Comparison of F-18 FDG PET CT and PET MRI With C-11 Acetate PET CT and PET MRI in the Diagnosis of Active Multiple Myeloma Disease: a Pilot Study
Phase: PHASE2
Conditions: Multiple Myeloma
Sponsor: Michael C Roarke, MD

 
 
Comparison of F-18 FDG PET CT 
and PET MRI with C-11 acetate 
PET CT and PET MRI in the 
diagnosis of active multiple 
myeloma disease: a pilot study 
 
 NCT03262389 
 
6/6/2017 

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Michael C. Roarke, M.D. 
 
CONFIDENTIAL 
 
 
Comparison of F-18 FDG PET CT and PET MRI with C-11 acetate PET CT and PET 
MRI in the diagnosis of active multiple myeloma disease: a pilot study 
 
 
 
 
 
 
Regulatory Sponsor: 
Michael C. Roarke, M.D. 
Department of Diagnostic Radiology 
Mayo Clinic in Arizona 
13400 East Shea Blvd 
Scottsdale AZ 85259 
480-301-6865 
Roarke.michael@mayo.edu 
 
 
 
Study Product: 
C-11 acetate 
Protocol Number: (IRBe) 
16-007867 
 
 
 
 
 
 
 
Initial version: [03/21/2017] Version (1.0)  
Revised: 
[06/06/2017] Version (2.0) 
Revised: 
[date] Version (3.0) 
 
 

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Table of Contents 
 
STUDY SUMMARY ...................................................................................................................................... 5 
1 
INTRODUCTION ................................................................................................................................. 6 
1.1 
BACKGROUND .................................................................................................................................... 6 
1.2 
INVESTIGATIONAL AGENT .................................................................................................................... 6 
1.3 
PRECLINICAL DATA ............................................................................................................................. 6 
1.4 
CLINICAL DATA TO DATE..................................................................................................................... 7 
1.5 
DOSE RATIONALE................................................................................................................................ 7 
1.6 
RISKS AND BENEFITS ........................................................................................................................... 7 
2 
STUDY OBJECTIVES .......................................................................................................................... 7 
3 
STUDY DESIGN ................................................................................................................................... 8 
3.1 
GENERAL DESCRIPTION ....................................................................................................................... 8 
3.2 
NUMBER OF SUBJECTS ......................................................................................................................... 8 
3.3 
DURATION OF PARTICIPATION .............................................................................................................. 9 
3.4 
PRIMARY STUDY ENDPOINTS .............................................................................................................. 10 
3.5 
SECONDARY STUDY ENDPOINTS ......................................................................................................... 10 
3.6 
PRIMARY SAFETY ENDPOINTS ............................................................................................................ 10 
3.7 
IDENTIFICATION OF SOURCE DATA ...................................................................................................... 10 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ...................................................... 10 
4.1 
INCLUSION CRITERIA ......................................................................................................................... 10 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 10 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ....................................................................... 11 
4.4 
EARLY WITHDRAWAL OF SUBJECTS .................................................................................................... 11 
4.4.1 
When and How to Withdraw Subjects ........................................................................................ 11 
5 
STUDY DRUG .................................................................................................................................... 11 
5.1 
DESCRIPTION .................................................................................................................................... 11 
5.2 
TREATMENT REGIMEN ....................................................................................................................... 12 
5.3 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ......................................................................... 12 
5.4 
PACKAGING ...................................................................................................................................... 12 
5.5 
RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................................. 12 
5.5.1 
Storage ................................................................................................................................... 12 
5.5.2 
Dispensing of Study Drug ......................................................................................................... 12 
5.5.3 
Return or Destruction of Study Drug ......................................................................................... 12 
6 
STUDY PROCEDURES ...................................................................................................................... 13 
6.1 
DAY 0 .............................................................................................................................................. 13 
6.2 
DAY 1 .............................................................................................................................................. 13 
6.3 
DAY 2 .............................................................................................................................................. 14 
6.4 
DAY 3 .............................................................................................................................................. 15 
6.5 
SCHEDULE OF EVENTS ....................................................................................................................... 16 
7 
STATISTICAL PLAN ......................................................................................................................... 17 
7.1 
SAMPLE SIZE DETERMINATION ........................................................................................................... 17 
7.2 
STATISTICAL METHODS ..................................................................................................................... 17 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ............................................................................................. 18 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 18 
8.1 
DEFINITIONS ..................................................................................................................................... 18 

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8.2 
RECORDING OF ADVERSE EVENTS ....................................................................................................... 20 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS .......................................... 20 
8.3.1 
Sponsor-Investigator reporting: notifying the Mayo IRB ............................................................. 21 
8.4 
STOPPING RULES ............................................................................................................................... 22 
8.5 
MEDICAL MONITORING ..................................................................................................................... 22 
9 
DATA HANDLING AND RECORD KEEPING .................................................................................. 22 
9.1 
CONFIDENTIALITY ............................................................................................................................. 22 
9.2 
SOURCE DOCUMENTS ........................................................................................................................ 23 
9.3 
CASE REPORT FORMS ........................................................................................................................ 23 
9.4 
RECORDS RETENTION ........................................................................................................................ 24 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 24 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 24 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 24 
11 
ETHICAL CONSIDERATIONS ......................................................................................................... 25 
12 
STUDY FINANCES ............................................................................................................................ 25 
12.1 
FUNDING SOURCE ......................................................................................................................... 25 
13 
PUBLICATION PLAN ....................................................................................................................... 25 
14 
REFERENCES ................................................................................................................................... 26 
 
 
 
 
 
 
 
 

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List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
 
 
 
 
 
 
 

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Study Summary 
Title 
Comparison of F-18 FDG PET CT and PET MRI with C-11 acetate 
PET CT and PET MRI in the diagnosis of active multiple myeloma 
disease: a Pilot Study 
Running Title 
C-11 acetate vs. FDG with PET/CT and PET/MRI in Myeloma 
Protocol Number 
16-007867 
Phase 
Pilot study 
Methodology 
Prospective observational repeated-measure study design 
Overall Study 
Duration 
12 weeks 
Subject Participation 
Duration 
Approx. 270 minutes, over 2 days, in the nuclear medicine suite. 
Single or Multi-Site  
Single 
Objectives 
1. Our primary interest is to investigate which tracer and imaging 
technique combination (FDG PET/MRI, C11 PET/CT, C11 PET/MRI) 
can detect more clinically significantly MM lesions compared to the 
standard technique (FDG PET/CT). 
2. Secondary Objectives: Evaluate which tracer and imaging technique 
combination (FDG PET/CT, FDG PET/MRI, C11 PET/CT, C11 
PET/MRI) best distinguishes the clinically significant MM lesions from 
other lesions detected. 
Number of Subjects 
10 
Diagnosis and Main 
Inclusion Criteria 
Clinically diagnosed multiple myeloma spectrum disease. Adult patients 
who are able to provide informed consent.   
Study Product, Dose, 
Route, Regimen 
C-11 acetate, 10 mCi, intravenous injections 
Duration of 
Administration 
Bolus injection 
Reference therapy 
F-18 FDG 
Statistical 
Methodology 
Objective 1. Repeated measures ANOVA. Univariate one-way repeated 
measures ANOVA F-test is used to calculate the sample size.  
 
Objective 2. One way repeated measure analysis of variance will be 
employed to detect if there is any difference among the average scores 
of detected MM lesion in each technique.   
 
When the sample size is 10, a single-group repeated measures analysis of 
variance with a 0.05 significant level will have 80% power to detect a 
difference in means across the 4 levels by an effect size of 0.32. 
 
 

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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 
 
This project will study differing radiopharmaceutical and imaging approaches in patients with 
multiple myeloma spectrum disease. The use of carbon-11 (C-11) acetate as a positron emission 
tomography (PET) tracer to detect multiple myeloma has shown promise in a small number of 
recent research publications. The current standard clinical PET tracer being used, F-18 
fluorodeoxyglucose (F-18 FDG), has some limitations due to the fact that up to 30% of 
myelomas do not show increased glucose pathway activity. In these patients, recent reports 
suggest that exploiting the intracellular acetate pathway rather than the glucose pathway may 
more reliably detect the presence of active myeloma deposits. 
 
The study would include any consent-able adult patient over the age of 20 who is scheduled for a 
diagnostic FDG PET/CT scan for evaluation of multiple myeloma (MM) for the following 
indications: new diagnosis, high risk smoldering MM, relapse as defined by investigator. 
 
Acetate is a key component in cellular reactions which result in the oxidative metabolism (via 
participation in the citric acid cycle in mitochondria), synthesis of fatty acids (in production of 
cell membranes), and in nuclear histone acetylation (which regulates gene expression). Cell 
membrane synthesis and gene expression are both important upregulated functions within cancer 
cells. Intravenously injected C-11 acetate is a radiopharmaceutical which acts identically to 
normal non-radioactive C-11 acetate in the body. The radioactivity associated with the acetate 
metabolic pathways can be imaged with positron emission tomographic devices, revealing and 
permitting visual differentiation of benign versus cancerous tissue by a radiologist.  
 
Our study also incorporates use of a new FDA-approved hybrid PET/MRI technique. This 
additional modality will permit a four-way technique comparison combination which has not to 
date been reported. 
1.2 
Investigational Agent 
 
The investigational agent for this study C-11 acetate is to be manufactured in the Mayo Clinic 
Arizona radiochemistry facility. 
 
1.3 
Preclinical Data 
 
C-11 acetate has been used safely worldwide in patients with cardiovascular disease and cancer 
over many years. (1-7). For this study non-pharmacologic doses of C-11 acetate will be 
administered and should not have metabolic effects. 

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1.4 
Clinical Data to Date 
 
F-18 FDG is a glucose analogue that relies on tumor glucose uptake in order to reveal sites of 
metabolically active tumor. However, 30% of myelomas, such as the non-secretory type, have 
relatively low rates of glucose metabolism. (8) Recent work in cell metabolism has revealed that 
in the hypoxic environment of malignant tumors, glucose metabolism is shunted toward lactate 
production, necessitating an alternative source of acetylCoA for cell membrane fatty acid 
production. It is believed that in these hypoxic conditions, the acetate uptake pathway becomes a 
more important route to cell proliferation via cell membrane fatty acid synthesis (9, 10) and 
nuclear histone acetylation (important in gene transcription from nuclear DNA). (11)  A small 
number of research studies have reported on the efficacy of C-11 acetate, with Ho et all reporting 
that the sensitivity / specificity of C-11 acetate PET is superior at 84.6%/100% vs. 57.7%/93.1% 
for F-18 FDG PET. (7) 
 
On the technology front, combined hybrid PET/MRI devices are now FDA approved for 
diagnostic imaging.  PET MRI may improve detection of diffuse marrow infiltration and thereby 
improve diagnostic utility of the PET data compared to PET CT. To our knowledge, there have 
been no published reports on the imaging of C-11 acetate for myeloma with PET MR. 
1.5 
Dose Rationale  
 
The dose of C-11 acetate selected for use in the study patients is 10-15 mCi (370-555 MBq) 
based on prior published reports by Ho et al. (7). The tracer must be given intravenously. 
1.6 
Risks and Benefits 
 
C-11 acetate is otherwise identical to endogenous acetate from the pharmacokinetic standpoint. 
Therefore the study radiopharmaceutical itself will have no nonphysiological action. The main 
theoretical risk involves the exposure to the radioactivity associated with the C-11 isotope 
incorporation. This exposure has been calculated to be lower than the standard tracer used, F-18 
FDG.(see calculations). The main imaging risk involves exposure to the x-rays used to produce 
the CT images. However, the exposure is limited to the same low-dose technique involved in 
production of standard clinically performed PET/CT. Patients with contraindications to 
PET/MRI will be excluded (metal foreign body fragments or incompatible implanted metallic 
medical devices). 
 
2 Study Objectives 
 
Primary Objective: 
Our primary interest is to investigate which tracer and imaging technique combination (FDG 
PET/MRI, C11 PET/CT, C11 PET/MRI) can detect more clinically significantly MM lesions 
compared to the standard technique (FDG PET/CT). 
 
 
 

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Secondary Objective: 
Evaluate which tracer and imaging technique combination (FDG PET/CT, FDG PET/MRI, C11 
PET/CT, C11 PET/MRI) best distinguishes the clinically significant MM lesions from other 
lesions detected. 
 
3 Study Design 
 
This study will be a prospective, observational repeated-measure study to compare the standard 
technique of F-18 FDG PET/CT with the study techniques of F-18 FDG PET/MRI, C-11 acetate 
PET/CT and C-11 acetate PET/MRI in the detection of active multiple myeloma in human 
patients.  
 
The doses of C-11 acetate will be administered intravenously. F-18 FDG is already an FDA-
approved intravenous radiopharmaceutical. We anticipate study duration of 12 weeks, if patient 
recruitment proceeds as expected. 
 
3.1 
General Description 
Our investigation is titled Comparison of F-18 FDG PET CT and PET MRI with C-11 acetate 
PET CT and PET MRI in the diagnosis of active multiple myeloma disease: a Pilot Study. This 
study will be a prospective, observational repeated-measure study to compare the standard 
technique of F-18 FDG PET/CT with the study techniques of F-18 FDG PET/MRI, C-11 acetate 
PET/CT and C-11 acetate PET/MRI in the detection of active multiple myeloma in human 
patients. This pilot study of 10 patients will help guide development of a subsequent future 
prospective study involving a larger cohort of patients. The doses of C-11 acetate will be 
administered intravenously. F-18 FDG is already an FDA-approved intravenous 
radiopharmaceutical. We anticipate study duration of 12 weeks, if patient recruitment proceeds 
as expected. 
 
Our primary interest is to investigate which tracer and imaging technique combination (FDG 
PET/MRI, C11 PET/CT, C11 PET/MRI) detects the greatest number of clinically significantly 
MM lesions compared to the standard technique (FDG PET/CT). 
 
Our secondary objective is to evaluate which tracer and imaging technique combination (FDG 
PET/CT, FDG PET/MRI, C11 PET/CT, C11 PET/MRI) best distinguishes the clinically 
significant MM lesions from other lesions detected. 
 
3.2 
Number of Subjects 
Ten subjects who have completed all phases of the protocol are required. In order to ensure this, 
it may be necessary to screen a small number of additional candidates, perhaps up to 5 total, to 
ensure we reach our study target of ten complete studies. For example, if an enrolled subject 
cannot or will not return for the second day of imaging, we will recruit and enroll a replacement 
subject. 
 

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3.3 
Duration of Participation 
 
There are a total of 4 visits over approximately 32 days. The first 3 visits will be at the Mayo 
Clinic Arizona campus. The fourth visit involves a phone call. There is an allowed 14 day 
window between Day 0 and Day 1. There is an allowed 14 day window between Day 1 and Day 
2. There is an allowed 4 day window between Day 2 and Day 3.  
 
 
 
 
  
 

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3.4 
Primary Study Endpoints 
 
Our primary interest is to investigate which tracer and imaging technique combination (FDG 
PET/MRI, C11 PET/CT, C11 PET/MRI) can detect more clinically significantly MM lesions 
compared to the standard technique (FDG PET/CT). 
 
3.5 
Secondary Study Endpoints 
 
Evaluate which tracer and imaging technique combination (FDG PET/CT, FDG PET/MRI, C11 
PET/CT, C11 PET/MRI) best distinguishes the clinically significant MM lesions from other 
lesions detected. 
3.6 
Primary Safety Endpoints 
 
Adverse events will be monitored through the vital signs evaluated prior to and after 
investigational product administration. 
 
3.7 
Identification of Source Data 
 
Source data for this study will not be directly collected in the Case Report Form (CRF), but will 
be captured in supportive documentation (study source documents, EMR). 
 
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
• Patients being staged for multiple myeloma as follows: new diagnosis, high risk 
smoldering MM, relapsed as defined by investigator 
• Patients who have undergone standard of care workup  
• Patients > 20 years old. 
• 300 pounds or less  
• Can provide informed consent  
• Scheduled for a clinically indicated F-18 FDG PET scan 
• English speaking 
 
 
4.2 
Exclusion Criteria 
• Pregnant, breast feeding 
• Concurrent active non-MM malignancy 
• Contraindication to PET MRI  
• Previous Type I or Type II Diabetes mellitus or a fasting blood glucose >150 mg/dl 

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6 Study Procedures 
6.1 
Day 0 
Informed consent discussion held with subject by research coordinator and consent form signed. 
Women of child bearing potential are required to have a serum pregnancy test. Women who are 
surgically sterile and/or greater than or equal to 12 months post-menopausal are not considered 
as child bearing potential. 
 
Remind patient of overnight fast after 11 pm, except plain water. Review eligibility criteria to 
confirm all inclusion criteria are met and no exclusion criteria are met.  
6.2 
Day 1 
1. Vital signs (sitting blood pressure, heart rate, respiratory rate, temperature) and finger-
stick blood glucose are measured by the radiology nurse, who records the results on the 
source document.  
 
2. Investigator MD to see patient, review vital signs and in lay language discuss study 
objectives, explain the imaging procedures, answer questions. MD signs and dates the 
source document. 
 
3. Subject is brought to the injection room and the radiopharmaceutical is infused 
intravenously.  
 
4. Subject is brought to relax room for one-hour F-18 FDG uptake period. Subject is 
instructed to remain at rest in the reclining chair, refrain from talking, chewing gum, or 
getting out of the chair for non-urgent reasons. 
 
5. Subject is brought into the PET/CT imaging suite, placed on the scanner table, and 
imaging carried out. 
 
6. Immediately following the PET/CT scan, the subject is brought to the PET/MRI suite and 
imaging carried out. 
 
7. At the completion of the PET/MRI, the patient is brought back to the interview or relax 
room and vital signs (sitting blood pressure, heart rate, respiratory rate, temperature) are 
re-checked by the radiology nurse, with the research coordinator recording the results.  
 
8. Investigator MD is called by research coordinator to perform post-procedure vital sign 
review, interview the patient and answer any questions.  
 
9. Subject is discharged with instructions for overnight fast except for plain water, 
beginning at 11 pm. 
 
10. Research coordinator places all study data forms in the study binder. 

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6.3 
Day 2 
1. Vital signs (sitting blood pressure, heart rate, respiratory rate, temperature) and finger-
stick blood glucose are measured by the radiology nurse, and the results are recorded on 
the source document provided by the research coordinator.  
 
2. Investigator MD to see patient, review vital signs and in lay language discuss study 
objectives, explain the imaging procedures, answer questions. MD signs and dates source 
document. 
 
3. Subject is brought to the injection room and the radiopharmaceutical is infused 
intravenously.  
 
4. Subject is immediately brought to the scan room, positioned on the scanning table, and at 
ten minutes post-injection, PET/CT performed. 
 
5. Immediately following the PET/CT scan, the subject is brought to the relax room for a 60 
minute wait at rest in the reclining chair. 
 
6. After 60 minutes, the subject is brought to the injection room for the second C-11 acetate 
injection. (NOTE: If the second run of C-11 acetate fails quality control testing, steps 7-
11 of the protocol would be postponed until the next day, or within one week). 
 
7. Subject is immediately brought to the scan room, positioned on the scanning table, and at 
ten minutes post-injection, PET/MRI performed. 
 
8. At the completion of the PET/MRI, the patient is brought back to the interview or relax 
room and vital signs (sitting blood pressure, heart rate, respiratory rate, temperature) are 
re-checked by the radiology nurse, who records the results on the source document 
provided by the research coordinator.  
 
9. Investigator MD is called by research coordinator to perform post-procedure vital sign 
review, interview the patient and answer any questions. MD signs and dates the source 
document. 
 
10. Subject is discharged. 
 
11. Research coordinator places all study data forms in the study binder. 
 
 
 
 
 
 

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6.4 
Day 3 
1. Research coordinator calls 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. Subject is asked about impressions 
of the experience and whether they believe any additional comfort measures could have 
been taken. 
 
2. Investigator MD is notified of results by the research coordinator. MD signs and dates 
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. 
 
Imaging Techniques 
PET/CT: Standard clinical Mayo Clinic whole-body PET/CT acquisition protocol. 
 
PET/MR: PET/MRI myeloma acquisition study protocol: 
Whole Body Localizer 
       Station 1                                      
       Station 2                                      
       Station 3                                      
       Station 4          
 
PET Task Whole Body                 
    Bed 1   3:00                               
        MRAC 1                            
        AX LAVA-Flex 1                
    Bed 2    4:00                              
       MRAC 2                            
       AX LAVA-Flex 2     
    Bed 3    4:00                              
       MRAC 3                            
       AX LAVA-Flex 3        
    Bed 4     3:00                            
       MRAC 4                            
       AX LAVA-Flex 4         
     Bed 5        3:00                          
        MRAC 5                            
        AX LAVA-Flex 5                
    Bed 6      3:00                            
        MRAC 6                            
        AX LAVA-Flex 6                
    Bed 7      3:00                            
        MRAC 7                            
        AX LAVA-Flex  7              
 
Comfort Modification: may remove body coils when acquisition of that area is complete, only if 
needed to keep the subject comfortable. 
 

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6.5 
Schedule of Events 
 
 
Study Activity 
Day 0 
Day 1 e 
Day 2 f 
Day 3 g 
Informed consent 
X 
 
 
 
History (confirm myeloma spectrum diagnosis). 
Record result on source document. 
X 
 
 
 
Chart information recorded on study source 
document  (height, weight, diabetic, pregnancya 
and breast feeding status, bone marrow biopsy 
(if obtained) %, beta-2-microglobulin level (if 
obtained). 
X 
 
 
 
Vital signs prior to and following imaging 
sessions recorded on source document (sitting 
blood pressure, respiratory rate, temperature, 
heart rate) 
 
X 
X  
 
Finger-stick blood glucose prior to imaging 
 
X 
X 
 
CBCb, CMPc, SPEPd, Immunoglobulins, Serum 
free light chains. Within 4 weeks of study. 
Obtained as routine clinical tests, not research. 
Study coordinator will take data from EMR to 
enter on source/CRF.  
X 
 
 
 
Pregnancy test (serum), if applicable a 
X 
 
 
 
Adverse event evaluation. Results recorded on 
source document. 
 
X 
X 
    X 
PET scans 
 
X 
X 
 
Follow-up call re: adverse events. Result 
recorded on source document. 
 
 
 
X 
 
a Women of child bearing potential are required to have a serum pregnancy test. Women who are surgically sterile and/or greater 
than or equal to 12 months post-menopausal are not considered as child bearing potential. Pregnant women will not be allowed to 
participate in this study 
b CBC (complete blood count); red blood cells (RBCs), white blood cells (WBCs), platelets (PLTs), hemoglobin (Hgb), RBC 
indices, and WBC differential 
c CMP (Comprehensive Metabolic Panel; if available, but not required to participate); Glucose, Calcium, Proteins, Albumin, 
Total Protein, Sodium, Potassium, CO2 (carbon dioxide, bicarbonate), Chloride, BUN (blood urea nitrogen), Creatinine, ALP 
(alkaline phosphatase), ALT (alanine amino transferase), AST (aspartate amino transferase), Bilirubin 
d Serum Protein Electrophoresis 
e Day 1 visit to occur within 14 days of Day 0 visit 
f Day 2 visit to occur within 14 days of Day 1 visit 
g Day 3 visit to occur within 4 days of Day 2 visit 
 
 

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7 Statistical Plan 
7.1 
Sample Size Determination 
When the sample size is 10, as planned in this pilot study, a single-group repeated measures 
analysis of variance with a 0.05 significant level will have 80% power to detect a difference in 
means across the 4 levels by an effect size of 0.32.  Assuming a standard deviation at each level 
to be 2.2 and a between level correlation to be 0.6, the average difference will be detected in this 
scenario is 0.78. 
 
7.2 
Statistical Methods 
 
Descriptive Statistics 
 
Primary Hypothesis: There is no difference in the number of clinically significant MM lesions 
detected by FDG PET/MRI, C11 PET/CT, C11 PET/MRI compared to the standard technique 
FDG PET/CT.  
 
The patients will go through all of the 4 techniques and the number of clinically significant MM 
lesions detected by each technique will be collected. Our primary outcome is the number of MM 
lesions detected by each technique, which can vary from 0 to 13 with 5 or 6 lesions as an average 
for the MM patients. It is a repeated measures ANOVA design and our primary interest if to see 
if there is a within subject effect – if the number of MM lesions detected by each technique 
differ.  
If the overall test is significant, post-hoc comparisons between the scores of the three new 
techniques (FDG PET/MRI, C11 PET/CT, C11 PET/MRI) and the standard technique (FDG 
PET/CT) will be carried out with Bonferroni correction for multiple comparison. 
 
Secondary Hypothesis 1: There is no difference in the clarity scoring of the MM lesions among 
the 4 techniques. 
 
The primary interest of Objective 2 is to compare the clarity of the detected MM lesions across 
the 4 techniques. A score demonstrating clarity of the lesion will be assigned to each detected 
lesion with higher score means clearer of the lesion image. One way repeated measure analysis 
of variance will be employed to detect if there is any difference among the average scores of 
detected MM lesion in each technique.  If the overall test is significant, post-hoc comparisons 
between the scores of the three new techniques (FDG PET/MRI, C11 PET/CT, C11 PET/MRI) 
and the standard technique (FDG PET/CT) will be carried out with Bonferroni correction for 
multiple comparison.  
 
Explore Objectives:   
Explore which are the risk factors for having more MM lesions: CMP (Comprehensive 
Metabolic Panel) Glucose, Calcium, Proteins, Albumin, Total Protein, Sodium, Potassium, CO2 
(carbon dioxide, bicarbonate), Chloride, BUN (blood urea nitrogen), Creatinine, ALP (alkaline 
phosphatase), ALT (alanine amino transferase), AST (aspartate amino transferase), Bilirubin; 

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SPEP (Serum Protein Electrophoresis). Immunoglobulins, Serum Free light chains; Bone 
marrow biopsy % and beta-2-microglobulin level (if obtained). Linear regression model with 
correlated data (the MM lesions detected by each technique) will be utilized to investigate the 
association between the potential risk factors and the number of MM lesions detected for each 
patient. 
 
Handling of Missing Data 
Since our sample size is 10, and they will get their imaging done in two days, we don’t anticipate 
any missing data.  
 
Multiplicity 
We only have one primary outcome for our primary research interest.  There will be no concern 
of multiple testing for the overall group testing. But if we see an overall effect and we will do 
post-hoc comparisons of the numbers of detected MM lesions between the three new techniques 
(FDG PET/MRI, C11 PET/CT, C11 PET/MRI) and the standard technique (FDG PET/CT). 
Bonferroni correction for multiple comparison will be used to address multiplicity issue.  
 
Interim Analysis 
There will not be interim analysis for our 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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Adverse Event 
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.  
 
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.  
 
Adverse Event Reporting Period 
The study treatment follow-up period is defined as the end of the day 3 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. 
 
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-
investigator, any subsequent event(s) that the subject, or the subject’s personal physician, 
believes might reasonably be related to participation in this study.  
 
 

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Abnormal Laboratory Values 
All laboratory values associated with this study will be a part of the patients 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. 
 
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 log.  The 
sponsor-investigator will evaluate the event and determine the necessary follow-up and reporting 
required. 
 
 

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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 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. 
 
8.4 
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. 
 
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. 
 
 
 

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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 
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 
CRFs will be organized in a binder, maintained in a locked cabinet in the research coordinator’s 
office. 
 
A dedicated Excel spreadsheet, with track-changes enabled, will be maintained in a secure folder 
discussed above. This spreadsheet will serve as the data aggregation instrument. 
 
 
Data Processing 
The data will be analyzed via the statistical methods outlined in this document. 
 
 
Data Security and Confidentiality 
A study-specific Excel spreadsheet is employed to consolidate and analyze data from the written 
CRFs and printed data from the EMR. It will be a password protected file within a secured folder 
with permissions limited to study staff on the RADPUBLIC server. This constitutes several 
layers of permissions one must pass in order to access the Excel sheet. Patient-specific 
information will only be available on the written CRF. Only the patient number will be entered 
on the spreadsheet. 
 
 

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Data Quality Assurance 
Any data copied over from the written CRFs or the EMR will be double checked by the study 
staff member who does the entering in an ongoing basis during the study. The CRFs and EMR 
lab printouts will be kept in 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. Review of study progress every 2 weeks on a regular basis and 
documentation of this review in study review log, even when there are not irregularities or 
remedial measures which need to be taken. 
10.2 Auditing and Inspecting 
 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, 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 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. 
 
 
 

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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 study will be funded in part by a grant from the Mayo Clinic Clinical Research 
Subcommittee Arizona Opportunity Fund; these funds must be used within the 2016 calendar 
year only. These funds will not carry over into 2017 or beyond. Any additional funds that may be 
needed will be supplied by the Mayo Clinic Arizona Radiology Department. 
 
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. 
Roarke, in conjunction with Co-I. Dr. Fonseca, 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. Hicks RJ1, Kalff V, et al.: Assessment of right ventricular oxidative metabolism by positron 
emission tomography with C-11 acetate in aortic valve disease. Am J Cardiol. 1991 Apr 
1;67(8):753-7. 
 
2. Kalff V1, Hicks RJ, Hutchins G et al.: Use of carbon-11 acetate and dynamic positron 
emission tomography to assess regional myocardial oxygen consumption in patients with acute 
myocardial infarction receiving thrombolysis or coronary angioplasty. Am J Cardiol. 1993 Mar 
1;71(7):529-35. 
 
3. Rubin PJ1, Lee DS, Dávila-Román VG : Superiority of C-11 acetate compared with F-18 
fluorodeoxyglucose in predicting myocardial functional recovery by positron emission 
tomography in patients with acute myocardial infarction. Am J Cardiol. 1996 Dec 
1;78(11):1230-5. 
 
4. Grassi I, Nanni C, Allegri V etal.: 
The clinical use of PET with (11)C-acetate. Am J Nucl Med Mol Imaging. 2012;2(1):33-47. 
Epub 2011 Dec 15. 
 
5. Mohsen B, Giorgio T, Rasoul ZS et al.: Application of C-11-acetate positron-emission 
tomography (PET) imaging in prostate cancer: systematic review and meta-analysis of the 
literature. BJU Int. 2013 Dec;112(8):1062-72. doi: 10.1111/bju.12279. Epub 2013 Aug 13.  
 
6. Chi-Lai Ho, Simon C.H. Yu and David W.C. Yeung : 11C-Acetate PET Imaging in 
Hepatocellular Carcinoma and Other Liver Masses. J Nucl Med February 1, 2003 vol. 44 no. 2 
213-221. 
 
7. Ho CL, Chen S, Leung YL et al.: 11C-acetate PET/CT for metabolic characterization of 
multiple myeloma: a comparative study with 18F-FDG PET/CT. J Nucl Med. 2014 
May;55(5):749-52. doi: 10.2967/jnumed.113.131169. Epub 2014 Mar 27. 
 
8. Ravi Vij, Kathryn J. Fowler, and Monica Shokeen: New Approaches to Molecular Imaging of 
Multiple Myeloma J Nucl Med 2016; 57:1–4. 
 
9. Kamphorst JJ, Chung MK, Fan J, Rabinowitz JD: Quantitative analysis of acetyl-CoA 
production in hypoxic cancer cells reveals substantial contribution from acetate. Cancer Metab. 
2014 Dec 11; 2:23. doi: 10.1186/2049-3002-2-23. 
 
10. Yoshii Y, Furukawa T, Yoshii H, et al: Cytosolic acetyl-CoA synthetase affected tumor cell 
survival under hypoxia: the possible function in tumor acetyl-CoA/acetate metabolism. Cancer 
Sci. 2009 May; 100(5):821-7. 
 
11. Comerford S, Zhiguang Huang, Xinlin Du, et al:  Acetate Dependence of Tumors. Cell 159, 
1591–1602, December 18, 2014.