Clinical trial NCT03404648
Conditions: Prostate Adenocarcinoma
Keywords: high risk prostate cancer C11-choline PET/MR mpMRI
Sponsor: Mayo Clinic
Start date: 2017-11-01; Completion date: 2020-01-23
Enrollment: 19 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to find out if a PET/MR scan in combination with standard MRI and CT scans can improve the early detection and treatment of patients with prostate cancer.

Detailed description:
High risk prostate cancer patients will undergo C11-Choline PET/MR whole body fusion scan and pelvic mpMRI for accurate staging. The PET/MR imaging findings, including the primary lesion with the prostate bed and pelvic lymph nodes, will be correlated with the histopathologic result. Researchers aim to provide accurate one-stop shopping opportunity in diagnosis and staging of high risk prostate cancer using the C11-choline PET/MR scan.

Arms: arm 1: Subjects will receive C-11 choline PET Tracer and Gadobutrol prior to the one time Positron emission tomography (PET/MR scanner) imaging and Multiparametric Magnetic resonance imaging (mpMRI).
Interventions: intervention 1: C-11 choline PET tracer intervention 2: Gadobutrol intervention 3: PET/MR scanner
Intervention descriptions: intervention 1: C-11 choline PET tracer, One dose, totally 12-14 millicurie (mCi), intravenous administration while patient is lying on the table. intervention 2: Single dose of Gadavist® (Gadobutrol, Bayer) at no more than 0.1 mmol/kg will be administrated intravenously. intervention 3: C11-PET/MR and pelvic mpMRI scan for prostate cancer.

Protocol documents:
Prot_SAP_000.pdf: 
Staging of Untreated Patients with Very 
High-risk and High-risk Prostate 
Carcinoma Utilizing Hybrid C11-choline 
PET/MR and Pelvic Multiparametric MRI 
for Personalized Precise Treatment: a 
Pilot Study 
 
 
NCT03404648 
 
05/03/2019 


Staging Prostate Carcinoma with Hybrid C11-choline PET/MR and mpMRI 
 
Version 3 
 
 
Revised 05/03/2019 
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Ming Yang, M.D.  
 
CONFIDENTIAL 
 
 
Staging of Untreated Patients with Very High-risk and High-risk Prostate 
Carcinoma Utilizing Hybrid C11-choline PET/MR and Pelvic 
Multiparametric MRI for Personalized Precise Treatment: a Pilot Study 
 
 
PI:  
 
Ming Yang, M.D., Dept. of Radiology 
 
Co-PI:  
Akira Kawashima, M.D., Ph.D., Dept. of Radiology 
 
 
 
Regulatory Sponsor: 
Ming Yang, M.D. 
Department of Diagnostic Radiology 
Mayo Clinic in Arizona 
13400 East Shea Blvd 
Scottsdale AZ 85259 
 
Yang.ming@mayo.edu  
 
Study Product: 
C-11 choline 
Protocol Number: (IRBe) 
 
16-007897  
 
IND Number: 
134646 
 
 
 
 
 
Initial version:  
9/26/2016 
Version (1.0)  
Revised:  
 
2/27/2017 
Version (2.0) 
Revised:  
 
4/24/2017 
Version (2.1)  
 
 
 
 


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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 5 
1 
INTRODUCTION ................................................................................................................................. 6 
1.1 
BACKGROUND .................................................................................................................................... 6 
1.2 
INVESTIGATIONAL AGENT .................................................................................................................... 7 
1.3 
CLINICAL DATA TO DATE..................................................................................................................... 7 
1.4 
DOSE RATIONALE................................................................................................................................ 7 
1.5 
RISKS AND BENEFITS ........................................................................................................................... 7 
2 
STUDY OBJECTIVES .......................................................................................................................... 8 
3 
STUDY DESIGN ................................................................................................................................... 8 
3.1 
GENERAL DESCRIPTION ....................................................................................................................... 8 
3.2 
NUMBER OF SUBJECTS: ........................................................................................................................ 9 
3.3 
DURATION OF PARTICIPATION .............................................................................................................. 9 
3.4 
PRIMARY STUDY ENDPOINTS .............................................................................................................. 16 
3.5 
SECONDARY STUDY ENDPOINTS ......................................................................................................... 16 
3.6 
PRIMARY SAFETY ENDPOINTS ............................................................................................................ 16 
3.7 
IDENTIFICATION OF SOURCE DATA ...................................................................................................... 17 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ...................................................... 17 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 17 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 17 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ....................................................................... 18 
4.4 
EARLY WITHDRAWAL OF SUBJECT ...................................................................................................... 18 
4.4.1 
When and How to Withdraw Subjects ........................................................................................ 18 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .............................................................. 18 
5 
STUDY DRUG .................................................................................................................................... 19 
5.1 
DESCRIPTION .................................................................................................................................... 19 
5.2 
TREATMENT REGIMEN ....................................................................................................................... 19 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ................................................................ 19 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ......................................................................... 19 
5.5 
SUBJECT COMPLIANCE MONITORING ................................................................................................... 19 
5.6 
PRIOR AND CONCOMITANT THERAPY .................................................................................................. 19 
5.7 
PACKAGING ...................................................................................................................................... 19 
5.8 
MASKING/BLINDING OF STUDY........................................................................................................... 19 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................................. 20 
5.9.1 
Receipt of Drug Supplies .......................................................................................................... 20 
5.9.2 
Storage ................................................................................................................................... 20 
5.9.3 
Dispensing of Study Drug ......................................................................................................... 20 
5.9.4 
Return or Destruction of Study Drug ......................................................................................... 20 
6 
STUDY PROCEDURES ...................................................................................................................... 21 
6.1 
DAY 0 .............................................................................................................................................. 21 
6.2 
DAY 1 .............................................................................................................................................. 21 
6.3 
DAY 2- FOLLOW UP PROCEDURES ....................................................................................................... 22 


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7 
STATISTICAL PLAN ......................................................................................................................... 25 
7.1 
SAMPLE SIZE DETERMINATION ........................................................................................................... 25 
7.2 
STATISTICAL METHODS ..................................................................................................................... 25 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ............................................................................................. 26 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 26 
8.1 
DEFINITIONS ..................................................................................................................................... 26 
8.2 
RECORDING OF ADVERSE EVENTS ....................................................................................................... 28 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .......................................... 29 
8.3.1 
Sponsor-Investigator reporting: notifying the Mayo IRB ............................................................. 29 
8.3.2 
Sponsor-Investigator reporting: Notifying the FDA ..................................................................... 30 
8.4 
STOPPING RULES ............................................................................................................................... 31 
8.5 
MEDICAL MONITORING ..................................................................................................................... 31 
8.5.1 
Internal Data and Safety Monitoring ......................................................................................... 31 
9 
DATA HANDLING AND RECORD KEEPING .................................................................................. 31 
9.1 
CONFIDENTIALITY ............................................................................................................................. 31 
9.2 
SOURCE DOCUMENTS ........................................................................................................................ 31 
9.3 
CASE REPORT FORMS ........................................................................................................................ 32 
9.4 
RECORDS RETENTION ........................................................................................................................ 33 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 33 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 33 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 33 
11 
ETHICAL CONSIDERATIONS ......................................................................................................... 34 
12 
STUDY FINANCES ............................................................................................................................ 34 
12.1 
FUNDING SOURCE ......................................................................................................................... 34 
12.2 
SUBJECT STIPENDS OR PAYMENTS .................................................................................................. 34 
13 
PUBLICATION PLAN ....................................................................................................................... 34 
14 
REFERENCES ................................................................................................................................... 35 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
 
Adverse Event/Adverse Experience 
BCR  
Biochemically recurrence 
CFR 
 
Code of Federal Regulations 
CRF 
 
Case Report Form 
CT 
 
Computerized Tomography 
DSMB  
Data and Safety Monitoring Board 
eGFR  
estimated Glomerular Filtration Rate 
FDA  
Food and Drug Administration 
FDG  
Fluorodeoxyglucose 
GCP  
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
 
Investigator’s Brochure 
 
IND 
 
Investigational New Drug Application 
IRB 
 
Institutional Review Board 
mpMRI 
Multiparemetric magnetic resonance imaging 
PCa 
 
Prostate cancer 
PET/CT 
Positron Emission Tomography/Computerized Tomography 
PET/MR 
Positron Emission Tomography/Magnetic Resonance  
PHI 
 
Protected Health Information 
PI 
 
Principal Investigator 
PSA 
 
Prostate specific antigen 
SAE 
 
Serious Adverse Event/Serious Adverse Experience 
SOP 
 
Standard Operating Procedure 
T 
 
Tesla 
 
 
 


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Study Summary 
Title 
Staging of Untreated Patients with Very High-risk and High-risk 
Prostate Carcinoma Utilizing Hybrid C11-choline PET/MR and 
Pelvic Multiparametric MRI for Personalized Precise Treatment: a 
Pilot Study 
Running Title 
C11-choline PETMR and pelvic mpMRI on primary prostate cancer 
Protocol Number 
16-007897  
Phase 
NA 
Methodology 
Prospective, pilot study 
Overall Study 
Duration 
16 weeks 
Subject Participation 
Duration 
90 minutes, single day, in the nuclear medicine suite.  
Single or Multi-Site  
Single 
Objectives 
1): Test whether a hybrid combination of focused C-11 choline 
PET/MR and pelvic mpMRI on a PET/MR system is feasible.  
2): Determine the efficacy (added values) of a hybrid combination of 
molecular focused C-11 choline PET/MR and functional and anatomic 
pelvic mpMRI in comparison with clinical findings.  
3): Determine the efficacy (added values) of a torso C-11 choline 
PET/MR in comparison with conventional CT and bone scan in 
depicting metastasis to lymph node and bone. 
Number of Subjects 
20 
Diagnosis and Main 
Inclusion Criteria 
Clinically diagnosed high and very high risk prostate cancer. Adult 
patients who are able to provide informed consent.   
Study Product, Dose, 
Route, Regimen 
C-11 choline PET tracer, One dose, totally 12-14 mCi, intravenous 
administration while patient is lying on the table 
Duration of 
Administration 
1 study day 
Reference therapy 
None 
Statistical 
Methodology 
Descriptive statistics will be used, including sensitivity, specificity, and 
accuracy, based on histopathological correlation. 
 
 
 
 
 
 
 


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1 Introduction 
 
This document is a protocol for a human research study. This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  
 
1.1 
Background 
 
Prostate cancer is the most common solid cancer in men in the United States and the second most 
common cancer death in American men1. Early and correct diagnosis of prostate cancer together 
with accurate staging is vital for appropriate clinical management strategy. To date, 
morphological and functional pelvic mpMRI and molecular imaging C11-choline PET have been 
playing vital roles in standard of care of prostate cancer.   
 
Pelvic mpMRI, typically including T1-weighted, T2-weighted, diffusion-weighted imaging 
(DWI) and dynamic contrast-enhanced imaging (DCEI) with or without MR spectroscopic 
imaging (MRSI), is an established imaging modality and has been increasingly utilized for lesion 
detection and characterization, monitoring for active surveillance, detection of local recurrence 
in suspect cases, and MR guided intervention. In a prospective study of 70 consecutive patients 
with histopathologic correlation, the sensitivity, specificity, false-positive and false-negative 
rates, and the accuracy of mpMRI for extracapsular extension and seminal vesicle invasion have 
been reported to be 78.2% and 80%, 80.9% and 97%, 19.1% and 3.7%, 21.7% and 20%, 80% 
and 95.7%, respectively2. However, the major limitation of pelvic mpMRI is the distant 
metastasis outside the field of view of prostate cancer.  
 
Choline, a component of the phosphatidylcholines increased in prostate cancer, can be 
radiolabelled with either 11Carbon (C11-choline) and 18Fluoro (F11-choline). Unlike F18- 
fludeoxyglucose (FDG) tumoral uptake, which depends on increased cellular glycolytic pathway 
activity, choline uptake depends on active cell membrane synthesis, a metabolic pathway which 
more reliably reflects tumor metabolism in prostate cancer. C-11 choline PET has been shown to 
help identify sites of metastatic disease in men with biochemical recurrence after primary 
treatment failure. In the past decade, multiple investigations have demonstrated satisfactory 
sensitivity and specificity for the detection of recurrent PCa patients, and led to the FDA 
approval of C-11 choline production at Mayo Clinic 20123-5.  
 
Additional effort has been taken to compare pelvic mpMRI and C11-choline PET in BCR PCa 
patients and demonstrated complimentary role of them for restaging prostatectomy patients with 
suspected recurrent disease. Kitajima K and colleagues compared the C11-choline PETCT with 
pelvic mpMRI with endorectal coil in detection of local recurrence, pelvic nodal metastasis and 
distant metastasis. They found that mpMRI is superior to C11-choline in detection of local 
recurrence; PET is superior for pelvic lymph node metastasis6.  
 
The newly FDA approved hybrid GE SIGNA 3T PET/MR scanner provides an opportunity to 
investigate the clinical value of combined C11-PET/MR and pelvic mpMRI in primary prostate 
cancer. It is anticipated that the improved comprehensive imaging techniques may more 


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accurately stage untreated patients with high risk prostate cancer as well as better characterize 
the intra-parenchymal tumor. Therefore, we wish to determine the feasibility and efficacy (added 
value) of a hybrid, combined torso and focused C-11 choline PET/MR with pelvic mpMRI in 
characterizing and staging very high-risk and high-risk prostate cancer patients, which could 
provide a more accurate tumor characterization and staging information and lead to 
individualized precise treatment.  
1.2 
 Investigational Agent 
 
The investigational agent for this study is C11-choline, a cyclotron synthesized PET tracer to be 
manufactured in the Mayo Clinic Arizona radiochemistry facility.  
 
 
1.3 
Clinical Data to Date 
 
Since 2000, there have been several studies investigating clinical role of choline PET and 
PETCT in diagnosing and staging primary prostate cancer. However, there is limited sensitivity 
and specificity in differentiating primary prostate cancer from normal prostate tissue due to 
overlapping choline uptake by hyperplasic prostate tissue, high-grade intraprostatic epithelial 
neoplasia (HGPIN), prostatitis, BPH, even urinary excreted activity in the base of urinary 
bladder and urethra. In addition, there is no proven significant correlation between C11-choline 
uptake by localized primary prostate cancer and serum PSA level, Gleason score7,8. Therefore, 
there is clinical consensus of limited clinical value of choline PET and PETCT in characterizing 
primary PCa.  
 
However, the pursuit of combined advantages of choline PET and pelvic mpMRI in PCa persists. 
In one recent clinical trial, it is found that fused F18-Choline PET/MR images could provide 
added value for MR guided transrectal prostate biopsies9.  
 
1.4 
Dose Rationale  
 
The dose of C-11 choline selected for use in the study patients is 12-14 mCi,(444-518 MBq) 
based on prior published reports 6, 10, 11. The tracer must be given intravenously. 
 
1.5 
Risks and Benefits 
 
C-11 choline is involved in phosphorylation process integrated into phospholipids in the cell 
membrane as part of phosphatidylcholine, which is vital in prostate cancer cell. The main risk 
involves the exposure to the radioactivity associated with the C-11 isotope incorporation. This 
exposure has been calculated to be much lower than the F-18 FDG. In addition, there is no 
radiation risk related to MR scan. For MR safety concern, each subject will undergo MR safety 
screening performed by PET/MR technologist prior to imaging.  


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2 
Study Objectives 
 
Primary Objective: 
1) Test whether a hybrid combination of focused C-11 choline PET/MR and pelvic mpMRI 
on a PET/MR system is feasible 
 
Secondary Objective(s): 
1) Determine the efficacy (added values) of a hybrid combination of molecular focused C-
11 choline PET/MR and functional and anatomic pelvic mpMRI in comparison with 
clinical findings. 
2) Determine the efficacy (added values) of a torso C-11 choline PET/MR in comparison 
with conventional CT and bone scan in depicting metastasis to lymph node and bone. 
3 
Study Design 
 
This study will be a prospective study to test and optimize the feasibility of hybrid 3T PET/MR 
scan in diagnosing and staging high and very high risk prostate cancer patients.  
 
The FDA approved C-11 choline PET tracer at a dose of 12-14 mCi will be administered 
intravenously prior to fused PET/MR scan, and prior to diagnostic pelvic mpMRI scan while 
patient lying in the scanner.  
 
In addition, single dose of Gadavist® (Gadobutrol, Bayer) is at no more than 0.1 mmol/kg will 
be administrated intravenously for pelvic mpMRI.   
 
The whole imaging procedure will be conducted on an FDA approved GE SIGNA 3T PET/MR 
scanner.  
 
The C11-choline PET/MR and pelvic mpMRI findings and results will be compared with serum 
PSA level, Gleason score, clinical CT and nuclear medicine whole body bone scintigraphy 
findings, and histopathological results obtained through standard of care management. 
 
Our primary interest is to investigate the feasibility of hybrid C11-Cholime PET/MR fusion and 
pelvic mpMRI in imaging primary prostate cancer. 
3.1 
General Description 
 
It is possible that improved comprehensive imaging techniques may more accurately stage 
untreated patients with high risk prostate cancer as well as better characterize the intra-
parenchymal tumor. It is of interest to focus on potential synergy between molecular focused C-
11 choline PET and functional and anatomic pelvic mpMRI. Therefore, we wish to determine the 
feasibility and efficacy (added value) of a hybrid, combination of torso and focused C-11 choline 
PET/MR with pelvic mpMRI on a clinical 3T PET/MR system in characterizing and staging very 
high-risk and high-risk prostate cancer patients, which could provide a more accurate tumor 
characterization and staging information and lead to individualized precise treatment. 
 


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3.2 
Number of Subjects: 
A total of twenty subjects will complete the study. Additional candidates may be screened to 
ensure completion of twenty subjects. 
 
3.3 
Duration of Participation 
 
Subjects will complete one day of in-department participation. A second study day will consist 
of a phone call to the subject after completion of day 1. 
 
Human subjects will be subject to Mayo Department of Radiology policies and procedures.  
Candidates for enrollment will be first queried by the study coordinator for possible exclusion 
using the departmental MRI safety guidelines for clinical MRI.  The study coordinator will 
review the medical history and use the subject’s serum creatinine level to determine his eGFR 
based on patient age, gender, and ethnicity.  If necessary, the subject will undergo a blood test to 
determine an up-to-date creatinine level, performed at no expense to the subject.  eGFR will be 
determined prior to performing any contrast-enhanced scan. 
 
 
 
Patient flow in the nuclear suite 
 
 
 
 
 
 
 
 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treated naïve patients with high risk or very high risk prostate cancer (NCCN risk 
stratification), who require clinical imaging evaluation including 1) pelvic 
mpMRI, 2) abdominopelvic CT, 3) bone scan, and 4) other imaging studies as 
clinically indicated.  
C-11 choline PET/MR on GE Signa PET/MR System at 3 Tesla at one session (70-
80 
minutes) 
Part 1: C-11 choline torso (multi-station) PET/MR with C-11 choline injection  
Part 2: Hybrid (simultaneous acquisition) dedicated focused pelvic PET/MR pelvic 
multiparametric MRI without and with gadolinium MR contrast.  


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IMAGING TECHNIQUES  
 
PET/MR scanner/equipment  
 
Clinical GE SIGNA 3 Tesla PET/MR system 
 
 
PET/MRI Technique (Figure 1) 
 
1. There are two integrated components of fused PET/MR and focused Pelvic mpMRI 
a. Indications/Protocols: Primary prostate cancer. 
 
Part 
Description of imaging sequences 
1 
Torso (multi-station) PET/MR fusion scan with injection dose of C-11 choline 
2 
Hybrid 
focused 
(single-station) 
PET/MR 
and 
mpMRI 
of 
the 
pelvis 
(simultaneous acquisition of pelvic PET/MR and mpMRI without and with IV 
gadolinium contrast at the same table position) 
 
• Parts 1 and 2 will be done at one session with the patient on the same PET/MR table.  
• .   
• The entire PET/MR fusion with focused pelvic mpMRI scanning time is 75-80 minutes.  
Part 1:  Torso PET/MR Fusion Scan with C-11 choline 
 
• 
Coil: Three pieces of array coils from vertex of head to the level of upper thigh; No use 
of endorectal coil. 
• 
Patient supine, head first  
• 
Arms down for all procedures   
• 
Metallic objects should be removed from the patient whenever possible 
 
PET Tracer:   
 
While patient lying on scanner table, 444-518MBq (12-14i mCi) C-11 choline will be 
injected as a bolus through a catheter inserted into a large peripheral vein. 
 
Scan Range:  
 
 
• Routinely from upper thigh to vertex of head, otherwise specified  
 
 
 
 


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Scan direction for PET  
 
• 
Inferior to superior   
• 
Start imaging immediately after the injection of tracer and acquire images with 2–5 
minutes per bed position (totally about 5-6 bed positions). The total scanning duration is 
around 25-30 minutes 
 
MR attenuation correction:   
 
• 
Simultaneous PET/MR imaging with PET emission data reconstructed in 3D time-of-
flight mode at multiple bed positions. During each bed position, coronal Dixon fat/water 
sequence, in-phase, and out-phase images will be performed for MR segmented 
attenuation correction. 
• 
Diagnostic quality axial LAVA-FLEX only was obtained simultaneously with PET 
emission imaging acquisition at each bed position.  
 
Part 2:  Hybrid Focused PET/MR and mpMRI of the Pelvis (simultaneous acquisition of 
pelvic PET/MR and mpMRI without and with IV gadolinium contrast) 
 
MR contrast agent and medicine 
 
• 
For a contrast-enhanced scan the technologist will load and connect a power injector for 
administration of contrast material via a peripheral venous access.  The contrast material 
and dose are both determined by the radiologist subject to departmental policy.  
 
• 
Typically a single dose of Gadavist® (gadobutrol, Bayer) is used for studies of the 
prostate gland at our institution.  The target contrast dose is no more than 0.1 mmol/kg 
for subjects with eGFR of higher than 30 mL/minute/1.73 m2.  Those with a GFR of 30 
or less will not be admissible to the study.  Contrast material is administered at 3 ml/sec 
followed by a saline flush of 20 ml at 3 ml /sec. 
 
• 
1 mg of glucagon will be administered subcutaneously at the start of the scan as an anti-
peristaltic. Glucagon will not be given if the patient has a history of DM. 
 
 
The following multiparametric prostate MR protocol will be applied. Simultaneous PET 
emission image will also be acquired. The total mpMRI scan time is around 40-50 minutes. 
 
• 
Multiparametric MRI of the pelvis technique utilizing an institutional clinical MRI 
protocol. 
 
 


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Sites 
Image sequences 
Pelvis 
 
Axial T1-weighted LAVA-FLEX* 
 
Axial DWI 
Prostate (high resolution with small FOV) 
 
Sagittal T2 FRFSE 
 
Axial T2 FRFSE 
 
Axial FOCUS DWI 
 
Coronal T2 FRFSE  
 
Axial DCE 
Pelvis 
 
Post Gd ax LAVA-FLEX (water only, fat only) 
 
* Axial T1-weighted LAVA-FLEX acquired in Part1. may be used for pre-contrast T1-
weighted images. 
 
Image review: 
• PET/MR fusion study, including PET emission data, MRAC image and focused pelvis 
PET/MR fusion images will be sent to MIM Vista workstation for review by an 
independent, experienced board certified nuclear medicine radiologist without knowing 
clinical findings except for high risk prostate cancer.  
• Focused mpMRI of pelvis images will be sent to PACS for review by an independent, 
experienced board certified body MR radiologist without knowing clinical findings 
except for high risk prostate cancer.  
 
Evaluation of imaging findings:  
Reviewers review images to evaluation imaging findings without knowing clinical findings 
except all subjects are recently diagnosed with very high-risk or high-risk prostate cancer. 
Readout workflow is illustrated in Figure 2. The scores will be recorded and stored in a secured 
REDCap file.  
 
Pelvic mpMRI:  
1. Lesion detection and characterization utilizing PI-RADS version 2 (15). 
2. Tumor staging utilizing AJCC TNM staging system (3) 
3. Detection of suspicious pelvic lymph nodes.  
4. Detection of suspicious osseous lesion in the pelvis.  
 


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Torso and focused C-11 choline PET/MR:  
1. Lesion detection and characterization. 
2. Tumor staging 
3. Detection of suspicious pelvic and extrapelvic lymph nodes.  
4. Detection of suspicious osseous lesion in the pelvis and extrapelvic regions. 
5. Document SUV in the region of interest (ROI) if possible.  
 
Reference standards 
1. Histopathology results when available 
2. Clinical imaging study (CT, bone scan, etc).  
3. Clinical follow-up (progression or regression at follow-up routine clinical imaging after 
treatment).  
 
Prostate tumor localization and characterization: Focused C-11 choline PET/MR and pelvic 
mpMRI findings to be correlated with clinical prostate biopsy and surgery results.  
Lymph node metastases: Torso and focused C-11 choline PET/MR and pelvic mpMRI findings 
to be correlated with clinical CT, lymph node biopsy, and surgery results 
Bone metastases: Torso and focused C-11 choline PET/MR and pelvic mpMRI findings to be 
correlated with whole body bone scan, F-18 NaF PET/CT (if available), CT, dedicated MRI, and 
biopsy results.  
 
 
 
 




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Figure 2. Workflow of Readout Sessions (parts 1-3)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Torso C-11 choline 
PET/MR 
by NM radiologist  
(see part 2) 
Bone scan  
by other NM staff  
 
CT  
by other abdominal 
imaging staff  
 
Part 1: Torso C-11 choline PET/MR fusion 
Part 2: Focused pelvic mpMRI with C11-choline PET 
Focused C-11 choline 
PET/MR 
by NM radiologist  
Pelvic mpMRI 
by body imaging radiologist  
Fusion C-11 choline PET/MR and pelvic mpMRI 
by a consensus review  
with NM radiologist and body imaging radiologist  
Pelvic mpMRI 
by body imaging radiologist  
Bone scan  
by other NM staff  
 
CT  
by body imaging 
radiologist  
2 wks after clinical 
interpretation of C-11 
choline PET/MR 
2 wks after clinical 
interpretation of pelvic mp MRI 
Part 3: Bone scan and CT 


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Table 1. Summary of imaging finding evaluation  
 
 
C-11 choline PET/MR 
(research) 
Clinical 
imaging exams 
Reference standard 
Findings 
Local T staging: 
Prostate 
Focused pelvic C-11 
choline PET/MR 
Pelvic mpMRI 
Pathology results  
(biopsy, surgery if 
available) 
Localization 
Characterization 
Local tumor (T) 
staging 
Metastasis to pelvic lymph nodes(N) 
 
Pelvis 
Focused C-11 choline 
PET/MR 
Pelvic mpMRI 
CT 
Pathology results  
(biopsy, surgery if 
available) 
Localization 
SUV values 
 
Torso 
Torso C-11 choline 
PET/MR 
CT 
Pathology results  
(biopsy, surgery if 
available) 
Localization 
SUV values 
Metastasis to pelvic bone (M) 
 
Pelvis 
Torso and focused C-
11 choline PET/MR 
Pelvic mpMRI 
CT 
Bone scan 
Pathology results  
(biopsy, surgery if 
available) 
Localization 
SUV values 
 
Extra-pelvis 
Torso C-11 choline 
PET/MR 
CT 
Bone scan 
Pathology results  
(biopsy, surgery if 
available) 
Localization 
SUV values 
Visceral metastasis (M) 
Visceral 
metastasis (M) 
Torso C-11 choline 
PET/MR 
CT 
Pathology results  
(biopsy, surgery if 
available) 
Localization 
SUV values 
 
3.4 
Primary Study Endpoints 
Patient: Completion of all imaging examinations with laboratory results. 
 
Data analysis:   
Objective 1: Descriptive study. With biopsy and/or surgical histopathology as gold 
standard, the sensitivity, specificity and accuracy of PET/MR will be calculated. 
 
3.5 
Secondary Study Endpoints 
NONE 
3.6 
Primary Safety Endpoints 
Since C-11 choline is an essential nutrient needed for physiologic process as an integrated part of 
cell membrane component, and the quantities actually administered are in the micromolar range, 
there are no expected adverse reactions due to the primary study drug. The primary safety 
endpoint would be documentation of either lack of reaction to C-11 choline injection or detailed 
description of any adverse reaction (rash, fever, hypotension, dyspnea, chest pain) and treatment 
measures undertaken.  
 
 


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3.7 
Identification of Source Data 
 
The following source data will be directly recorded on the Case Report Form (CRF):  
• Vital signs 
• Events 
• Dosage of C-11 choline, route of administration 
• Patient Reported Outcomes 
 
 
The following source data will not be directly collected in the Case Report Form (CRF), but will 
be captured in supportive documentation (study source documents, EMR): 
• Laboratory results can be utilized from outside facilities for this study 
• Prostate biopsy reports and pathology reports can be utilized from outside facilities for 
this study. 
 
 
 
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
• Adults, age 18 and older 
• Untreated male patients with high-risk and very high-risk prostate cancer, who require 
clinical pelvic mpMRI, CT, and bone scan as standard clinical care for diagnosis and 
management of prostate cancer.  
 
 
4.2 
Exclusion Criteria 
 
• Patients who already received primary treatment or neo-adjuvant therapy.  
• Patients who refuse undergoing routine clinical imaging (i.e., pelvic mpMRI, CT, bone 
scan) for staging. Reimbursement of pelvic mpMRI may be provided. CT and bone scan 
may be done elsewhere outside of Mayo Clinic but should be of diagnostic quality. 
Research C-11 choline PET/MR will not substitute pelvic mpMRI, CT, or bone scan in 
this study. 
• Patients cannot tolerate MRI (e.g., claustrophobia, severe back pain or spasm, involuntary 
movement [e.g., tremor, dystonia]).  
• Patients have total hip arthroplasty (THA), which can cause substantial susceptibility 
artifact and degrade image quality of mpMRI.  
• Patients have cardiac pacemaker, cochlear implants, neurostimulator, medical device 
which is unsafe at 3 Tesla, or foreign metallic body in the eyes or orbit.  
• Patients have contraindication to gadolinium based MR contrast agents (e.g., renal 
failure, severe reaction to gadolinium based MR contrast agents). eGFR should be above 
30 within 30 days the time of mpMRI.  


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4.3 
Subject Recruitment, Enrollment and Screening 
 
Subjects who are scheduled to undergo standard care of primary prostate cancer diagnosis and 
staging will be identified, informed about this study and referred to our study coordinator by 
urologists from their clinical practice schedule. C11-choline PET/MR imaging could be 
performed before and/or after routine clinical imaging.   
 
 
4.4 
Early Withdrawal of Subject 
If a subject cannot finish the PET/MR imaging due to claustrophobia, he will be withdrawn.  
After PET/MR imaging, if a subject declines to undergo clinical evaluation and standard care of 
imaging, he will be withdrawn.  
 
We plan to recruit a replacement subject in the event that a subject withdraws early to maintain 
the target number of 10 subjects. 
 
4.4.1 When and How to Withdraw Subjects 
Subjects may be withdrawn from the study if consent is withdrawn, if they no longer satisfy 
enrollment criteria or if they are unable to continue participation due to discomfort.   
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
The C-11 choline PET/MR data will be retained for potential future analysis. Data collected on 
study subjects up to the time of withdrawal will remain as part of the study in a secured database 
in order for the study to maintain scientific validity.   
Regardless of enrollment status, subjects will be contacted to collect Day 2 follow up 
information. This information will be recorded in the case report form documentation. 
 
 
 


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5 Study Drug  
5.1 
Description 
 
C-11 choline is identical to endogenous choline in the human body. Choline is a central molecule 
in cellular metabolism via the citric acid cycle (as acetyl CoA), in cell membrane fatty acid 
synthesis, and in gene expression regulation through acetylation of nuclear histones. 
5.2 
Treatment Regimen 
 
A total of 12-14 mCi,(444-518 MBq)  doses are dispensed. The doses are described based on the 
amount of radioactivity since the actual quantity of choline is in the micromolar range, as is true 
for many radiopharmaceuticals. 
5.3 
Method for Assigning Subjects to Treatment Groups 
 
All study subjects will undergo the same protocol. 
5.4 
Preparation and Administration of Study Drug 
 
Choline C11 Injection is prepared on site at the Mayo Clinic PET Radiochemistry Facility in 
Phoenix, AZ.  Cyclotron produced C11-carbon dioxide is used as a precursor to generate C11-
methyl iodide followed by C11-choline.  All chemistry is performed using automated 
radiochemical synthesizers inside lead-lined hot cells. 
 
Following quality control testing, the drug product is packaged in a 6 mL sterile shielded syringe 
containing approximately 12-14 mCi. . 
  
5.5 
Subject Compliance Monitoring 
C-11 choline is only administered under direct supervision of study personnel. 
5.6 
Prior and Concomitant Therapy 
None. 
 
5.7 
Packaging 
The drug product is packaged in a 6 mL sterile syringe containing approximately 12-14 mCi  of 
radioactivity.  It is placed inside a lead syringe shield and labeled with the date, batch number, 
radioactive assay, drug product name, and the following statement “Caution: New Drug—
Limited by Federal (or United States) law to investigational use”.  It is then placed inside 
specially designed tungsten lined pneumatic tube capsule and sent to the PET imaging suite. 
 
5.8 
Masking/Blinding of Study  
 


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The interpreters of the imaging tests will be blinded to any patient information. However, the 
type of tracer and imaging approach will be apparent due to inherent differences in the 
techniques. 
5.9 
Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
 
The drug product will be manufactured on the same campus as the imaging suite and will be 
delivered via pneumatic tube. 
 
 
5.9.2 Storage 
 
Choline C 11 Injection should be stored at 25oC (77oF); excursions permitted to 15 to 30oC (59 
to 86oF) (see USP Controlled Room Temperature).  The solution should be used within 120 
minutes of the end of synthesis calibration time.   
 
5.9.3 Dispensing of Study Drug 
The dosage administered will be recorded on the CRF. 
5.9.4 Return or Destruction of Study Drug 
 
After injection of the C 11 choline the syringe will be assayed for residual radioactivity, to be 
used in calculation of the precise injected dose. The syringe will then disposed of in the 
radioactive container for 3-4 hours, about ten half-life durations of C11-Choline (C11-Choline 
half-life of 20 minutes). 
 
 
 
 


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6 Study Procedures 
Patients who have completed or will complete diagnostic body CT scan and nuclear medicine 
bone scan as part of standard care will be recruited and consented for participation in the study  
 
PET/MRI is preferably scheduled 6 weeks after prostate biopsy to minimize the effects of post 
biopsy hemorrhage.  
 
 
 
6.1 
Day 0 
 
Informed consent discussion with subject by research coordinator. Consent form signed by 
subject. Medical records will be reviewed by study coordinator. Subject’s eGFR will be 
determined.  If current serum creatinine level is unavailable, labs will be obtained for review. 
 
Subject will be reminded to drink 48 ounces of water the day prior to study procedures. On the 
morning of the procedure, subjects will be counseled to fast for four hours prior to the procedure 
and drink 24 ounces of water.    
 
 
 
6.2 
Day 1 
 
The patient will be screened for MR safety prior to entering the scan room, which may include 
the use of ferromagnetic screening. 
 
 
1. Vital signs (sitting blood pressure, heart rate, respiratory rate, temperature) are measured 
by the radiology nurse, who records the results on the source document.  
 
2. Investigator MD or research coordinator to see patient, review vital signs and discuss 
study objectives, explain the imaging procedures, answer questions. MD will sign and 
date the source document. 
 
3. Subject is brought to the PET/MR imaging suite. Total dose of 12-14 mCi  C-11 choline 
is injected I.V.  
 
4.  Torso PET/MR fusion scan is completed. Imaging time 20-30 minutes. 
 
 
5.  Pelvic mpMRI with PET data of pelvis completed. Imaging time 40-45.  
 
6. Following completion of imaging, subject will return to the relax room and vital signs ( 
sitting blood pressure, heart rate, respiratory rate and temperature) will be re-checked by 


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the radiology nurse, with the study coordinator recording the data in the source 
documents. 
 
 
7. Subject will be discharged.  
 
 
 
6.3 
Day 2- Follow up Procedures 
 
1. Research coordinator will call patient to ask if patient has experienced fever, shortness of 
breath, palpitations, headache or other symptoms. If any of the above have been 
experienced, investigator MD is immediately notified.  
 
2. Investigator MD is notified of results by the research coordinator. MD will sign and date 
source document. 
 
3. All pre-data analysis study data forms and consent are confirmed intact and in the study 
binder. Binder is kept in a secured file cabinet in the research coordinators office. 
 
 
 
 


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6.4 Schedule of Events 
 
 
 
 
 
 
 
 
 
Study Activity 
 
 
Day 0 
 
Day 1 
 
Day 2 
(follow up) 
 
Informed consent 
 
X 
 
 
Medical records review. Confirm study 
inclusion criteria.  Data recorded on source 
document.   
 
X 
 
 
Subject eGFR determined. Labs obtained if  
Current serum creatinine is unavailable. 
 
X 
 
 
Vital signs prior to and following imaging 
sessions recorded on source document (sitting 
blood pressure, respiratory rate, temperature, 
heart rate) 
 
X 
 
 
Torso PET/MR fusion scan 
 
X 
 
 
Pelvic  mpMRI  (SOC) 
 
X 
 
Adverse event evaluation. Results recorded on 
source document. 
 
 
X 
 
Follow-up call to collect adverse events. 
Result recorded on source document. 
 
 
X 


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7 Statistical Plan 
7.1 
Sample Size Determination 
 
Our null hypothesis is the hybrid C11-choline PET/MR and pelvic multiparametric MRI will 
have an equal accuracy of detecting patients with malignant lymph nodes in the very high 
risk/high risk prostate cancer patients compared to that in the conventional CT and bone scan 
method.    With 20 patients, a McNemar’s test with a 0.05 two-sided significance level will have 
82% power to reject the null hypothesis if the difference in accuracy of the two methods is 0.3 or 
greater and assume discordant pairs is expected to be 0.31.  
7.2 
Statistical Methods 
 
Descriptive Statistics 
 
Descriptive statistics will be used to describe the average time of the total procedure, patients’ 
tolerance and satisfaction level about the procedure.   Paired t-test will be used to compare the 
suspicious lymph nodes and suspicious osseous lesions in the pelvis and extrapelvic regions 
detected by hybrid C11-choline PET/MR and pelvic multiparametric MRI method and by 
conventional CT and bone scan to investigate if the new method is able to detect more lymph 
nodes and osseous lesions compared to the conventional method. Paired t-test will also be used 
to compare the average SUV of lymph nodes and osseous lesions in the pelvis and extrapelvic 
regions by new method with that by conventional method to investigate if the new method 
provided more clarity in terms detecting the lymph nodes and lesions compared to the old 
method. If the patients’ biopsy and surgery results available, sensitivity, specificity, positive 
predictive value and negative predictive value of detecting malignant lymph nodes and osseous 
lesions by the new method and by conventional method will be estimated and compared using 
McNemar’s test.  
 
Handling of Missing Data 
 
As the sample size is 20 and imaging is completed over one day, no missing imaging data is 
anticipated.   
 
 
Multiplicity 
 
In current project, there is one primary objective and we don't have to adjust for multiple 
comparison.  
 
 
 
 
 


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Interim Analysis 
 
There will not be interim analysis for the study. 
 
 
7.3 
Subject Population(s) for Analysis 
 
All-completed population:  Only subjects who completed ALL study related procedures and 
follow-up will be included 
 
 
 
 
 
8 Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may be 
physical, psychological, financial, social, economic, or legal) or increased risk for the 
subject or others (including individuals who are not research subjects). These include: (1) 
death; (2) life threatening adverse experience; (3) hospitalization - inpatient, new, or 
prolonged; (4) disability/incapacity - persistent or significant; (5) birth defect/anomaly; (6) 
breach of confidentiality and (7) other problems, events, or new information (i.e. 
publications, DSMB reports, interim findings, product labeling change) that in the opinion 
of the local investigator may adversely affect the rights, safety, or welfare of the subjects 
or others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already 
described as potential risks in the protocol, consent document, not listed in the 
Investigator’s Brochure, or not part of an underlying disease. A problem or event is 
"unanticipated" when it was unforeseeable at the time of its occurrence. A problem or 
event is "unanticipated" when it occurs at an increased frequency or at an increased 
severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
 
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An untoward or undesirable experience associated with the use of a medical product (i.e. drug, 
device, biologic) in a patient or research subject. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well 
defined and include; 
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant disability or incapacity 
• birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-investigator 
may have adversely affected the rights, safety, or welfare of the subjects or others, or 
substantially compromised the research data. 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-
serious adverse events.  
 
Adverse Event Reporting Period 
 
The study treatment follow-up period is defined as the end of the day 2 follow-up phone call for 
the study (1 day following the last administration of study treatment). This phone call concludes 
the Adverse Event Reporting Period. 
 
 
Preexisting Condition 
 
A preexisting condition is one that is present at the start of the study.  A preexisting condition 
should be recorded as an adverse event if the frequency, intensity, or the character of the 
condition worsens during the study period. 
 
 
 
General Physical Examination Findings 
 
At screening, any clinically significant abnormality should be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities that 
meet the definition of an adverse event must also be recorded and documented as an adverse 
event.  
 
Post-study Adverse Event 
 
All unresolved adverse events should be followed by the sponsor-investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.  At the last 
scheduled visit, the sponsor-investigator should instruct each subject to report, to the sponsor-


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investigator, any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  
 
Abnormal Laboratory Values 
 
Laboratory values associated with this study will be a part of the patient’s clinical medical 
record, and clinically indicated. No follow up laboratory values will be obtained following 
imaging. 
 
 
 
Hospitalization, Prolonged Hospitalization or Surgery 
 
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event unless specifically instructed otherwise in 
this protocol.  Any condition responsible for surgery should be documented as an adverse event 
if the condition meets the criteria for an adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an 
adverse event in the following circumstances:  
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures 
for a preexisting condition.  Surgery should not be reported as an outcome of an adverse 
event if the purpose of the surgery was elective or diagnostic and the outcome was 
uneventful. 
• Hospitalization or prolonged hospitalization for therapy of the target disease of the study, 
unless it is a worsening or increase in frequency of hospital admissions as judged by the 
clinical investigator. 
 
8.2 
Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document, and also in the appropriate adverse 
event section of the case report form (CRF) or in a separate adverse event worksheet.  All clearly 
related signs, symptoms, and abnormal diagnostic, laboratory or procedure results should 
recorded in the source document. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been ultimately 
determined that the study treatment or participation is not the probable cause.  Serious adverse 
events that are still ongoing at the end of the study period must be followed up, to determine the 
final outcome.  Any serious adverse event that occurs during the Adverse Event Reporting 
Period and is considered to be at least possibly related to the study treatment or study 
participation should be recorded and reported immediately. 
 
 
 


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8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event Worksheet 
and log.  The sponsor-investigator will evaluate the event and determine the necessary follow-up 
and reporting required. 
 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs 
according to the Mayo IRB Policy and Procedures. 
 
The sponsor-investigator will review all adverse event reports to determine if specific reports 
need to be made to the IRB and FDA.  The sponsor-investigator will sign and date the adverse 
event report when it is reviewed.  For this protocol, only directly related SAEs/UPIRTSOs will 
be reported to the IRB. 
 
The relationship of an AE to the Investigational Drug is a clinical decision by the sponsor-
investigator (PI) based on all available information at the time of the completion of the CRF and 
is graded as follows: 
 
1. Not related: a reaction for which sufficient information exists to indicate that the etiology is 
unrelated to the study drug; the subject did not receive the study medication or the temporal 
sequence of the AE onset relative to administration of the study medication is not reasonable or 
the event is c1early related to other factors such as the subject’s clinical state, therapeutic 
intervention or concomitant therapy. 
 
2. Unlikely: a clinical event, including laboratory test abnormality, with a temporal relationship 
to drug administration which makes a causal relationship improbable and in which other drugs, 
chemicals, or underlying disease provide plausible explanations. 
 
3. Possible: a clinical event, including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug but which could also be explained by concurrent disease 
or other drugs or chemicals; information on drug withdrawals may be lacking are unclear. 
 
4. Probable: a clinical event including laboratory test abnormality, with a reasonable time 
sequence to administration of the drug, unlikely to be attributed to concurrent disease or other 
drugs or chemicals and which follows a clinically reasonable response on withdrawal (de-
challenge): re-challenge information is not required to fulfi1 this definition. 
 
5. Definite: a reaction that follows a reasonable temporal sequence from administration of the 
drug, or in which the drug level has been established in body fluids or tissues, that follows a 
known or expected response pattern to the suspected drug, and that is confirmed by improvement 
on stopping or reducing the dosage of the drug, and reappearance of the reaction on repeated 
exposure (re-challenge). 
 
 
 


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The maximum intensity of an AE during a day should be graded according to the definitions 
below and recorded in details as indicated on the CRF. If the intensity of an AE changes over a 
number of days, then separate entries should be made having distinct onset dates.  
 
1. Mild: AEs are usually transient, requiring no special treatment, and do not interfere with 
patient’s daily activities. 
 
2. Moderate: AEs typically introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities, but are usually ameliorated by simple therapeutic measures. 
 
3. Severe: AEs interrupt a patient's usual daily activity and traditionally require systemic drug 
therapy or other treatment. 
 
 
 
8.3.2 Sponsor-Investigator reporting: Notifying the FDA 
 
The sponsor-investigator will report to the FDA all unexpected, serious suspected adverse 
reactions according to the required IND Safety Reporting timelines, formats and requirements. 
 
Unexpected fatal or life threatening suspected adverse reactions where there is evidence to 
suggest a causal relationship between the study drug/placebo and the adverse event, will be 
reported as a serious suspected adverse reaction.  This will be reported to the FDA on FDA Form 
3500A, no later than 7 calendar days after the sponsor-investigator’s initial receipt of the 
information about the event. 
 
Other unexpected serious suspected adverse reactions where there is evidence to suggest a causal 
relationship between the study drug/placebo and the adverse event, will be reported as a serious 
suspected adverse reaction.  This will be reported to the FDA on FDA Form 3500A, no later than 
15 calendar days after the sponsor-investigator’s initial receipt of the information about the 
event. 
 
Any clinically important increase in the rate of serious suspected adverse reactions over those 
listed in the protocol or product insert will be reported as a serious suspected adverse reaction.  
This will be reported to the FDA on FDA Form 3500A no later than 15 calendar days after the 
sponsor-investigator’s initial receipt of the information about the event. 
 
Findings from other studies in human or animals that suggest a significant risk in humans 
exposed to the drug will be reported.  This will be reported to the FDA on FDA Form 3500A, no 
later than 15 calendar days after the sponsor-investigators initial receipt of the information about 
the event. 
 
 
 


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8.4 
Stopping Rules  
Stopping rules not applicable as standard radiology safety procedures will be followed. 
 
 
8.5 
Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 10  “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
 
 
8.5.1 Internal Data and Safety Monitoring  
 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her 
site.  This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 10  “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (long term survival status that 
the subject is alive) at the end of their scheduled study period. 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents.  Examples of these original documents, and data records 


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include: hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and complete, 
microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files, and 
records kept at the pharmacy, at the laboratories, and at medico-technical departments involved 
in the clinical trial. 
9.3 
Case Report Forms 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, write 
“N/D”.  If the item is not applicable to the individual case, write “N/A”.  All entries should be 
printed legibly in black ink.  If any entry error has been made, to correct such an error, draw a 
single straight line through the incorrect entry and enter the correct data above it.  All such 
changes must be initialed and dated.  Do not erase or use “white-out” for errors.  For clarification 
of illegible or uncertain entries, print the clarification above the item, then initial and date it.  If 
the reason for the correction is not clear or needs additional explanation, neatly include the 
details to justify the correction. 
 
Data Management 
 
Case report forms will be organized in a binder, maintained in a locked cabinet in the research 
coordinator’s office. 
 
 
Data Processing 
 
Data will be analyzed via the statistical methods outlined in this protocol.   
 
Data Security and Confidentiality 
 
Patient identification codes will be used.  A number will be assigned to all subjects and any 
published report will not identify subjects by name.  
 
A study-specific REDCAP file will be utilized to consolidate and analyze data from the written 
CRFs and printed data from the EMR. The file will be a password protected within a secured 
folder with permissions limited to study staff. Several layers of permissions are required to 
access the study data.  Patient-specific information will only be available on the written CRF. 
Only the patient number will be entered on the spreadsheet. 
 
 
Data Quality Assurance 
 
Data transcribed from the written CRFs or the EMR will be double checked by the study staff 
member on an ongoing basis during the study. The CRFs and EMR lab printouts will be kept in 


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the study binder. At the end of the study, the PI, Co-PI or a Co-investigator will again double 
check all data entered into the spreadsheet from the CRFs and printout EMR sheets for each 
subject to detect any transcription errors. 
 
 
9.4 
Records Retention 
 
The sponsor-investigator will maintain records and essential documents related to the conduct of 
the study.  These will include subject case histories and regulatory documents. 
 
 
The sponsor-investigator will retain the specified records and reports for; 
1. Up to 2 years after the marketing application is approved for the drug; or, if a marketing 
application is not submitted or approved for the drug, until 2 years after shipment and 
delivery of the drug for investigational use is discontinued and the FDA has been so 
notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS 669717,   
            whichever is longer. 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
The Principal Investigator will review study process, progress, and data security in conjunction 
with the research coordinator. Study progress will be reviewed on a weekly basis and 
documentation of this review will be recorded in the study review log, even when there are not 
irregularities or remedial measures which need to be taken.  Study data will be reviewed 
throughout the study to ensure the validity of the data in addition to the protection of study 
subjects.  
 
In order to assist the sponsor-investigator in complying with Food and Drug Administration 
regulations, the Mayo Clinic Office of Research Regulatory Support will provide assistance with 
clinical monitoring activities as a service for the sponsor-investigator.  Clinical trial monitoring 
requires review of the study data generated throughout the duration of the study to ensure the 
validity and integrity of the data along with the protection of human research subjects.   
 
10.2 Auditing and Inspecting 
 
The investigator will permit study-related monitoring, audits, and inspections by the IRB and 
government regulatory agencies, of all study related documents (e.g. source documents, 
regulatory documents, data collection instruments, study data etc.).  The investigator will ensure 


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the capability for inspections of applicable study-related facilities (e.g. pharmacy, diagnostic 
laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
11 Ethical Considerations 
 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the sponsor-investigator before commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the Approved IRB consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject or the subject’s legally authorized representative, and the individual obtaining the 
informed consent. 
 
 
12 Study Finances 
12.1 Funding Source 
This project will be financially supported by Department of Radiology, at Mayo Clinic in 
Arizona. 
 
12.2 Subject Stipends or Payments 
No stipends or payments will be provided to study subjects. 
13 Publication Plan 
 
We intend to submit the results of this pilot study for publication to nuclear medicine, molecular 
imaging, or oncology journals as is deemed justified by the results of the data analysis. P.I. Dr. 
Yang, in conjunction with Co-I Dr. Kawashima, will determine the best publication plan to 
pursue. Permission and agreement will be sought from each co-author attached to this project.  
 


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14 References 
1. Siegel, R. L., et al. (2016). "Cancer statistics, 2016." CA Cancer J Clin 66(1): 7-30. 
2. Turkbey, B., et al. (2010). "Prostate cancer: value of multiparametric MR imaging at 3 T 
for detection--histopathologic correlation." Radiology 255(1): 89-99. 
3. Castellucci, P., et al. (2009). "Influence of trigger PSA and PSA kinetics on 11C-Choline 
PET/CT detection rate in patients with biochemical relapse after radical prostatectomy." J 
Nucl Med 50(9): 1394-1400. 
4. Giovacchini, G., et al. (2010). "Predictive factors of [(11)C]choline PET/CT in patients 
with biochemical failure after radical prostatectomy." Eur J Nucl Med Mol Imaging 
37(2): 301-309. 
5. Mitchell, C. R., et al. (2013). "Operational characteristics of (11)c-choline positron 
emission tomography/computerized tomography for prostate cancer with biochemical 
recurrence after initial treatment." J Urol 189(4): 1308-1313. 
6. Kitajima, K., et al. (2014). "Detection of recurrent prostate cancer after radical 
prostatectomy: comparison of 11C-choline PET/CT with pelvic multiparametric MR 
imaging with endorectal coil." J Nucl Med 55(2): 223-232. 
7. Picchio M, et al. (2015). Imaging biomarkers in prostate cancer: role of PET/CT and 
MRI. Eur J Nucl Med Mol Imaging. 2015 Apr;42(4):644-55. 
8. Reske, S. N., et al. (2006). "Imaging prostate cancer with 11C-choline PET/CT." J Nucl 
Med 47(8): 1249-1254. 
9. Piert, M., et al. (2016). "18F-Choline PET/MRI: The Additional Value of PET for MRI-
Guided Transrectal Prostate Biopsies." J Nucl Med 57(7): 1065-1070. 
10. Tolvanen, T., et al. (2010). "Biodistribution and radiation dosimetry of [(11)C]choline: a 
comparison between rat and human data." Eur J Nucl Med Mol Imaging 37(5): 874-883. 
11. Scattoni, V., et al. (2007). "Detection of lymph-node metastases with integrated 
[11C]choline PET/CT in patients with PSA failure after radical retropubic prostatectomy: 
results confirmed by open pelvic-retroperitoneal lymphadenectomy." Eur Urol 52(2): 
423-429. 
 
 
 
 
 
 
 
                                                     
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