Clinical trial NCT03103490
Conditions: Cardiac Sarcoidosis Myocardial Inflammation
Keywords: PET/MR
Sponsor: Stanford University
Start date: 2017-08-02; Completion date: 2021-09-28
Enrollment: 45 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The investigators will evaluate the detection of cardiac sarcoidosis or inflammation using 18F-FSPG PET/MRI (or PET/CT for participants with metal implants).

Detailed description:
PET/MRI scans will be performed with a whole-body PET/MR imaging system capable of simultaneous PET and MR imaging (SIGNA, GE Healthcare, Milwaukee, WI). Approximately 45-60 minutes after IV injection of 8 mCi of 18F-FSPG, PET emission scanning and MRI acquisition T1 weighted scanning will begin imaging both whole body and the heart.

Arms: arm 1: Patients receive 18F-FSPG for detection of Cardiac Sarcoidosis or Inflammation
Interventions: intervention 1: 18F-FSPG
Intervention descriptions: intervention 1: Patients receive 8mCi of 18F-FSPG and undergo PET/MRI imaging (or PET/CT for patients with metal implants) to determine the ability of 18F-FSPG to localize to cardiac sarcoidosis or myocardial inflammation.

Protocol documents:
Prot_000.pdf: 
IRB-40376 v.3.0 
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18F-FSPG PET/MRI or PET/CT Imaging of Cardiac Sarcoidosis or Inflammation 
Protocol Director  
Andrei Iagaru, MD 
300 Pasteur Drive
 
Stanford, CA 94305 
Phone:  650-725-4711 
Fax:  650-498-5047 
Email:  aiagaru@stanford.edu  
 
Co-Investigators  
Carina Mari, MD 
300 Pasteur Drive
 
Phone:  650-725-4711 
Fax:  650-498-5047 
Email:  drmari@stanford.edu  
Guido Davidzon, MD  
300 Pasteur Drive
 
Stanford, CA 94305 
Phone:  650-725-4711 
Email:  gdavidzon@stanford.edu  
Ronald Witteles, MD  
300 Pasteur Drive
 
Phone:  650-498-4343 
Fax: 650-725-1599 
Email:  witteles@stanford.edu  
Biostatistician  
Andrei Iagaru, MD 
300 Pasteur Drive
 
Stanford, CA 94305 
Phone:  650-725-4711 
Fax:  650-498-5047 
Email:  aiagaru@stanford.edu  
Study Coordinator 
, DPT or designate 
300 Pasteur Drive, Stanford, CA 94305 
Phone: 
 
Fax: 
 
Email: 
 
 
Protocol IRB-40376  //  NCT03103490 
Protocol version 3  //  18 MAR2020 
 


IRB-40376 v.3.0 
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Table of Contents 
1.OBJECTIVES ................................................................................................................. 6 
2.BACKGROUND ............................................................................................................. 6 
2.1.Study Disease ............................................................................................................ 6 
2.2.Study Agent/Device/Imaging procedure ................................................................ 7 
2.3.Clinicaltrials.gov ........................................................................................................ 8 
    3. Participant population 
3.1.Inclusion Criteria ....................................................................................................... 8 
3.2.Exclusion Criteria ...................................................................................................... 9 
    4.STUDY PROCEDURE: ....................................................................................... 9 
     5. ADVERSE EVENTS AND REPORTING PROCEDURE 
6.REGULATORY CONSIDERATIONS .......................................................................... 10 
6.1.Data and Safety Monitoring Plan .......................................................................... 10 
6.2.Confidentiality .......................................................................................................... 10 
7.MEASUREMENTS ....................................................................................................... 10 
7.1.Primary and Secondary Outcome measures ...................................................... 10 
7.2.Measurement Methods ........................................................................................... 10 
7.3.Measurement Time Points ..................................................................................... 10 
7.4.Response Review .................................................................................................... 10 
7.5.Secondary Outcome ............................................................................................... 10 
8.STATISTICAL CONSIDERATIONS ........................................................................... 10 
8.1.Statistical Design .................................................................................................... 10 
8.2.Randomization ......................................................................................................... 10 
8.3.Interim analyses ...................................................................................................... 10 
8.4.Descriptive Statistics and Exploratory Data Analysis ....................................... 10 
8.5.Primary Analysis ..................................................................................................... 10 
8.6.Secondary Analysis ................................................................................................ 10 
8.7.Sample Size .............................................................................................................. 10 
8.8.Accrual estimates .................................................................................................... 10 
8.9.Criteria for future studies ....................................................................................... 10 
9.REFERENCES ............................................................................................................. 12 
 
 


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TITLE 
18F-FSPG PET/MRI or PET/CT 
Imaging of Cardiac Sarcoidosis or 
Inflammation 
STUDY PHASE 
2 
INDICATION 
Suspected cardiac sarcoid 
INVESTIGATIONAL PRODUCT OR 
PROCEDURE 
18F-FSPG 
PRIMARY OBJECTIVE(S) 
To evaluate if 18F-FSPG PET/MRI or 
PET/CT will identify cardiac sarcoid 
SAMPLE SIZE  
20 
GOALS 
To allow the referring physicians in 
the cardiology group to provide their 
patients a specific molecular imaging 
test for sarcoidosis. 
 
To improve the PET/MRI or PET/CT 
protocol. 


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SCHEMA 
 
 
 
 
 
 
 
 
 
 
Eligible participant with known or suspected cardiac sarcoid 
18F-FSPG PET/MRI or PET/CT 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
F-18 
Fluorine-18 
IRB 
Institutional Review Board 
IV 
Intravenous 
PET/MRI 
Positron emission tomography – magnetic resonance imaging 
SUV 
Standardized Uptake Value 
FSPG 
(4S)-4-(3-18F-Fluoropropyl)-L-Glutamate 


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1. OBJECTIVE 
We hypothesize that increased 18F-FSPG uptake will be detected in cardiac sarcoid or 
inflammation using PET/MRI or PET/CT.  
2. BACKGROUND 
  
2.1. Study Disease 
Sarcoidosis is a multisystem granulomatous disorder of unknown etiology, which can result in 
myocardial inflammation [1]. Myocardial inflammation can also result from other causes 
including myocarditis. Identifying cardiac involvement in the setting of sarcoidosis or myocarditis 
remains challenging. Approximately 5% of patients with sarcoidosis have clinically apparent 
cardiac involvement, yet autopsy series indicate that cardiac involvement is present in up to 
25% of cases [1]. The diagnostic yield of endomyocardial biopsy is reported at less than 20% 
[2].  
Previous studies have demonstrated high diagnostic accuracy of both cardiac magnetic 
resonance imaging (MRI) [3-5] and 18F-labelled fluoro-2-deoxyglucose (FDG) positron emission 
tomography (PET) [6, 7] for detection of cardiac sarcoidosis and myocardial inflammation. To 
date, simultaneous PET/MRI evaluation of cardiac sarcoidosis has only been described in 
limited case reports [8]. Despite relative success, patient compliance is affected by the need for 
12 hours low-carb diet prior to the scan [9]. Therefore, other radiopharmaceuticals should be 
investigated.  
System xC- is composed of xCT and 4F2hc, mediating cellular cystine uptake for glutathione 
synthesis to protect cells from oxidative stress [10]. System xC- may play a role in the innate 
and adaptive immune system. Upregulation of system xC- expression was observed in activated 
macrophages and granulocytes [11]. Induction of system xC-may be an autoprotective 
mechanism from the high levels of released reactive oxygen species. Activation of 
T-lymphocytes has been reported to involve expression of system xC- in antigen-presenting 
cells [12]. Upregulation of xCT occurs during activation and differentiation of B lymphocyte. On 
the other hand, very low or no expression of xCT was detected in peripheral leukocytes, 
thymus, spleen, and lymph nodes in humans [13]. These results suggest that system xC-is a 
key player in the active phase of inflammation. 
(4S)-4-(3-18F-Fluoropropyl)-L-Glutamate (18F FSPG) is a L-glutamate derivative that is 
specifically taken up by system xC- as previously demonstrated in tumor models and cancer 
patients [14, 15]. 18F FSPG has also demonstrated increased uptake in inflammation and 
infection [16]. PET imaging with 18F FSPG does not require a diet or special preparation prior to 
the scan; hence, we expect increased patient compliance when compared to 18F FDG in the 
evaluation of cardiac sarcoidosis or inflammation. 


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Figure 1.  53 year old man with sarcoidosis: 18F-FDG (A) and 18F-FSPG (B) present similar 
major uptake involving pleura, supraclavicular lymph nodes, and thoracic lymph nodes. Sun 
Young Chae et al. J Nucl Med 2016;57:67-69. 
2.2. Study Agent/Device/Imaging procedure 
18F-FSPG PET/MRI or PET/CT Imaging of Cardiac Sarcoidosis or Inflammation 
Methods: Here we will evaluate the detection of cardiac sarcoidosis or inflammation using 
18F-FSPG PET/MRI or PET/CT.  PET/CT will be used for patients with metal implants who are 
not eligible for MRI due to safety reasons.  We will recruit patients from Division of Cardiology 
(Sarcoidosis Clinic) at Stanford University.  We plan to recruit a total of 50 patients over 4 years 
who have suspected cardiac sarcoidosis or inflammation, after receiving 18F FDG PET/CT as 
standard of care.  Potential subjects will undergo preliminary evaluation to ensure eligibility, 
receive and sign an informed consent and be enrolled in the trial. 
PET/MRI scans will be performed with a whole-body PET/MR imaging system capable of 
simultaneous PET and MR imaging (SIGNA, GE Healthcare, Milwaukee, WI), 45-60 minutes 
after injection of (+/-20%) 8 mCi of 18F-FSPG.  The system consists of a 3T MR imager that 
contains a PET detector based on lutetium oxyorthosilicate scintillators coupled to silicon 
photomultiplier detector (SiPM) technology. PET events will be detected throughout the entire 
cardiac MRI acquisition in one bed position centered over the heart. A coronal T1-weighted 3D 
encoded spoiled gradient-echo sequence will be acquired for attenuation correction. 
Cardiac MRI sequences will include breath-hold, ECG-triggered balanced cine SSFP for 
assessment of ventricular size and function by a stack of short axis slices (slice thickness 8 mm, 
TR 3.0 ms, TE 1.5 ms, flip angle 50°, temporal resolution 35 ms; in-plane resolution 1.7×1.4 
mm), and two-dimensional (2D) turbo inversion-recovery magnitude T2-weighted imaging in 
short axis for assessment of myocardial inflammation and edema (slice thickness 8 mm, TR 
2000 ms, TE 44 ms, flip angle 180°, inversion time 180 ms, in-plane resolution 1.3×1.4 mm). 
Late gadolinium enhanced (LGE) imaging will be performed 15 minutes following administration 


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of 0.15 mmol/kg bodyweight of MultiHance (Bracco Diagnostics Inc, Monroe Township, NJ) 
employing a 2D inversion recovery gradient-recalled echo sequence (IR GRE) in short-axis 
(slice thickness 8 mm, TR 6.5 ms, TE 1.5 ms; flip angle 20°; inversion times 220-360 ms; 
in-plane resolution 1.8×1.4 mm). Two-, three- and four-chamber LGE planes will also be 
obtained. 
PET/CT will be performed using Discovery MI PET/CT scanner (GE Healthcare). In brief, 
PET/CT images will be acquired in 3D mode approximately 45-60 minutes after injection of 18F 
FSPG. First, a vertex to mid-thighs scan is done, followed by dedicated imaging of the heart 
over 1 bed. ToF is standard on the digital PET/CT system. Data driven gating will be acquired 
according to the vendor’s protocol (once commercially available). The PET emission scan is 
corrected using segmented attenuation data of the CT scan. The PET images are reconstructed 
both with a standard iterative algorithm (OSEM, two iterative steps, 28 subsets), as well as a 
regularized reconstruction algorithm (Q.Clear®) provided by GE Healthcare.  
Interpretation of Results: All images are reformatted into axial, coronal, and sagittal views and 
viewed with the software available in the Nuclear Medicine and Molecular Imaging Clinic (MIM 
Vista). PET images will be interpreted by two radiologists in consensus (A.I. and G.D.). A third 
reader (C.M.) will serve as referee to achieve consensus. 
PET image interpretation will begin with identification of areas of myocardial 18F-FSPG uptake 
on PET/MRI images using multi-planar reformations and maximum-intensity projections. 
Myocardial 18F-FSPG uptake will be globally classified into one of four patterns (none, diffuse, 
focal, or focal on diffuse) for each participant. Diffuse, focal and focal on diffuse patterns of 
18F-FSPG uptake will be considered to be positive findings indicative of cardiac involvement. 
Myocardial segments will be evaluated for focal 18F-FSPG activity using the 17-segment model 
recommended by the American Heart Association (AHA). The presence or absence of RV free 
wall 18F-FSPG activity will also be evaluated. The whole-body PET/MRI or PET/CT acquisition 
will be evaluated for findings of extra-cardiac sarcoid. 
For cardiac MRI analysis, left and right ventricular (LV and RV) endocardial borders will be 
manually contoured on short-axis SSFP images to assess for end-diastolic and end-systolic 
volumes, and ejection fraction (EF). LV epicardial borders will also be manually contoured to 
assess LV mass. Presence of T2-hyperintensity and LGE will be qualitatively assessed by 
visual inspection of all available images and will be graded as present or absent using the AHA 
17-segment model. The pattern of LGE will be classified as either CAD type or non-CAD type as 
described previously [17]. The presence or absence of RV free wall LGE was also evaluated. 
2.3. Clinicaltrials.gov  
The study is registered at ClinicalTrials.gov (NCT03103490). 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
 
3.1. Inclusion Criteria 
• Patient is ≥ 18 years old at the time of the scan  
• Patient with known or suspected cardiac sarcoidosis referred for standard of care 18F FDG 
PET/CT 


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• Patient is capable of complying with study procedures  
• Patient can remain still for duration of imaging procedure 
3.2. Exclusion Criteria 
• Patient is pregnant or nursing  
• Metallic implants (contraindicated for MRI; these patients will get PET/CT)  
• History of renal insufficiency (only for MRI contrast administration) 
4. STUDY PROCEDURE: 
Patients will be injected with 18F-FSPG and undergo the PET/MRI or PET/CT image 
acquisition after a 45-60 minute delay.  
PET/MRI 
First, a localizer MRI scan will be performed to define the table positions after correct positioning 
of the spatial acquisition window. A coronal 2-point Dixon 3-dimensional volumetric interpolated 
breath-hold T1-weighted MRI sequence will be acquired and used for the generation of 
attenuation maps and for anatomic allocation of the PET results. Simultaneously with the start of 
the MRI sequences, the PET acquisition will start at the same table position, thus ensuring 
optimal temporal and regional correspondence between MRI and PET data. The PET 
acquisition time will be continuous during the MRI exam, taking delayed acquisition times and 
radioactive decay into account. The MRI scans will be acquired during breath-hold in the 
standard cardiac views including 2,3,4 chamber views and stacked axial and short axis views. 
Some patients may be given an IV (intravenous) gadolinium-based contrast injection as part of 
the PET/MRI research study to enhance the results of the study. 10 minutes after contrast 
injection, MRI delayed enhancement images may be obtained in the standard cardiac views. 
The protocol director or one of the co-investigators will decide the administration of contrast. 
PET/CT 
First, a vertex to mid-thighs scan is done, followed by dedicated imaging of the heart over 1 bed. 
ToF is standard on the digital PET/CT system. Data driven gating will be acquired according to 
the vendor’s protocol (once commercially available). The PET emission scan is corrected using 
segmented attenuation data of the CT scan. The PET images are reconstructed both with a 
standard iterative algorithm (OSEM, two iterative steps, 28 subsets), as well as a regularized 
reconstruction algorithm (Q.Clear®) provided by GE Healthcare.  
5. ADVERSE EVENTS AND REPORTING PROCEDURES 
The administration of the radioactive substance will feel like a slight pinprick when given by 
IV injection.  Patients who are claustrophobic may feel some anxiety while positioned in the 
scanner.  Also, some patients find it uncomfortable to hold one position for more than a 
few minutes.  The subjects will not feel anything related to the radioactivity of the substance in 
their body.  Because the radioactivity is very short-lived, the radiation exposure is low.  The 
substance amount is so small that it does not affect the normal processes of the body.   
This research study involves exposure to radiation from one 18F-FSPG PET/MRI scan. The 
effective dose from one typical administration of 18F-FSPG is 4.5 mSv, approximately equal to 
10% of the limit that radiation workers (for example, a hospital x-ray technician) are allowed to 
receive in one year. This radiation exposure is for research purposes only. 


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In case you cannot undergo MRI due to metal implants, PET/CT will be done. CT in PET/CT will 
add 5 mSv for a total of 9.5 mSv, approximately equal to 20% of the limit that radiation workers 
(for example, a hospital x-ray technician) are allowed to receive in one year. 
Adverse events will be graded according to CTCAE v5.0.  Both Serious and Non-Serious 
Adverse Events will be clearly noted in source documentation and listed on study specific Case 
Report Forms (CRFs).  The Protocol Director (PD) or designee will assess each Adverse Event 
(AE) to determine whether it is unexpected according to the Informed Consent, Protocol 
Document, or Investigator’s Brochures, and related to the investigation. All Serious Adverse 
Events (SAEs) will be tracked until resolution and 30 days after the last dose of the study 
treatment.  
6. REGULATORY CONSIDERATIONS 
6.1. Data and Safety Monitoring Plan 
The principal investigator will be responsible for monitoring the safety of subjects who have 
enrolled in the study.  
6.2. Confidentiality 
All data including data forms, PET/MRI reports, and clinical information will be stored in a 
locked, secure location within the Division of Nuclear Medicine and Molecular Imaging. Data will 
only be accessed by members of the research team assigned to data collection or analysis. No 
information derived from this study will be provided to the subject's personal physician, a 
government agency, or any other person or group. 
7. MEASUREMENTS 
N/A.  This is a pilot study evaluating feasibility of the exam as measured by completed 
exams and diagnostic quality images. 
8. STATISTICAL CONSIDERATIONS 
N/A.  This is a small pilot study with no statistical analysis included. 
8.1. Criteria for future studies 
 
If sarcoid is identified in more than 50% of the cases, a larger study will be planned. 


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Appendix: Inclusion/Exclusion Criteria Checklist  
Protocol Title: 
18F-FSPG PET/MRI or PET/CT Imaging of Cardiac Sarcoidosis 
or Inflammation 
Protocol Number: 
IRB-40376  
Principal Investigator: 
Andrei Iagaru, MD 
 
Inclusion Criteria – Yes must be checked to be eligible 
(From IRB approved protocol) 
Yes 
No 
Supporting  
Documentation 
1. Patient is ≥ 18 years old at the time of the scan  
☐ 
☐ 
☐ 
2. Patient with known or suspected cardiac sarcoidosis 
☐ 
☐ 
☐ 
3. Patient is capable of complying with study 
procedures 
☐ 
☐ 
☐ 
4. Patient can remain still for duration of imaging 
procedure 
☐ 
☐ 
☐ 
 
 
*All subject files must include supporting documentation to confirm subject eligibility.  The method of 
confirmation can include, but is not limited to, laboratory test results, radiology test results, subject 
self-report, and medical record review.   
 
i. 
Statement of Eligibility 
By signing this form of this trial, I verify that this subject is [☐eligible / ☐ ineligible] for participation in the 
study. This study is approved by the Stanford Cancer Institute Scientific Review Committee, the Stanford 
IRB, and has finalized financial and contractual agreements as required by Stanford School of Medicine’s 
Research Management Group.   
PI/ SubPI Signature: 
Date: 
Printed Name: 
 
Study Coordinator Signature: 
Date: 
Printed Name: 
Exclusion Criteria – No must be checked to be eligible 
(From IRB approved protocol) 
Yes 
 
No 
 
N/A 
Supporting 
Documentation 
 
1. Patient is pregnant or nursing 
☐ 
☐ 
☐ 
☐ 
2. Metallic implants (contraindicated for MRI; these 
patients will get PET/CT) 
☐ 
☐ 
☐ 
☐ 
3. History of renal insufficiency (only for MRI contrast 
administration) 
☐ 
☐ 
☐ 
☐ 
Secondary Reviewer Signature: 
Date: 
Printed Name: 


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2. 
Vignaux O. Cardiac Sarcoidosis: Spectrum of MRI Features. American Journal of 
Roentgenology 2005;184:249-254. 
3. 
Patel MR, Cawley PJ, Heitner JF, Klem I, Parker MA, Jaroudi WA, et al. Detection of 
Myocardial Damage in Patients With Sarcoidosis. Circulation 2009;120:1969-1977. 
4. 
Vignaux O, Dhote R, Duboc D, Blanche P, Devaux J-Y, Weber S, et al. Detection of 
Myocardial Involvement in Patients with Sarcoidosis Applying T2-Weighted, 
Contrast-Enhanced, and Cine Magnetic Resonance Imaging: Initial Results of a 
Prospective Study. Journal of Computer Assisted Tomography 2002;26:762-767. 
5. 
Smedema J-P, Snoep G, van Kroonenburgh MPG, van Geuns R-J, Dassen WRM, Gorgels 
APM, et al. Evaluation of the Accuracy of Gadolinium-Enhanced Cardiovascular 
Magnetic Resonance in the Diagnosis of Cardiac Sarcoidosis. Journal of the American 
College of Cardiology 2005;45:1683-1690. 
6. 
Blankstein R, Osborne M, Naya M, Waller A, Kim CK, Murthy VL, et al. Cardiac 
Positron Emission Tomography Enhances Prognostic Assessments of Patients With 
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7. 
Youssef G, Leung E, Mylonas I, Nery P, Williams K, Wisenberg G, et al. The Use of 
18F-FDG PET in the Diagnosis of Cardiac Sarcoidosis: A Systematic Review and 
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Okumura W, Iwasaki T, Toyama T, Iso T, Arai M, Oriuchi N, et al. Usefulness of Fasting 
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Vené R, Delfino L, Castellani P, Balza E, Bertolotti M, Sitia R, et al. Redox Remodeling 
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Koglin N, Mueller A, Berndt M, Schmitt-Willich H, Toschi L, Stephens AW, et al. 
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Mittra ES, Koglin N, Mosci C, Kumar M, Hoehne A, Keu KV, et al. Pilot Preclinical and 


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Clinical Evaluation of (4S)-4-(3-[18F]Fluoropropyl)-L-Glutamate (18F-FSPG) for 
PET/CT Imaging of Intracranial Malignancies. PLOS ONE 2016;11:e0148628. 
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Chae SY, Choi C-M, Shim TS, Park Y, Park C-S, Lee HS, et al. Exploratory Clinical 
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