Molecular and Magnetic Resonance Imaging Biomarkers of Facet Joint Pain of the Lumbar Spine With PET/MRI
Phase: NA
Conditions: Low Back Pain
Sponsor: Mayo Clinic

 
Study Title:  Molecular and Magnetic Resonance Imaging Biomarkers of Facet 
Joint Pain of the Lumbar Spine with PET/MRI 
 
Version:  1; 5/17/2017 
 
NCT#:  02921490 
 

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Molecular and Magnetic Resonance Imaging Biomarkers of Facet Joint Pain of 
the Lumbar Spine with PET/MRI  
Version 1;  5/17/2017 
 
Investigators: 
 
The investigators collectively have extensive expertise in all the relevant areas including spine 
intervention, clinical spinal pain evaluation, neuroradiology, nuclear medicine, and biostatistics. 
 
Vance Lehman, MD   PI, Spine interventionalist, neuroradiologist 
Bradley Kemp, PhD 
Co-PI, Nuclear medicine physicist 
Timothy Maus, MD  Spine interventionalist, neuro/MSK radiologist 
Randy Shelerud, MD  PMR clinician 
Jeffrey Brault, MD 
PMR clinician 
Michael Halasy, PA 
PMR clinician  
Felix Diehn, MD 
Spine interventionalist, neuroradiologist 
Mark Nathan, MD 
Nuclear Medicine Physician 
Stephen Broski, MD Nuclear Medicine Physician 
Rickey Carter, PhD 
Biostatistician 
 
 
1. Background/Significance 
 
Low back pain (LBP), often due to facet joint pain, is a very prevalent and costly condition. 
Percutaneous facet joint intervention is expensive on a per patient session and per facet joint 
basis. This is typically prescribed to all 4 lowest lumbar facet joints in a given patient since both 
conventional imaging findings and clinical exam reliably identify specific painful facet joints. 
Identification of reliable biomarkers to predict facet joint pain and response to percutaneous 
treatment is needed. We have retrospective data demonstrating that bone agents such as 
Tc99m MDP may not be specific for location of patients’ facet joint pain (1) and seems to have 
low effectiveness for predicting response to steroid injection in clinical practice in other spinal 
locations (2). FDG PET may be more specific for inflammatory change than a bone radiotracer. 
Although there are some prior retrospective studies assessing both signal change on fat 
suppressed MRI (3) and bone radiotracers (4-5), there is no proven or widely used imaging 
biomarker.  Specifically, these prior studies all retrospective, unblinded, have unclear methods 
of evaluation of facet joint abnormality, have unclear methods of joint enumeration, and none 
confirmed facet joint pain with the gold standard test, comparative medial branch blocks.   
A prospective randomized blinded study using comparative medial branch blocks will ultimately 
be needed. However, it is now clear that initial exploratory study is necessary to ensure 
appropriate study design prior to committing to prospective study. Our currently unpublished 
data (6) indicate that we need to develop sound imaging parameters allowing for low 
interobserver variability of interpretation, need to establish prevalence of potential imaging 
biomarkers in the relevant population, and need to select the best biomarker(s) as initial steps. 

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Combined MR/PET has number advantages: 1. This allows near-simultaneous assessment of 2 
imaging biomarkers to avert criticism of discordance due to biomarker fluctuation, 2. MRI data 
is probably much more useful than CT data, 3. MRI may be preferred over CT if FDG PET activity 
proves a promising biomarker for this purpose, and 4. this will allow minimization of radiation 
dose. 
 
2. Specific Aims 
 
1. 
Determine the value of FDG PET and MRI imaging biomarker status in clinical 
decision making and concordance with initial clinical impression. 
2. 
Determine the approximate frequency of each independently studied imaging 
biomarker to facilitate power calculations. 
3. 
Determine if FDG PET activity and MR biomarkers are highly correlated and thus 
potential surrogates, or if these are discrepant and possibly complementary. 
4. 
Perform an exploratory evaluation of DWI for assessment of fact joints. 
5. 
Assess the concordance of findings on gadolinium enhanced MRI with T2 fat-
suppressed MRI using both axial and sagittal images to determine if gadolinium 
administration will be necessary for future clinical investigation. 
 
We plan to screen up to 40 patients to ensure we enroll 10 subjects. 
 
3. Hypothesis/Study Category: 
 
This is an exploratory study investigating the utility of FDG PET activity and MRI signal change 
around facet joints in the clinical management of low back pain.  This study will help determine 
if such imaging biomarkers could change clinical management.  Additionally, this will provide 
data that will be vital to planning a larger prospective study evaluating the ability of imaging 
biomarkers to predict response to comparison medial branch blocks and RF ablation for 
treatment of facet joint pain.  Such a prospective study could not be adequately designed 
without this initial exploratory component. 
 
4. Methodology 
 
4.1. Patient Enrollment 
 
Eligibility criteria - inclusion: 
1. Male and female patients over the age of 50-100 years with clinically suspected 
facetogenic low back pain. 
2. Patients must be considered to have at least a 60% chance of having facet joints as the 
major source of low back pain based on overall clinical impression. 
3. All patients will undergo a standardized clinical exam by an experienced physical 
medicine and rehabilitation clinician to confirm clinical suspicion of axial low back pain. 
4. Patients with either unilateral or bilateral axial low back pain may be enrolled. 
 

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Eligibility criteria - exclusion: 
1. Pregnancy 
2. Prior lumbar back surgery 
3. History of endovascular repair of abdominal aortic aneurysm or other postoperative 
change likely to introduce imaging artifact to the lumbar spine 
4. Suspected spine infection 
5. Known osseous metastatic or other osseous malignancy 
6. Facet joint percutaneous treatment within the past 2 months 
7. History of major lumbar spine trauma 
8. Inability to provide own consent 
9. Claustrophobia, cardiac pacemaker/wires in place, any absolute contraindication to MRI  
10. Impaired renal function indicated by a GFR less than 30 
11. Gadolinium allergy 
12. Highly radiosensitive medical conditions 
13. Patients who are unable to lay quietly for 60 minutes of imaging 
 
4.2 Patient Preparation 
 
A Review Preparatory to Research will be conducted by the study coordinators to determine 
if the patient meets inclusion criteria including a pre-screen for MRI safety and body habitus 
and whether the patient’s schedule will allow for study participation.  
 
4.3 Patient Scanning Protocol 
 
The PET/MR study consists of an injection of 12 mCi (+/-10%) fluorodeoxyglucose (FDG) and 
an uptake period of 60 minutes followed by a PET/MRI on the Signa PET/MR system. 
Patients will need to fast for 18 hours prior to the injection.  The patients may require a 
creatinine check per routine MRI clinical protocol. Patients may request sedation to make 
the scan more comfortable.  They will be given Ativan by mouth to relax by the MR/PET 
nurse.  As per Radiology Departmental policy, the additional MR images obtained during the 
study will also be given a full clinical read by the staff radiologists to ensure no unexpected 
findings. 
Patients will undergo one scan for this study. 
 
MRI Sequences 
1. 
Sagittal and axial T2 images with fat saturation Lumbar spine 
2. 
Sagittal and axial T1 images with gadolinium and fat saturation lumbar spine 
3. 
A T1 series without fat saturation (volumetric) lumbar spine 
4. 
Axial DWI images lumbar spine 
 
 
 

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PET images 
1. 18F-FDG PET images of the lumbar spine, reformatted in axial and sagittal planes 
 
4.4 Dosimetry 
 
Each patient will receive 12 mCi (+/-10%) F18 FDG 
 
5. Initial Clinical Assessment 
 
1. Patients will undergo a standardized clinical exam by Jeffrey Brault, MD, Randy 
Shelerud, MD or Michael Halasy, PA from the physical medicine rehabilitation 
department. 
2. The clinician will score the likelihood of the lumbar facet joint(s) as a structural source of 
pain in each patient using a standardized checklist of clinical and physical exam features 
and overall clinical impression. The patient must have at least 1 clinical and 1 physical 
exam feature consistent with facet joint pain. 
3. The clinician will qualitatively score his/her confidence that the axial low back pain is 
derived from facet joints using a percentile (i.e. 60-100%).  
4. Determination of the likelihood of facet joint pain on the basis of results from prior 
imaging with fat saturated sequences will not be permitted to avoid selection bias. 
However, it is not practical to keep clinicians blinded from prior clinical imaging tests. 
5. Indicate the treatment plan (including specific facet joints to be treated percutaneously 
by either steroid injection or medial branch blocks/radiofrequency ablation).  
6. The severity (0-10 scale) and duration of pain (months) on each side will be recorded.  
7. Patients will undergo the PET/MR examination as soon as both patient and scanner 
availability allows; the imaging study must be within 3 months of this clinical 
assessment. 
 
6. Image Analysis 
 
Lumbar facet joint levels (e.g. L4/L5) will be enumerated by the PI prior to scoring for 
consistency.  
 
MRI Images 
1. Two readers will view images independently. The MRI readers will be blinded to the PET 
images/results.  
2. Peri-facet signal change for every lumbar facet joint on MRI will be determined by 2 
neuroradiologists using an established 0-4 grading scale for T2 fat-suppressed images 
first (blinded to the gadolinium enhanced images). 
3.  Peri-facet signal change for every lumbar facet joint on MRI will be determined by 2 
neuroradiologists using an established 0-4 grading scale for gadolinium enhanced T1 fat-
suppressed images. 
4. Dichotomous qualitative assessment of presence of pure synovial enhancement will be 
scored separately. 

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5. Dichotomous qualitative assessment of facet joint effusion will be scored separately. 
6. DWI/ADC images will be examined as an exploratory component, each joint rated as 
normal, increased DWI signal, or true restricted diffusion by visual inspection. 
7. After each group of up to 5 studies (or fewer), the 2 readers will re-review the studies 
together to establish consensus and document reasons for interobserver variability. 
8. The consensus facet joint scores will then be grouped into 3 categories for comparison 
to PET data and clinical translation: 1 = normal (0/4), 2= mild peri-facet signal change (1-
2/4), 3 = high grade peri-facet signal change (3-4/4). 
9. After each group of 5 studies, the 2 readers will re-review the studies together to 
establish consensus and identify/document reasons for interobserver variability (if any). 
10. The overall score for each lumbar facet joint (L1/L2 through L5/S1) will represent the 
highest of the 2 consensus grades (of T2 fatsat and T1 fatsat with gad). 
PET Images 
1. Patients will receive a routine clinical dose of F18 FDG and undergo PET imaging at a 
standard recorded interval. 
2. Every lumbar facet joint will be rated as either normal or having increased activity on 
qualitative visual inspection independently by 2 nuclear medicine physicians on a scale 
of normal, mildly increased, or markedly increased (high grade).   
3. Maximum standard uptake value (SUV-max) will also be determined and will be 
compared to the SUV-max of the adjacent normal vertebral body (avoiding areas 
increased in association with degenerative disc disease).  
4. The PET readers can view anatomic T1 images for coregistration, but will be blinded to 
the fat-suppressed MR images/results.   
5. After each group of up to 5 studies (or fewer), the 2 readers will re-review the studies 
together to establish consensus and identify/document reasons for interobserver 
variability (if any).  
6. The consensus rating by visual inspection will establish the qualitative score. 
 
6.1 Clinical Evaluation after Imaging 
 
The clinician will be serially unblinded to MRI and PET data in the following sequence for 
each patient; this need not be done during an actual patient recheck. The clinician shall 
remain blinded to the QREADS radiology report. Qualitative scores are used for PET since 
the MRI scale is qualitative and since quantitative cut-off values for SUV-max do not 
currently exist: 
1. Unblinded to facet joints positive for high-grade MRI change based on overall scores 
2. Unblinded to all positive facet joints on MRI based on overall scores (low grade and 
high grade) 
3. Unblinded to facet joints positive for marked FDG PET activity based on qualitative 
scores 
4. Unblinded to all positive facet joints on FDG PET based on qualitative scores (low 
grade and high grade) 
  

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For each of these 4 iterations, the clinician will score if: 
1.  The data is concordant or discordant with the clinical impression (dichotomous 
yes/no) 
2.  The data would change clinical management (dichotomous yes/no) 
 
These 2 scores will be performed with the assumption the biomarker is an accurate 
predictor of facet joint pain and/or response to percutaneous treatment. Without this 
assumption, the results would have no impact on management. This will be done 
independently on each side per patient. 
Note that the results could be concordant with clinical impression, but still alter 
management (for example clinically suspected left L5/S1 facet joint pain with a positive 
biomarker at only the left L4/L5 facet joint). 
Finally, the clinician will indicate which facet joint(s) he/she would specifically prescribe 
percutaneous treatment for using both clinical and all available PET/MRI data. Note that the 
PET/MRI data is not an absolute determinant here.  The clinician may believe strongly that a 
facet joint should undergo percutaneous treatment based on clinical data alone. 
The actual clinical management is left to the discretion of the clinician for this phase of 
evaluation. He/she may choose to treat the patient based on clinical information alone or 
clinical and PET/MRI information. The clinical course including level of pain, response to 
injections, etc. of the patients may be followed up to 1 year after the PET/MR by chart 
review for descriptive purposes/analysis, but the patients will not be formally contacted. 
 
6.2 Primary Data Analysis 
 
1. The concordance of qualitative scores of FDG activity with clinical impression will be 
determined (high grade and all grades). 
2. The concordance of overall scores of MR findings with clinical impression will be 
determined (high grade and all grades). 
3. The frequency with which the qualitative scores of FDG activity altered clinical 
management will be scored (high grade and all grades). 
4. The frequency with which the overall scores of MR findings altered clinical management 
will be scored (high grade and all grades). 
5. For each patient, the number (and level) of facet joints prescribed percutaneous 
treatment will be determined in these 3 categories: 
a. Number of facet joints with unchanged treatment recommendation 
b. Number of new facet joints that would be treated with PET/MR data 
c. Number of facet joints initially prescribed treatment based on clinical exam that 
would not undergo percutaneous treatment with PET/MR data. 
6. The degree of concordance of FDG PET activity and MRI findings will be scored. 
7. The frequency of upgrading the overall score with gadolinium images versus T2 images 
alone will be determined. 
8. The frequency of pure facet joint synovial enhancement or effusion without peri-facet 
signal change will be determined.   

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9. Qualitative FDG PET scores will be compared to SUV-max scores (absolute and as a ratio 
to normal vertebral body activity) to determine if quantitative thresholds can be 
established for future investigation. 
10. The concordance of DWI results with other imaging findings and clinical data will be 
assessed for exploratory purposes. 
11. Interobserver variability for both FDG PET scores and MRI scores will be examined. 
6.3 
Data Archival 
 
All reconstructed image data will be transferred to a DICOM archive system for long-term 
storage.  The clinical patient images will be sent to QREADS and MIDIA. 
6.4 
Patient Confidentiality 
 
All patient image data will be anonymized prior to the image analysis and blinded review.  
Image data will be sent directly from the scanners to a Mayo Clinic DICOM receiver (a PACS 
for researchers called Notion, supported by Radiology Informatics) that will anonymize the 
patient data using predefined rules.  In this manner the same patient will have the same 
anonymization rules applied, independent of when or what system they were scanned on.  
Both the original and anonymized data are archived in MIDIA and a log that patients that 
have been anonymized are maintained. 
7. 
Data Safety Monitoring Board (DSMB) 
 
The Principal Investigator (PI) will be responsible for ensuring participants’ safety on a daily 
basis.  Monitoring participant safety, evaluate the progress of the study, to review procedures 
for maintaining the confidentiality of data, the quality of data collection, management, and 
analyses. 
 
The PI will be informed of serious adverse events as soon as they occur and will notify the NIA 
and (e.g. DSMB) within 24 hours of notification. The (e.g. DSMB) will meet twice annually, 
either in-person or by teleconference call to review study progress, data quality, and 
participants safety 
7.1 
Human Studies Aspects 
 
Both male and female adult patients will be screened and enrolled in this study.   
For women of childbearing potential, both pregnancy and breast feeding will be addressed.  
If a patient has childbearing potential, a pregnancy test will be performed.  If the 
pregnancy test is negative, the scan may proceed.  If the pregnancy test is positive, the 
scan will not proceed and the patient is documented as a screening failure.   If a patient is 
breastfeeding, they are given written instructions to pump and discard their milk or pump 
and store it for a minimum of 8 hours per the MRI scanning technologist.  It is safe for a 
mother to continue breastfeeding after administration of gadolinium (again instructed to 
discard for at least 8 hours due to FDG activity as stated above).  However, if the mother 

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desires, she can abstain from breastfeeding for 24 hours with active expression and 
discarding of breastmilk (7).  Sedation will be administered.  
 
No monetary compensation will be provided. All research costs related to this protocol will 
be paid for by the Department of Radiology.  
 
The MRI results will be recorded in the participant’s electronic health record. Because the 
PET scan portion of the PET/MRI scan is being evaluated, no results will be included in their 
electronic health record. 
8. 
Budget 
All research costs related to this protocol will be paid for by the Department of Radiology.  See 
attached letter from Dr. Kent Thielen in Appendix 3. 
Because this is a novel imaging modality, clinical PET/MR procedure codes that will support FDA 
and CMS approved indications have yet to be developed and will be based on the results of 
developmental studies. Radiology RIMS codes specific to this development initiative will be 
utilized and indicate the study is a development project and there are no patient charges 
associated with the release of a clinical report.    Additionally, Study Coordinator effort will be 
paid by the Department of Radiology 
9. 
References 
1. Lehman VT, Murphy RC, Kaufmann TJ, Diehn FE, Murthy NS, Wald JT, et al. Frequency of 
discordance between facet joint activity on technetium Tc99m methylene 
diphosphonate SPECT/CT and selection for percutaneous treatment at a large 
multispecialty institution AJNR Am J Neuroradiol 2014;35(3):609-614. 
2. Verdoorn JA, Lehman VT, Diehn FE, Maus TP. – Increased 99mTc MDP Activity in the 
Costovertebral and Costotransverse Joints on SPECT-CT: Is It Predictive of Associated 
Pain or Response to Percutaneous Treatment? Diagnost Interv Radiol (In Press) 
3. Czervionke LF, Fenton DS. Fat-saturated MR imaging in the detection of inflammatory 
facet arthropathy (facet synovitis) in the lumbar spine Pain Med. 2000;9(4):400-406. 
4. Pneumaticos SG, Chatziioannou SN, Hipp JA, Moore WH, Esses SI. Low back pain: 
prediction of short-term outcome of facet joint injection with bone scintigraphy. 
Radiology 2006;238(2):693-698. 
5. Dolan AL, Ryan PJ, Arden NK, Stratton R, Wedley JR, Hamann W, et al. The value of 
SPECT scans in identifying back pain likely to benefit from facet joint injection. Br J 
Rheumatol 1996;35(12):1269-1273. 
6. Lehman VT, Murphy RC, Schenck LA, et al.  Comparison of facet joint activity on 99mTc-
MDP SPECT/CT with facet joint signal change on MRI with fat suppression (submitted). 
7. https://www.infantrisk.com/sites/default/files/files/Radiocontrast%20Breastfeeding.pd
f 
Appendix 1: Radiology Funding Letter 

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                                                                                                                 PET/MR Research Committee 
                                                                                                                 Department of Radiology 
                                                                                                                 Mayo Clinic Rochester 
 
 
To:      Vance Lehman, MD: PI 
Barbara Foreman: Study Coordinator 
The following is an excerpt from the minutes of the PET/MR Research Committee meeting dated 
8/13/15: 
With regard to developmental funding for the proposal entitled “molecular and MRI biomarkers 
of Facet Joint Pain” version #1 dated 5/14/15 from Dr. Lehman and colleagues.  The Committee 
reviewed Dr. Lehman’s responses to the committee’s requested proposal modifications and also 
reviewed the IRB protocol version submitted on behalf of Dr. Lehman.  These items have been 
recorded in the Committee’s records.  The committee approved developmental funding for this 
proposal.     
 
The Committee approves 10 PET/MR slots to be paid for by Department of Radiology PET/MR 
Development Funds.  These are internally funded through the department and no formal budget 
is required for the performance of the PET/MR scans.  This approval serves as documentation of 
“Mayo Funding/No Funds” in Section 12 of the IRBe application.  Slots are up to 1.5 hours with 
the ultimate goal of scanning for less than 1 hour.  The proponent is reminded that funding of 
PET/MR scans will begin on 8/31/15 and sunset on 5/1/16, with the possibility of extension upon 
request.   
 
Approval of additional PET/MR scans may be considered by the PET/MR Research Committee 
after completion of the specified scans and an interim review by the PET/MR Research 
Committee. 
 
Please contact Rose Busta for details of how to claim 3 scholarship days the committee has 
approved for the PE or Co-Investigators to use in the development of this project.   
 
The committee requests the proponent proceed with a formal protocol for IRBe submission 
which may include review by: 
 
Nuclear Medicine Research Committee 
Radiology Research Committee 
Radiation Safety Clinical Trials Committee 
Rose Busta, Secretary 
 
cc:  Geoffrey Johnson, MD, PhD 

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