLWKDVWDUWGDWHRQRUDIWHUWKH
LQMHFWLRQGDWHRI)IOXFLFORYLQHRUWKRVHZLWKDVWDUWGDWHEHIRUHWKHLQMHFWLRQGDWHRI
)IOXFLFORYLQHEXWZKLFKFRQWLQXHGZLWKDVWRSGDWHRQRUDIWHUWKHLQMHFWLRQGDWHRI
)IOXFLFORYLQH
,IPHGLFDWLRQGDWHVDUHLQFRPSOHWHDQGLWLVQRWFOHDUZKHWKHUWKHPHGLFDWLRQZDV
FRQFRPLWDQWLWZLOOEHDVVXPHGWREHFRQFRPLWDQW
7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVZKRWRRNDQ\PHGLFDWLRQVZLOOEHSUHVHQWHG
E\FHQWHUDQGRYHUDOOE\PHGLFDWLRQFODVVVWDQGDUGLVHGPHGLFDWLRQQDPHVVRUWHGLQ
GHFUHDVLQJIUHTXHQF\IRUDOOVXEMHFWVIURPWKH6$)VHSDUDWHO\IRUSULRUPHGLFDWLRQV
DQGFRQFRPLWDQWPHGLFDWLRQV
$OOSULRUDQGFRQFRPLWDQWPHGLFDWLRQVZLOOEHOLVWHGLQFOXGLQJUHSRUWHGQDPH
PHGLFDWLRQFODVVVWDQGDUGLVHGPHGLFDWLRQQDPHLQGLFDWLRQGRVHGRVHXQLW
frequency, route of administration, start date and end date or ‘ongoing’ flag.
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH11 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP

2WKHU6XEMHFW&KDUDFWHULVWLFV
1RWDSSOLFDEOH
 $GPLQLVWUDWLRQRI,QYHVWLJDWLRQDO3URGXFW
7KHYROXPHRIXQGLOXWHGIOXFLFORYLQHDFWLYLW\RIIOXFLFORYLQHDQGLQMHFWLRQVLWHUHDFWLRQ
GXULQJDQGIROORZLQJIOXFLFORYLQHDGPLQLVWUDWLRQZLOOEHVXPPDULVHGIRUVXEMHFWVLQWKH
6$)
$OOIOXFLFORYLQHDGPLQLVWUDWLRQGDWDZLOOEHOLVWHGLQIXOO
 ()),&$&<(9$/8$7,21
$OOOLVWLQJVZLOOEHEDVHGRQWKH)$6XQOHVVVSHFLILHGRWKHUZLVH
 3ULPDU\(IILFDF\9DULDEOH
7KHSULPDU\HIILFDF\YDULDEOHLVWKHFKDQJHLQPDQDJHPHQWSODQDVVHVVHGE\
FRPSDULQJSUH)IOXFLFORYLQH3(7&7PDQDJHPHQWSODQZLWKWKHSRVW)
IOXFLFORYLQH3(7&7PDQDJHPHQWSODQIRUVXEMHFWVZLWKDSRVLWLYH)IOXFLFORYLQH
3(7&7VFDQ
 6HFRQGDU\(IILFDF\9DULDEOHV
7KHVHFRQGDU\HIILFDF\YDULDEOHVDUH
x 3HUVXEMHFWLPSDFW\HVQRRI)IOXFLFORYLQH3(7&7RQSUH3(7LQWHQGHG
YHUVXVSRVW3(7DFWXDOVXEMHFWPDQDJHPHQW
x 7KHUDWHRIGHWHFWLRQRIDQ\GLVHDVHVLWHE\)IOXFLFORYLQH3(7&7LQWKH
VWXG\SRSXODWLRQ
x 7KHUDWHRIGHWHFWLRQRI
o 3URVWDWLFEHGDQGRWKHUSHOYLFGLVHDVH
o 'LVWDQWPHWDVWDVHVLHERQHPHWDVWDVHVYLVFHUDOPHWDVWDVHVRUQRQ
UHJLRQDOQRGDOPHWDVWDVHV

ZLWK)IOXFLFORYLQH3(7&7LQWKHVWXG\SRSXODWLRQ
x 7KH339RI)IOXFLFORYLQH3(7&7WRGHWHFWUHJLRQDOO\UHFXUUHQWGLVHDVH
FRPSDUHGWRDGMXGLFDWLRQSDQHOGHFLVLRQ
x 7KH339RI)IOXFLFORYLQH3(7&7WRGHWHFWGLVWDQWPHWDVWDVHVFRPSDUHGWR
DGMXGLFDWLRQSDQHOGHFLVLRQ
 'HILQLWLRQRI5HJLRQ/HYHOV
7ZRPDLQUHJLRQVZLOOEHDQDO\VHGWKHSURVWDWHDQGSURVWDWHEHGDQGWKHH[WUD
SURVWDWLFUHJLRQ
7KHSURVWDWHDQGSURVWDWHEHGLQFOXGHWKHIROORZLQJOHVLRQORFDWLRQV
x 3URVWDWHEHGOHIW
x 3URVWDWHEHGULJKW
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH12 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
x 3HULSKHUDO]RQHOHIW
x 3HULSKHUDO]RQHULJKW
x &HQWUDOJODQGOHIW
x &HQWUDOJODQGULJKW
x /HIWVHPLQDOYHVLFOH
x 5LJKWVHPLQDOYHVLFOH

7KHH[WUDSURVWDWLFUHJLRQVLQFOXGHWKHIROORZLQJOHVLRQORFDWLRQV
x /\PSKQRGHV
o 3HOYLFO\PSKQRGHV
 &RPPRQLOLDFOHIW
 &RPPRQLOLDFULJKW
 ,QWHUQDOLOLDFOHIW
 ,QWHUQDOLOLDFULJKW
 ([WHUQDOLOLDFOHIW
 ([WHUQDOLOLDFULJKW
 2EWXUDWRUOHIW
 2EWXUDWRUULJKW
 3UHVDFUDOOHIW
 3UHVDFUDOULJKW
 3HULUHFWDODQWHULRU
 3HULUHFWDO
SRVWHULRU
 ,QJXLQDOOHIW
 ,QJXLQDOULJKW
o 5HWURSHULWRQHDOO\PSKQRGHV
 3DUDDRUWLF
 5HWURDRUWLF
 3DUDFDYDO
 5HWURFDYDO
 $RUWRFDYDO
 5HWURFUXUDOOHIW
 5HWURFUXUDOULJKW
o 2WKHUO\PSKQRGHV
 ,QWUDSHULWRQHDO
 0HGLDVWLQDOOHIW
 0HGLDVWLQDOULJKW
 $[LOODU\OHIW
 $[LOODU\ULJKW
 &HUYLFDOOHIW
 &HUYLFDOULJKW
x 6RIWWLVVXHVSDUHQFK\PD
o /XQJXSSHUOREHOHIW
o /XQJXSSHUOREHULJKW
o /XQJPLGGOHOREHOHIW
o /XQJPLGGOHOREHULJKW
o /XQJORZHUOREHOHIW
o /XQJORZHUOREHULJKW
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH13 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
o %UDLQOHIW
o %UDLQULJKW
o /LYHUOHIW
o /LYHUULJKW
o 6SOHHQ
o 6XEFXWDQHRXVFXWDQHRXV
o 0XVFOH
o %RZHO
x %RQHV
o 6NXOO
 6NXOOEDVHPD[LOODOHIW
 6NXOOEDVHPD[LOODULJKW
 0DQGLEOHOHIW
 0DQGLEOHULJKW
o 1HFN
 9HUWHEUD&
 9HUWHEUD&
 9HUWHEUD&
 9HUWHEUD&
 9HUWHEUD&
 9HUWHEUD&
 9HUWHEUD&
 9HUWHEUD7
 9HUWHEUD7
 9HUWHEUD7
 9HUWHEUD7
 9HUWHEUD7
 9HUWHEUD7
 9HUWHEUD7
 9HUWHEUD7
 9HUWHEUD7
 9HUWHEUD7
 9HUWHEUD7
 9HUWHEUD7
 9HUWHEUD/
 9HUWHEUD/
 9HUWHEUD/
 9HUWHEUD/
 9HUWHEUD/
 6DFUXPOHIW
 6DFUXPULJKW
 6DFUXPFHQWUDO
o &KHVW
 VWULEOHIW
 VWULEULJKW
 QGULEOHIW
 QGULEULJKW
 UGULEOHIW
 UGULEULJKW
 WKULEOHIW
 WKULEULJKW
 WKULEOHIW
 WKULEULJKW
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH14 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
 WKULEOHIW
 WKULEULJKW
 WKULEOHIW
 WKULEULJKW
 WKULEOHIW
 WKULEULJKW
 WKULEOHIW
 WKULEULJKW
 WKULEOHIW
 WKULEULJKW
 WKULEOHIW
 WKULEULJKW
 WKULEOHIW
 WKULEULJKW
 6WHUQXP
 &ODYLFOHOHIW
 &ODYLFOHULJKW
 6FDSXODOHIW
 6FDSXODULJKW
o 3HOYLV
 ,OLXPOHIW
 ,OLXPULJKW
 6XSHULRUSXELF
UDPXVOHIW
 6XSHULRUSXELF
UDPXVULJKW
 ,QIHULRUSXELF
UDPXVOHIW
 ,QIHULRUSXELF
UDPXVULJKW
 3XELFERG\OHIW
 3XELFERG\ULJKW
 ,VFKLXPOHIW
 ,VFKLXPULJKW
o $SSHQGLFXODU
 3UR[LPDOKXPHUXVOHIW
 3UR[LPDOKXPHUXVULJKW
 3UR[LPDOIHPXUOHIW
 3UR[LPDOIHPXUULJKW

 6WDWLVWLFDO$QDO\VLV

3ULPDU\(IILFDF\$QDO\VLV
7KHSULPDU\HIILFDF\DQDO\VLVZLOOEHEDVHGRQWKH($6DQGZLOOEHUHSHDWHGRQWKH
336DVDVHFRQGDU\DQDO\VLV&RPSDULVRQVEHWZHHQWKHRULJLQDOWUHDWPHQWSODQDQG
WKHUHYLVHGWUHDWPHQWSODQZLOOEHFDWHJRULVHGDVQRFKDQJHPDMRUFKDQJHRURWKHU
FKDQJH7KHGHILQLWLRQVRIWKHFKDQJHFDWHJRULHVDUHOLVWHGEHORZ
x 1RFKDQJHWKHRULJLQDOWUHDWPHQWSODQLVWKHVDPHDVWKHUHYLVHGWUHDWPHQW
SODQ
x 0DMRUFKDQJHWKHRULJLQDOWUHDWPHQWSODQLVQRWWKHVDPHDVWKHUHYLVHG
WUHDWPHQWSODQDQGWKHJURXSLQJIRUWKHRULJLQDOWUHDWPHQWSODQLVQRWWKHVDPH
DVWKHJURXSLQJIRUWKHUHYLVHGWUHDWPHQWSODQ
7KHVHZLOOEHIXUWKHUVSOLWDQGSUHVHQWHGDFFRUGLQJWRWKHIROORZLQJFDWHJRULHV
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH15 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
- 6DOYDJHRU1RQFXUDWLYHV\VWHPLFWKHUDS\WR:DWFKIXOZDLWLQJ
- 6DOYDJHWKHUDS\WR1RQFXUDWLYHV\VWHPLFWKHUDS\
- 1RQFXUDWLYHV\VWHPLFWKHUDS\WR6DOYDJHWKHUDS\
- $OWHUQDWLYH0DMRUFKDQJH
x 2WKHUFKDQJHWKHRULJLQDOWUHDWPHQWSODQLVQRWWKHVDPHDVWKHUHYLVHG
WUHDWPHQWSODQEXWWKHJURXSLQJIRUWKHRULJLQDOWUHDWPHQWSODQLVWKHVDPHDV
WKHJURXSLQJIRUWKHUHYLVHGWUHDWPHQWSODQ
7KHVHZLOOEHIXUWKHUVSOLWDQGSUHVHQWHGDFFRUGLQJWRWKHIROORZLQJFDWHJRULHV
- 0RGLILHG57ILHOGSODQ
- 0RGLILHGDQGURJHQGHSULYDWLRQUHJLPHQ
- $OWHUQDWLYH2WKHUFKDQJH
*URXSLQJVRIWUHDWPHQWSODQVDUHGHWDLOHGLQWKHIROORZLQJWDEOH

2ULJLQDO7UHDWPHQW
3ODQ
*URXSLQJIRU
2ULJLQDO7[3ODQ
5HYLVHG7UHDWPHQW
3ODQ
*URXSLQJIRU
5HYLVHG7[3ODQ
:DV
DQGURJHQ
GHSULYDWLRQ WKHUDS\
SODQQHG
$QGURJHQ
'HSULYDWLRQ
7KHUDS\
$QGURJHQ
GHSULYDWLRQWKHUDS\
$QGURJHQ
GHSULYDWLRQWKHUDS\


$FWLYHVXUYHLOODQFH
$FWLYHVXUYHLOODQFH


&KHPRWKHUDS\
&KHPRWKHUDS\
6DOYDJH
UDGLRWKHUDS\ WR WKH
SURVWDWHEHG
6DOYDJH
5DGLRWKHUDS\

6DOYDJH
UDGLRWKHUDS\ WR WKH
SURVWDWHEHG
6DOYDJH
5DGLRWKHUDS\
6DOYDJH
UDGLRWKHUDS\ WR WKH
SURVWDWH EHG ZLWK
ERRVW
WR
DUHDV
JXLGHG
E\
FRQYHQWLRQDO
LPDJLQJ
6DOYDJH
UDGLRWKHUDS\ WR WKH
SURVWDWH EHG ZLWK
ERRVW
WR
DUHDV
JXLGHG
E\
FRQYHQWLRQDO
LPDJLQJ

6DOYDJH
UDGLRWKHUDS\ WR WKH
SURVWDWH EHG ZLWK
ERRVW
WR
DUHDV
JXLGHG
E\
IOXFLFORYLQH
)
3(7&7
6DOYDJH
UDGLRWKHUDS\ WR WKH
SURVWDWH EHG DQG
ZKROHSHOYLV
6DOYDJH
5DGLRWKHUDS\
6DOYDJH
UDGLRWKHUDS\ WR WKH
SURVWDWH EHG DQG
ZKROHSHOYLV
6DOYDJH
5DGLRWKHUDS\
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH16 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
2ULJLQDO7UHDWPHQW
3ODQ
*URXSLQJIRU
2ULJLQDO7[3ODQ
5HYLVHG7UHDWPHQW
3ODQ
*URXSLQJIRU
5HYLVHG7[3ODQ
6DOYDJH
UDGLRWKHUDS\ WR WKH
SURVWDWH EHG DQG
ZKROH SHOYLV ZLWK
ERRVW
WR
DUHDV
JXLGHG
E\
FRQYHQWLRQDO
LPDJLQJ
6DOYDJH
UDGLRWKHUDS\ WR WKH
SURVWDWH EHG DQG
ZKROH SHOYLV ZLWK
ERRVW
WR
DUHDV
JXLGHG
E\
FRQYHQWLRQDO
LPDJLQJ

6DOYDJH
UDGLRWKHUDS\ WR WKH
SURVWDWH EHG DQG
ZKROH SHOYLV ZLWK
ERRVW
WR
DUHDV
JXLGHG
E\
IOXFLFORYLQH
)
3(7&7
6DOYDJH
FU\RWKHUDS\
6DOYDJH
&U\RWKHUDS\
6DOYDJH
FU\RWKHUDS\
6DOYDJH
&U\RWKHUDS\

6DOYDJH
FU\RWKHUDS\
ZLWK
WUHDWPHQW
SODQ
JXLGHG
E\
IOXFLFORYLQH
)
3(7&7
6DOYDJH
EUDFK\WKHUDS\
6DOYDJH
%UDFK\WKHUDS\
6DOYDJH
EUDFK\WKHUDS\
6DOYDJH
%UDFK\WKHUDS\

6DOYDJH
EUDFK\WKHUDS\ ZLWK
WUHDWPHQW
SODQ
JXLGHG
E\
IOXFLFORYLQH
)
3(7&7
6DOYDJH+,)8
6DOYDJH+,)8
6DOYDJH+,)8
6DOYDJH+,)8

6DOYDJH +,)8 ZLWK
WUHDWPHQW
SODQ
JXLGHG
E\
IOXFLFORYLQH
)
3(7&7
6DOYDJH
SURVWDWHFWRP\
6DOYDJH
3URVWDWHFWRP\
6DOYDJH
SURVWDWHFWRP\
6DOYDJH
3URVWDWHFWRP\

6DOYDJH
SURVWDWHFWRP\ ZLWK
WDUJHWHG UHVHFWLRQ 
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH17 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
2ULJLQDO7UHDWPHQW
3ODQ
*URXSLQJIRU
2ULJLQDO7[3ODQ
5HYLVHG7UHDWPHQW
3ODQ
*URXSLQJIRU
5HYLVHG7[3ODQ
VDPSOLQJ
RI
IOXFLFORYLQH
)
SRVLWLYH
DUHDV
RXWVLGH
FRQYHQWLRQDO
VXUJLFDOILHOG
6DOYDJH
SURVWDWHFWRP\ DQG
OLPLWHG O\PSK QRGH
GLVVHFWLRQ
6DOYDJH
SURVWDWHFWRP\ DQG
OLPLWHG O\PSK QRGH
GLVVHFWLRQ

6DOYDJH
SURVWDWHFWRP\ DQG
OLPLWHG O\PSK QRGH
GLVVHFWLRQ
ZLWK
WDUJHWHG UHVHFWLRQ 
VDPSOLQJ
RI
IOXFLFORYLQH
)
SRVLWLYH
DUHDV
RXWVLGH
VXUJLFDO
ILHOG
6DOYDJH
SURVWDWHFWRP\ DQG
H[WHQGHG
O\PSK
QRGH
GLVVHFWLRQ
LQFOXGLQJ
LQWHUQDO
DQG H[WHUQDO LOLDF
DQG
REWXUDWRU
QRGHV
6DOYDJH
SURVWDWHFWRP\ DQG
H[WHQGHG
O\PSK
QRGH
GLVVHFWLRQ
LQFOXGLQJ
LQWHUQDO
DQG H[WHUQDO LOLDF
DQG
REWXUDWRU
QRGHV

6DOYDJH
SURVWDWHFWRP\ DQG
H[WHQGHG
O\PSK
QRGH
GLVVHFWLRQ
LQFOXGLQJ
LQWHUQDO
DQG H[WHUQDO LOLDF
DQG
REWXUDWRU
QRGHV
ZLWK
WDUJHWHG UHVHFWLRQ 
VDPSOLQJ
RI
IOXFLFORYLQH
)
SRVLWLYH
DUHDV
RXWVLGH
VXUJLFDO
ILHOG


7DUJHWHG
VDOYDJH
WUHDWPHQW
RI
IOXFLFORYLQH
)
7DUJHWHGVDOYDJH
WUHDWPHQW
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH18 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
2ULJLQDO7UHDWPHQW
3ODQ
*URXSLQJIRU
2ULJLQDO7[3ODQ
5HYLVHG7UHDWPHQW
3ODQ
*URXSLQJIRU
5HYLVHG7[3ODQ
SRVLWLYH H[WUDSHOYLF
ERQ\DUHDV


2WKHU
2WKHU

7KHFODVVLILFDWLRQDQGVXEFODVVLILFDWLRQRIFKDQJHLQWUHDWPHQWPDQDJHPHQWSODQ
ZLOOEHDJUHHGSULRUWRGDWDEDVHORFN
7KHQXPEHUSHUFHQWDJHDQGH[DFWFRQILGHQFHLQWHUYDO&,RIVXEMHFWVZLWKDQG
ZLWKRXWDFKDQJHLQPDQDJHPHQWSODQDIWHU)IOXFLFORYLQH3(7&7VFDQUHVXOWV
EHFRPHDYDLODEOHZLOOEHSUHVHQWHGIRUWKH($6,QDGGLWLRQWKHQXPEHUDQG
SHUFHQWDJHRIVXEMHFWVZLWKFKDQJHVFDWHJRULVHGDVPDMRURURWKHUZLOOEHSUHVHQWHG
DORQJZLWKLWV&,7KHVHVXPPDULHVZLOOEHUHSHDWHGVHSDUDWHO\IRUVXEMHFWV
ZLWKDSRVLWLYHDQGDQHJDWLYH)IOXFLFORYLQH3(7&7VFDQDQGIRUVXEMHFWVZLWKRXW
SURVWDWHFWRP\DQGZLWKSURVWDWHFWRP\$OOWKHVHVXPPDULHVZLOOEHUHSHDWHGXVLQJ
WKH336
'HWDLOVRIWKHLQWHQGHGPDQDJHPHQWSODQUHYLVHGPDQDJHPHQWSODQDQG
FDWHJRULVDWLRQRIFKDQJHLQPDQDJHPHQWSODQZLOOEHOLVWHG

6HFRQGDU\(IILFDF\$QDO\VHV
 &KDQJHLQDFWXDOPDQDJHPHQWSODQ
7KHQXPEHUSHUFHQWDJHDQGH[DFW&,IRUWKHSHUFHQWDJHRIVXEMHFWVLQWKH($6
ZLWKFOLQLFDOO\VLJQLILFDQWGHYLDWLRQVLQDFWXDOPDQDJHPHQWIURPWKHUHYLVHG
PDQDJHPHQWSODQDIWHU)IOXFLFORYLQH3(7&7VFDQUHVXOWVEHFRPHDYDLODEOHZLOO
EHSUHVHQWHGIRURYHUDOODQGIRUVXEMHFWVZLWKSRVLWLYHDQGZLWKQHJDWLYH)
IOXFLFORYLQH3(7&7VFDQV
$OOPDQDJHPHQWSODQGHYLDWLRQVZLOOEHOLVWHGLQIXOO
 'LDJQRVWLFSHUIRUPDQFHRI)IOXFLFORYLQH
'LDJQRVWLFSHUIRUPDQFHZLOOEHDVVHVVHGE\FDOFXODWLQJVHQVLWLYLW\VSHFLILFLW\
3RVLWLYH3UHGLFWLYH9DOXH339DQG1HJDWLYH3UHGLFWLYH9DOXH139XVLQJVXEMHFW
EDVHGDQDO\VHV)XUWKHUFDOFXODWLRQVZLOOEHPDGHIRULQWUDSURVWDWLFSURVWDWHEHG
DQGH[WUDSURVWDWLFGLVHDVH5HIHUHQFHWHVWVZLOOEHWKHDGMXGLFDWLRQSDQHOGHFLVLRQ
7KH$GMXGLFDWLRQ3DQHOZLOOIROORZWKH$GMXGLFDWLRQ0DQXDOWKDWSURVSHFWLYHO\
GRFXPHQWVWKHSURFHVVHVWREHXVHGWRGHWHUPLQHDGHFLVLRQFRQFHUQLQJWKHUHVXOW
RIWKH)IOXFLFORYLQH3(7&7VFDQYVVWDQGDUGRIWUXWK7KHQXPEHUDQG
SHUFHQWDJHRILQGHWHUPLQDWHUHVSRQVHVZLOOEHUHSRUWHG
7KHVHQVLWLYLW\VSHFLILFLW\339DQG139ZLOOEHFDOFXODWHGDV
x 6HQVLWLYLW\ 7373)1
x 6SHFLILFLW\ 71)371
x 339 7373)3
x 139 71)171
ZKHUH7371)3DQG)1UHIHUWRWUXHSRVLWLYHWUXHQHJDWLYHIDOVHSRVLWLYHDQG
IDOVHQHJDWLYHUHVXOWVUHVSHFWLYHO\
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH19 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
'HILQLWLRQVRIWKHVHVXPPDULHVZLOOEHEDVHGRQWKHWDEOHEHORZ


'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH20 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP




5HIHUHQFHWHVWV



3RVLWLYH
1HJDWLYH

)OXFLFORYLQH
)VFDQ
UHVXOWV
3RVLWLYH
7UXH3RVLWLYH
73
)DOVH3RVLWLYH
)3
73)3
1HJDWLYH
)DOVH1HJDWLYH
)1
7UXH1HJDWLYH
71
)171


73)1
)371
Q

7KHQXPEHUSHUFHQWDJHDQGH[DFW&,VRI73)3)1DQG71DVZHOODVWKH
SRLQWHVWLPDWHVH[SUHVVHGLQSHUFHQWDJHVDQGWKHLUDVVRFLDWHGH[DFW&,VRI
WKH6HQVLWLYLW\6SHFLILFLW\339DQG139ZLOOEHSUHVHQWHGDWWKHVXEMHFWOHYHODQG
WKHUHJLRQOHYHOIRUWKH)$6ZKHUHWKHUHJLRQOHYHOHVWLPDWHVZLOOEHFDOFXODWHG
VHSDUDWHO\IRUHDFKUHJLRQSURVWDWLFUHJLRQDQGH[WUDSURVWDWLFUHJLRQ7KHUHJLRQ
OHYHOUHVXOWVZLOOEHGHULYHGDWWKHVXEMHFWOHYHOIRUHDFKUHJLRQUHVXOWLQJLQRQH
RXWFRPHIRUHDFKVXEMHFWLQHDFKUHJLRQ)RUWKHVXEMHFWOHYHODQDO\VLVLIDVXEMHFW
KDVDWOHDVWRQHSRVLWLYHUHVXOWWKHVXEMHFWZLOOEHFDWHJRULVHGDVSRVLWLYH,IDOORID
subject’s results are negative the subject will be categorised as negative.  For the 
UHJLRQOHYHODQDO\VLVLIDVXEMHFWKDVDWOHDVWRQHSRVLWLYHUHVXOWIURPWKHSURVWDWLF
UHJLRQWKHVXEMHFWZLOOEHFDWHJRULVHGDVSRVLWLYHIRUWKHSURVWDWLFUHJLRQ,IDOOUHVXOWV
UHODWHGWRWKHSURVWDWLFUHJLRQDUHQHJDWLYHIRUDVXEMHFWWKDWVXEMHFWZLOOEH
FDWHJRULVHGDVQHJDWLYHIRUWKHSURVWDWLFUHJLRQ6LPLODUFODVVLILFDWLRQUXOHVDSSO\IRU
WKHH[WUDSURVWDWLFUHJLRQ
1RWHWKDWWKHVXEJURXSDQDO\VHVZLOORQO\EHSHUIRUPHGLIWKHUHDUHVXIILFLHQWGDWDIRU
WKHVHDQDO\VHVWREHPHDQLQJIXO
7KHVHHVWLPDWHVZLOOEHUHSHDWHGVHSDUDWHO\IRUUHJLRQDOO\UHFXUUHQWGLVHDVH
SURVWDWHSURVWDWHEHGSHOYLFO\PSKQRGHVDQGGLVWDQWPHWDVWDVHVUHWURSHULWRQHDO
O\PSKQRGHVRWKHUO\PSKQRGHVVRIWWLVVXHSDUHQFK\PDDQGERQHVDVXPPDU\IRU
O\PSKQRGHVRYHUDOOZLOODOVREHSUHVHQWHG2QFHDJDLQWKHUHJLRQOHYHOUHVXOWVZLOO
EHGHULYHGDWWKHVXEMHFWOHYHODQGVXEMHFWVZLOOEHFDWHJRULVHGDVSRVLWLYHRU
QHJDWLYHIRUHDFKUHJLRQLQDVLPLODUPDQQHUWRWKDWGHVFULEHGDERYHIRUWKHSURVWDWLF
UHJLRQ
7KHVHVXEMHFWDQGORFDWLRQOHYHOVXPPDULHVZLOOEHUHSHDWHGE\WKHIROORZLQJ
EDVHOLQH36$VXEJURXSV
x –
x !–
x !–
x !–
x –
x –
x !
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH21 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
DQGDFURVVWKHIROORZLQJEDVHOLQH*OHDVRQVFRUHFDWHJRULHVDQG$OO
WKHVHVXPPDULVHZLOOEHUHSHDWHGIRUWKH336
$OO)IOXFLFORYLQH3(7&7UHVXOWVRWKHULPDJLQJUHVXOWVDQGDGMXGLFDWLRQGHFLVLRQ
GDWDZLOOEHOLVWHG
 'HWHFWLRQUDWHV
7KHGHWHFWLRQUDWH'5ZLOOEHFDOFXODWHGDV73)3QIURPWKHDERYHWDEOH
7KHSRLQWHVWLPDWHH[SUHVVHGLQSHUFHQWDJHRIWKH'5ZLOOEHSUHVHQWHGDWWKH
UHJLRQOHYHODQGDWWKHVXEMHFWOHYHODVZHOODVIRUWKHSURVWDWLFEHGRWKHUSHOYLF
GLVHDVHDQGGLVWDQWPHWDVWDVHV7KHVHUDWHVZLOOEHSUHVHQWHGIRUDOOVXEMHFWVIURP
WKH)$6DQG336RYHUDOODQGDFURVVDUDQJHRIEDVHOLQH36$YDOXHV
x –
x !–
x !–
x !–
x –
x –
x !
WRGHWHUPLQHWKHRSWLPXP36$WKUHVKROGIRUOHVLRQGHWHFWLRQ
7KHGHWHFWLRQUDWHVZLOODOVREHVXPPDULVHGDFURVVWKHIROORZLQJEDVHOLQH*OHDVRQ
VFRUHFDWHJRULHVDQG
$OOGHWHFWLRQUDWHGDWDZLOOEHOLVWHG
 7UHDWPHQWUHVSRQVHDVDVVHVVHGE\FKDQJHLQ36$
%DVHOLQH36$LVWKHPRVWUHFHQW36$PHDVXUHPHQWSULRUWRVDOYDJHWKHUDS\IRU
VXEMHFWVZKRKDGVDOYDJHWUHDWPHQWDQGWKHPRVWUHFHQW36$PHDVXUHPHQWSULRUWR
WKH)IOXFLFORYLQH3(7&7IRUQRQVDOYDJHVXEMHFWV7UHDWPHQWUHVSRQVHZKLFKLV
EDVHGRQWKHSHUFHQWDJHFKDQJHLQ36$IURPEDVHOLQHWRWKHODVWYDOXHUHSRUWHGLV
GHILQHGDV
x GHFUHDVHLQ36$ZLOOEHFRQVLGHUHGWREHDUHVSRQVHWRWUHDWPHQW
x LQFUHDVHRUGHFUHDVHZLOOEHFODVVLILHGDVVWDEOHGLVHDVH
x LQFUHDVHLQ36$ZLOOEHFODVVLILHGDVGLVHDVHSURJUHVVLRQ
7KHQXPEHUSHUFHQWDJHDQGH[DFW&,RIVXEMHFWVKDYLQJDWUHDWPHQWUHVSRQVH
VWDEOHGLVHDVHDQGGLVHDVHSURJUHVVLRQDVDVVHVVHGE\FKDQJHLQ36$ZLOOEH
SUHVHQWHGRYHUDOODQGVHSDUDWHO\IRUVXEMHFWVLQWKH($6ZKRKDGVDOYDJHWUHDWPHQW
IRUVXEMHFWVZKRKDGQRQVDOYDJHWUHDWPHQWIRUWKRVHZLWKDFKDQJHLQPDQDJHPHQW
SODQDQGIRUVXEMHFWVZLWKQRFKDQJHLQPDQDJHPHQWSODQE\WUHDWPHQWDQGE\
GLVHDVHORFDWLRQ/RFDOGLVHDVH([WUDSURVWDWLFGLVHDVHIROORZLQJWKH)IOXFLFORYLQH
3(7&7VFDQ
,QDGGLWLRQWKHSHUFHQWDJHFKDQJHLQ36$IURPEDVHOLQHWRWKHODVWYDOXHUHSRUWHG
ZLOOEHVXPPDULVHGRYHUDOODQGE\VXEMHFWVZKRKDGDFKDQJHLQPDQDJHPHQWSODQ
YHUVXVWKRVHZKRGLGQRWKDYHDFKDQJHLQPDQDJHPHQWSODQIROORZLQJWKH)
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH22 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
IOXFLFORYLQH3(7&7VFDQ7KHSHUFHQWDJHFKDQJHLQ36$IURPEDVHOLQHWRWKHODVW
YDOXHUHSRUWHGZLOODOVREHVXPPDULVHGIRUVXEMHFWVZKRKDGGLVHDVHLQWKHSURVWDWH
RQO\DQGIRUVXEMHFWVZKRKDYHH[WUDSURVWDWLFGLVHDVHDQGE\WUHDWPHQW
)LQDOO\DZDWHUIDOOSORWRIWKHPD[LPXPSHUFHQWDJHUHGXFWLRQLQ36$GXULQJWKH
PRQWKZLQGRZZLOOEHSUHVHQWHGRQWKH\D[LVDQGHDFKVXEMHFWZLOOEHUHSUHVHQWHG
E\ D EDU RQ WKH [D[LV  7KH EDUV ZLOO EH RUGHUHG LQ GHVFHQGLQJ RUGHU RI WKH
PDJQLWXGHRIWKHSHUFHQWDJHFKDQJHLQ36$YDOXH 
7UHDWPHQWUHVSRQVHDQGWKHIDFWRUVXVHGWRDVVHVVWKHUHVSRQVHZLOOEHOLVWHGLQIXOO

+DQGOLQJRI'URSRXWVRU0LVVLQJ'DWD
6XEMHFWVZKRZLWKGUHZIURPWKHVWXG\SULRUWRFRPSOHWLRQZLOOEHVXPPDULVHG
:LWKGUDZQVXEMHFWVZLOOQRWEHGLUHFWO\UHSODFHGDQGQRLPSXWDWLRQRIPLVVLQJGDWD
ZLOOEHFRQGXFWHG

,QWHULP$QDO\VHVDQG'DWD0RQLWRULQJ
1RLQWHULPDQDO\VLVLVSODQQHGIRUWKLVVWXG\

([DPLQDWLRQRI6XEJURXSV
1RVXEJURXSDQDO\VHVZLOOEHFRQGXFWHGGXULQJWKHVWXG\
 6$)(7<(9$/8$7,21
$OOVDIHW\HYDOXDWLRQVZLOOEHSHUIRUPHGRQWKHVDIHW\DQDO\VLVVHW6$)XQOHVV
VSHFLILHGRWKHUZLVH
$OOVDIHW\WDEOHVZLOOEHSUHVHQWHGE\FHQWUHDQGRYHUDOO
6XEMHFWVZLOOEHLQFOXGHGDQGFRXQWHGLQVXPPDU\WDEOHVRQO\LIWKH\KDYHDYDLODEOH
GDWD
)RUODERUDWRU\SDUDPHWHUVYLWDOVLJQVDQG(&*EDVHOLQHZLOOEHGHILQHGDVWKHODVW
PHDVXUHSULRUWRIOXFLFORYLQH)DGPLQLVWUDWLRQLQFOXGLQJGD\RIDGPLQLVWUDWLRQLI
DYDLODEOH
 $GYHUVH(YHQWV
$GYHUVHHYHQWV$(ZLOOEHFRGHGXVLQJWKHODWHVWYHUVLRQRIWKH0HG'5$
GLFWLRQDU\
$WUHDWPHQWHPHUJHQWDGYHUVHHYHQW7($(LVGHILQHGDVDQ$(ZLWKVWDUWGDWHWLPH
RQRUDIWHUWKHVWDUWGDWHWLPHRI)IOXFLFORYLQHDGPLQLVWUDWLRQRU$(VZLWK
ZRUVHQLQJLQWHQVLW\RQRUDIWHUWKHVWDUWGDWHWLPHRI)IOXFLFORYLQHDGPLQLVWUDWLRQ
RUZKHQWKH$(KDVDVWDUWWLPHZLWKLQPLQXWHSULRUWRWKHVWDUWWLPHRI)
IOXFLFORYLQHDGPLQLVWUDWLRQ
$(VZLWKXQNQRZQVWDUWGDWHWLPHZLOOEHDVVXPHGWREHWUHDWPHQWHPHUJHQWXQOHVV
WKHHQGGDWHWLPHLVNQRZQWREHEHIRUHWKH)IOXFLFORYLQHDGPLQLVWUDWLRQ
6XPPDU\WDEOHVZLOOEHSURGXFHGIRUDOO7($(VRFFXUULQJXSWRGD\VDIWHUWKH)
IOXFLFORYLQHDGPLQLVWUDWLRQLHRFFXUULQJEHWZHHQGD\DQGGD\
$QRYHUDOOVXPPDU\RI7($(VZLOOEHFUHDWHGLQFOXGLQJ
x QXPEHURI7($(VDQGQXPEHURIVXEMHFWVZLWK7($(V
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH23 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
x QXPEHURI7($(VDQGQXPEHURIVXEMHFWVZLWK7($(VDVVRFLDWHGZLWKWKH
LQMHFWLRQVLWH
x QXPEHURIVHULRXV7($(VDQGQXPEHURIVXEMHFWVZLWKVHULRXV7($(V
x QXPEHURIVXEMHFWVZLWK7($(VE\&7&$(JUDGH*UDGHWR*UDGH
x QXPEHURIVXEMHFWVZLWK7($(VE\UHODWLRQVKLSWRIOXFLFORYLQHGHILQLWHO\
SUREDEO\SRVVLEO\XQUHODWHG
x QXPEHURIVXEMHFWVZLWK7($(VWKDWDUHUHODWHGWRRUXQUHODWHGWRIOXFLFORYLQH
ZKHUHUHODWHG7($(VDUHWKRVHFODVVLILHGDVGHILQLWHO\SUREDEO\DQGSRVVLEO\
UHODWHG
7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVH[SHULHQFLQJ7($(VZLOOEHSUHVHQWHGE\
V\VWHPRUJDQFODVV62&DQGSUHIHUUHGWHUP376\VWHPRUJDQFODVVDQG
SUHIHUUHGWHUPZLOOEHSUHVHQWHGLQGHFUHDVLQJIUHTXHQF\RIWKHWRWDOQXPEHURI
VXEMHFWVZLWK7($(V,IDVXEMHFWH[SHULHQFHGPRUHWKDQRQHWUHDWPHQWHPHUJHQW
DGYHUVHHYHQWWKHVXEMHFWZLOOEHFRXQWHGRQFHIRUHDFKV\VWHPRUJDQFODVVDQG
RQFHIRUHDFKSUHIHUUHGWHUP
7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVH[SHULHQFLQJ7($(VZLOOEHSUHVHQWHGE\
62&37DQG&7&$(JUDGH62&DQG37ZLOOEHSUHVHQWHGLQGHFUHDVLQJ
IUHTXHQF\RIWKHWRWDOQXPEHURIVXEMHFWVZLWK7($(V,IDVXEMHFWH[SHULHQFHGPRUH
WKDQRQH7($(WKHVXEMHFWZLOOEHFRXQWHGRQFHIRUHDFK62&DQGRQFHIRUHDFK
37DWWKHZRUVWVHYHULW\
7KHQXPEHUDQGSHUFHQWDJHRIVXEMHFWVH[SHULHQFLQJ7($(VZLOOEHSUHVHQWHGE\
62&37UHODWLRQVKLSWRVWXG\GUXJDQGZKHWKHUWKH7($(LVUHODWHGWRWKHVWXG\
GUXJ62&DQG37ZLOOEHSUHVHQWHGLQGHFUHDVLQJIUHTXHQF\RIWKHWRWDOQXPEHURI
VXEMHFWVZLWK7($(V,IDVXEMHFWH[SHULHQFHGPRUHWKDQRQH7($(WKHVXEMHFWZLOO
EHFRXQWHGRQFHIRUHDFK62&DQGRQFHIRUHDFK37DWWKHFORVHVWUHODWLRQVKLSWR
VWXG\GUXJ
$OODGYHUVHHYHQWVZLOOEHOLVWHGDQG7($(VZLOOEHLGHQWLILHG$(VRFFXUULQJXSWR
GD\VDIWHU)IOXFLFORYLQHDGPLQLVWUDWLRQZLOOEHIODJJHG$OO6$(VZLOOEHOLVWHG
VHSDUDWHO\
 &OLQLFDO/DERUDWRU\(YDOXDWLRQ
 +HPDWRORJ\
+HPDWRORJ\YDOXHVZLOOEHVXPPDULVHGE\SDUDPHWHUDQGYLVLWDQGDOVRIRUFKDQJH
IURPEDVHOLQHODVWSUHVFDQYDOXHYVILUVWSRVWVFDQYDOXH
$OOKDHPDWRORJ\YDOXHVZLOOEHOLVWHGVKRZLQJUHIHUHQFHUDQJHVIODJJLQJDEQRUPDO
ILQGLQJV
 %LRFKHPLVWU\
%LRFKHPLVWU\YDOXHVZLOOEHVXPPDULVHGE\SDUDPHWHUDQGYLVLWDQGDOVRIRUFKDQJH
IURPEDVHOLQHODVWSUHVFDQYDOXHYVILUVWSRVWVFDQYDOXH
$GGLWLRQDOO\IURPWKHVHUXPFUHDWLQLQHOHYHOVPJG/FUHDWLQLQHFOHDUDQFH&U&O
ZLOOEHGHULYHGXVLQJWKH&RFNFURIW*DXOWIRUPXOD&RFNURIW':DQGWKH
JORPHUXODUILOWUDWLRQUDWH*)5ZLOOEHGHULYHGXVLQJWKHPRGLILFDWLRQRIGLHWLQUHQDO
GLVHDVH0'5'IRUPXOD/HYH\$6DVIROORZV
'RFX6LJQ(QYHORSH,'(%)'($


6\QHTXDQRQVWXG\QR%/6

%OXH(DUWK'LDJQRVWLFVVWXG\QR%('

'DWH0$5

3DJH24 RI24
9HUVLRQ$PHQGPHQW)LQDO
67IRUP
x &RFNFURIW*DXOWIRUPXOD&U&OP/PLQ DJH:HLJKWLQNJLI
IHPDOH&UHDWLQLQH
x 0'5'IRUPXOD*)5P/PLQ [&UHDWLQLQHDJHLI
VXEMHFWLVEODFNLIIHPDOH
CrCl and GFR categories (30 mL/min, >30 60, >60 90, >90 mL/min) will be 
VXPPDULVHGDQGDVKLIWWDEOHRIEDVHOLQHVWDWXVDJDLQVWWKHVWDWXVRQRUDIWHU)
IOXFLFORYLQHDGPLQLVWUDWLRQZLOOEHSUHVHQWHG
$OOELRFKHPLVWU\YDOXHVZLOOEHOLVWHGVKRZLQJUHIHUHQFHUDQJHVDQGIODJJLQJ
DEQRUPDOILQGLQJV
 8ULQDO\VLVGLSVWLFN
$OOXULQDO\VLVUHVXOWVZLOOEHOLVWHG
 9LWDO6LJQV
9LWDOVLJQYDOXHVZLOOEHVXPPDULVHGE\SDUDPHWHUDQGWLPHSRLQWDQGDOVRIRU
FKDQJHIURPEDVHOLQH
'HWDLOVRIYLWDOVLJQVGDWDZLOOEHOLVWHG
 (OHFWURFDUGLRJUDSK\
(OHFWURFDUGLRJUDP(.*LQWHUSUHWDWLRQLVUHFRUGHGSUHGRVHSUHVFDQDQGZLWKLQ
GD\VRIWKHVFDQ(.*REVHUYHG47FDQGFKDQJHIURPEDVHOLQHZLOOEHVXPPDULVHG
E\YLVLW,QDGGLWLRQDVXPPDU\RIWKHLQFLGHQFHRIRXWOLHUVLQDEVROXWH47FLQWHUYDOV
!!DQG!PVHFDQGWKHFKDQJHIURPEDVHOLQHLQ47FLQWHUYDOV!
DQG!PVHFERWKSRVLWLYHDQGQHJDWLYHFKDQJHVZLOOEHSUHVHQWHG
7KHRYHUDOOLQWHUSUHWDWLRQRIWKH(.*1RUPDO$EQRUPDO1&6DQG$EQRUPDO&6
ZLOODOVREHVXPPDULVHGE\YLVLW$OO(.*UHVXOWVZLOOEHOLVWHGLQFOXGLQJRYHUDOO
LQWHUSUHWDWLRQDQGFKDQJHIURPEDVHOLQH
 5()(5(1&(6
&RFNURIW':*03UHGLFWLRQRIFUHDWLQLQHFOHDUDQFHIURPVHUXPFUHDWLQLQH
Nephron
+LQW]H-3DVV1&66//&$YDLODEOHZZZQFVVFRP.D\VYLOOH8WDK
86$
/HYH\ $6 & -  8VLQJ VWDQGDUGL]HG VHUXP FUHDWLQLQH YDOXHV LQ WKH
PRGLILFDWLRQRIGLHWLQUHQDOGLVHDVHVWXG\HTXDWLRQIRUHVWLPDWLQJJORPHUXODU
ILOWUDWLRQUDWHAnn Intern Med


'RFX6LJQ(QYHORSH,'(%)'($