Feasibility Assessment of Next-generation PET Technology and Procedures
Phase: NA
Conditions: New-generation Digital PET/CT Imaging
Sponsor: University of Cincinnati

Protocol Title: 
Feasibility Assessment of Next-generation PET 
Technology and Procedures 
 
Protocol Date: 
September 12, 2017 
 
Research Project Number: 
RP0506 
 
Principal Investigator: 
Michael V. Knopp, MD, PhD 
Professor of Radiology and Novartis Chair of 
Imaging Research 
Vice Chair of Research, Department of 
Radiology 
395 West 12th Avenue, 4th Floor 
Columbus, OH 43210 
 
Knopp.16@osu.edu  
 
Office: 614-293-9998 
Fax: 614-293-9275 
 
 
 
 
 

PI: Michael V. Knopp, MD, PhD 
RP0506 
 
Page 2 of 9 
 
I. Objectives  
 
The purpose of this study is to assess the feasibility of investigational Positron Emission Tomography 
(PET) imaging using the new generation digital detector PET technology for new procedures beyond 
the current standard of care: 
 
1. To enable innovative PET imaging in association with a clinical trial to add potential future 
biomarker readouts for disease characterization and therapy management. 
2. To generate preliminary and comparative imaging data for potential confirmatory clinical trials 
using innovative imaging timepoints, acquisition, dose, and timing approaches, and/or post-
processing procedures.  
3. To explore digital PET imaging for new indications where PET is not currently considered a 
standard of care diagnostic procedure in order to be able to design future clinical trials. 
 
II. Background and Rationale 
 
PET imaging is increasingly being used as a diagnostic modality in cancer detection and staging, 
neuro-molecular assessment, cardiovascular-molecular imaging, physiological/musculoskeletal 
imaging, and response assessment. Additionally, PET imaging is utilized in the detection and 
assessment of inflammatory processes. Constant advances in detector techonology, image acquisition, 
and post-processing approaches could lead to the increased utility of PET in many currently unmet 
clinical scenarios.  
 
We have already performed an intra-individual comparison trial demonstrating advanced capabilities 
of digital PET technology in regard to lesion detection, lesion characterization, quantification, duration 
of scan time, and reduction of radiation dose. The digital PET is now fully FDA approved and in this 
trial we need to generate preliminary data in order to design prospective clinical trials that allow the 
validation of a hypothesis. We have demonstrated the safety of the system [now FDA approved] and 
the overall efficacy in relation to current clinical care practice standards, however, the technology 
enables the change of those standards for which we need to demonstrate the clinical feasibility that we 
have either shown in pre-clinical PET imaging or via simulations. 
 
This research focuses on evaluating the new capabilities of PET imaging which may be improved or 
enabled by a new generation of fully digital PET systems. In order to change clinical practice, we need 
to first generate data on the potential capabilities of this major technology improvement. We will be 
performing and evaluating investigational PET/CT imaging beyond the current standard of care 
practice. Prior studies by our team have already performed comparisons between the new and current 
PET imaging, however the digital PET studies were constrained by being performed as a comparison 
to standard of care. In this clinical trial, we can conduct research studies at innovative time points or 
using innovative procedures currently not covered by insurance, such as repeat imaging prior to 
treatment or midway through treatment for replanning purposes or to find better quantitative readouts 
to improve diagnosis and disease management. We intend to conduct PET imaging also for indications 
not typically covered by insurance, such as cardiac, neuro-related, or orthopeadic/sportsmedicine 
indications. We may also perform imaging with FDA approved radiotracers beyond their normal use 
(off-label) to explore the synergistic capabilities of the new generation of PET imaging.  

PI: Michael V. Knopp, MD, PhD 
RP0506 
 
Page 3 of 9 
 
III. Procedures 
 
A. Research Design 
 
This prospective study will utilize investigational PET acquisitions on the newly available 
digital photon counting detector platform to develop and optimize PET acquisition and post-
processing techniques as well as to generate preliminary and comparative data for potential 
confirmatory clinical trials. We will assess these innovations  in regard but not limited to visual 
inspection of lesions, normal tissue, sentinel nodes and imaging artifacts, semi-quantitative 
and blinded reader analysis. The PET methodologies we plan to use as part of this study will 
allow us to obtain morphological, functional and molecular information in ways beyond any 
current standard of care imaging procedures. 
 
We anticipate recruiting patients from 3 general populations. 1 – Patients enrolled in a clinical 
trial where innovative PET imaging may be beneficial to the trial, although not necessarily the 
individual patient. This would include patients enrolled in a clinical trial exploring a new 
treatment approach for whom imaging at other timepoints in treatment would not be covered 
by insurance and therefore not considered standard of care (SOC). 2 – Any patient with a 
concern for a medical condition / question not yet fully resolved by SOC practice for whom a 
treating physician believes that a research PET may have a potential to address the medical 
question and help for future patients with similar questions. For example, this could include a 
patient presenting with heel pain for whom standard x-ray shows no confirmation of injury, 
but the physician feels an innovative PET bone scan could help identify the cause of the pain. 
3 – Any patient having a SOC PET scan who would be interested in receiving an investigational 
scan, either as part of or in addition to the SOC scan. This would include patients already 
scheduled for a SOC scan who would be willing to have an investigational PET acquisition 
immediately following the standard acquisition for example acquired with a shorter scan time. 
This would also include patients who have already had a SOC PET examination, but would be 
willing to have a second, investigational PET exam, with a significantly reduced radiotracer 
dose for example.Thus the radiation dose and exposure associated with the investigational 
imaging would be in addition to any standard of care imaging, although the two will be 
combined whenever appropriate. 
 
Patients will be asked to provide study personnel with authorization to access their medical 
records for follow-up on future related procedures as well as the current outcome of their 
standard of care imaging. Additionally, participants will be asked if their imaging data from 
this study can be used in a de-identified manner in the future for comparison with other imaging 
data or as preliminary data for the protocol development of clinical trials. 
 
B. Sample 
 
The study population will include 200 evaluable patients as identified by study team members, 
referring physicians, or patient self-identification based on study recruitment materials or 
awareness from clinical trial websites such as clinicaltrials.gov. 
 

PI: Michael V. Knopp, MD, PhD 
RP0506 
 
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Inclusion Criteria: 
• Male and female volunteers greater than or equal to 18 years of age having a medical 
diagnosis which justifies exploratory PET imaging. 
 
Exclusion Criteria:  
• Participants who are pregnant or lactating. 
• Prisoners. 
• Subjects incapable of giving informed written consent or who are unlikely to complete 
the imaging procedure. 
 
C. Measurement / Instrumentation 
 
Studies will be carried out using FDA approved PET scanners. PET is routinely used for 
clinical diagnostic studies. 
 
At this time, we will be evaluating imaging using FDA approved radiopharmaceuticals at dose 
ranges not exceeding the label. These include Fluorine-18 florbetapir, F-18 sodium fluoride, 
F-18 fluorodeoxyglucose, F-18 flutemetamol, F-18 florbetaben, and Rubidium-82 chloride. 
 
 
D. Detailed study procedures 
 
After patients have expressed interest to participate they will be provided with the informed 
consent and study brochure material. For each participant, written informed consent will be 
obtained prior to any protocol related activities in a private area with a study team member or 
at the time of a physician consult as part of a clinical visit. As part of this procedure, study 
personnel will approach eligible participants and explain verbally and in writing the nature, 
duration, and purpose of the study as well as all associated risks and benefits. They will inform 
the participant that they may withdraw from the study at any time. The patient will be given 
time to ask questions and review the consent form on their own. During the consent process, 
the patient will be asked if they are willing to provide a release of their medical records 
pertaining to future procedures/injuries for the next 10 years. If the patient agrees, they will 
undergo the non-standard of care PET/CT imaging as designated by the study PI. 
 
Injection: 
The PET radiopharmaceutical will be injected into a pre-positioned IV line either in a dedicated 
injection suite or while the patient is placed on the PET imaging system in order to enable 
dynamic/perfusion imaging.  
 
Image Collection:  
Patients will be asked to simply lie on the table of the PET system for the duration of the 
investigational PET/CT. The duration of the table time associated with this research study will 
be dependent upon the purpose of the individual study, however the procedures will be very 
similar to a clinical scan. Following radiotracer injection, imaging may then be performed 
continuously for up to 2 hours, if dynamic imaging is being performed. If static imaging is 
being performed, the patient may rest during the uptake period, in the normal clinical injection 
space. At the conclusion of the investigational imaging session, the patient will be released 

PI: Michael V. Knopp, MD, PhD 
RP0506 
 
Page 5 of 9 
with similar instructions to those given to a standard of care PET/CT patient. Participants will 
not undergo more than a total of 2 hours of continuous imaging time in consideration of their 
potential discomfort from lying still in one position. 
 
Release of Medical Records: 
The patient will be asked if they are interested in releasing access to their medical records for 
up to 10 years after their participation in this study in order to allow study personnel to track 
the outcome and/or related procedures in the future. The patient can revoke their consent to 
this question at any time by contacting the Principal Investigator. 
 
E. Risks, Benefits, Safety and Confidentiality:  
 
The patient will be injected with an FDA approved radiopharmaceutical for the PET imaging 
session. The dose of the radiopharmaceutical will never exceed the recommended FDA dosing 
limits, and we anticipate that imaging will typically be done at substantially lower than 
maximum levels.  
 
Risks: 
The occurance of any adverse events due to the conduct of the study is not forseen. Risks 
associated with the investigational PET are considered very rare and are the same type of 
physical events that could occur in any normal PET scan. These would include pinching of 
skin, minor falls or bumps. Normal risks of a nuclear medicine scan from injection of a 
radiopharmaceutical include allergic reactions, swelling, infections, intravenous injuries, 
bruising, pain, and discomfort. Clinical guidelines for the PET will be followed according to 
OSUWMC hospital policy.  
 
The CT scan performed will be used for attenuation correction of the PET imaging and for 
anatomic correlation of the PET images. The CT scan also involves radiation exposure. Long 
term exposure to radiation may slightly increase one’s risk for cancer. The exposure risk is 
cumulative over a lifetime, and the total should be kept as low as possible.  The exact long-
term risks from radiation are not known.  To give the participant an idea about how much 
radiation they will receive from PET/CT scan we will make a comparison with an every-day 
situation. Everyone is exposed to unavoidable radiation each year, known as background 
raditaion. Some of this radiation comes from space and some from naturally-occurring 
radioactive forms of water and minerals. This research gives the participant’s body at most the 
equivalent of about 5 extra years' worth of this natural radiation. 
 
Benefits: 
It is hoped that the information from this study will provide preliminary, investigational 
information regarding the pathophysiological status of the disease/ailment/injury and may 
contribute to a more personalized diagnostic and/or therapeutic management in the future.  All 
information obtained will be labeled as investigational in any communication to participating 
and/or referring physicians. The subject can request that a research report is provided to their 
healthcare provider of choice. 
 
Safety Monitoring:  

PI: Michael V. Knopp, MD, PhD 
RP0506 
 
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The well being of the subject will be monitored in a similar manner to all non-invasive imaging 
methodologies as participation does not present more than minimal risk. The Principal 
Investigators or Co-Investigators or Key Personnel are able to respond immediately to ensure 
the safety of the patients participating in the research study. The Principal and/or Co-
Investigators or Key Personnel will be present at the time of all PET acquisitions to ensure 
this.   
 
The duration of data acquisition in the PET system per patient is limited to no more than 2 
hours total consisting of one or more acquisition series. There is no limit to the number of times 
an individual patient may participate in this study.  
 
In the event of any medical emergency, accident or trauma while the subject is in the facility, 
our contingency plans for emergency situations are as they would be for any medical facility 
and clinical imaging facility. Our emergency protocol fully prepares us to provide access to 
emergency treatment for our patients, resuscitation, life support and medical care as needed.   
 
Confidentiality of Records: 
All paper and electronic data/information will be de-identified prior to any review or analysis. 
All paper documents will be stored in a locked file cabinet with limited access in the 
Department of Radiology at The Ohio State University.  All electronic data obtained through 
PACS or IHIS will be stored in a de-identified manner on password protected servers with 
limited access in the Department of Radiology at The Ohio State University. In the Informed 
Consent, we are asking subjects for release of medical records for up to ten years, as well as 
the use of de-identified data for other future studies. This data may be kept indefinitely by  the 
Wright Center of Innovation for further assessment or reference. No individual identities will 
be used in any publications resulting from this study.  If the subject has authorized the use of 
de-identified data for other research studies as comparative data, the de-identified data may be 
shared with collaborative investigators as well as research databases. The established processes 
to verify de-identified data will always be adhered to. Officials from examining bodies such as 
the U.S. Food and Drug Administration or NIH may inspect records pertaining to this study.  
 
F. Internal Validity 
 
Image data will be evaluated at a minimum following standard published procedures. This 
includes but is not limited to visual evaluation of lesions, normal tissue, sentinel nodes and 
imaging artifacts, semi-quantitative analysis, blinded reader analysis, and using various 
methods for image post-processing. This should ensure internal and external validity of the 
data and avoid study bias. Functional and molecular read outs will be developed according to 
established methodologies. 
 
Managing and verifying the internal validity is an important task in this exploratory research 
program in order to develop the appropriate methodology to be validated in prospective clinical 
trials.  
 
As there is an opportunity that the staff member administering the facility experience can 
potentially bias the subject, we will perform training sessions with the staff prior to them 
administering the facility experience. We will also perform from time to time an observational 

PI: Michael V. Knopp, MD, PhD 
RP0506 
 
Page 7 of 9 
assessment by a study member participating in the subject facility experience with the task to 
observe the team member administering the facility experience in order to ensure that no bias or 
systematic errors occur.  
 
In this exploratory study where we use perception and observation-based assessments, we will 
have to constantly assess the potential sources of systematic errors or bias in order to ensure that 
we may derive conclusions that warrant generalization to other contexts. 
We will assess the different factors impacting internal validity of the data sets we generate. For 
the specific factors we will address the following considerations. The following text uses material 
presented 
at 
https://en.wikipedia.org/wiki/Internal_validity 
and 
is 
hereby 
specifically 
acknowledged. 
 
Temporal precedence: 
Potential lack of clarity how one experience may influence a subsequent experience as that might 
be a cause and effect relationship. 
 
Confounding: 
A major threat to the validity of causal inferences is confounding. Observations in one variable 
may relate to another manipulated variable. Where spurious relationships cannot be ruled out, 
hypothesis would have to be appropriately developed. 
 
Selection bias: 
Selection bias refers to the problem that, at pre-test, differences between groups exist that may 
interact with the independent variable and thus be 'responsible' for the observed outcome. 
Researchers and participants bring to the experiment a myriad of characteristics, some learned and 
others inherent. For example, sex, weight, hair, eye, and skin color, personality, mental 
capabilities, and physical abilities, but also attitudes like motivation or willingness to participate. 
During the selection step of the research study, if an unequal number of test subjects have similar 
subject-related variables there is a threat to the internal validity. If subjects in two groups to be 
compared are not alike with regard to the independent variable, but similar in one or more of the 
subject-related variables, it may jeopardize the internal validity. 
 
Self-selection to participate in this research can have a negative effect on the interpretive power of 
the dependent variable, this is especially known for online surveys where individuals of specific 
demographics opt into the test at higher rates than other demographics. 
 
History: 
Events outside of the study/experiment or between repeated measures of the dependent variable 
may affect participants' responses to experimental experiences. Often, these are large scale events 
(natural disaster, political change, etc.) that affect participants' attitudes and behaviors such that it 
becomes impossible to determine whether any change on the dependent measures is due to the 
independent variable, or the historical event. 
 
Maturation: 
Subjects may change during the course of the experiment or even between measurements. Both 
permanent changes, such as physical growth and temporary ones like fatigue, provide "natural" 

PI: Michael V. Knopp, MD, PhD 
RP0506 
 
Page 8 of 9 
alternative explanations; thus, they may change the way a subject would react to the independent 
variable. So upon completion of the study, the researcher may not be able to determine if the cause 
of the discrepancy is due to time or the independent variable. 
 
Repeated testing: 
Repeatedly measuring the participants may lead to bias. Participants may remember the answers 
or may be conditioned to know that they are being tested. Repeatedly taking (the same or similar) 
tests usually leads to score gains. 
 
Instrument change: 
The instrument used during the testing process can change the experiment, an aspect that we will 
managed via device quality control to the largest extent possible. This also refers to observers 
being more concentrated or primed, or having unconsciously changed the criteria they use to make 
judgments. This can also be an issue with self-report measures such as facility perceptions given 
at different times. In this case the impact may be mitigated through the use of retrospective 
pretesting. If any instrumentation changes occur, the internal validity of the main conclusion is 
affected. 
 
Differential attrition: 
This error occurs if inferences are made on the basis of only those participants that have 
participated from the start to the end. However, participants may have dropped out of the study 
before completion, and maybe even due to the study or experiment itself. If this attrition is 
systematically related to any feature of the study, the administration of the independent variable, 
the instrumentation, or if dropping out leads to relevant bias between groups, a whole class of 
alternative explanations may be possible that account for the observed differences. 
 
Selection-maturation interaction: 
This occurs when the subject-related variables, color of hair, skin color, etc., and the time-related 
variables, age, physical size, etc., interact. If a discrepancy between the two groups occurs between 
the testing, the discrepancy may be due to the age differences in the age categories. 
 
Experimenter bias: 
Experimenter bias occurs when the individuals who are conducting an experiment 
inadvertently affect the outcome by non-consciously behaving in different ways to members 
of control and experimental groups. It is possible to eliminate the possibility of experimenter 
bias through the use of double blind study designs, in which the experimenter is not aware of 
the condition to which a participant belongs. 
 
G. Incidental Findings 
 
Any incidental findings discovered will be correlated to any accessible standard of care 
imaging. If these incidental findings were not previously reported on standard of care imaging, 
the subject will be contacted according to the previous choice/request indicated on the 
informed consent form.  
 
 

PI: Michael V. Knopp, MD, PhD 
RP0506 
 
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H. Data Analysis 
The purpose of this trial is to perform exploratory assessment and as such will only use 
descriptive statistics. We do not intend to perform a statistical assessment beyond classifying the 
characteristics of pilot data and comparing observational trends either to the standard of care 
imaging data or other known reference data. For our purposes, imaging that presents lower 
imaging quality will not be pursued for further evaluation. Only images that suggest equivalent 
or improved image quality or diagnostic information compared to current standard of care 
imaging approaches would be evaluated for the potential use as data towards the design of a 
formal clinical trial and/or funding applications.