Total-Body Parametric 18F-FDG PET of COVID-19
Phase: NA
Conditions: Covid19
Sponsor: University of California, Davis

 
  
 
 Total-Body Parametric 18F-FDG PET of COVID-19 
NCT04841707 
 
 
Protocol 1697954  
 
 
 
Protocol Version dated May 24 2021 
 

PROTOCOL TITLE: Total-Body Parametric 18F-FDG PET of COVID-19 
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Protocol Version 1.9 (05/24/2021) 
1) Protocol Title 
Title:  Total-Body Parametric 18F-FDG PET of COVID-19 
Protocol Version Date: May 24, 2021 
2) Objectives 
This is a single-center, pilot study to investigate the organ responses in subjects with 
COVID-19. We hypothesize that multiparametric imaging with dynamic 
18F-
fluorodeoxyglucose (FDG) positron emission tomography (PET) can monitor the 
functional changes in patients with COVID-19. The primary objective is to measure the 
change between COVID-19 patients and normal subjects; the secondary objective is to 
measure the change in COVID-19 patients between baseline and 4-month follow up. We 
will primarily assess the pulmonary blood-air barrier (BAB) permeability to glucose but 
will also evaluate the FDG perfusion-metabolism changes in different organs such as brain, 
heart, and kidney. All the functional parameters are derived from a single 18F-FDG 
dynamic PET scan on the EXPLORER total-body PET/CT scanner which is uniquely 
available in the UC Davis Medical Center.  
3) Background 
Coronavirus disease 2019 (COVID-19) is a highly infectious respiratory disease caused by 
the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [1, 2]. The majority 
of patients who are COVID-19 positive have mild symptoms [2]. However, approximately 
20% of the patients can develop acute respiratory distress syndrome (ARDS) [3-6], a 
common cause of respiratory failure [7] that is associated with a high mortality rate of 
about 40% in general [7, 8] and even higher in COVID-19 [6, 9]. The complicatedness of 
COVID-19 is further increased by the fact that “silent hypoxia” exists in many patients 
[10]. Those patients can breathe normally with a low blood oxygenation level but may be 
already at a late, very ill stage by the time they are admitted into the hospital.  
There is an urgent need for new methods, especially noninvasive imaging methods, to 
characterize COVID-19 severity and early prediction of ARDS. Existing methods for risk 
stratification in patients with COVID-19 include clinical exams and laboratory tests which 
mainly evaluate the body as a whole and do not evaluate the changes specifically in the 
lungs. Pulmonary function tests are also available. Nevertheless, many patients can have 
well-preserved lung mechanics while the disease severity keeps worsening, such as in those 
patients demonstrating silent hypoxia [10]. X-ray imaging, ultrasound, and computed 
tomography (CT) can image the lungs but focus on anatomical imaging. The anatomical 
changes may not occur before the disease reaches a late stage. Metabolic imaging with 18F-
fluorodeoxyglucose (FDG) positron emission tomography (PET) only demonstrated mixed 
results.  
Lung blood-air barrier (BAB, a.k.a. alveolar-capillary barrier) is formed by the epithelial 
cells of the alveolar wall, endothelial cells of the capillaries, and basement membrane [11]. 
BAB plays a crucial role for normal gas exchange in the lungs for taking in oxygen and 
releases carbon dioxide [11]. Increased BAB permeability has been well documented as a 
pathophysiological hallmark of early ARDS [7] and is closely associated with decreased 

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expression of angiotensin-converting enzyme 2 (ACE2) [12]. In patients with COVID-19, 
the ACE2 receptor is the entry gate for the SARS-Cov-2 virus to enters the host cells [13, 
14]. The virus binding can inhibit the normal role of ACE2 in protecting from lung injury, 
resulting in increased damage to pulmonary endothelial cells, alveolar epithelial cells, and 
microangiopathy as confirmed by a very recent autopsy study of COVID-19 patients [15]. 
These types of injury may increase BAB permeability and lead to protein-rich liquid build-
up in the alveoli, which in turn impairs gas exchange [16, 17]. Therefore, the proposed 
study is aimed at assessing BAB permeability as a biomarker of COVID-19 severity.  
However, clinical assessment of BAB permeability is not trivial. Transpulmonary 
thermodilution can evaluate pulmonary vascular permeability using the ratio of 
extravascular lung water over pulmonary blood volume [18]. Nevertheless, the method is 
invasive, associated with complications [19], and affected by the type of ARDS [19]. 
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) or DCE-CT may be 
used for imaging vascular permeability but their applications have been mainly limited in 
brain and tumors [20, 21] with a short axial field of view coverage. In addition, the contrast 
agents are associated with potential toxicity and injury to the kidney and brain [22-25]. 
Patients with COVID-19 are at higher risks for contrast toxicity because the virus already 
attacks multiple organs including the kidney and brain [26-29]. 68Ga-DTPA PET was 
 
 
Figure 1 (a-d): Total-body dynamic 18F-FDG PET imaging in a patient with metastatic kidney cancer (A) 
and enabled multiparametric imaging (B-D). As compared to the clinical standardized uptake value (SUV) 
image (B), the parametric image of FDG influx rate Ki (C) can achieve higher lesion-to-background (e.g., 
the liver) contrast. In addition to glucose metabolism imaging by Ki, total-body dynamic PET also enables 
multiparametric characterization of tumors and organs using additional physiologically important 
parameters, for example, glucose transport rate K1 (D), across the entire body.  
 

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Protocol Version 1.9 (05/24/2021) 
utilized for vascular permeability imaging [30-32]. However, the radiotracer is not widely 
accessible in clinics or would take a long process for clinical translation.  
We are developing a single-tracer multiparametric imaging method using PET and the 
widely available radiotracer 18F-FDG [33-35]. Different from the standard clinical usage 
of 18F-FDG PET only for metabolic imaging, we exploit dynamic PET imaging and 18F-
FDG tracer kinetic modeling to enable simultaneous multiparametric imaging of glucose 
transport and metabolism. While conventional dynamic PET imaging has been mainly 
restricted to single-organ imaging because of the limited axial field-of-view (FOV) of 
traditional PET scanners (15-30 cm), the world’s first EXPLORER total-body PET scanner 
[36, 37] has a long axial FOV of 194 cm with ultrahigh sensitivity and allowing 
simultaneous dynamic imaging of the entire human body. An example of multiparametric 
images from a total-body dynamic 18F-FDG PET scan of cancer patients is shown in Figure 
1 [38]. In addition to the metabolic imaging as assessed by either the standardized uptake 
value (SUV) or FDG net influx rate (Ki), the parametric image of FDG K1 provides an 
additional dimension of information (glucose blood-to-tissue transport rate) on top of the 
images of glucose metabolism.  
In most organs and tumors, FDG K1 can 
be considered as a surrogate of blood 
flow (perfusion). However, this not the 
case in the lungs. Our recent theoretical 
analysis has identified that lung FDG K1 
may represent BAB permeability based 
on the fact that the extraction of 18F-FDG 
in lung tissues is small (less than 10%). 
This is theoretically justified by the 
classic 
Renkin-Crone 
model 
[39], 
K1=FE = F(1-e-PS/F) where F represents 
blood flow, E is the extraction fraction of 
FDG and PS describes the product of 
tracer permeability and surface area. 
When E is small (PS≪F), K1 ≈ F×PS/F 
 
 
Figure 3. Correlation of lung FDG K1 (reflecting BAB 
permeability to glucose) with age.  
 
 
Figure 2. Parametric images of lung FDG K1 of a healthy subject on the coronal plane (A) and transverse 
plane (B). Shown are maximum intensity projection images.  

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= PS, thus reflecting permeability, not blood flow. Given the association of BAB 
permeability with pulmonary ACE2 level [12], our working hypothesis is that lung FDG 
K1 correlates with lung injury severity in COVID-19. Specifically, we hypothesize that 
lung FDG K1 increases in patients diagnosed with COVID-19 as compared to normal 
subjects and decreases at 4-month follow-up as compared to its baseline due to more 
complete recovery. Successful testing of these hypotheses will establish lung FDG K1 as a 
noninvasive imaging biomarker of COVID-19 severity, which has the potential to be 
applied for risk stratification and early assessment of therapeutic response. We have 
generated the quantification data in 5 healthy subjects. Figure 3 shows lung FDG K1 versus 
subject age. While the sample size is small here, the plot shows a trend that increased age 
is associated with increased lung FDG K1 and hence increased BAB permeability. This 
preliminary result is consistent with the observation that elderly is at higher risk of COVID-
19, which may be explained by the increased BAB permeability.  
From a total-body dynamic FDG-PET scan, we are also able to measure the perfusion-
metabolism pattern for other organs. Some of these organs (e.g., brain, kidney, heart) were 
previously reported of possible damages in patients with COVID-19 [26-29]. We will also 
study the functional changes in different organs in each of the proposed comparisons. 
 
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Protocol Version 1.9 (05/24/2021) 
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4) Inclusion and Exclusion Criteria 
We anticipate enrolling participants with a range of infection severity, from those 
hospitalized, to those who had outpatient treatment. 
Inclusion Criteria. Potential participants must meet all of the following criteria to be 
eligible for study entry. 
• COVID-19 positive patients will have a previous positive COVID-19 test and 
radiologic findings, and/or a positive SARS-CoV-2 antibody test and be in early 
recovery. 
• First PET/CT visit needs to be within 8 weeks of COVID-19 diagnosis. 
• Ability to understand and willingness to sign an informed consent form. 
• Ability to adhere to the study visit schedule and other protocol requirements. 
• All persons ≥18 years of age. 
Exclusion Criteria. Potential participants who meet any of the following criteria will be 
excluded from study entry.  
• Pregnant or lactating persons. 
• Any condition that would prohibit the understanding or rendering of informed 
consent. 
• Unable to lie supine for 1-hour imaging with PET. 
• Prisoners. 
• Any comorbidity that, in the opinion of the investigator, could compromise protocol 
objectives.  
5) Study Timelines 
We anticipate fifteen participants will be enrolled into this pilot study. We estimate the 
recruitment period to last 12 months. Medical records of enrolled participants will be 
followed for one year to determine the clinical outcome. The primary analysis is anticipated 
to be completed in two years. 
6) Study Endpoints 
The primary endpoint of this study is to evaluate if there is a significant increase in BAB 
permeability (as assessed by lung FDG K1) and changes in organ perfusion-metabolism 
between subjects diagnosed with COVID-19 and normal subjects (of which the 
EXPLORER scans are already available through another trial). The secondary endpoint is 
to evaluate the changes in patients with COVID-19 between baseline and 4-month follow-
up in a patient’s recovery phase. 

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Protocol Version 1.9 (05/24/2021) 
7) Procedures Involved 
COVID-19 Testing: Potential participants with only a previous positive COVID-19 test 
(viral RNA) lacking radiologic findings, will be asked to undergo a SARS-CoV-2 
antibody test prior to enrollment. Prior to the baseline PET/CT scan, each participant 
must have a negative viral PCR COVID-19 test at least 14 days following their positive 
COVID-19 test.  These tests will be paid by the study. 
 
PET/CT Scans: Each participant will undergo two 18F-FDG PET/CT scans, one at baseline 
and one at 4-month (+/- 2 weeks) follow-up (Figure 4). A member of the research study 
team will reach out to the participant prior to the 4-month scan to inquire about the status 
and date of COVID-19 vaccination. For each scan, participants will be asked to arrive for 
the study visits at the UC Davis EXPLORER Molecular Imaging Center (3195 Folsom 
Blvd, Sacramento, CA). A urine pregnancy test will be administered, at no charge, to all 
participants 18 to 60 years old able to become pregnant, unless documented hysterectomy 
or bilateral ovarian removal is available. Participants will then have a  routine finger stick 
test for measuring blood sugar level. A technologist will place a thin plastic needle (IV) 
into a vein at the arm of an eligible participant. The technologist will then instruct the 
participant to lie supine in the EXPLORER PET/CT scanner. The participant will first 
undergo an ultra low-dose X-ray CT imaging for attenuation correction purpose. After that, 
a standard dose of 18F-FDG will be injected into the participant through the IV in a period 
of 10 seconds. The time when FDG is injected should be recorded. The PET scan 
commences 10 seconds before the FDG injection and lasts for 60 minutes. After the PET 
scan, the participant gets off the scanner.  
Cognitive Screening: Participants will also undergo screening with the Mini-Cog 
instrument.  The Mini-Cog1 is a standardized 3-minute instrument utilized to screen for 
cognitive impairment.  
 
The acquired total-body dynamic PET/CT data will be reconstructed into a sequence of 
dynamic images. An image-derived input function will be extracted from the dynamic 
 
1 Borson, Soo, et al. "The mini‐cog: a cognitive ‘vital signs’ measure for dementia screening in multi‐
lingual elderly." International journal of geriatric psychiatry 15.11 (2000): 1021-1027. 
 
 
Figure 4: Study protocol. 
 

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Protocol Version 1.9 (05/24/2021) 
image sequence and kinetic quantification in the lungs and other organs will be performed 
using the dynamic PET images.  
The PET/CT images created for this study are for research and are not meant to evaluate 
subject health, as they would be if they were part of a clinical (non-research) visit to the 
doctor or hospital. The images will not receive any routine clinical review by radiologists 
who interpret PET/CT scans. This means that some findings may be overlooked or 
misinterpreted. However, if the PET/CT technologists do notice findings that cause 
concern, they will notify the Study Radiologist. Additionally, if a member of the research 
team notices any findings that cause concern while conducting image review for study 
purposes, they will notify the Study Radiologist. The Study Radiologist will conduct a brief 
review of part of the study images for quality purposes. If the Study Radiologist thinks a  
clinical problem is present, one of the IRB-approved study physicians will discuss these 
possible problems with the subject within 8 weeks or immediately upon recognition of any 
critical finding that requires immediate and/or urgent intervention as described in the 
Department of Radiology Critical Findings policy (full dataset of images are sometimes 
not available for review in less than 3 days). Upon written request, we will provide the 
subject with a copy of a subset of their CT images to take to the physician of their choosing. 
A subset of PET images may also be shared with the subject unless the images from the 
study are clinically uninterpretable. In addition, the sponsor may restrict sharing of PET 
images due to the nature of the research protocol. We will send a standard letter to the 
designated licensed medical provider identified by the subject, unless one of the study 
physicians is part of the subject’s care. The standard letter will state that (i) the subject’s 
images were acquired exclusively for a research study and incidental findings that may be 
related to a medical condition were observed by a UC Davis radiologist; (ii) the images did 
not receive any dedicated routine clinical review and findings may have been overlooked 
or misinterpreted; (iii) the subject’s physician can contact the study doctor at any time if 
there are any concerns regarding the study or the subject’s findings. 
 
8) Data and/or Specimen Management and Confidentiality 
All data and images acquired for research purposes will be coded with a research number. 
Subjects will be assigned sequential ID codes (1-15). Subject identifiers and personal 
health information (PHI) will be removed from the DICOM header of PET/CT images to 
protect patient confidentiality  
Risk of loss of confidentiality and privacy will be mitigated by hospital EMR and PACS 
password security and by the protection of consent forms and datasheets with PHI are 
secured in a locked office and locked file cabinets in the EXPLORER Molecular Imaging 
Center office. Links in the data to the medical record will be removed before research 
personnel analyze the data. Access to the code key will be restricted to the investigators 
and coordinator(s) during the course of the study. 
Once informed consent is obtained through a method approved by UC Davis, clinical data 
will be collected from the electronic medical record, including recent laboratory tests, 
cardiac function assessment, and imaging variables. Patient’s blood pressure, heart rate, 
and weight will also be obtained for the most recent visit.  

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9) Data and/or Specimen Banking 
N/A 
10) Provisions to Monitor the Data to Ensure the Safety of Subjects 
This study does NOT involve the administration of therapeutic agents. This study does 
NOT replace any of the safety monitoring that patients undergo as part of standard clinical 
care. 
18F-FDG PET/CT is routinely used in clinical oncology, cardiology and neurology. 
Intervention for adverse events that occur during PET/CT scanning will be the 
responsibility of hospital radiology or nuclear medicine technicians and physician on duty.  
11) Withdrawal of Subjects 
Patients will be informed that they have the right to withdraw from the study at any time 
for any reason, without prejudice to their medical care. The investigators also have the right 
to withdraw patients from the study for any of the following reasons: 
• Known or suspected pregnancy - this is verified as part of the clinical process since 
this test is clinically contraindicated on pregnant patients. 
• Circumstance(s) deemed by the Nuclear Medicine clinician to be contraindicated 
for PET/CT 
• Patient request 
12) Risks to Subjects 
Minor and uncommon clinical risks: 
• Additional discomfort from lying on the scanner table for 60 additional minutes 
Serious and rare risks: 
• Loss of privacy or confidentiality 
It is worth noting that all the risks listed below are similar to standard-of-care PET/CT test 
in oncological patients. 
Minor and common clinical risks: 
• The placement of the intravenous needle in a vein may cause temporary discomfort 
and a small bruise may form.  
• Discomfort due to lying in the PET/CT scanner for 1 hour 
Moderate and uncommon clinical risks: 
• Infection at the site with the intravenous catheter is placed.  
Radiation risks: 
• PET/CT involves a radiation exposure that is typical of other diagnostic tests using 
ionizing radiation  
• The amount of radiation exposure received in this study is below the levels that are 
thought to result in a significant risk of harmful effects. 

PROTOCOL TITLE: Total-Body Parametric 18F-FDG PET of COVID-19 
Page 10 of 11 
 
Protocol Version 1.9 (05/24/2021) 
13) Potential Benefits to Subjects 
There are no direct benefits to the study subjects. The result of the study will benefit future 
patients once the methods are fully developed. 
14) Multi-Site Research 
This is a single-site study. 
15) Community-Based Participatory Research 
N/A 
16) Sharing of Results with Subjects 
The images acquired in this study are experimental and cannot be used by subjects or their 
clinicians for treatment decision-making.  No results will be shared with patients or 
clinicians. 
17) Prior Approvals 
Prior approval from the Radiation Use Committee will be obtained before the submission 
of this protocol for IRB approval. 
 
18) Provisions to Protect the Privacy Interests of Subjects 
The rights and welfare of subjects will be protected by the use of subject codes and the 
removal of all PHI identifiers from the research data and images. The subject code key 
used to link subject identities to coded data will be kept on a password-protected space to 
separate it from the clinical data and images. All identifiers, including the code key used 
to link subjects to coded data, will be destroyed by electronic deletion at the end of the 
study. Protected health information will not be re-used or disclosed to any other person or 
entity, expect as required by law or for authorized oversight of the research project. 
19) Compensation for Research-Related Injury 
The research does not involve more than minimal risk to subjects. If a subject is injured as 
a result of being in this study, the University of California will provide necessary medical 
treatment. The costs of the treatment may be billed to the subject’s insurance company just 
like any other medical costs. The University and the study sponsor do not normally provide 
any other form of compensation for injury. Subjects do not lose any legal rights by signing 
the informed consent form. 
20) Economic Burden to Subjects 
There are no additional expenses either to the study subjects or to the insurers. Study 
participants will be provided with $100 gift cards after the completion of each scanning 
visit to compensate for transportation and other trip costs associated with their participation 
in this study. 

PROTOCOL TITLE: Total-Body Parametric 18F-FDG PET of COVID-19 
Page 11 of 11 
 
Protocol Version 1.9 (05/24/2021) 
21) Drugs or Devices 
There are no drugs or devices being tested on this protocol. The EXPLORER total-body 
PET/CT is FDA approved for routine clinical use. 
22) Review Requirements 
Are there any contractual obligations or other considerations that 
require IRB review of this research, or review at intervals other than 
those required by the Common Rule or FDA? If yes, check box: 
 
 Yes 
 
 No