Clinical trial NCT03861091
Conditions: Lung Neoplasm
Sponsor: Wake Forest University Health Sciences
Start date: 2019-07-12; Completion date: 2022-03-02
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a double blind randomized controlled study investigating the efficacy of a single dose of 150 mg risedronate (a bone anti-resorptive) vs a single dose of placebo given prior to SBRT for peripheral lung tumors that are within 2 cm of the chest wall. Our hypothesis is that the use of a single dose of 150 mg risedronate will eliminate or greatly reduce the rapid bone loss that occurs with radiation induced early osteoclast recruitment/activation.

Patients will be given either a single dose of 150 mg risedronate or placebo at the time of their treatment mapping "simulation" CT scan. Typically, radiation treatments begin at 1 - 3 weeks following this mapping scan, as each treatment plan requires detailed physics calculations and quality assurance checks.

All CT imaging referenced below is performed as a routine standard of care surveillance and is necessary for cancer treatment follow-up. These chest CT scans that are utilized in this research protocol would be performed every 3 months regardless of inclusion on this trial.

Detailed description:
2.1 Primary Objective(s)

The primary objective is to assess the percent change in bone mean cortical thickness within regions of bone receiving 30 Gy or more at 3 months after SBRT. The % change in mean cortical thickness will be compared between patients who received risedronate and those who received placebo.

2.2 Secondary Objective(s)

In addition to the primary objective, the investigators will further analyze the remaining routine follow-up chest CT scans, for mean cortical thickness change in regions of bone that received 0 - 10 Gy, \>10 - 20 Gy, \> 20 - 30 Gy, \> 30 - 40 Gy, and \> 40 Gy at all time points including 3 months, 6 months, 9 months, and 12 months. These scans are standard of care and would be performed regardless of inclusion on this trial. This will allow us to determine the potential persistence of effects from SBRT and bisphosphonate use.

The investigators will assess and compare the incidence and grade (per modified CTCAE v.5) of radiation induced chest wall pain within the radiation treatment portal (within the 50% isodose line) at time of each routine follow up visit (3 months, 6 months, 9 months, and 12 months post SBRT). The purpose of utilizing a placebo and double-blind design is that chest wall pain is a subjective finding. Furthermore, it is unclear if chest wall pain from radiation is directly due to bone damage, nerve damage, muscle irritation, or a combination of all of these factors. The use of placebo will help us reduce the potential for bias in pain assessment.

The investigators will assess and compare the incidence of rib and vertebral fractures (as noted on CT imaging) that occur within 12 months of irradiation and are within the radiation treatment field. The radiation treatment field will be defined as within the 50% isodose line.

The urine concentration of an osteoclast-specific biomarker, urinary N-telopeptide (NTX) indicating osteoclast activity will be assessed prior to SBRT and at each routine follow up visit (at 3 months, 6 months, 9 months, and 12 months post SBRT).

Arms: arm 1: Risedronate 150 mg given once 7-21 days prior to initiation of SBRT arm 2: Matching placebo, dose not applicable given once 7-21 days prior to initiation of SBRT
Interventions: intervention 1: risedronate intervention 2: Matching placebo
Intervention descriptions: intervention 1: Risedronate 150 mg Oral Given once 7 - 21 days prior to initiation of SBRT intervention 2: Dose not applicable, given once 7-21 days prior to initiation of SBRT

Protocol documents:
Prot_SAP_000.pdf: 
A Randomized Clinical Trial of Prophylactic Risedronate for Patients with Peripheral Lung Tumors Treated with SBRT 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC 99518 
ClinicalTrials.gov:  NCT03861091
Principal Investigator: 
Name and Title 
Michael Farris, M.D. 
Department / Section Name 
Radiation Oncology 
r 
Biostatistician: 
Name and Title 
Beverly Levine, Ph.D. 
Department / Section Name 
Biostatistics Core 
Study Coordinators: 
Name and Title 
Sheri Whittington 
Regulatory Contact: 
Name and Title 
Cindy Miller, AAS 
Participating Institution(s):  
Wake Forest Baptist Comprehensive Cancer Center 
---High Point Regional Medical Center (part of WFBH) 
Version Date: 
12/24/18 (original) 
Amended: 
07/09/19, 07/16/19, 07/24/19, 12/18/19, 01/24/20, 02/20/20, 08/15/20, 
10/27/20, 04/13/21, 5/21/21, 10/22/21, 01/11/22, 02/23/2023 
Confidential: 


A Randomized Clinical Trial of Prophylactic Risedronate for Patients with Peripheral Lung Tumors Treated with SBRT 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC 99518 
Protocol Version Date 02/23/23 
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Table of Contents 
SCHEMA ........................................................................................................................................................... 5 
1.0 
Introduction and Background ................................................................................................................. 6 
2.0 
Objectives ............................................................................................................................................ 11 
2.1 
Primary Objective(s) ......................................................................................................................... 11 
2.2 
Secondary Objective(s) .................................................................................................................... 12 
2.3 
Exploratory Objectives ..................................................................................................................... 12 
3.0 
Patient Selection .................................................................................................................................. 13 
3.1 
Inclusion Criteria .............................................................................................................................. 13 
3.2 
Exclusion Criteria ............................................................................................................................. 13 
3.3 
Inclusion of Women and Minorities ................................................................................................... 14 
4.0 
Registration Procedures ....................................................................................................................... 14 
5.0 
Study Outcomes and Study Measures ................................................................................................. 15 
5.1 
Primary Outcome ............................................................................................................................. 15 
5.2 
Secondary Outcomes ....................................................................................................................... 15 
5.3 
Exploratory Outcomes ...................................................................................................................... 15 
6.0 
Treatment Plan .................................................................................................................................... 16 
6.1 
Treatment Administration ................................................................................................................. 16 
6.2 
General Concomitant Medication and Supportive Care Guidelines .................................................. 17 
6.3 
Duration of Therapy ......................................................................................................................... 17 
6.4 
Duration of Follow-up ....................................................................................................................... 18 
6.5 
Criteria for Removal from Study ....................................................................................................... 19 
6.6 
Study Calendar ................................................................................................................................ 20 
7.0 
Measurement of Effect ......................................................................................................................... 21 
7.1 
Cortical Thickness Mapping Approach and Radiation Dose Mapping ............................................... 21 
7.2 
Incidence and Grade of Chest Wall Pain .......................................................................................... 22 
7.3 
Detection of Rib/Vertebral Body fractures......................................................................................... 22 
7.4 
Urine Biomarkers of Osteoclastic Activity and Bone Turnover .......................................................... 22 
7.5 
Evaluable for toxicity: ....................................................................................................................... 23 
8.0 
Adverse Events List and Reporting Requirements ............................................................................... 23 
8.1 
Adverse Event List for Stereotactic Body Radiotherapy (SBRT) ....................................................... 23 
8.2 
Adverse Event List for Risedronate .................................................................................................. 24 
8.3 
Adverse Event Characteristics ......................................................................................................... 24 
8.4 
DSMC SAE Reporting Requirements ............................................................................................... 25 


A Randomized Clinical Trial of Prophylactic Risedronate for Patients with Peripheral Lung Tumors Treated with SBRT 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC 99518 
Protocol Version Date 02/23/23 
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8.5 
WFUHS IRB AE Reporting Requirements ........................................................................................ 25 
8.6 
Sponsor Reporting Requirements .................................................................................................... 26 
9.0 
Pharmaceutical Information.................................................................................................................. 26 
9.1 
Pharmaceutical Accountability .......................................................................................................... 26 
9.2 
Product Information for ACTONEL® (risedronate sodium) tablets .................................................... 26 
9.3 
Creation of Risedronate Placebo ...................................................................................................... 27 
10.0 
Data Management ............................................................................................................................... 27 
11.0 
Statistical Considerations ..................................................................................................................... 28 
11.1 
Analysis of Primary Objective ........................................................................................................... 28 
11.2 
Analysis of Secondary Objectives .................................................................................................... 28 
11.3 
Analysis of Exploratory Objectives ................................................................................................... 29 
11.3.1 Rib neurovascular bundles ............................................................................................................... 29 
11.3.2 Urinary markers of bone turnover ..................................................................................................... 29 
11.3.3 Urinary markers of pain-associated cytokines .................................................................................. 29 
11.4 
Power and Sample Size ................................................................................................................... 29 
11.5 
Estimated Accrual Rate .................................................................................................................... 29 
11.6 
Estimated Study Length ................................................................................................................... 30 
11.7 
Interim Analysis Plan ........................................................................................................................ 30 
References ...................................................................................................................................................... 31 
Appendix A – Eligibility Checklist ..................................................................................................................... 34 
Appendix B – Protocol Registration Form ........................................................................................................ 36 
Appendix C – Race & Ethnicity Verification Form ............................................................................................ 37 
Appendix D – Mandatory DSMC SAE Reporting Guidelines ............................................................................ 38 
Appendix E – Adverse Event Log .................................................................................................................... 45 
Appendix F – 30 day Treatment Follow-up Form ............................................................................................. 46 
Appendix G – Current Medications Form ......................................................................................................... 47 
Appendix H – Medication administration form .................................................................................................. 48 
Appendix I – Off-Study Form ........................................................................................................................... 49 
Appendix J – ECOG KPS Conversion ............................................................................................................. 50 
Appendix K – Toxicity Modified CTCAE Grading for Chest Wall Pain .............................................................. 51 
Appendix N –Radiation Treatment Details ....................................................................................................... 52 
Appendix O – Cortical Thickness Change........................................................................................................ 53 
Appendix P – Urinary NTX Measurement ........................................................................................................ 54 
Appendix Q – Fracture Incidence .................................................................................................................... 55 


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Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC 99518 
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Appendix R - Urine Collection and Delivery to Storage in – 80 C freezer ......................................................... 56 


A Randomized Clinical Trial of Prophylactic Risedronate for Patients with Peripheral Lung Tumors Treated with SBRT 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC 99518 
Protocol Version Date 02/23/23 
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SCHEMA 


A Randomized Clinical Trial of Prophylactic Risedronate for Patients with Peripheral Lung Tumors Treated with SBRT 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC 99518 
Protocol Version Date 02/23/23 
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1.0 
Introduction and Background 
1.1 
Synopsis 
Approximately half of the 1.7 million new cancer diagnoses annually will be treated with ionizing 
radiation therapy (RT).  Improvements in screening and treatment continue to decrease mortality.  As a 
result, long term sequelae of therapy have become a major concern1-3.  
Thoracic stereotactic body radiation therapy (SBRT) for the treatment of primary or metastatic lung 
tumors near the chest wall unavoidably delivers high doses of radiation to the surrounding normal ribs 
or vertebrae and can predispose patients to significant chest wall pain (CWP), radiation induced rib 
fractures (RIRF) or even vertebral fractures4-6.  Rates of toxicity have been correlated with dose 
received by the chest wall. On average, around 35% of patients develop grade 3 or higher CWP when 
greater than 30 cc of chest wall receives 30 Gy or more7.   
In clinical practice this is a very common scenario and a difficult dosimetric constraint to achieve.  The 
incidence of rib fractures within the first year of treatment has been reported as high as 40%6,8-13.  
Patients can experience severe pain, compromised ventilation, and impaired quality of life. In the 
elderly, decreased oxygen saturation as a result of compromised ventilation can reduce life expectancy 
14. Radiation related bone injury is not limited to the ribs and SBRT however.  Rather, it is a source or
morbidity at multiple skeletal locations. The five year post-RT pelvic fracture rate is ~30% in women
treated for the most common gynecologic malignancy, endometrial adenocarcinoma15,16.  Likewise,
hazard ratios for RT induced hip and femoral neck fracture indicate significant increased risk at five
years post-RT for cervical (1.66), rectal (1.65), and anal (3.16) cancers17.  Alarmingly, the rate of
incomplete healing is high with RT-induced fractures, which greatly contributes to morbidity18,19.
Therefore, RT-induced bone damage is a persistent and major source of functional impairment, pain,
and mortality in many cancer survivors.
The exact mechanisms of RT-induced bone damage are unclear.  Historically, persistent damage to 
osteoblasts was thought to play a role by lowering bone formation and bone mineral density over time20-
23. However, we recently discovered that local RT rapidly increases the number and activity of
osteoclasts in rodents 24, and we have shown this burst of osteoclast activity causes substantial early
bone loss22.  This is now well-accepted25-32. By suppressing osteoclast activity during RT using an
antiresorptive bisphosphonate, risedronate, we prevented this rapid bone loss in rodents22.  This is
illustrated in Fig. 1 and Fig. 2.  Suppressing early osteoclast activity is an appealing therapeutic
approach for preventing RT-induced fractures.  A variety of urinary biomarkers have been linked to
increased osteoclastic activity in osteoporotic populations, and the most frequently tested marker is
urinary NTX N-telopeptide. 33.  These biomarkers have been assessed following radiation to the pelvis
with or without bisphosponates and were shown to decrease with the addition of bisphosphonates34.
We have devised a novel 3D mapping approach which utilizes DICOM computed tomography (CT) 
images and allows us to visualize and quantify the changes in bone cortical thickness (C.Th) following 
RT and associate bone changes with RT dose distribution.  (Fig. 3)  Furthermore, we illustrated dose-
dependent cortical thinning to the exact sites of eventual fracture in patients receiving lung SBRT near 
the chest wall, as well as bone loss to discrete, weight-bearing sub-regions of the femoral neck after RT 
for pelvic cancers4,35.  In areas of the ribs receiving > 30 Gy approximately 92% of treated patients 
developed significant cortical thinning by 3 months, and 2 patients developed rib fractures by as early 
as 6 months33.  Using this mapping technique, we have also illustrated significant and persistent cortical 
thickness changes as early as 2 months post treatment in the treated vertebrae of nonhuman primates 
receiving single fraction high dose chest RT (Fig. 4)36.   


A Randomized Clinical Trial of Prophylactic Risedronate for Patients with Peripheral Lung Tumors Treated with SBRT 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC 99518 
Protocol Version Date 02/23/23 
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Clinical relevance 
On review of treatment planning records over the last month in our department, we have treated 18 
patients who would have qualified for inclusion on this study.  This is a reasonable representation of our 
average SBRT treatment population.  More than 2/3 of our SBRT plans unavoidably exceed 
standardized dosimetry constraints for the ribs/chest wall, and roughly 30-40% of our patient population 
complains of chest wall pain requiring narcotics/analgesics after SBRT. Typically this occurs within 3 - 8 
months.  This presents clinicians with a difficult decision to either compromise on effective tumor dose 
by reducing the dose per fraction, or accept a higher risk of chest wall toxicity with more intensive 
fractionations proven to have better local tumor control.    
Conclusions: 
We aim to determine if single dose prophylactic suppression of early RT induced osteoclast activity with 
bisphosphonates diminishes or prevents RT induced cortical bone thinning, fracture, and pain.    
Figure 1. MicroCT images are shown of trabecular bone in the proximal tibial metaphysis (Tibia) and 
distal femoral metaphysis (Femur) from mice that were non-irradiated (No IR) and those who were 
irradiated (IR) then sacrificed 1 week later.  In the irradiated mice, a 2 Gy dose of x-rays was 
administered with a PBS placebo injected subcutaneously (IR+ Placebo) or with subcutaneous 
risedronate injections (IR+ Risedronate).   


A Randomized Clinical Trial of Prophylactic Risedronate for Patients with Peripheral Lung Tumors Treated with SBRT 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC 99518 
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Figure 2. Trabecular number vs time in mice.  The blue boxes represent mice that were not irradiated 
and were given a PBS placebo injected subcutaneously (No IR +Placebo), while the red triangles  and 
green circles represent mice that received a 2 Gy dose of x-rays was administered with a PBS placebo 
injected subcutaneously (IR+ Placebo) or with subcutaneous risedronate injections (IR+ Risedronate). 
Figure 3. A) Illustration of cortical thickness vector measurement for a rib. (B) This is performed 
thousands of times on each CT scan to create cortical thickness maps for all ribs with a color scale 
corresponding to thickness in millimeters.  (C) Radiation dose is associated with locations showing rib 
thinning.  (D) Cortical thinning and subsequent rib fracture is visually evident at 3 and 6 months post 
SBRT in an area of chest wall that received nearly the tumor prescription dose (square box). 


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Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC 99518 
Protocol Version Date 02/23/23 
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Figure 4.  A) Non-human primate rhesus monkeys received a single fraction 10 Gy to the whole  
  chest, and isodose curves illustrating radiation dose distribution are shown.  B) Cortical thickness 
  maps illustrated dose dependent cortical thickness loss at 2 months post radiation.   
1.2 
Risedronate Background Information 
Much of the following detailed information below was obtained from the product monograph from 
Allegran Pharma Co. Markham, Ontario L6G0B5 August 2017, Submission Control 205107.   In some 
instances, this information was directly reproduced from the product monograph. 
Background information on the study agent:  
ACTONEL® (risedronate sodium hemi-pentahydrate) is a commonly used bisphosphonate medication 
that is FDA approved for the indications below.  
o
Treatment and prevention of osteoporosis in postmenopausal women
o
Treatment of osteoporosis in men, to improve bone mineral density
o
Treatment and prevention of glucocorticoid-induced osteoporosis in men and women
o
Paget's disease of bone
Clinical studies and use with radiation 
Risedronate has been utilized in multiple large prospective clinical trials and was shown to significantly  
reduce vertebral fracture incidence in patients with low bone mass and vertebral fractures, regardless  
of age, years since menopause or disease severity at baseline.  A North American trial illustrated a 
significant reduction in the 1-year rate of new vertebral fractures by 65% compared to placebo.  
Similarly, a multinational trial also illustrated a 61% reduction in the 1-year rate of new vertebral 
fractures.  
There are no contraindications to concurrent use of risedronate and chest external beam radiation.  
Bisphosphonates are not routinely discontinued during SBRT for lung tumors.  There is a known risk of 
jaw osteonecrosis that may occur following dental surgery or spontaneously with bisphosphonates, 
however this is not a reported finding in the ribs.   Osteoradionecrosis in the jaw is a separate process 


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WFBCCC 99518 
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that can occur when treating head and neck cancers without bisphosponates and is a result of poor 
vasculature in the mandible.   In the setting of head and neck cancer treatment with radiotherapy, we 
would discontinue bisphosphonates, however this is not extrapolated to other parts of the body when 
receiving radiotherapy while on bisphosphonates  
Clinical studies have been performed with concurrent use of bisphosphonates and radiation therapy in 
the pelvis without excess toxicity.  Choo et al, conducted a randomized trial in patients with prostate 
cancer receiving placebo or risedronate concurrently with external beam radiation and androgen 
deprivation therapy37. They illustrated prevention of bone mineral density (BMD) loss at 2 years and 
significant suppression of bone turnover biomarkers in patients receiving risedronate.  There were no 
excess or unexpected toxicities due to concurrent risedronate and RT.   
Simiarly, Gierloff et al. illustrated that the addition of zolendronate with radiation in patients with 
metastatic bone disease, prevented early radiation induced bone collagen degradation when compared 
to placebo34.  There was significant reduction in urine excretion markers of degradation including 
hydroxylysylpyridinoline and lysylpyridinoline.  Again, no excess toxicity was noted with the concurrent 
use of bisphosphonates and radiation.  
Pharmacokinetics: 
Drug Interactions: 
No specific drug-drug interaction studies were performed with risedronate sodium film-coated tablets. 
Animal studies have demonstrated that risedronate is highly concentrated in bone and is retained only 
minimally in soft tissue. No metabolites have been detected systemically or in bone. The binding of 
risedronate to plasma proteins in humans is low (24%), resulting in minimal potential for interference 
with the binding of other drugs. In an additional animal study, there was also no evidence of hepatic 
microsomal enzyme induction. In summary, risedronate sodium is not systemically metabolized, does 
not induce cytochrome P450 enzymes and has low protein binding. Risedronate sodium is therefore not 
expected to interact with other drugs based on the effects of protein binding displacement, enzyme 
induction or metabolism of other drugs. In vitro studies suggest that the amount of EDTA contained in 
the ACTONEL DR formulation (approximately 1.5 mM) will not significantly affect aqueous solubility of 
antivirals (nelfinavir, lamivudine, emtricitabin) and drugs with a narrow therapeutic index (digoxin, 
lithium carbonate, potassium chloride). Thus, co-administration with ACTONEL DR is not likely to alter 
their absorption. 


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Patients in clinical trials were exposed to a wide variety of commonly used concomitant medications 
(including NSAIDs, H2-blockers, proton pump inhibitors, antacids, calcium channel blockers, beta-
blockers, thiazides, glucocorticoids, anticoagulants, anticonvulsants, cardiac glycosides). While there 
was no apparent evidence of clinically relevant interactions in the clinical trials, such interactions cannot 
be ruled out on the basis on these data.  
Metabolism: 
There is no evidence that risedronate is systemically metabolized. 
Route of elimination: 
Approximately half of the absorbed dose is excreted in urine within 24 hours, and 85% of an 
intravenous dose is recovered in the urine over 28 days. The mean renal clearance is 105 mL/min (CV 
= 34%) and mean total clearance is 122 mL/min (CV = 19%), with the difference primarily reflecting 
non-renal clearance or clearance due to adsorption to bone. The renal clearance is not concentration 
dependent, and there is a linear relationship between renal clearance and creatinine clearance. 
Unabsorbed drug is eliminated unchanged in feces. Once risedronate is absorbed, the serum 
concentration-time profile is multi-phasic with an initial halflife of about 1.5 hours and a terminal 
exponential half-life of 480 hours. Although the elimination rate of bisphosphonates from human bone is 
unknown, the 480 hour half-life is hypothesized to represent the dissociation of risedronate from the 
surface of bone. 
Special Populations and Conditions 
Pediatrics: Risedronate pharmacokinetics have not been studied in patients < 18 years of age. 
Geriatrics: Bioavailability and disposition are similar in elderly (> 65 years of age) and 
      younger subjects. No dosage adjustment is necessary. 
Gender: Bioavailability/disposition following oral administration are similar in men and women. 
2.0 
Objectives 
This is a double blind randomized controlled study investigating the efficacy of a single dose of 150 mg 
risedronate (a bone anti-resorptive) vs a single dose of placebo given prior to SBRT for peripheral lung 
tumors that are within 2 cm of the chest wall.  Our hypothesis is that the use of a single dose of 150 mg 
risedronate will eliminate or greatly reduce the rapid bone loss that occurs with radiation induced early 
osteoclast recruitment/activation. 
Patients will be given either a single dose of 150 mg risedronate or placebo at the time of their 
treatment mapping “simulation” CT scan or within 7-21 days of the start of SBRT.  Typically, radiation 
treatments begin at 1 – 3 weeks following this mapping scan, as each treatment plan requires detailed 
physics calculations and quality assurance checks. 
All CT imaging referenced below is performed as a routine standard of care surveillance and is 
necessary for cancer treatment follow-up.  These chest CT scans that are utilized in this research 
protocol would be performed every 3 months regardless of inclusion on this trial.  
2.1 
Primary Objective(s) 
2.1.1 The primary objective is to assess the percent change in bone mean cortical thickness 
within regions of bone receiving 30 Gy or more at 3 months after SBRT.  The % change 


A Randomized Clinical Trial of Prophylactic Risedronate for Patients with Peripheral Lung Tumors Treated with SBRT 
Wake Forest Baptist Comprehensive Cancer Center 
WFBCCC 99518 
Protocol Version Date 02/23/23 
Page 12 of 56 
in mean cortical thickness will be compared between patients who received risedronate 
and those who received placebo.  
2.2 
Secondary Objective(s) 
2.2.1 In addition to the primary objective, we will further analyze the remaining routine follow-
up chest CT scans, for mean cortical thickness change in regions of bone that received 
0 – 10 Gy, >10 – 20 Gy, > 20 – 30 Gy, > 30 – 40 Gy, and > 40 Gy at all time points 
including 3 months, 6 months, 9 months, and 12 months.  These scans are standard of 
care and would be performed regardless of inclusion on this trial.  This will allow us to 
determine the potential persistence of effects from SBRT and bisphosphonate use.    
2.2.2 We will assess and compare the incidence and grade (per modified CTCAE v.5) of 
radiation induced chest wall pain within the radiation treatment portal (within the 50% 
isodose line) at time of each routine follow up visit (3 months, 6 months, 9 months, and 
12 months post SBRT).  The purpose of utilizing a placebo and double-blind design is 
that chest wall pain is a subjective finding.  Furthermore, it is unclear if chest wall pain 
from radiation is directly due to bone damage, nerve damage, muscle irritation, or a 
combination of all of these factors.  The use of placebo will help us reduce the potential 
for bias in pain assessment. 
2.2.3 We will assess and compare the incidence of rib and vertebral fractures (as noted on CT 
imaging) that occur within 12 months of irradiation and are within the radiation treatment 
field.  The radiation treatment field will be defined as within the 50% isodose line. 
2.2.4 The urine concentration of an osteoclast-specific biomarker, urinary N-telopeptide (NTX) 
indicating osteoclast activity will be assessed prior to SBRT and at each routine follow 
up visit (at 3 months, 6 months, 9 months, and 12 months post SBRT).    
2.3 
Exploratory Objectives 
2.3.1 We will analyze novel anatomic dosimetric substructures on already completed radiation 
plans such as rib neurovascular bundles.  These anatomical structures will be contoured 
onto the stored planning CT scans and the raystation planning system will allow us to 
calculate the dose that these structures received.  We will assess the relation between 
this calculated dose and development of/grade of chest wall pain during follow-up.   The 
standard structure that is routinely contoured for these cases is a crude rind 
encompassing 2-3 cm of the entire chest wall.  We are hypothesizing that dose to 
specific substructures in the chest wall may be more useful in the prediction of chest wall 
pain development. 
2.3.2 If funding permits, we will analyze, and compare between groups, the urine 
concentration of markers of bone turnover activity.  These will all be assessed prior to 
SBRT and at the 6 month follow up visit post SBRT. 
2.3.3 We will analyze and compare between groups the urine concentrations of pain-
associated cytokines prior to SBRT and at the 6 month follow up visit post SBRT. Also, if 
funding permits, the urine concentration of pain-related neurotrophic growth factors 
(proNGF, proBDNF, GDNF), and neuropeptides (CGRP and Substance P) will be 
measured. 


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3.0 
Patient Selection 
Biopsy is not required for enrollment.  
The lung tumor may be a lung primary tumor or a metastatic tumor to the lung. 
Prior radiation to any part of the body including the lungs, breast, or thorax is permitted. 
3.1 
Inclusion Criteria 
3.1.1 Patients must be 18 years or older, but there is no upper limit on age of inclusion. 
3.1.2 Patients must have a peripheral lung tumor that is amenable to SBRT as determined by 
the treating radiation oncologist. To be classified as a peripheral lung tumor, the tumor 
edge (the edge of the gross tumor volume or GTV in radiation treatment planning 
software) must be within 2 cm of the chest wall. This is determined by the treating 
radiation oncologist. The chest wall is defined as the chest wall musculature or 
ribs/vertebrae immediately adjacent to the lungs.   
3.1.3 Patients must have ECOG status of 0-3 
3.1.4 Patients must have a life expectancy of at least 3 months as determined by the treating 
radiation oncologist. 
3.1.5 Patients must have the ability to understand and the willingness to sign an IRB-approved 
informed consent document. 
3.2 
Exclusion Criteria 
Prior radiation to any part of the body including the lungs or thorax is not an exclusion criteria 
3.2.1 Tumor edge is greater than 2 cm from the chest wall.  The edge of tumor is the edge of 
the gross tumor volume or GTV as defined in radiation treatment planning software.  
This is determined by the treating radiation oncologist. 
3.2.2 Tumors that are expected to require more than 10 fractions of radiation as determined 
by the treating radiation oncologist.  
3.2.3 History of using bone anti-resorptive agents including bisphosphonates or RANK-L 
inhibitors within the last 1 year. 
3.2.4 Inability to stand or sit upright for at least 30 minutes, which is necessary for ingestion of 
risedronate.  
3.2.5 Hypocalcemia defined as serum total calcium lower than 8.5 mg/dL on most recent 
bloodwork that is within 3 months of administration of study drug/placebo   
3.2.6 Severe renal impairment (EGFR <30 mL/min) on most recent bloodwork that is within 3 
months of administration of study drug/placebo 
3.2.7 Known allergy to risedronate or other bisphosphonates 


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WFBCCC 99518 
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3.2.8 Surgery affecting the bone or dental operations within the last 6 months 
*This will be explicitly asked and documented in the EMR by treating radiation
oncologist
3.2.8.1 Dental operations do not include routine cleaning or cavity fillings
3.2.8.2 Dental operations that exclude patients refer to any manipulation of mandible.
3.2.9 Positive urine pregnancy test in women of child bearing potential within 1 week of 
registration.  Pregnant women are excluded from this study because radiation has clear 
teratogenic and potentially abortifacient risks. 
3.3 
Inclusion of Women and Minorities 
Men and women of all races and ethnicities who meet the above-described eligibility criteria are 
eligible to participate in this study. The study consent form will also be provided in Spanish for 
Spanish-speaking participants.  
Based on WFBCCC population estimates, we may expect approximately 44% of participants to 
be women. Translating this to our sample size estimate of 84 patients, we may enroll 
approximately 42 women. We may enroll approximately 10-13% Black or African American 
patients. Based on our catchment area and hospital demographics we do not expect high 
accruals of individuals of Hispanic/ Latino, American Indian/Alaska Native or Asian ancestry; 
however, no individual will be excluded from the study if they satisfy the above 
inclusion/exclusion criteria. Should we not meet or exceed these estimates, the PI will engage 
the Office of Cancer Health Equity to discuss strategies to enhance recruitment in these target 
populations. 
4.0 
Registration Procedures 
All patients entered on any WFBCCC trial, whether treatment, companion, or cancer control trial, must 
be linked to the study in EPIC within 24 hours of Informed Consent. Patients must be registered prior to 
the initiation of treatment.  You must perform the following steps in order to ensure prompt registration 
of your patient: 
1.0 Complete the Eligibility Checklist (Appendix A) 
2.0 Complete the Protocol Registration Form (Appendix B) 
3.0 Alert the Cancer Center registrar by phone, and then send the signed Informed Consent Form, 
Eligibility Checklist and Protocol Registration Form to the registrar, either by fax or e-mail. 
Contact Information: 
Protocol Registrar PHONE (336) 713-6767 
Protocol Registrar FAX (336) 713-6772 
Protocol Registrar E-MAIL (registra@wakehealth.edu) 
*Protocol Registration is open from 8:30 AM - 4:00 PM, Monday-Friday.
4.0 Fax/e-mail ALL eligibility source documents with registration. Patients will not be registered without 
all required supporting documents. 
Note: If labs were performed at an outside institution, provide a printout of the results. 
Ensure that the most recent lab values are sent. 
To complete the registration process, the Registrar will:   
o
assign a patient study number
o
randomize the patient
o
other appropriate actions
o
register the patient on the study


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5.0 
Study Outcomes and Study Measures 
All CT imaging referenced below is performed as a routine standard of care and necessary for cancer 
treatment follow-up.  These chest CT scans utilized in this research protocol would be performed every 
3 months regardless of inclusion on this trial.  
5.1 
Primary Outcome 
5.1.1 The primary outcome measure is the percent change in mean cortical thickness (C.Th) 
of bones receiving 30 Gy or more at 3 months post SBRT, when compared to pre-SBRT 
cortical thickness 
5.2 
Secondary Outcomes 
5.2.1 The change in mean C.Th of bones will be assessed in regions of bone that received 0 
– 10 Gy, >10 – 20 Gy, > 20 – 30 Gy, > 30 – 40 Gy, and > 40 Gy at all time points
including 3 months, 6 months, 9 months, and 12 months.
5.2.2 Chest wall pain incidence and grade will be collected as per modified CTCAE v. 5 within 
the within the 50% isodose line. Appendix K  
5.2.3 Incidence of rib and vertebral fractures (as noted on CT imaging) that occur within 12 
months of irradiation and are within the within 50% isodose line.   
5.2.4 The urine concentration of an osteoclast-specific biomarker, urinary N-telopeptide (U-
NTX) indicating osteoclastic activity will be assessed prior to SBRT and at each routine 
follow up visit (at 3 months, 6 months, 9 months, and 12 months post SBRT). 
5.3 
Exploratory Outcomes 
5.3.1 We will contour the neurovascular bundle that runs in the intercostal space for each 
patient within at least 3 cm of the planning tumor volume.  We will then utilize stored 
treatment planning information and the raystation planning system to calculate the dose 
that this nerve bundle received at the time of treatment.  As patients have already been 
assessed for development of chest wall pain at each follow up, we will assess for a dose 
response relationship between the dose to the nerve bundle and the subsequent 
development of and grade of any chest wall pain per the CTCAE v5.   
5.3.2 Urine concentrations (pg/mL) of markers of bone turnover activity such as P1NP 
(procollagen type 1 pro-peptide), sclerostin, OPG (osteoprotegerin), TRAP5B, and 
pentosidine (an advanced glycation end-product (AGE)); will be analyzed  using  
ELISAs.  These markers will be assessed prior to SBRT and at the 6 month follow up 
visit post SBRT). 
5.3.3 Urine concentrations (pg/mL) of pain-associated cytokines derived from the Isoplexis 
Codeplex Secretome Human Adaptive Immune and Innate Immune Chips which include 
GM-CSF, IL-1β,  IL-7,IL-17A, TNF-α, PDGF-BB, and VEGF will be assessed prior to 
SBRT and at the 6 month follow up visit post SBRT. In addition, other pro-inflammatory 
cytokines may be measured and analyzed on these chips as available. Also, if funding 
permits, the urine concentration (pg/mL) of pain-related neurotrophic growth factors 
(proNGF, proBDNF, GDNF) and neuropeptides (CGRP and Substance P) will be 
measured by ELISA. 


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6.0 
Treatment Plan 
6.1 
Treatment Administration 
Treatment will be administered on an outpatient basis.  
Reported adverse events and potential risks of SBRT and risedronate are described in Section 8. 
REGIMEN DESCRIPTION 
Agent 
Dose 
Route 
Schedule 
Risedronate 
150 mg 
Oral 
Given once 7 – 21 days prior 
to initiation of SBRT 
Matching Placebo 
N/A 
Oral 
Given once 7 – 21 days prior 
to initiation of SBRT 
Standard of care radiation therapy with SBRT will be given over the course of 3 – 10 fractions to a total 
dose of 50 – 60 Gy at the discretion of the treating radiation oncologist. Specific dose fractionations 
between 3 – 10 fractions and constraints will be at the discretion of the treating radiation oncologist and 
may be prescribed every day or every other day.  Respecting the following constraints are encouraged 
but meeting these constraints is not required for inclusion in the study.  In many cases meeting the rib 
constraint will not be possible. 
Treatment planning will be performed utilizing a vac lock or body fix bag and optional abdominal 
compression at the discretion of the treating radiation oncologist.  Planning CT chest may be performed 
with or without contrast at the discretion of the treating radiation oncologist.  Utilization of motion 
management with 4D cinematic CT or a slow scan is required for determination of the internal target 
volume (ITV).  Clinical treatment volume (CTV) creation is not necessary and is not our standard 
treatment paradigm with SBRT for peripheral lung tumors.  The planning target volume (PTV) is 
generally created as a 0.5 cm expansion from the ITV, however the exact dimensions of this expansion 
are at the discretion of the treating radiation oncologist.    
The following are encouraged but not required dose constraints. 
Three Fractions 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose (Gy) 
Endpoint (≥Grade 3) 
Spinal Cord 
<0.5 cc 
18 Gy (6 Gy/fx) 
22 Gy (7.33 Gy/fx) 
myelitis 
Cauda Equina 
<5 cc 
21.9 Gy (7.3 Gy/fx) 
24 Gy (8 Gy/fx) 
neuritis 
Sacral Plexus 
<3 cc 
22.5 Gy (7.5 Gy/fx) 
24 Gy (8 Gy/fx) 
neuropathy 
Esophagus* 
<5 cc 
21 Gy (7 Gy/fx) 
27 Gy (9 Gy/fx) 
stenosis/fistula 
Ipsilateral Brachial 
Plexus 
<3 cc 
22.5 Gy (7.5 Gy/fx) 
24 Gy (8 Gy/fx) 
neuropathy 
Heart/Pericardium 
<15 cc 
24 Gy (8 Gy/fx) 
30 Gy (10 Gy/fx) 
pericarditis 
Great vessels 
<10 cc 
39 Gy (13 Gy/fx) 
45 Gy (15 Gy/fx) 
aneurysm 
Trachea and 
Ipsilateral Bronchus* 
<4 cc 
15 Gy (5 Gy/fx) 
30 Gy (10 Gy/fx) 
stenosis/fistula 
Skin 
<10 cc 
22.5 Gy (7.5 Gy/fx) 
24 Gy (8 Gy/fx) 
ulceration 
Stomach 
<10 cc 
21 Gy (7 Gy/fx) 
24 Gy (8 Gy/fx) 
ulceration/fistula 
Duodenum* 
<5 cc 
15 Gy (5 Gy/fx) 
24 Gy (8 Gy/fx) 
ulceration 
Jejunum/Ileum* 
<5 cc 
16.2 Gy (5.4 Gy/fx) 
27 Gy (9 cGy/fx) 
enteritis/obstruction 
Colon* 
<20cc 
20.4 Gy (6.8 Gy/fx) 
30 Gy (10 Gy/fx) 
colitis/fistula 
Rectum* 
<20cc 
20.4 Gy (6.8 Gy/fx) 
30 Gy (10 Gy/fx) 
proctitis/fistula 
Bladder wall 
<20 cc 
15 Gy (5 Gy/fx) 
30 Gy (10 Gy/fx) 
cystitis/fistula 
Femoral Heads  
<10 cc 
21.9 Gy (7.3 Gy/fx) 
necrosis 
Renal hilum 
<2/3 volume 
18.6 Gy (6.2 Gy/fx) 
malignant hypertension 
Five Fractions 


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Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose (Gy) 
Endpoint (≥Grade 3) 
Spinal Cord 
<0.5 cc 
22.5 Gy (4.5 Gy/fx) 
30 Gy (6 Gy/fx) 
myelitis 
Cauda Equina 
<5 cc 
30 Gy (6 Gy/fx) 
34 Gy (6.4 Gy/fx) 
neuritis 
Sacral Plexus 
<3 cc 
30 Gy (6 Gy/fx) 
32 Gy (6.4 Gy/fx) 
neuropathy 
Esophagus* 
<5 cc 
27.5 Gy (5.5 Gy/fx) 
35 Gy (7 Gy/fx) 
stenosis/fistula 
Ipsilateral Brachial 
Plexus 
<3 cc 
30 Gy (6 Gy/fx) 
32 Gy (6.4 Gy/fx) 
neuropathy 
Heart/Pericardium 
<15 cc 
32 Gy (6.4 Gy/fx) 
38 Gy (7.6 Gy/fx) 
pericarditis 
Great vessels 
<10 cc 
47 Gy (9.4 Gy/fx) 
53 Gy (10.6 Gy/fx) 
aneurysm 
Trachea  
and  
Ipsilateral Bronchus* 
<4 cc 
18 Gy (3.6 Gy/fx) 
38 Gy (7.6 Gy/fx) 
stenosis/fistula 
Skin 
<10 cc 
30 Gy (6 Gy/fx) 
32 Gy (6.4 Gy/fx) 
ulceration 
Stomach 
<10 cc 
28 Gy (5.6 Gy/fx) 
32 Gy (6.4 Gy/fx) 
ulceration/fistula 
Duodenum* 
<5 cc 
18 Gy (3.6 Gy/fx) 
32 Gy (6.4 Gy/fx) 
ulceration 
Jejunum/Ileum* 
<5 cc 
19.5 Gy (3.9 Gy/fx) 
35 Gy (7 Gy/fx) 
enteritis/obstruction 
Colon* 
<20cc 
25 Gy (5 Gy/fx) 
38 Gy (7.6 Gy/fx) 
colitis/fistula 
Rectum* 
<20cc 
25 Gy (5 Gy/fx) 
38 Gy (7.6 Gy/fx) 
proctitis/fistula 
Bladder wall 
<20 cc 
18.3 Gy (3.65Gy/fx) 
38 Gy (7.6 Gy/fx) 
cystitis/fistula 
Femoral Heads  
<10 cc 
30 Gy (6 Gy/fx) 
necrosis 
Renal hilum  
<2/3 volume 
23 Gy (4.6 Gy/fx) 
malignant hypertension 
Ten Fractions 
Serial Tissue 
Volume 
Volume Max (Gy) 
Max Point Dose (Gy) 
Endpoint (≥Grade 3) 
Spinal Cord 
<0.5 cc 
32 Gy (3.2 Gy/fx) 
36 Gy (3.6 Gy/fx) 
myelitis 
Cauda Equina 
<5 cc 
36 Gy (3.6 Gy/fx) 
40 Gy (4.0 Gy/fx) 
neuritis 
Sacral Plexus 
<3 cc 
37 Gy (3.7 Gy/fx) 
44 Gy (4.4 Gy/fx) 
neuropathy 
Esophagus* 
<5 cc 
40 Gy (4 Gy/fx) 
50 Gy (5.0 Gy/fx) 
stenosis/fistula 
Ipsilateral Brachial 
Plexus 
<3 cc 
37 Gy (3.7 Gy/fx) 
44 Gy (4.4 Gy/fx) 
neuropathy 
Heart/Pericardium 
<15 cc 
39 Gy (3.9 Gy/fx) 
45 Gy (4.5 Gy/fx) 
pericarditis 
Great vessels 
<10 cc 
58 Gy (5.8 Gy/fx) 
64 Gy (6.4 Gy/fx) 
aneurysm 
Trachea and 
Ipsilateral Bronchus* 
<4 cc 
32 Gy (3.2 Gy/fx) 
50 Gy (5.0 Gy/fx) 
stenosis/fistula 
Skin 
<10 cc 
38 Gy (3.8 Gy/fx) 
45 Gy (4.5 Gy/fx) 
ulceration 
Stomach 
<10 cc 
35 Gy (3.5Gy/fx) 
45 Gy (4.5 Gy/fx) 
ulceration/fistula 
Duodenum* 
<5 cc 
32 Gy (3.2 Gy/fx) 
45 Gy (4.5 Gy/fx) 
ulceration 
Jejunum/Ileum* 
<5 cc 
32 Gy (3.2 Gy/fx) 
45 Gy (4.5 Gy/fx) 
enteritis/obstruction 
Colon* 
<20cc 
36 Gy (3.6 Gy/fx) 
50 Gy (5.0 Gy/fx) 
colitis/fistula 
Rectum* 
<20cc 
38 Gy (3.8 Gy/fx) 
52 Gy (5.2 Gy/fx) 
proctitis/fistula 
Bladder wall 
<20 cc 
32 Gy (3.2 Gy/fx) 
54 Gy (5.4 Gy/fx) 
cystitis/fistula 
Femoral Heads   
<10 cc 
38 Gy (3.8 Gy/fx) 
necrosis 
Renal hilum  
<2/3 volume 
35 Gy (3.5 Gy/fx) 
malignant hypertension 
6.2 
General Concomitant Medication and Supportive Care Guidelines 
Patients should receive full supportive care, including transfusions of blood and blood products, 
erythropoietin, antibiotics, antiemetics, etc., as clinically indicated. Anti-inflammatory or narcotic 
analgesics may be offered as needed for chest wall pain, however use of these medications must be 
noted. Medications considered necessary for the patient's well-being may be given at the discretion of 
the investigator, i.e., chronic treatments for concomitant medical conditions, as well as agents required 
for life-threatening medical problems, etc. The reason(s) for treatment, dosage, and dates of treatment 
should be recorded on the flow sheets. 
6.3 
Duration of Therapy 
The hypothesized bone structural benefit of bisphosphonates with radiation is due to inhibition of early 
osteoclast activation within as little as 1 week of SBRT.  In our preclinical studies, risedronate was only 


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Protocol Version Date 02/23/23 
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given just prior to irradiation, and it was not given at all after irradiation was completed.  Osteoclast 
activation only lasted for 1 week post irradiation in rodent models.  In non-human primate models, the 
first follow up scans were performed at 2 months post irradiation, and these scans indicated maximal 
bone loss had already occurred which was persistent but not worsening on subsequent scans.  For this 
reason, risedronate will be given only once prior to SBRT, at a dose of 150 mg, which is the 
recommended monthly dose in the setting of osteoporosis in post-menopausal females.   
SBRT is given over the course of 3 to 10 treatments and generally this is performed over the course of 
1.5 - 2 weeks.  Radiation treatments are given every day or every other day Monday through Friday 
with the exclusion of the weekends or major holidays.  In the absence of treatment delays due to 
adverse events, radiation treatments may continue until the planned treatment dose is reached or until 
one of the following criteria applies: 
•
Intercurrent illness that prevents further administration of treatment,
•
Unacceptable adverse event(s)
•
Patient decides to withdraw from the study
General or specific changes in the patient's condition render the patient unacceptable for further 
treatment in the judgment of the investigator. 
6.4 
Duration of Follow-up 
Follow-up for serious adverse events and mortality after the single dose of 150 mg of risedronate or 
placebo is administered will take place during the routine clinic visits during radiation treatment. 
Radiation treatments will occur within 1 – 3 weeks of taking the study drug.   The 30 day follow-up 
window that is part of mandatory DSMC-SAE reporting will be considered 30 days from the end of all 
treatments of radiation.   This visit can be either a phone call or a visit in person to review adverse 
events and may be conducted and documented in the medical record by either research study staff 
RNs or the treating physician.  A window of +/- 7 business days is allowed for the 30 day followup 
assessment. 
Specific toxicity related to radiation pneumonitis, radiation fibrosis, and chest wall pain will be collected 
at each followup point as per appendices K – M.   
Patients removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event. 
Patients will be followed for a minimum of 3 months for assessment of the primary objective.  
Patients will be ideally followed in total for 12 months after completion of radiation therapy for the 
purposes of this study.    
In the event that patients develop progressive disease or a new cancer, requiring additional 
chemotherapy they will be withdrawn from further study directed followup.  In these situations, the 
followup schedules and imaging become dramatically different from what is directed on this protocol.  
Additionally further systemic chemotherapy treatments can heavily alter bone density/cortical thickness. 
As such, if patients develop new disease requiring additional systemic chemotherapy treatment outside 
of their initial SBRT, they will be withdrawn from study for further follow ups/study directed imaging. Any 
data that was collected prior to study withdrawal will still be used in analysis.  Immunotherapy or 


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hormonal therapy for breast or prostate cancer will not be considered reasons for withdrawal.  
Cryoablation or radiofrequency ablation will not be considered a reason for withdrawal from study.     
6.5 
Criteria for Removal from Study 
Patients will be removed from study when any of the criteria listed in section 3.2 or 6.4 applies.  As 
above if patient develop progressive or new disease requiring additional systemic chemotherapy, they 
will be removed from study for further protocol directed assessments.   


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6.6 
 Study Calendar 
a Pre-SBRT CT chest scan will be the treatment planning scan.  Fracture incidence will be assessed on CT scans  
b Urine pregnancy test (women of childbearing potential) performed within 1 week of treatment planning simulation for radiation. 
c. Given once at 7 – 21 days prior to initiation of SBRT
d. For urine sample pick-up and transport, call Jeff Willey at 864-506-0672 (mobile), 336-713-7637 (office). If not available, call Alex Borg at 973-865-
4279 (mobile). 
e. At the 30-Day time point this can be collected over the phone
f. Every 3 month follow-up, and CT imaging will have a window of +/- 8 wks
g. Appendix N may be completed during SBRT but should be completed within 12 weeks of completing SBRT
All pre-study activities must be completed within 12 weeks of the start of study drug including labs
Baseline 
Prior to 
SBRT 
Dosing (7-
21 days 
before 
SBRT) 
During 
SBRT 
1 
month 
Post 
SBRT 
3 f 
months 
post 
SBRT 
6 f 
months 
Post 
SBRT 
9 f 
months 
Post 
SBRT 
12 f 
months 
Post 
SBRT 
Informed consent 
X 
Demographics 
Medical history 
History of diabetes 
Physical exam 
Performance status 
Vital signs 
Height, Weight, M2 
X 
Current Medications list 
X 
X 
Current or prior use of rank ligand 
inhibitors, bisphosphonates, and steroids 
with dates of use and dose as per 
Appendix G.h.   
X 
X 
X 
X 
X 
CT chest with or without contrast 
Xa 
X 
X 
X 
X 
Risedronate or placebo 
Xc 
Urine sampled 
X 
X 
X 
X 
X 
Serum Calcium  
EGFR 
Serum Creatinine 
Pregnancy testb 
X 
Adverse event evaluation 
(Appendix E) 
X 
Specific Radiation Related Chest wall 
Toxicity (Appendix K) 
Xe 
X 
X 
X 
X 
Follow up phone call for assessment of 
adverse events without imaging 
(Appendix F)   
X 
Fracture Incidence (Appendix Q) 
X 
X 
X 
X 
X 
Radiation Treatment Details 
(Appendix N) 
Xg 


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7.0 
Measurement of Effect 
7.1 
Cortical Thickness Mapping Approach and Radiation Dose Mapping 
We will utilize our published novel method of cortical thickness mapping as outlined below.   
Ribcage and vertebral cortical thickness mapping will be performed for each patient utilizing the CT 
scan at time of “simulation” or treatment planning/mapping and routine standard of care follow-up 
imaging at 3 months, 6 months, 9 months, and 12 months, which would be performed regardless of 
inclusion on this study.    
The bony anatomy of the thorax will be segmented for each CT scan using automated thresholding 
techniques and manual editing in Mimics (v16.0 Materialise, Leuven, Belgium) for Windows.  Individual 
contours of the entire ribs and vertebral bodies from cervical (C) level C7 through thoracic (T) level T12 
will be constructed in treatment planning software.   
These contours will be utilized to construct 3D surfaces containing over 100,000 vertices throughout the 
bony thorax using Stradwin software (v5.0 Cambridge University, Cambridge, England) for Windows.  
Our unique cortical bone mapping algorithm relies on a global cortical density measurement, which is 
factored into a piecewise defined Heaviside step function derived from the convolution of the in-plane 
and out-of-plane point spread functions (PSFs) of each CT scan.  
The global cortical bone density for each CT scan will be determined by collecting density 
measurements at each vertex.  The CT values along a 12 mm line normal to the cortical surface at 
each of the approximately 50,000 vertices of the 3D rib surfaces will be obtained and applied to the 
validated Ct.Th estimation model constrained by the cortical density and out-of-plane blur.  
Cortical thickness maps will be constructed using the pre-SBRT planning CT scan and 3 month post-
SBRT follow up CT scan for each treated patient for evaluation of the primary objective.  We will 
similarly perform this analysis at the 6 months, 9 months, and 12 months post SBRT time points for 
evaluation of secondary objectives.  
The received radiation doses to the surface of the ribcage at each vertex will be obtained in MIM and 
then registered to the corresponding Ct.Th map using iterative closest point (ICP) registration in 
MATLAB (v2014a, MathWorks, Natick, MA). Each rib will be subdivided into evenly spaced cylindrical 
subsections (30 subsections per rib) along its centerline using a custom MATLAB algorithm.  
Rib vertices from the pre-SBRT CT scans will be spatially aligned with the post-SBRT CT in 3D Slicer 
(v 3.6, http://www.slicer.org) in Windows to define homologous rib subsections on the post-SBRT CT 
scan. A rigid transform consisting of translation and rotation operations will be computed and applied to 
align the pre- and post- treatment ribcage surfaces. A series of approximately twenty-five points will be 
manually selected on the ribcage surface to derive each transform. An affine transform will then be 
computed using an iterative closest point (ICP) algorithm and applied to the transformed ribcage 
surface to account for geometric interscan variation.  The mean dose and Ct.Th for each homologous 
rib region will be calculated from the Ct.Th and dose measurements at all vertices within that region.  
Bone within the treatment field (within the 50% isodose line) will be segmented into homologous 
regions receiving dose at 10 Gy intervals, of 0-10 Gy, > 10 – 20Gy, >20 – 30 Gy, > 30 – 40 Gy, and 
>40 Gy, and in each region the mean cortical thickness will be calculated.  The % change in cortical
thickness will be compared in each region between patients who received risedronate and those who
received placebo.


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7.2 
Incidence and Grade of Chest Wall Pain 
Patients will be assessed at each routine follow up for development and or resolution of any chest wall 
pain/discomfort within the 50% isodose line.  This will be graded per modified CTCAE v.5.   
7.3 
Detection of Rib/Vertebral Body fractures 
The incidence of rib and or vertebral fractures within the radiation treatment field within the 50% 
isodose line will be collected from standard follow-up CT imaging at 3, 6, 9, and 12 months post SBRT.  
7.4 
Urine Biomarkers of Osteoclastic Activity and Bone Turnover 
A single urine sample will be collected at baseline and at each follow up point (3,6,9,12 months).  
Samples will be collected in clinic and immediately transported to the laboratory of Dr. Jeffrey Willey on 
campus for storage in an minus 80 degrees C freezer designed for lab specimen storage.  Urinary N-
telopeptide (U-NTX) will be measured using ELISA based on an immobilized synthetic peptide with a 
specific sequence of amino acids matching a section of the N telopeptide (NTX) of type 1 collagen.  
Samples will be destroyed in biohazard waste immediately after analysis is complete.   
The following detailed information on collection and analysis is provided from pacific biomarkers 
https://pacbio.com/biomarker/assay-detail/148/ 
Specimen Type: Urine (2nd morning void preferred; do not add preservative) 
Optimum Volume: 1 mL 
Stability: 
Reporting units: nM BCE/mmol Cr (normalized) 
Method: ELISA 
Biological or Clinical Significance: 
Bone resorption is a function of osteoclasts.  These cells remove the mineral from bone and break 
down the organic matrix that is primarily comprised of type I collagen.  Collagen is a cross-linked 
fibrous protein that forms the fabric of bone and most other connective tissues. Bone contains three 
polypeptide chains wound together in a helical structure.  The ends of these chains (known as 
telopeptides) provide the intermolecular cross-linking that gives collagen its strength and resiliency.  As 
these cross-linked domains from bone and other skeletal connective tissues are broken down, the 
pyridinoline cross-linking domains are released and ultimately excreted into the urine in the form of 
small peptides bound to pyridinoline (70%) and free pyridinoline (30%).  One type of peptide-bound 
pyridinoline is the cross-linked N-telopeptide (NTX) which is unique to type I bone collagen.  NTX can 
be used to identify fast losers of bone, to monitor therapy, to measure dose response, or to determine 
patient compliance with therapeutic prescription(s).  


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A growing body of clinical studies has shown that urinary NTx provides a sensitive marker of human 
bone resorption. Its specificity is based on originating solely from type I collagen, being particularly 
enriched as a cross-linking structure in bone type I collagen and being produced directly as a 
proteolytic neoepitope by osteoclast activity during bone resorption. Analysis of urine specimens has 
certain advantages, including ease of collection and reduced biohazard precautions for clinical 
laboratory personnel than with bloodbased specimens. However, the obtained results need to be 
normalized to creatinine.   
Principle of Test Method: 
The NTX assay is a competitive, enzyme-linked immunosorbent assay (ELISA) for the quantitative 
measurement of the NTX in human urine. NTX is reported as a normalized ratio to urinary creatinine in 
order to account for variations in urine flow rate. Therefore NTX and urine creatinine are preferably 
tested from the same aliquot. 
7.5 
Evaluable for toxicity: 
All patients will be evaluable for toxicity from the time of their first treatment with risedronate, which will 
be given prior to start of SBRT 
8.0 
Adverse Events List and Reporting Requirements 
8.1 
Adverse Event List for Stereotactic Body Radiotherapy (SBRT) 
Likely risk and side effects 
o
Fatigue
o
Redness of irritation of the skin in the treatment area
o
Hair loss in the treatment area
o
For tumors near the esophagus, irritation of the esophagus and sore throat/difficulty swallowing
o
Some soreness of the ribs with an increased risk of rib fracture

Treatment for such symptoms usually consists of rest, heat, and pain medication.
o
Damage to surrounding normal lung and/or collapse of a portion of treated lung
o
Changes in the lungs as the tumor shrinks

This includes expected "scarring".

In most patients, no noticeable symptoms will result from this lung damage.
Less likely risk and side effects 
o
Cough
o
Difficulty breathing

Decrease in lung function parameters

Which may result in temporary or permanent need for supplemental oxygen
o
Increased phlegm production
o
Fever
o
Severe pain or skin damage leading to an open wound
o
Damage to the stomach or bowel

This can lead to ulceration or perforation with a risk of infection and death.
o
Damage to the spinal cord

can cause numbness, weakness, tingling, and/or inability to use the arms and/or legs


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o
Damage to the large blood vessels surrounding the heart

This could cause coughing up of blood and possibly death
o
Damage to the heart muscle, which can cause heart attack, heart failure, or death
o
Damage to the lining of the heart, which can cause fluid accumulation around the heart

This may cause chest pain, shortness of breath, and/or irregular or rapid heart beat
o
Tumors near vertebrae there is increased risk of vertebral compression fracture

If vertebral fracture is already present, there is risk of progression of fracture.
o
With any radiation therapy, there may be a very small chance that the radiation could cause a
secondary cancer. The excess cancer risk from the radiation is estimated to be about 3.416%
with at least 7 years between the receipt of radiation and the second cancer forming. The
lifetime cancer risk is about 20% assuming several decades of follow-up.
o
No additional scans outside of standard of care will be taken for this study.
8.2 
Adverse Event List for Risedronate 
Likely risk and side effects 
o
Bone and joint pain
o
Abdominal discomfort/indigestion
Uncommon/Rare risk and side effects 
o
Eye pain, redness, swelling, sensitivity to light and or decreased vision
o
Glossitis
o
Jaw osteonecrosis with pain in the mouth or teeth
o
Numbness or feeling of heaviness in the jaw
o
Poor healing of gums
o
Loose teeth
Very rare 
o
Allergic and skin reactions

Hives, rash with or without blisters

Facial/tongue/lip swelling, trouble swallowing or breathing
o
Symptoms of low blood calcium (Numbness, tingling, muscle spasms)
8.3 
Adverse Event Characteristics 
•
CTCAE term (AE description) and grade:  The descriptions and grading scales found in
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will
be utilized for AE reporting. All appropriate treatment areas should have access to a copy of
the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from the
CTEP web site (http://ctep.cancer.gov).
•
A modified CTCAE 5 chest wall pain grading scale accounting for control with NSAID vs
Narcotic, gabapentin, or nerve block use is included in Appendix K
•
We have no mechanistic reason to suspect that concurrent use of risedronate with radiation
will increase pulmonary toxicities and these medications are not contraindicated during
SBRT.  Preliminary review of our own small retrospective database of patients concurrently
receiving SBRT while on bone anti-resorptive therapies has not yielded any excess or un-
expected toxicity.    However, as there is only limited retrospective data in this setting, we
will plan to assess for excess pulmonary toxicities once 50% of patients have been recruited
and reached the 3 month followup point. If there is > 30% grade 3 or higher pneumonitis, we
will discontinue the study.


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•
Expectedness:
o
AEs can be ‘Unexpected’ or ‘Expected’
o
(see Section 7.1 above) for expedited reporting purposes only.
•
Attribution of the AE:
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.4 
DSMC SAE Reporting Requirements 
The Data and Safety Monitoring Committee (DSMC) is responsible for reviewing SAEs for WFBCCC 
Institutional studies as outlined in Appendix D. DSMC currently requires that all unexpected 4 and all 
grade 5 SAEs on these trials be reported to them for review. All WFBCCC Clinical Protocol and Data 
Management (CPDM) staff members assisting a Principal Investigator in investigating, documenting 
and reporting an SAE qualifying for DSMC reporting are responsible for informing a clinical member of 
the DSMC as well as the entire committee via the email notification procedure of the occurrence of an 
SAE. 
8.5 
WFUHS IRB AE Reporting Requirements 
Any unanticipated problems involving risks to subjects or others and adverse events shall be promptly 
reported to the IRB, according to institutional policy. Reporting to the IRB is required regardless of the 
funding source, study sponsor, or whether the event involves an investigational or marketed drug, 
biologic or device. Reportable events are not limited to physical injury, but include psychological, 
economic and social harm. Reportable events may arise as a result of drugs, biological agents, 
devices, procedures or other interventions, or as a result of questionnaires, surveys, observations or 
other interactions with research subjects. 
All members of the research team are responsible for the appropriate reporting to the IRB and other 
applicable parties of unanticipated problems involving risk to subjects or others. The Principal 
Investigator, however, is ultimately responsible for ensuring the prompt reporting of unanticipated 
problems involving risk to subjects or others to the IRB. The Principal Investigator is also responsible 
for ensuring that all reported unanticipated risks to subjects and others which they receive are reviewed 
to determine whether the report represents a change in the risks and/or benefits to study participants, 
and whether any changes in the informed consent, protocol or other study-related documents are 
required. 
Any unanticipated problems involving risks to subjects or others occurring at a site where the study has 
been approved by the WFUHS IRB (internal events) must be reported to the WFUHS IRB within 7 
calendar days of the investigator or other members of the study team becoming aware of the event. 
Any unanticipated problems involving risks to subjects or others occurring at another site conducting 
the same study that has been approved by the WFUHS IRB (external events) must be reported to the 
WFUHS IRB within 7 calendar days of the investigator or other members of the study team becoming 
aware of the event. 


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Any event, incident, experience, or outcome that alters the risk versus potential benefit of the research 
and as a result warrants a substantive change in the research protocol or informed consent 
process/document in order to insure the safety, rights or welfare of research subjects. 
8.6 
Sponsor Reporting Requirements 
This study has full support of the Thoracic multidisciplinary committee and has been presented for the 
Disease Oriented Team (DOT) for review with core senior faculty.  Additionally, we have full support of 
the departments of medical oncology and radiation oncology.  We will be applying for R grant funding, 
as well as funding through the NCORP and radiation oncology institute.   
9.0 
Pharmaceutical Information 
A list of the adverse events and potential risks associated with the investigational or commercial agents 
administered in this study can be found in Section 8.2.  We are in the process of submitting this 
protocol for IND exemption through the FDA and have completed the necessary paperwork for this. 
9.1 
Pharmaceutical Accountability 
Risedronate (Actonel) is commercially available. 
9.2 
Product Information for ACTONEL® (risedronate sodium) tablets 
Product description: Risedronate is a pyridinyl bisphosphonate.  The chemical name is [1-hydroxy-2-
(3-pyridinyl)ethylidene]bis[phosphonic acid] monosodium salt.  It has an affinity for bone hydroxyapatite 
and inhibits osteoclast mediated bone resorption.    
Solution preparation: 
Risedronate sodium is a fine, white to off-white, odorless, crystalline powder. It is soluble in water and 
in aqueous solutions, and essentially insoluble in common organic solvents.  It is given orally in tablet 
form. 
Dosage forms and ingredients:  
The following information below was obtained from the product monograph from Allegran 
Pharma Co. Markham, Ontario L6G0B5 August 2017, Submission Control 205107 
ACTONEL®  
Medicinal Ingredients: Each risedronate sodium tablet for oral administration contains the equivalent of 
5, 30, 35, or 150 mg of anhydrous risedronate sodium in the form of the hemipentahydrate with small 
amounts of monohydrate. Nonmedicinal Ingredients (Film-coated Tablets): Crospovidone, ferric oxide 
red (35 mg), ferric oxide yellow (5 and 35 mg), hydroxypropyl cellulose, hypromellose, indigo carmine 
(150 mg), lactose monohydrate (5, 30 and 35 mg), magnesium stearate, microcrystalline cellulose, 
polyethylene glycol, colloidal silicon dioxide and titanium dioxide.  


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Storage requirements and Stability:  
All dosages are recommended for storage and are stable at controlled room temperature 20° to 25°C 
(68° to 77°F) 
Route of administration: 
Disposal:  
There are no specific disposal recommendations for Actonel.  
9.3 
Creation of Risedronate Placebo 
The Wake Forest Investigational Drug Service (IDS) Pharmacy staff under leadership of Brian 
Strittmatter PharmD, MS is currently involved with an unrelated research protocol that also utilizes 150 
mg of risedronate vs placebo.  Therefore, we already have the necessary infrastructure in place for 
creation of a look-alike placebo and randomization.   
10.0 Data Management 
Data Collection Form 
Data Storage Location 
Informed consent document 
EPIC 
Protocol registration form 
WISER/OnCore 
All CT scans imaging and reports 
EPIC/PACS 
Adverse event log Appendix E 
Oncore 
Current Medications (Appendix G) 
Oncore 
Medication/Placebo administration form  
(Appendix H) 
Oncore 
Specific radiation related toxicities 
Modified CTCAE Chest wall pain 
Radiation pneumonitis  
Radiation Fibrosis 
(Appendix K and the pre-filled AE log) 
OnCore 
Radiation Treatment Details (Appendix N) 
OnCore 
Cortical Thickness Change (Appendix O) 
OnCore 
Urine bone turn over data (Appendix P) 
OnCore 
Fracture Incidence (Appendix Q) 
OnCore 
Adverse Events Log 
WISER/OnCore 
Biomarkers of Bone Turnover Activity 
REDCap 
Pain-Associated Cytokines 
REDCap 


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Double Blind Design 
We will work cooperatively with our IDS pharmacy supplying each patient either a single tablet of risedronate 
150 mg or a single tablet of placebo.  We will work directly with IDS pharmacy staff 336-716-3258, to procure 
identical placebo tablets as well as procedures for un-blinding and drug masking.   As the hospital already has 
an unrelated protocol utilizing 150 mg risedronate vs placebo, many of these procedures are already in place.  
Patients will enroll though CDPM and be randomized through OnCore, but the investigator will not have 
knowledge of the randomization arm to which any patient has been assigned.  The dispensing pharmacy will 
provide blinded samples and only the pharmacy will hold keys to un-blinding.  At the conclusion of the study, 
when all patients have completed 12 months of follow up, the investigators will be unblinded to randomization 
of each patient.   
11.0 Statistical Considerations 
11.1 Analysis of Primary Objective 
The percent change in mean cortical thickness within regions receiving 30 Gy or more will be 
calculated from time of the treatment planning CT scan to 3 months post SBRT.  This % change 
will be compared between the patients receiving risedronate and those receiving placebo.    
11.2 Analysis of Secondary Objectives 
11.2.1 
 Percent change in cortical thickness across all time points 
The percent change in mean cortical thicknesses from baseline will be assessed 
at 3 months, 6 months, 9 months, and 12 months post SBRT separately within 
regions of bone receiving  0 – 10 Gy, >10 – 20 Gy, > 30 – 40 Gy, and >40Gy.  
These outcomes will be compared using repeated measures analysis of 
variance (ANOVA). 
11.2.2 
Incidence and grade of chest wall pain 
The incidence and grade of chest wall pain occurring inside the 50% isodose line 
will be collected and reported per modified CTCAE v5.0 (Appendix K) at 3 
months, 6 months, 9 months, and 12 months post SBRT for all patients.  Results 
will be compared between patients receiving placebo or risedronate.  The 
incidence of G3 or greater chest wall pain will also be correlated with the volume 
of chest wall receiving at least 30 Gy or greater.  The chest wall contour is 
defined as a 2 cm expansion from lung, from the costovertebral angle to the 
sternum.     
11.2.3 
Incidence of rib or vertebral fractures 
The incidence of rib or vertebral fractures within the treatment field occurring at 
any time during the entire course of the study (12 months), will be reported and 
compared between patients receiving placebo or risedronate. 


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11.2.4 
Urinary excretion of N-telopeptide (NTX) 
The concentration of urinary NTX will be assessed at each time point from 
baseline to the conclusion of the study at 12 months.  Results will be directly 
compared in each group.  
11.3 Analysis of Exploratory Objectives 
11.3.1 
Rib neurovascular bundles 
We will evaluate the correlation between calculated doses to specific 
substructures in the chest wall and patient-reported pain, stratified by treatment 
group. 
11.3.2 
Urinary markers of bone turnover 
We will conduct repeated measures analyses on urinary markers of bone 
turnover activity (one model per marker) and assess whether there is evidence of 
meaningful group by time interaction in the markers. 
11.3.3 
Urinary markers of pain-associated cytokines 
Similar to above, we will conduct repeated measures analyses on urinary makers 
of pain-related biomarkers (cytokines and growth factors) where again we will be 
focused on examining evidence of group by time interaction. 
11.4 Power and Sample Size 
Per analysis of our retrospective human data and preclinical data, we estimate that the mean 
cortical thickness for both cases and controls pre SBRT will be approximately 1.35 mm.  At 3 
months, in the absence of any treatment, we estimate approximately 16.7% loss of cortical 
thickness to bones to 1.13 mm (thus resulting in a mean change of 0.22 mm in controls) within 
the treatment field in regions of bone receiving ≥ 30 Gy.  Conservatively, if risedronate use limits 
loss of cortical thickness by at least half on a percentage scale (i.e., expected cortical thickness 
at 3 months in treatment group 8.4% lower, or 1.24 mm, corresponding to an expected mean 
change in treatment group of 0.11 mm), and assuming a standard deviation of delta cortical 
thickness in both treatment and control patients of 0.20,4 then with a power of 0.80 and a one-
tailed alpha of 0.05, we anticipate that we will need 42 patients per group to achieve desired 
power to illustrate significantly higher preservation of cortical thickness at 3 months post SBRT.   
There is no human data to accurately estimate how significantly risedronate will limit bone loss 
following SBRT, however in our pre-clinical rodent models, cortical thickness was preserved in 
all mice receiving risedronate and in two mice cortical thickness increased.  We have no 
mechanistic reason to suspect that risedronate would cause increased bone loss and therefore 
are utilizing a one-tailed alpha in our calculations.   
11.5 Estimated Accrual Rate 
On review of treatment planning records for the last 1 month in our department here at the main 
campus of Wake Forest Hospital, we have treated 18 patients who would have qualified for 
inclusion on this study.  This is a reasonable representation of our average treatment 
population.  Conservatively, we estimate accrual of 5 – 10 patients per month.  Roughly 2/3 of 
our SBRT plans unavoidably exceed dosimetric constraints for the ribs/chest wall. 


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11.6 Estimated Study Length 
2 - 3 years 
11.7 Interim Analysis Plan 
There is no interim analysis of primary or secondary objectives planned for this study.   
Toxicity analysis: 
We have no mechanistic reason to suspect that concurrent use of risedronate with radiation will 
increase pulmonary toxicities, and these medications are not contraindicated during SBRT.  
Preliminary review of our own small retrospective database of patients concurrently receiving 
SBRT while on bone anti-resorptive therapies has not yielded any excess or un-expected 
toxicity.    However, as there is only limited retrospective data in this setting, we will plan to 
assess for excess pulmonary toxicities once 50% of patients have been recruited and reached 
the 3 month followup point. If there is > 30% grade 3 or higher pneumonitis, we will discontinue 
the study. 


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Farris M, McTyre ER, Okoukoni C, et al. Cortical Thinning and Structural Bone Changes in Non-Human
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Choo R, Lukka H, Cheung P, et al. Randomized, double-blinded, placebo-controlled, trial of risedronate
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The following Appendices are required for all WFBCCC cancer treatment protocols. 
Add additional appendices as needed. 
ALL data collection forms must be included as protocol appendices at the time the protocol is submitted to the 
WFBCCC Protocol Review Committee (PRC) for review. 


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Appendix A – Eligibility Checklist
IRB Protocol No. 
WFBCCC Protocol No. 99518 
Study Title: CCCWFU # 99518 
A Randomized Clinical Trial of Prophylactic Risedronate for Patients with Peripheral Lung Tumors Treated with 
SBRT 
Principal Investigator:  Michael Farris MD 
Inclusion Criteria 
(as outlined in study protocol) 
Criteria 
is met 
Criteria is 
NOT met 
Source Used to Confirm * 
(Please document dates and lab results) 
Patients must be 18 years or older, but there 
is no upper limit on age of inclusion. 
□ 
□ 
Patients must have a peripheral lung tumor 
that is amenable to SBRT as determined by 
the treating radiation oncologist. To be 
classified as a peripheral lung tumor, the 
tumor edge (the edge of the gross tumor 
volume or GTV in radiation treatment 
planning software) must be within 2 cm of the 
chest wall. This is determined by the treating 
radiation oncologist. The chest wall is defined 
as the chest wall musculature or 
ribs/vertebrae immediately adjacent to the 
lungs.    
□ 
□ 
Patients must have ECOG status of 0-3 
□ 
□ 
Patients must have life expectancy of at least 3 
months as determined by the treating radiation 
oncologist 
□ 
□ 
Patients must have the ability to understand and 
the willingness to sign an IRB-approved informed 
consent document (either directly or via a 
legally authorized representative) 
□ 
□ 
Exclusion Criteria 
(as outlined in study protocol) 
Criteria 
NOT 
present 
Criteria is 
present 
Source Used to Confirm * 
(Please document dates and lab results) 
Tumor edge is greater than 2 cm from the 
chest wall.  The edge of tumor is the edge of 
the gross tumor volume or GTV as defined in 
radiation treatment planning software.  This is 
determined by the treating radiation 
oncologist 
□ 
□ 
Tumors that are expected to require more 
than 10 fractions of radiation as determined 
by the treating radiation oncologist. 
□ 
□ 
History of using bone anti-resorptive agents 
including bisphosphonates or RANK-L 
inhibitors within the last 1 year. 
□
□ 


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Inability to stand or sit upright for at least 30 
minutes, which is necessary for ingestion of 
risedronate.  
□ 
□ 
Hypocalcemia defined as serum total calcium 
lower than 8.5 mg/dL on most recent 
bloodwork that is within 3 months of 
administration of study drug/placebo 
□ 
□ 
Severe renal impairment 
(EGFR <30 mL/min) on most recent 
bloodwork that is within 3 months of 
administration of study drug/placebo 
□ 
□ 
Known allergy to zoledronate or other 
bisphosphonates 
□ 
□ 
Surgery affecting the bone or dental 
operations within the last 6 months 
Dental operations do not include routine 
cleaning or cavity fillings  
Dental operations that exclude patients refer 
to any manipulation of mandible 
*This will be explicitly asked and documented
by treating radiation oncologist in the EMR
□ 
□ 
Positive urine pregnancy test in women of 
child bearing potential within 1 week of 
registration.  Pregnant women are excluded 
from this study because radiation has clear 
teratogenic and potentially abortifacient risks. 
□ 
□ 
This subject is      
 eligible /  ineligible     for participation in this study. 
OnCore Assigned PID: ___ ___ ___ ___ ___ ___ ___ ___  
Signature of research professional confirming eligibility: _______________________ 
Date: ___ ___ / ___ ___ / ___ ___ 
Signature of Treating Physician:  _____________________________________ 
Date:  ___ ___ / ___ ___ / ___ ___ 
Signature of Principal Investigator**:  _____________________________________ 
Date:  ___ ___ / ___ ___ / ___ ___ 
* Examples of source documents include clinic note, pathology report, laboratory results, etc. When listing the source, specifically state which document
in the medical record was used to assess eligibility. Also include the date on the document. Example: “Pathology report, 01/01/14” or “Clinic note,
01/01/14”
**Principal Investigator signature can be obtained following registration if needed


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Appendix B – Protocol Registration Form 
DEMOGRAPHICS 
Patient: Last Name: _____________________ First Name: ___________________________ 
MRN:          ___ ___ ___ ___ ___ ___ ___ ___ DOB (mm/dd/yy): ___ ___ / ___ ___ / ___ ___ 
ZIPCODE:  ___ ___ ___ ___ ___ 
SEX:   
  Male      Female 
Ethnicity (choose one):   Hispanic 
Non-Hispanic
Race (choose all that 
apply): 
 WHITE           BLACK            ASIAN 
 PACIFIC ISLANDER                 NATIVE AMERICAN 
Height:   ___ ___.___ inches 
Weight: ___ ___ ___.___lbs.(actual) 
Surface Area: ___ ___.___m2  
Primary Diagnosis: ____________________________________________________________ 
Date of Diagnosis: ___ ___ /___ ___/___ ___ 
 
Performance Status: ___  ECOG  
Protocol Registrar can be contact by calling 336-713-6767 between 8:30 AM and 4:00 PM, Monday – Friday. 
Compete the eligibility checklist in WISER and then give the completed Eligibility Checklist and Protocol Registration Form 
must be hand delivered, faxed or e-mailed to the registrar at 336-713-6772 or registra@wakehealth.edu, respectively. 
PROTOCOL INFORMATION 
Date of Registration: 
___ ___ / ___ ___ / ___ ___ 
MD Name (last) : 
______________________  
Date protocol treatment started: 
___ ___ / ___ ___ / ___ ___ 
Informed written consent: 
(consent must be signed prior to registration) 
YES  NO
Date Consent Signed: 
___ ___ / ___ ___ / ___ ___ 
PID # (to be assigned by OnCore): 
___ ___ ___ ___ ___ ___ ___ ___ 


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Appendix C – Race & Ethnicity Verification Form 
Thank you so much for helping us to verify your race and ethnicity to ensure the quality of our 
information. As a brief reminder, the information you provide today will be kept confidential. 
1. Are you:
Hispanic or Latino/a 
Not Hispanic or Latino/a 
2. What is your race? One or more categories may be selected.
White or Caucasian 
Black or African American 
American Indian or Alaskan Native 
Asian 
Native Hawaiian or Other Pacific Islander 
Other, Please Specify: ___________________________ 
Internal use only: 
 Name: ____________________ MRN#: ____________________ 
Was the self-reported race and ethnicity of the participant verified at the time of consent? 
Yes        No 
Was a discrepancy found?       Yes         No 
  If yes, please provide what is currently indicated in the EMR: 
Ethnicity: ____________________ 
Race: ____________________ 
Additional comments: __________________________________________________________________ 
_____________________________________________________________________________________ 
_____________________________________________________________________________________


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Appendix D – Mandatory DSMC SAE Reporting Guidelines 
Data and Safety Monitoring 
Committee (DSMC) Serious Adverse 
Event (SAE) Notification SOP 
Date: 02/11/2021 
Mandatory DSMC SAE Reporting Requirements in WISER 
This document describes reporting requirements of adverse events from WFBCCC 
Investigator Initiated interventional trials to the Data and Safety Monitoring Committee 
(DSMC). A trial is considered a WFBCCC Investigator Initiated interventional trial if the 
following criteria are met: 
1) The Principal Investigator (PI) of the trial is a member of a department at the
Wake Forest University Baptist Medical Center.
2) WFBCCC is considered as the primary contributor to the design, implementation
and/or monitoring of the trial.
3) The trial is designated as “Interventional” using the Clinical Research
Categories definitions provided by the NCI in the Data Table 4
documentation.
(https://cancercenters.cancer.gov/GrantsFunding/DataGuide#dt4)
There are two distinct types of WFBCCC Investigator Initiated interventional trials based 
on where patient enrollment occurs.  These include: 
1) Local WFBCCC Investigator Initiated interventional trials defined as trials where all
patients are enrolled from one of the WFBCCC sites. These include the main
outpatient Cancer Center clinics (located in Winston-Salem) as well as WFBCCC
affiliate sites located in Bermuda Run (Davie Medical Center), Clemmons,
Lexington, High Point, or Wilkesboro.
2) Multi-Center WFBCCC Investigator Initiated interventional trials defined as trials
where patients are enrolled from other sites in addition to WFBCCC sites.
There are three types of trials that are included in this category:
a. Trials sponsored by the NCI Community Oncology Research Program
(NCORP) that are conducted at multiple sites where the PI is a member of a
department at the Wake Forest University Baptist Medical Center.
b. Trials sponsored by Industry that are conducted at multiple sites and the
PI is a member of a department at the Wake Forest University Baptist
Medical Center.
c.
Trials sponsored by WFBCCC that are conducted at multiple sites and the
PI is a member of a department at the Wake Forest University Baptist
Medical Center.
All Adverse Events (AEs) and Serious Adverse Events (SAEs) that occur on any patients 


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enrolled on WFBCCC Investigator Initiated Interventional trials must be entered into the 
WISER system. The only exception to this requirement is for patients enrolled on NCORP 
trials at non- WFBCCC sites. AEs and SAEs for NCORP patients enrolled at WFBCCC sites 
must be entered into the WISER system. Once these AEs and SAEs are entered in WISER, 
certain actions must be taken regarding the reporting of specific Adverse Events to the 
DSMC. 
All Adverse Events that occur during protocol intervention (defined below) and are coded 
as either 1) unexpected grade 4, 2) unplanned inpatient hospitalization > 24 hours 
(regardless of grade), or grade 5 (death) must be reported to the DSMC using the using 
the SAE console in WISER. 
A research nurse or clinical research coordinator when made aware that an adverse event 
meets one of the above criteria has occurred on a WFBCCC Investigator Initiated 
interventional trial, is responsible for informing a clinical member of the DSMC by phone 
(or in-person) about the adverse event. The nurse/coordinator should contact the treating 
physician prior to calling the DSMC clinical member to obtain all details of the SAE, as well 
as all associated toxicities to be recorded along with the SAE. In addition, this nurse or 
coordinator is responsible for entering the adverse event information into the SAE console 
in WISER.  Once the adverse event has been entered into the SAE console an email 
informing the entire DSMC will be generated. 
THESE REPORTING REQUIREMENTS APPLY TO any staff member on the study team for a WFBCCC 
Institutional Interventional trial. Ultimately, the protocol PI has the primary responsibility for AE 
identification, documentation, grading and assignment of attribution to the investigational 
agent/intervention. However, when an AE event as described above is observed, it is the 
responsibility of the person who observed the event to be sure that it is reported to the DSMC. 
What is considered during protocol intervention? 
During protocol intervention is considered to be the time period while a patient is on study 
treatment or during the time period within 30 days of last study treatment (even if patient 
begins a new (non-study) treatment during the 30 days). This window of 30 days should be 
the standard window to be used in all protocols unless a specific scientific rationale is 
presented to suggest that a shorter window can be used to identify events. If it is a trial 
sponsored by Industry and the sponsor requires a longer window for monitoring of SAEs, 
then the longer window of time specified by the sponsor should be followed. 
What is considered as an Unexpected Grade 4 event? 
Any grade 4 event that was not specifically listed as an expected adverse event in the 
protocol should be considered as unexpected. A grade 4 adverse event can be considered to 
be unexpected if it is an event that would not be expected based on the treatment being 
received or if it is unexpected based on the health of the patient. In either case, if there is 
any uncertainty about whether a grade 4 adverse event is expected or unexpected it should 
be reported to DSMC. 


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DSMC notification responsibilities of the person (e.g., nurse) handling the reporting/documenting of 
the SAE in WISER: 
1. Make a phone call (or speak in person) to the appropriate clinical member of the
DSMC according to the schedule as listed below (page if necessary).
2. Enter a new SAE into the SAE module that is located in the Subject>> CRA Console in
WISER WITHIN 24 HOURS of first knowledge of the event. Information can be
entered and saved, but the DSMC members will not be notified until a date is
entered into the  DSMC Notification Date Field. This will ensure that all persons that
need to be made aware of the event (i.e., PI, study team members and DSMC
members) will be notified; remember to file a copy of the confirmation.
3. Document that the appropriate person(s) on the DSMC has been contacted. Indicate
the name of the DSMC clinician that was contacted and the date and time contacted
in the Event Narrative field in the SAE console of the particular subject.
4. Document whether or not the protocol should be suspended based on the
discussion with the DSMC clinician. This is the major function of the email
notification. Enter whether the protocol should be suspended in the Event Narrative
Field.
5. Follow up/update the clinical member(s) of DSMC regarding any new developments
or information obtained during the course of the SAE investigation and reporting
process.
Elements needed to complete the SAE form in the Subject Console in WISER (see Screen Shot 3): 
1. Event Date
2. Reported Date
3. Reported by
4. If Grade 5, enter Death Date
5. If Grade 5, enter Death occurred: within 30 days
6. Event Narrative: Brief description (include brief clinical history relevant to this event,
including therapies believed related to event). Begin narrative with the DSMC clinician
who was notified and Date/Time notified. In addition, state attribution by DSMC
clinician as either “Unrelated”, “Unlikely”, “Possibly”, “Probably”, or “Definitely”.
Always include the following here:
i.
DSMC clinician name, date/time contacted and comments
ii. Date of last dose before the event
iii. Is suspension of the protocol needed? Y/N
7. Treating Physician comments
8. PI comments, if available
9. Protocol Attribution after discussion with DSMC clinician
10. Outcome (Fatal/Died, Intervention for AE Continues, Migrated AE, Not Recovered/Not
Resolved, Recovered/Resolved with Sequelae, Recovered/Resolved without Sequelae,
Recovering and Resolving)
11. Consent form Change Required? Y/N
12. SAE Classification *This is required in order for the email notification to be sent*


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13. Adverse Event Details – Enter all details for each AE associated with the SAE.
a. Course start date
b. Category
c.
AE Detail
d. Comments
e. Grade/Severity
f.
Unexpected Y/N
g. DLT Y/N
h. Attributions
i.
Action
j.
Therapy
k. Click ADD to attach the AE Detail to the SAE.
14. Enter Date Notified DSMC -- *This is required for the email notification to be sent*
15. Click Submit. The auto-generated notification email will disseminate within 5 minutes.
If you do not receive an email within 5 minutes, check that you have entered the
“Date Notified DSMC” and the “SAE Classification”. If these have been entered and
the email still has not been received, take a screen shot of the SAE in WISER and
immediately email it out to all of the DSMC members listed in this SOP. In the subject
line, indicate that this is a manual transmission of the SAE in lieu of the auto-
generated email. It is required that a notification goes to the DSMC members
immediately so that their assessment can be obtained within the 24 hour period
requirement. Contact the Cancer Center Programmer/Analyst to alert that there is an
issue with the auto-generated email.
The Clinical Members of DSMC to Notify by Phone or Page: 
Monday 
Tuesday 
Wednesday Thursday 
Friday 
Saturday Sunday 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes Goodman 
Reed 
Porosnicu 
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu
Seegars 
Lesser 
Hughes 
Goodman 
Reed 
Porosnicu Seegars 
Glenn Lesser, MD – Hematology  Oncology Mercedes Porosnicu, MD-- Hematology 
Oncology Ryan Hughes, MD – Radiation Oncology 
Michael Goodman, MD -- Hematology Oncology 
Daniel Reed, MD -- Hematology Oncology 
Mary Beth Seegars, MD -- Hematology Oncology
Definition of Unavailable: 
As a general guideline if the first clinician that is contacted does not respond to the phone 
call or page within 30 minutes, then initiate contact with the next DSMC clinician listed in the 


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table above on the particular day the SAE is being reported. Allow up to 30 minutes for the 
new DSMC clinician to respond to a phone call or page before contacting the next member in 
the table. These times (30 minutes) are a general guideline. Best judgment as a clinical 
research professional should be used giving considerations of the time of day, severity of the 
SAE, and other circumstances as to when it is appropriate to contact backup clinicians. If the 
event occurs near the end of day, then leave messages (voice or email) as appropriate and 
proceed with submitting the DSMC notification form. It is important to take reasonable steps 
and to document that some type of contact has been initiated to one or more of the clinical 
members of DSMC. 
DSMC CLINICAN RESPONSIBILITY: 
It is the responsibility of the DSMC clinician to review all reported events, evaluate the events 
as they are reported; and communicate a response to the Investigator, event reporter and 
the members of DSMC. The review will include but not be limited to the information 
reported; there may be times when additional information is needed in order for an 
assessment to be made and further communication directly with the investigator may be 
warranted. DSMC reserves the right to disagree with the Investigator's assessment. If DSMC 
does not agree with the Investigator, DSMC reserves the right to suspend the trial pending 
further investigation. If there is any immediate danger or harm that could be present for a 
future patient based on the information provided in the DSMC report then an immediate 
suspension of enrollment should be considered. 
AMENDMENTS TO PREVIOUS REPORTS 
If all pertinent information is unavailable with the initial submission, once the additional 
information is available do not submit a new report. Rather, go to the original email that 
was sent to the DSMC and using that email “reply to all”. Entitle this new email 
“Amendment for (list date of event and patient ID)” this will avoid duplications of the same 
event. List the additional information being reported. This information needs to be entered 
into WISER as well. To do this, go to the Subject console and click SAEs on the left column. 
Click on the appropriate SAE number that needs updating. Then click Update. This will allow 
additional  information to be added. 
Acronyms 
AE – Adverse Event 
DSMC-Data and Safety Monitoring Committee 
SAE-Serious Adverse Event 
WFBCCC – Wake Forest Baptist Comprehensive Cancer Center 
NCI-National Cancer Institute 
WISER –Wake Integrated Solution for Enterprise Research 


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Screen Shots: 
The following screen shots come from the SAE Console within the Subject Console in WISER. 
Screen Shot 1: 
Screen Shot 2:


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Screen Shot 3: 
Screen Shot 4: 


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Appendix E – Adverse Event Log 
WFBCCC Adverse Event (AE) Log 
PI: _________________   Subject PID: 
________________ 
MRN: ________________ 
Cycle #: _________   
 Cycle Start Date: ____________    Cycle Start Time: ___________  
  Cycle End Date: ____________ 
  Cycle End Time: ____________ 
Advers
e Event 
CTC 
Term 
Lab 
Val
ue 
Gra
de 
(1-5) 
per 
CTC 
Sta
rt 
Dat
e 
En
d 
Dat
e 
Attribution 
DEF=Definit
e 
PROB=Prob
able 
POSS=Possi
ble 
UNLK=Unlik
ely 
UNRL=Unrel
ated 
Expect
ed 
N=No 
Y=Yes 
Serious 
Adverse Event 
Detail 
NO=No  
LT=Life 
Threatening 
DTH=Death 
DIS=Disability 
HOS=Hospitaliz
ation 
CA=Caused 
congenital 
anomaly  
RI=Required 
intervention to 
prevent 
impairment 
Dose 
Limiti
ng 
Toxitit
y 
(DLT)    
N=No 
Y=Yes 
Action 
Taken 
NO=None   
DR=Dose 
Reduced 
RI=Regimen 
Interrupted  
TD=Therapy 
discontinued 
INTR=Interru
pted then 
reduced 
Therapy 
Given  
NO=None  
SYM=Sympto
matic  SUP= 
Supportive  
VSUP=Vigoro
us supportive 
Reportab
le?  
IRB-IRB 
DSMC-
DSMC   
FDA-FDA 
SPON-
Sponsor 
(Mark all 
that 
apply) 
Adver
se 
Event 
Repor
t 
(AER) 
Filed  
N=No 
Y=Yes 
Outcome  
R=Recove
red 
TX=Still 
under 
treatment/ 
observatio
n A=Alive 
with 
sequalae 
D=Died 
Treating 
MD 
Initials/D
ate 
 Radiation 
Pneumonitis
 Radiation 
Fibrosis
Serious Adverse Event: Hospitalization; Disability; Birth Defect; Life-threatening; Death. 
CTCAE Version 5 
DSMC- Safety and Toxicity Review Committee 
Version 1/10/18 


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Appendix F – 30 day Treatment Follow-up Form 
Study Number: __ __ __ __ __ 
PID: ___ ___ ___ ___ ___ ___ ___ ___ 
Investigator: M.D. 
Date: ___ ___/___ ___/___ ___ 
Instructions: Complete this form to follow-up with patients for adverse events. 
Name of Person Competing form_____________________________ 
Did the subject have any adverse events in the last 30 days?   Yes 
   No 
 
If yes, please describe nature and grade of AE (Note*: If an SAE occurs in this period, 
report the event as required in Appendix D): 
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________
____________________________________________________________________________ 
Was the subject removed from the study by the PI?  Yes 
   No 
 
Did the subject withdraw from the study?  Yes 
   No 
 
Did the subject complete the full course of SBRT and take the study drug?  Yes 
  No 


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Appendix G – Current Medications Form 
Study Number: ___ ___ ___ ___ ___ 
 PID: ___ ___ ___ ___ ___ ___ ___ ___ 
PI: 
_________________________________ 
 Date (mm/dd/yyyy): ___ ___/___ ___/___ ___ ___ ___ 
Instructions: Fill this form out at the baseline/pre-study 
Study Visit: 
Baseline           
 3 mo. Post SBRT               
 6 mo. Post SBRT              
 9 mo. Post SBRT         
 12 mo. Post SBRT  
Has the patient taken steroid medications in the last 3 months? (Y/N)  
Has the patient ever taken any medications that fall within the class of bisphosphonates or rank ligand inhibitors? (Y/N) 
If Y, list dose/frequency__________ and treatment dates ___________ 
Current Medications List 
Prescription Medications: 
Name of 
Medication 
Dose 
Units 
Frequency 
Condition 
Medication 
Taken For 
Start date 
(mm/dd/yy) 
Stop date 
(mm/dd/yy) 
Formulation 
Route 
Notes 


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Appendix H – Medication administration form 
Date/Time of drug administration: ______________________ 
Pharmacist distributing medication: ________________ 


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Appendix I – Off-Study Form 
Study Number: __ __ __ __ __ 
PID: ___ ___ ___ ___ ___ ___ ___ ___ 
Investigator:, M.D. 
Date: __ __/__ __/__ __ 
Instructions: Complete this form if the patient either withdraws consent or is removed from the 
study.  
Name of Person Competing form_____________________________ 
Did the subject meet eligibility criteria for study enrollment?   Yes 
  No 
Was the subject removed from the study per physician decision?  Yes 
   No 
(if yes, move to #5) 
Did the patient withdraw consent to participate in the study?  Yes 
   No 
(if yes move to #1) 
Reason for patient withdrawal: 
1. 
 Unacceptable toxicity from DRUG(s) 
2. 
 Did not want to participate anymore. Reason: 
____________________________________________________________________ 
3. 
Other: ____________________________________ 
4. Please specify what portion of the study the subject wishes to withdraw from:
 For just the DRUG(s) administration only 
 For all components of the research study (including follow up in the medical 
record)  
Reason(s) for Removal: 
5. 
 Patient exhibited progression of disease 
6. 
 Unacceptable toxicity from DRUG(s) 
7. 
 Investigator’s discretion to withdraw patient from the study because continued 
participation in the study is not in the patient’s best interest (*Describe below) 
8. 
 Undercurrent illness: a condition, injury, or disease unrelated to the intended disease 
for which the study is investigating, that renders continuing the treatment unsafe or 
regular follow-up impossible (*Describe below) 
9. 
 General or specific changes in the patient’s condition that renders the patient 
ineligible for further investigational treatment (*Describe below) 
10. 
 Non-compliance with investigational treatment, protocol-required evaluations or 
follow-up visits (*Describe below) 
11. 
 Termination of the clinical trial by the clinical sponsor 
Comment: 
If reason for withdrawal includes #7, 8, 9, or 10 then please add comments clarifying this 
information)________________________________________________________________ 


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Appendix J – ECOG KPS Conversion 
ECOG-KPS Conversion 


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Appendix K – Toxicity Modified CTCAE Grading for Chest Wall Pain 
To be completed by study nurse 
Person completing study form:  
Printed: ______________________ Signature: ________________________ 
Follow up at ___ mo after completion of SBRT 


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Appendix N –Radiation Treatment Details 
To be completed by the treating physician following completion of treatment planning. 
Completed by ___________________ 
Date ______________ 
If prior radiation treatment to the thorax, including prior treatment for breast cancer 
Construct an EQD2 composite plan if possible and prior records are available 
Dates of start and completion of prior radiation plan ________ to ________ 
Site of prior RT: _____________________________ 
If lung, note anatomic side and lobe: _____________________________ 
If breast, note inclusion or exclusion of regional nodal volumes:_______________________ 
Composite V20 lungs minus current plan GTV on EQD2 using a/b 3:  _______________(%) 
Composite EQD2 using a/b 3 maximal point dose to the chest wall: _________ (Gy)   
For the Current Radiation Plan 
Radiation 
Prescription 
Dose (Gy) 
# of Fractions 
V20 Lungs minus 
GTV (%) 
Maximal point 
dose to rib bone 
(Gy) 
Volume (cc) of 
chest wall 
contour receiving 
> 30 Gy


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Appendix O – Cortical Thickness Change 
To be completed by the treating physician following completion of all data collection. 
Routine CT DICOM images will be stored in PACS imaging system in the electronic medical 
record indefinitely.   Following conclusion of the study, the following information will be assessed 
utilizing cortical thickness mapping procedures with treatment planning simulation CT images, 
radiation dosimetric plans, and routine follow up CT scans.  The chest wall contour will be 
defined as a 2 cm expansion from the lung parenchyma from the costovertebral angle to the 
sternum. Cortical thickness maps will be created for all CT scans.  For each patient the following 
information will be collected. 


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Appendix P – Urinary NTX Measurement 
To be completed following completion of all specimen and protocol data collection. 


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Appendix Q – Fracture Incidence 
*Fracture incidence is determined by the treating radiation oncologist utilizing direct examination
of the CT images compared side by side with the treatment plan.  The isodose lines can be
easily inspected on the treatment plan utilizing planning software to correlate followup imaging
with the area treated.  If there is any question of the proximity of the fracture to the treated
region, followup images can be fused together with the treatment plan images for exact
correlation.  Rib fractures are generally easy to see by direct inspection of the CT images and if
present are also typically commented on in the body of the CT report.    If bone fracture is not
described in the CT report, it can be assessed by the radiation oncologist.


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Appendix R - Urine Collection and Delivery to Storage in – 80 C 
freezer 
Person collecting urine sample _______________ Date _______ 
Delivered to storage in – 80 C freezer 

ICF_001.pdf: 
Official Title: A Randomized Clinical Trial of Prophylactic Risedronate for Patients With Peripheral 
Lung Tumors Treated With SBRT
NCT03861091
IRB-Approved Date:  12/16/21


CCCWFU 99518
Page 1 of 12
Adult Consent Form
Version: 01.24.20 (corrected)
Department of Radiation Oncology
A RANDOMIZED CLINICAL TRIAL OF PROPHYLACTIC RISEDRONATE FOR 
PERIPHERAL LUNG TUMORS 
UNDERGOING STEREOTACTIC BODY RADIOTHERAPY 
Informed Consent Form to Participate in Research
Michael Farris, MD.  Principal Investigator
SUMMARY
You are invited to participate in a research study. The purpose of this research is to help find 
ways to avoid bone loss which may be caused by radiation.  You are invited to be in this study 
because you have a lung tumor that is located near your ribs or your backbone.  In order to treat 
the tumor completely, it is very difficult to avoid getting some radiation to these normal 
bones because they are so close to the tumor.  When radiation interacts with normal bones, it 
can cause bone loss and can lead to breaks in the bone or cracks which might 
cause pain.  Sometimes, patients can have pain in these bones or in the chest even if there is not a 
break in the bone.  
In this study, you will receive standard radiation treatments that would be offered regardless of 
your involvement in this study.  On this study however, before you start the radiation, you will 
be given one tablet to take by mouth.  The tablet will contain either a placebo or a medicine 
named risedronate.  Risedronate is a type of drug called a bisphosphonate.  This type of medicine 
is commonly used to decrease bone loss in people who have osteoporosis, but it has not been 
given to stop bone loss that is caused by radiation.   The placebo tablet will look exactly like the 
risedronate tablet, but it will not have any active medicine inside of it.  The placebo is believed to 
have no effect on your bones.  A computer will choose if you get the placebo tablet or the 
risedronate medicine tablet.  Neither you, nor your doctor will know if the tablet that you take 
contains medicine or placebo while you are on the study.   
The only non-standard part of treatment in this trial is taking this tablet one time. Otherwise, you 
will receive standard of care radiation and standard of care follow-up scans that you would 
otherwise have regardless of your participation in this trial. 
We will also collect one urine sample before you receive radiation, and at each follow up 
appointment.  These urine samples will be stored in a laboratory freezer and will be tested for 
markers of bone breakdown.  After the urine is tested it will be disposed of.
All research studies involve some risks.  The most common risks from the risedronate tablet in 
with this study are bone and joint pain, or abdominal discomfort/indigestion 
There is the possibility that you may benefit from participation in this study.  Your participation 
in this study is voluntary.  You do not have to participate in this study if you do not want to.  
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There may be other choices available to you.  Some other choices may include radiation without 
the tablet.  You will not lose any services, benefits, or rights you would normally have if you 
choose not to participate. 
The remainder of this form contains a more complete description of this study. Please read this 
description carefully. You can ask any questions if you need help deciding whether to join the 
study. The person in charge of this study is Michael Farris MD, PI.  If you have questions, 
suggestions, or concerns regarding this study or you want to withdraw from the study his/her 
contact information is: 
 (clinic & after-hours).
If you have any questions, suggestions or concerns about your rights as a volunteer in this 
research, contact the Institutional Review Board at 
 or the Research Subject 
Advocate at Wake Forest at 
.
INTRODUCTION
You are invited to be in a research study. Research studies are designed to gain scientific 
knowledge that may help other people in the future. You are being asked to take part in this 
study because you have a lung tumor that is near your ribs or backbone.  It will be difficult to 
avoid getting some radiation dose to these bones and radiation may cause some thinning of these 
bones after treatment is finished.  Your participation is voluntary. Please take your time in 
making your decision as to whether or not you wish to participate. Ask your study doctor or the 
study staff to explain any words or information contained in this informed consent document that 
you do not understand. You may also discuss the study with your friends and family.
WHY IS THIS STUDY BEING DONE?
The purpose of this research study is to test if a drug that is used to prevent bone loss in patients 
with osteoporosis, will also stop or decrease bone loss that is caused by radiation.  This could 
potentially lead to fewer rib or backbone fractures and could mean participants experience less 
chest or back pain after radiation.  
Risedronate has been approved by the US Food and Drug Administration (FDA), but it has not 
been approved for use to avoid bone loss caused by radiation.
In this study, risedronate will be compared to placebo. A placebo is a substance, like a sugar pill, 
that is not thought to have any effect on your disease or condition. In this study you will either 
receive the active study medication, risedronate or placebo, which is not active. Placebos are 
used in research studies to see if the drug being studied really does have an effect.  
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?
There will be 84 people at Wake Forest University Baptist Medical Center will take part in this 
study.  This hospital is the only research site. 
WHAT IS INVOLVED IN THE STUDY?
If you take part in this study, you will be randomized into one of the study groups receiving a 
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one-time dose of a tablet that is either placebo or risedronate before you receive radiation.  
Randomization means that you are put into a group by chance.  Randomization will not affect 
your radiation treatment or your follow up after treatment.  It is like flipping a coin. You will 
have an equal chance of being placed in either group.  
You will take the tablet of risedronate or placebo about 1 to 3 weeks before you start radiation 
therapy.  The only part of this study that is not standard of care is taking this one-time dose of a 
risedronate tablet or a placebo tablet before you start radiation.  Otherwise, all aspects of your 
care will be standard of care that you would receive regardless of inclusion on this study. 
Neither you, nor the investigator, will know if you are receiving risedronate or placebo until the 
study is completed, and you have finished 1 year of followup.   This is done so that a fair 
evaluation of results can be made. This information is available to the researchers if needed in an 
emergency.
Before radiation begins, you will have a treatment planning session. You will lie in a specific 
position, possibly within a frame device or on a large plastic bag filled with tiny foam balls like a 
bean bag. The purpose of the frame or bag is to hold your body as still as possible for planning 
and treatment. After you are positioned, doctors will check your breathing and see how your 
organs move. The doctors will try to limit the effect of that movement on the position of your 
tumor by timing your breathing. They may use a device to control the depth of your breathing. 
They may use a device to monitor the rate and pattern of your breathing. This is so that they will 
be able to deliver the radiation to the tumor while accounting for the effect of breathing.  In order 
to plan the radiation, you will have a CT scan that may or may not use contrast.  Contrast would 
be given as an injection in the vein and sometimes helps us see the areas that we are trying to 
treat more clearly.  Radiation treatments will generally be given over the course of 3 – 10 
treatments. This is often with one treatment per day given Monday through Friday or sometimes 
given every other day. When radiation is given in this short course it is typically called 
stereotactic body radiotherapy (SBRT).
After radiation therapy is completed, you will receive a phone call 30 days afterward to ask 
about any side effects or illnesses you may have experienced during this time.  You will see your 
radiation doctor in clinic every 3 months with a new CT scan of your chest, and you be asked 
questions about any chest or back pain or soreness that you may have experienced after radiation.  
Your cancer doctor will follow your standard CT chest scans to see how well the radiation 
controlled your tumor, and to check that there are no new lung tumors.  For the purposes of this 
study, we will use these same CT scans to check the bone thickness of your ribs and backbone 
which may have received some radiation dose.  You will likely continue to follow your cancer 
every 3 – 6 months for a much longer time with your radiation doctor, but for the purposes of 
this study, you will only be asked specific questions about this study for one year after you finish 
radiation.    On this study we will also collect one urine sample before you receive radiation, and 
at each follow up appointment.  These samples will be stored in a laboratory freezer and will be 
tested for markers of bone breakdown.  After the urine is tested it will be disposed of.  After 1 
year has passed from your radiation treatment, you will no longer be asked to provide a urine 
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sample at your follow-up visits.
HOW LONG WILL I BE IN THE STUDY?
You will be in this study for one year after you complete radiation treatment.  This study will not 
require any extra visits to the hospital or extra imaging outside of your routine standard of care 
treatment and follow up.
You can stop participating at any time. If you decide to stop participating in the study we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
safety consequences.   
WHAT ARE THE RISKS OF THE STUDY?
Being in this study involves some risk to you. You should discuss the risk of being in this study 
with the study staff. 
A risk to this study that you should be aware of is the possibility of jaw bone pain with 
bisphosphonate medications.  This is a small risk, generally less than 5%, but it can happen any 
time that bisphosphonates are used   
There are currently no clearly reported side effects from the combination of bisphosphonates and 
radiation therapy to the lungs.  These medications have been given at the same time as radiation 
in patients undergoing radiation for to various sites in the body and no excess toxicities were 
reported.  There is no contra-indication (meaning warnings or known side effects that prevent 
use) for the use of bisphosphonates and radiation to the lung.  These medications are not 
routinely discontinued during radiation therapy.  However, bisphosphonates are not currently 
FDA approved for use as a preventative bone loss medication before radiation therapy.  
Because some patients on this study will receive placebo, there is a risk of bone loss near the 
treated tumor and chest or back pain or soreness.  This risk would be present regardless of 
inclusion on this trial.  It is not clear if the bisphosphonate medicine studied in this trial will 
prevent radiation therapy from causing these problems.  However, it is clear that patients with 
tumors near the chest wall who receive a high dose of radiation, will likely experience some 
bone loss.  The risk of rib fracture or chest wall pain can exceed 30 – 40%. 
Risks and side effects related to the radiation and separately risk related to the risedronate 
medication that we are studying are detailed below.
The side effects of SBRT are listed below with likelihood:
Likely risk and side effects
o
Fatigue
o
Redness of irritation of the skin in the treatment area
o
Hair loss in the treatment area
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o
For tumors near the esophagus, irritation of the esophagus and sore 
throat/difficulty swallowing
o
Some soreness of the ribs with an increased risk of rib fracture

Treatment for such symptoms usually consists of rest, heat, and pain 
medication.
o
Damage to surrounding normal lung and/or collapse of a portion of treated lung
o
Changes in the lungs as the tumor shrinks

This includes expected "scarring".

In most patients, no noticeable symptoms will result from this lung 
damage.
Less likely risk and side effects
o
Cough
o
Difficulty breathing

Decrease in lung function parameters

May result in temporary or permanent need for supplemental oxygen 
o
Increased phlegm production 
o
Fever
o
Severe pain or skin damage leading to an open wound
o
Damage to the stomach or bowel

This can lead to ulceration or perforation with a risk of infection and 
death. 
o
Damage to the spinal cord

can cause numbness, weakness, tingling, and/or inability to use the arms 
and/or legs
o
Damage to the large blood vessels surrounding the heart

This could cause coughing up of blood and possibly death 
o
Damage to the heart muscle, which can cause heart attack, heart failure, or death
o
Damage to the lining of the heart, which can cause fluid accumulation around the 
heart

This may cause chest pain, shortness of breath, and/or irregular or rapid 
heart beat 
o
  Tumors near vertebrae there is increased risk of vertebral compression fracture

If vertebral fracture is already present, there is risk of progression of 
fracture.
o
With any radiation therapy, there may be a very small chance that the radiation 
could cause a secondary cancer. The excess cancer risk from the radiation is 
estimated to be about 1 - 3% with at least 7 years between the receipt of radiation 
and the second cancer forming.  
The side effects of Risedronate are listed below with likelihood:
Likely risk and side effects
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o
Bone and joint pain
o
Abdominal discomfort/indigestion
Uncommon/Rare risk and side effects
o
Eye pain, redness, swelling, sensitivity to light and or decreased vision
o
Glossitis (swelling of the tongue)
o
Jaw osteonecrosis with pain in the mouth or teeth
o
Numbness or feeling of heaviness in the jaw 
o
Poor healing of gums
o
Loose teeth
Very rare
o
Allergic and skin reactions 

Hives, rash with or without blisters

Facial/tongue/lip swelling, trouble swallowing or breathing
o
Symptoms of low blood calcium (Numbness, tingling, muscle spasms)
In addition to these risks above there is a slight risk of a breach of confidentiality.  We will do 
our best to protect your confidential information.  There also may be other side effects that we 
cannot predict. You should tell the research staff about all the medications, vitamins and 
supplements you take and any medical conditions you have. This may help avoid side effects, 
interactions and other risks.  
Taking part in this research study may involve providing information that you consider 
confidential or private.  Efforts, such as coding research records, keeping research records secure 
and allowing only authorized people to have access to research records, will be made to keep 
your information safe.
Whether or not you participate in this study, treatment with SBRT means you will be exposed to 
amounts of radiation above what you would normally receive in daily life. To be sure that you do 
not receive an unhealthy amount of radiation during your participation in this study or otherwise, 
you should let your study doctor know if you have had, or are going to have, any other scans or 
x-rays as part of your medical or dental care. It is very important that you let your study doctor 
know if you already are participating in, or plan to participate in, any other treatment or research 
study that involves radiation exposure. 
Reproductive Risks 
Due to unknown risks and potential harm to the unborn fetus, sexually active women of 
childbearing potential must use a reliable method of birth control while participating in this 
study. Reliable methods of birth control are: abstinence (not having sex), oral contraceptives, 
intrauterine device (IUD), DepoProvera, tubal ligation, or vasectomy of the partner (with 
confirmed negative sperm counts) in a monogamous relationship (same partner). An acceptable, 
although less reliable, method involves the careful use of condoms and spermicidal foam or gel 
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and/or a cervical cap or sponge. We encourage you to discuss this issue further with your 
physicians if you have any questions.
Pregnant women are excluded from participation in this study because radiation has clear 
teratogenic and potentially abortifacient risks.  Some methods of birth control are not 100% 
reliable, therefore a pregnancy test is required at least 10 days from your last normal menstrual 
period, if you are a sexually active woman of childbearing potential.  This can be done by testing 
the blood or the urine and must be performed within 1 week of starting radiation treatments.  
Contraceptive Measures for Males
Your participation in this research study may damage your sperm, which could cause harm to a 
child that you may father while on this study. Such harm may be currently unforeseeable. If you 
are sexually active, you must agree to use a medically acceptable form of birth control in order to 
be in this study.  Medically acceptable contraceptives include: (1) surgical sterilization (such as a 
vasectomy), or (2) a condom used with a spermicide. Contraceptive measures such as Plan B 
(TM), sold for emergency use after unprotected sex, are not acceptable methods for routine use. 
You should inform your partner of the potential for harm to an unborn child. She should know 
that if pregnancy occurs, you will need to report it to the study doctor, and she should also 
promptly notify her doctor.
ARE THERE BENEFITS TO TAKING PART IN THE STUDY?
If you agree to take part in this study, there may or may not be direct benefit to you. We hope the 
information learned from this study will benefit other people in the future. Based on animal 
studies and some human studies, researchers believe that bisphosphonate medications like the 
one used in this study can stop or slow the loss of bone that is caused by radiation therapy. This 
has not been studied in the case of high dose radiation to tumors near the ribs or backbone.  
Because individuals respond differently to therapy, no one can know in advance if it will be 
helpful in your particular case.
WHAT OTHER CHOICES ARE THERE?
You do not have to be in this study to receive treatment. You should talk to your doctor about all 
the choices you have. Instead of being in this study, you have these options:  the same standard-
of-care SB Radiation Therapy (as outlined in this consent) without the risedronate medicine.  
WHAT ARE THE COSTS?
Research study costs, including any study medications and procedures related directly to the 
study, will be paid for by the study. However, tests and procedures that are done as part of your 
routine cancer care, which would be done regardless of your participation in this study, will be 
the responsibility of you or your insurance company.  For this study in particular, we will extract 
data and results from the following routine-care procedures:  physical exams, CT scans, blood 
labs, and pregnancy testing (if applicable.)
WILL YOUR RESEARCH RECORDS BE CONFIDENTIAL?
The results of this research study may be presented at scientific or medical meetings or published 
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in scientific journals.  Your identity and/or your personal health information will not be disclosed 
unless it is authorized by you, required by law, or necessary to protect the safety of yourself or 
others.  There is always some risk that even de-identified information might be re-identified. 
 
Participant information may be provided to Federal and other regulatory agencies as required.  
The Food and Drug Administration (FDA), for example, may inspect research records and learn 
your identity if this study falls within its jurisdiction.
The purpose of this research study is to obtain data or information on the effectiveness of 
risedronate to prevent bone loss that is caused by radiation.  The results will be provided to the 
sponsor, the Food and Drug Administration, and other federal and regulatory agencies as 
required.
 
This research is covered by a Certificate of Confidentiality from the National Institutes of 
Health. The researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a 
court subpoena, unless you have consented for this use. Information, documents, or 
biospecimens protected by this Certificate cannot be disclosed to anyone else who is not 
connected with the research except, if there is a federal, state, or local law that requires 
disclosure (such as to report child abuse or communicable diseases but not for federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings, see below); if you have 
consented to the disclosure, including for your medical treatment; or if it is used for other 
scientific research, as allowed by federal regulations protecting research subjects. 
 
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by the NIH which is funding in part this project or for information that must 
be disclosed in order to meet the requirements of the federal Food and Drug Administration 
(FDA).  You should understand that a Certificate of Confidentiality does not prevent you from 
voluntarily releasing information about yourself or your involvement in this research. If you 
want your research information released to an insurer, medical care provider, or any other person 
not connected with the research, you must provide consent to allow the researchers to release it.
 The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, 
state, or local law  
 
WILL YOU BE PAID FOR PARTICIPATING?
You will receive no payment or other compensation for taking part in this study.
WHO IS SPONSORING THIS STUDY?
This study is being sponsored by the Wake Forest Thoracic Multidisciplinary Tumor Committee 
and in part by the NIH, as it utilizes support of cancer center personnel in the departments of 
statistics and protocol editing.  The sponsor is providing money or other support to Wake Forest 
University Health Sciences to help conduct this study. The researchers do not, however, hold a 
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direct financial interest in the sponsor or the product being studied.
WHAT HAPPENS IF YOU EXPERIENCE AN INJURY OR ILLNESS AS A 
RESULT OF PARTICIPATING IN THIS STUDY?
Should you experience a physical injury or illness as a direct result of your participation in this 
study, Wake Forest University School of Medicine maintains limited research insurance 
coverage for the usual and customary medical fees for reasonable and necessary treatment of 
such injuries or illnesses. To the extent research insurance coverage is available under this policy 
the reasonable costs of these necessary medical services will be paid, up to a maximum of 
$25,000. Wake Forest University Baptist Medical Center holds the insurance policy for this 
coverage. It provides a maximum of $25,000 coverage for each claim and is limited to a total of 
$250,000 for all claims in any one year. The Wake Forest University School of Medicine, and 
the North Carolina Baptist Hospitals, Incorporated do not assume responsibility to pay for these 
medical services or to provide any other compensation for such injury or illness. Additional 
information may be obtained from the Medical Center’s Director of Risk and Insurance 
Management, at 
.
If you are injured, the insurer may require information such as your name, social security 
number, and date of birth in order to pay for your care.  This is because the insurer is required by 
law to report any payments made to cover the care of any persons who are members of a 
government insurance plan to the Department of Health and Human Services.
You do not give up any legal rights as a research participant by signing this consent form. For 
more information on medical treatment for research related injuries or to report a study related 
illness, adverse event, or injury you should call Michael Farris, M.D. at 
 or 
. 
WHAT ABOUT MY HEALTH INFORMATION?
In this research study, any new information we collect from you and/or information we get from 
your medical records or other facilities about your health or behaviors is considered Protected 
Health Information. The information we will collect for this research study includes: History and 
physicals, pathology, labs, imaging and lung function tests.
If this research study involves the diagnosis or treatment of a medical condition, then Protected 
Health Information collected from you during this study will be placed in your medical record, 
and may be used to help treat you, arrange payment for your care, or assist with Medical Center 
operations.  
We will make every effort to keep your Protected Health Information private. We will store 
records of your Protected Health Information in a cabinet in a locked office or on a password 
protected computer. 
Your personal health information and information that identifies you (“your health information”) 
may be given to others during and after the study. This is for reasons such as to carry out the 
study, to determine the results of the study, to make sure the study is being done correctly, to 
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provide required reports and to get approval for new products.  
Some of the people, agencies and businesses that may receive and use your health information 
are the research sponsor; representatives of the sponsor assisting with the research; investigators 
at other sites who are assisting with the research; central laboratories, reading centers or analysis 
centers; the Institutional Review Board; representatives of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital; representatives from government agencies such as 
the Food and Drug Administration (FDA) or the Office of Human Research Protections (OHRP), 
the Department of Health and Human Services (DHHS) and similar agencies in other countries.  
1) The study investigator and his/her staff, or others at Wake Forest University Health Sciences 
who oversee research 
2) Other people or laboratories providing services for this research project on behalf of Wake 
Forest University Health Sciences and Wake Forest University Baptist Medical Center 
3) Representatives from government agencies such as the Food and Drug Administration (FDA), 
NCI (National Cancer Institute), the Department of Health and Human Services (DHHS) and 
similar agencies in other countries.
Some of these people, agencies and businesses may further disclose your health information. If 
disclosed by them, your health information may no longer be covered by federal or state privacy 
regulations.  Your health information may be disclosed if required by law. Your health 
information may be used to create information that does not directly identify you. This 
information may be used by other researchers. You will not be directly identified in any 
publication or presentation that may result from this study unless there are photographs or 
recorded media which are identifiable.
Monitors, auditors, IRB or other regulatory agencies will be granted direct access to the 
participant’s original medical record for verification of clinical trial procedures or data, without 
violating confidentiality of the participant and to the extent permitted by other applicable laws.
If required by law or court order, we might also have to share your Protected Health Information 
with a judge, law enforcement officer, government agencies, or others. If your Protected Health 
Information is shared with any of these groups, it may no longer be protected by federal or state 
privacy rules.
Any Protected Health Information collected from you in this study that is maintained in the 
research records will be kept for at least six years after the study is finished. At that time any 
research information not already in your medical record will either be destroyed, or it will be de-
identified. Any research information entered into your medical record will be kept for as long as 
your medical record is kept by the Medical Center. You will not be able to obtain a copy of your 
Protected Health Information in the research records until all activities in the study are 
completely finished.
You can tell Dr. Farris that you want to take away your permission to use and share your 
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Protected Health Information at any time by sending a letter to this address:
Michael Farris M.D.
 
However, if you take away permission to use your Protected Health Information you will not be 
able to be in the study any longer. We will stop collecting any more information about you, but 
any information we have already collected can still be used for the purposes of the research 
study.
By signing this form, you give us permission to use your Protected Health Information for this 
study.
If you choose to participate in this study, your medical record at Wake Forest University Baptist 
Medical Center will indicate that you are enrolled in a clinical trial.  Information about the 
research and any medications or devices you are being given as a participant may also be 
included in your medical record.  This part of the medical record will only be available to people 
who have authorized access to your medical record.  If you are not a patient at this Medical 
Center, a medical record will be created for you anyway to ensure that this important information 
is available to doctors in case of an emergency.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this Web site at any time. 
Laboratory test results and other medical reports created as a result of your participation in the 
research study may be entered into the computer systems of Wake Forest University Health 
Sciences and North Carolina Baptist Hospital.  These will be kept secure, with access to this 
information limited to individuals with proper authority, but who may not be directly involved 
with this research study.
A North Carolina Baptist Hospital (NCBH) medical record will be created for all study 
participants. Information about your participation in the study will be placed in the NCBH 
medical record, along with any routine medical test results that were obtained at NCBH as part 
of this study. 
WHAT ARE MY RIGHTS AS A RESEARCH STUDY PARTICIPANT?
Taking part in this study is voluntary. You may choose not to take part, or you may leave the 
study at any time. Refusing to participate or leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study, we 
encourage you to talk to the investigators or study staff first to learn about any potential health or 
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safety consequences. The investigators also have the right to stop your participation in the study 
at any time. This could be because it is felt by the treating physician to be in your best medical 
interest, your condition worsened, new information becomes available, or you had an unexpected 
reaction. Additionally, this could occur because you failed to follow instructions, or because the 
entire study has been stopped
You will be given any new information we become aware of that would affect your willingness 
to continue to participate in the study.
WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?
For questions about the study or in the event of a research-related injury, contact the study 
investigator, Michael Farris M.D. at
 (clinic & after-hours) or 
 
(office). 
The Institutional Review Board (IRB) is a group of people who review the research to protect 
your rights. If you have a question about your rights as a research participant, or you would like 
to discuss problems or concerns, have questions or want to offer input, or you want to obtain 
additional information, you should contact the Chairman of the IRB at 
 or the 
Research Subject Advocate at 
.
You will be given a copy of this signed consent form. 
SIGNATURES
I agree to take part in this study. I authorize the use and disclosure of my health information as 
described in this consent and authorization form.  If I have not already received a copy of the 
Privacy Notice, I may request one or one will be made available to me.  I have had a chance to 
ask questions about being in this study and have those questions answered.  By signing this 
consent and authorization form, I am not releasing or agreeing to release the investigator, the 
sponsor, the institution or its agents from liability for negligence.
Subject Name (Printed):_____________________________
Subject Signature: _________________________________ Date: ________Time:_______ am pm 
Person Obtaining Consent (Printed):_____________________________
Person Obtaining Consent:___________________________ Date:_________ Time:________ am pm
WFU School of Medicine 
Institutional Review Board 
IRB Number:IRB00056835
Meeting Date Approved 12/16/2021          
Version Valid Until: 12/15/2022