Conditions: Cardiac Sarcoidosis
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 15
Healthy volunteers: no

Brief summary:
The Researchers are trying to determine if 68Ga-DOTATATE PET/CT imaging will have a similar accuracy as 18FDG PET/CT in diagnosing cardiac sarcoidosis and if it will be able to do so without the need for complex patient dietary preparation that is required with 18FDG PET/CT.

Detailed description:
Prospective study of 15 consecutive patients with suspected or newly diagnosed cardiac sarcoidosis (CS) who are referred for a clinically indicated 18FDG (and 13NH3) PET/CT scan for cardiac sarcoidosis (CS) will be approached to undergo a 68Ga-DOTATATE PET/CT scan. Comparison will then be made between the 68Ga-DOTATATE PET/CT and the 18FDG and 13NH3 PET/CT to determine if 68Ga-DOTATATE detects CS.

Arms:
arm 1: 68Ga-DOTATATE PET/CT scan, 18FDG PET/CT scan and 13NH3 PET/CT scan will be performed on each subject

Interventions: intervention 1: 68Ga-DOTATATE PET/CT intervention 2: 18FDG PET/CT scan intervention 3: 13NH3 PET/CT scan
Intervention descriptions: intervention 1: 5.4 mCi of 68Ga-DOTATATE will be administered by intravenous route. intervention 2: This scan will be performed as part of the planned clinical care for the patient. Dose of 18FDG will be administered intravenously in accordance with the institutional policy and accepted norms. CT attenuation scan will also be performed as part of this examination per institutional protocol. intervention 3: This scan will be performed as part of the planned clinical care for the patient. Dose of 13NH3 will be administered intravenously in accordance with the institutional policy and accepted norms. CT attenuation scan will also be performed as part of this examination per institutional protocol.

Protocol document:
Prot_SAP_000.pdf: 
 
 
68Ga-DOTATATE PET/CT Assessment ofCardiac 
Sarcoidosis 
 
 
NCT03549598 
 
3/22/2018 


 
68Ga-DOTATATE PET/CT Assessment ofCardiac 
Sarcoidosis 
 
 
 
 
 
 
Principal Investigator: 
JohnP. Bois 
Assistant Professor of Medicine 
Mayo Clinic 
Department of Cardiovascular Diseases 
200 First Street SW 
Rochester, MN 55905 
 
 
Co-Investigators 
  
 
 
 
 
 
 
 
 
 
 
 
 
Funding Sponsor: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CV Prospective Grant (FP00095637) 
 
 
Study Product: 
68Ga-DOTATATE 
  
 
 
 
 
 
 
 


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Study Summary 
Title 
 68Ga-DOTATATE PET/CT Assessment of Cardiac Sarcoidosis 
 
Study Design 
Prospective study of 15 consecutive patients with suspected or newly 
diagnosed cardiac sarcoidosis (CS) who are referred for a clinically 
indicated 18FDG (and 13NH3) PET/CT scan for cardiac sarcoidosis (CS) 
will be approached to undergo a 68Ga-DOTATATE PET/CT scan. 
Comparison will then be made between the 68Ga-DOTATATE PET/CT 
and the 18FDG and 13NH3 PET/CT to determine if 68Ga-DOTATATE 
detects CS. 
Study Center(s) 
Mayo Clinic, Rochester MN Campus 
Primary Objective 
To determine if 68Ga-DOTATATE PET/CT will have a similar 
accuracy as 18FDG and 13NH3 PET/CT in diagnosing CS  and if it will 
be able to do so without the need for complex patient dietary 
preparation that is required with 18FDG PET/CT. 
Number of Subjects 
15 consecutive patients 
Main Inclusion 
Criteria and 
Diagnosis  
Primary inclusion criteria are 1) patients over the age of 18 years of 
age who are referred for clinically indicated 18FDG and 13NH3 PET/CT 
for cardiac sarcoidosis (CS) 2) have clinically suspected, or newly 
diagnosed CS 3) are not-pregnant or nursing 4) consent to undergo a 
68Ga-DOTATATE PET/CT scan.  
 
Diagnosis of CS by 68Ga-DOTATATE will be determined by the 
presence or absence of myocardial uptake of 68Ga-DOTATATE using 
similar methodology as previously reported (1,2). 
Study Product, 
Dose, Route, 
Regimen, Duration 
 5.4 mCi of 68Ga-DOTATATE will be administered by intravenous 
route. 60 minutes following administration, a low-dose transmission 
CT thorax scan will be performed for attenuation purposes followed by 
a cardiac PET emission scan obtained in the three-dimensional list 
mode. 
 


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Statistical 
Methodology 
Primary Efficacy Analysis:  
Nominal continuous variables will be represented as the mean +/- SD 
and categorical variables will be noted as the number and percentage of 
total. Pearson chi-square test will be utilized to determine statistical 
significance for continuous variables whereas a Student’s two-sample 
t-test will be implemented to determine statistical significance for 
continuous variables. Univariate and multivariate analyses will be 
performed when relevant. Statistical significance will be set a priori as 
a p-value less than 0.05. Concordance and discordance of 68Ga-
DOTATATE PET/CT with 18FDG and 13NH3 PET/CT for the presence 
or absence of CS will be calculated and utilizing 18FDG and 13NH3 
PET/CT as the “gold-standard” for CS, the sensitivity and specificity 
of 68Ga-DOTATATE for the detection of CS will be determined. All 
statistical analyses will be performed using JMP Pro 9 (SAS Institute 
INC. Cary, North Carolina).  
 
Safety:  
The overall safety profile will be assessed in terms of imaging agent 
related adverse events, and vital signs.  
 


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1 Introduction 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures.  
1.1 
Background/Rationale 
Optimizing our imaging capabilities for patients with CS is critical as it has diagnostic (3), 
prognostic (4) and therapeutic implications (5). However, our current diagnostic techniques have 
several limitations. Detection of CS by endomyocardial biopsy has sensitivity as low as 20% (6). 
Gallium-67 single photon emission tomography (SPECT) scintigraphy and echocardiography 
also have a reported sensitivity of 40% and 25% respectively (7,8). MRI has improved sensitivity 
for detection of CS at 75% (9) but may be problematic in CS patients with an intracardiac device. 
Perhaps more critical is that MRI lacks the ability to help differentiate active from inactive CS, 
which is critical for treatment planning and follow-up. Among the various invasive and 
noninvasive techniques, 18FDG PET/CT has the highest sensitivity for the detection of CS (10) 
but requires specific dietary preparation that is difficult for patients to follow and is not 
completely effective at eliminating physiologic 
18FDG uptake. The latter may lead to 
inconclusive scan results in up to 30% of patients undergoing 18FDG PET/CT imaging for CS 
(11-16). Furthermore, the dietary preparation is particularly challenging for diabetic patients. A 
more ideal PET/CT tracer for CS imaging that would not demonstrate physiologic myocardial 
uptake, and therefore would not require special dietary preparation, would streamline our 
diagnostic practice and thereby benefit our patients. Moreover, such an agent would eliminate 
the need for extra staffing time to discuss dietary procedures with patients and ultimately lead to 
fewer studies needing to be cancelled or repeated due to uncertain results. 68Ga DOTATATE is a 
radiotracer targeted to somatostatin receptors which has been recently FDA and CMS approved 
to image neuroendocrine tumors (17). However, 68Ga-DOTATATE may also be utilized off-label 
to image activated inflammatory cells, including macrophages and multinucleated giant cells that 
accumulate in granulomatous inflammation such as in sites of CS.  When activated, these cells 
express somatostatin receptors in high abundance. Ga-DOTATATE binds to these receptors, and 
therefore labels sites of active CS which can be then detected on a PET/CT scanner (18). 68Ga-
DOTATATE, however, is not taken up in normal myocardial tissues (2). Therefore, unlike 
18FDG, CS imaging with 
68Ga-DOTATATE may obviate the need for complex patient 
preparation protocols and consequently may limit the incidence of uninterpretable scans, 
improve patient satisfaction and potentially improve diagnostic accuracy. 
 
 
1.2 
Radioisotope 
1.2.1 
68Ga-DOTATATE (information 1.2.1.1-1.2.1.3 provided by the Food and Drug Administration 
(FDA) (https://www.accessdata.fda.gov/drugsatfda). 
 
 


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1.2.1.1 Description 
“Dotatate, also known as DOTA-0-Tyr3-Octreotate, is a cyclic 8 amino acid peptide with a 
covalently bound chelator (dota). The peptide has the amino acid sequence: H-D-Phe-Cys-Tyr-
D-Trp-Lys-ThrCys-Thr-OH, and contains one disulfide bond. Dotatate has a molecular weight of 
1435.6 Daltons.” Figure from FDA.gov. 
 
 
1.2.1.2 Mechanism of Action 
“Ga 68 dotatate binds to somatostatin receptors, with highest affinity for subtype 2 receptors 
(sstr2). It binds to cells that express somatostatin receptors including malignant cells, which 
overexpress sstr2 receptors. Gallium 68 (
68
Ga) is a β+ emitting radionuclide with an emission 
yield that allows positron emission tomography (PET) imaging.” 
 
1.2.1.3 Pharmacokinetics 
“Distribution Ga 68 dotatate distributes to all sstr2-expressing organs such as pituitary, thyroid, 
spleen, adrenals, kidney, pancreas, prostate, liver, and salivary glands. There is no uptake in the 
cerebral cortex or in the heart, and usually thymus and lung uptakes are low.  
Elimination A total of 12% of the injected dose is excreted in urine in the first four hours post-
injection.” 
 


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1.2.1.4 Dose 
5.4 mCi of 68Ga-DOTATAE will be administered. 
1.2.1.5 Cardiac Experience 
There are three critical components to support feasibility of the proposed project: 1) Clinically 
indicated 18FDG PET/CT (performed with 13NH3 PET/CT as the standard of care) is already 
being performed at Mayo Clinic Rochester routinely with an average 4-5 studies per week and 
preliminary data have been presented at national meetings based upon these studies, (19) (20) 2) 
The use of 68Ga-DOTATATE to image CS is predicated upon sound scientific reasoning, and 3) 
There are initial reports that 68Ga-DOTATATE may in fact be able to image CS. 
  
1) 18FDG PET/CT can detect CS but is imperfect: PET/CT/ has proven to 
have the highest diagnostic accuracy for the detection of CS (10) with a 
reported sensitivity of 89% (10) and specificity as high as 97% (21). 
However, these results are predicated upon sufficient dietary preparation. 
Unfortunately, dietary preparation is often inadequate (11). Indeed, in our 
own MCR patient population, one-fifth of patients had suboptimal dietary 
preparation which ultimately compromised image quality and test 
accuracy (19). As a result, multiple efforts have been undertaken to 
enhance dietary preparation for 18FDG PET/CT CS imaging (12-15). 
Despite these ongoing efforts, there remains no uniform means for dietary 
preparation. Furthermore, these preparation procedures are onerous and 
include strict fasting, specific diet adherence and potentially the use of 
heparin. This is likely the reason for poor compliance with dietary 
preparations (16). It also requires extra nuclear laboratory personnel time 
to contact patients and instruct them regarding the dietary procedures. For 
patients with diabetes mellitus, additional coordination must be made with 
the Department of Endocrinology. Given these issues, further efforts are 
warranted to identify another means by which to accurately image patients 
with known or suspected CS. 
 
FDG PET/CT for detecting CS also requires the concomitant use of 
myocardial perfusion PET/CT or SPECT imaging as the standard of care 
(cite SNMMI/ASNC expert consensus document), given the issues of 
physiologic FDG uptake and nonspecific findings and the potential for 
scar detection. This is associated with increased costs, greater cyclotron (if 
and 13NH3 ammonia is used) and labs efforts, more patient time, and 
additional radiation exposure. A single scan with a single tracer has the 
potential to reduce effort and costs and increase patient satisfaction. 
  
18FDG PET/CT in CS Feasibility at Mayo Clinic: The multidisciplinary 
team we have assembled at Mayo Clinic has developed expertise in 
diagnosis and care of the CS population (12,13,19,20,22-26). Furthermore, 
we have one of the largest, if not largest CS practice in the nation with 
approximately 4-5 patients undergoing 18FDG PET/CT per week. This has 
allowed our technicians and nursing staff along with our physicians to 


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create a streamlined practice in performing cardiac imaging in this patient 
population. As a result our physician team members are lead authors on 
national guidelines (24) and our technicians are conducting national talks 
to educate other imaging staff on optimizing 18FDG PET/CT in CS (19). 
  
2)     The use of 68Ga-DOTATATE is predicated upon sound scientific 
reasoning: 
68Ga-DOTATATE is a somatostatin receptor targeted 
radiotracer traditionally used to image neuroendocrine tumors (17). 
However, 68Ga-DOTATATE may also be utilized to image inflammatory 
cells typically seen in CS, including macrophages and multinucleated 
giant cells, because these cells express somatostatin receptors (18). 68Ga-
DOTATATE, however, is not taken up in normal myocardial tissue (2). 
Therefore, unlike 18FDG, CS imaging with 68Ga-DOTATATE may 
obviate the need for complex patient preparation protocols and 
consequently may limit the number of uninterpretable scans, improve 
patient satisfaction and potentially improve diagnostic accuracy. 
  
3)     Initial reports of 68Ga-DOTATATE for CS: There are two studies of 
which the investigators are aware that examine the feasibility of 
somatostatin receptor ligands, such as 68Ga-DOTATATE, to image CS. 
The initial study compared PET/CT imaging with a radiolabeled 
somatostatin receptor ligand to cardiac magnetic resonance imaging 
(CMR) for detection of CS (1). This study demonstrated a 96.1% 
concordance rate between the two imaging modalities and concluded that 
the use of a somatostatin receptor ligand to detect CS was feasible. The 
second investigation imaged 19 patients with suspected CS with both 
18FDG PET/CT and 68Ga-DOTATATE (2). The authors demonstrated that 
68Ga-DOTATATE outperformed 18FDG PET/CT with a100% accuracy for 
the detection of CS and a 100% inter-observer agreement in regards to the 
68Ga-DOTATATE results. Both of these studies offer evidence that 68Ga-
DOTATATE will be a promising agent for the detection of CS. 
  
68Ga-DOTATATE Feasibility at Mayo Clinic: Mayo Clinic is a leader in 
68Ga-DOTATATE production and imaging having already imaged over 
400 oncologic patients since October 2016. Furthermore, Mayo Clinic has 
proven expertise in the production of 68Ga-DOTATATE with patents 
currently pending. Finally, members of the current grant application team 
(GJ and AK) are nationally recognized in the developing field of 68Ga-
DOTATATE imaging (27). 
 
2 Study Objectives 
To determine if 68Ga-DOTATATE PET/CT imaging will have a similar accuracy as 18FDG 
PET/CT with 13NH3 in diagnosing CS and if it will be able to do so without the need for complex 
patient dietary preparation that is required with 18FDG PET/CT. 


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3 Study Design 
The proposed investigation is a feasibility study designed to assess the efficacy of 68Ga-
DOTATATE PET/CT imaging in the CS population.  We propose imaging 15 consecutive 
patients initially (with an intention to do a larger study) with the standard of care approach 
of both 18FDG and 13NH3 PET/CT and a research 68Ga-DOTATATE PET/CT. The study 
group will include adult patients who undergo assessment in Mayo Clinic’s CS clinic and 
have suspected or newly diagnosed CS based upon clinical evaluation. A typical proposed 
timeline of events for each patient processed through the study is as follows (note exact 
timeline may vary based on patient appointment schedule): 
1)     Up to 4-6 weeks prior to visit: Patient charts will be reviewed prior to their initial 
appointment in the CS clinic. After review, the physician head of the CS clinic (LB) will 
refer candidates that have clinically suspected (7), or newly diagnosed CS and who will be 
referred for a clinically indicated 18FDG and 13NH3 PET/CT to the primary investigator 
(JB). JB or other designated staff will contact the potential study candidates via phone or 
email (using a phone/email script) to determine their potential interest in the study. If the 
patient expresses an interest in the study, a consent form will be sent in advance for their 
review. Patients may consent remotely if they choose or can also be consented in-person.  
Potential study subjects will also be notified that they will be contacted during their visit for 
participation in the study. 
2)     Day 1: During their 18FDG and 13NH3 PET/CT assessment, potential study candidates 
who have not been consented will be approached by the study coordinator to inquire about 
their participation in the study. If the patient meets all criteria and agrees to participate in 
the study, then written consent will be obtained at that time. 
4)     Day 2 or 3  (1-2 days after 18FDG and 13NH3 PET/CT): Those study candidates who 
consent to the investigation will then undergo the study 68Ga-DOTATATE PET/CT scan. 
The patient will be provided with a brief survey at the end of their imaging session which 
will be conducted by the study coordinator to assess which protocol (if either) they 
preferred from a patient experience. Note patients will be allowed to complete the 68Ga-
DOTATATE PET/CT study within a month of the 18FDG and 13NH3 PET/CT exam as long 
as no intervening immunomodulatory therapy has been administered. 
5)     Chart and imaging review will be conducted for each of the 15 patients in the study 
for purposes of drafting the study manuscript.  
  
Phone 
Introduction 
Image Visit #1 
18FDG and 
13NH3  
PET/CT 
Imaging 
Image Visit #2 
68Ga-DOTATATE 
PET/CT Imaging 
Phone Introduction 
X 
  
  
Clinically Indicated 18FDG 
and 13NH3  PET/CT 
  
X 
  


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3.1 
Study Endpoints 
 
1. Assess utilizing both qualitative and quantitative methods the myocardial 68Ga-
DOTATATE uptake in patients with and without active CS as determined by 18FDG and 
13NH3 PET/CT. 
2. Determine the concordance and discordance of 68Ga-DOTATATE with 18FDG and 13NH3 
PET/CT for the presence or absence of CS utilizing 18FDG and 13NH3 PET/CT as the 
“gold-standard” for CS. Determine the sensitivity and specificity of 68Ga-DOTATATE 
for the detection of CS will be determined. 
3. Calculate physician confidence in study interpretation for both 68Ga-DOTATATE and 
18FDG and 13NH3 PET/CT. 
4. Compare patient satisfaction between the 18FDG and 13NH3 PET/CT and 68Ga-
DOTATATE protocols. 
5. Utilize information obtained from the current pilot as a foundation to pursue potentially 
larger trials. 
 
4 Subject Selection and Withdrawal 
4.1 
Inclusion Criteria 
1) 18 years of age or older 
2) Referred for and undergo clinically indicated 18FDG PET/CT scan for CS 
3) Have clinically suspected, or newly diagnosed CS 
4) Are able to complete both the clinically indicated 18FDG and 13NH3 PET/CT and the 
68Ga-DOTATATE scan and do so within one month of each other without the 
introduction of CS directed therapy between the scans 
4.2 
Exclusion Criteria 
1) Pregnant or nursing 
2) Unable or unwilling to give consent for 68Ga-DOTATATE PET/CT scan 
3) Are on an active immunosuppressive/immunomodulatory therapy 
 
Research 
68Ga-
DOTATATE PET/CT 
  
  
X 


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4.3 
Early Withdrawal of Subjects 
4.3.1 
When and How to Withdraw Subjects 
The criteria for enrollment must be followed explicitly. If a subject who does not meet 
enrollment criteria is inadvertently enrolled, that subject should be discontinued from the study.  
A subject may voluntarily discontinue participation in this study at any time.  The investigator 
may also, at his or her discretion, discontinue the subject from participating in this study at any 
time.  If a subject is prematurely discontinued from participation in the study for any reason, at 
any time, at either the investigator’s discretion or the subject’s request, an effort must be made to 
document the reason(s) why a subject fails to return to the study clinic for necessary visits or is 
discontinued from the study.  The primary reason for discontinuing participation in the study 
must be stated and may include, but is not limited to, one of the following: 
 
 Occurrence of intolerable adverse events 
 Withdrawal of consent for imaging by patient 
 Noncompliance with protocol, e.g., the patient fails to appear at one or more imaging 
procedures 
 Development of an intercurrent illness, injury, or medical condition likely to interfere with 
subject safety, the overall assessment, or the required administration of study medication 
 Pregnancy 
 Development of any condition for which the investigator feels treatment withdrawal is 
justified 
 Termination of the study  
Subjects withdrawn from the study will not be replaced, regardless of the reason for withdrawal. 
An effort must be made to determine why a subject fails to return for the necessary visits or is 
dropped from the study.  
 
5 Study Procedures 
5.1 
Informed Consent 
The investigator will provide for the protection of the subjects by following all applicable 
regulations. The IRB must review the informed consent form used during the informed consent 
process. 
Before any procedures specified in this protocol are performed, a subject must: 
 Be informed of all pertinent aspects of the study and all elements of informed consent.  
 Be given time to ask questions and time to consider the decision to participate. 
 Voluntarily agree to participate in the study.  
 Sign and date an IRB/IEC-approved informed consent form. 
 


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(If a procedure is done routinely as standard of care, then it is not study-specific, and it may be 
done before the consent is signed.) 
 
6 Methods  
 
6.1 
PET/CT Imaging  
6.1.1 
PET/CT Imaging Protocol 
A GE Discovery 690XT, Discovery Molecular Insights (DMI) or 710 PET/CT system (GE 
Healthcare, Waukesha, WI) will be utilized in performing the studies. The imaging system 
consists of full ring Cerium-doped Lutetium Yttrium Orthosilicate (LYSO) crystals. 128x128 
PET matrix size with zoomed 41.9 cm field of view centered over the heart will be used to obtain 
the PET images. Furthermore, three-dimensional list mode acquisition will be employed. Three-
dimensional iterative reconstruction algorithm with time-of-flight correction, CT attenuation, 
scatter, randoms, normalization, decay and dead time correction will be utilized. Three-
dimensional Hanning post-filter with a 10 mm cut-off will also be used.  
 
A 64 slice-spiral CT will be employed with auto exposure control with modulated current in 
order to maintain consistent noise index (noise index set at 33 with mA range 10-180). For our 
CT attenuation imaging tube ration is 0.5 s, kV is 120 and pitch is 0.98. Slice thickness is 3.75 
mm and slice increment is 3.27 mm. Matrix size is 512 x 21. 
 
As per all of our clinical 18FDG PET/CT CS studies 13NH3 will be administered to optimize 
diagnostic accuracy for CS. This same perfusion map will be used for the 68Ga-DOTATAE 
imaging portion (no additional ammonia N-13 will be given for the 68Ga-DOTATATE study). 
6.1.2 
Analysis of PET data 
 
Once the cardiac PET/CT images are obtained they will be assessed for the presence of CS 
utilizing similar methodologies which were previously published (1,2,24).  
 
Qualitative assessment of 18FDG and 13NH3 PET/CT and 68Ga-DOTATATE for each study 
subject will be made by two different study investigators (JB and AK) who will be blinded to the 
patient clinical history, laboratory data and any other imaging assessment (including the 
corresponding CS study-i.e. when reading the 68Ga-DOTATATE study investigators will be 
blinded to the 18FDG results and vice versa) at the time of interpretation. For both 18FDG and 
68Ga-DOTATATE cardiac uptake study investigators will classify the patient into one of four 
categories of radionuclide uptake: none, diffuse, focal, and focal on diffuse or diffuse. The 
portions of the myocardium that demonstrate uptake will be documented in accordance with the 
17 segment American Heart Association model (28). In concordance with national 
guidelines(24), 18FDG and 68Ga-DOTATATE examinations will be interpreted simultaneously 
with 13NH3 to allow for assessment of myocardial perfusion.  Both 18FDG and 68Ga-DOTATATE 
studies will then be labeled as positive for CS, negative for CS or inconclusive.  
 
Any discordance between the findings of the two investigators in regards to the presence or 
absence of CS as well as the extent will be reviewed by additional investigators (GJ or PC) and 
final determination in regards to classification of the patient will be made.  


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Semiquantitative determination of radionuclide uptake will be determined by using commercially 
available software to calculate maximum standard uptake value (SUVmax) of 18FDG and 68Ga-
DOTATATE in the heart. This data will be correlated with patient clinical data obtained from the 
medical record. 
 
The two study investigators (JB and AK) who are reviewing all studies will rank their confidence 
level for interpretation for each scan on a 5 point scale (1=least confident, 5= most confident).  
Results will then be compared between the two study modalities. 
 
After completion of both their 18FDG and 13NH3
 and 68Ga-DOTATATE studies, a study 
coordinator will administer a patient survey regarding their experience with each protocol which 
will consist three questions. The first two question will ask the patient to rate the ease of 
undergoing each study on a 5 point scale (1=easiest, 5=hardest). The third question will ask the 
patient which study they preferred (18FDG, 68Ga-DOTATATE or equal) with a comment section 
for why. 
 
7 Statistical Plan 
General Considerations 
Continuous data (e.g., age) will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, SD, median, minimum value (min), and maximum 
value (max). For each continuous variable, the corresponding mean, median, minimum and 
maximum will be presented to 1 decimal place and the SD to 2 decimal places, unless otherwise 
specified.  
Categorical variables (e.g., qualitative presence of absence of 68Ga-DOTATATE) will be 
summarized using counts and percentages. Percentages will be presented to 1 decimal place. 
Summaries of continuous and categorical data will be presented, as appropriate. 
Incomplete/Missing data: Missing data (e.g., dates, post-baseline values) will not be imputed, 
unless otherwise specified; i.e., all missing values and missing post-baseline values will remain 
as missing in all statistical analyses and listings, unless otherwise specified. 
Outliers: No formal statistical analyses will be performed to detect and/or remedy the presence 
of statistical outliers. 
Additionally, all subject data, including derived variables, will be presented in subject data 
listings; listings will display all subjects who were randomized or enrolled in the study.   
7.1.1 
Background Characteristics  
7.1.1.1 Demographics and Baseline Characteristics 
Demographics and baseline characteristics (age, sex, race, ethnicity, weight, height and body 
mass index [BMI]) will be summarized.  
7.1.2 
 Efficacy Analysis 
7.1.2.1 Analysis of Primary Efficacy Endpoint 
Nominal continuous variables will be represented as the mean +/- SD and categorical variables 
will be noted as the number and percentage of total. Pearson chi-square test will be utilized to 
determine statistical significance for continuous variables whereas a Student’s two-sample t-test 
will be implemented to determine statistical significance for continuous variables. Univariate and 


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multivariate analyses will be performed when relevant. Statistical significance will be set a priori 
as a p-value less than 0.05. Concordance and discordance of 68Ga-DOTATATE with 18FDG and 
13NH3 PET/CT for the presence or absence of CS will be calculated and utilizing 18FDG PET/CT 
as the “gold-standard” for CS, the sensitivity and specificity of 68Ga-DOTATATE for the 
detection of CS will be determined. Given that this is a pilot study no power calculation will be 
performed. All statistical analyses will be performed using JMP Pro 9 (SAS Institute INC. Cary, 
North Carolina).  
 
8 Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency (i.e. not described in study-related documents 
such as the IRB-approved protocol or consent form, the investigators brochure, etc.) 
 Related or possibly related to participation in the research (i.e. possibly related means 
there is a reasonable possibility that the incident experience, or outcome may have been 
caused by the procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including 
physical, psychological, economic, or social harm). 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study. Abnormal results of diagnostic procedures are considered 
to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
In the following differentiation between medical history and AEs (see below), the term 
“condition” may include abnormal physical examination findings, symptoms, or diseases. 
 Conditions that started before signing of informed consent and for which no symptoms or 
treatment are present until signing of informed consent are recorded as medical history 
(e.g. seasonal allergy without acute complaints). 
 Conditions that started before signing of informed consent and for which symptoms or 
treatment are present after signing of informed consent, at unchanged intensity, are 
recorded as medical history. 
 Conditions that pertain to efficacy variables of this study, i.e. findings on PET and which 
are considered pre-existing medical conditions, are not considered AEs unless there is 
worsening. This also implies that the indication for the imaging procedure and the 
confirmation of a diagnosis will not be considered as an AE. 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that 
is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 


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 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
 
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 period during which adverse events will be reported is defined as 24 hours post 
injection of the radiotracer.   
 
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 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 investigator should instruct each subject to report any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to 
participation in this study.  The investigator should notify the study sponsor of any death or 
adverse event occurring at any time after a subject has discontinued or terminated study 
participation that may reasonably be related to this study.  The sponsor should also be notified if 
the investigator should become aware of the development of cancer or of a congenital anomaly 
in a subsequently conceived offspring of a subject that has participated in this study.  
 
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 and 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 required to allow efficacy measurement for 
the study. 
 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. 


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8.2 
Recording of Adverse Events 
At each contact with the subject, the investigator 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 module of the case report form (CRF).  All clearly related signs, symptoms, and abnormal 
diagnostic procedures results should recorded in the source document, though should be grouped 
under one diagnosis. 
 
All adverse events occurring during the imaging AE reporting period must be recorded.  The 
clinical course of each event should be followed until resolution, stabilization, or until it has been 
determined that the study treatment or participation is not the 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 after the study period and is considered to be 
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 
Investigators must conform to the adverse event reporting timelines, formats and requirements of 
the various entities to which they are responsible, but at a minimum those events that must be 
reported are those that are: 
 related to study participation, 
 unexpected, and  
 serious or involve risks to subjects or others  
(see definitions, section 8.1).   
 
If the report is supplied as a narrative, the minimum necessary information to be provided at the 
time of the initial report includes: 
 Study identifier 
 Subject number 
 A description of the event 
 Date of onset 
 Current status 
 Whether study was discontinued 
 The reason why the event is classified as 
serious.  
 
8.3.1 
Investigator reporting: notifying the Mayo Clinic IRB 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the 
Mayo Clinic IRB as a written report of the event (including a description of the event with 
information regarding its fulfillment of the above criteria, follow-up/resolution and need for 
revision to consent form and/or other study documentation). 
 
8.4 
Safety Monitoring 
Subject safety will be monitored continuously by the Investigators. This safety monitoring will 
include careful assessment and appropriate reporting of adverse events and a regular assessment 
of the number and type of serious adverse events. 
 


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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.   
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. 
 
Source documents for the imaging protocol will be kept in a secure location by the principal 
investigator (Dr. Bois) or his designee.  
9.3 
Data Management Plan 
We will create a database to store patient data. This database will be programmed in REDCap 
(Research Electronic Data Capture). REDCap is a secure, web-based application with the 
capacity for direct export to Excel and common statistical packages (SPSS, SAS, Strata, R). 
REDCap has electronic CRF (eCRF)s, real-time data entry validation, audit trails, user 
authentication, data logging and encryption. It is HIPAA compliant with mechanisms in place to 
ensure confidentiality. In addition, logical data checks will be used to assess data quality for mis-
entry. Suspect data entries will be flagged for re-review and confirmation by the investigative 
team. When data are complete and all suspect entries addressed for a time period, the database 
will be “locked” for analysis. Analysis will use only this final locked version. 
 
9.4 
Data Sharing Plan 
Clinical data will be exported from REDCap into proper statistical software format for analysis. 
The final dataset will be provided in proper format to investigators participating in data analysis. 
The mode of data sharing will be by downloading from REDCap from secure accounts. Data will 
be secured by electronic safeguards.   
 
10 Ethical Considerations 
This study is to be conducted accordance with applicable US government regulations and 
international standards of Good Clinical Practice, and applicable institutional research policies 
and procedures. 


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This protocol and any amendments will be submitted to Mayo Clinic Internal Review Board 
(IRB), in agreement with local legal prescriptions, for formal approval of the study conduct.  
 
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 IRB-approved consent form, must be 
obtained before that subject undergoes any study procedure. The consent form must be signed by 
the subject or legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent.  
11 Study Finances 
11.1 Funding Source 
CV Prospective Grant (FP00095637) 
 
11.2 Conflict of Interest 
The primary investigator and other study investigators have no relevant conflicts of interest. 
 
 
12 References 
 
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